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PF-04745637

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Graphical abstract: The discovery of a potent series of carboxamide TRPA1 antagonists

PF-04745637

cas 1917294-46-2

MW 509.00, MF C27 H32 Cl F3 N2 O2

Cyclopentanecarboxamide, 1-(4-chlorophenyl)-N-[2-[4-hydroxy-4-(trifluoromethyl)-1-piperidinyl]-3-phenylpropyl]-

rac-1-(4-Chlorophenyl)-N-f2-r4-hvdroxy-4-(trifluoromethyl)piperidin-1-vn-3-phenylpropyDcyclopentanecarboxamide

PRODUCT PATENT WO-2016067143-A1
Applicants: PFIZER INC. [US/US]; 235 East 42nd Street New York, New York 10017 (US)
Inventors: SWAIN, Nigel Alan; (GB).
PRYDE, David Cameron; (GB).
RAWSON, David James; (GB).
RYCKMANS, Thomas; (GB).
SKERRATT, Sarah Elizabeth; (GB).
AMATO, George Salvatore; (US).
MARRON, Brian Edward; (US).
REISTER, Steven Michael; (US).

Image result for PFIZER

TrpA1 is a member of the Transient Receptor Potential (Trp) family of ion channels. It was first described as being activated in response to noxious cold. It is activated by a number of exogenous chemical compounds and some endogenous inflammatory mediators. It has also been reported to be activated in response to mechanical stress.

There is substantial evidence for the involvement of TrpA1 in the physiology of pain, including neuropathic and inflammatory pain, and in pruritus (itch). For example, see:

Bautista, D.M. et al., “TRPA 1: A Gatekeeper for Inflammation” , Annu. Rev. Physiol.2013, 75, 181-200;

Bishnoi, M. & Premkumar, L.S., “Changes in TRP Channels Expression in Painful

Conditions”, Open Pain Journal 2013, 6(Suppl. 1), 10-22;Brederson, J.-D. et al., “Targeting TRP channels for pain relief, Eur. J. Pharmacol.2013, 716, 61-76;

Radresa, O. et al., “Roles of TRPAI in Pain Pathophysiology and Implications for the Development of a New Class of Analgesic Drugs”, Open Pain Journal 2013, 6(Suppl. 1), 137-153; and Toth, B.I. & Biro, T., “TRP Channels and Pruritus” , Open Pain Journal 2013, 6(Suppl.1), 62-80.

There is a continuing interest in finding new compounds that interact with TrpA1.

Image result for SWAIN, Nigel AlanNigel Swain

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016067143&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

E8 that is 1-(4-chlorophenyl)-/V-[2-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-3-phenylpropyl]-cyclopentanecarboxamide, or a pharmaceutically acceptable salt thereof. This compound is represented by formula (lE).

Example 1

rac-1-(4-Chlorophenyl)-N-f2-r4-hvdroxy-4-(trifluoromethyl)piperidin-1-vn-3-phenylpropyDcyclopentanecarboxamide

Method 1

To a solution of rac-1-(1-amino-3-phenylpropan-2-yl)-4-(trifluoromethyl)piperidin-4-ol (Preparation 2, 50 mg, 0.214 mmol) in DMF (1 mL) was added 1-(4-chlorophenyl)cyclopentanecarboxylic acid (37 mg, 0.165 mmol), DIPEA (0.035 mL, 0.198 mmol) and EDCI (38 mg, 0.198 mmol), followed by HOBt (30 mg, 0.198 mmol) and the reaction was stirred at room temperature for 18 hours. Water was added and the reaction stirred for a further 2 hours. DCM was added with further stirring for 1 hour followed by elution through a phase separation cartridge. The organic filtrate was concentrated in vacuo. The residue was dissolved in MeOH and treated with ethereal HCI with standing for 18 hours. The resulting suspension was filtered and triturated with EtOAc, heptanes and TBME to afford the title compound as the hydrochloride salt (69 mg, 82%).

1H NMR (400MHz, DMSO-d6): δ ppm 1.50-1.60 (m, 4H), 1.70-1.90 (m, 4H), 2.15-2.25 (m, 2H), 2.40-2.48 (m, 2H), 2.70-2.80 (m, 1 H), 3.05-3.25 (m, 6H), 3.47-3.62 (m, 2H), 6.38 (br s, 1 H), 7.20-7.40 (m, 9H), 7.80 (br m, 1 H).

MS m/z 509 [M+H]+

Example 1 may also be prepared according to the following method:

A mixture of 1-(4-chlorophenyl)cyclopentanecarboxylic acid (25.7 g, 114 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid-hexafluoro phosphate (49.4 g, 130 mmol) and N,N-diisopropylethylamine (40 mL, 229 mmol) in DMF (475 mL) was stirred at room temperature for 15 minutes. To this mixture was added a solution of 1-(1-amino-3-phenylpropan-2-yl)-4-(trifluoromethyl)piperidin-4-ol (Preparation 2, 31.4 g, 104 mmol) in DMF (200 mL). The reaction was stirred at room temperature for 18 hours before partitioning between EtOAc (600 mL) and saturated aqueous sodium hydrogen carbonatesolution (600 mL). The aqueous layer was washed with EtOAc (2 x 600 mL). The combined organic layers were washed with water (600 mL), brine (600 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0: 1 to 1 : 1 EtOAc: heptanes to afford the title compound (44 g, 76%).

1H NMR (400MHz, CDCI3): δ ppm 1.35 (br s, 1 H), 1.49-1.85 (m, 6H), 1.90-1.99 (m, 2H), 2.25-2.55 (m, 7H), 2.56-2.70 (m, 1 H), 2.75-3.00 (m, 4H), 3.23-3.31 (m, 1 H), 5.87 (br s, 1 H), 7.07 (d, 2H), 7.16-7.30 (m, 7H).

MS m/z 509 [M+H]+

Examples 2 and 3

IS) and (R)-1-(4-Chlorophenyl)-N-f2-r4-hvdroxy-4-(trifluoromethyl)piperidin-1-vn-3-phenylpropyl)cyclopentanecarboxamide

Example 2

To a suspension of (S)-1-(1-amino-3-phenylpropan-2-yl)-4-(trifluoromethyl)piperidin-4-ol (Preparation 3, 70 mg, 0.232 mmol) and 1-(4-chlorophenyl)cyclopentanecarboxylic acid (57.3 mg, 0.255 mmol) in acetonitrile (0.8 mL) was added triethylamine (0.133 mL, 0.928 mmol) followed bypropylphosphonic anhydride (50% wt solution in EtOAc, 0.21 mL, 0.35 mmol). The reaction was stirred at room temperature for 1.5 hours after which the solution was purified directly by silica gel column chromatography eluting with 0-30% EtOAc in heptanes to afford the title compound (75 mg, 64%).

[a]D20 = +9.6 in DCM [20 mg/mL]

ee determination:

Column: ChiralTech AD-H, 250×4.6 mm, 5 micron.

Mobile phase A: CO2; Mobile phase B: MeOH with 0.2% ammonium hydroxide Gradient: 5% B at 0.00 mins, 60% B at 9.00 mins; hold to 9.5 mins and return to 5% B at 10 mins. Flow rate 3 mL/min.

Rt = 5.047 minutes, ee = 95%

Example 2 may also be prepared from rac-1-(4-chlorophenyl)-N-{2-[4-hydroxy-4- (trifluoromethyl)piperidin-1-yl]-3-phenylpropyl}cyclopentanecarboxamide(Example 1).

The racemate was separated into two enantiomers using preparative chiral chromatography as described below:

Chiralpak IA, 4.6x250mm, 5 micron.

Mobile phase: Hexane:DCM:EtOH:DEA 90:8:2:0.1

Flow rate: 1 mL/min

Rt = 8.351 minutes and Rt = 10.068 minutes

The first eluting isomer is Example 2: (S)-1-(4-chlorophenyl)-N-{2-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]-3-phenylpropyl}cyclopentanecarboxamide. ee = 100% The second eluting isomer is Example 3: (R)-1-(4-chlorophenyl)-N-{2-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]-3-phenylpropyl}cyclopentanecarboxamide. ee = 99.62% The compound of Example 2 prepared from the chiral separation method is identical by a-rotation and retention time to the compound of Example 2 prepared as the single enantiomer described above.

MS m/z 509 [M+H]+

1H NMR (400MHz, DMSO-d6): δ 1.30-1.80 (m, 10H), 2.20-2.30 (m, 1 H), 2.35-2.60 (m, 6H), 2.65-2.85 (m, 4H), 3.00-3.15 (m, 1 H), 5.50 (br s, 1 H), 6.95-7.00 (m, 1 H), 7.05-7.15 (m, 2H), 7.20-7.35 (m, 6H) ppm

PAPER

The discovery of a potent series of carboxamide TRPA1 antagonists

D. C. Pryde,*a   B. Marron,b   C. G. West,b   S. Reister,b   G. Amato,b  K. Yoger,b   K. Padilla,b   J. Turner,c   N. A. Swain,a   P. J. Cox,c  S. E. Skerratt,a   T. Ryckmans,d   D. C. Blakemore,a  J. Warmuse and   A. C. Gerlachb  
*Corresponding authors
aPfizer Worldwide Medicinal Chemistry, Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, UK
bIcagen, Inc., 4222 Emperor Boulevard, Suite 350, Durham, USA
cNeuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, UK
dPfizer Worldwide Medicinal Chemistry, Ramsgate Road, Sandwich, UK
ePfizer Worldwide Medicinal Chemistry, Neuroscience and Pain Research Unit, Groton, USA
Med. Chem. Commun., 2016, Advance Article

DOI: 10.1039/C6MD00387G, http://pubs.rsc.org/en/Content/ArticleLanding/2016/MD/C6MD00387G?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract

. Please note PF-6667294 is Compound 4 and PF-4746537 is Compound 8.

A series of potent and selective carboxamide TRPA1 antagonists were identified by a high throughput screen. Structure–activity relationship studies around this series are described, resulting in a highly potent example of the series. Pharmacokinetic and skin flux data are presented for this compound. Efficacy was observed in a topical cinnamaldehyde flare study, providing a topical proof of pharmacology for this mechanism. These data suggest TRPA1 antagonism could be a viable mechanism to treat topical conditions such as atopic dermatitis.

Graphical abstract: The discovery of a potent series of carboxamide TRPA1 antagonists
str1  str2
 hydrochloride salt (69 mg, 82%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 1.50–1.60 (m, 4H), 1.70– 1.90 (m, 4H), 2.15–2.25 (m, 2H), 2.40–2.48 (m, 2H), 2.70–2.80 (m, 1H), 3.05–3.25 (m, 6H), 3.47–3.62 (m, 2H), 6.38 (br s, 1H), 7.20–7.40 (m, 9H), 7.80 (br m, 1H). MS m/z 509 [M + H]+ .

 

Image result for The discovery of a potent series of carboxamide TRPV1 antagonists

Discovery and development of TRPV1 antagonists

https://en.wikipedia.org/wiki/Discovery_and_development_of_TRPV1_antagonists

/////////////PF-04745637, PF 04745637, PF04745637, PFIZER, PRECLINICAL, TRPV1 antagonists,  atopic dermatitis, 1917294-46-2

c1(ccccc1)CC(CNC(=O)C3(c2ccc(cc2)Cl)CCCC3)N4CCC(CC4)(O)C(F)(F)F


Filed under: Preclinical drugs, Uncategorized Tagged: 1917294-46-2, PF-04745637, PF04745637

Ibipinabant Revisited

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Ibipinabant.svg

Ibipinabant

cas  464213-10-3; UNII-O5CSC6WH1T; BMS-646256; SLV-319;
Molecular Formula: C23H20Cl2N4O2S
Molecular Weight: 487.4015 g/mol

(4S)-5-(4-chlorophenyl)-N-(4-chlorophenyl)sulfonyl-N’-methyl-4-phenyl-3,4-dihydropyrazole-2-carboximidamide

1H-Pyrazole-1-carboximidamide, 3-(4-chlorophenyl)-N’-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N-methyl-4-phenyl-, (4S)-

(4S)-3-(4-Chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N’-methyl-4-phenyl-1H-pyrazole-1-carboximidamide

1H-Pyrazole-1-carboximidamide, 3-(4-chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N‘-methyl-4-phenyl-, (4S)-

(-)-(4S)-N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine

4S)-()-3-(4-Chlorophenyl)-N-methyl-N-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine

It was originally developed by Solvay, which was acquired by Abbott in 2010.

SLV 319, UNII:O5CSC6WH1T, (S)-SLV 319, BMS 646256, JD 5001

  • Originator Solvay
  • Class Antipsychotics; Imides; Obesity therapies; Pyrazoles; Small molecules; Sulfonamides
  • Mechanism of ActionCannabinoid receptor CB1 antagonists

Ibipinabant, also known as BMS-646256, JD-5001 and SLV-319, is a potent and highly selective CB1 antagonist. It has potent anorectic effects in animals, and was researched for the treatment of obesity, although CB1 antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB1 antagonists

Ibipinabant (SLV319, BMS-646,256) is a drug used in scientific research which acts as a potent and highly selective CB1antagonist.[1] It has potent anorectic effects in animals,[2] and was researched for the treatment of obesity, although CB1 antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB1 antagonists.[3][4][5]

Ibipinabant.png

Image for figure Chart 1

Inventors Josephus H.M. Lange, Cornelis G Kruse,Jacobus Tipker, Jan Hoogendoorn
Applicant Solvay Pharmaceuticals B.V.

PATENT

WO 2002076949

https://www.google.com/patents/WO2002076949A1?cl=en

Example IV

(-)-(4S)-N-methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5- dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine

(-)-(4S)-N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine (7.16 gram, 0.0147 mol)) ([α25 D] = -150°, c = 0.01 , MeOH) (melting point: 169-170 °C) was obtained via chiral chromatographic separation of racemic N-methyl-N’-((4-chlorophenyl)sulfonyl)-3- (4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine (18 gram, 0.037 mol) using a Chiralpak AD, 20 μm chiral stationary phase. The mobile phase consisted of a mixture of hexane/ethanol (80/20 (v/v)) and 0.1 % ammonium hydroxide (25 % aqueous solution).

Example III N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine

Part A: To a solution of N-((4-chlorophenyl)sulfonyl)carbamic acid methyl ester (CAS: 34543-04-9) (2.99 gram, 12.0 mmol) and pyridine (4 ml) in 1 ,4-dioxane (20 ml) is added 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (3.39 gram, 13.2 mmol) and the resulting mixture is stirred for 4 hours at 100 °C After concentration in vacuo the residue is dissolved in dichloromethane, successively washed with water, 1 N HCI and water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to a volume of 20 ml. Methyl-tert-butyl ether (60 ml) is added and the resulting solution is concentrated to a volume of 20 ml. The formed crystals are collected by filtration and recrystallised from methyl-te/τ-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1-carboxamide (4J5 gram, 76 % yield) Melting point: 211-214 °C

Part B: A mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro- 4-phenyl-1 H-pyrazole-1 -carboxamide (3.67 gram, 7J5 mmol) and phosphorus pentachloride (1.69 gram, 8.14 mmol) in chlorobenzene (40 ml) is heated at reflux for 1 hour. After thorough concentration in vacuo, the formed N-((4- chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1- carboximidoyl chloride is suspended in dichloromethane and reacted with cold methylamine (1.5 ml). After stirring at room temperature for 1 hour, the mixture is concentrated in vacuo. The residue is crystallised from diethyl ether to give N-methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- 1 H-pyrazole-1 -carboxamidine (2.29 gram, 61 % yield). Melting point: 96-98 °C(dec).

PATENT

WO 2008074816

https://google.com/patents/WO2008074816A1?cl=en

PAPER

An expedient atom-efficient synthesis of the cannabinoid CB1receptor inverse agonist ibipinabant

  • Abbott Healthcare Products B.V., Chemical Design & Synthesis Unit, C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands

http://www.sciencedirect.com/science/article/pii/S0040403911000955

http://dx.doi.org/10.1016/j.tetlet.2011.01.068

Image for unlabelled figure

A novel synthetic route to the highly selective and orally active cannabinoid CB1 receptor inverse agonist ibipinabant is described which combines the use of inexpensive, commercially available reagents and mild reaction conditions with a high degree of atom-efficiency. The method is expected to enable the rapid synthesis of a variety of sulfonylguanidines.

PAPER

JD-5006 and JD-5037: Peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities

  • Jenrin Discovery, 2515 Lori Lane North, Wilmington, DE 19810, USA

http://dx.doi.org/10.1016/j.bmcl.2012.08.004

http://www.sciencedirect.com/science/article/pii/S0960894X12009936

Clip

http://molpharm.aspetjournals.org/content/87/2/197.full.pdf

Paper

Lange et al (2005) Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity. Bioorg.Med.Chem.Lett. 15 4794. PMID: 16140010.

http://www.sciencedirect.com/science/article/pii/S0960894X05010139

http://dx.doi.org/10.1016/j.bmcl.2005.07.054

Paper

Lange et al (2004) Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB1 cannabinoid receptor antagonists. J.Med.Chem. 47 627. PMID:14736243.

A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB1 and hCB2) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitroCB1 antagonistic activities and in general exhibited high CB1 vs CB2 receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C4 position as 4S. Bioanalytical studies revealed a high CNS−plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB1 receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH2 moiety with a -NHCH3 group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80

Abstract Image

4S)-()-3-(4-Chlorophenyl)-N-methyl-N-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (80) and (4R)-(+)-3-(4-chlorophenyl)-N-methyl-N-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (81). Chiral preparative HPLC separation of racemic 67 (18 g, 0.037 mol) using a Chiralpak AD, 20 μm chiral stationary phase yielded 80 (7.16 g, 0.0147 mol) and 81 (7.46 g, 0.0153 mol), respectively. The mobile phase consisted of a mixture of n-hexane/ethanol (80/20 (v/v)) and 0.1% NH4OH (25% aqueous solution).
DESIRED
80: [ ] = −150°, c = 0.01, MeOH; mp 171−172 °C;
1H NMR (400 MHz, DMSO-d6) δ 2.94 (d, J = 4 Hz, 3H), 3.96 (dd, J = 11 and 4 Hz, 1H), 4.46 (t, J = 11 Hz, 1H), 5.05 (dd, J = 11 and 4 Hz, 1H), 7.20−7.35 (m, 5H), 7.45 (dt, J = 8 and 2 Hz, 2H), 7.53 (dt, J = 8 and 2 Hz, 2H), 7.77 (dt, J = 8 and 2 Hz, 2H), 7.82 (dt, J = 8 and 2 Hz, 2H), 8.19 (br d, J = 4 Hz, 1H);
HRMS (C23H21Cl2N4O2S) [M+H]+:  found m/z 487.0768, calcd 487.0762. Anal. (C23H20Cl2N4O2S) C, H, N.
UNDESIRED
81:  [ ] = + 150°, c = 0.01, MeOH; mp 171−172 °C; 1H NMR (400 MHz, DMSO-d6) δ 2.94 (d, J = 4 Hz, 3H), 3.96 (dd, J = 11 and 4 Hz, 1H), 4.46 (t, J = 11 Hz, 1H), 5.05 (dd, J = 11 and 4 Hz, 1H), 7.20−7.35 (m, 5H), 7.45 (dt, J = 8 and 2 Hz, 2H), 7.53 (dt, J = 8 and 2 Hz, 2H), 7.77 (dt,J = 8 and 2 Hz, 2H), 7.82 (dt, J = 8 and 2 Hz, 2H), 8.19 (br d, J = 4 Hz, 1H); HRMS (C23H21Cl2N4O2S) [M+H]+:  found m/z 487.0749, calcd 487.0762. Anal. (C23H20Cl2N4O2S) C, H, N.

Paper

Org. Process Res. Dev., 2012, 16 (4), pp 567–576
Modeling-Based Approach Towards Quality by Design for the Ibipinabant API Step
This work presents a process modeling-based methodology towards quality by design that was applied throughout the development lifecycle of the ibipinabant API step. By combining mechanistic kinetic modeling with fundamental thermodynamics, the degradation of the API enantiomeric purity was described across a large multivariate process knowledge space. This knowledge space was then narrowed down to the process design space through risk assessment, target quality specifications, practical operating conditions for scale-up, and plant control capabilities. Subsequent analysis of process throughput and yield defined the target operating conditions and normal operating ranges for a specific pilot-plant implementation. Model predictions were verified via results obtained in the laboratory and at pilot-plant scale. Future efforts were focused on increasing fundamental process knowledge, improving model confidence, and using a risk-based approach to reevaluate the design space and selected operating conditions for the next scale-up campaign.
API process at the time of the first pilot-plant campaign

Figure

changed to

 

Figure

Process for the second pilot-plant implementation

 

Process parameter ranges and typical results from approximately 20 lab experiments conducted on the process shown in Scheme

Figure

Figure

Figure

Figure 3. Ishikawa diagram for the API step, highlighting factors that potentially affect the enantiomeric purity of the product. Factors shown in blue were accounted for in the sulfonylation reaction and distillative crystallization models. Factors shown in red were not included in the models

table 3. Process parameter ranges and number of parameter levels utilized for model-based prediction of sulfonylation reaction conversion and degradation of API enantiopurity during the distillative crystallization
process parameter min. value max. value # of “levels”
sulfonylation reaction model
temp. (°C) 5 35 7
4-chlorobenzenesulfonyl chloride (equiv) 1.0 1.2 6
conc. (mL/g) 5 10 6
reaction time (h) 2 5 4
distillative crystallization model
pressure (mbar) 300 1013 6
residual 2(AP) 0.05 2.0 6
distillation time (h) 8 48 4
distillation end point (wt % EtOH) 90 98 3

REFERENCES

1: Schirris TJ, Ritschel T, Herma Renkema G, Willems PH, Smeitink JA, Russel FG. Mitochondrial ADP/ATP exchange inhibition: a novel off-target mechanism underlying ibipinabant-induced myotoxicity. Sci Rep. 2015 Sep 29;5:14533. doi: 10.1038/srep14533. PubMed PMID: 26416158; PubMed Central PMCID: PMC4586513.

2: Chorvat RJ, Berbaum J, Seriacki K, McElroy JF. JD-5006 and JD-5037: peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities. Bioorg Med Chem Lett. 2012 Oct 1;22(19):6173-80. doi: 10.1016/j.bmcl.2012.08.004. Epub 2012 Aug 20. PubMed PMID: 22959249.

3: Tomlinson L, Tirmenstein MA, Janovitz EB, Aranibar N, Ott KH, Kozlosky JC, Patrone LM, Achanzar WE, Augustine KA, Brannen KC, Carlson KE, Charlap JH, Dubrow KM, Kang L, Rosini LT, Panzica-Kelly JM, Flint OP, Moulin FJ, Megill JR, Zhang H, Bennett MJ, Horvath JJ. Cannabinoid receptor antagonist-induced striated muscle toxicity and ethylmalonic-adipic aciduria in beagle dogs. Toxicol Sci. 2012 Oct;129(2):268-79. doi: 10.1093/toxsci/kfs217. Epub 2012 Jul 21. PubMed PMID: 22821849.

4: Dawes J, Allenspach C, Gamble JF, Greenwood R, Robbins P, Tobyn M. Application of external lubrication during the roller compaction of adhesive pharmaceutical formulations. Pharm Dev Technol. 2013 Feb;18(1):246-56. doi: 10.3109/10837450.2012.705299. Epub 2012 Jul 20. PubMed PMID: 22813432.

5: Leane MM, Sinclair W, Qian F, Haddadin R, Brown A, Tobyn M, Dennis AB. Formulation and process design for a solid dosage form containing a spray-dried amorphous dispersion of ibipinabant. Pharm Dev Technol. 2013 Mar-Apr;18(2):359-66. doi: 10.3109/10837450.2011.619544. Epub 2012 Jan 23. PubMed PMID: 22268601.

6: Rohrbach K, Thomas MA, Glick S, Fung EN, Wang V, Watson L, Gregory P, Antel J, Pelleymounter MA. Ibipinabant attenuates β-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight. Diabetes Obes Metab. 2012 Jun;14(6):555-64. doi: 10.1111/j.1463-1326.2012.01563.x. Epub 2012 Feb 24. PubMed PMID: 22268426.

7: Lynch CJ, Zhou Q, Shyng SL, Heal DJ, Cheetham SC, Dickinson K, Gregory P, Firnges M, Nordheim U, Goshorn S, Reiche D, Turski L, Antel J. Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels. Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E540-51. doi: 10.1152/ajpendo.00258.2011. Epub 2011 Dec 13. PubMed PMID: 22167524; PubMed Central PMCID: PMC3311290.

8: Gamble JF, Leane M, Olusanmi D, Tobyn M, Supuk E, Khoo J, Naderi M. Surface energy analysis as a tool to probe the surface energy characteristics of micronized materials–a comparison with inverse gas chromatography. Int J Pharm. 2012 Jan 17;422(1-2):238-44. doi: 10.1016/j.ijpharm.2011.11.002. Epub 2011 Nov 10. PubMed PMID: 22100516.

9: Sinclair W, Leane M, Clarke G, Dennis A, Tobyn M, Timmins P. Physical stability and recrystallization kinetics of amorphous ibipinabant drug product by fourier transform raman spectroscopy. J Pharm Sci. 2011 Nov;100(11):4687-99. doi: 10.1002/jps.22658. Epub 2011 Jun 16. PubMed PMID: 21681752.

10: Gamble JF, Tobyn M, Dennis AB, Shah T. Roller compaction: application of an in-gap ribbon porosity calculation for the optimization of downstream granule flow and compactability characteristics. Pharm Dev Technol. 2010 Jun;15(3):223-9. doi: 10.3109/10837450903095342. PubMed PMID: 22716462.

11: Zhang H, Patrone L, Kozlosky J, Tomlinson L, Cosma G, Horvath J. Pooled sample strategy in conjunction with high-resolution liquid chromatography-mass spectrometry-based background subtraction to identify toxicological markers in dogs treated with ibipinabant. Anal Chem. 2010 May 1;82(9):3834-9. doi: 10.1021/ac100287a. PubMed PMID: 20387806.

12: Lange JH, van der Neut MA, den Hartog AP, Wals HC, Hoogendoorn J, van Stuivenberg HH, van Vliet BJ, Kruse CG. Synthesis, SAR and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles as potent cannabinoid CB(1) receptor antagonists. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1752-7. doi: 10.1016/j.bmcl.2010.01.049. Epub 2010 Jan 20. PubMed PMID: 20137935.

References

  1.  Lange, JH; Coolen, HK; Van Stuivenberg, HH; Dijksman, JA; Herremans, AH; Ronken, E; Keizer, HG; Tipker, K; et al. (2004). “Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists”. Journal of Medicinal Chemistry. 47 (3): 627–43. doi:10.1021/jm031019q. PMID 14736243.
  2.  Need, AB; Davis, RJ; Alexander-Chacko, JT; Eastwood, B; Chernet, E; Phebus, LA; Sindelar, DK; Nomikos, GG (2006). “The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats”.Psychopharmacology. 184 (1): 26–35. doi:10.1007/s00213-005-0234-x. PMID 16328376.
  3.  Lange, JH; Van Stuivenberg, HH; Veerman, W; Wals, HC; Stork, B; Coolen, HK; McCreary, AC; Adolfs, TJ; Kruse, CG (2005). “Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity”. Bioorganic & Medicinal Chemistry Letters. 15 (21): 4794–8. doi:10.1016/j.bmcl.2005.07.054. PMID 16140010.
  4.  Srivastava, BK; Joharapurkar, A; Raval, S; Patel, JZ; Soni, R; Raval, P; Gite, A; Goswami, A; et al. (2007). “Diaryl dihydropyrazole-3-carboxamides with significant in vivo antiobesity activity related to CB1 receptor antagonism: synthesis, biological evaluation, and molecular modeling in the homology model”. Journal of Medicinal Chemistry. 50 (24): 5951–66. doi:10.1021/jm061490u. PMID 17979261.
  5.  Srivastava, BK; Soni, R; Joharapurkar, A; Sairam, KV; Patel, JZ; Goswami, A; Shedage, SA; Kar, SS; et al. (2008). “Bioisosteric replacement of dihydropyrazole of 4S-(−)-3-(4-chlorophenyl)-N-methyl-N’-(4-chlorophenyl)-sulfonyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) a potent CB1 receptor antagonist by imidazole and oxazole”. Bioorganic & Medicinal Chemistry Letters. 18 (3): 963–8. doi:10.1016/j.bmcl.2007.12.036. PMID 18207393.
Patent ID Date Patent Title
US9174965 2015-11-03 Pyrimidinylpiperidinyloxypyridone analogues as GPR119 modulators
US2015133479 2015-05-14 PYRIMIDINYLPIPERIDINYLOXYPYRIDONE ANALOGUES AS GPR119 MODULATORS
US8940716 2015-01-27 Bicyclic heteroaryl compounds as GPR119 modulators
US8853205 2014-10-07 Heteropyrrole analogs acting on cannabinoid receptors
US8729084 2014-05-20 Benzofuranyl analogues as GPR119 modulators
US2014080788 2014-03-20 NOVEL BICYCLIC NITROGEN CONTAINING HETEROARYL TGR5 RECEPTOR MODULATORS
US8513265 2013-08-20 [6, 6] and [6, 7]-bicyclic GPR119 G protein-coupled receptor agonists
US8513424 2013-08-20 Pyridone GPR119 G protein-coupled receptor agonists
US8476283 2013-07-02 [6, 5]â??bicyclic GPR119 G protein-coupled receptor agonists
US8314095 2012-11-20 [6, 6] and [6, 7]-bicyclic GPR119 G protein-coupled receptor agonists
Ibipinabant
Ibipinabant.svg
Systematic (IUPAC) name
4S-(−)-3-(4-chlorophenyl)-N-methyl-N’-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine
Identifiers
CAS Number 464213-10-3 Yes
ATC code none
PubChem CID 9826744
ChemSpider 24765166 
UNII O5CSC6WH1T 
KEGG D09349 Yes
ChEMBL CHEMBL158784 
Chemical data
Formula C24H22Cl2N4O2S
Molar mass 501.427

///////// 464213-10-3,  UNII-O5CSC6WH1T,  BMS-646256,  SLV-319, Ibipinabant, JD 5001, solvay, abbott

c2cc(Cl)ccc2C1=NN(C(NC)=NCS(=O)(=O)c3ccc(Cl)cc3)CC1c4ccccc4


Filed under: Uncategorized

Analytical Lifecycle: USP “Statistical Tools”, Analytical Target Profile and Analytical Control Strategy

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DRUG REGULATORY AFFAIRS INTERNATIONAL

Image result for statistical toolsAnalytical Lifecycle: USP <1210> “Statistical Tools”, Analytical Target Profile and Analytical Control Strategy

The United States Pharmacopeia (USP) is currently undertaking further steps towards a comprehensive analytical lifecycle approach by publishing a draft of a new General Chapter <1210> Statistical Tools for Procedure Validation and two Stimuli Articles regarding Analytical Target Profile and AnalyticalControl Strategy in Pharmacopeial Forum. Read more about the life cycle concept for analytical procedures.

http://www.gmp-compliance.org/enews_05565_Analytical-Lifecycle–USP–1210–%22Statistical-Tools%22–Analytical-Target-Profile-and-Analytical-Control-Strategy_15438,15608,Z-PDM_n.html

Following the recently announced elaboration of a new general chapter <1220> “The Analytical Procedure Lifecycle” the United States pharmacopeia (USP) is now proceeding in its approach for a comprehensive analytical lifecycle concept. A further step towards this approach is the draft of a new USP General Chapter <1210> Statistical Tools for Procedure Validation which has been published in Pharmacopeial Forum (PF) 42(5) in September 2016. Comment deadline is November 30, 2016.

Additionally, two Stimuli Articles regarding “Analytical Control Strategy” and “Analytical…

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How to document a Product Transfer? Example templates!

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DRUG REGULATORY AFFAIRS INTERNATIONAL

str1

All participants of the GMP training course “Product Transfer” will receive a special version of the Guideline Manager CD including documents and templates useable for site change projects.

Click

http://www.gmp-compliance.org/eca_mitt_05359_15221,Z-PEM_n.html

According to the European GMP-Rules, written procedures for tranfser activities and their documentation are required. For example, a Transfer SOP, a transfer plan and a report are now mandatory and will be checked during inspections.

As participant of the GMP education course “Product Transfer” in Berlin, from 25-27 October 2016 you will receive a special version of the Guideline Manager CD with a special section concerning product transfers. This section contains, amongst others, a Transfer SOP and a template for a Transfer Plan. Both documents are in Word format and can immediately be used after adoption to your own situation.

Regulatory Guidance Documents like the WHO guideline on transfer of technology in pharmaceutical manufacturing and the EU/US…

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ORM 10921

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Figure

ORM 10921

UNII-D26C95A960; D26C95A960; ORM-12741; ORM12741; ORM 12741; ORM-10921;

(1S,12bS)-1-(Methoxymethyl)-1-methyl-2,3,4,6,7,12b-hexahydro-1H-[1]benzofuro[2,3-a]quinolizine

(1S,12bS)-1-(methoxymethyl)-1-methyl-2,3,4,6,7,12b-hexahydro-[1]benzofuro[2,3-a]quinolizine

285.38, C18 H23 N O2

2H-Benzofuro[2,3-a]quinolizine, 1,3,4,6,7,12b-hexahydro-1-(methoxymethyl)-1-methyl-, (1S,12bS)-

cas 610782-82-6

Belle David Din, Reija Jokela, Arto Tolvanen,Antti Haapalinna, Arto Karjalainen, Jukka Sallinen, Jari Ratilainen
Applicant Orion Corporation

UNII-D26C95A960.png

Image result for Orion Corporation

David Din Belle

David Din Belle

Senior research scientist at Orion Corporation

https://fi.linkedin.com/in/david-din-belle-a2594115

Jari Ratilainen

Jari Ratilainen

https://fi.linkedin.com/in/jari-ratilainen-6a566218

Image result for Reija Jokela

Reija Jokela

https://fi.linkedin.com/in/reija-jokela-06499a1a

The basic drug substance candidate ORM10921 (MW = 285.38),

IUPAC name [1R*,12bR*)-(−)-1,3,4,6,7,12b-hexahydro-1-methoxymethyl-1-methyl-2H-benzofuro [2,3-a]quinolizine],

and its hydrochloric salt were synthesized by Orion Pharma, Finland.

The absolute configuration was assigned by optical rotation and later by single-crystal X-ray diffraction (see Supporting Information). The optical purity of the material was >97%.

  • Originator Juvantia Pharma (CEASED); Orion
  • Class Neuropsychotherapeutics
  • Mechanism of Action Alpha 2c adrenergic receptor antagonists

Highest Development Phases

  • Discontinued Major depressive disorder; Schizophrenia

Most Recent Events

  • 10 May 2006 Discontinued – Phase-I for Schizophrenia in Finland (unspecified route)
  • 10 May 2006 Discontinued – Preclinical for Depression in Finland (unspecified route)
  • 15 Nov 2002 Preclinical trials in Schizophrenia in Finland (unspecified route)

Image result for ORM 10921

Figure 1: Chemical structure of the study compound. Molecular Formula: C18H23NO2 · HCl · ½ H2O; Molecular Weights: 285.39 (free base), 321.85 (hydrochloride) 330.86 (hydrochloride hemihydrate). ORM-10921 · HCl is a single stereoisomer with the (1R*,12bR*) configuration.

The alpha adrenergic receptors can be divided on a pharmacological basis into alphal- and alpha2-adrenoceptors, which can both be further divided into subtypes. Three genetically encoded subtypes, namely alpha2A-, alpha2B- and alpha2C-adrenoceptors, have been discovered in human. Accordingly, alpha2- adrenoceptors in humans have been subdivided into three pharmacological subtypes known as alpha2A-, alpha2B- and alpha2C-adrenoceptors. A fourth, pharmacologically defined subtype, alpha2D, is known in rodents and in some other mammals, and it corresponds to the genetically defined alpha2A-adrenoceptors.

The alpha2-adrenoceptor subtypes have distinct tissue distributions and functional roles. For instance, while alpha2A-adrenoceptors are widely expressed in various tissues, alpha2C-adrenoceptors are concentrated in the CNS, and they appear to play a role in the modulation of specific CNS-mediated behavioural and physiological responses. Compounds that are non-specific to any of the above-mentioned alpha2 subtypes, and compounds that are specific to certain alpha2 subtypes, are already known. For example, atipamezole is a non-specific alpha2 antagonist. Atipamezole has been described in, for example, EP-A-183 492 (cf. p.13, compound XV) and Haapalinna, A. et al., Naunyn-Schmiedeberg’s Arch. Pharmacol. 356 (1997) 570-582. U.S. Patent No. 5,902,807 describes compounds that are selective antagonists for the alpha2C subtype and may be used in the treatment of mental illness, e.g. mental disturbance induced by stress. Such compounds include, for example, MK-912 and BAM- 1303. Furthermore, WO-A-99 28300 discloses substituted imidazole derivatives having agonist-like activity for alpha2B- or 2B/2C-adrenoceptors. hi addition, WO 01/64645 relates to derivatives of quinoline useful as alpha2 antagonists, as well as to selective alpha2C antagonist agents. The disclosures of all documents cited above in this paragraph are incorporated by reference herein.

Several arylquinolizine derivatives and related compounds have been described in the literature, some of which possess valuable pharmaceutical effects. For example, U.S. Patents No. 4,806,545 and 4,044,012 describe 1,1-disubstituted indolo[2,3-«]quinolizidines useful as vasodilators and antihypoxic agents. Further, substituted arylquinolizine derivatives, described for example in U.S. Patent No. 4,686,226 possessing alpha2-adrenoceptor antagonistic activity are useful for example as antidepressant, antihypertensive, or antidiabetic agents or platelet aggregation inhibitors. In addition, U.S. Patent No. 3,492,303 relates to indolo[2,3- α]quinolizidines useful as central nervous system depressants.

PATENT

WO 2003082866

https://www.google.com/patents/WO2003082866A1?cl=en

///////////

CC1(CCCN2C1C3=C(CC2)C4=CC=CC=C4O3)COC


Filed under: Uncategorized Tagged: ORM 10921

Ranolazine

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Ranolazine.svgChemSpider 2D Image | Ranolazine | C24H33N3O4

Ranolazine

雷诺嗪

  • MF C24H33N3O4
  • MW 427.536

Sponsor/Developer: Gilead

Mechanism of action: Late sodium current inhibitor

Indication (Phase): Type 2 diabetes (Phase III)

A Phase 3 Study of Ranolazine in Subjects With Type 2 Diabetes Who Are Not Well Controlled on Metformin Alone (currently recruiting participants as of August 2012, ClinicalTrials.gov Identifier: NCT01555164, see the link here)

Chemical Name of Ranolazine: (RS)-N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide

N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide

1-Piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-
CAS 95635-55-5 [RN]

QA-2943

Ranexa®

Ranexa, Ranolazine
Ranexa;CVT 303;RS 43285-003
Solubility (25°C) * In vitro DMSO 86 mg/mL (201.15 mM)
Ethanol 20 mg/mL (46.77 mM)
Water <1 mg/mL (<1 mM)
In vivo

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02829034 Recruiting Pulmonary Hypertension University of Pennsylvania|Brigham and Womens Hospital|Un  …more July 2016
NCT02817932 Recruiting Healthy Male Individuals A.Menarini Asia-Pacific Holdings Pte Ltd March 2016 Phase 1
NCT02687269 Not yet recruiting Myocardial Stunning Policlinico Universitario Agostino Gemelli March 2016 Phase 4
NCT02653833 Recruiting Muscular Dystrophy Cedars-Sinai Medical Center December 2015 Phase 0
NCT02611596 Not yet recruiting Silent Myocardial Ischemia|Type 2 Diabetes Walter Reed National Military Medical Center November 2015

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Active Substance
The chemical name of ranolazine is (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2- methoxyphenoxy)propyl] piperazineacetamide. Ranolazine is a white to off-white solid, very slightly soluble in water. It is freely soluble in aqueous buffered solutions at pH levels below 4.4 and soluble in several organic solvents e.g. dichloromethane and methanol. The chemical structure is well characterised by means of elemental analysis, UV, IR, 1 H-NMR, 13C-NMR chemical ionization, electron impact mass spectra and x-ray diffraction. Ranolazine exhibits a chiral center and is obtained as a racemic mixture that consists of a 1:1 ratio of (R) and (S) enantiomers. This is confirmed by demonstrating that ranolazine does not exhibit any optical rotation of plane polarized light in polarimeter measurements. Both enantiomers exhibit pharmacological activity. Regarding polymorphism, crystallisation studies were conducted using different solvents, crystallization conditions and vapor diffusion experiments. In these studies three crystalline forms named as Form I, Form II, Form III and one amorphous form were identified. Form I is the only one that was thermodynamically stable, Form II and Form III are kinetically unstable. The synthetic process used for the synthesis of ranolazine has been shown to produce only Form I. Extreme conditions that are not relevant to the synthetic process are required to convert ranolazine to other solid-state forms (amorphous and two other crystalline forms, Form II and Form III)
Manufacture
Ranolazine is manufactured using a three step synthetic process followed by purification, drying and milling. The starting materials are 2,6-dimethylaniline (2,6-DMA), chloroacetyl chloride (CAC), piperazine dihydrochloride and guaiacol glicydil ether (GGE). The synthetic process has been adequately described the critical process parameters have been identified and are controlled with appropriate in-process controls. Data from four validation batches have been provided that demonstrate that the manufacturing process is capable to consistently produce batches of active substance that comply with the predefined specifications. A detailed discussion about potential impurities and their origin has been provided in line with ICH Guideline Q3A(R). Three specified impurities arising from the route of synthesis and one arising from the staring materials have been identified. There are also eight unspecified potential impurities.
Ranolazine, its enantiomers, and three metabolites (RS-88390, RS-89961, and RS-88772) were shown to have moderate affinity for α1A-and α1B-adrenergic receptors. Ranolazine, its S-enantiomer, and the same three metabolites had a similar affinity for β1-adrenergic receptors, with the R-enantiomer having no significant binding activity. The affinity of ranolazine for β2-adrenergic receptors was slightly lower, with the S-enantiomer and metabolites RS-88390 and RS-88772 having a similar affinity as the racemate. The metabolite RS-89961 had a higher affinity for β2-adrenergic receptors, whereas the R-enantiomer had no significant binding activity.
………CLICK FOR REFERNCE
also
Ranolazine HCl
N-(2,6-二甲基苯基)-4-[2-羟基-3-(2-甲氧苯氧基)丙基]-1-哌嗪乙酰胺盐酸盐
CAS 95635-56-6
Molecular Formula C24H35Cl2N3O4
MW 500.46

Ranolazine, developed by CV Therapeutics whom Gilead Sciences bought in 2009, is also sold under the trade name Ranexa for the treatment of  chronic angina (chest pain).

Ranolazine, a partial fatty acid oxidation inhibitor available that is also a late sodium channel inhibitor as an oral extended-release tablet, has been developed and launched by Gilead Palo Alto (formerly CV Therapeutics; CVT), a wholly owned subsidiary of Gilead Sciences, under license from Roche Bioscience (formerly Syntex)

Ranolazine, sold under the trade name Ranexa by Gilead Sciences, is a drug to treat angina that was first approved in 2006.

Angina also known as Angina pectoris is indication for heart disease caused by lack of blood circulation to the heart. The most widespread reason for the angina is Atherosclerosis. In coronary heart disease patients, arteries become narrow and stiff when compared with the healthy heart arteries. These narrow and stiff arteries cause difficulties to reach oxygen rich blood for heart. About 17 million Americans are suffering with coronary heart diseases and about 9 millions are suffering with chronic angina. Ranolazine is the one of the medicament used to manage chronic angina, developed by Roche Bioscience (formerly Syntex) and marketed by CV Therapeutics. USFDA was approved Ranolazine 2 under brand name of Ranexa® in January 27, 2006. Subsequently European medical agency (EMEA) approved in July 09, 2008. Latter on it was approved in few other developing countries. Ranexa ® is available in market in the form of 500 mg and 1000 mg film coated tablet and the maximum daily dosage should be less than 2.0g. Over dosage of Ranexa ® lead to dizziness, nausea, and vomiting. Worldwide sales of Ranexa® by December 2011 is about 400 millions USD (~2000 crores) with the consumption of 1, 00, 678 kg. Major contribution is from USA i.e. about 300 millions USD. ……..CLICK

(5) (a) Kluge, A. F.; Clark, R. D.; Strosberg, A. M.; Pascal, J. G.; Whiting, R. United states patent, US 4,567,264, 1986. (b) Kluge, A. F.; Clark, R. D.; Strosberg, A. M.; Pascal, J. C.; Whiting, R. L. European patent, EP 0,126,449, 1987. (c) Kluge, A. F.; Clark, R. D.; Strosberg, A. M.; Pascal, J. C.; Whiting, R. Canadian patent, CA 1256874, 1987.

Amongst the various synthetic routes described for the preparation of Ranolazine, some of the key approaches are discussed here under. Kluge.F.A et al 5 have reported two synthetic approaches for preparation of Ranolazine 2 using commercially available 2-Methoxy phenol 25 and 2, 6-dimethyl aniline 20 as key starting materials. The first synthetic route commenced with the synthesis of methyl oxirane derivative 27. Key intermediate methyl oxirane derivative 27 was synthesized from 25 and epichlorohydrin 26 in presence of NaOH employing Williamson reaction conditions. Thus obtained 27 treated with piperazine 23 in ethanol to obtain hydroxyl piperazine derivative 33. Thereafter, reaction of hydroxyl piperazine derivative 33 with phenyl acetamide derivative 22 in dimethylformamide afforded dihydrochloride salt of ranolazine 2, which was treated with ammonia to furnish ranolazine 2(Scheme 3.1).

Second synthetic path way for the preparation of ranolazine involves the condensation of piperazinyl acetamide intermediate 24 and methyl oxirane 27 in mixture of methanol and toluene (Scheme 3.2).

Mingfieng.S et al reported7 similar approach for the synthesis of Ranolazine 2 utilizing hydroxy propyl halide intermediate 94 instead of methyl oxirane compound 27. The requisite hydroxy propyl halide intermediate 94 prepared by reacting 2-methoxy phenol 25 with 1, 3- dichloropropan-2-ol 93 in presence of NaOH and mixture of ethanol & water as shown in Scheme 3.3.

(7) Lisheng, W.; Xiaoyu, F.; Hong-yuan, Z. Journal of Guangxi University (Natural Science Edition), 2003, 28, 301-303.

Eva.C.A et al.6 discovered an alternative synthetic path way for preparation of Ranolazine. As depicted in Scheme 3.3 reaction of phenyl acetamide derivative 22 with diethanolamine in presence of triethylamine and subsequent chlorination using thionyl chloride furnishes dichloro compound 91. Condensation of dichloro compound 91 with amino isopropanol derivative 92 provided Ranolazine 2. Amino isopropanol derivative 92 is achieved by reaction of methyl oxirane compound 27 with ammonia.

(6) Agai-Csongor, E.; Gizur, T.; Haranyl, K.; Trischler, F.; DemeterSzabo, A.; Csehi, A.; Vajda, E.; Szab-Koml si, G. European patent, EP 483932 A1, 1992.

str1

2 with 99.9% purity.

IR (KBr, cm–1): 3331 (Amine, NH), 3002 (Aromatic, =CH), 2955, 2936 and 2834 (Ali, CH), 1686 (Amide, C=O), 1592 and 1495 (Aromatic, C═C), 1254 and 1022 (Ether, C-O-C) & 1125 (C-N).

1H NMR (500 MHz, DMSO–d6): δH 9.1 (s, 1H, N-H), 6.8-7.1 (m, 6H, ArH), 4.8 (s, 1H, OH), 3.9 (s, 1H, CH), 3.8-3.9 (dd, 2H, J=6.5 Hz, 10.7 Hz, CH2), 3.8 (s, 3H, CH3), 3.1 (s, 2H, CH2), 2.4-2.6 (m, 10H, CH2) 2.1 (s, 6H, CH3).

13C NMR (500 MHz, DMSO–d6): 18.23, 39.16, 39.83, 39.50, 39.76, 39.87, 53.18, 53.31, 55.50, 61.13, 61.44, 66.63, 71.96, 112.37, 113.64, 120.74, 120.03, 126.32, 127.62, 134.97, 135.06, 148.36, 149.17, 167.97.

M/S (m/z): 428.4(M+ + H).

CHN analysis: Anal. Calcd for C24H33N3O4 (427.54): C 67.42, H 7.78, N 9.83.; Found: C 67.62 H 7.47, N 9.68.

Title: Ranolazine
CAS Registry Number: 95635-55-5
CAS Name: N-(2,6-Dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide
Additional Names: (±)-4-[2-hydroxy-3-(o-methoxyphenoxy)propyl]-1-piperazineaceto-2¢,6¢-xylidide; (±)-1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoylmethyl]piperazine
Trademarks: Ranexa (CV Therapeutics)
Molecular Formula: C24H33N3O4
Molecular Weight: 427.54
Percent Composition: C 67.42%, H 7.78%, N 9.83%, O 14.97%
Literature References: Anti-ischemic agent which modulates myocardial metabolism. Prepn: A. F. Kluge et al., EP 126449;eidem, US 4567264 (1984, 1986 both to Syntex). HPLC resolution of enantiomers: E. Delée et al., Chromatographia 24, 357 (1987). Clinical trial in angina: B. R. Chaitman et al., J. Am. Coll. Cardiol. 43, 1375 (2004). Review of pharmacology and clinical development: J. G. McCormack et al., Gen. Pharmacol. 30, 639-645 (1998); R. S. Schofield, J. A. Hill, Expert Opin. Invest. Drugs11, 117-123 (2002).
Derivative Type: Dihydrochloride
CAS Registry Number: 95635-56-6
Manufacturers’ Codes: RS-43285
Molecular Formula: C24H33N3O4.2HCl
Molecular Weight: 500.46
Percent Composition: C 57.60%, H 7.05%, N 8.40%, O 12.79%, Cl 14.17%
Properties: White crystalline powder from methanol/ether, mp 164-166°. Readily sol in water.
Melting point: mp 164-166°
Therap-Cat: Antianginal.

Image result for Ranolazine SYNTHESIS

Image result for ranexa

Medical uses

Ranolazine is used to treat chronic angina.[1] It may be used concomitantly with β blockers, nitrates, calcium channel blockers,antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.[2]

Image result for ranolazine

Contraindications

Some contraindications for ranolazine are related to its metabolism and are described under Drug Interactions. Additionally, in clinical trials ranolazine slightly increased QT interval in some patients[3] and the FDA label contains a warning for doctors to beware of this effect in their patients.[2] The drug’s effect on the QT interval is increased in the setting of liver dysfunction; thus it is contraindicated in persons with mild to severe liver disease.[4]

Image result for ranolazine

Side effects

The most common side effects are dizziness (11.8%) and constipation (10.9%).[1] Other side effects include headache and nausea.[3]

Biological Activity

Description Ranolazine is a calcium uptake inhibitor via the sodium/calcium channel, used to treat chronic angina.
Targets Calcium channel [1]
In vitro Ranolazine is found to bind more tightly to the inactivated state than the resting state of the sodium channel underlying I(NaL), with apparent dissociation constants K(dr)=7.47 mM and K(di)=1.71 mM, respectively. Ranolazine at 5 mM and 10 mM reversibly shortens the duration of TCs and abolishes the after contraction.[1] Ranolazine inhibits the late component of INa and attenuates prolongation of action potential duration when late INa is increased, both in the absence and presence of IK-blocking drugs. Ranolazine (10 mM) reduces by 89% the 13.6-fold increase in variability of APD caused by 10 nM ATX-II. [2]
In vivo Ranolazine significantly and reversibly shortens the action potential duration (APD) of myocytes stimulated at either 0.5 or 0.25 Hz in a concentration-dependent manner in left ventricular myocytes of dogs. [1] Ranolazine (10 mM) significantly increases glucose oxidation 1.5-fold to 3-fold under conditions in which the contribution of glucose to overall ATP production is low (low Ca, high FA, with insulin), high (high Ca, low Fa, with pacing), or intermediate in working heart of rats. Ranolazine (10 mM) similarly increases glucose oxidation in normoxic Langendorff hearts (high Ca, low FA; 15 mL/min) of rats. Ranolazine significantly improves functional outcome in reperfused ischemic working hearts, which is associated with significant increases in glucose oxidation. [3]
Features

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) × mouse Km(3)  = 11.2 mg/kg
rat Km(6)

References

[1] Undrovinas AI, et al. J Cardiovasc Electrophysiol,?006, 17 Suppl 1, S169-S177.

[2] Song Y, et al. J Cardiovasc Pharmacol,?004, 44(2), 192-199.3]

Baptista T, et al. Circulation,?996, 93(1), 135-142.

Drug interactions

Ranolazine is metabolized mainly by the CYP3A enzyme. It also inhibits another metabolizing enzyme, cytochrome CYP2D6.[2] For this reason, the doses of ranolazine and drugs that interact with those enzymes need to be adjusted when they are used by the same patient.

Ranolazine should not be used with drugs like ketoconazole, clarithromycin, and nelfinavir that strongly inhibit CYP3A nor with drugs that activate CYP3A like rifampin and phenobarbital.[2]

For drugs that are moderate CYP3A inhibitors like diltiazem, verapamil, erythromycin, the dose of ranolazine should be reduced.[2]

Drugs that are metabolized by CYP2D6 like tricyclic antidepressants may need to be given at reduced doses when administered with ranolazine.[2]

Mechanism of action

Ranolazine inhibits persistent or late inward sodium current (INa) in heart muscle[5] in a variety of voltage-gated sodium channels.[6] Inhibiting that current leads to reductions in elevated intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle.[3] The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.[2]

Legal status

Ranolazine was approved by the FDA in January 2006, for the treatment of patients with chronic angina as a second-line treatment in addition to other drugs.[3] In 2007 the label was updated to make ranolazine a first-line treatment, alone or with other drugs.[3] In April 2008 ranolazine was approved by the European EMEA for use in angina.[7]

History

In 1996, CV Therapeutics licensed the North American and European rights to ranolazine from Syntex, a subsidiary of Roche, which had discovered the drug and had developed it through Phase II trials in angina.[8] In 2006, CV Therapeutics acquired the remaining worldwide rights to ranolazine from Roche.[9] In 2008 CV Therapeutics exclusively licensed rights for ranolazine in Europe and some other countries to Menarini.[10] In 2009, Gilead acquired CV Therapeutics.[11] In 2013 Gilead expanded the partnership with Menarini to include additional countries, including those in Asia.[12]

Image result for ranolazine

Ranolazine (CAS NO.: 95635-55-5), with its systematic name of 1-Piperazineacetamide, N-(2,6-dimethylphenyl)-4-(2-hydroxy-3-(2-methoxyphenoxy)propyl)-, could be produced through many synthetic methods.

Following is one of the synthesis routes:
The acylation of 2,6-dimethylaniline (II) with chloroacetyl chloride in the presence of triethylamine in dichloromethane affords N-(2,6-dimethylphenyl) chloroacetamide (III), which is condensed with piperidine (IV) in refluxing ethanol to yield N-(2,6-dimethylphenyl)-2-piperazinoacetamide IV). At last, this compound is condensed with 3-(2-methoxyphenoxy)-12-epoxypropane (VI) in refluxing methanol toluene.

Image result for ranolazine

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Paper

“All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

*Corresponding authors
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India
E-mail: akchakraborti@niper.ac.in,akchakraborti@rediffmail.com
Green Chem., 2013,15, 756-767

DOI: 10.1039/C3GC36997H

A novel strategy of ‘all water chemistry’ is reported for a concise total synthesis of the novel class anti-anginal drug ranolazine in its racemic (RS) and enantiopure [(R) and (S)] forms. The reactions at the crucial stages of the synthesis are promoted by water and led to the development of new water-assisted chemistries for (i) catalyst/base-free N-acylation of amine with acyl anhydride, (ii) base-free N-acylation of amine with acyl chloride, (iii) catalyst/base-free one-pot tandem N-alkylation and N-Boc deprotection, and (iv) base-free selective mono-alkylation of diamine (e.g., piperazine). The distinct advantages in performing the reactions in water have been demonstrated by performing the respective reactions in organic solvents that led to inferior results and the beneficial effect of water is attributed to the synergistic electrophile and nucleophile dual activation role of water. The new ‘all water’ strategy offers two green processes for the total synthesis of ranolazine in two and three steps with 77 and 69% overall yields, respectively, and which are devoid of the formation of the impurities that are generally associated with the preparation of ranolazine following the reported processes.

Damodara Naidu Kommi

Damodara Naidu Kommi

Prof. Asit K. Chakraborti

Picture
Graphical abstract: “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

Image result for ranolazineImage result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazineImage result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazineImage result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

Image result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazineImage result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

Image result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

PATENT

https://www.google.com/patents/US20130090475

Ranolazine, chemically known as (±)-N-(2,6-dimethylplenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, is represented by the formula as given below.

Figure US20130090475A1-20130411-C00002

Ranolazine, a novel agent used to treat angina pectoris type coronary heart disease, was developed by American CV Therapeutica Company (now known as Gilead Sciences Company). Ranolazine has firstly been appeared on the market in US in 2006 and could be used to treat myocardial infarction, congestive heart disease, angina and arhythmia etc. The mechanism of action of ranolazine is to inhibit partial fatty acid oxidation, which changes fatty acid oxidation to glucose oxidation in heart, and thereby reduces the cardiac oxygen consumption. Ranolazine is the only antianginal agent without changing heart rate or blood pressure.

The processses for the preparation of ranolazine, which could be roughly divided into two types as shown in FIG. 1 and FIG. 2, were disclosed in International Application Publication No. WO 2010/025370, WO 2010/023687, WO 2009/153651, WO 2008/139492, WO 2008/047388, WO 2006/008753, Chinese patent No. CN101560196, CN101544617, CN1915982, the United States patent No. US2008312247, the publication China Pharmacist, 2007, 10(12), 1176-1177, Chinese Journal of Medicinal Chemistry, 2003, 13(5), 283-285, and Chinese Journal of Pharmaceuticals, 2004, 35(11): 641-642.

The process described in FIG. 1 (method 1) involves reacting [(2,6-dimethylphenyl)-carbamylmethyl]-peperazine with 1-(2-methoxyphenoxy)-2,3-epoxypropane to obtain ranolazine, in which comprises the steps of:

a) condensing 2,6-xylidine with chloroacetyl chloride in the presence of base to get amide, which is further reacted with piperazine by a substitution reaction of N-monoalkylation to get N-(2,6-dimethylphenyl)-1-piperazineacetamide, and

b) condensing guaiacol with epoxy chloropropane to get 1-(2-methoxyphenoxy)-2,3-epoxypropane.

As the condensation is carried out in the alkaline environment, the epoxy ring becomes easy to open loop, and thus the products comprise mixtures of open-looped and looped form, thereby requiring rigorous separation conditions and being difficult to achieve the desired purity in the following reaction.

The process described in FIG. 2 (method 2) involves reacting 2-chloro-N-(2,6-dimethylphenyl)-acetamide with 1-(2-methoxyphenoxy)-3-(N-piperazine)-2-hydroxypropane to get ranolazine, in which comprises the steps of:

a) condensing 2,6-xylidine with chloroacetyl chloride in the presence of base to get 2-chloro-N-(2,6-dimethylphenyl)-acetamide, and

b) condensing guaiacol with epoxy chloropropane to get 1-(2-methoxyphenoxy)-2,3-epoxypropane, which is further reacted with piperazine to get 1-(2-methoxyphenoxy)-3-(N-piperazine)-2-hydroxypropane.

As the condensation is carried out in the alkaline environment, the epoxy ring becomes easy to open loop, and thus the products comprise mixtures of open-looped and looped form, thereby requiring rigorous separation conditions and being difficult to achieve the desired purity in the following reaction. The monosubstitution reaction of N-alkylation reacted with peperazine is further difficult to be controlled to produce the desired products.

Compared with method 2, method 1 could be easier to be industrialized as the quality of intermediates obtained by method 1 could be easier to be controlled and also the method 1 could be easier to be operated. But in the repeated experiments, it was found that it still had a lot of difficulties in realizing the industrialization by method 1 although it could be easier to be operated as there are mixtures including open-looped and looped products rather than single product produced when guaiacol (o-methoxyphenol) was reacted with epoxy chloropropane, so the operation of distillatory separation would still need very high temperature (above 250° C.) and very low vacuum degree (5 mm Hg) with the disadvantages of high energy consumption, high facilities investment and tedious operation. And in the following condensation reaction, there are a lot of products were produced during the reaction so as to make the quality of the products hard to be controlled.

Example 1Preparation of N-(2,6-dimethylphenyl)-1-piperazinylacetamide1.1: Preparation of 2-chloro-N-(2,6-dimethylphenyl)-acetamid

Figure US20130090475A1-20130411-C00006

30.5 g (0.252 mol) of 2,6-xylidine, 100 ml of ethyl acetate, 26.5 g (0.25 mol) of sodium carbonate were successively added into a 250 ml of 3-neck flask and placed in an ice-water bath. 36.5 g (0.323 mol) of chloroacetyl chloride was dissolved in 50 ml of ethyl acetate and then the mixture was dropwise added into the 3-neck flask till completion. The ice-water bath was removed and the reaction was carried out for 3 h at the room temperature. The reaction product was slowly added 100 ml of water in an ice-water bath, stirred for 10 min and filtered. The filter cake as white needle solid was washed and dried under vacuum to get 46.3 g of 2-chloro-N-(2,6-dimethylphenyl)-acetamide having a yield of 93%

1.2: Preparation of N-(2,6-dimethylphenyl)-1-piperazinylacetamide

Figure US20130090475A1-20130411-C00007

58.3 g (0.3 mol) of piperazine hexahydrate was dissolved in 230 ml of ethanol and 50.0 g (0.25 mol) of 2-chloro-N-(2,6-dimethylphenyl)-acetamide was subsquently added. The mixture was heated under reflux for 3 h till completion. The reaction product was cooled to room temperature and filtered. The filter was concentrated under reduced pressure and 80 ml of water was added. The mixture was extracted with dichloromethane and the organic layer was concentrated under vacuum at 60° C. to get 39.4 g of N-(2,6-dimethylphenyl)-1-piperazinylacetamide having a yield of 63%. 1HNMR (CDCl3): 2.23˜2.27,s, 6H, 2.67,s, 4H, 2.96˜2.98,t, 4H, 3.19˜3.21,s, 2H, 7.08˜7.26,m, 3H, 8.69,s, 1H.

Example 2Preparation of Ring-Opening Halide2.1: Preparation of 1-chloro-3-(2-methoxyphenoxy)-2-propylalcohol

Figure US20130090475A1-20130411-C00008

26 g (0.65 mol) of sodium hydroxide, 150 ml of water, 150 ml of ethanol, 62 g (0.5 g) of guaiacol were successively added into a reaction flask and 103 g (0.8 mol) of 1,3-dichloro-2-propylalcohol was slowly dropwise added till completion. The mixture was heated up to 45° C. for 24 h. The reaction product was extracted three times with 150 ml of dichloromethane each and the organic layer was combined, dried with anhydrous magnesium chloride and distilled under reduced pressure. The fraction at 160° C. and a pressure of 2 kp was collected to get 73.6 g of faint yellow liquid having a yield of 68%. 1HNMR (CDCl3): 3.44˜3.46,d, 1H, 3.69-3.78,dd, 2H, 3.85,s, 3H, 4.11˜4.12,d, 2H; 4.18˜4.22 μm, 1H, 6.89˜7.00,m, 4H. The result confirmed that the yellow liquid was 1-chloro-3-(2-methoxyphenoxy)-2-propylalcohol.

2.2: Preparation of 1-bromo-3-(2-methoxyphenoxy)-2-propylalcohol

Figure US20130090475A1-20130411-C00009

26 g (0.65 mol) of sodium hydroxide, 150 ml of water, 150 ml of ethanol, 62 g (0.5 g) of guaiacol were successively added into a reaction flask and 174.4 g (0.8 mol) of 1,3-dibromo-2-propylalcohol was slowly dropwise added till completion. The mixture was heated up to 45° C. for 10 h. The reaction product was extracted three times with 150 ml of dichloromethane each and the organic layer was combined, dried with anhydrous magnesium chloride and distilled under reduced pressure. The fraction at 160° C. and a pressure of 2 kp was collected to get 103 g of faint yellow liquid of 1-bromo-3-(2-methoxyphenoxy)-2-propylalcohol having a yield of 79%.

Example 3Preparation of Ranolazine3.1: 1-chloro-3-(2-methoxyphenoxy)-2-propylalcohol as a raw material

Figure US20130090475A1-20130411-C00010

2.5 g (0.01 mol) of 1-chloro-3-(2-methoxyphenoxy)-2-propylalcohol, 3.1 g (0.012 mol) of N-(2,6-dimethylphenyl)-1-piperazinylacetamide, 4.1 g (0.03 mol) of potassium carbonate, 25 ml of methanol and 50 ml of toluene were successively added into a reaction flask and heated under reflux for 4.5 h till completion.

The fraction whose main ingredient was methanol was collected by atmospheric distillation at boiling point of 62-68° C. and then filtrated. The filtrate was washed with 3N HCl to get 50 ml of liquid having a pH of 1-2 and further treated with 50 ml of saturated sodium carbonate solution to adjust pH to 9-10. The product was extracted three times with 20 ml of dichloromethane each and the lower organic phase was combined. After the dichloromethane was removed by distillation under reduced pressure and rotary evaporation, the yellow viscous liquid was obtained and then further dissolved in about 10 ml of methonal. The tetrahydrofuran was then dropwise added under reflux till turbidity. The product was slowly crystallized with cooling and filtrated to get 3.42 g of white solid having a yield of 80.1% by vacuum drying at 40° C

1HNMR (CDCl3): 2.22,s, 6H, 2.60˜2.62,t, 4H, 2.75,s, 6H, 3.21,s, 2H, 3.45,s, 3H; 3.85,s, 3H, 4.02˜4.04,t, 2H, 4.16,s, 1H, 6.88˜6.90,t, 2H, 6.91˜6.96,m, 2H, 7.08˜7.1,m, 3H, 8.65,s, 1H. The result confirmed that the compound obtained is ranolazine. Purity by HPLC (area normalization method): 99.1%.

PATENT

https://www.google.com/patents/CN102875490A?cl=zh

Ranolazine piperazine derivatives, chemical name: (±) -1- [3- (2_ methoxyphenoxy) -2_-hydroxypropyl] -4- [N- (2, 6- dimethylphenyl) carbamoylmethyl] piperazine. Ranolazine is a novel antianginal drugs, which can provide metabolic myocardial protection at the cellular level by improving myocardial energy, while heart rate, blood pressure and hemodynamic impact, has a good prospect. [0004] Currently, the literature synthetic routes ranolazine can be grouped into three: a route: literature (Wolff HeartFailure Reviews, 2002,7 (2): 187- 203.) Using 2_ [N, N- two – ( 2-chloroethyl) amino] -2,6-dimethyl-acetanilide and 3- (2-methoxyphenoxy) -2-propanol of the -I-, amino cyclization to synthesize the desired product. The advantage of this method is to avoid the use of large amounts of piperazine, but the drawback is six steps required to complete the reaction step is long, the total yield is low, is not applicable to industrial production. Route II: literature (US, 4567264; LI Shu-chun Chinese Journal of Medicinal Chemistry, 2003, 13 (5): 283-285) piperazine used directly as the raw material, the advantage of a four-step reaction process is shorter, but due to the direct use of piperazine N- (2,6- dimethylphenyl) -2-chloro – acetamide (2) the reaction, in order to avoid generating disubstituted compound and increased the yield dropping proportion piperazine, piperazine need to consume a large amount. Route III: Document (Qin Mingli, Xinyang Normal University, 2007,20 (2): 226-229) synthetic routes and route only difference is that two different priorities on the piperazine ring substituted on. After two routes have two places noteworthy: how to avoid the generation of disubstituted compounds and the compound (4), (it) is purified.

Image result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

Synthesis of Compound (3)

In the synthesis of the compound (3), since piperazine simultaneous introduction of two groups, by changing the reaction conditions, to seek optimal reaction molar ratio, in order to optimize the synthesis process, to improve the yield. Since the formation of crystalline anhydrous piperazine water easily precipitated in the solvent methylene chloride, anhydrous conditions so the need to control and make the feed ratio of I: 2 Avoid disubstituted product formation. Methanol can also be used as solvent to avoid precipitation of piperazine, and generates less disubstituted, but did not significantly increase yield (61.5%), it is still producing less toxic with methylene chloride as the solvent, control anhydrous conditions. Removed by filtration and the compound (3) excess piperazine, after the solvent is evaporated, dissolved in water, filtered off disubstituted extracted with methylene chloride, in high purity in the latter studies, may be mono-substituted piperazine as the raw material, and then and then removing the protecting group, thereby avoiding the generation of double substitution also improves the yield.

Synthesis [0008] Compound (5)

When the use of trifluoroacetic acid deprotection, since the compound (4) itself has two salt-forming groups, so the need to increase the TFA feeding, paper, compound (4): trifluoroacetic acid = 1: 6 feeding, the reaction was stirred at room temperature for two hours after the end, and then try to solvent evaporated to dryness, a small amount of ethyl acetate was added and then repeatedly evaporated with divisible trifluoroacetic acid. Finally ethanol: petroleum ether = 1: 1.4 was recrystallized to give compound (5).

Synthesis [0009] Compound (I),

Document (Mcaroon, J Med Chem, 1981,24 (11): 1320- 1328) with methanol – toluene system, literature (US, 4567264) with DMF system. Considering the safety, environmental protection, price, cost, industrial production and other factors, we use isopropyl alcohol as a solvent. In this step, less side reaction byproducts concentrated in raw materials, in strict accordance with the reaction so after molar ratio, TLC detection, should be enough to make up the raw materials, to minimize raw material residues, reducing the difficulty of recrystallization.

[0010]

Specific implementation methods

Synthesis below with embodiments of the present invention will be further described in Example a N- (2,6- dimethylphenyl) -2-chloroacetamide (2)

In 3000ml three-neck flask, into 2,6-dimethylaniline (45. 53 g, 0. 375 mol), toluene (750 ml), sodium carbonate (39. 75g, 0. 375 mol), water (750 ml ), with vigorous stirring slowly added dropwise chloroacetyl chloride (50. 90 g, 0. 45mol), temperature 20~35 ° C (ice water bath). During the reaction, TLC detection reaction process. After completion of the reaction, ice-water bath cooling and crystallization, filtration, washed with toluene, recrystallized from 50% ethanol to give the compound (2), white needles (64. 53g, yield of 86. 9%, mp: 148 ~149 ° C).

Synthesis Example Two N-BOC’s [0011] implementation

In three 250ml flask inputs piperazine (3. 07g, 0. 0356mol), dichloromethane 50ml, piperazine with vigorous stirring to dissolve. Was slowly added dropwise while piperazine (2. 99g, 0. 0347mol dissolved in 50ml of methylene chloride), a BOC anhydride (7. 30g, was dissolved in 50ml of methylene chloride), temperature (Γ 5 ° C. After the addition was complete, the reaction was stirred overnight .TLC detection process. after completion of the reaction, a white solid was filtered off. the filtrate was concentrated, dissolved in water IOOml, a white solid was filtered off. the filtrate with dichloromethane (50ml X3 times). the organic layer was dried over anhydrous sodium sulfate , the drying agent was removed by filtration and the filtrate evaporated to give the compound (3), white needle crystals 4. 07g, yield 65. 3%, 1H-NMR (CDCL3):.. 3. 75 (s, 4H), 2 86 ~2. 91 (m, 4H,), I. 99 Cs, 1H), I. 45 (s, 9H).

[0012] Example (2,6-dimethylphenyl) Synthesis of (N-B0C piperazinyl) acetamide (4) of the three N- -1-.

[0013] In 150ml three-necked flask was added N-BOC piperazine (3) (5. 40g, O. 0289mol), the compound (2) (5. 71g, 0.0289mo, potassium carbonate (4. OOgO. 0202mol) in dry ethanol 10ml, was heated 4h, TLC detection progress of the reaction. after completion of the reaction, water was added 10ml, extracted with ethyl acetate (30mlX2). The organic layer was dried over anhydrous sodium sulfate, filtered off and the filtrate was concentrated and dried U. homogeneous, with ethyl .: petroleum ether = 1: 32 recrystallized compound (4) (white solid, 8 Olg, yield 79. 6%, mp: 119~120 ° C; 1H-NMR3 (s, 7. 09, 3H, Ar-H), 3. 50 (q, 4H, J = 4. 8), 3. 22 (s, 2H), 2.64 (q, 4H, J = 4.8), 2. 23 (s, 6H, 2 X CH3), 1.611 (s, 9H, 3X CH3);.. 13CNMR (167.95,154.43,134.78,133.35,128.14,127.08,79.83,61.65,53.40,43.37,26 24,18 47).

[0014] Fourth Embodiment N- (2,6-dimethylphenyl) -1-piperazine acetamide put in 50ml round bottom flask N- (2,6-dimethylphenyl) -1 – (N-BOC piperazine) -acetamide (4) (. 4 30g, O. 121mol), trifluoroacetic acid (8. 24g, 0 0722mol.), ethyl acetate 6ml, was stirred at room temperature under reflux for 2h, TLC detection reaction process . After completion of the reaction, the solvent evaporated to dryness to give a white solid. With ethanol: petroleum ether = 1: 14 recrystallized compound

(5), a white powder (2. 82g, yield 92. 5%, mp:. 130~131 .., 1H-NMR3 9. 573 (s, IN-H), 9 043 (s, 2XN- H), 7 · 187~7. 087 (t, 3X Ar-H), 3. 66 (s, 4H), 3. 27 (s, 2H), 3. 07 (s, 4Η) ^ _

2. 142 (s, 6Η, 2 X CH3).

Four cases of ranolazine dihydrochloride (I) Synthesis of [0015] implementation

In three 150ml round bottom flask was added the compound (3) (5. OOg, O. 02mol), isopropyl alcohol (35. Oml), was slowly added dropwise at the reflux temperature of the compound (5) (4. 14g, 0. 023mol ), continued under reflux conditions I. 5h, TLC detection progress of the reaction, the reaction was complete, cooled and added to the reactor 9. Oml 12mol / L of concentrated hydrochloric acid solution was adjusted to pH 2 and concentrated to near dryness to give bright yellow brown liquid, repeatedly adding ethanol, rotary evaporation to a white solid. Absolute ethanol and recrystallized to give compound (the I), as a white solid (6. 80g, yield 78. 7%, mp: 217 ~219 ° C (Dec) j1H-NMR (DMS0-d6): 10. 17 ( s, 1H, -CONH-), 7.21 ~6.87 (m, 7H, Ar-H), 4. 42 (m, 1H, -OCH2CHCH2-), 4. 23 (s, 2H, -CH2N), 4. 00 ~3.92 (m, 2H, -OCH2CHCH2), 3. 77 (s, 3H, -OCH3), 2. 67~2. 50 (m, 8H, 2 X -NCH2CH2N-), 2. 33 ~I. 91 ( m, 2H, -OCH2CHCH2), 2. 17 (s, 6H, 2 X CH3); MS (m / e): 427. 54).

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Image result for Ranolazine SYNTHESIS

An in silico modelling based biocatalytic approach for the synthesis of drugs and drug intermediates in enantiopure forms is a rationalized methodology over the organo-chemical routes. In this study, enzyme-ligand based docking was carried out using (RS)-ranolazine, as the model drug for the screening of a suitable biocatalyst for the kinetic resolution of the racemic drug. The differential interaction of the two enantiomers with the lipase was analyzed on the basis of docking score and H-bond interaction with the amino acid residues, which helped to define the trans-esterification mechanism. Ranolazine [N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy)-3-(2-methoxyphenoxy)propylpiperazin-1-yl]acetamide], an anti-anginal drug, significantly reduces the frequency of anginal attack and has also been used for the treatment of ventricular arrhythmias, and bradycardia. Various lipases were examined via computational as well as wet lab screening and Candida antartica lipase in the form of CLEA was the most efficient one for the (S)-selective kinetic resolution of (RS)-ranolazine, with highest conversion and enantiomeric excess. This is the first report of the chemo-enzymatic synthesis of (S)-ranolazine where the whole drug molecule was used for lipase catalysis. The present study showed that the combination of in silico studies and a classical wet lab approach could change the paradigm of biocatalysis.

Graphical abstract: In silico approach towards lipase mediated chemoenzymatic synthesis of (S)-ranolazine, as an anti-anginal drugImage result for Ranolazine SYNTHESISImage result for Ranolazine SYNTHESIS

In silico approach towards lipase mediated chemoenzymatic synthesis of (S)-ranolazine, as an anti-anginal drug

*
Corresponding authors
a
Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research, Sec-67, S. A. S. Nagar-160062, India
E-mail: ucbanerjee@niper.ac.in
RSC Adv., 2016,6, 49150-49157

DOI: 10.1039/C6RA06879K

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https://www.researchgate.net/publication/259824588_Synthesis_of_Ranolazine_Derivatives_Containing_the_1_S_4_S_-25-Diazabicyclo221Heptane_Moiety_and_Their_Evaluation_as_Vasodilating_Agents

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Image result for Synthesis of Ranolazine Derivatives Containing the (1S,4S)-2,5-Diazabicyclo[2.2.1]Heptane Moiety and Their Evaluation as Vasodilating Agents

 

OTHER NMR…….http://onlinelibrary.wiley.com/store/10.1111/cbdd.12285/asset/supinfo/cbdd12285-sup-0001-SupplementaryData.pdf?v=1&s=1c11a72432d0627b201f1bd37dab7ef913b0ff1f

OF Epimer (S,S,S)-5, Epimer (S,S,R)-5

PATENT

WO-2016142819

Ranolazine is marketed under the brand name Ranexa® and is indicated for the treatment of chronic angina. Ranexa may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. Ranolazine is a racemic mixture, chemically described as 1-piperazineacetamide, N-(2, 6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy) propyl]-, (±)- indicated by compound of formula (1).

(1)

U.S. Patent No. 4,567,264 teaches two methods for the preparation process of Ranolazine. Method 1 disclosed reaction of 2-methoxyphenol compound of formula (2) with epichlorohydrin in presence of water, dioxane and NaOH to obtain l-(2-methoxyphenoxy)-2, 3-epoxypropane compound of formula (3) which is condensed with piperazine in presence of ethanol to obtain 2-(2-methoxyphenoxy)-l-(piperazin-l-yl) ethanol compound of formula (4). Reacting 2, 6-Dimethylaniline compound of formula (5) with chloroacetyl chloride in presence of TEA and MDC to obtain 2-chloro-N-(2,6-dimethylphenyl) acetamide compound of formula (6). Compound of formula (4) was condensed with compound of formula (6) in presence of dimethylformamide to obtain Ranolazine compound of formula (1). The method (1) is depicted below as scheme (I).

Scheme (I) (1)

US ‘264 taught another method for preparation of Ranolazine by condensing compound of formula (6) with piperazine in presence of ethanol to obtain N-(2, 6-dimethylphenyl)-2-(piperazin-l-yl) acetamide compound of formula (7). Compound of formula (3) was condensed with compound of formula (7) in presence of mixture of methanol and toluene at reflux temperature. The obtained Ranolazine is purified by column chromatography on silica gel. Excess of hydrochloric acid in methanol was added to get dihydrochloride salt of Ranolazine which was converted into its free base by suspending it in ether and stirred with excess of dilute aqueous potassium carbonate to get Ranolazine free base. The scheme is depicted below by Scheme (II).

Scheme (II) (!)

EP0483932A1 disclosed condensation of condensation of N, N-bis (2-chloro ethyl)-amino]-2,6-dimethyl acetanilide compound of formula (9) with l-[3-(2-methoxyphenoxy)-2-hydroxy]propylamine compound of formula (8) to obtain Ranolazine base. The base was purified by column chromatography; hydrochloride salt was formed by treating with methanolic HCI. The detailed impurity profile study was not reported for Ranolazine. The synthetic scheme is depicted below in scheme (III).

Chinese patent application No.102875490 disclosed condensation of compound of formula (6) with N-Boc-piperazine to obtain compound of formula (10) in the presence of K2CO3 in EtOH, removal of Boc group by means of TFA in EtOAc gives compound of formula (7) which is then converted into Ranolazine. The synthetic scheme is depicted below in scheme (IV).

Scheme (IV)

Organic Process Research & Development 2012, 16, 748-754 disclosed condensation of compound of formula (6) with piperazine in methanol to produce compound of formula (7), in which unwanted solid bis alkylated compound of formula (11) was filtered. The resulting filtrate pH adjusted to 5.0-5.5 with 44% phosphoric acid solution to recover piperazine monophosphate monohydrate salt. The compound of formula (7) was extracted with MDC.

PCT application No. 2008/047388 disclosed a process for the preparation Ranolazine, by reacting 2, 6-dimethyl aniline with Chloroacetyl chloride in the presence of base in water. The resulting amide intermediate is reacted with piperazine, and the resulting piperazine derivative is further condensed with l-(2-methoxyphenoxy)-2,3-epoxypropane in an inert solvent to produce crude Ranolazine, which is further purified by crystallizing from organic solvents selected from alcohols or aromatic hydrocarbons. Ranolazine obtained in the disclosed art does not have satisfactory purity for pharmaceutical use. Unacceptable amounts of impurities are generally formed along with Ranolazine. In addition, the processes involve the additional step of column chromatographic purifications, which are generally undesirable for large-scale operations.

As described above the cited literature processes suffer from many drawbacks like use of excess amount of piperazine during the reaction, which is difficult to handle in large scale; generation of large amount of effluent due to excessive use of piperazine, that is difficult to recover and recycle; Ranolazine obtained as an oil is difficult to handle in large scale production and laborious chromatographic

techniques are used for purification of Ranolazine.

It is observed that pharmaceutically acceptable salts of Ranolazine when prepared from impure Ranolazine do not meet the pharmaceutical acceptable quality. There is therefore, an unfulfilled need to provide industrially feasible process for the preparation of Ranolazine free base and its acid addition salt with high purity. The present invention provides Ranolazine of high purity by using phosphate salt of piperazine to prepare Ranolazine. In this process, excess of unreacted piperazine is easy to recover and recycle in the next reactions. Thus it is easy to avoid the generation of large amount of effluent due to reuse of piperazine, which are generally desirable for large-scale operations thereby making the process commercially feasible.

All the available literature uses unprotected piperazine and protected piperazine leading to formation of dimer impurities which are difficult to remove from the product and also resulting in poor overall yield of the product. The maximum daily dosage of Ranolazine is 2 g; therefore, known and unknown impurities must be controlled below 0.05% in the final drug substance.

From the above known fact our main target is:

1. To study the detailed impurity profile to and to control the formation of all the impurities below the desired limit (NMT 0.05%).

2. To obtained the Cost effective process by utilizing the maximum consumption of piperazine in the form of piperazine monophosphate salt there by reducing formation of unwanted impurities and also reusing recovered piperazine.

All the available literature uses unprotected piperazine and protected piperazine leading to formation of dimer impurities which are difficult to remove from the product and also resulting in poor overall yield of the product.

EXAMPLES

The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.

Example 1 :

Preparation of [(2, 6-Dimethylphenyl)-amino carbonyl methyl) chloride (6)

To 0.74 kg of potassium carbonate and 2.51ml of water, was added. 500 gm of 2,6-Dimethyl aniline in 1.25 L of Acetone at 0-5 °C. 650 gm of Chloroacetyl chloride was added to the reaction mixture below 5 °C and stirred for 3 hrs. 2500 ml of water was added, stirred for 1 hr, filtered the product, washed with water and dried at 75 °C to get [(2,6- Dimethylphenyl)-amino carbonyl methyl] chloride (6). Yield: 95%; purity >98%

Example 2:

Preparation of l-(2-Methoxy phenoxy)-2, 3-epoxy propane (3)

Added 2.5 L of water to R.B Flask, 80 gms of NaOH was added and stirred to dissolve. Added 500 gms of Guaiacol, 1.12 Kg of Epichlorohydrine and stirred at 25-350C for 5-6 h. The organic layer was separated. To the Epichlorohydrine layer charged 160 gms NaOH dissolved in 2.5 L of water and stirred at 25-30°C for 3-4 h. The organic layer was separated and washed with 150 gms NaOH dissolved in 1.5 L of water. Excess Epichlorohydrine was recovered by distillation of the product layer at 90°C under vacuum (600-700 mmHg) to give 650-680 gms of oil. To the crude oil was added 3.0 L of Isopropanol and cooled to 0°C and filtered the product to get l-(2- Methoxy phenoxy)-2,3-epoxy propane (3).

Yield: 80%; purity >98%.

Example 3:

Preparation of piperazine monophosphate monohydrate

Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with O-phosphoric acid. After stirring for 1-2-h at room temperature. Filtered the reaction mass and solid was isolated as piperazine monophosphate monohydrate.

Example 4:

Preparation of compound of formula (7)

Added 1000 ml of water to R.B Flask. 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with O-phosphoric acid. After stirring for 1-2- h at room temperature. Filtered the reaction mass and solid was isolated as piperazine monophosphate monohydrate and charged further to R.B Flask containing 1000 ml water. 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30°C and adjusted the pH to 5.5-6.0 with dilute sodium hydroxide solution filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride to obtained compound of formula (7).

Example 5:

Preparation of Ranolazine

Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with O-phosphoric acid, 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30°C and adjusted pH to 5.5-6.0 with dilute sodium hydroxide solution and filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of l-(2-Methoxy phenoxy)-2, 3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml methanol and refluxed for 5-6 h. Cooled the reaction mass to room temperature and added 500 ml water and cooled to 0°C. Filtered the product to get crude Ranolazine. Yield: 80%; purity >99%.

Example 6:

Preparation of Ranolazine from recovered piperazine monophosphate monohydrate

Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. Added recovered piperazine monophosphate monohydrate and pH was adjusted to 5.0-5.5 with O-phosphoric acid, 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30°C and adjusted pH 5.5-6.0 with dilute sodium hydroxide solution and filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium

hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of l-(2-Methoxy phenoxy)-2,3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml methanol and refluxed for 5-6 h. Cooled the reaction mass to room temperature and added 500 ml water and cooled to 0°C. Filtered the product to get crude Ranolazine. Yield: 80%; purity >99%.

Example 7:

Preparation of Ranolazine.

Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with O-phosphoric acid. 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30°C, adjusted pH to 5.5-6.0 with dilute sodium hydroxide solution and filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of l-(2-Methoxy phenoxy)-2,3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml isopropyl alcohol, refluxed for 5-6 h. cooled the reaction mass to 0°C. Filtered the product to get crude Ranolazine. Yield: 80%; purity >98%.

Example 8:

Preparation of Ranolazine

Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with O-phosphoric acid. After stirring for 1-2- h at room temperature. Filtered the reaction mass and solid was isolated as piperazine monophosphate monohydrate and charged further to R.B Flask containing 1000 ml water. 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30°C and adjusted the pH to 5.5-6.0 with dilute sodium hydroxide solution filtered. Filtrate was washed

with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of l-(2-Methoxy phenoxy)-2,3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml methanol and refluxed for 5-6 h. Cooled the reaction mass to room temperature, added 500 ml water, cooled to 0°C and filtered the product to get crude Ranolazine. Yield: 80%; purity >99%.

Example 9:

Purification of Ranolazine

Added 300 ml of methanol to R.B Flask, 100 gms of crude ranolazine piperazine and heated to dissolve. Added Activated charcoal and filtered the hot solution through hyflo and washed the hyflo with 100 ml methanol. Reaction mixture was cooled to room temperature. 200 ml water was added and was cooled further to 0-5°C. Filtered to afford pure Ranolazine. Yield: 90%; purity >99.9%.

PATENT

WO2006008753,

https://www.google.com/patents/WO2006008753A1?cl=en

US Patent 4567264 describes the preparation of Ranolazine base from basic stages by condensing [(2,6-dimethyphenyl) amino; carbonyl methyl] – chloride (II) with l-[3-(2-metlioxyphenoxy)-2- hydroxypropyl]piperazine.(III) The base was purified by column chromatography and isolated as oil. The hydrochloride salt was prepared in methanol using hydrochloric acid and the salt was isolated by addition of ether.

Figure imgf000003_0001

Ranolazine Base

EP 0483932 describes the preparation of Ranolazine base by condensation of α-[ N3N -bis (2-cWoroetiiyl)-amino]-2,6-dimetliylacetanilide hydrochloride (IV) with l-[3-(2-methoxy phenoxy)-2-hydroxy]-propylamine (V). The base was purified using column chromatography and hydrochloride was formed by treating with metholic hydrochloric acid and crystallized by addition of diethyl ether as co solvent to obtain a product with melting point 229- 230 0C.

Figure imgf000004_0001

Ranolazine base

It is a long standing need to avoid the formation of oil and obtain the product directly as solid there by eliminating laborious and expensive column chromatographic methods and achieving the higher yields of Ranolazine diliydrochloride. More over the prior art does not teach, any features such as polymorphic forms of the drug which may have varying pharmacological effects

Example-1:

Preparation of l-[3-(2-Metkoxyphenoxy)-2-hydroxypropyl ] piperazine

100 gms l-(2-methoxyphenoxy)-2,3-epoxypropane was added in a 60 min at 0-5 0C to 192 gms of anhydrous piperazine dissolved in 500 ml methanol. Reaction mixture is stirred further for 2 Hrs at 0-5 0C. It is quenched in 400 ml DMW & filtered. The product is obtained by extraction with MDC from the saturated aqueous layer with sodium chloride. 65 gms of acetic acid and 400 ml water is added in the MDC layer. Aqueous layers was separated and basified with 100 ml liquor ammonia. The product was extracted with 500 ml methylene dichloride and isolated by evaporation of solvent. The residue was used as such in the next reaction.

Yield =80 gms. HPLC purity = 96-$k %.

ExampIe-2 r-

Preparation of crude (+)-l-[3~(2-Methoxyphenoxy)-2-hydroxypropyl]-4- [N-(2,6-dimethylphenyl)carbamoylmethyl] piperazine dihydrochloride.

A mixture of 90 gms l-[3-(2-Memoxyphenoxy)-2-hydroxypropyl ] piperazine, 85 gms [(2,6-dimethylphenyl) aminocarbonyl methyl)chloride, 120 gms anhydrous potassium carbonate and 3.6 gms sodium iodide in 260 ml dimethyl formamide is stirred at room temperature (30-35 0C) for 18 Hrs. The reaction mixture is quenched in 1600 ml water and extracted thrice with 300 ml methylene dichloride each time . Combined methylene dichloride layer is treated with a mixture of 1100 ml aqueous hydrochloric acid ( 35 %) & 900 ml water. Acidic aqueous layer is basified with ammonia, extracted with methylene dichloride and solvent is evaporated to get Ranolazine base. ; Yield = 140 gms ,

The above Ranolazine base is taken in 2160 j ml j acetone and 100 hydrochloric acid gas dissolved in isopropyl alcohol is added at room temperature till pH is acidic. The precipitated dihydrochloride compound is Filtered, is washed with acetone to give the Ranolazine dihydrochloride Yield = 144 gm.

Example-3 :-

Preparation of Crystalline (+)-l-[3-(2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-diniethylphenyl)carbamoylmethyl] piperazine dihydrochloride.

100 gms of Crude (+)-l-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[N- (2,6-dimemylplienyl)caitamoyhnetliyl] piperazine dihydrochloride is dissolved to get a clear solution in 500 ml methanol., The solution is cooled to room temperature and further cooled to 100C. The product is filtered, washed with 2 X 50 ml methanol and dried at 75 degree C for 10 Hrs. get crystalline Form -A of Ranolazine diliydrochloride] ;: characterized .by XRD & DSC as shown in Figure |I and II.

Example-4: –

Preparation of Amorphouse (+)-l-[3-(2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoylmethyl] piperazine dihydrochloride

100 gms Ranolazine diliydrochloride is added in 500 ml water and heated to get a clear solution. Water is distilled off under reduced pressure, the residue is cooled to room temperature to obtain, amorphous form characterized by a XRD pattern (Figure III ) and DSC (Figure IV) exhibiting a broad endotherm around 80 and exotherm bet 220-224 and followed by endotherm 150-156 0C.

Example-5: –

Preparation of Amorphouse ,(+)-l-[3-(J2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbampylitnethyl] piperazine dihydrochloride

100 gms Ranolazine dihydrochloride is added ;i| in 2000 ml ethanol containing 10 % water and heated to get a clear: solution. Solvent is distilled off under reduced pressure, the residue is cooled to room temperature to obtain amorphous form characterized by a XRD pattern (Figure m ) and DSC (Figure IV) exhibiting a broad endotherm around 80 and exotherm bet 220-224 and followed by endotherm 150-156 0C.

Example -6:~

Preparation of Ranolazine base from its di hydrochloride salt

20 gms Ranolazine dihydrohloride at room temperature is added to a mixture containing 150 ml water and 50 ml acetone and 20 ml liquor ammonia. It is stirred for two hrs. The precipitated base, was . filtered and dried under vacuum at 70 0C to get crystalline form of Ranolazine base characterized by XRD & DSC as shown in Figure V & VI. Yield = 12 gms.

CLIP

Improved Process for Ranolazine: An Antianginal Agent

Research and Development, Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46 and 54, Bachupally, Qutubullapur, Ranga Reddy-500 072, Andhra Pradesh, India
§ Research and Development, Macleods Pharmaceuticals Limited, G-2, Mahakali Caves Road, Shanthi Nagar, Andheri (E), Mumbai-400 093, Maharashtra, India
Department of Chemistry, University College of Science, Osmania University, Hyderabad-500 007, Andhra Pradesh, India
Org. Process Res. Dev., 2012, 16 (5), pp 748–754
DOI: 10.1021/op300026r
Publication Date (Web): April 12, 2012,*E-mail: vummenthalapv@yahoo.co.in. Fax: +91-40-44346285. Telephone: +91-9849210408.
An improved process has been developed for the active pharmaceutical ingredient, ranolazine with 99.9% purity and 47% overall yield (including three chemical reactions and one recrystallization). Formation and control of all the possible impurities is described. All the solvents used in the process were recovered and reused. The unreacted piperazine is recovered as piperazine monophosphate monohydrate salt.
Abstract Image

References

  1. Banon D et al. The usefulness of ranolazine for the treatment of refractory chronic stable angina pectoris as determined from a systematic review of randomized controlled trials. Am J Cardiol. 2014 Mar 15;113(6):1075-82. PMID 24462341
  2.  “Ranexa (ranolazine) Extended-Release Tablets, for Oral Use. Full Prescribing Information”. Gilead Sciences, Inc. Foster City, CA 94404. Retrieved8 September 2016.
  3. ^ Jump up to:a b c d e Kloner RA, et al. Efficacy and safety of ranolazine in patients with chronic stable angina. Postgrad Med. 2013 Nov;125(6):43-52. PMID 24200760
  4. Jump up^ “FDA Approves New Treatment for Chest Pain”. FDA News. 2006-01-31. Retrieved2011-03-02.
  5.  D Noble and P J Noble. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium–calcium overload Heart. Jul 2006; 92(Suppl 4): iv1–iv5.PMID 16775091 PMCID 1861316
  6. Jump up^ Sokolov, S; Peters, CH; Rajamani, S; Ruben, PC (2013). “Proton-dependent inhibition of the cardiac sodium channel Nav1.5 by ranolazine” (PDF). Frontiers in Pharmacology. 4: 78. doi:10.3389/fphar.2013.00078. PMC 3689222free to read. PMID 23801963. Retrieved8 September 2016.
  7. Jump up^ EMEA Ranolazine page at the EMEA
  8. Jump up^ CV Therapeutics press release. April 1, 1996 CV Therapeutics Licenses Late-Stage Anti-Anginal Drug from Syntex (U.S.A.), an Affiliate of Roche Holding Ltd.
  9. Jump up^ CV Therapeutics, 22 June 2006 CV Therapeutics Acquires Rights to Ranolazine in Asia
  10. Thepharmaletter.com 22 September 2008 Italy’s Menarini to pay up to $385 million for rights to CV Thera’s Ranexa
  11. Jump up^ Reuters, via the New York Times. 12 March 2009. Gilead, a White Knight, to Buy CV Therapeutics
  12.  Menarini press release. 18 June 2013 Memarii Group announces agreement with Gilead Sciences to commercialize Ranexa® (ranolazine) in 50 new countries
  13. http://shodhganga.inflibnet.ac.in/bitstream/10603/19311/11/11_chapter%203.pdf

External links

CN1404471A * Feb 22, 2001 Mar 19, 2003 Cv Therapeutics Substituted piperazine compound
Reference
1 * “Green Chemistry” 20,130,131 Damodara N. Kommi ET Al. ” All Water Chemistry ” for A Concise Total Synthesis of Novel, class at The Anti-anginal Drug (the RS), (R & lt), and (S) -ranolazine 756-767 1-9 Vol. 15,
2 * “Tetrahedron Letters” 20080304 Sadula Sunitha et al. An efficient and chemoselective Br nsted acidic ionic liquid-catalyzed N-Boc protection of amines 2527-2532 1-9 Vol. 49,
3 * N. KOMMI the ET AL .: DAMODARA ” ” All Water Chemistry “for A Concise Total Synthesis of Novel, class at The Anti-anginal Drug (the RS), (R & lt), and (S) -ranolazine “, “GREEN CHEMISTRY”, Vol. 15, 31 January 2013 (2013-01-31) , pages 756 – 767
4 * Sunitha the ET AL .: SADULA ” An Efficient and chemoselective Brønsted acidic Ionic Liquid-Catalyzed N of Boc-Protection of Amines “, “TETRAHEDRON LETTERS”, Vol 49, 4 March 2008 (2008-03-04), Pages 2527 -. 2532
5 * Qin Mingli et al: ” Study on the Synthesis of ranolazine ..”, “Xinyang Normal University: Natural Science”, vol 20, no 2, 30 April 2007 (2007-04-30), pages 226 – 229

RANEXA (ranolazine) Extended-release Tablets

Ranolazine is a racemic mixture, chemically described as 1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-. It has an empirical formula of C24H33N3O4, a molecular weight of 427.54 g/mole, and the following structural formula:

RANEXA® (ranolazine) Structural Formula Illustration

Ranolazine is a white to off-white solid. Ranolazine is soluble in dichloromethane and methanol; sparingly soluble in tetrahydrofuran, ethanol, acetonitrile, and acetone; slightly soluble in ethyl acetate, isopropanol, toluene, and ethyl ether; and very slightly soluble in water.

RANEXA tablets contain 500 mg or 1000 mg of ranolazine and the following inactive ingredients: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, and titanium dioxide. Additional inactive ingredients for the 500 mg tablet include polyvinyl alcohol, talc, Iron Oxide Yellow, and Iron Oxide Red; additional inactive ingredients for the 1000 mg tablet include lactose monohydrate, triacetin, and Iron Oxide Yellow.

Ranolazine
Ranolazine.svg
Systematic (IUPAC) name
(RS)-N-(2,6-Dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide
Clinical data
AHFS/Drugs.com Monograph
MedlinePlus a606015
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
By mouth (tablets)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 35 to 50%
Protein binding ~62%
Metabolism Extensive in liver (CYP3A,CYP2D6) and intestine
Biological half-life 7 hours
Excretion Renal (75%) and fecal (25%)
Identifiers
CAS Number 142387-99-3 Yes
ATC code C01EB18 (WHO)
PubChem CID 56959
IUPHAR/BPS 7291
DrugBank DB00243 Yes
ChemSpider 51354 Yes
UNII A6IEZ5M406 Yes
ChEBI CHEBI:87681 
ChEMBL CHEMBL1404 Yes
Chemical data
Formula C24H33N3O4
Molar mass 427.537 g/mol
Chirality Racemic mixture

////////////////////Ranolazine, 盐酸雷诺嗪 ,雷诺嗪 , Antianginal


Filed under: Uncategorized Tagged: Antianginal, 盐酸雷诺嗪, 雷诺嗪, Ranolazine

Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600E Inhibitor

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Abstract Image

str1

N-(5-amino-2-tert-butyl)-11-fluorbenzol[f]thiazol-[4,5-h]-quinazolin-10-yl)-2,6-difluorbenzolsulfonamide = Dabrafenib_photo (2)

C23H18F3N5O2S2 (Mr = 517.09)

Solution of 5 mg (9.6 μmol) dabrafenib in 2 ml THF was irradiated at 365 nm with 5.4 W for 2 min. This procedure was repeated 18 times at room temperature. The reaction batches were combined. The total initial weight of dabrafenib was 101 mg (190 μmol). The solvent was removed under reduced pressure and the residue was purified by the flash chromatography (SiO2 reversed phase, MeOH/water gradient 50:50 to 100:0) to give compound 2 as a yellowish solid (36.2 mg, 70.0 μmol, yield: 37%).

1H-NMR (DMSO-d6 , 300 MHz): δ = 1.52 (s, 9 H, H-8), 7.28 (m, 2 H, NH2), 7.28 (ddd, 5 J = 0.4 Hz, 4 J = 1.7 Hz, 3 J = 8.5 Hz, 3 J = 8.9 Hz, 2 H, H-18), 7.59 (dd, 3 J = 7.4 Hz, 3 J = 7.8 Hz, 1 H, H-13), 7.71 (tt, 4 J = 6.1 Hz, 3 J = 8.5 Hz, 1 H, H-19), 8.56 (dd, 4 J = 0.9 Hz, 3 J = 9.3 Hz, 1 H, H-14), 9.79 (s, 1 H, H-2), 11.01 (s, 1 H, NH) ppm.

13C-NMR (DMSO-d6 , 300 MHz): δ = 30.4 (s, C-8), 38.3 (s, C-7), 110.9 (d, 4 JCF = 1.6 Hz, C-3), 113.4 (dd, 2 JCF = 22.7 Hz, 2 JCH = 3.5 Hz, C-18), 114.6 (d, 3 JCF = 10.3 Hz, C-9), 117.4 (d, 2 JCF = 16.1 Hz, C-16), 117.6 (dd, 4 JCF = 0.54 Hz, 2 JCH = 4.4 Hz, C-13), 120.8 (d, 2 JCF = 12.3 Hz, C-10), 125.4 (s, C-13), 129.3 (d, 3 JCF = 3.9 Hz, C-15), 130.6 (s, C-5), 135.9 (tt, 3 JCF = 10.9 Hz, 2 JCH = 3.3 Hz, C-19), 148.8 (dd, 2 JCF = 0.54 Hz, 2 JCH = 7.2 Hz, C-12), 149.2 (s, C-4), 150.1 (s, C-11), 157.1 160.5 (dd, 3 JFF = 257.3 Hz, 2 JCF = 3.61 Hz, C-4), 157.9 (s, C-2), 162.1 (s, C-1), 184.0 (s, C-6) ppm.

15N-HMBC (DMSO-d6 , 300 MHz): δ = 9.79/-119.60, 11.01/-268.37 ppm. 19F-NMR (DMSO-d6 , 300 MHz): δ = -121.03 (s, 1 F, F-11), -107.18 (m, 2 F, F-17) ppm.

HRMS (EI, 205 °C, THF): m/z = 517.0849 [M]+ .

LC-MS (ESI, 70 eV, MeOH): tR = 9.3 min; m/z (%) = 518.1 (100) [M+H]+

IR (ATR):  ̃ = 3490 (N-H), 3176 (arom. C-H), 2926 (C-H3), 1696 (N=N), 1613 (N-H), 1587, 1522, 1488, 1469 (arom. C=C), 1342 (sulfonamide), 1277, 1240, 1174 (C-F) cm-1 .

Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600E Inhibitor

Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00340
Publication Date (Web): September 20, 2016
Copyright © 2016 American Chemical Society
*E-mail: cpeifer@pharmazie.uni-kiel.de. Tel: +49-431-880-1137.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract

Dabrafenib (Tafinlar) was approved in 2013 by the FDA as a selective single agent treatment for patients with BRAFV600E mutation-positive advanced melanoma. One year later, a combination of dabrafenib and trametinib was used for treatment of BRAFV600E/K mutant metastatic melanoma. In the present study, we report on hitherto not described photosensitivity of dabrafenib both in organic and aqueous media. The half-lives for dabrafenib degradation were determined. Moreover, we revealed photoinduced chemical conversion of dabrafenib to its planar fluorescent derivative dabrafenib_photo 2. This novel compound could be isolated and biologically characterized in vitro. Both enzymatic and cellular assays proved that 2 is still a potent BRAFV600E inhibitor. The intracellular formation of 2 from dabrafenib upon ultraviolet irradiation is shown. The herein presented findings should be taken in account when handling dabrafenib both in preclinical research and in clinical applications.

////////Photoinduced Conversion, Antimelanoma Agent,  Dabrafenib, Novel Fluorescent BRAFV600E Inhibitor, BRAFV600E; Dabrafenib, fluorescent probe kinase inhibitor photoinduced conversion


Filed under: Uncategorized Tagged: Antimelanoma Agent, BRAFV600E; Dabrafenib, dabrafenib, fluorescent probe, kinase inhibitor, Novel Fluorescent BRAFV600E Inhibitor, Photoinduced Conversion

Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist from Zydus Cadila

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Indian flag
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(S)-3-(4-((3-((isopropyl(thiophen-3- ylmethyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
str1
Calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate
Calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate
 

The compounds of theese type lower blood glucose, regulate peripheral satiety, lower or modulate triglyceride levels and/or cholesterol levels and/or low-density lipoproteins (LDL) and raises the high-density l ipoproteins (HDL) plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) is beneficial. Thus, it could be used in the treatment and/or prophylaxis of obesity, hyperlipidemia, hypercholesteremia, hypertension, atherosclerotic disease events, vascular restenosis, diabetes and many other related conditions.

The compounds of are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions such as arteriosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders. -These compounds  are useful for the treatment and/or prophylaxis of metabolic disorders loosely defined as Syndrome X. The characteristic features of Syndrome X include initial insulin resistance followed by hyperinsulinemia, dyslipidemia and impaired glucose tolerance. The glucose intolerance can lead to non-insulin dependent diabetes mel litus (N I DDM, Type 2 diabetes), which is characterized by hyperglycemia, which if not controlled may lead to diabetic complications or metabolic disorders caused by insulin resistance. Diabetes is no longer considered to be associated only with glucose metabol ism, but it affects anatomical and physiological parameters, the intensity of which vary depending upon stages/duration and severity of the diabetic state. The compounds of this invention are also useful in prevention, halting or slowing progression or reducing the risk of the above mentioned disorders along with the resulting secondary diseases such as cardiovascular diseases, l ike arteriosclerosis, atherosclerosis; diabetic retinopathy, diabetic neuropathy and renal disease including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal diseases, like microalbuminuria and albuminuria, which may be result of hyperglycemia or hyperinsulinemia.

Diabetes mellitus is a serious disease affl icting over 1 00 mi l lion people worldwide. In the United States, there are more than 12 mill ion diabetics, with 600,000 new cases diagnosed each year.

Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal glucose homeostasis resulting in elevated blood sugar. There are many- types of diabetes, but the two most common are Type 1 (also referred to as insulin- dependent diabetes mellitus or IDDM) and Type II (also referred to as non- insulin-dependent diabetes mellitus or NIDDM).

The etiology of the different types of diabetes is not the same; however, everyone with diabetes has two things in common: overproduction of glucose by the liver and little or no ability to move glucose out of the blood, into the cells where it becomes the body’s primary fuel.

People who do not have diabetes rely on insulin, a hormone made in the pancreas, to move glucose from the blood into the cells of the body. However, people who have diabetes either don’t produce insulin or can’t efficiently use the insulin they produce; therefore, they can’t move glucose into their cells. Glucose accumulates in the blood creating a condition called hyperglycemia, and over time, can cause serious health problems.

Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic components. The metabolic syndrome, generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced insulin secretion and/or ineffective insulin action. The vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormal ities in the peripheral and autonomic nervous systems are also part of the diabetic syndrome.

About 5% to 10% of the people who have diabetes have IDDM. These individuals don’t produce insulin and therefore must inject insulin to keep their blood glucose levels normal . IDDM is characterized by low or undetectable levels of endogenous insulin production caused by destruction of the insulin-producing β cells of the pancreas, the characteristic that most readily distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabetes, strikes young and older adults alike.

Approximately 90 to 95% of people with diabetes have Type II (or NIDDM). NIDDM subjects produce insulin, but the cells in their bodies are insulin resistant: the cells don’t respond properly to the hormone, so glucose accumulates i n their blood. NIDDM is characterized by a relative disparity between endogenous insulin production and insulin requirements, leading to elevated blood glucose levels. In contrast to IDDM, there is always some endogenous insulin production in NIDDM; many NIDDM patients have normal or even elevated blood insul in levels, whi le other NIDDM patients have inadequate insul in production ( otwein, R. et al. N. Engl. J. Med. 308, 65-71 ( 1983)). Most people diagnosed with NIDDM are age 30 or older, and half of all new cases are age 55 and older. Compared with whites and Asians, NIDDM is more common among Native Americans, African-Americans, Latinos, and Hispanics. In addition, the onset can be insidious or even clinically non-apparent, making diagnosis difficult.

The primary pathogenic lesion on NIDDM has remained elusive. Many have suggested that primary insulin resistance of the peripheral tissues is the initial event. Genetic epidemiological studies have supported this view. Similarly, insulin secretion abnormalities have been argued as the primary defect in NIDDM. It is l ikely that both phenomena are important contributors to the disease process (Rimoin, D. L., et. al. Emery and Rimoin’s Principles and Practice of Medical Genetics 3rd Ed. 1 : 1401 – 1402 ( 1996)).

Many people with NIDDM have sedentary lifestyles and are obese; they weigh approximately 20% more than the recommended weight for their height and build. Furthermore, obesity is characterized by hyperinsul inemia and insul in resistance, a feature shared with NIDDM, hypertension and atherosclerosis.

The G-protein -coupled receptor GPR 40 functions as a receptor for long-chain free fatty acids (FFAs) in the body and as such is impl icated in a large number of metabolic conditions in the body. For example it has been alleged that a GPR 40 agonist promotes insulin secretion whilst a GPR 40 antagonist inhibits insulin secretion and so depending upon the circumstances the agonist and antagonist may be useful as therapeutic agents for the number of insul in related conditions such as type 2 diabetes, obesity, impaired glucose tolerance, insul in resistance, neurodegenerative diseases and the like.

There is increasing evidences that lipids can also serve as extracel lular l igands for a specific class of receptors and thus act as “nutritional sensors” (Nolan CJ et al. J. Clinic. Invest., 2006, 1 1 6, 1 802- 1 812The free fatty acids can regulate cell function. Free fatty acids have demonstrated as ligands for orphan G protein-coupled receptors (GPCRs) and have been proposed to play a critical role in physiological glucose homeostasis.

GPR40, GPR 120, GPR41 and GPR43 exemplify a growing number of GPCRs that have been shown to be activated by free fatty acids. GPR40 and GPR 120 are activated by medium to long-chain free fatty acids whereas GPR 41 and GPR 43 are activated by short-chain fatty acid (Brown AJ et al, 2003).

GPR 40 is highly expressed on pancreatic β-cells, and enhances glucose- stimulated insulin secretion {Nature, 2003, 422, 1 73- 1 76, J. Bio. Chem. 2003, 278, 1 1303- 1 13 1 1 , Biochem. Biophys. Res. Commun. 2003, 301, 406-4 10).

Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40 is reported {Lett, to Nature 2003, 422, 1 73- 1 76).

GlaxoSmith line Research and Development, US published an article in Bioorg. Med. Chem. Lett. 2006, 16, 1840- 1 845 titled Synthesis and activity of small molecule GPR40 agonists. (Does this describe GW9508?)Another article titled Pharmacological regulation of insul in secretion in ΜΓΝ6 cells through the fatty – acid receptor GPR40: Identification of agonist and antagonist small molecules is reported in

Br. J. Pharmacol. 2006, 148, 619-928 from GlaxoSmithKl i ne. USA (Does this describe GW9508?) ‘

GW 9508.

Solid phase synthesis and SAR of small molecule agonists for the. GPR 40 receptor is published in Bioorg. Med. Chem. Lett. 2007, 16, 1 840- 1 845 by Glaxo Smith line Res. 8c Dev. USA, including those with the following structures.

Johnson & Johnson Pharmaceutical Research and development , USA published

Synthesis and Biological Evaluation of 3-Aryl-3-(4-phenoxy)-propanoic acid as a Novel Series of G-protein -coupled receptor 40 agonists J. Med. Chem. 2007,

76, 2807-2817)

National Institutes of Health, Bethesda, Maryland publ ished “Bidirectional Iterative Approach to the Structural Delineation of the Functional Chemo print in GPR 40 for agonist Recognition (J. Med. Chem. 2007. 50, 298 1 -2990).

Discov roglucinols of the following formula

as a new class of GPR40 (FFAR 1 ) agonists has been publ ished by Piramal Li fe Sciences, Ltd. in Bioorg. Med. Chem. Lett. 2008, 1 8, 6357-6361

Synthesis and SAR of 1 ,2,3,4-tctrahydroisoquinoline- l -ones as novel G-protein coupled receptor40(GPR40) antagonists of the following formula has been published in Bioorg. Med. Chem. Lett. 2009, 79, 2400-2403 by Pfizer

Piramal Life Sciences Ltd. published “Progress in the discovery and development of small molecule modulators of G-protei n coupled receptor 40(GPR40/FFA 1 /FFAR1 ), an emerging target for type 2 diabetes” in Exp. Opin. Therapeutic Patents 2009, 19(2), 237 -264.

There was a report published in Zhonggno Bingli Shengli ^Zazhi 2009, 25(7), 1376- 1380 from Sun Yat. Sen University, Guangzhou, which mentions the role GPR 40 on lipoapoptosis.

A novel class of antagonists for the FFA’s receptor GPR 40 was published in Biochem. Biophy. Res. Commun. 2009 390, 557-563.

N41 (DC260126)

Merck Res. Laboratories published “Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists” having the following formula in Bioorg. Med. Chem. Lett. 2010 20, 1298- 1 301

Discovery of TA -875, a potent, selective, and oral ly bioavai lable G PR 40 agonist is reported by Takeda Pharmaceutical Ltd. ACS Med. Chem. Lett. 2010,

7(6), 290-294

In another report from University of Southern Denmark” Structure -Activity of Dihydrocinnamic acids and discovery of potent FFA l (GPR40) agonist TUG-469″ is reported in ACS Me -349.

The free fatty acid 1 receptor (FFAR 1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated insul in secretion, has emerged as an attractive target for the treatment of type 2 diabetes (ACS Med. Chem. Lett. 2010, 1 (6), 290-294).

G-protein coupled receptor (GPR40) expression and its regulation in human pancreatic islets: The role of type 2 diabetes and fatty acids is reported in Nutrition Metabolism & Cardiovascular diseases 2010, 2(9( 1 ), 22-25

Ranbaxy reported “Identification of Berberine as a novel agonist of fatty acid receptor GPR40” in Phytother Res. 2010, 24, 1260-63.

The following substituted 3-(4-aryloxyaryI)-propanoic acids as GPR40 agonists are reported by Merck Res. Lab. in Bioorg. ed. Chem. Lett. 201 1 , 21, 3390-3394

4 EC50=0.970 μΜ 5. EC50=2.484 μΜ

CoMSIA study on substituted aryl alkanoic acid analogs as GPR 40 agonists is reported Chem. Bio. Drug. Des. 201 1 , 77, 361 -372

Takeda further published “Design, Synthesis and biological activity of potential and orally available G-protein coupled receptor 40 agonists” in J. Med. Chem. 201 1 , 54(5), 1365- 1 378.

Amgen disclosed a potent oral ly bioavai lable GPR 40 agonist AMG-837 in Bioorg. Med. Chem. Lett.

Discovery of phenylpropanoic acid derivatives containing polar functional ities as Potent and orally bioavailable G protein-coupled receptor 40 Agonist for the treatment of type 2 Diabetes is reported in J. Med. Chem. 2012, 55, 3756-3776 by Takeda.

Discovery of AM- 1638: A potent and orally bioavailable GPR40/FFA 1 full agonist is reported in ACS Med. Chem. Lett. 2012, 3(9), 726-730.

 

Ranjit Desai

Ranjit Desai

Sr Vice President. Head-Chemistry
Zydus Research Centre, Ahmedabad · Chemistry

Sameer Agarwal

Sameer Agarwal

Cadila Healthcare Ltd., India

Sameer Agarwal has obtained Master’s in Chemistry from IIT, Delhi and was awarded DAAD (German Govt. Scholarship) fellowship to purse research project at Karlsruhe University, Germany. He has received PhD degree from Technical University, Dresden, Germany in the field of Synthetic and bio-organic chemistry under direction of Prof. Dr. Hans-Joachim Knölker, FRSC, a well-known scientist of present times for his contribution towards Alkaloid Chemistry. He worked as Research Scientist (Post-Doc), JADO Technologies, (collaboration with Max Planck Institute (MPI) of Molecular Cell Biology and Genetics and Chemsitry Department, Technical University), Germany. He then decided to return to his home country and working with Zydus Research Centre, Cadila Healthcare Ltd., Ahmedabad as Principal Scientist / Group Leader in the area of basic drug discovery and his research interest includes discovery of cardio metabolic, anti-inflammatory and oncology drugs. He has large number of publications in international journals and patents and is a reviewer of many prestigious journals including American Chemical Society.

Paper

Identification of an Orally Efficacious GPR40/ FFAR1 Receptor Agonist

ArticleinACS Medicinal Chemistry Letters · September 2016
DOI: 10.1021/acsmedchemlett.6b00331
Abstract Image

GPR40/FFAR1 is a G protein-coupled receptor predominantly expressed in pancreatic β-cells and activated by long-chain free fatty acids, mediating enhancement of glucose-stimulated insulin secretion. A novel series of substituted 3-(4-aryloxyaryl)propanoic acid derivatives were prepared and evaluated for their activities as GPR40 agonists, leading to the identification of compound 5, which is highly potent in in vitro assays and exhibits robust glucose lowering effects during an oral glucose tolerance test in nSTZ Wistar rat model of diabetes (ED50 = 0.8 mg/kg; ED90 = 3.1 mg/kg) with excellent pharmacokinetic profile, and devoid of cytochromes P450 isoform inhibitory activity

Synthesis of compound 5 is depicted in Scheme 1a.

The reductive amination1 of commercially available 3-thiophene-aldehyde (3) and isopropyl amine using sodium triacetoxyborohydride resulted in secondary amine intermediate 4. Compound 4 on further reductive amination under similar conditions with aldehyde intermediate, (S)-3-(4-((3-formylbenzyl)oxy)phenyl)hex-4-ynoic acid (8), afforded 2d in high yields. The aldehyde intermediate, 8 was obtained from (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (6) as shown in Scheme 1b. Acid 6 was synthesized via 5-step reported procedure using commercially available 4-hydroxybenzaldehyde and Meldrum’s acid.2 Resolution of racemic acid 6 was accomplished via diastereomeric salt formation with (1S,2R)-1-amino-2-indanol followed by salt break with aqueous acid to furnish compound 6. Treatment of 6 with of 40% aqueous tetrabutylphosphonium hydroxide (nBu4POH) in THF, followed by addition of 3-formyl benzyl bromide (7), afforded aldehyde intermediate 8. Compound 2d was further converted to its corresponding calcium salt (5) in two-step sequence with excellent chemical purity.

Scheme 1a. Synthesis of Compounds 2d and 5. Reagent and Conditions: (a) CH(CH3)2NH2, NaB(OAc)3H, CH3COOH, dry THF, 0 ᵒC to r.t., 16 h; (b) Comp 8, NaB(OAc)3H, CH3COOH, dry THF, 0 ᵒC to r.t., 16 h; (c) NaOH, MeCN/H2O, r.t., 3 h; (d) CaCl2, MeOH/H2O, r.t., 16 h.

BASE

(S)-3-(4-((3-((isopropyl(thiophen-3- ylmethyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid (1.557 g, 3.34 mmol, 43.0 % yield) as wax solid.

1H NMR (400 MHz, DMSO-d6): δ = 12.35 (br s, 1H), 7.44 (q, J = 3.2 Hz, 2H), 7.32 – 7.24 (m, 6H), 7.04 (d, J = 4.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.06 (s, 2H), 3.93 (d, J = 2.4 Hz, 1H), 3.51 (d, J = 8.8 Hz, 4H), 2.84 (sept, J = 6.4 Hz, 1H), 2.57 (d, J = 8 Hz, 2H), 1.77 (d, J = 2.4 Hz, 3H), 1.01 (d, J = 6.4 Hz, 6H);

13C NMR and DEPT: DMSO-d6, 100MHz):- δ = 172.35 (C), 157.63 (C), 142.13 (C), 141.44 (C), 137.42 (C), 133.93 (C), 128.73 (CH), 128.64 (CH), 128.43 (CH), 127.99 (CH), 127.73 (CH), 126.28 (CH), 122.21 (CH), 115.10 (CH), 81.16 (C), 78.52 (C), 69.69 (CH2), 52.90 (CH2), 48.64 (CH), 48.49 (CH2), 43.44 (CH2), 33.15 (CH), 17.92 (CH3), 3.66 (CH3);

MS (EI): m/z (%) = 462.35 (100) (M+H) + ;

IR (KBr): ν = 3433, 2960, 2918, 2810, 1712, 1608, 1510, 1383, 1240, 1174, 1109, 1018 cm-1 .

CA SALT

calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate (1.51 g, 1.536 mmol, 46% yield) as white powder. mp: 124.5 o C;

1H NMR (400 MHz, DMSO-d6): δ = 7.43 – 7.42 (m, 2H), 7.28 – 7.24 (m, 6H), 7.04 (d, J = 4.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 5.02 (s, 2H), 4.02 (s, 1H), 3.50 (d, J = 7.2 Hz, 4H), 2.84 – 2.77 (sept, J = 6.4 Hz, 1H), 2.43 (dd, J1 = 6.8 Hz, J2 = 7.2 Hz, 1H), 2.28 (dd, J1 = 6.8 Hz, J2 = 7.2 Hz, 1H), 1.73 (s, 3H), 0.99 (d, J = 6.4 Hz, 6H);

13C NMR and DEPT (100 MHz, DMSO-d6): δ = 177.78 (C), 157.23 (C), 142.11 (C), 141.4 (C), 137.46 (C), 135.81 (C), 128.83 (CH), 128.62 (CH), 128.40 (CH), 127.94 (CH), 127.69 (CH), 126.26 (CH), 122.18 (CH), 114.77 (CH), 83.18 (C), 77.32 (C), 69.66 (CH2), 52.89 (CH2), 48.59 (CH), 48.48 (CH2), 46.86 (CH2), 33.52 (CH), 17.88 (CH3), 3.78 (CH3);

MS (EI): m/z (%) = 462.05 (100) (M+H)+ ;

ESI-Q-TOF-MS: m/z [M+H]+ calcd for [C28H31NO3S + H]+ : 462.6280; found: 462.4988;

IR (KBr): ν = 3435, 2960, 2918, 2868, 2818, 1608, 1550, 1508, 1440, 1383, 1359, 1240 cm-1 ;

HPLC (% Purity) = 99.38%; Calcium Content (C56H60CaN2O6S2) Calcd.: 4.17%. Found: 3.99%.

 COMPD Ca salt

Calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate

Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist

Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad-382 210, India
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00331
*(S.A.) E-mail: sameeragarwal@zyduscadila.com or sameer_ag@yahoo.com., *(R.C.D.) E-mail: ranjitdesai@zyduscadila.com. Fax:+91-2717-665355. Tel: +91-2717-665555.
Ranjit Desai

Sr Vice President, Head Chemistry

Zydus Cadila

2012 – Present (4 years)Zydus Research Centre, Ahmedabad, India

Pankaj Patel, chairman and MD, Cadila Healthcare Ltd
Dr. Mukul Jain

Senior Vice President at Zydus Research Centre

Prashant Deshmukh

Prashant Deshmukh

Research Officer at Zydus Cadila

Dr. Poonam Giri

Dr. Poonam Giri

Principal Scientist at Zydus Research Centre

Bhadresh Rami

Bhadresh Rami

Debdutta Bandyopadhyay

Debdutta Bandyopadhyay

Senior General manager at Zydus Research Centre

Suresh Giri

Suresh Giri

Research Scientist

 References
1. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures. J. Org. Chem., 1996, 61 (11), 3849–3862.
2. Walker, S. D.; Borths, C. J.; DiVirgilio, E.; Huang, L.; Liu, P.; Morrison, H.; Sugi, K.; Tanaka, M.; Woo, J. C. S.; Faul, M. M. Development of a Scalable Synthesis of a GPR40 Receptor Agonist. Org. Process Res. Dev. 2011, 15, 570–580.
3. Desai, R. C., Agarwal, S. Novel Heterocyclic Compounds, Pharmaceutical Compositions and Uses Thereof. Indian Pat. Appl. 2025/MUM/2015, 25 May 2015.
4. Cheng, Z., Garvin, D., Paguio, A., Stecha, P., Wood, K., & Fan, F. Luciferase Reporter Assay System for Deciphering GPCR Pathways. Current Chemical Genomics, 2010, 4, 84–91. http://doi.org/10.2174/1875397301004010084
5. Arkin, M. R., Connor, P. R., Emkey, R., et al. FLIPR™ Assays for GPCR and Ion Channel Targets. 2012 May 1 [Updated 2012 Oct 1]. In: Sittampalam, G. S., Coussens, N. P., Nelson, H., et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004. Available from: http://www.ncbi.nlm.nih.gov/books/NBK92012/
6. Garbison, K. E., Heinz, B. A., Lajiness, M. E. IP-3/IP-1 Assays. 2012 May 1. In: Sittampalam, G. S., Coussens, N. P., Nelson, H., et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004. Available from: http://www.ncbi.nlm.nih.gov/books/NBK92004/
7. Milić, A., Mihaljević, V.B., Ralić, J. et al. A comparison of in vitro ADME properties and pharmacokinetics of azithromycin and selected 15-membered ring macrolides in rodents. Eur J Drug Metab Pharmacokinet, 2014, 39, 263. doi:10.1007/s13318-013-0155-8
8. Bell, R. H.; Hye, R. J. Animal models of diabetes mellitus: physiology and pathology. J. Surg. Res. 1983, 35, 433-460.
9. Shafrir, E. Animal models of non insulin dependent diabetes. Diabetes Metab Rev. 1992, 8, 179- 208.

 

Paper
Development of a Scalable Synthesis of a GPR40 Receptor Agonist
Chemical Process Research and Development, Amgen Inc., Thousand Oaks, California 91320, United States
Org. Process Res. Dev., 2011, 15 (3), pp 570–580
*Tel: 805-313-5152. Fax: 805-375-4532. E-mail: walkers@amgen.com.
Abstract Image

Early process development and salt selection for AMG 837, a novel GPR40 receptor agonist, is described. The synthetic route to AMG 837 involved the convergent synthesis and coupling of two key fragments, (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (1) and 3-(bromomethyl)-4′-(trifluoromethyl)biphenyl (2). The chiral β-alkynyl acid 1 was prepared in 35% overall yield via classical resolution of the corresponding racemic acid (±)-1. An efficient and scalable synthesis of (±)-1 was achieved via a telescoped sequence of reactions including the conjugate alkynylation of an in situ protected Meldrum’s acid derived acceptor prepared from 3. The biaryl bromide 2 was prepared in 86% yield via a 2-step Suzuki−Miyaura coupling−bromination sequence. Chemoselective phenol alkylation mediated by tetrabutylphosphonium hydroxide allowed direct coupling of 1 and 2 to afford AMG 837. Due to the poor physiochemical stability of the free acid form of the drug substance, a sodium salt form was selected for early development, and a more stable, crystalline hemicalcium salt dihydrate form was subsequently developed. Overall, the original 12-step synthesis of AMG 837 was replaced by a robust 9-step route affording the target in 25% yield.

Image result for AMG 837
CAS [1291087-14-3] AMG 837
 Image result for AMG 837
“Enantioselective Synthesis of a GPR40 Agonist AMG 837 via Catalytic Asymmetric Conjugate Addition of Terminal Alkyne to α,β-Unsaturated Thioamide” Yazaki, R.; Kumagai, N.; Shibasaki, M. Org. Lett. 2011, 13, 952.   highlighted by Synfacts 2011, 6, 586.
NMR

/////////fatty acids, FFAR1 GPR40, GPR40 agonist, insulin secretion, type 2 diabetes, GPR40/FFAR1 Receptor Agonist, ZYDUS CADILA
c1(ccc(cc1)OCc2cc(ccc2)CN(Cc3ccsc3)C(C)C)[C@H](CC(=O)O[Ca]OC(C[C@@H](c4ccc(cc4)OCc5cc(ccc5)CN(Cc6ccsc6)C(C)C)C#CC)=O)C#CC
c1(ccc(cc1)OCc2cc(ccc2)CN(Cc3ccsc3)C(C)C)[C@H](CC(=O)O)C#CC

Filed under: Uncategorized Tagged: fatty acids, FFAR1, GPR40, GPR40 agonist, GPR40/FFAR1 Receptor Agonist, insulin secretion, TYPE 2 DIABETES, zydus cadila

Green Solvent – A sustainable option – Dr. Denis Prat, SANOFI, France

Identifying “green chemistry” industrialisation barriers through case-studies

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Green Chemistry International

Nitesh Mehta

Nitesh Mehta

Convenor of Industrial Green Chemistry World and Founder – Director of Newreka Green Synth Technologies Pvt Ltd

nitesh.mehta@newreka.co.in

Identifying “green chemistry” industrialisation barriers through case-studies
– Mr. Nitesh Mehta, Founder Director, Newreka Green Synth Technologies Pvt. Ltd., India

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GNE-272

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GNE-272

(S)-1-(3-((2-fluoro-4-(1-methyl-1H-pyrazol-4- yl)phenyl)amino)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin- 5(4H)-yl)ethanone

1-[3-[2-fluoro-4-(1-methylpyrazol-4-yl)anilino]-1-[(3S)-oxolan-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone

CAS 1936428-93-1

Molecular Formula: C22H25FN6O2
Molecular Weight: 424.471303 g/mol

GENENTECH, INC. [US/US]; 1 DNA Way South San Francisco, California 94080-4990 (US).
CONSTELLATION PHARMACEUTICALS, INC. [US/US]; 215 First Street Suite 200 Cambridge, Massachusetts 02142 (US)

ROMERO, F. Anthony; (US).
MAGNUSON, Steven; (US).
PASTOR, Richard; (US).
TSUI, Vickie Hsiao-Wei; (US).
MURRAY, Jeremy; (US).
CRAWFORD, Terry; (US).
ALBRECHT, Brian, K.; (US).
COTE, Alexandre; (US).
TAYLOR, Alexander, M.; (US).
LAI, Kwong Wah; (CN).
CHEN, Kevin, X.; (CN).
BRONNER, Sarah; (US).
ADLER, Marc; (US).
EGEN, Jackson; (US).
LIAO, Jiangpeng; (CN).
WANG, Fei; (CN).
CYR, Patrick; (US).
ZHU, Bing-Yan; (US).
KAUDER, Steven; (US)

Chromatin is a complex combination of DNA and protein that makes up chromosomes. It is found inside the nuclei of eukaryotic cells and is divided between heterochromatin (condensed) and euchromatin (extended) forms. The major components of chromatin are DNA and proteins. Histones are the chief protein components of chromatin, acting as spools around which DNA winds. The functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication. The chromatin structure is controlled by a series of post-translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the “histone tails” which extend beyond the core nucleosome structure. Histone tails tend to be free for protein-protein interaction and are also the portion of the histone most prone to post-translational modification. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation. These epigenetic marks are written and erased by specific enzymes that place the tags on specific residues within the histone tail, thereby forming an epigenetic code, which is then interpreted by the cell to allow gene specific regulation of chromatin structure and thereby transcription.

Of all classes of proteins, histones are amongst the most susceptible to post-translational modification. Histone modifications are dynamic, as they can be added or removed in response to specific stimuli, and these modifications direct both structural changes to chromatin and alterations in gene transcription. Distinct classes of enzymes, namely histone acetyltransferases (HATs) and histone deacetylases (HDACs), acetylate or de-acetylate specific histone lysine residues (Struhl K., Genes Dev., 1989, 12, 5, 599-606).

Bromodomains, which are approximately 1 10 amino acids long, are found in a large number of chromatin-associated proteins and have been identified in approximately 70 human proteins, often adjacent to other protein motifs (Jeanmougin F., et al., Trends Biochem. Sc , 1997, 22, 5, 151-153; and Tamkun J.W., et al., Cell, 1992, 7, 3, 561-572).

Interactions between bromodomains and modified histones may be an important mechanism underlying chromatin structural changes and gene regulation. Bromodomain-containing proteins have been implicated in disease processes including cancer, inflammation and viral replication. See, e.g., Prinjha et al,, Trends Pharm. Sci., 33(3):146-153 (2012) and Muller et al , Expert Rev. , 13 (29): 1 -20 (September 201 1 ).

Cell-type specificity and proper tissue functionality requires the tight control of distinct transcriptional programs that are intimately influenced by their environment.

Alterations to this transcriptional homeostasis are directly associated with numerous disease states, most notably cancer, immuno-inflammation, neurological disorders, and metabolic diseases. Bromodomains reside within key chromatin modifying complexes that serve to control distinctive disease-associated transcriptional pathways. This is highlighted by the observation that mutations in bromodomain-containing proteins are linked to cancer, as well as immune and neurologic dysfunction. Hence, the selective inhibition of bromodomains across a specific family, such as the selective inhibition of a bromodomain of CBP/EP300, creates varied opportunities as novel therapeutic agents in human dysfunction.

There is a need for treatments for cancer, immunological disorders, and other

CBP/EP300 bromodomain related diseases.

PATENT

WO-2016086200

Scheme 1

Scheme 2

Scheme 3

Scheme 4

General procedure for Intermediates A & B

Intermediate A

Intermediate

General procedure for Intermediates F & G

Intermediate F

Intermediate G

Step 1:

(R)-tetrahydrofuran-3-yI methanesulfonate

To a solution of (^)-tetrahydrofuran-3-ol (25 g, 253.7 mmol) in DCM (250 mL) at 0 °C was added triethylamine (86 g, 851.2 mmol) and mesyl chloride (39 g, 340.48 mmol) dropwise. The mixture was stirred at room temperature for 12 h. The reaction was quenched with water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated in vacuo to give the title compound (47 g, 99%) as a brown oil. Ή NMR (400 MHz, CDC13) δ 5.35 – 5.27 (m, 1H), 4.05 – 3.83 (m, 4H), 3.04 (s, 3 H), 2.28 – 2.20 (m, 2 H).

Step 2:

(S)-tert-butyl 3-bromo-l-(tetrahydrofuran-3-yI)-6,7-dihydro-li/-pyrazolo[43- c] pyridine-5(4H)-carboxylate

To a solution of tert-butyl 3-bromo-6,7-dihydro-lH-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate A, 24.8 g, 82 mmol) in DMF (200 mL) was added Cs2C03 (79 g, 246 mmol) and (/?)-tetrahydrofuran-3-yl methanesulfonate (17.4 g, 98 mmol). The mixture was heated to 80 °C for 12 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography

(petroleum ether / EtOAc = from 10 : 1 to 3 : 1) to give the title compound (Intermediate F, 50 g, 71 %) as a yellow oil. Ή NMR (400 MHz, DMSO-i ) δ 4.97 – 4.78 (m, 1H), 4.13 (s, 2H), 3.98 – 3.86 (m, 2H), 3.81 – 3.67 (m, 2H), 3.56 (t, J= 5.6 Hz, 2H), 2.68 (t, J= 5.6 Hz, 2H), 2.33 – 2.08 (m, 2H), 1.38 (s, 9H).

Step 3:

(5)-l-(3-bromo-l-(tetrahydrofuran-3-yl)-6,7-dihydro-lH-pyrazoIo[4,3-c]pyridin-5(4//)- yl)ethanone

To a solution of (S)-tert-buty\ 3-bromo- 1 -(tetrahydrofuran-3-yl)-6,7-dihydro-lH-pyrazolo [4,3 -c]pyridine-5(4H)-carboxy late (29 g, 78 mmol) in DCM (300 mL) was added trifluroacetic acid (70 mL) dropwise. The mixture was stirred at room temperature for 2 h. The solvent was concentrated in vacuo and the crude residue was re -dissolved in DMF (100 mL). The mixture was cooled to 0 °C before triethylamine (30 g, 156 mmol) and acetic anhydride (8.7 g, 86 mmol) were added dropwise. The mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with water (200 mL) at 0 °C and extracted with EtOAc (150 mL x 3). The combined organic layers were dried over anhydrous Na2S0 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM / MeOH = 30 : 1) to give the title compound (Intermediate G, 21.3 g, 87%) as a white solid. lH NMR (400 MHz, CDC13) δ 4.78 – 4.67 (m, 1H), 4.45 -4.29 (m, 2H), 4.15 – 4.06 (m, 2H), 3.96 – 3.92 (m, 2H), 3.88 – 3.70 (m, 2H), 2.71 – 2.67 (m, 2H), 2.38 – 2.34 (m, 2H), 2.16 (s, 3H).

PATENT

US-20160158207

Example 300 1-[3-[2-fluoro-4-(1-methylpyrazol-4- yl)anilino]-1-[(3S)-tetrahydrofuran-3- yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-5-yl]ethanone
1H NMR (400 MHz, DMSO- d6) δ 8.03 (s, 1H), 7.83-7.68 (m, 3H), 7.36-7.33 (m, 1H), 7.32-7.21 (m, 1H), 4.88- 4.84 (m, 1H), 4.40-4.33 (m, 2H), 4.03-3.99 (m, 2H), 3.84- 3.67 (m, 7H), 2.79-2.64 (m, 2H), 2.26-2.21 (m, 2H), 2.08-2.05 (m, 3H) 425

General Procedure for Intermediates F & G


Step 1

(R)-tetrahydrofuran-3-yl methanesulfonate


      To a solution of (R)-tetrahydrofuran-3-ol (25 g, 253.7 mmol) in DCM (250 mL) at 0° C. was added triethylamine (86 g, 851.2 mmol) and mesyl chloride (39 g, 340.48 mmol) dropwise. The mixture was stirred at room temperature for 12 h. The reaction was quenched with water (100 mL) and extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (47 g, 99%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 5.35-5.27 (m, 1H), 4.05-3.83 (m, 4H), 3.04 (s, 3H), 2.28-2.20 (m, 2H).

Step 2

(S)-tert-butyl 3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate


      To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate A, 24.8 g, 82 mmol) in DMF (200 mL) was added Cs2CO3 (79 g, 246 mmol) and (R)-tetrahydrofuran-3-yl methanesulfonate (17.4 g, 98 mmol). The mixture was heated to 80° C. for 12 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=from 10:1 to 3:1) to give the title compound (Intermediate F, 50 g, 71%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 4.97-4.78 (m, 1H), 4.13 (s, 2H), 3.98-3.86 (m, 2H), 3.81-3.67 (m, 2H), 3.56 (t, J=5.6 Hz, 2H), 2.68 (t, J=5.6 Hz, 2H), 2.33-2.08 (m, 2H), 1.38 (s, 9H).

Step 3

(S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone


      To a solution of (S)-tert-butyl 3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (29 g, 78 mmol) in DCM (300 mL) was added trifluroacetic acid (70 mL) dropwise. The mixture was stirred at room temperature for 2 h. The solvent was concentrated in vacuo and the crude residue was re-dissolved in DMF (100 mL). The mixture was cooled to 0° C. before triethylamine (30 g, 156 mmol) and acetic anhydride (8.7 g, 86 mmol) were added dropwise. The mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with water (200 mL) at 0° C. and extracted with EtOAc (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=30:1) to give the title compound (Intermediate G, 21.3 g, 87%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.78-4.67 (m, 1H), 4.45-4.29 (m, 2H), 4.15-4.06 (m, 2H), 3.96-3.92 (m, 2H), 3.88-3.70 (m, 2H), 2.71-2.67 (m, 2H), 2.38-2.34 (m, 2H), 2.16 (s, 3H).

OTHER ISOMER

Example 299 1-[3-[2-fluoro-4-(1-methylpyrazol-4- yl)anilino]-1-[(3R)-tetrahydrofuran-3- yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-5-yl]ethanone
1H NMR (400 MHz, DMSO- d6) δ 8.03 (s, 1H), 7.83-7.67 (m, 3H), 7.39-7.34 (m, 1H), 7.26-7.21 (m, 1H), 4.87- 4.77 (m, 1H), 4.41-4.34 (m, 2H), 4.02-3.97 (m, 2H), 3.83 (s, 3H), 3.81-3.67 (m, 4H), 2.77-2.66 (m, 2H), 2.26- 2.22 (m, 2H), 2.08-2.05 (m, 3H) 425

PAPER

Abstract Image

The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure–activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50 = 0.02 μM, BRET IC50 = 0.41 μM, BRD4(1) IC50 = 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.

Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300

Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States
Wuxi Apptec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People’s Republic of China
§ Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States
J. Med. Chem., Article ASAP
*Phone: +1-650-467-6384. E-mail: romero.frank@gene.com.

UNDESIRED R ISOMER

In a similar procedure to59, the title compound was prepared from (S)-tetrahydrofuran-3-yl
methanesulfonate and purified by Prep-TLC (DCM / MeOH = 15 : 1) to give the title
compound as a light yellow solid.

1H NMR (400 MHz, CDCl3) δ 7.76–7. 42 (m,1H), 7.68 (s, 1H), 7.53 (s, 1H), 7.20–7.12 (m, 2H), 5.86–5.77 (m, 1H), 4.79–4.69 (m, 1H),4.47–4.29 (m, 2H), 4.25–4.08 (m, 2H), 4.06–3.72 (m, 4H), 3.99 (s, 3H), 2.76–2.65 (m, 2H),
2.49–2.28 (m, 2H), 2.25–2.12 (m, 3H).

13C NMR (100 MHz, CDCl3) δ 169.81, 169.36,151.71 (d, J = 238.9 Hz), 145.51, 144.64, 137.83, 136.32, 135.89, 126.35, 121.41, 116.44 (d,J = 26.0 Hz), 111.88, 103.09 (d, J = 24.0 Hz), 71.94, 68.10, 57.65, 43.24, 42.24, 39.02, 37.83,32.49, 22.01.

LCMS M/Z (M+H) 425.

[α]27D +8.8 (c 0.78, CHCl3, 99% ee).

DESIRED S ISOMER

(S)-1-(3-((2-fluoro-4-(1-methyl-1H-pyrazol-4- yl)phenyl)amino)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin- 5(4H)-yl)ethanone

aReagents and conditions: (a) 4-bromo-2-fluoro-1-isothiocyanato-benzene, KOtBu, THF, rt (b) CH3I, 40 °C, 51%; (c) hydrazine monohydrate, EtOH, 85 °C; 96%; (d) 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, dioxane / water, Na2CO3, Pd(dppf)Cl2, 100 °C, 63%; (e) (R)-tetrahydrofuran-3-yl methanesulfonate, Cs2CO3, DMF, 90 oC, 42%.

The crude residue was purified by silica gel chromatography (DCM / MeOH = 100:1) to give (S)-1-(3-((2-fluoro-4-(1- methyl-1H-pyrazol-4-yl)phenyl)amino)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1Hpyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone as a light yellow solid.

1H NMR (400 MHz, CDCl3) δ 7.76–7.72 (m, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 7.20–7.12 (m, 2H), 5.86–5.77 (m, 1H), 4.79–4.69 (m, 1H), 4.47–4.29 (m, 2H), 4.25–4.08 (m, 2H), 4.06– 3.72 (m, 4H), 3.99 (s, 3H), 2.76–2.65 (m, 2H), 2.49–2.28 (m, 2H), 2.25–2.12 (m, 3H).

13C NMR (100 MHz, CDCl3) δ 169.8, 169.4, 151.7 (d, J = 238.9 Hz), 145.5, 144.64, 137.83, 136.3, 135.9, 126.4, 121.4, 116.4 (d, J = 26.0 Hz), 111.9, 103.1 (d, J = 24.0 Hz), 71.9, 68.1, 57.7, 43.2, 42.2, 39.0, 37.8, 32.5, 22.0.

LCMS m/z (M+H) 425.

[α]27 D -11.0 (c 1.0, CHCl3, 99% ee).

HRMS m/z 425.2093 (M + H+ , C22H25FN6O2, requires 425.2057).

//////////GNE-272, Genentech, CBP, EP300, cancer, immune system regulation,  1936428-93-1

[H][C@@]1(CCOC1)N1N=C(NC2=C(F)C=C(C=C2)C2=CN(C)N=C2)C2=C1CCN(C2)C(C)=O


Filed under: Uncategorized Tagged: 1936428-93-1, CANCER, CBP, EP300, GENENTECH, GNE-272, immune system regulation

Clenbuterol

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Clenbuterol.svg

Clenbuterol

image

  • Clenbuterol hydrochloride, NAB-365, Siropent

Clenbuterol, marketed as Dilaterol, Spiropent, Ventipulmin,[1] is a sympathomimetic amine used by sufferers of breathing disorders as a decongestant and bronchodilator. People with chronic breathing disorders such as asthma use this as a bronchodilator to make breathing easier. It is most commonly available as the hydrochloride salt, clenbuterol hydrochloride.[2]

Image result for Clenbuterol

Effects and dosage

Clenbuterol is a β2 agonist with some structural and pharmacological similarities to epinephrine and salbutamol, but its effects are more potent and longer-lasting as a stimulant and thermogenic drug. It causes an increase in aerobic capacity, central nervous system stimulation, blood pressure, and oxygen transportation. It increases the rate at which body fat is metabolized while increasing the body’s basal metabolic rate (BMR). It is commonly used for smooth muscle-relaxant properties as a bronchodilator and tocolytic.

Clenbuterol is also prescribed for treatment of horses, but equine use is usually the liquid form.

Human use

Clenbuterol is approved for use in some countries, free or via prescription, as a bronchodilator for asthma patients.[3]

Image result for Clenbuterol

Legal status

Clenbuterol is not an ingredient of any therapeutic drug approved by the US Food and Drug Administration[3] and is now banned forIOC-tested athletes.[4] In the US, administration of clenbuterol to any animal that could be used as food for human consumption is banned by the FDA.[5][6]

Clenbuterol is a therapeutic drug for asthma and COPD, approved for human use in some countries in Europe (Bulgaria and Russia) and Asia (China).

Image result for clenbuterol before and after

Weight-loss drug

Although often used by bodybuilders during their “cutting” cycles,[citation needed] the drug has been more recently known to the mainstream, particularly through publicized stories of use by celebrities such as Victoria Beckham,[4] Britney Spears, and Lindsay Lohan, [7] for its off-label use as a weight-loss drug similar to usage of other sympathomimetic amines such as ephedrine, despite the lack of sufficient clinical testing either supporting or negating such use.

Image result for clenbuterol side effects on men

Image result for Clenbuterol SYNTHESIS

Image result for Clenbuterol SYNTHESIS

By bromination of 4-amino-3,5-dichloroacetophenone (I) with Br2 in CHCl3 to give 4-amino-3,5-dichloro-alpha-bromoacetophenone (II), m.p. 140-5 C, which is condensed with tert-butylamine (III) in CHCl3 to 4-amino-3,5-dichloro-alpha-tertbutylaminoacetophenone hydrochloride (IV), m.p. 252-7 C; this product is finally reduced with NaBH4 in methanol.

Synthesen von neuen Amino-Halogen-substituierten Phenyl-aminothanolen. Arzneim-Forsch Drug Res 1972, 22, 5, 861-869

CLIP

Synthesis and Characterization of Bromoclenbuterol

Ravi Kumar Kannasani*, Srinivasa Reddy Battula, Suresh Babu Sannithi, Sreenu Mula and Venkata Babu VV

R&D Division, RA Chem Pharma Limited, API, Hyderabad, Telangana, India

*Corresponding Author:
Ravi Kumar Kannasani
R&D Division, RA Chem Pharma Limited
API, Prasanth Nagar, Hyderabad, Telangana, India
Tel: +919000443184
E-mail: kannasani.ravi@rachempharma.com

http://www.omicsonline.org/open-access/synthesis-and-characterization-of-bromoclenbuterol-2161-0444-1000397.php?aid=79341

Citation: Kannasani RK, Battula SR, Sannithi SB, Mula S, Babu VVV (2016) Synthesis and Characterization of Bromoclenbuterol. Med Chem (Los Angeles) 6:546-549. doi:10.4172/2161-0444.1000397

Clenbuterol, it is most commonly available as the hydrochloride salt, clenbuterol hydrochloride. Clenbuterol, marketed as Dilaterol, Spiropent, Ventipulmin, and also generically as clenbuterol, is a sympathomimetic amine used for breathing disorders as a decongestant and bronchodilator. People with chronic breathing disorders such as asthma use this as a bronchodilator to make breathing easier. Clenbuterol is a β2 agonist with some structural and pharmacological similarities to epinephrine and salbutamol, but its effects are more potent and longerlasting as a stimulant and thermogenic drug. It causes an increase in aerobic capacity, central nervous system stimulation, blood pressure, and oxygen transportation. It increases the rate at which body fat is metabolized while increasing the body’s BMR. It is commonly used for smooth muscle-relaxant properties as a bronchodilator and tocolytic. Clenbuterol is also prescribed for treatment of horses, but equine use is usually the liquid form

Clenbuterol Hydrochloride was first synthesized at Thomae; a Boehringer Ingelheim research facility in Biberach, Germany, in 1967. The synthesis of Clenbuterol Hydrochloride was patented in the United States in 1970. After comprehensive clinical trials, Clenbuterol Hydrochloride was approved for the treatment of reversible airway obstruction in Germany in 1976 and later as a veterinary pharmaceutical for the treatment of bronchiolytic disorders in Germany in 1980. Boehringer Ingelheim markets Clenbuterol Hydrochloride as Spirospent for Human Pharmaceuticals and as Ventipulmin for Veterinary Pharmaceuticals. Clenbuterol Hydrochloride is not approved by the Federal Drug Administration for human use in the United States.

As per the available literature [47], clenbuterol hydrochloride was synthesized from 4-amino acetophenone (Scheme 1). Initially 4-amino acetophenone (1) was reacted with chlorine to afford 4-amino-3,5- dichloro acetopheneone (2) which was further reacted bromine to give 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone (3). The obtained bromo compound was reacted tertiary butyl amine to afford 2-(tertbutylamino)- 1-(4-amino-3,5-dichlorophenyl)ethanone (4), which was further reduced with sodium borohydride to give clenbuterol base (5) and converted in to hydrochloride salt by using alcoholic HCl to get clenbuterol hydrochloride (6).

In the synthesis of clenbuterol hydrochloride, first step was a double chlorination of 4-aminoacetophenone (1) through an electrophillic aromatic substitution reaction to yield 4-amino-3,5- dichloroacetophenone (2). Due to the ortho/para directing, amino group and the meta directing, electron withdrawing, acetyl group, chlorination of 4-aminoacetophenone occurs primarily at the 3 and 5 positions over the 2 and 6 positions. Therefore, under chlorination would produce only the mono chlorinated impurity, 4-amino-3- chloroacetophenone. Under these conditions, over chlorination does not result in the addition of chlorine to the 2 and 6 positions because the amino and acetyl groups do not direct that addition. Even though chlorides are ortho/para directing and direct to the 2 and 6 position, chlorides are also deactivating. After close observation on this chlorination reaction, it was noted that the formed mono chlorinated impurity (Scheme 2) (4-amino-3-chloro acetophenone) caused the formation of process related impurity (bromoclenbuterol) in clenbuerol synthesis.

References for above

Image result for clenbuterol side effects on men

References

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  3. ^ Jump up to:a b “Clenbuterol”. Daily Mail. 2009-10-01. Retrieved 2010-04-07
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  12. Jump up^ Dittmeier, Bobbie (May 7, 2012). “Mota suspended 100 games for positive test”.MLB.com. Major League Baseball. Retrieved May 7, 2012.
  13. Jump up^ Snyder, Whitney (2010-09-30). “Alberto Contador Tests Positive For Banned Substance”. Huffington Post.
  14. Jump up^ Radioshack suspends Li after doping positive
  15. Jump up^ “Three Minor League players suspended”. MLB.com. September 30, 2010.
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  17. Jump up^ CAS Sanction Contador with two year ban in clenbuterol case, cyclingnews.com, 6 February 2012
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  20. Jump up^ “FIFA alarmed by use of food supplements”. September 5, 2012.
  21. Jump up^ Clenbuterol found in most players at Under-17 World Cup – ESPN
  22. Jump up^ Boxer Erik Morales banned for two years for failed drug test – BBC Sport
  23. Jump up^ Leafs’ Ashton suspended 20 games for violating PED policy – Article – TSN
  24. Jump up^ swim swam.com
  25. Jump up^ Antidopingový výbor ČR
  26. Jump up^ http://bigstory.ap.org/article/1c81c75a99cc4bbea4d97cbc90d9e6df/yankees-minor-league-pitcher-cedeno-suspended-72-games
  27. Jump up^ Collingwood players Lachie Keeffe and Josh Thomas accept two-year bans for clenbuterol positive test – ABC News (Australian Broadcasting Corporation)
  28. Jump up^ No Cookies | Herald Sun
  29. Jump up^ “Heavyweight champ ‘Big Daddy’ Browne seeking legal advice over banned substance reports”. ABC News. Retrieved 2016-03-22.
  30. Jump up^ “Australia’s first world heavyweight champion boxer Lucas Browne fails drug test”. The Sydney Morning Herald. Retrieved 2016-03-22.
  31. Jump up^ “Raul Mondesi Jr. suspended 50 games for PEDs found in cold medicine”. CBS News. May 10, 2016.
  32. Jump up^ Francisco Vargas issued temporary license after failed drug test – Ring TV
  33. Jump up^ “Clenbuterol – SteroidAbuse .com”. http://www.steroidabuse.com. Retrieved 2016-03-10.
  34. Jump up^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 325–326.
  35. Jump up^ “Horse meat investigation. Advice for consumers”. Enforcement and regulation. Food Standards Agency. Retrieved 19 May 2013.
  36. ^ Jump up to:a b “Clenbuterol”, Food Safety and Inspection Service (FSIS), July 1995, Retrieved 8 April 2015
  37. Jump up^ China bans production, sale of clenbuterol to improve food safety Retrieved 08/22/2012
  38. Jump up^ European Commission Retrieved 08/22/2012
  39. Jump up^ Anti Doping Advisory Notes Retrieved 08/22/2012
  40. Jump up^ “Pigs fed on bodybuilder steroids cause food poisoning in Shanghai”. AFP. 2006-09-19. Retrieved 2006-09-19.
  41. Jump up^ “China: 70 ill from tainted pig organs”. CNN. 2009-02-23. Retrieved 2010-04-30.
  42. Jump up^ Wang Ying (2009-02-23). “70 ill after eating tainted pig organs”. China Daily.
  43. Jump up^ “China to launch one-year crackdown on contaminated pig feed – xinhuanet.com”.Xinhua. 2011-03-28. Retrieved 2011-03-29.
  44. Jump up^ Bottemiller, helena (April 26, 2011). “Amid Scandal, China Bans More Food Additives”.Food Safety News. Retrieved August 22, 2012.
  45. Jump up^ “Import Alert 68-03”. http://www.accessdata.fda.gov. Retrieved 2016-03-10.
  46. Jump up^ Planipart Solution for Injection 30 micrograms/ml: Uses, National Office of Animal Health

External links

Clenbuterol
Clenbuterol.svg
Clenbuterol ball-and-stick model.png
Clenbuterol (top),
and (R)-(−)-clenbuterol (bottom)
Systematic (IUPAC) name
(RS)-1-(4-Amino-3,5-dichlorophenyl)-2-(tert-butylamino)ethan-1-ol
Clinical data
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • C
Routes of
administration
Oral (tablets, oral solution)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 89–98% (orally)
Metabolism Hepatic (negligible)
Biological half-life 36–48 hours
Excretion Feces and urine
Identifiers
CAS Number 37148-27-9 Yes
ATC code R03AC14 (WHO)R03CC13 (WHO)QG02CA91 (WHO)
PubChem CID 2783
DrugBank DB01407 Yes
ChemSpider 2681 Yes
UNII XTZ6AXU7KN Yes
KEGG D07713 Yes
ChEBI CHEBI:174690 Yes
ChEMBL CHEMBL49080 Yes
Chemical data
Formula C12H18Cl2N2O
Molar mass 277.19
Chirality Racemic mixture

///////////


Filed under: Uncategorized Tagged: Clenbuterol

Tedatioxetine Revisited

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Tedatioxetine.svg

Tedatioxetine

TEDATIOXETINE; UNII-5H681S8O3S; Lu AA24530; 508233-95-2;
Molecular Formula: C18H21NS
Molecular Weight: 283.43104 g/mol
4-{2-[(4-Méthylphényl)sulfanyl]phényl}pipéridine
508233-95-2 [RN]
Lu AA24530
Piperidine, 4-[2-[(4-methylphenyl)thio]phenyl]
  • OriginatorLundbeck A/S
  • DeveloperLundbeck A/S; Takeda
  • ClassAntidepressants; Anxiolytics; Piperidines
  • Mechanism of ActionBiogenic monoamine uptake inhibitors; Serotonin 2C receptor antagonists; Serotonin 3 receptor antagonists
  • Generalised anxiety disorder; Major depressive disorder

Most Recent Events

  • 10 May 2016Discontinued – Phase-I for Generalised anxiety disorder in USA, Japan (PO)
  • 10 May 2016Discontinued – Phase-I for Major depressive disorder in USA, Japan (PO)
  • 30 Jul 2015Tedatioxetine is still in phase I trials for Major depressive disorders and Generalised anxiety disorder in USA and Japan

Tedatioxetine (Lu AA24530) is an antidepressant that was discovered by scientists at Lundbeck; in 2007 Lundbeck and Takedaentered into a partnership that included tedatioxetine but was focused on another, more advanced Lundbeck drug candidate,vortioxetine.[1]

Tedatioxetine is reported to act as a triple reuptake inhibitor (5-HT > NE > DA) and 5-HT2A, 5-HT2C, 5-HT3 and α1A-adrenergic receptor antagonist.[2][3][4][5]

As of 2009, it was in phase II clinical trials for major depressive disorder,[5] but there have been no updates since then, and as of August 2013 it was no longer displayed on Lundbeck’s product pipeline.[6][7]

On May 10, 2016, all work on tedatioxetine stopped.[8]

PATENT

WO 2016151328

PATENT

WO 2015090160

Tedatioxetine chemical name 4- (2- (4-methylphenyl group)) phenylpiperidine by Lundbeck developed for the treatment of severe depression, it is a monoamine reuptake inhibitor, a monoamine reuptake transporter inhibitors, 5-HT3 antagonists and 5-HT2c receptor antagonist. For the treatment of major depressive disorder and generalized anxiety, II clinical study in. Tedatioxetine has the following structure:
According to the literature, the current synthesis routes are the following:
WO 2003/029232 discloses Tedatioxetine first preparation method, as shown in the following Scheme,
The method of low yield, the product is not easy purification by column chromatography requires; more important is the preparation of the compound N-Boc- piperidin-4-ol of the need to use butyl lithium, and reaction was carried out at lower temperatures, not conducive to industrial production.
WO 2009109541 provides a, as shown in the above-described method for improved routes following synthetic route,
Bn- replaced with Boc-, dehydroxylation switch to TFA and Et 3 of SiH, yield improved despite increased. But there are many shortcomings.Deficiencies mainly reflected in the following aspects: the compound used in the expensive starting 2-bromo benzene iodine source and a catalyst of palladium and a bidentate phosphine ligand 3, an increase of production cost; preparation of compound needed 4:00 butyl lithium reagent to the more dangerous, the need at a low temperature reaction. This will bring in the production of a big security risk, is not conducive to the operation; when dehydroxylation
Preparation of 2- (4-methyl-phenyl mercapto) phenylpiperidine hydrobromide, to use a lot of trifluoroacetate (15eq), post-processing is too much trouble and the environment have a greater pollution.
Given 4- [2- (4-methylphenyl) phenyl] piperidine and salts thereof possess excellent pharmacological properties, and deficiencies of the prior processes, is necessary to develop a suitable industrial production, easy to operate and environmentally friendly preparation process.

2- (4-methyl-phenylthio) benzaldehyde prepared as in Example 1
Direction of Na 2 CO. 3 stirred mixture (11g, 105mmol) and 30mlDMF added 4-methyl-thiophenol (12.4g, 100mmol), stirred for 20 minutes. To the mixture was slowly added 2-bromobenzaldehyde (18.4g, 100mmol); a pending completion of the addition, under nitrogen, was heated to 100 deg.] C for 6 hours. After completion of the reaction, the reaction solution was cooled to room temperature, 100ml of water was added and stirred for 30 minutes. Filtered, washed with water (30ml) and dried in vacuo to give the filter cake was washed with 20.5g pale green solid; After n-hexane to give 18.5g pale yellow solid was recrystallized from 2- (4-phenylthio) benzaldehyde (mp: 52- 54 ℃), 81% yield. 2- (4-methyl-phenylthio) benzaldehyde Example 2 Preparation of
To the K 2 CO. 3 stirred mixture (15g, 110mmol) and 30mlDMA added 4-methyl-thiophenol (12.6g, 102mmol), stirred for 20 minutes. To the mixture was slowly added 2-chlorobenzaldehyde (14g, 100mmol); a pending completion of the addition, under nitrogen, the reaction was heated to 100 deg.] C for 7 hours. After completion of the reaction, the reaction solution was cooled to room temperature, 100ml of water was added and stirred for 30 minutes. Filtered, washed with water (30ml) and dried in vacuo to give the filter cake was washed with 19.7g pale green solid; After n-hexane to give 17g as a pale yellow solid was recrystallized from 2- (4-phenylthio) benzaldehyde (melting point: 51-53 ℃), a yield of 77.5%
2- (4-methyl-phenylthio) benzaldehyde Example 3 Preparation of
Ask NaOH (4.2g, 105mmol) and stirred 50ml 1,4-dioxane was added 4-methyl-thiophenol (12.4g, 100mmol), stirred for 30 minutes. To the mixture was slowly added 2-iodo-benzaldehyde (23.1g, 100mmol); a pending completion of the addition, under nitrogen, was heated under reflux for 5 hours.After completion of the reaction, the reaction solution was cooled to room temperature, 50ml of water was added, extraction separated; the organic phase was washed with 50ml of ethyl acetate, and the combined organic phases were washed with 20% aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, filtration and concentration gave 21g viscous liquid, and cooled to solidify; after n-hexane to give 18.1g pale yellow solid was recrystallized from 2- (4-phenylthio) benzaldehyde (m.p.: 53-54 ℃), close rate of 79%.
Example 4 Preparation of 3- [2 (4-methyl) phenyl] pentanedioic acid
1) Preparation of ethyl-2-cyano-3- (2- (4-methyl) phenyl) acrylate
2- (4-methylphenyl thio) benzaldehyde (4g, 17.5mmol), ethyl cyanoacetate (2.4g 21mmol) and toluene (30ml) was added a mixture of glacial acetic acid (5ml) and piperidine (0.3 ml of) stirred for 10 minutes; heated to reflux, and isolating the resulting water trap. Completion of the reaction, cooled to room temperature; the reaction was washed with 30ml water and 30ml saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate; filtered, and concentrated to give 5.0g yellow liquid (solidifies on cooling), yield 86%. It was used directly in the next reaction without purification.
2) Preparation of Diethyl 2,4-diethyl-3- (2- (4-methyl) phenyl) glutarate
Sodium methoxide (1.9g, 35mmol) and dry THF (30ml) was stirred and cooled to mix 0-5 ℃, was added dropwise diethyl malonate (4.6g, 35mmol), stirred for 15 minutes at room temperature dropwise Bi; dropwise obtained above in step 2-cyano-3- (2- (4-methyl) phenyl) acrylate (5g, 15.4mmol) and dry tetrahydrofuran (40ml) solution; BI dropwise, at room temperature stirred for 13 hours. Completion of the reaction, the reaction mixture was added 150ml20% aqueous ammonium chloride solution, followed by extraction separated; the aqueous phase was extracted with ethyl acetate, the combined organic phase was dried over anhydrous magnesium sulfate; filtered, and concentrated to give 5.4 g of a viscous liquid, yield 78%. It was used directly in the next reaction without purification.
Was added 6N hydrochloric acid (70ml), was heated at reflux for 3 days the material obtained in the above step (5.4 g of); completion of the reaction, slowly cooled to room temperature, added 50ml of ethyl acetate, stirred for 30 minutes to precipitate a solid from the solution, filtered and washed with 20ml washed with ethyl acetate, and dried in vacuo at 50 ℃ 10 hours to give 2.7g of white solid 3- [2 (4-methylphenyl) phenyl] glutaric acid (melting point: 191-195 ℃), in 58% yield.
Example 5 Preparation of 3- [2- (4-phenylthio) phenyl] pentanedioic acid
To ethyl acetoacetate (13g, 100mmol) and piperidine (1.7g, 10mmol) was added a mixture of 2- (4-methyl-phenylthio) benzaldehyde (11.5g, 50mmol), room temperature for 1 day to give a yellow viscous semi-solid, 2.7g of sodium methoxide was added. after stirring for 1 hour cure, stand for 2 days.To the above mixture was added ethanol (180ml) and 40% aqueous sodium hydroxide (140ml) was stirred and heated to reflux for 4-5 hours the reaction. Completion of the reaction the heating was stopped, and after cooling to room temperature, the solvent was distilled off under reduced pressure; the residue after distillation under cooling in an ice water bath, and treated dropwise with concentrated hydrochloric acid (150ml) adjusted to pH 1-2. 300ml ethyl acetate was added, the aqueous phase was extracted with 300ml of ethyl acetate, and the combined organic phases were washed with 300ml water; the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to 500ml of the solvent. The residue was cooled to room temperature, stirred for 2 hours. The title compound was isolated by filtration through with ethyl acetate (20ml) and was washed and dried at 50 deg.] C in vacuo overnight to give 21.5g of white solid 3- [2 (4-methylphenyl) phenyl] glutaric acid (melting point: 194-196 ℃) yield 65%.
1HNMR(DMSO‐d6):δ2.28(S,3H),2.54‐2.65(m,4H),4.09‐4.16(m,1H),7.08‐7.17(m,4H),7.21‐7.26(m,3H),7.39(d,J=8.1Hz,1H),12.15(s,2H).ESI‐MS(m/z):353.10[M+Na]+.
Example 6 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine-2,6-dione
Mixing the compound 3- [2 (4-methyl) phenyl] glutaric acid (10g, 30mmol) and urea (5.4g, 90mmol) prepared in Step stirred and heated to 146 deg.] C for 4 hours ; after completion of the reaction was monitored by TLC, cooled to 80 deg.] C, was slowly added 70ml of water and 70ml of ethanol was stirred for 30 minutes; cooled to room temperature and stirred for 1 hour. The title compound was filtered absolute ethanol (170ml) and recrystallized from 50 deg.] C overnight and dried in vacuo to give 8.0g white solid 4- [2- (4-methylphenyl) phenyl] piperidine-2,6-di -one (mp: 164-166 ℃), yield 86%
1HNMR(CDCl3):δ2.33(S,3H),2..86(dd,J=17.2,4.4Hz,2H),2.69‐2.76 (m,2H),3.99‐4.08(m,1H),7.10‐7.15(m,4H),7.18‐7.30(m,4H),8.78(brs,1H).ESI‐MS(m/z):312.1[M+H]+.
7 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine-2,6-dione Example
In four of 250ml equipped with a condenser reaction flask was added 3- [2 (4-methyl) phenyl] glutaric acid (10g, 30mmol) and urea (14.4g, 240mmol) and the mixture was stirred and heated to 146 deg.] C for 4 hours; TLC monitoring completion of the reaction, cooled to 100 deg.] C, was slowly added 70ml of water and 70ml of ethanol was stirred for 30 minutes; cooled to room temperature and stirred for 1 hour. The title compound was filtered absolute ethanol (170ml) and recrystallized from 50 deg.] C overnight and dried in vacuo to give 7.8g white solid 4- [2- (4-methylphenyl) phenyl] piperidine-2,6-di -one (mp: 165-166 ℃), yield 84%.
8 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine-2,6-dione Example
In four of 250ml equipped with a condenser reaction flask was added 3- [2 (4-methyl) phenyl] pentanedioic acid (5g, 15mmol) and urea (1.8g, 30mmol) and the mixture was stirred and heated to 143 deg.] C for 4 hours; cool to 100 deg.] C, was slowly added 35ml of water and 35ml of ethanol was stirred for 30 minutes; cooled to room temperature and stirred for 1 hour. The title compound was filtered absolute ethanol (70ml) and recrystallized from 50 deg.] C overnight and dried in vacuo to give an off-white solid 2.9g of 4- [2- (4-methylphenyl) phenyl] piperidine-2,6-dione (Melting point: 163-166 ℃), a yield of 63%.
9 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine-2,6-dione Example
The compound prepared in the step of 3- [2 (4-methyl) phenyl] glutaric acid (10g, 30mmol) and urea (3.6g, 60mmol) were mixed and stirred and heated to 146 deg.] C for 4 hours ; after completion of the reaction was monitored by TLC, cooled to 80 deg.] C, was slowly added 70ml of water and 70ml of ethanol was stirred for 30 minutes; cooled to room temperature and stirred for 1 hour. The title compound was filtered, absolute ethanol (45 ml of) and recrystallized from 50 deg.] C overnight and dried in vacuo to give 8.0g white solid 4- [2- (4-methylphenyl) phenyl] piperidine-2,6 dione (melting point: 164-166 ℃), yield 86%.
10 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine-2,6-dione Example
A step of preparing the compound 3- [2 (4-methylphenyl) phenyl] glutaric acid (19.8g, 60mmol) and urea (21.6g, 360mmol) were mixed and stirred and heated to 144 deg.] C for 4 hours; after completion of the reaction was monitored by TLC, cooled to 100 deg.] C, slowly added water 140ml 140ml ethanol and stirred for 30 min; cooled to room temperature and stirred for 1 hour. The title compound was filtered, absolute ethanol (350ml) and recrystallized from 50 deg.] C overnight and dried in vacuo to give a white solid 16.5g of 4- [2- (4-methylphenyl) phenyl] piperidine-2,6 dione (melting point: 164-166 ℃), yield 88%.
Example 11 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine
Tetrahydro lithium aluminum (5.1g, 39mmol) with 140ml of tetrahydrofuran were mixed and stirred ice bath cooled to 8 ℃, under nitrogen, was added dropwise 4- (2-mercapto-methylphenyl) piperidine-2,6-phenyl one (7g) in tetrahydrofuran (140ml) solution, so that the temperature does not exceed 20 ℃; dropping was completed, the reaction at room temperature for 5 hours. The reaction solution was cooled in an ice-water bath, was slowly added dropwise 30ml of water, stirred for 20 minutes. The reaction mixture was added sodium sulfate (20g), stirred for 30 minutes. Filtered and the filtrate was concentrated to give a colorless liquid (4.5g), cooled to solidify to a white solid of 4- [2- (4-methylphenyl) phenyl] piperidine.
Example 12 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine
The reaction flask was added 100ml four 1mol / l borane tetrahydrofuran solution (40ml, 40mmol), cooled to ice bath 5 ℃; under nitrogen was added dropwise 4- (2-mercapto-methylphenyl) piperidine-2-phenyl , 6-dione (3.1g) in tetrahydrofuran (40ml) solution, so that the temperature does not exceed 10 ℃; dropping was completed, the reaction at room temperature for 20 hours. The reaction solution was cooled to 0 deg.] C, and slowly added dropwise 1mol / l HCl (30mL), dropwise finished warming at reflux for 5 hours; of THF was removed and concentrated, 30ml of ethyl acetate and washed with an aqueous solution, a saturated aqueous sodium bicarbonate was added to adjust the pH> 10 , followed by addition of 50ml of ethyl acetate, the organic phase was dried, filtered and concentrated to give 1.8g of a colorless liquid, and cooled to solidify to a white solid of 4- [2- (4-methyl) phenyl] piperidine.
Example 13 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine
The a 2 mol / L the BH 3 .CH 3 the SCH 3 (20 mL) and diethylene glycol dimethyl ether 20ml were mixed and stirred ice bath cooled to 10 ℃, solution of 4- (2-mercapto-methyl-phenyl) phenylpiperidine pyridine 2,6-dione (3.1g) in diethylene glycol dimethyl ether (60ml) solution, so that the temperature does not exceed 20 ℃; dropping was completed, the reaction at room temperature 0.5 hours, then slowly heated to 120 deg.] C for 10 hours. The reaction solution was cooled to 0 deg.] C, and slowly added dropwise 30ml of methanol, a dropping was completed, the mixture was stirred overnight at room temperature; was added 4mol / l HCl / EA (10ml ), was heated to 100 deg.] C for 4 hours; the resulting residue was distilled under reduced pressure was dissolved in 30ml water, saturated aqueous sodium bicarbonate was added to adjust the pH> 10, followed by addition of 50ml of ethyl acetate, the organic phase was dried, filtered and concentrated to give a pale red liquid; after column chromatography (hexane – acetic acid – ethanol 10 : 1.5: 0.5) to give a white solid (0.9g) 4- [2- (4- methylphenylsulfanyl) phenyl] piperidine after purification.
14 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine hydrochloride Example
The step resulting 4- [2- (4-methylphenyl) phenyl] piperidine (4g, 14mmol) was added to absolute ethanol (30ml) and heated to 50 deg.] C to dissolve; 4mol slowly added dropwise / l hydrogen chloride – ethyl acetate solution (4ml), 40 minutes with the reaction temperature; cooled to 5-10 ℃ stirred for 2 hours, filtered through a cake when the ethanol (5ml) and washed with 44 ℃ overnight and dried in vacuo to give 3.2 g of white solid 4- [2- (4-methylphenyl) phenyl] piperidine hydrochloride (melting point: 222-225 ℃), 75% yield.
15 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine hydrochloride Example
4- [2- (4-methylphenyl) phenyl] piperidine (4g, 14mmol) was added to acetone (20ml) and heated to 50 deg.] C to dissolve; 37% was gradually added dropwise concentrated hydrochloric acid ( 1.5ml), 40 minutes with the reaction temperature; cooled with stirring to 5-10 ℃ 2 hours, filtered through a cake of acetone (5ml) and washed with 44 ℃ vacuum dried overnight to give 3.6g of white solid 4- [2- ( 4-methylphenyl) phenyl] piperidine hydrochloride (melting point: 224-227 ℃), in 80% yield.
Example 16 Preparation of 4- [2- (4-methylphenyl) phenyl] piperidine hydrochloride embodiment
Tetrahydro Lithium aluminum (19g, 500mmol) and 200ml of tetrahydrofuran were mixed and stirred at room temperature was added dropwise 4- (2-mercapto-methylphenyl) piperidine-2,6-dione phenyl (31.1g, 100mmol) and tetrahydrofuran ( 200ml) solution, the temperature does not exceed 35 ℃; dropping was completed, the reaction heated under reflux for 3 hours. The reaction solution was cooled in an ice-water bath, was slowly added dropwise 100ml of saturated aqueous sodium sulfate solution, stirred for 60 minutes. The reaction mixture was added ethyl acetate (200ml) and anhydrous magnesium sulphate (50g) was stirred for 60 minutes. Filtered and the filtrate was concentrated to give a colorless liquid. Was added to 80ml of acetone and heated to 40 ℃ dissolved, was added quickly 4mol / l hydrogen chloride – ethyl acetate solution (10ml), seeded, stirred for 20 minutes to precipitate a white solid. 40 ℃, slowly dropping the remaining hydrogen chloride – ethyl acetate solution (20ml). Drop Bi, 5-10 ℃ for 3 hours. The filtered cake in acetone (30ml) and washed with 44 ℃ when dried in vacuo overnight to give 20.8g of white solid 4- [2- (4-methylphenyl) phenyl] piperidine hydrochloride (melting point: 225-228 ℃), yield 66%.
TLC:Rf 0.15(chloroform:methanol=9:1);1HNMR(CDCl3):δ6.83(d,J=8.1Hz,1H),6.74(d,J=1.9Hz,1H),6.68(dd,J=8.1,1.9Hz,1H),4.75(m,1H),3.68(s,3H),3.36(m,1H),3.31(br,2H),3.02‐2.94(m,2H),2.58‐2.52(m,2H),1.94‐1.39(m,12H).

References

External links

Patent ID Date Patent Title
US2010144788 2010-06-10 4- [2- (4-METHYLPHENYLSULFANYD-PHENYL] PIPERIDINE WITH COMBINED SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITION FOR THE TREATMENT OF ADHD, MELANCHOLIA, TREATMENT RESISTENT DEPRESSION OR RESIDUAL SYMPTOMS IN DEPRESSION
US2010137366 2010-06-03 4- [2- (4-METHYLPHENYLSULFANYL) PHENYL] PIPERIDINE FOR THE TREATMENT OF IRRITABLE BOWEL SYNDROME (IBS)
US2010105730 2010-04-29 LIQUID FORMULATIONS OF SALTS OF 4-[2-(4-METHYLPHENYLSULFANYL)PHENYL]PIPERIDINE
US7683053 2010-03-23 PHENYL-PIPERAZINE DERIVATIVES AS SEROTONIN REUPTAKE INHIBITORS
US2009264465 2009-10-22 CRYSTALLINE FORMS OF 4- [2- (4-METHYLPHENYLSULFANYL) -PHENYL] PIPERIDINE WITH COMBINED SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITION FOR THE TREATMENT OF NEUROPATHIC PAIN
US7148238 2006-12-12 Phenyl-piperazine derivatives as serotonin reuptake inhibitors
US7144884 2006-12-05 Phenyl-piperazine derivatives as serotonin reuptake inhibitors
US7138407 2006-11-21 Phenyl-piperazine derivatives as serotonin reuptake inhibitors
Patent ID Date Patent Title
US2015073018 2015-03-12 CRYSTALLINE FORMS OF 4-[2-(4-METHYLPHENYLSULFANYL)-PHENYL] PIPERIDINE
US8920840 2014-12-30 Enteric tablet
US2014296290 2014-10-02 THERAPEUTIC USES OF COMPOUNDS HAVING AFFINITY TO THE SEROTONIN TRANSPORTER, SEROTONIN RECEPTORS AND NORADRENALIN TRANSPORTER
US2014163043 2014-06-12 PHENYL-PIPERAZINE DERIVATIVES AS SEROTONIN REUPTAKE INHIBITORS
US2013190352 2013-07-25 CRYSTALLINE FORMS OF 4-[2-(4-METHYLPHENYLSULFANYL)-PHENYL] PIPERIDINE WITH COMBINED SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITION FOR THE TREATMENT OF NEUROPATHIC PAIN
US8476279 2013-07-02 Phenyl-piperazine derivatives as serotonin reuptake inhibitors
US8110567 2012-02-07 PHENYL-PIPERAZINE DERIVATIVES AS SEROTONIN REUPTAKE INHIBITORS
US2011053978 2011-03-03 THERAPEUTIC USES OF COMPOUNDS HAVING AFFINITY TO THE SEROTONIN TRANSPORTER, SEROTONIN RECEPTORS AND NORADRENALIN TRANSPORTER
US2011054178 2011-03-03 PROCESS FOR THE MANUFACTURE OF [PHENYLSULFANYLPHENYL]PIPERIDINES
US2011039890 2011-02-17 4-[2, 3-Difluoro-6-(2-fluoro-4-methyl-phenylsulfanyl)-phenyl]-piperidine
Tedatioxetine
Tedatioxetine.svg
Tedatioxetine ball-and-stick model.png
Systematic (IUPAC) name
4-{2-[(4-methylphenyl)sulfanyl]phenyl}piperidine
Legal status
Legal status
  • Investigational
Identifiers
CAS Number 508233-95-2 Yes
ATC code none
PubChem CID 9878913
ChemSpider 8054590 Yes
KEGG D10170 
Synonyms Lu AA24530; Lu-AA-24530
Chemical data
Formula C18H21NS
Molar mass 283.43 g/mol

//////////////tedatioxetine, WO 2016151328, Lu AA24530, 508233-95-2

CC1=CC=C(C=C1)SC2=CC=CC=C2C3CCNCC3


Filed under: Uncategorized Tagged: 508233-95-2, Lu AA24530, tedatioxetine, WO 2016151328

BMT-145027

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str2

BMT-145027

CAS ?

MF C23H14ClF3N4
MW: 438.0859

3-(4-chloro-3-(trifluoromethyl)phenyl)-4-cyclopropyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile

3-(4-chloro-3- (trifluoromethyl)phenyl)-4-cyclopropyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile

1H NMR (600 MHz, DMSO-d6) δ = 14.46 (br. s., 1H), 8.24 (s, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.84 (dd, J=6.1, 2.7 Hz, 2H), 7.61 – 7.55 (m, 3H), 2.50 – 2.45 (m, 1H), 0.74 – 0.68 (m, 2H), 0.65 – 0.59 (m, 2H).

13C NMR (126 MHz, DMSO-d6) δ 160.5, 155.0, 153.0, 144.1, 138.3, 135.4, 133.9, 132.0, 131.2, 130.3, 129.7, 128.9, 128.9, 128.8, 127.0 (q, J=30.5 Hz), 118.1, 112.4, 103.9, 14.6, 9.4.

LCMS (method A) tR, 2.01 min, MS Anal. Calcd. for [M+H]+ C23H15ClF3N4: 439.09; found: 439.15.

LC/MS HPLC methods: method A: Column: Phenomenex Luna 30 x 2.0 mm 3um; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 2 min; Flow: 1 mL/min.

DETAILS WILL BE UPDATED…………

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Senior Research Investigator II at Bristol-Myers Squibb

Highly effective leader seeking to apply innovative thinking and critical analysis to strategy and scientific challenges. Diverse educational background, including recent MBA studies, provides foundation for excellent communication, collaboration, and team building across organizational functions. Experience includes 13 years of cutting-edge scientific research in a global work environment, specializing in the fields of organic chemistry and drug discovery.

Experience

Senior Research Investigator II

Bristol-Myers Squibb

July 2014 – Present (2 years 4 months)Wallingford, CT

Oncology Discovery Chemistry, Program: Bromodomain and Extra-Terminal Inhibitor Program, undisclosed target

 

 

BMT-145027 is a potent mGluR5 PAM with no inherent mGluR5 agonist activity. BMT-145027 is a non-MPEP site PAM to demonstrate in vivo efficacy. BMT-145027 has mGluR5 PAM EC50 = 47 nM, with fold shit = 3.5, and is effective in mouse NOR. The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling in association with the N-methyl-D-aspartate receptor (NMDAR).

Abstract Image

The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling in association with the N-methyl-d-aspartate receptor (NMDAR). We describe the synthesis of 1H-pyrazolo[3,4-b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs) without inherent agonist activity. A facile and convergent synthetic route provided access to a structurally diverse set of analogues that contain neither the aryl-acetylene-aryl nor aryl-methyleneoxy-aryl elements, the predominant structural motifs described in the literature. Binding studies suggest that members of our new chemotype do not engage the receptor at the MPEP and CPPHA mGluR5 allosteric sites. SAR studies culminated in the first non-MPEP site PAM, 1H-pyrazolo[3,4-b]pyridine 31 (BMT-145027), to improve cognition in a preclinical rodent model of learning and memory.

Development of 1H-Pyrazolo[3,4-b]pyridines as Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators

Matthew D. Hill*, Haiquan Fang, Jeffrey M. Brown, Thaddeus Molski, Amy Easton, Xiaojun Han, Regina Miller, Melissa Hill-Drzewi, Lizbeth Gallagher, Michele Matchett, Michael Gulianello, Anand Balakrishnan, Robert L. Bertekap, Kenneth S. Santone, Valerie J. Whiterock, Xiaoliang Zhuo, Joanne J. Bronson, John E. Macor, and Andrew P. Degnan
Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00292, http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00292

*Tel: 1-203-677-7102. Fax: 1-203-677-7884. E-mail: matthew.hill@bms.com.

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SIMILAR STR

str1

1929593-12-3
C23 H15 F3 N4, 404.39
1H-Pyrazolo[3,4-b]pyridine-5-carbonitrile, 4-cyclopropyl-6-phenyl-3-[4-(trifluoromethyl)phenyl]-
A Multicomponent Approach to Highly Substituted 1H-Pyrazolo[3,4-b]pyridines
Synthesis (2016), 48, (14), 2201-2204.

A Multicomponent Approach to Highly Substituted 1H-Pyrazolo[3,4-b]pyridines

Matthew D. Hill*

  • Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA   Email:matthew.hill@bms.com

DOI: 10.1055/s-0035-1562230

Compound 12 (500 mg, 65% yield: 1H NMR (500 MHz, DMSO-d6 δ 14.41 (br. s., 1H, 7.86 – 7.80 (m, 3H, 7.76 (dt, J=7.1, 1.6 Hz, 1H, 7.61 – 7.51 (m, 5H, 2.48 – 2.45 (m, 1H, 0.73 – 0.66 (m, 2H, 0.62 – 0.57 (m, 2H. 13C NMR (400 MHz, DMSO-d6 δ 159.98, 154.67, 152.15, 144.68, 137.75, 135.74, 132.69, 129.87, 129.71, 129.14, 128.99, 128.34, 128.24, 128.21, 117.61, 111.88, 103.05, 14.01, 8.75. IR (film: 3228 (s, 3052 (w, 2228 (m, 1581 (s, 1555 (s, 1503 (w, 1447 (m, 1284 (m cm–1. HRMS (ESI: m/z [M+H]+ calcd for C22H16N4Cl: 371.1058; found: 371.1053.

Compound 13 (103 mg, 28% yield: 1H NMR (500 MHz, DMSO-d6 δ 14.50 (br. s., 1H, 8.03 (d, J=7.9 Hz, 2H, 7.92 – 7.80 (m, 4H, 7.63 – 7.55 (m, 3H, 2.51 (br. s., 1H, 0.65 (d, J=7.6 Hz, 2H, 0.56 (d, J=4.3 Hz, 2H. MS (ESI: m/z = 405.15 [M+H]+.

 

 

///////////BMT-145027, glutamat mGluR5 novel object recognition positive allosteric modulator,  schizophrenia

c1(c(c(c2c(n1)nnc2c3ccc(c(c3)C(F)(F)F)Cl)C4CC4)C#N)c5ccccc5

ClC(C=C1)=C(C(F)(F)F)C=C1C2=NNC3=C2C(C4CC4)=C(C#N)C(C5=CC=CC=C5)=N3


Filed under: Uncategorized Tagged: BMT-145027

MCC 950

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Image result for MCC950

MCC 950

256373-96-3 (sodium salt); 210826-40-7 (free form).

MCC950; CP-456773; CAS 210826-40-7; DSSTox_CID_27301; DSSTox_RID_82252; DSSTox_GSID_47301;

CP-456,773; CRID3

1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonylurea

C20H24N2O5S
Molecular Weight: 404.47996 g/mol

CP-456773, also known as MCC950 and CRID3, is a potent and selective cytokine release inhibitor and NLRP3 inflammasome inhibitor for the treatment of inflammatory diseases. CP-456773 inhibits interleukin 1β (IL-1β) secretion and caspase 1 processing. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. MCC950 is a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.

Image result for MCC950

Formula C20H23N2NaO5S
MW 426.5
CAS 256373-96-3

sodium ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((4-(2-hydroxypropan-2-yl)furan-2-yl)sulfonyl)amide

Image result for MCC950

PAPER

Identification, Synthesis, and Biological Evaluation of the Major Human Metabolite of NLRP3 Inflammasome Inhibitor MCC950

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00198
*E-mail: uqarob15@uq.edu.au. Fax: +61-7-3346-2090. Phone: +61-7-3346-2204., *E-mail: m.cooper@uq.edu.au. Fax: +61-7-3346-2090. Phone: +61-7-3346-2044.

Abstract

Abstract Image

MCC950 is an orally bioavailable small molecule inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that exhibits remarkable activity in multiple models of inflammatory disease. Incubation of MCC950 with human liver microsomes, and subsequent analysis by HPLC–MS/MS, revealed a major metabolite, where hydroxylation of MCC950 had occurred on the 1,2,3,5,6,7-hexahydro-s-indacene moiety. Three possible regioisomers were synthesized, and coelution using HPLC–MS/MS confirmed the structure of the metabolite. Further synthesis of individual enantiomers and coelution studies using a chiral column in HPLC–MS/MS showed the metabolite was R-(+)- N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (2a). Incubation of MCC950 with a panel of cytochrome P450 enzymes showed P450s 2A6, 2C9, 2C18, 2C19, 2J2, and 3A4 catalyze the formation of the major metabolite 2a, with a lower level of activity shown by P450s 1A2 and 2B6. All of the synthesized compounds were tested for inhibition of NLRP3-induced production of the pro-inflammatory cytokine IL-1β from human monocyte derived macrophages. The identified metabolite 2a was 170-fold less potent than MCC950, while one regioisomer had nanomolar inhibitory activity. These findings also give first insight into the SAR of the hexahydroindacene moiety.

str1

PATENT

WO 2001019390

http://www.google.co.in/patents/WO2001019390A1?cl=en

Synthesis of precursors will be update soon……………


Novel synthesis of 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methylethyl)furan-2-sulfonyl]urea, an antiinflammatory agent
PAPER

Synthetic Communications (2003), 33, (12), 2029-2043.

http://dx.doi.org/10.1081/SCC-120021029

A novel synthesis of the anti-inflammatory agent 1-(1,2,3,5,6,7- hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl] urea 1 is described. Sulfonamide 5 was prepared starting from ethyl 3-furoate 2. Key steps were a one-pot sulfonylation with chlorosulfonic acid in methylene chloride followed by pyridinium salt formation and reaction with phosphorus pentachloride to provide ethyl 2-(chlorosulfonyl)-4-furoate 7. This sulfonyl chloride was treated with ammonium bicarbonate to form sulfonamide 8, followed by treatment with excess methyl magnesium chloride to provide 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide 5. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene 16 was prepared from indan in five steps. The formation of the desired sulfonyl urea was carried out both with the isolated isocyanate 16 and via an in situ method.

1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methylethyl)-furan-2-sulfonylurea 1 has been in development for treatment of inflammation. [1] The synthetic route to furan sulfonamide 5 used by its discoverer Mark Dombroski in Medicinal Chemistry is shown in Sch. 1. The starting material was ethyl 3-furoate 2. This was treated with excess methyl magnesium chloride to provide the 3-furanyl-tertiary alcohol 3. Furan alcohol 3 was deprotonated with methyl lithium followed by s-butyl lithium at low temperature and reacted with liquid sulfur dioxide to generate sulfinic acid 4. Without isolation, sulfinic acid 4 was oxidized to sulfonamide 5 with hydroxylamine O-sulfinic acid via a procedure described by workers at Merck.[2] We were interested in finding a synthesis of furan sulfonamide 5 and its conversion to sulfonylurea 1 that would be suitable for scale up. In this article, we describe the discovery of a better bulk process to sulfonamide 5 from the same starting material and a procedure to form the desired sulfonylurea without isolating the isocyanate of 4-amino-1,2,3,5,6,7-hexahydro-s-indacene.

1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy- 1-methyl-ethyl)-furan-2-sulfonyl Urea (1) ………….. anhydrous sodium salt weighed 4.9 g. mp 239 C. 1 H NMR (D2O, 400 MHz) 7.35 (s, 1), 6.81 (s, 1), 6.65 (s, 1), 2.53 (m, 4), 2.41 (m, 4), 1.73 (m, 4), 1.31 (s, 6). 13C NMR (D2O, 100 MHz) 159.87, 151.82, 143.89, 140.49, 138.77, 134.87, 129.58, 118.38, 112.02, 68.24, 32.67, 30.10, 29.53, 25.34. Anal. calcd. for C20H23N2O5SNa: C, 56.33; H, 5.44; N, 6.57; S, 7.52. Found: C, 56.19; H, 5.40; N, 6.34; S, 7.42. N

CLIPS

Image result for MCC950

Dr Rebecca Coll, PostDoctoral Researcher, Inflammasome Lab, UQ Fellow

Rebecca completed her PhD research under Prof. Luke O’Neill in Trinity College Dublin at one of the leading laboratories in the innate immunity field. For her work on the regulation of TLR signalling she received the International Endotoxin and Innate Immunity Society Young Investigator Award in 2012. However, her main research focus has been inflammasomes and their therapeutic targeting by small molecule drugs. Her recent first author publication on MCC950 in Nature Medicine has been widely acclaimed (the subject of seven commentaries in leading journals and attention from 24 international news outlets) and is already a highly cited paper. She joined the Schroder group in May 2014 with the goal of defining the molecular target of MCC950 as part of a broader collaboration between the Schroder, Cooper and O’Neill labs.

Email: r.coll@imb.uq.edu.au

Office Telephone: +61 7 3346 2351

Lab Telephone: +61 7 3346 2071

Institute for Molecular Bioscience

Google Scholar

Research Gate

Researcher ID

A collaboration between scientists from Dublin’s Trinity College (Ireland) and the University of Queensland (Australia) identified a compound able to inhibit an inflammatory process common to many diseases, including Alzheimer’s disease. The study entitled “A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases” was published on line in the journal Nature Medicine.

Pathogenesis of several diseases, including Alzheimer’s, have a strong inflammatory component. Inflammatory processes can be triggered by molecules of the NOD-like receptor (NLR) family such as NLRP3. Once activated, this molecule leads to a cascade of events known as the NLRP3 inflammasome that ultimately causes the production of inflammatory factors. Aberrant activation of NLRP3 is responsible for increased inflammatory responses in complex diseases such as multiple sclerosis, Muckle-Wells syndrome, type 2 diabetes, Alzheimer’s disease and atherosclerosis.

Targeting this molecule can overcome the side effects of other anti-inflammatory drugs commonly used: “Drugs like aspirin or steroids can work in several diseases, but can have side effects or be ineffective. What we have found is a potentially transformative medicine, which targets what appears to be the common disease-causing process in a myriad of inflammatory diseases,” said Luke A J O’Neill, one of the team leaders.

Previous studies identified NLRP3 inhibitors, though neither very potent nor specific. This research team now identified a specific inhibitor of NLRP3 inflammasome, the molecule MCC950. They observed that it inhibits NLRP3 in mouse models of multiple sclerosis with consequent attenuation of disease progression. MCC950 also blocks production of inflammatory factors in blood samples from patients with a severe inflammatory disorder, Muckle-Wells syndrome. These results demonstrated the pharmaceutical potential of this specific NLRP3 inhibitor.

“MCC950 is blocking what was suspected to be a key process in inflammation. There is huge interest in NLRP3 both among medical researchers and pharmaceutical companies and we feel our work makes a significant contribution to the efforts to find new medicines to limit it,” said Rebecca Coll, the paper’s first author.

The researchers were able to demonstrate the potential of MCC950 in multiple sclerosis, an inflammatory disease of the central nervous system (CNS). However, the target for MCC950 is strongly implicated in other diseases of the CNS such as Alzheimer’s and Parkinson’s diseases indicating that it has the potential to treat all of these conditions. The fact that MCC950 can be orally administered further enhances the potential of this molecule as a therapeutic drug.

“MCC950 is able to be given orally and will be cheaper to produce than current protein-based treatments, which are given daily, weekly, or monthly by injection. Importantly, it will also have a shorter duration in the body, allowing clinicians to stop the anti-inflammatory action of the drug if the patient ever needed to switch their immune response back to 100% in order to clear an infection.” said Matt Cooper, chemist and also co-senior author in this study.

REFERENCES

1: Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015 Nov 5;6:262. doi: 10.3389/fphar.2015.00262. eCollection 2015. Review. PubMed PMID: 26594174; PubMed Central PMCID: PMC4633676.

2: Baker PJ, Boucher D, Bierschenk D, Tebartz C, Whitney PG, D’Silva DB, Tanzer MC, Monteleone M, Robertson AA, Cooper MA, Alvarez-Diaz S, Herold MJ, Bedoui S, Schroder K, Masters SL. NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5. Eur J Immunol. 2015 Oct;45(10):2918-26. doi: 10.1002/eji.201545655. Epub 2015 Aug 24. PubMed PMID: 26173988.

3: Krishnan SM, Dowling JK, Ling YH, Diep H, Chan CT, Ferens D, Kett MM, Pinar A, Samuel CS, Vinh A, Arumugam TV, Hewitson TD, Kemp-Harper BK, Robertson AA, Cooper MA, Latz E, Mansell A, Sobey CG, Drummond GR. Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice. Br J Pharmacol. 2016 Feb;173(4):752-65. doi: 10.1111/bph.13230. Epub 2015 Jul 31. PubMed PMID: 26103560; PubMed Central PMCID: PMC4742291.

4: Groß CJ, Groß O. The Nlrp3 inflammasome admits defeat. Trends Immunol. 2015 Jun;36(6):323-4. doi: 10.1016/j.it.2015.05.001. Epub 2015 May 16. PubMed PMID: 25991463.

5: Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, Cooper MA, O’Neill LA. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015 Mar;21(3):248-55. doi: 10.1038/nm.3806. Epub 2015 Feb 16. PubMed PMID: 25686105; PubMed Central PMCID: PMC4392179.

Patent ID Date Patent Title
US2016008420 2016-01-14 Treatment Of HIV-1 Infection And AIDS
US2015343011 2015-12-03 Treatment Of HIV-1 Infection And AIDS
US2005064519 2005-03-24 Methods of using GST-Omega-2
US2003143230 2003-07-31 Combination of an IL-1/18 inhibitor with a TNF inhibitor for the treatment of inflammation
EP0964849 2003-06-04 SULFONYL UREA DERIVATIVES AND THEIR USE IN THE CONTROL OF INTERLEUKIN-1 ACTIVITY
US6433009 2002-08-13 Sulfonyl urea derivatives and their use in the control of interleukin-1 activity
US6166064 2000-12-26 Sulfonyl urea derivatives and their use in the control of interleukin-1 activity
US6022984 2000-02-08 Efficient synthesis of furan sulfonamide compounds useful in the synthesis of new IL-1 inhibitors
EP0976742 2000-02-02 A synthesis of furan sulfonamide compounds useful in the synthesis of IL-1 inhibitors
WO9832733 1998-07-30 SULFONYL UREA DERIVATIVES AND THEIR USE IN THE CONTROL OF INTERLEUKIN-1 ACTIVITY

/////////cytochrome P450, inflammasome, MCC950, metabolite, microsome NLRP3MCC950, CP-456,773,  CRID3, 256373-96-3,  210826-40-7 , 

CC(C)(C1=COC(=C1)S(=O)(=O)NC(=O)NC2=C3CCCC3=CC4=C2CCC4)O


Filed under: Uncategorized Tagged: 210826-40-7, 256373-96-3, 773, CP-456, CRID3, cytochrome P450, inflammasome, MCC950, metabolite, microsome, NLRP3

BMS-986115

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Figure imgf000170_0002

BMS-986115
CAS 1584647-27-7

(2R,3S)-N-((3S)-5-(3-Fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin- 3-yl)-2, -bis(3,3,3-trifluoropropyl)succinamide

MW: 574.4945,  C26-H25-F7-N4-O3, UNII: LSK1L593UU

10-Nitrooleate, CTK3B7458, CTK3C3167, 9-Octadecenoic acid, 10-nitro-, 875685-46-4, AG-L-63109, 9-Octadecenoic acid, 10-nitro-, (9E)-, 88127-53-1

FOR advanced solid tumors

  • Originator Bristol-Myers Squibb
  • Class Antineoplastics
  • Mechanism of Action Amyloid precursor protein secretase inhibitors; Notch signalling pathway inhibitors
  • Phase I Solid tumours

Most Recent Events

  • 30 Aug 2016Bristol-Myers Squibb terminates a phase I trial for Solid tumours (late-stage disease, second-line therapy or greater) in USA, Australia and Canada (NCT01986218)
  • 25 Jan 2016Bristol-Myers Squibb completes enrolment in its phase I trial for Solid tumours in USA, Australia and Canada (NCT01986218)
  • 31 Dec 2013Phase-I clinical trials in Solid tumours (late-stage disease) in Canada & Australia (Oral)

DETAILS WILL BE UPDATED SOON………….

BMS-986115 is an orally bioavailable, gamma secretase (GS) and pan-Notch inhibitor, with potential antineoplastic activity. Upon administration, GS/pan-Notch inhibitor BMS 986115 binds to GS and blocks the proteolytic cleavage and release of the Notch intracellular domain (NICD), which would normally follow ligand binding to the extracellular domain of the Notch receptor. This prevents both the subsequent translocation of NICD to the nucleus to form a transcription factor complex and the expression of Notch-regulated genes. This results in the induction of apoptosis and the inhibition of growth of tumor cells that overexpress Notch. Overexpression of the Notch signaling pathway plays an important role in tumor cell proliferation and survival

 

Bristol-Myers Squibb
Ashvinikumar V. Gavai, George V. Delucca,Daniel O’MALLEY, Patrice Gill, Claude A. Quesnelle, Brian E. Fink, Yufen Zhao,Francis Y. Lee,
Applicant Bristol-Myers Squibb Company

str2

Ashvinikumar Gavai

Claude Quesnelle

Claude Quesnelle
Senior Research Investigator/Chemist at Bristol-Myers Squibb

str2

RICHARD LEE

 

 

 

Patrice Gill

Patrice Gill

Research scientist at BMS

Dan O’Malley (Rice University)
Currently: Bristol-Myers Squibb

PICTURES WILL BE UPDATED………….

useful for the treatment of conditions related to the Notch pathway, such as cancer and other proliferative diseases.

Notch signaling has been implicated in a variety of cellular processes, such as cell fate specification, differentiation, proliferation, apoptosis, and angiogenesis. (Bray, Nature Reviews Molecular Cell Biology, 7:678-689 (2006); Fortini, Developmental Cell 16:633-647 (2009)). The Notch proteins are single-pass heterodimeric transmembrane molecules. The Notch family includes 4 receptors, NOTCH 1-4, which become activated upon binding to ligands from the DSL family (Delta-like 1, 3, 4 and Jagged 1 and 2).

The activation and maturation of NOTCH requires a series of processing steps, including a proteolytic cleavage step mediated by gamma secretase, a multiprotein complex containing Presenilin 1 or Presenilin 2, nicastrin, APH1, and PEN2. Once NOTCH is cleaved, NOTCH intracellular domain (NICD) is released from the membrane. The released NICD translocates to the nucleus, where it functions as a transcriptional activator in concert with CSL family members (RBPSUH, “suppressor of hairless”, and LAG1). NOTCH target genes include HES family members, such as HES- 1. HES- 1 functions as transcriptional repressors of genes such as HERP 1 (also known as HEY2), HERP2 (also known as HEY1), and HATH1 (also known as ATOH1).

The aberrant activation of the Notch pathway contributes to tumorigenesis. Activation of Notch signaling has been implicated in the pathogenesis of various solid tumors including ovarian, pancreatic, as well as breast cancer and hematologic tumors such as leukemias, lymphomas, and multiple myeloma. The role of Notch inhibition and its utility in the treatment of various solid and hematological tumors are described in Miele, L. et al, Current Cancer Drug Targets, 6:313-323 (2006); Bolos, V. et al, Endocrine Reviews, 28:339-363 (2007); Shih, I.-M. et al, Cancer Research, 67: 1879- 1882 (2007); Yamaguchi, N. et al., Cancer Research, 68: 1881-1888 (2008); Miele, L., Expert Review Anti-cancer Therapy, 8: 1 197-1201 (2008); Purow, B., Current Pharmaceutical Biotechnology, 10: 154-160 (2009); Nefedova, Y. et al, Drug Resistance Updates, 1 1 :210-218 (2008); Dufraine, J. et al, Oncogene, 27:5132-5137 (2008); and Jun, H.T. et al, Drug Development Research, 69:319-328 (2008).

There remains a need for compounds that are useful as Notch inhibitors and that have sufficient metabolic stability to provide efficacious levels of drug exposure. Further, there remains a need for compounds useful as Notch inhibitors that can be orally or intravenously administered to a patient.

U.S. Patent No. 7,053,084 Bl discloses succinoylamino benzodiazepine compounds useful for treating neurological disorders such as Alzheimer’s Disease. The reference discloses that these succinoylamino benzodiazepine compounds inhibit gamma secretase activity and the processing of amyloid precursor protein linked to the formation of neurological deposits of amyloid protein. The reference does not disclose the use of these compounds in the treatment of proliferative diseases such as cancer.

Applicants have found potent compounds that have activity as Notch inhibitors and have sufficient metabolic stability to provide efficacious levels of drug exposure upon intravenous or oral administration. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.

Image result for BMS 906024

Image result for BMS 906024 synthesis

PATENTS

US-20150166489-A1

US-20140087992-A1

PATENT

WO-2014047372-A1

https://www.google.com/patents/WO2014047372A1?cl=en

Figure imgf000041_0001

Figure imgf000042_0001

Scheme 3

Figure imgf000044_0001
Figure imgf000045_0001

XII XI

Scheme 4

Figure imgf000047_0001

Intermediate S-l : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000053_0001

Intermediate S-IA: 3,3,3-Trifluoro ropyl trifluoromethanesulfonate

Figure imgf000053_0002

[00180] To a cold (-25 °C) stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in DCM (120 mL) was added Tf20 (24.88 mL, 147 mmol) over 3 min, and the mixture was stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-l-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half its volume, then purified by loading directly on a silica gel column (330g ISCO) and the product was eluted with DCM to afford Intermediate S-IA (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDC13) δ ppm 4.71 (2 H, t, J= 6.15 Hz), 2.49-2.86 (2 H, m).

Intermediate S-1B: (4S)-4-Benzyl-3-(5,5,5-trifluoropentanoyl)-l,3-oxazolidin-2-one

Figure imgf000054_0001

[00181] To a stirring solution of 5,5,5-trifluoropentanoic acid (14.76 g, 95 mmol) and DMF (0.146 rriL) in DCM (50 mL) was slowly added oxalyl chloride (8.27 mL, 95 mmol). After 2h, the mixture was concentrated to dryness. A separate flask was changed with (S)-4-benzyloxazolidin-2-one (16.75 g, 95 mmol) in THF (100 mL) and then cooled to -78 °C. To the solution was slowly added n-BuLi (2.5M, 37.8 mL, 95 mmol) over 10 min, stirred for 10 min, and then a solution of the above acid chloride in THF (50 mL) was slowly added over 5 min. The mixture was stirred for 30 min, and then warmed to room temperature. The reaction was quenched with sat aq NH4C1. Next, 10% aq LiCl was then added to the mixture, and the mixture was extracted with Et20. The organic layer was washed with sat aq NaHC03 then with brine, dried (MgSC^), filtered and concentrated to dryness. The residue was purified by Si02 chromatography (ISCO, 330 g column, eluting with a gradient from 100% hexane to 100% EtOAc) to afford the product Intermediate S-IB; (25.25 g, 85%): 1H NMR (400 MHz, CDC13) δ ppm 7.32-7.39 (2 H, m), 7.30 (1 H, d, J= 7.05 Hz), 7.18-7.25 (2 H, m), 4.64-4.74 (1 H, m), 4.17-4.27 (2 H, m), 3.31 (1 H, dd, J= 13.35, 3.27 Hz), 3.00-3.11 (2 H, m), 2.79 (1 H, dd, J= 13.35, 9.57 Hz), 2.16-2.28 (2 H, m), 1.93-2.04 (2 H, m).

Intermediate S-IC: tert- utyl (3R)-3-(((4S)-4-benzyl-2-oxo-l,3-oxazolidin-3- yl)carbonyl)-6,6,6-trifluoroh xanoate

Figure imgf000054_0002

[00182] To a cold (-78 °C), stirred solution of Intermediate S-IB (3.03 g, 9.61 mmol) in THF (20 mL) was added NaHMDS (1.0M in THF) (10.6 mL, 10.60 mmol) under a nitrogen atmosphere. After 2 hours, tert-butyl 2-bromoacetate (5.62 g, 28.8 mmol) was added neat via syringe at -78 °C and stirring was maintained at the same temperature. After 6 hours, the reaction mixture was warmed to room temperature. The reaction mixture was partitioned between saturated NH4C1 and EtOAc. The organic phase was separated, and the aqueous phase was extracted with EtOAc (3x). The combined organics were washed with brine, dried (Na2s04), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO

CombiFlash Rf, 5% to 100% solvent A/B = hexanes/EtOAc, REDISEP® Si02 120g). Concentration of the appropriate fractions provided Intermediate S-1C (2.79 g, 67.6%) as a colorless viscous oil: 1H NMR (400 MHz, CDC13) δ ppm 7.34 (2 H, d, J= 7.30 Hz), 7.24-7.32 (3 H, m), 4.62-4.75 (1 H, m, J= 10.17, 6.89, 3.43, 3.43 Hz), 4.15-4.25 (3 H, m), 3.35 (1 H, dd, J= 13.60, 3.27 Hz), 2.84 (1 H, dd, J= 16.62, 9.57 Hz), 2.75 (1 H, dd, J = 13.35, 10.07 Hz), 2.47 (1 H, dd, J= 16.62, 4.78 Hz), 2.11-2.23 (2 H, m), 1.90-2.02 (1 H, m), 1.72-1.84 (1 H, m), 1.44 (9 H, s).

Intermediate S-ID: (2R)-2-( -tert-Butoxy-2-oxoethyl)-5,5,5-trifluoropentanoic acid

Figure imgf000055_0001

[00183] To a cool (0 °C), stirred solution of Intermediate S-1C (2.17 g, 5.05 mmol) in THF (50 mL) and water (15 mL) was added a solution of LiOH (0.242 g, 10.11 mmol) and H202 (2.065 mL, 20.21 mmol) in H20 (2 mL). After 10 min, the reaction mixture was removed from the ice bath, stirred for lh, and then cooled to 0 °C. Saturated aqueous NaHCC”3 (25 mL) and saturated aqueous Na2s03 (25 mL) were added to the reaction mixture, and the mixture was stirred for 10 min, and then partially concentrated. The resulting mixture was extracted with DCM (2x), cooled with ice and made acidic with cone. HC1 to pH 3. The mixture was saturated with solid NaCl, extracted with EtOAc (3x), and then dried over MgS04, filtered and concentrated to a colorless oil to afford Intermediate S-ID, 1.2514g, 92%): 1H NMR (400 MHz, CDCI3) δ ppm 2.83-2.95 (1 H, m), 2.62-2.74 (1 H, m), 2.45 (1 H, dd, J= 16.62, 5.79 Hz), 2.15-2.27 (2 H, m), 1.88-2.00 (1 H, m), 1.75-1.88 (1 H, m), 1.45 (9 H, s). Intermediate S-l : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid, and Intermediate S-1E: (2R,3R)-3-(tert-butoxycarbonyl)- 6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid

Figure imgf000056_0001

(S-1E)

[00184] To a cold (-78 °C) stirred solution of Intermediate S-1D (5 g, 18.50 mmol) in THF (60 mL) was slowly added LDA (22.2 mL, 44.4 mmol, 2.0M) over 7 min. After stirring for 2 hr, Intermediate S- 1 A (6.38 g, 25.9 mmol) was added to the reaction mixture over 3 min. After 60 min, the reaction mixture was warmed to -25 °C

(ice/MeOH/dry ice) and stirred for an additional 60 min at which time sat aq NH4C1 was added. The separated aqueous phase was acidified with IN HC1 to pH 3, and then extracted with Et20. The combined organic layers were washed with brine (2x), dried over MgS04, filtered and concentrated to provide a 1 :4 (II :I1E) mixture (as determined by 1H NMR) of Intermediate S-l and Intermediate S-1E (6.00 g, 89%) as a pale yellow solid. 1H NMR (500 MHz, CDC13) δ ppm 2.81 (1 H, ddd, J = 10.17, 6.32, 3.85 Hz), 2.63- 2.76 (1 H, m), 2.02-2.33 (4 H, m), 1.86-1.99 (2 H, m), 1.68-1.85 (2 H, m), 1.47 (9 H, s).

[00185] To a cold (-78 °C), stirred solution of a mixture of Intermediate S-l and Intermediate S-1E (5.97 g, 16.30 mmol) in THF (91 mL) was added LDA (19 mL, 38.0 mmol, 2.0M in THF/hexane/ethyl benzene) dropwise via syringe over 10 min (internal temperature never exceeded -65 °C, J-KEM® probe in reaction solution). The mixture was stirred for 15 min, and then warmed to room temperature (24 °C water bath), stirred for 15 min, and then cooled to -78 °C for 15 min. To the reaction mixture was added Et2AlCl (41 mL, 41.0 mmol, 1M in hexane) via syringe (internal temperature never exceeded -55 °C), and the mixture was stirred for 10 min, and then warmed to room temperature (24 °C bath) for 15 min and then back to -78 °C for 15 min. Meanwhile, a 1000 mL round bottom flask was charged with MeOH (145 mL) and precooled to -78 °C. With vigorous stirring the reaction mixture was transferred via cannula over 5 min to the MeOH. The flask was removed from the bath, ice was added followed by the slow addition of IN HC1 (147 mL, 147 mmol). Gas evolution was observed as the HC1 was added. The reaction mixture was allowed to warm to room temperature during which the gas evolution subsided. The reaction mixture was diluted with EtOAc (750 mL), saturated with NaCl, and the organic phase was separated, washed with a solution of potassium fluoride (8.52 g, 147 mmol) and IN HC1 (41 mL, 41.0 mmol) in water (291 mL), brine (100 mL), and then dried (Na2s04), filtered and concentrated under vacuum. 1H NMR showed the product was a 9: 1 mixture of Intermediate S-l and Intermediate S- 1E. The enriched mixture of Intermediate S-l and Intermediate S-1E (6.12 g, >99% yield) was obtained as a dark amber solid: 1H NMR (400 MHz, CDC13) δ ppm 2.64-2.76 (2 H, m), 2.04-2.35 (4 H, m), 1.88-2.00 (2 H, m), 1.71-1.83 (2 H, m), 1.48 (9 H, s).

Alternate procedure to make Intermediate S-l :

Intermediate S-IF: (2R,3 -1 -Benzyl 4-tert-butyl 2,3-bis(3,3,3-trifluoropropyl)succinate

Figure imgf000057_0001

[00186] To a stirred solution of a 9: 1 enriched mixture of Intermediate S-l and Intermediate S-1E (5.98 g, 16.33 mmol) in DMF (63 mL) were added potassium carbonate (4.06 g, 29.4 mmol) and benzyl bromide (2.9 mL, 24.38 mmol), the mixture was then stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (1000 mL), washed with 10% LiCl (3×200 mL), brine (200 mL), dried (Na2S04), filtered, concentrated, and then dried under vacuum. The residue was purified by Si02 chromatography using a toluene:hexane gradient. Diastereomerically purified

Intermediate S-IF (4.81g, 65%) was obtained as a colorless solid: 1H NMR (400 MHz, chloroform-d) δ 7.32-7.43 (m, 5H), 5.19 (d, J= 12.10 Hz, 1H), 5.15 (d, J= 12.10 Hz, 1H), 2.71 (dt, J= 3.52, 9.20 Hz, 1H), 2.61 (dt, J= 3.63, 9.63 Hz, 1H), 1.96-2.21 (m, 4H), 1.69-1.96 (m, 3H), 1.56-1.67 (m, 1H), 1.45 (s, 9H).

Intermediate S-l : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000058_0001

[00187] To a solution of Intermediate S-1F (4.81 g, 10.54 mmol) in MeOH (100 mL) was added 10% palladium on carbon (wet, Degussa type, 568.0 mg, 0.534 mmol) in a H2– pressure flask. The vessel was purged with N2 (4x), then purged with H2 (2x), and finally, pressurized to 50 psi and shaken overnight. The reaction vessel was

depressurized and purged with nitrogen. The mixture was filtered through CELITE®, washed with MeOH and then concentrated and dried under vacuum. Intermediate S-1 (3.81 g, 99% yield)) was obtained as a colorless solid: 1H NMR (400 MHz, chloroform-d) δ 2.62-2.79 (m, 2H), 2.02-2.40 (m, 4H), 1.87-2.00 (m, 2H), 1.67-1.84 (m, 2H), 1.48 (s, 9H).

Alternate procedure to make Intermediate S-1 :

Intermediate S-1 : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000058_0002

[00188] Intermediate S-1 as a mixture with Intermediate S-IE was prepared in a similar procedure as above from Intermediate S-1D to afford a 1 :2.2 mixture of

Intermediate S-1 and Intermediate S-IE (8.60 g, 23.48 mmol), which was enriched using LDA (2.0 M solution in THF, ethyl benzene and heptane, 28.2 mL, 56.4 mmol) and diethyl aluminum chloride (1.0 M solution in hexane, 59 mL, 59.0 mmol) in THF (91 mL). After workup as described above, the resulting residue was found to be a 13.2: 1 (by 1H NMR) mixture of Intermediate S-1 and Intermediate S-IE, which was treated as follows: The crude material was dissolved in MTBE (43 mL). Hexanes (26 mL) were slowly charged to the reaction mixture while maintaining a temperature below 30 °C. The reaction mixture was stirred for 10 min. Next, tert-butylamine (2.7 mL, 1.1 eq) was charged slowly over a period of 20 minutes while maintaining a temperature below 30 °C. This addition was observed to be exothermic. The reaction mixture was stirred for 2 hrs below 30 °C and then filtered. The solid material was washed with 5:3 MTBE: hexane (80 mL), and the filtrate was concentrated and set aside. The filtered solid was dissolved in dichloromethane (300 mL), washed with IN HC1 (lOOmL), and the organic layer was washed with brine (100 mL x 2), and then concentrated under reduced pressure below 45 °C to afford Intermediate S-l (5.46 g, 64%).

A second alternate procedure for preparing Intermediate S-l :

Intermediate S-1G: tert- utyl 5,5,5-trifluoropentanoate

Figure imgf000059_0001

[00189] To a stirred solution of 5,5,5-trifluoropentanoic acid (5 g, 32.0 mmol) in THF (30 mL) and hexane (30 mL) at 0 °C, was added tert-butyl 2,2,2-trichloroacetimidate (11.46 mL, 64.1 mmol). The mixture was stirred for 15 min at 0 °C. Boron trifluoride etherate (0.406 mL, 3.20 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. To the clear reaction mixture was added solid NaHC03 (5 g) and stirred for 30 min. The mixture was filtered through MgSC^ and washed with hexanes (200 mL). The solution was allowed to rest for 45 min, and the resulting solid material was removed by filtering on the same MgSC^ filter again, washed with hexanes (100 mL) and concentrated under reduced pressure without heat. The volume was reduced to about 30 mL, filtered through a clean fritted funnel, washed with hexane (5 mL), and then concentrated under reduced pressure without heat. The resulting neat oil was filtered through a 0.45μιη nylon membrane filter disk to provide Intermediate S-1G (6.6 g, 31.4 mmol 98% yield) as a colorless oil: 1H NMR (400 MHz, CDC13) δ ppm 1.38 (s, 9 H) 1.74-1.83 (m, 2 H) 2.00-2.13 (m, 2 H) 2.24 (t, J= 7.28 Hz, 2 H). Intermediate S-1H: (4S)-4-(Propan-2-yl)-3-(5,5,5-trifluoropentanoyl)-l,3-oxazolidin-2- one

Figure imgf000060_0001

[00190] To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min. The solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)-l,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at -78 °C was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride, dissolved in THF (20 mL), was added via cannula over 15 min. The reaction mixture was warmed to 0 °C, and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4C1, and the mixture was extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2s04), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B = hexanes/EtOAc, REDISEP® Si02 120g). Concentration of the appropriate fractions provided Intermediate S-1H (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDC13) δ ppm 4.44 (1 H, dt, J= 8.31, 3.53 Hz), 4.30 (1 H, t, J= 8.69 Hz), 4.23 (1 H, dd, J= 9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J= 13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J= 7.05 Hz), 0.88 (3 H, d, J= 6.80 Hz).

Intermediate S-1I: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2- oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate, and Intermediate S-U: (2R,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2- (3 ,3 ,3 -trifluoropropyl)hexanoate

Figure imgf000061_0001

[00191] To a cold (-78 °C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under a nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol). The mixture was then warmed to 0 °C to give a 0.5M solution of LDA. A separate vessel was charged with Intermediate S-1H (2.45 g, 9.17 mmol). The material was azeotroped twice with benzene (the RotoVap air inlet was fitted with a nitrogen inlet to completely exclude humidity), and then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to -78 °C, was added the LDA solution (21.0 mL, 10.5 mmol) and the mixture was stirred at -78 °C for 10 min, then warmed to 0 °C for 10 min., and then cooled to -78 °C. To a separate reaction vessel containing Intermediate S-1G (3.41 g, 16.07 mmol), also azeotroped twice with benzene, was added toluene (15.3 mL), cooled to -78 °C and LDA (37.0 mL, 18.5 mmol) was added. The resulting solution was stirred at -78 °C for 25 min. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate and stirred at -78 °C for an additional 5 min, at which time the septum was removed and solid powdered bis(2- ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reaction vessel and the septum was replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40 °C) with rapid swirling and with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 min, was then poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2s04), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B = hexanes/EtOAc, REDISEP® Si02 120g). Concentration of the appropriate fractions provided a mixture of Intermediate S- II and Intermediate S-1J (2.87 g, 66%) as a pale yellow viscous oil. 1H NMR showed the product was a 1.6: 1 mixture of diastereomers S-1LS-1J as determined by the integration of the multiplets at 2.74 and 2.84 ppm: 1H NMR (400 MHz, CDC13) δ ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.01 (1 H, ddd, J= 9.54, 6.27, 3.51 Hz), 2.84 (1 H, ddd, J = 9.41, 7.28, 3.64 Hz), 2.74 (1 H, ddd, J= 10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m, J = 10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3 H, m), 1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m). Intermediate S-1 : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid, and Intermediate S-IE: (2R,3R)-3-(tert-Butoxycarbonyl)- 6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid

Figure imgf000062_0001

(S-IE)

[00192] To a cool (0 °C), stirred solution of Intermediate S-1I and Intermediate S-1 J (4.54 g, 9.51 mmol) in THF (140 mL) and water (42 mL) were sequentially added hydrogen peroxide (30% in water) (10.3 g, 91 mmol) and LiOH (685.3 mg, 28.6 mmol). The mixture was stirred for 1 hr. At this time the reaction vessel was removed from the cold bath and then stirred for 1.5 hr. To the reaction mixture were added saturated NaHC03 (45 mL) and saturated Na2s03 (15 mL), and then the mixture was partially concentrated under reduced pressure. The resulting crude solution was extracted with DCM (3x). The aqueous phase was acidified to pH~l-2 with IN HC1, extracted with DCM (3x) and then EtOAc (lx). The combined organics were washed with brine, dried (Na2s04), filtered and concentrated under reduced pressure to provide a mixture of Intermediates S-1 and S-IE (3.00 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDC13) δ ppm 2.76-2.84 (1 H, m, diastereomer 2), 2.64-2.76 (3 H, m), 2.04-2.35 (8 H, m), 1.88- 2.00 (4 H, m), 1.71-1.83 (4 H, m), 1.48 (9 H, s, diastereomer 1), 1.46 (9 H, s,

diastereomer 2); 1H NMR showed a 1.7: 1 mixture of S-1E:S-1F by integration of the peaks for the t-butyl groups. Intermediate S-1 : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid, and Intermediate S-IF: (2R,3R)-3-(fert-Butoxycarbonyl)- 6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid

Figure imgf000063_0001

[00193] To a cold (-78 °C) stirred solution of diisopropylamine (1.7 mL, 11.93 mmol) in THF (19 mL) under a nitrogen atmosphere was added n-BuLi (2.5M in hexanes) (4.8 mL, 12.00 mmol). The mixture was stirred for 5 min and then warmed to 0 °C. In a separate vessel, to a cold (-78 °C) stirred solution of the mixture of Intermediates S-1 and S-1E (1.99 g, 5.43 mmol) in THF (18 mL) was added the LDA solution prepared above via cannula slowly over 25 min. The mixture was stirred for 15 min, then warmed to room temperature (placed in a 24 °C water bath) for 15 min, and then again cooled to -78 °C for 15 min. To the reaction mixture was added Et2AlCl (1M in hexane) (11.4 mL, 11.40 mmol) via syringe. The mixture was stirred for 10 min, warmed to room

temperature for 15 min and then cooled back to -78 °C for 15 min. Methanol (25 mL) was rapidly added, swirled vigorously while warming to room temperature, and then concentrated to ~l/4 the original volume. The mixture was dissolved in EtOAc and washed with IN HC1 (50 mL) and ice (75 g). The aqueous phase was separated and extracted with EtOAc (2x). The combined organics were washed with a mixture of KF (2.85g in 75 mL water) and IN HC1 (13 mL) [resulting solution pH 3-4], then with brine, dried (Na2s04), filtered and concentrated under reduced pressure to give a 9: 1 (S-LS-1E) enriched diastereomeric mixture (as determined by 1H NMR) of Intermediate S-1 and Intermediate S-1E (2.13 g, >99%) as a pale yellow viscous oil: 1H NMR (400 MHz, CDC13) δ ppm 2.64-2.76 (2 H, m), 2.04-2.35 (4 H, m), 1.88-2.00 (2 H, m), 1.71-1.83 (2 H, m), 1.48 (9 H, s).

Intermediate S-2: (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3- fluoropropyl)hexanoic acid

Figure imgf000064_0001

Intermediate S-2: (2R,3S)-3-(tert-Butoxycarbonyl)-7,7,7-trifluoro-2-(3,3,3- trifluoropropyl)heptanoic acid, and Intermediate S-2A: (2R,3R)-3-(tert-Butoxycarbonyl)- 7,7,7-trifluoro-2-(3,3,3-trifluoropropyl)heptanoic acid

Figure imgf000064_0002

(S-2A)

[00194] To a cold (-78 °C), stirred solution of Intermediate S-1D (1.72 g, 6.36 mmol) in THF (30 mL) was slowly added LDA (7.32 mL, 14.6 mmol) over 7 min. After stirring for 1 h, 4,4,4-trifluorobutyltrifluoromethanesulfonate (2.11 g, 8.11 mmol) was added to the reaction mixture over 2 min. After 15 min, the reaction mixture was warmed to -25 °C (ice/MeOH/dry ice) for lh, and then cooled to -78 °C. After 80 min, the reaction was quenched with a saturated aqueous NH4C1 solution (10 mL). The reaction mixture was further diluted with brine and the solution was adjusted to pH 3 with IN HC1. The aqueous layer was extracted with ether. The combined organics were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide a mixture of Intermediates S-2 and S-2A (2.29 g, 95%) as a colorless oil. 1H NMR (400MHz, chloroform-d) δ 2.83-2.75 (m, 1H), 2.64 (ddd, J = 9.9, 6.7, 3.6 Hz, 1H), 2.32-2.03 (m, 5H), 1.98-1.70 (m, 3H), 1.69-1.52 (m, 3H), 1.50-1.42 (m, 9H). 1H NMR showed a 1 :4.5 mixture (S-2:S-2A) of diastereomers by integration of the peaks for the t- Bu groups.

Intermediate S-2: (2R,3S)-3-(fert-Butoxycarbonyl)-7,7,7-trifluoro-2-(3,3,3- trifluoropropyl)heptanoic acid, and Intermediate S-2A: (2R,3R)-3-(tert-Butoxycarbonyl)- 7,7,7-trifluoro-2-(3,3,3-trifluoropropyl)heptanoic acid

Figure imgf000065_0001

[00195] A mixture of Intermediate S-2 and Intermediate S-2A (2.29 g, 6.02 mmol) was dissolved in THF (38 mL) to give a colorless solution which was cooled to -78 °C. Then, LDA (7.23 mL, 14.5 mmol) (2.0M in heptane/THF/ethylbenzene) was slowly added to the reaction mixture over 3 min. After stirring for 15 min, the reaction mixture was placed in a room temperature water bath. After 15 min the reaction mixture was placed back in a -78 °C bath and then diethylaluminum chloride (14.5 mL, 14.5 mmol) (1M in hexane) was added slowly over 5 min. The reaction mixture was stirred at -78 °C. After 15 min, the reaction mixture was placed in a room temperature water bath for 10 min, and then cooled back to -78 °C. After 15 min, the reaction was quenched with MeOH (30.0 mL, 741 mmol), removed from the -78 °C bath and concentrated. To the reaction mixture was added ice and HC1 (60.8 mL, 60.8 mmol) and the resulting mixture was extracted with EtOAc (2x 200 mL). The organic layer was washed with potassium fluoride (3.50g, 60.3 mmol) in 55 mL H20 and 17.0 mL of IN HC1. The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide an enriched mixture of Intermediate S-2 and Intermediate S-2A (2.25g, 98% yield) as a light yellow oil. 1H NMR (400MHz, chloroform-d) δ 2.83-2.75 (m, 1H), 2.64 (ddd, J= 9.9, 6.7, 3.6 Hz, 1H), 2.32-2.03 (m, 5H), 1.98-1.70 (m, 3H), 1.69-1.52 (m, 3H), 1.50-1.42 (m, 9H). 1H NMR showed a 9: 1 ratio in favor of the desired diastereomer Intermediate S-2.

Intermediate S-2B: (2R,3S)-1 -Benzyl 4-tert-butyl 2,3-bis(4,4,4-trifluorobutyl)succinate

Figure imgf000065_0002

[00196] To a stirred 9: 1 mixture of Intermediate S-2 and Intermediate S-2A (2.24 g, 5.89 mmoL) and potassium carbonate (1.60 g, 11.58 mmoL) in DMF (30 mL) was added benzyl bromide (1.20 mL, 10.1 mmoL)). The reaction mixture was stirred at room temperature for 19 h. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with 10% LiCl solution (3 x 100 mL), brine (50 mL), and then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash 0%> to 100% solvent A/B = hexane/EtOAc, REDISEP® Si02 220 g, detecting at 254 nm, and monitoring at 220 nm). Concentration of the appropriate fractions provided Intermediate S-2B (1.59 g, 57.5%). HPLC: RT = 3.863 min (CHROMOLITH® SpeedROD column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), 1H NMR (400MHz, chloroform-d) δ 7.40-7.34 (m, 5H), 5.17 (d, J= 1.8 Hz, 2H), 2.73-2.64 (m, 1H), 2.55 (td, J= 10.0, 3.9 Hz, 1H), 2.16-1.82 (m, 5H), 1.79-1.57 (m, 3H), 1.53-1.49 (m, 1H), 1.45 (s, 9H), 1.37-1.24 (m, 1H).

Intermediate S-2: (2R,3S)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(4,4,4- trifluorobutyl)hexanoic acid

Figure imgf000066_0001

[00197] To a stirred solution of Intermediate S-2B (1.59 g, 3.37 mmoL) in MeOH (10 mL) and EtOAc (10 mL) under nitrogen was added 10%> Pd/C (510 mg). The atmosphere was replaced with hydrogen and the reaction mixture was stirred at room temperature for 2.5 h. The palladium catalyst was filtered off through a 4 μΜ polycarbonate film and rinsed with MeOH. The filtrate was concentrated under reduced pressure to give intermediate S-2 (1.28 g, 99%). 1H NMR (400MHz, chloroform-d) δ 2.76-2.67 (m, 1H), 2.65-2.56 (m, 1H), 2.33-2.21 (m, 1H), 2.17-2.08 (m, 3H), 1.93 (dtd, J= 14.5, 9.9, 5.2 Hz, 1H), 1.84-1.74 (m, 2H), 1.70-1.52 (m, 3H), 1.48 (s, 9H).

Intermediate A- 1 : (2-Amino-3 -methylphenyl)(3 -fluorophenyl)methanone

Figure imgf000067_0001

Intermediate A-1 A: 2-Amino- -methoxy-N,3-dimethylbenzamide

Figure imgf000067_0002

[00198] In a 1 L round-bottomed flask was added 2-amino-3-methylbenzoic acid (11.2 g, 74.1 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (14.45 g, 148 mmol) in DCM (500 mL) to give a pale brown suspension. The reaction mixture was treated with Et3N (35 mL), HOBT (11.35 g, 74.1 mmol) and EDC (14.20 g, 74.1 mmol) and then stirred at room temperature for 24 hours. The mixture was then washed with 10% LiCl, and then acidified with IN HCl. The organic layer was washed successively with 10%> LiCl and aq NaHC03. The organic layer was decolorized with charcoal, filtered, and the filtrate was dried over MgSC^. The mixture was filtered and concentrated to give 13.22 g (92% yield) of Intermediate A-1A. MS(ES): m/z = 195.1 [M+H+]; HPLC: RT = 1.118 min. (H20/MeOH with TFA, CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm); 1H NMR (500MHz, chloroform-d) δ 7.22 (dd, J= 7.8, 0.8 Hz, 1H), 7.12-7.06 (m, 1H), 6.63 (t, J= 7.5 Hz, 1H), 4.63 (br. s., 2H), 3.61 (s, 3H), 3.34 (s, 3H), 2.17 (s, 3H).

Intermediate A- 1 : (2-Amino-3 -methylphenyl)(3 -fluorophenyl)methanone

Figure imgf000067_0003

[00199] In a 500 mL round-bottomed flask, a solution of l-fluoro-3-iodobenzene (13.61 mL, 116 mmol) in THF (120 mL) was cooled in a -78 °C bath. A solution of n- BuLi, (2.5M in hexane, 46.3 mL, 116 mmol) was added dropwise over 10 minutes. The solution was stirred at -78 °C for 30 minutes and then treated with a solution of

Intermediate A-1 A (6.43 g, 33.1 mmol) in THF (30 mL). After 1.5 hours, the reaction mixture was added to a mixture of ice and IN HCl (149 mL, 149 mmol) and the reaction flask was rinsed with THF (5 ml) and combined with the aqueous mixture. The resulting mixture was diluted with 10% aq LiCl and the pH was adjusted to 4 with IN NaOH. The mixture was then extracted with Et20, washed with brine, dried over MgS04, filtered and concentrated. The resulting residue was purified by silica gel chromatography (220g ISCO) eluting with a gradient from 10% EtOAc/hexane to 30% EtOAc/hexane to afford Intermediate A-l (7.11 g, 94% yield) as an oil. MS(ES): m/z = 230.1 [M+H+]; HPLC: RT = 2.820 min Purity = 99%. (H20/MeOH with TFA, CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm).

Intermediate B-1 : (S)-3-Amino-5-(3-fluorophenyl)-9-methyl-lH-benzo[e][l,4]diazepin- 2(3H)-one

Figure imgf000085_0001

Intermediate B-1 A: (S)-Benzyl (5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro benzo[e] [ 1 ,4]diazepin-3-yl)carbamate

Figure imgf000085_0002

(B-1A)

[00225] In a 1 L round-bottomed flask, a solution of 2-(lH-benzo[d][l,2,3]triazol-l- yl)-2-((phenoxycarbonyl)amino)acetic acid (J. Org. Chem., 55:2206-2214 (1990)) (19.37 g, 62.0 mmol) in THF (135 mL) was cooled in an ice/water bath and treated with oxalyl chloride (5.43 mL, 62.0 mmol) and 4 drops of DMF. The reaction mixture was stirred for 4 hours. Next, a solution of Intermediate A- 1 (7.11 g, 31.0 mmol) in THF (35 mL) was added and the resulting solution was removed from the ice/water bath and stirred at room temperature for 1.5 hours. The mixture was then treated with a solution of ammonia, (7M in MeOH) (19.94 mL, 140 mmol). After 15 mins, another portion of ammonia, (7M in MeOH) (19.94 mL, 140 mmol) was added and the resulting mixture was sealed under N2 and stirred overnight at room temperature. The reaction mixture was then concentrated to ~l/2 volume and then diluted with AcOH (63 mL) and stir at room temperature for 4 hours. The reaction mixture was then concentrated, and the residue was diluted with 500 mL water to give a precipitate. Hexane and Et20 were added and the mixture was stirred at room temperature for 1 hour to form an orange solid. Et20 was removed under a stream of nitrogen and the aqueous layer was decanted. The residue was triturated with 40 mL of iPrOH and stirred at room temperature to give a white precipitate. The solid was filtered and washed with iPrOH, then dried on a filter under a stream of nitrogen to give racemic Intermediate B-1A (5.4 g, 41.7%yield).

[00226] Racemic Intermediate B-1A (5.9 g, 14.3 mmol) was resolved using the Chiral SFC conditions described below. The desired stereoisomer was collected as the second peak in the elution order: Instrument: Berger SFC MGIII, Column: CHIRALPAK® IC 25 x 3 cm, 5 cm; column temp: 45 °C; Mobile Phase: C02/MeOH (45/55); Flow rate: 160 mL/min; Detection at 220 nm.

[00227] After evaporation of the solvent, Intermediate B-1A (2.73 g, 46% yield) was obtained as a white solid. HPLC: RT = 3.075 min. (H20/MeOH with TFA,

CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm).

Chiral HPLC RT: 8.661 min (AD, 60% (EtOH/MeOH)/heptane) > 99%ee. MS(ES): m/z = 418.3 [M+H+];1H NMR (500MHz, DMSO-d6) δ 10.21 (s, 1H), 8.38 (d, J= 8.3 Hz, 1H), 7.57-7.47 (m, 2H), 7.41-7.29 (m, 8H), 7.25-7.17 (m, 2H), 5.10-5.04 (m, 3H), 2.42 (s, 3H).

Intermediate B-l : (S)-3-Amino-5-(3-fluorophenyl)-9-methyl-lH-benzo[e][l,4]diazepin- 2(3H)-one.

[00228] In a 100 mL round-bottomed flask, a solution of Intermediate B-1A (2.73 g, 6.54 mmol) in acetic acid (12 mL) was treated with HBr, 33% in HOAc (10.76 mL, 65.4 mmol) and the mixture was stirred at room temperature for 1 hour. The solution was diluted with Et20 to give a yellow precipitate. The yellow solid was filtered and rinsed with Et20 under nitrogen. The solid was transferred to 100 mL round bottom flask and water was added (white precipitate formed). The slurry was slowly made basic with saturated NaHC03. The resulting tacky precipitate was extracted with EtOAc. The organic layer was washed with water, dried over MgS04, and then filtered and

concentrated to dryness to give Intermediate B-l (1.68 g, 91% yield) as a white foam solid. MS(ES): m/z = 284.2 [M+H+]; HPLC: RT = 1.72 min (H20/MeOH with TFA, CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm). 1H NMR (400MHz, DMSO-d6) δ 10.01 (br. s., 1H), 7.56-7.44 (m, 2H), 7.41-7.26 (m, 3H), 7.22-7.11 (m, 2H), 4.24 (s, 1H), 2.55 (br. s., 2H), 2.41 (s, 3H). [00229] The compounds listed below in Table 6 (Intermediates B-2 to B-3) were prepared according to the general synthetic procedure described for Intermediate B-l , using the starting materials Intermediate A- 10 and Intermediate A-4, respectively.

 

Example 1

(2R,3S)-N-((3S)-5-(3-Fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin- 3-yl)-2, -bis(3,3,3-trifluoropropyl)succinamide

Figure imgf000098_0001

Intermediate 1A: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3-(((S)-5-(3-fluorophenyl)-9-methyl- 2-0X0-2, 3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)carbamoyl)-2-(3,3 ,3- trifluoropropyl)hexanoat

Figure imgf000098_0002

[00240] In a 100 mL round-bottomed flask, a solution of Intermediate B-l (1683 mg, 5.94 mmol), Et3N (1.656 mL, 11.88 mmol), and Intermediate S-l in DMF (20 mL) was treated with o-benzotriazol-l-yl-A .A .N’.N’-tetramethyluronium tetrafluoroborate (3815 mg, 11.88 mmol) and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and saturated aqueous NaHC03. An off white precipitate formed and was filtered and washed with water. The resulting solid was dried on the filter under a stream of nitrogen to give Intermediate 1A (3.7 g, 99% yield). MS(ES): m/z =

632.4[M+H+]; HPLC: RT = 3.635 min Purity = 98%. (H20/MeOH with TFA,

CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm). 1H NMR (400MHz, methanol-d4) δ 7.53 (t, J = 4.5 Hz, 1H), 7.46-7.30 (m, 3H), 7.28-7.23 (m, 1H), 7.23-7.18 (m, 2H), 5.37 (s, 1H), 2.88 (td, J = 10.4, 3.4 Hz, 1H), 2.60 (td, J =

10.2, 4.1 Hz, 1H), 2.54-2.40 (m, 1H), 2.47 (s, 3 H), 2.33-2.12 (m, 3H), 1.98-1.69 (m, 4H), 1.51 (s, 9H). Intermediate IB: (2S,3R)-6,6,6-Trifluoro-3-(((S)-5-(3-fluorophenyl)-9-methyl-2-oxo-

2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoic acid

Figure imgf000099_0001

[00241] In a 250 mL round-bottomed flask, a solution of Intermediate 1A (3.7 g, 5.86 mmol) in DCM (25 mL) was treated with TFA (25 mL) and the resulting pale orange solution was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated to give Intermediate IB. HPLC: RT = 3.12 min (H20/MeOH with TFA, CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm).

MS(ES): m/z = 576.3 (M+H)+. 1H NMR (400MHz, methanol-d4) δ 7.54 (t, J= 4.5 Hz, 1H), 7.49-7.29 (m, 3H), 7.28-7.15 (m, 3H), 5.38 (br. s., 1H), 2.89 (td, J= 10.3, 3.7 Hz, 1H), 2.67 (td, J= 9.9, 4.2 Hz, 1H), 2.56-2.38 (m, 1H), 2.48 (s, 3 H), 2.34-2.13 (m, 3H), 2.00-1.71 (m, 4H).

Example 1 :

[00242] In a 250 mL round-bottomed flask, a solution of Intermediate IB (4.04 g, 5.86 mmol) in THF (50 mL) was treated with ammonia (2M in iPrOH) (26.4 mL, 52.7 mmol), followed by HOBT (1.795 g, 11.72 mmol) and EDC (2.246 g, 11.72 mmol). The resulting white suspension was stirred at room temperature overnight. The reaction mixture was diluted with water and saturated aqueous NaHC03. The resulting solid was filtered, rinsed with water and then dried on the filter under a stream of nitrogen. The crude product was suspended in 20 mL of iPrOH and stirred at room temperature for 20 min and then filtered and washed with iPrOH and dried under vacuum to give 2.83 g of solid. The solid was dissolved in re fluxing EtOH(100 mL) and slowly treated with 200 mg activated charcoal added in small portions. The hot mixture was filtered through CELITE® and rinsed with hot EtOH. The filtrate was reduced to half volume, allowed to cool and the white precipitate formed was filtered and rinsed with EtOH to give 2.57 g of white solid. A second recrystallization from EtOH (70 mL) afforded Example 1 (2.39 g, 70% yield) as a white solid. HPLC: RT = 10.859 min (H20/CH3CN with TFA, Sunfire C18 3.5μπι, 3.0x150mm, gradient = 15 min, wavelength = 220 and 254 nm); MS(ES): m/z = 575.3 [M+H+]; 1H NMR (400MHz, methanol-d4) δ 7.57-7.50 (m, 1H), 7.47-7.30 (m, 3H), 7.29-7.15 (m, 3H), 5.38 (s, 1H), 2.85-2.75 (m, 1H), 2.59 (td, J= 10.5, 4.0 Hz, 1H), 2.53-2.41 (m, 4H), 2.31-2.10 (m, 3H), 1.96-1.70 (m, 4H).

PAPER RELATED

 

Structure–activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors

Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, United States
Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
§ Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,United States
ACS Med. Chem. Lett., 2015, 6 (5), pp 523–527
*Phone: 609-252-5091. E-mail: ashvinikumar.gavai@bms.com.
Image result for BMS 906024 synthesis

Patent

http://www.google.co.in/patents/WO2012129353A1?cl=en

 

PATENT RELATED

US-20160060232-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=US159930181&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

 

PATENTS RELATED

US-20150284342-A1

US-20140357605-A1

US-20140100365-A1

Clip RELATED

For some disease targets, an indirect approach may be best. Or so Ashvinikumar V. Gavai and his colleagues atBristol-Myers Squibbfound in their quest toward a potential cancer drug. Gavai unveiled BMS-906024, which is an experimental—and slightly roundabout—treatment for a number of cancers, including breast, lung, and colon cancers, and leukemia.

Cancers have a tendency to relapse or to become resistant to treatments that once worked. Research at BMS and elsewhere had suggested that a family of proteins called Notch is implicated in that resistance and in cancer progression more generally. Gavai, director of oncology chemistry at BMS in Princeton, N.J., and his team set out to block Notch family signaling.

Notch family members lack enzymatic activity, so blocking them directly is difficult. Instead, BMS developed inhibitors of an enzyme that is essential for activating Notch signaling—γ-secretase.

09116-cover-bms906024

Company: Bristol-Myers Squibb

Target: pan-Notch

Disease: breast, lung, colon cancer; leukemia

Interfering with Notch, even in this indirect way, can have detrimental effects on the gastrointestinal tract. Only two of the four Notch family members are linked to that side effect, Gavai says. But he and his team think their drug will be most effective if it acts on all four family members roughly equally—a so-called pan-Notch inhibitor. By selecting a molecule that’s well tolerated in animals and carefully scheduling doses of the drug in humans, it could be possible to minimize side effects, he says.

The BMS team relied on Notch signaling assays in leukemia and breast cancer cell lines to find leads. They soon learned that for their molecules to work, three chiral centers had to be in the S,R,Sconfiguration. After that, they strove to make the molecules last in the bloodstream. They removed an isobutyl group and tweaked some other parts of their candidate’s succinamide side chain. It was tough to retain both a long half-life and activity against Notch, Gavai told C&EN. “You’d optimize one and lose the other.”

His team threaded the needle with BMS-906024. Their studies with mice suggest that a dose of 4–6 mg once a week could be effective in people. That’s lower than doses being tested for other Notch-targeted agents, according to the website clinicaltrials.gov. The mouse studies also back the idea that Notch is involved in cancer drug resistance and suggest that Notch could be a target for taking on cancer stem cells, which are notoriously resistant to chemotherapy.

BMS-906024 is in Phase I clinical trials, both alone and in combination with other agents. Patients with colon, lung, breast, and other cancers are receiving intravenous doses of the compound to determine its safety and optimum dose ranges.

09116-cover-BMScxd

(From left, front row) Gavai, Weifeng Shan, (second row) Aaron Balog, Patrice Gill, Gregory Vite, (third row) Francis Lee, Claude Quesnelle, (rear row) Wen-Ching Han, Richard Westhouse.

Credit: Catherine Stroud Photography

http://cen.acs.org/articles/91/i16/BMS-906024-Notch-Signaling-Inhibitor.html

Image result for BMS 906024 synthesis

 

PAPER RELATED

Abstract Image

An enantioselective synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one (S1) is described. The key step in the sequence involved crystallization-induced dynamic resolution (CIDR) of compound 7 using Boc-d-phenylalanine as a chiral resolving agent and 3,5-dichlorosalicylaldehyde as a racemization catalyst to afford S1 in 81% overall yield with 98.5% enantiomeric excess.

Crystallization-Induced Dynamic Resolution toward the Synthesis of (S)-7-Amino-5H,7H-dibenzo[b,d]-azepin-6-one: An Important Scaffold for γ-Secretase Inhibitors

Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
Bristol-Myers Squibb Company, P.O Box 4000, Princeton, New Jersey 08543-4000, United States
Org. Process Res. Dev., Article ASAP
Cited Patent Filing date Publication date Applicant Title
WO2000007995A1 * Aug 7, 1999 Feb 17, 2000 Du Pont Pharmaceuticals Company SUCCINOYLAMINO LACTAMS AS INHIBITORS OF Aβ PROTEIN PRODUCTION
WO2000038618A2 * Dec 23, 1999 Jul 6, 2000 Du Pont Pharmaceuticals Company SUCCINOYLAMINO BENZODIAZEPINES AS INHIBITORS OF Aβ PROTEIN PRODUCTION
WO2001060826A2 * Feb 16, 2001 Aug 23, 2001 Bristol-Myers Squibb Pharma Company SUCCINOYLAMINO CARBOCYCLES AND HETEROCYCLES AS INHIBITORS OF Aβ PROTEIN PRODUCTION
US6737038 * May 17, 2000 May 18, 2004 Bristol-Myers Squibb Company Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
US7053084 Feb 17, 2000 May 30, 2006 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7456172 Jan 13, 2006 Nov 25, 2008 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US20030134841 * Nov 1, 2002 Jul 17, 2003 Olson Richard E. Succinoylamino lactams as inhibitors of A-beta protein production
US20120245151 * Mar 22, 2012 Sep 27, 2012 Bristol-Myers Squibb Company Bisfluoroalkyl-1,4-benzodiazepinone compounds

 

//////////BMS-986115, BMS 986115, 3,5-dichlorosalicylaldehyde, Alzheimer’s disease, Boc-D-phenylalanine, CIDR;dibenzoazepenone DKR; Notch inhibitorsNotch inhibitor, SAR T-acute lymphoblastic leukemia, triple-negative breast cancer, γ-secretase inhibitor, PHASE 1, BMS, Bristol-Myers Squibb,  Ashvinikumar Gavai1584647-27-7, UNII: LSK1L593UU

Cc1cccc2c1NC(=O)[C@H](N=C2c3cccc(c3)F)NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)N


Filed under: Uncategorized Tagged: BMS-986115

ENZYMES AS GREEN CATALYSTS FOR PHARMACUETICAL INDUSTRY

BMS 986001, Censavudine, Festinavir

$
0
0

BMS 986001

Censavudine, Festinavir

Has anti-HIV activity. IN PHASE 2

CAS: 634907-30-5, UNII: 6IE83O6NGA, OBP 601, 4′-Ethynyl D4T, 4′-Ed4T, TDK-4-114

Molecular Formula, C12-H12-N2-O4, Molecular Weight, 248.2368

2′,3′-Didehydro-3′-deoxy-4′-ethynylthymidine, 

1-((2R,5R)-5-Ethynyl-5-(hydroxymethyl)-2H-furan-2-yl)-5-methyl-pyrimidine-2,4-dione, 

2′,3′-Didehydro-3′-deoxy-4′-ethynylthymidine

INNOVATOR= YALE UNIVERSITY

634907-30-5.pngChemSpider 2D Image | Censavudine | C12H12N2O4

Festinavir is a nucleoside reverse transcriptase inhibitor

(NRTI) which is being developed for the treatment of HIV infection. The drug has shown considerable efficacy in early development, and with perhaps less toxicity than some other NRTIs, such as the drug stavudine (marketed under the trade name ZERIT®).

Festinavir has the chemical form and the structural formula:

Festinavir was developed by Yale University in conjunction with two Japanese research scientists, and is protected by U.S. Patent No. 7,589,078, the contents of which are incorporated herein by reference. The ‘078 patent sets forth the synthesis of the primary compound, and other structural analogs. In addition, Oncolys BioPharma, Inc. of Japan has now published US 2010/0280235 for the production of 4′ ethynyl D4T. As starting raw material, the Oncolys method utilizes a substituted furan compound, furfuryl alcohol. In another publication by Nissan Chemical Industries of Japan, and set forth in WO 201 1/099443, there is disclosed a method for producing a beta-dihydrofuran deriving compound or a beta-tetrahydrofuran deriving compound. In this process, a diol compound is used as the starting material. Nissan has also published WO 2011/09442

directed to a process for the preparation of a β-glycoside compound. Two further publications, each to Hamari Chemicals of Japan, WO 2009/1 19785 and

WO 2009/125841, set forth methods for producing and purifying ethynyl thymide compounds. Pharmaset, Inc. of the U.S. has also published US 2009/0318380,

WO 2009/005674 and WO 2007/038507 for the production of 4’ -nucleoside analogs for treating HIV infection. Reference is also made to the BMS application entitled

“Sulfilimine and Sulphoxide Methods for Producing Festinavir” filed as a PCT application, PCT/US2013/042150 on May 22, 2013 (now WO2013/177243).

PAPER

Haraguchi, Kazuhiro; Bioorganic & Medicinal Chemistry Letters 2003, V 13(21), PG 3775-3777 

http://dx.doi.org/10.1016/j.bmcl.2003.07.009

http://www.sciencedirect.com/science/article/pii/S0960894X0300831X

Compounds having methyl, vinyl, and ethynyl groups at the 4′-position of stavudine (d4T: 2′,3′-didehydro-3′-deoxythymidine) were synthesized. The compounds were assayed for their ability to inhibit the replication of HIV in cell culture. The 4′-ethynyl analogue (15) was found to be more potent and less toxic than the parent compound stavudine.


Graphic

Image for unlabelled figure
Image for figure 3
Physical data for 15 are as follows: solid (mp 207–209 °C);
UV (MeOH) λmax 264 nm (ε 10800), λmin 235 nm (ε 4800);
1H NMR (CDCl3) δ 1.83 (3H, s, Me), 2.63 (1H, s, C≡CH), 3.47 (1H, br, OH), 3.88 (1H, d,Jgem=12.5 Hz, H-5′a), 3.96 (1H, d, Jgem=12.5 Hz, H-5′b), 5.91 (1H, dd, J1′,2′=1.1 Hz and J2′,3′=5.9 Hz, H-2′), 6.30 (1H, dd, J1′,3′=2.0 Hz and J2′,3′=5.9 Hz, H-3′), 7.16–7.17 (1H, m, H-1′), 7.44 (1H, d, J6,Me=1.1 Hz, H-6), 9.06 (1H, br, NH);
FAB-MS m/z 249 (M++H). Anal. calcd for C12H12N2O4·1/6H2O: C, 57.37; H, 4.95; N, 11.15. Found: C, 57.36; H, 4.69; N, 10.98.
PAPER
Scalable Synthesis of the Potent HIV Inhibitor BMS-986001 by Non-Enzymatic Dynamic Kinetic Asymmetric Transformation (DYKAT)
Angewandte Chemie, International Edition (2015), 54, (24), 7185-7188.
http://onlinelibrary.wiley.com/doi/10.1002/anie.201502290/abstract
http://onlinelibrary.wiley.com/store/10.1002/anie.201502290/asset/supinfo/anie_201502290_sm_miscellaneous_information.pdf?v=1&s=9c516d28bb61a8b090de88c2a75f5f50f060aaa9

Scalable Synthesis of the Potent HIV Inhibitor BMS-986001 by Non-Enzymatic Dynamic Kinetic Asymmetric Transformation (DYKAT)

  1. Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (USA)
  • Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (USA)

Described herein is the synthesis of BMS-986001 by employing two novel organocatalytic transformations: 1) a highly selective pyranose to furanose ring tautomerization to access an advanced intermediate, and 2) an unprecedented small-molecule-mediated dynamic kinetic resolution to access a variety of enantiopure pyranones, one of which served as a versatile building block for the multigram, stereoselective, and chromatography-free synthesis of BMS-986001. The synthesis required five chemical transformations and resulted in a 44 % overall yield.

white crystalline solid. 1: Rf = 0.8 (silica, MeOH:CH2Cl2,1:4);

M.P. = 196-207°C;

1 H NMR (d6-DMSO, 500 MHz): δ = 11.34 (s, 1 H), 6.88 (s, 1 H), 6.35 (d, J = 6.0 Hz, 6.05 (d, J = 6.0 Hz, 1 H), 5.45 (t, J = 5.5 Hz, 1 H), 3.69 (dd, J = 12.0, 1.5 Hz, 1 H), 3.64 (s, 1 H), 3.59 (dd, J = 12.0, 1.5 Hz, 1 H) 1.70 (s, 3 H) ppm;

13C NMR (d6-DMSO, 125 MHz): δ = 163.85, 150.82, 136.81, 135.54, 127.13, 109.04, 88.94, 86.60, 81.45, 77.39, 65.76, 12.23 ppm;

HRMS calcd for C12H12N2O4H+ [M + H+] 249.09 found 249.08.

PATENT

WO 2014172264

https://www.google.ch/patents/WO2014172264A1?cl=en

invention:

Step#l: Acetal Formation

Compound 1

85% yield

The starting material is 5-methylurdine, which is commercially available. The first step of the process is an acetal formation. 5-methyluridine is utilized and is treated with H2SO4 and acetaldehyde. Other acids available to the scientist, such as perchloric acid, will also work for this transformation. The solvent utilized for this step is acetonitrile (ACN), and other solvents may also be utilized as well. Once the starting material is consumed, a slurry is obtained and the product can be simply filtered off and dried to provide Compound 1 as a solid.

Acetal formation

Preparation of l-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2-methyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl)-5-methylpyrimidine-2,4(lH,3H)-dione

The following were added to a flask: 5-methyluridine (10 g, 38.70 mmol), acetonitrile (20 mL) and 70% perchloric acid (4.01 mL, 47.63 mmol). A solution of acetaldehyde (3.26 mL, 58.10 mmol) in acetonitrile (20 mL) was added dropwise over 1 h. The resulting solution was allowed to stir at 20 °C for 18 h. The resulting slurry was filtered and dried (50 °C, 25 mmHg) to afford Acetal (9.30 g, 84% yield) as white solid

XH NMR (400MHz, DMSO-d6) δ = 11.39 (s, 1H), 7.72 – 7.63 (m, 1H), 5.82 (d, J=3.0 Hz, 1H), 5.21 – 5.07 (m, 2H), 4.84 (dd, J=6.6, 2.5 Hz, 1H), 4.68 (dd, J=6.6, 3.0 Hz, 1H), 4.12 – 4.05 (m, 1H), 3.65 – 3.51 (m, 2H), 3.36 (s, 2H), 1.77 (s, 3H), 1.37 (d, J=5.1 Hz, 3H) 13C NMR (101MHz, DMSO-d6) δ = 163.77, 150.32, 137.64, 109.39, 104.50, 90.79, 86.16, 83.83, 81.37, 61.25, 19.76, 12.06

Step #2: Acetate protection

Compound 2

85% yield

The next step of the sequence is installation of a 4-biphenylacetate. Without being bound by any particular theory, this protecting step may be chosen for two reasons:

1) To provide a solid intermediate that can be easily isolated, and

2) Act as a directing group in the next step (set forth later on).

This reaction consists of reacting Compound 1 with 4-biphenyl acid chloride and pyridine in acetonitrile. In this reaction, pyridine is preferred as it allows the reaction to occur only at the -OH moiety of the molecule. It should also be noted that other polar solvents could be used, but acetonitrile allowed the desired product Compound 2 to be isolated as s solid.

Ac lation

Preparation of ((3aR,4R,6R,6aR)-2-methyl-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuro[3,4-d] [l,3]dioxol-4-yl)methyl [1,1′-biphenyl]-4-carboxylate.

Acetal (9.30 g, 32 mmol) was dissolved into acetonitrile (100 mL). Pyridine (1.3 eq) was added followed by the addition of 4-biphenylcarbonyl chloride (1.05 eq). The solution was heated to 50 °C and held for 2 h. The slurry was cooled to 20 °C and held for 2 h. The slurry was filtered and washed with acetonitrile (100 mL). The solids were dried (50 °C, 25 mmHg) to Compound 2 (85% yield).

XH NMR (400MHz, CHLOROFORM-d) δ = 8.10 (d, J=8.1 Hz, 2H), 7.62 (d, J=7.6 Hz, 2H), 7.67 (d, J=8.1 Hz, 2H), 7.55 – 7.36 (m, 3H), 7.09 (s, 1H), 5.71 (s, 1H), 5.26 (q, J=4.7 Hz, 1H), 5.03 (dd, J=6.6, 2.0 Hz, 1H), 4.91 (dd, J=6.7, 3.2 Hz, 1H), 4.73 – 4.63 (m, 1H), 4.61 – 4.50 (m, 2H), 2.02 (s, 3H), 1.85 – 1.76 (m, 3H), 1.52 (d, J=4.8 Hz, 3H)

1JC MR (101MHz, CHLOROFORM-d) δ = 164.02, 161.94, 148.20, 144.18, 137.85, 135.89, 128.20, 127.05, 126.36, 126.30, 125.35, 125.26, 1 14.49, 109.20, 103.88, 92.51, 83.36, 83.29, 79.87, 75.45, 75.13, 74.81, 62.54, 17.92, 10.32, -0.01

With the acetal and 4-biphenylacetate groups in place, the next reaction is a regioselective acetal opening utilizing TMSOTf (Trimethylsilyl trifluoromethane sulfonate, or other available Lewis acids)/Et3N to afford the corresponding silyl ether, which is cleaved in situ, to afford the 2-vinyloxy compound as Compound 3. Compound 3 may be prepared in a step-wise fashion (shown below), but in order to reduce the number of steps, it is possible to take Compound 3 and selectively form the desired 2-vinyl oxy regioisomer Compound 3. Those skilled in the art may recognize that the 4-biphenylacetate can be important to obtain high selectivity for this transformation.

Although a variety of Lewis acids may be utilized, TMSOTf is generally found to be more effective. Et3 is also a preferred reactant, as other amine bases are generally less effective. The ratio of TMSOTf to Ets is preferably within the range of about 1 : 1.3; if the reaction medium became acidic, Compound 3 would revert back to Compound 2. In terms of solvents, DCM (Dichloromethane) may be particularly effective, but toluene, CF3-PI1, sulfolane, and DCE (Dichloroethene) are also effective. The reaction can be worked up using aqueous acid, preferably K2HP04, or methanolic NH4F to quench the reaction, as well as remove the TMS-ether in situ.

TMSOTf-opening

Preparation of ((2R,3R,4R,5R)-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-(vinyloxy)tetrahydrofuran-2-yl)methyl [1,1′-biphenyl]-4-carboxylate

Compound 2 (20 g, 43.06 mmol) was dissolved into DCM (160 mL). Triethylamine (78 mL, 560 mmol) was added followed by the addition of TMSOTf (80.30 mL, 431 mmol). This solution was heated to 45 °C and held there until complete by HPLC analysis (6 h). Once complete, this solution was added to ammonium acetate (66.40 g, 861 mmol) in water (200 mL). After stirring for 20 min, the layers were separated. The organics were concentrated and the resulting residue was dissolved into EtOAc (200 mL). The organics were washed with the following solution (potassium phosphate monobasic (118 g, 861 mmol) in water (400 mL). The organics were then dried ( a2S04), filtered and concentrated. The resulting residue was purified by column chromatography [Silica gel; 20% to 90% EtOAc in Hexanes] to afford Compound 3 (15.8 g, 79% yield) as a solid.

XH NMR (400MHz, CHLOROFORM-d) 6 = 9.18 (br. s., IH), 8.18 – 8.06 (m, 2H), 7.73 -7.56 (m, 4H), 7.55 – 7.38 (m, 3H), 7.24 (d, J=1.3 Hz, IH), 6.59 (dd, J=14.0, 6.4 Hz, IH), 5.81 (d, J=2.0 Hz, IH), 4.84 (dd, J=12.6, 2.5 Hz, IH), 4.63 (dd, J=12.5, 4.2 Hz, IH), 4.59 – 4.44 (m, 3H), 4.40 – 4.26 (m, 2H), 1.70 (d, J=1.0 Hz, 3H)

13C MR (101MHz, CHLOROFORM-d) δ = 166.13, 163.65, 150.00, 149.67, 146.39, 139.66, 135.67, 130.16, 129.01, 128.40, 128.06, 127.32, 127.28, 111.43, 91.93, 89.44, 81.60, 80.19, 69.32, 63.06, 12.32

Step #4: Iodiiiation

Compound 4

Compound 3 75% yie|d

Next, Compound 3 is transformed into the iodide compound which is Compound 4. This can be accomplished by treating Compound 3 with (2.0 eq), PPI13 (2.0 eq.) and imidazole (4.0 eq). Other methods to install the iodide may also be utilized, such as mesylation/Nal, etc., but these may be less preferred. In addition, other halogen-bearing compounds such as Br2 and CI2 may be considered by the skilled scientist. Premixing imidazole, , and PPh3, followed by addition of Compound 3 in THF and heating at 60 °C allows smooth conversion to Compound 4. It is highly preferred to add all reagents prior to the addition of Compound 3; if not, the vinyloxy group will be cleaved. Other solvents, such as 2-MeTHF and PhMe may be utilized, but THF often provides the best yield.

Iodiiiation

Preparation of ((2R,3S,4S,5R)-3-iodo-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-(vinyloxy)tetrahydrofuran-2-yl)methyl [l,l’-biphenyl]-4-carboxylate

The following were added to a flask: imidazole (8.79 g, 129 mmol),

triphenylphosphine (16.94 g, 65 mmol), iodine 16.39 g, 65 mmol) and THF (525 mL). A solution of Compound 3 (15 g, 32 mmol) in THF (375 mL) was added. The solution was heated to 60 °C and was held at 60 °C for 4 h. Once complete by HPLC analysis (4 h), the solution was concentrated and the residue was purified by column chromatography [Silica gel; 10% to 60% EtOAc in Hexanes] to afford Compound 4 (17.0 g, 92% yield) as a solid.

XH NMR (400MHz, CHLOROFORM-d) δ = 9.25 (br. s., IH), 8.16 (d, J=8.3 Hz, 2H), 7.75 – 7.61 (m, 5H), 7.54 – 7.40 (m, 3H), 7.32 – 7.24 (m, 2H), 7.23 – 7.16 (m, 2H), 6.56 -6.45 (m, IH), 6.06 (d, J=1.5 Hz, IH), 4.89 (s, IH), 4.66 (dd, J=12.0, 6.9 Hz, IH), 4.56 (dd, J=12.0, 3.9 Hz, IH), 4.46 (d, J=4.0 Hz, IH), 4.39 – 4.26 (m, 2H), 4.13 (dt, J=7.1, 3.8 Hz, 1H), 2.06 – 1.97 (m, 3H)

1JC MR (101MHz, CHLOROFORM-d) δ = 165.96, 163.94, 150.27, 149.29, 146.28, 139.81, 137.88, 135.84, 130.37, 129.06, 129.01, 128.34, 128.25, 127.94, 127.31, 127.22, 125.32, 1 11.07, 91.37, 90.32, 89.18, 78.43, 69.15, 25.81, 21.49, 12.71

Step #5: Iodide Elimination

Compound 4

The next step of the sequence is to install the allyic moiety. Heating a solution of Compound 4 in toluene in the presence of DABCO (l,4-Diazabicyclo[2.2.2]octane) allows for elimination of the iodide. Other solvents, such as THF and DCE may be utilized, but toluene often provides the best conversion and yield. Other amine bases may be used in this transformation, but generally DABCO is preferred.

Elimination

Preparation of ((4R,5R)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-l (2H)-yl)-4-(vinyloxy)-4,5-dihydrofuran-2-yl)methyl [l,l’-biphenyl]-4-carboxylate

Compound 4 (17 g, 30 mmol) was dissolved into toluene (255 niL), and DABCO (10 g, 89 mmol) was added. The solution was heated to 90 °C and held there for 2 h. Once complete, the organics were washed with sat. aq. a2S203 (200 mL). The organics were then dried ( a2S04), filtered, and concentrated. The resulting residue was purified by column chromatography [Silica gel; 5% to 60% EtOAc in Hexanes] to yield

Compound 5 (10.9, 85% yield) as a foam.

XH NMR (400MHz, CHLOROFORM-d) δ = 8.93 (br. s., IH), 8.18 – 8.11 (m, 2H), 7.75 -7.61 (m, 5H), 7.55 – 7.39 (m, 4H), 6.95 (d, J=1.0 Hz, IH), 6.54 (d, J=2.0 Hz, IH), 6.46 (dd, J=14.3, 6.7 Hz, IH), 5.53 (d, J=2.5 Hz, IH), 5.09 (d, J=2.8 Hz, IH), 5.04 (d, J=6.6 Hz, 2H), 4.29 (dd, J=14.3, 2.4 Hz, IH), 4.23 (dd, J=6.7, 2.4 Hz, IH), 1.88 (d, J=1.0 Hz, 3H)

1JC MR (101MHz, CHLOROFORM-d) δ = 165.73, 159.58, 149.10, 146.49, 139.70, 134.51, 132.17, 132.07, 131.94, 131.92, 130.30, 129.01, 128.56, 128.44, 128.40, 127.73, 127.30, 127.28, 112.50, 99.16, 90.57, 90.23, 84.81, 58.68, 12.44

Step #6: Claisen Rearrangement

An important reaction in the sequence is the Claisen rearrangement. This reaction is utilized to install the quaternary stereocenter and the olefin geometry in the ring. Heating Compound 5 in benzonitrile at 190 °C for 2-3 hours allows for smooth conversion to Compound 6, and after chromatography, a 90% yield can be achieved.

Toluene (110 °C, 8 h) also works to provide the desired Compound 6 as a solid by simply cooling the reaction to 20 °C (no chromatography). Other solvents with boiling points over about 100°C may also be utilized.

Claisen Rearrangement

Preparation of ((2S,5R)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-(2-oxoethyl)-2,5-dihydrofuran-2-yl)methyl [l,l’-biphenyl]-4-carboxylate

Compound 5 (1 mmol) was dissolved into benzonitrile (10 mL). The solution was heated to 190 °C for 3 h. After cooling to 20 °C, the solution was purified by column chromatography [silica gel, 50:50 Hexanes:EtOAc] to afford Compound 6 (1 mmol).

Alternatively, Compound 5 (1 mmol) was dissolved into toluene (10 mL). The solution was heated to 110 °C and held for 12 h. Upon cooling to 20 °C, a slurry formed. The solids were filtered, washed (PhMe) and dried (50 °C, 25 mmHg) to afford

Compound 6 (1 mmol) as a white solid.

XH NMR (400MHz, CHLOROFORM-d) δ = 9.84 (t, J=1.8 Hz, 1H), 8.53 (br. s., 1H), 8.13 – 8.03 (m, J=8.3 Hz, 2H), 7.73 – 7.67 (m, 2H), 7.67 – 7.60 (m, 2H), 7.56 – 7.38 (m, 3H), 7.14 (d, J=1.3 Hz, 1H), 7.04 (t, J=1.5 Hz, 1H), 6.57 (dd, J=6.1, 2.0 Hz, 1H), 6.02 (dd, J=5.9, 1.1 Hz, 1H), 4.68 – 4.52 (m, 2H), 3.06 – 2.89 (m, 2H), 1.59 (d, J=1.0 Hz, 3H)

13C MR (101MHz, CHLOROFORM-d) δ = 198.33, 165.83, 163.35, 150.65, 146.56, 139.63, 136.24, 135.02, 130.21, 129.04, 128.44, 127.86, 127.49, 127.41, 127.28, 111.59, 90.03, 89.61, 67.33, 50.06, 12.06

ne Formation via elimination of Enol Nonaflate

The alkyne formation is performed by first treating Compound 6 with TMSCl (Trimethylsilyl chloride)/Et3N. NfF (Nonafluoro- 1 -butanesulfonyl fluoride) and P-base () are then added at -20 °C. After warming to 20 °C, the desired alkyne Compound 7 can be isolated in about 80 % yield. Initially, TMSCl is presumed to react at the NH moiety. NfF/P-base then reacts with the aldehyde to form the enol Nonaflate. Upon warming to 20 °C in the presence of P-base, the enol Nonaflate eliminates smoothly to the alkyne Compound 7. Without the TMSCl/Et3N, the yields are only -25%.

Alkyne formation

Preparation of ((2R,5R)-2-ethynyl-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2,5-dihydrofuran-2-yl)methyl [l,l’-biphenyl]-4-carboxylate

Compound 6 (1 g, 2.24 mmol) was dissolved into DMF (Dimethylformamide) (5 mL). (Other polar solvents could also have been used.) Triethylamine (406 uL, 2.91 mmol) was added and the solution was cooled to 0 °C. TMSCl (314 uL, 2.46 mmol) was added and the solution was allowed to stir at 0 °C for 30 min. The solution was then cooled to -20 °C, and NfF (484 uL, 2.69 mmol) was added and the solution was allowed to stir at -20 °C for 5 min. Phosphazane P l-base (1.54 mL, 4.93 mmol) was added

dropwise over 20 min. The solution was then allowed to warm to 20 °C and held for 20 h. The solution was then poured into water (50 mL) and extracted with DCM (100 mL). The organics were concentrated and the resulting residue was purified by column chromatography [Silica gel; 10% to 60% EtOAc in Hexanes] to afford Compound 7 (816 mg, 85% yield) as a solid.

XH NMR (400MHz, DMSO-d6) δ = 11.46 (s, 1H), 8.08 – 7.97 (m, J=8.6 Hz, 2H), 7.92 -7.80 (m, 2H), 7.73 (d, J=7.1 Hz, 2H), 7.59 – 7.39 (m, 3H), 7.06 (d, J=1.0 Hz, 1H), 6.89 (d, J=1.5 Hz, 1H), 6.61 (dd, J=5.6, 2.0 Hz, 1H), 6.23 (dd, J=5.6, 1.0 Hz, 1H), 4.66 (d, J=12.1 Hz, lH), 4.57 (d, J=11.6 Hz, 1H), 3.87 (s, 1H), 1.37 (s, 3H)

13C MR (101MHz, DMSO-d6) δ = 164.89, 163.57, 150.61, 145.13, 138.73, 135.30, 134.40, 129.94, 129.12, 128.49, 127.84, 127.78, 127.18, 126.98, 110.01, 89.37, 83.69, 80.01, 78.23, 66.89, 11.46

90% yield

The final step of the sequence is to remove the aromatic ester protecting group. This consists of hydrolysis by NaOH in aq. THF solution. The API is extracted into THF and then crystallized from THF/PhMe.

Deprotection

Preparation of l-((2R,5R)-5-ethynyl-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl)-5-methylpyrimidine-2,4(lH,3H)-dione (Ed4T)

Compound 7 (10 g, 23.40 mmol) was dissolved into THF (100 mL). 3N NaOH (10 mL) was added. The solution was allowed to stir at 20 °C for 12 h. The layers were split and the organics were kept. The organics were concentrated to reach a KF <1 wt%. Toluene (100 mL) was added, and solids crashed out of solution. The solids were filtered and washed with Toluene (100 mL). The solids were then dried (50 °C, 25 mmHg) to afford Festinavir (5.21 g, 90% yield) as a white solid.

XH NMR (400MHz, DMSO-d6) δ = 1 1.36 (s, 1H), 7.58 (s, 1H), 6.89 (s, 1H), 6.36 (d, J=6.1 Hz, 1H), 6.05 (d, J=6.1 Hz, 1H), 5.48 (t, J=5.6 Hz, 1H), 3.78 – 3.49 (m, 3H), 3.46 3.31 (m, 1H), 1.71 (s, 3H)

1JC MR (101MHz, DMSO-d6) δ = 163.80, 150.76, 136.75, 135.47, 127.06, 108.98, 88.87, 86.52, 81.37, 77.33, 65.68, 12.17.

PAPER

Tetrahedron (2009), 65(36), 7630-7636.

Volume 65, Issue 36, 5 September 2009, Pages 7630–7636

Cover image

Synthesis of (±)-4′-ethynyl-5′,5′-difluoro-2′,3′-dehydro-3′-deoxy- carbocyclic thymidine: a difluoromethylidene analogue of promising anti-HIV agent Ed4T

http://dx.doi.org/10.1016/j.tet.2009.06.095

PAPER

Nucleophilic Substitution at the 4‘-Position of Nucleosides: New Access to a Promising Anti-HIV Agent 2‘,3‘-Didehydro-3‘-deoxy-4‘-ethynylthymidine

School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
J. Org. Chem., 2006, 71 (12), pp 4433–4438
DOI: 10.1021/jo060194m

Journal of Organic Chemistry (2006), 71(12), 4433-4438.

http://pubs.acs.org/doi/abs/10.1021/jo060194m

Abstract Image

For the synthesis of 2‘,3‘-didehydro-3‘-deoxy-4‘-ethynylthymidine (8:  4‘-Ed4T), a recently reported promising anti-HIV agent, a new approach was developed. Since treatment of 1-(2,5-dideoxy-β-lglycero-pent-4-enofuranosyl)thymine with Pb(OBz)4 allowed the introduction of the 4‘-benzoyloxy leaving group, nucleophilic substitution at the 4‘-position became feasible for the first time. Thus, reaction between the 4‘-benzoyloxy derivative (14) and Me3SiC⋮CAl(Et)Cl as a nucleophile led to the isolation of the desired 4‘-“down”-ethynyl derivative (18) stereoselectively in 62% yield. As an application of this approach, other 4‘-substituted nucleosides, such as the 4‘-allyl (24a) and 4‘-cyano (26a) derivatives, were synthesized using organosilicon reagents. In these instances, pretreatment of 14 with MeAlCl2 was necessary.

figure

PATENTS

US75890782009-09-15Anti-viral nucleoside analogs and methods for treating viral infections, especially HIV infections

Patent ID Date Patent Title
US2016060252 2016-03-03 5-METHYLURIDINE METHOD FOR PRODUCING FESTINAVIR
US2015140610 2015-05-21 SULFILIMINE AND SULPHOXIDE METHODS FOR PRODUCING FESTINAVIR
US2015104511 2015-04-16 Pharmaceutical Antiretroviral Combinations Comprising Lamivudine, Festinavir and Nevirapine
US8927237 2015-01-06 Method for producing acyloxypyranone compound, method for producing alkyne compound, and method for producing dihydrofuran compound
US2012322995 2012-12-20 beta-DIHYDROFURAN DERIVING COMPOUND, METHOD FOR PRODUCING beta-DIHYDROFURAN DERIVING COMPOUND OR beta-TETRAHYDROFURAN DERIVING COMPOUND, beta-GLYCOSIDE COMPOUND, METHOD FOR PRODUCING beta GLYCOSIDE COMPOUND, AND METHOD FOR PRODUCING 4′-ETHYNYL D4T AND ANALOGUE COMPOUNDS THEREOF
US2012252751 2012-10-04 ANTI-VIRAL NUCLEOSIDE ANALOGS AND METHODS FOR TREATING VIRAL INFECTIONS, ESPECIALLY HIV INFECTIONS
US8193165 2012-06-05 Anti-viral nucleoside analogs and methods for treating viral infections, especially HIV infections
US2011312880 2011-12-22 POTENT CHIMERIC NRTI-NNRTI BIFUNCTIONAL INHIBITORS OF HIV-1 REVERSE TRANSCRIPTASE
US2011054164 2011-03-03 PRODUCTION PROCESS OF ETHYNYLTHYMIDINE COMPOUNDS FROM 5-METHYLURIDINE AS A STARTING MATERIAL
US2010280235 2010-11-04 METHOD FOR PRODUCING 4’ETHYNYL d4T

/////////BMS 986001, 634907-30-5, UNII: 6IE83O6NGA, OBP 601, 4′-Ethynyl D4T, 4′-Ed4T, TDK-4-114, PHASE 2

Cc1cn(c(=O)[nH]c1=O)[C@H]2C=C[C@](O2)(CO)C#C


Filed under: Phase2 drugs, Uncategorized Tagged: 4'-Ed4T, 4'-Ethynyl D4T, 634907-30-5, BMS 986001, OBP 601, phase 2, TDK-4-114, UNII: 6IE83O6NGA

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Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India

Recent Advances in Drug Development

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Ranitidine

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Ranitidine

Ranitidine, sold under the trade name Zantac among others, is a medication that decreases stomach acid production.[1] It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome.[1] There is also tentative evidence of benefit for hives.[2] It can be taken by mouth, by injection into a muscle, or into a vein.[1]

Common side effects include headaches and pain or burning if given by injection. Serious side effects may include liver problems, a slow heart rate, pneumonia, and the potential of masking stomach cancer.[1] It is also linked to an increased risk ofClostridium difficile colitis.[3] It is generally safe in pregnancy. Ranitidine is an H2 histamine receptor antagonist that works by blocking histamine and thus decreasing the amount of acid released by cells of the stomach.[1]

Ranitidine was discovered in 1976 at Glaxo Pharmaceuticals, now a part of GlaxoSmithKline.[4][5] It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic health system.[6] It is available as a generic medication.[1] The wholesale price in the developing world is about 0.01 to 0.05 USD per pill.[7] In the United States it is about 0.05 USD per dose.[1]

Image result for SYNTHESIS ranitidine.

Image result for SYNTHESIS ranitidine.

Image result for SYNTHESIS ranitidine.

Laboratory Synthesis Of Ranitidine

Synthesis Of Ranitidine
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Ranitidine Synthetic procedure/method of synthesis

The reaction of 5-dimethylaminomethyl-2-furanylmethanol (I) with 2-mercaptoethylamine (II) by means of aqueous HCl gives 2-[[(5-dimethylamino-methyl-2-furanyl)methylthio]ethaneamine (III), which is then condensed with N-methyl-1-methylthio-2-nitrotheneamine (IV) by heating at 120 C. Compound (IV) is obtained by reaction of 1,1-bis(methylthio)-2-nitroethene (V) with methylamine in refluxing ethanol
Ranitidine reference
  1. Serradell, M.N.; Blancafort, P.; Casta馿r, J.; Hillier, K.; Ranitidine. Drugs Fut 1979, 4, 9, 663
  2.  Price, B.J. et al. (Allen and Hanburys, Ltd.); US 4128658.
  3. Price, B.J.; Bradshaw, J.; Clitherow, J.W. (Allen & Hansburys Ltd.); Aminoalkyl furan derivatives.. DE 2734070; FR 2360587; US 4128658 ,DE 2734070; FR 2360587; US 4128658.

PAPER

Synthesis of ranitidine (Zantac) from cellulose-derived 5-(chloromethyl)furfural

Mark Mascal*a and   Saikat Duttaa  
*Corresponding authors
aDepartment of Chemistry, University of California Davis, 1 Shields Avenue, Davis, US
E-mail: mascal@chem.ucdavis.edu
Fax: 530-752-8995
Tel: 530-754-5373
Green Chem., 2011,13, 3101-3102

DOI: 10.1039/C1GC15537G

The biomass-derived platform chemical 5-(chloromethyl)furfural is converted into the blockbuster antiulcer drug ranitidine (Zantac) in four steps with an overall 68% isolated yield.

Graphical abstract: Synthesis of ranitidine (Zantac) from cellulose-derived 5-(chloromethyl)furfural

Image result for A new method for the synthesis of ranitidine.

Image result for A new method for the synthesis of ranitidine.

PROCESS

Image result for A new method for the synthesis of ranitidine.

2. Experimental Procedures

5-[[(2-Acetamidoethyl)thio]methyl]furfural 14

Sodium hydride (95%) (103 mg, 4.08 mmol) was added to a solution of Nacetylcysteamine (0.4051 g, 3.40 mmol) in dry THF (20 mL) under argon. The resulting suspension was stirred at RT for 30 min and a solution of CMF 12 (0.4912 g, 3.40 mmol) in dry THF (10 mL) was added dropwise over a 10 min period. The resulting light yellow solution was allowed to stir overnight at RT. The solvent was evaporated and saturated brine (50 mL) was added. The mixture was extracted with CH2Cl2 (2 × 50 mL) and the organic layers were combined and washed with saturated brine (100 mL). The organic layer was dried over Na2SO4. Charcoal (100 mg) was added and the mixture was stirred for 20 min and filtered. The solvent was evaporated to give 14 as a yellow liquid (0.7042 g, 91 %). 1H NMR (CDCl3, 300 MHz) 9.58 (1H, s), 7.21 (1H, d, J = 3.6 Hz), 6.48 (1H, s, br), 5.95 (1H, d, J = 3.6 Hz), 3.79 (2H, s), 3.45 (2H, q, J = 6.3 Hz), 2.72 (2H, t, J = 6.6 Hz), 2.00 (3H, s); 13C NMR (CDCl3, 75 MHz) 23.1, 27.8, 31.7, 38.4, 110.7, 121.9, 152.2, 158.9, 170.7, 177.4; IR (neat) 3298, 3101, 1663, 1548, 1512, 1287, 1022, 772 cm-1; HRMS (ESI): calculated for C10H14O3NS: [M+H]+ 228.0694: found 228.0690.

5-[[(2-Acetamidoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine 15

Me2NH (1.0 mL) was added to a solution of 14 (0.2105 g, 0.926 mmol) in dry methanol (20 mL) and the mixture was stirred at RT for 1 h. The resulting red solution was cooled to 0 °C and NaBH4 (98 %) (55 mg, 1.42 mmol) was added over a 5 min period. The mixture was allowed to come to RT and stirred for 30 min. The solvent was evaporated while keeping the bath temperature below 45 °C. The residue was dissolved in CH2Cl(50 mL) and filtered to remove inorganic impurities. The solvent was evaporated to give 15 (0.2145 g, 90 %) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz) 6.42 (1H, s, br), 6.09 (1H, s), 3.67 (2H, s), 3.37 (2H, s), 3.26 (2H, q, J = 6.0 Hz), 2.62 (2H, t, J = 6.4 Hz) 2.21 (6H, s), 1.93 (3H, s); 13C NMR (CDCl3, 75 MHz) 23.5, 28.4, 31.9, 38.7, 45.4, 56.2, 108.4, 109.9, 151.4, 152.1, 170.5; IR (neat) 3273, 2944, 1656, 1545, 1291, 1019, 729 cm- 1 ; HRMS (ESI): calculated for C12H21O2N2S: [M+H]+ 257.1322: found 257.1323.

5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine 5

A solution of 15 (0.2473 g, 0.965 mmol) in freshly prepared 2N aq NaOH (10 mL) was heated at reflux for 2 h. The mixture was cooled to RT and extracted with CH2Cl2 (3×30 mL). The organic layers were combined and washed with saturated brine, dried over Na2SO4, and evaporated to give 5 (0.1934 g, 94 %) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz) 6.02 (2H, s), 3.61 (2H, s), 3.33 (2H, s), 2.74 (2H, t, J = 6.3 Hz), 2.52 (2H, t, J = 6.6 Hz), 2.16 (6H, s); 13C NMR (CDCl3, 75 MHz) 28.2, 35.9, 40.9, 45.1, 55.9, 108.1, 109.5, 151.4, 152.1; IR (neat) 3359 cm-1, 2947, 2769, 1559, 1459, 1015, 797 cm-1; HRMS (ESI): calculated for C10H19ON2S: [M+H]+ 215.1212: found 215.1218.

N-[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N’-methyl-2-nitro- 1-Ethenediamine (Ranitidine) 1 The experimental procedure is modified from existing literature:2 A solution of 5 (0.1501 g, 0.700 mmol ) in distilled water (10 mL) was added dropwise over a period of 10 min to a suspension of 1-methylthio-1-methylamino-2-nitroethylene 7 (0.1041 g, 0.703 mmol) in distilled water (5 mL) with stirring. The resulting light yellow solution was placed in an oil bath at 55 °C and the mixture was stirred at that temperature overnight. Saturated brine (30 mL) was added and the mixture was extracted with CHCl3 (3×20 mL). The combined organic layer was dried over Na2SO4. Evaporation of the solvent gave 1 as a pale yellow oil (0.1935 g, 88 %). 1H NMR (CDCl3, 300 MHz, 56 oC) 10.23-10.15 (1H, br, NH), 6.57 (1H, s), 6.13 (2H, d, 6.0 Hz), 5.04 (1H, br, NH), 3.73 (2H, s), 3.41 (4H, s), 2.92 (2H, s), 2.76 (2H, t, 6.0 Hz), 2.24 (6H, s); 13C NMR (CDCl3, 75 MHz, 56 °C) 28.2, 30.6, 40.7, 44.6, 55.6, 97.9, 108.1, 109.1, 150.4, 152.1, 156.6; IR (neat) 3209, 2944, 2815, 2776, 1620, 1574, 1384, 1230, 1019, 761 cm-1; HRMS (ESI): calculated for C13H23O3N4S: [M+H]+ 315.1491: found 315.1497.

SEE NMR AT http://www.rsc.org/suppdata/gc/c1/c1gc15537g/c1gc15537g.pdf

Zantac (ranitidine) 300-mg tablet
Image result for RANITIDINE NMR

PATENT

Image result for A new method for the synthesis of ranitidine.

Patent EP0796256B1 – Process for preparing ranitidine – Google Patents

Google

Figure 00060001

HPLC

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An Improved HPLC Method for the Determination of Ranitidine …

Separation Science

An Improved HPLC Method for the Determination of Ranitidine Suitable for All Dosage Forms
PATENT
Image result for SYNTHESIS ranitidine.
CLIP
Image result for SYNTHESIS ranitidine.

CLIP

Image result for SYNTHESIS ranitidine.

The paper was found in Green Chemistry,“Synthesis of ranitidine (Zantac) from cellulose-derived 5-(chloromethyl)furfural” by Mark Mescal et al, Green Chemistry,  2011,13, 3101-3102, DOI: 10.1039/c1gc15537g.  Once again, I am beating the press before they print so I supplied the Digital Object Identifier.  I am sure the sales for Ranitidine are quite large; who doesn’t get heartburn at one time or another.  I think it is very fortunate the author shows you can use a starting material that can be derived from just about any source of cellulose.  I find it interesting how renewable feedstocks can be utilized in industry and become part of important commodities, such as plastics, pharmaceuticals, etc.  This paper refers to another discussing where the starting material was derived from.  Starting material can be sugars, cellulose or raw cellulosic biomass and the reaction can produce yields of 80-90 %. M.Mascal and E. B. Nikitin, Angew. Chem., Int. Ed., 2008, 47, 7924;furansOn with the show, though.  The original synthetic route was provided in the paper and I will provide it to you.

originalsynranit

Furfural 1 was reduced to give the furfuryl alcohol 2.  The furfuryl alcohol is methylaminated to give 3, which is reacted with cysteamine in concentrated HCl to give 4.  This is condensed with 1-methylthio-1-methylamino-2-nitroethylene to give the final product.  The patent literature has the yield < 50 % for the aminomethylation and subsequent reaction with cysteamine, but recently, these steps have been reported to have higher conversions.

newsynranit

This new synthesis, apart from using a renewable feedstock as a starting material, has synthetic steps with an average yield of 91 %, and requires no chromatography.  Note that N-acetylcysteamine was used as opposed to cysteamine in the first step, in high yield.  A reductive amination with methylamine gives 8 again in high yield.  Treatment with KOH provides the free amine 9 and  the final step is the condensation with the nitroethylene used in the previous synthesis

https://developingtheprocess.wordpress.com/2014/06/22/got-heartburn-here-is-a-synthesis-to-satisfy-that-appetite-for-good-chemistry/

Paper
Critical influence of 5-hydroxymethylfurfural aging and decomposition on the utility of biomass conversion in organic synthesis
Angewandte Chemie, International Edition (2016), 55, (29), 8338-8342
str1 str2
str1
5-HMF. 1H NMR (400 MHz, DMSO-d6) δ = 9.54 (s, 1H, C(O)H), 7.49 (d, J = 3.5 Hz, 1H, CHfuran), 6.60 (d, J = 3.5 Hz, 1H, CH-furan), 5.57 (t, J = 5.9 Hz, 1H, OH), 4.51 (d, J = 5.9 Hz, 2H, CH2OH). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 177.9 (C(O)H), 162.2, 151.7 (C-furan), 124.4, 109.7 (CH-furan), 55.9 (CH2OH). Anal. calcd. For C6H6O3 (126.11): C 57.14, H 4.80; found: C 57.08, H 4.79.

Abstract

Spectral studies revealed the presence of a specific arrangement of 5-hydroxymethylfurfural (5-HMF) molecules in solution as a result of a hydrogen–bonding network, and this arrangement readily facilitates the aging of 5-HMF. Deterioration of the quality of this platform chemical limits its practical applications, especially in synthesis/pharma areas. The model drug Ranitidine (Zantac®) was synthesized with only 15 % yield starting from 5-HMF which was isolated and stored as an oil after a biomass conversion process. In contrast, a much higher yield of 65 % was obtained by using 5-HMF isolated in crystalline state from an optimized biomass conversion process. The molecular mechanisms responsible for 5-HMF decomposition in solution were established by NMR and ESI-MS studies. A highly selective synthesis of a 5-HMF derivative from glucose was achieved using a protecting group at O(6) position.

PAPER
Phytochemical screening and investigation of antiulcer activity of Tridax procumbens
International Journal of Pharmacy and Technology (2015), 6, (4), 7679-7690
Lavanya Asula* , A. Sony John, Deepthi Kotturi, P. Srividyalaxmi, R. Soni and Y. Mamatha Kalyani Department of Pharmacy, Jawaharlal Nehru Technological University, Holy Mary Institute of Technology and Science College of Pharmacy Hyderabad, India. Email: lavanya.asula@gmail.com
PATENT
Waste gas treatment and methyl mercaptan recovery process in production process of cimetidine and ranitidine
cimetidine and ranitidine terms widely used in the treatment of stomach is bound to promote the continuous mass production of APIs, however, the raw material in the manufacturing process of the drug inevitably produce methyl mercaptan, dimethyl sulfide, a methylamine, carbon disulfide and nitromethane workshop emissions. Because of methyl mercaptan, dimethyl sulfide into the atmosphere having foul odor. Resulting in the production shop around smelling, and even affect the normal life of residents of several kilometers around. So some manufacturers use incineration method expects to dispose of the waste gas combustion, which reduces air pollution to some extent. But using incineration method has two drawbacks: one gas methyl mercaptan, dimethyl sulfide gas combustion higher value produce a few meters of flames burning heat generated while it is easy to burn incinerator, security posed by the chemical production big risk; on the other hand by a combustion method can not solve the odor problem, air pollution is still grim, because incomplete combustion, odor difficult to eliminate people’s sense of smell is particularly sensitive to the perception of mercaptans, while burning a large amount of sulfur dioxide in the same air pollution. There’s manufacturers to adopt authoritarian incinerator burning after the first use of chlorine dioxide generator eliminate odor, although this method has a certain smell to eliminate the effect of improving, but requires authoritarian equipment, increasing the cost of gas treatment and discharge sulfur dioxide into the air is still there.
PATENT
CN 102408398
Title: Ranitidine
CAS Registry Number: 66357-35-5
CAS Name: N-[2-[[[-5-[(Dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N¢-methyl-2-nitro-1,1-ethenediamine
Molecular Formula: C13H22N4O3S
Molecular Weight: 314.40
Percent Composition: C 49.66%, H 7.05%, N 17.82%, O 15.27%, S 10.20%
Literature References: Histamine H2-receptor antagonist which inhibits gastric acid secretion. Prepn: B. J. Price et al., FR2384765; eidem, US 4128658 (both 1978 to Allen & Hanburys). HPLC determn in plasma: P. F. Carey, L. E. Martin, J. Liq. Chromatogr. 1979, 1291. Pharmacological studies: J. Bradshaw et al., Br. J. Pharmacol. 66, 464 (1979); M. J. Daly et al., Gut 21,408 (1980). Efficacy in treatment of duodenal ulcers: A. Berstad et al., Scand. J. Gastroenterol. 15, 637 (1980); R. P. Walt et al.,Gut 22, 49 (1981). Review of pharmacology and therapeutic use: R. N. Brogden et al., Drugs 24, 267-303 (1982). Comprehensive description: M. Hohnjec et al., Anal. Profiles Drug Subs. 15, 533-561 (1986).
Properties: Solid, mp 69-70°.
Melting point: mp 69-70°
Derivative Type: Hydrochloride
CAS Registry Number: 66357-59-3
Manufacturers’ Codes: AH-19065
Trademarks: Azantac (GSK); Melfax (Apotex); Noctone (GEA); Raniben (Firma); Ranidil (Menarini); Raniplex (Fournier); Sostril (Cascan); Taural (Roemmers); Terposen (Vir); Trigger (Polifarma); Ulcex (Guidotti); Ultidine (GSK); Zantac (GSK); Zantic (GSK)
Molecular Formula: C13H22N4O3S.HCl
Molecular Weight: 350.86
Percent Composition: C 44.50%, H 6.61%, N 15.97%, O 13.68%, S 9.14%, Cl 10.10%
Properties: Off-white solid, mp 133-134°. Freely sol in acetic acid and water, sol in methanol, sparingly sol in ethanol. Practically insol in chloroform.
Melting point: mp 133-134°
Derivative Type: Bismuth citrate
CAS Registry Number: 128345-62-0
Additional Names: Ranitidine bismutrex
Manufacturers’ Codes: GR-122311X
Trademarks: Pylorid (GSK); Tritec (GSK)
Molecular Formula: C13H22N4O3S.C6H5BiO7
Molecular Weight: 712.48
Percent Composition: C 32.03%, H 3.82%, N 7.86%, O 22.46%, S 4.50%, Bi 29.33%
Literature References: Pharmacology and activity vs Helicobacter sp: R. Stables et al., Aliment. Pharmacol. Ther. 7, 237 (1993).
Therap-Cat: Antiulcerative.
Keywords: Antiulcerative; Histamine H2-Receptor Antagonist.

References

  1. ^ Jump up to:a b c d e f g “Ranitidine”. The American Society of Health-System Pharmacists. Retrieved Dec 1, 2015.
  2. Jump up^ Fedorowicz, Z; van Zuuren, EJ; Hu, N (14 March 2012). “Histamine H2-receptor antagonists for urticaria.”. The Cochrane database of systematic reviews. 3: CD008596.doi:10.1002/14651858.CD008596.pub2. PMID 22419335.
  3. Jump up^ Tleyjeh, IM; Abdulhak, AB; Riaz, M; Garbati, MA; Al-Tannir, M; Alasmari, FA; Alghamdi, M; Khan, AR; Erwin, PJ; Sutton, AJ; Baddour, LM (2013). “The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis.”. PLOS ONE. 8 (3): e56498. doi:10.1371/journal.pone.0056498.PMC 3587620free to read. PMID 23469173.
  4. Jump up^ Fischer, Janos (2010). Analogue-based Drug Discovery II. John Wiley & Sons. p. 4.ISBN 9783527632121.
  5. Jump up^ Hara, Takuji (2003). Innovation in the pharmaceutical industry the process of drug discovery and development. Cheltenham, U.K.: Edward Elgar. p. 94.ISBN 9781843765660.
  6. Jump up^ “WHO Model List of EssentialMedicines” (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
Ranitidine
Ranitidine.svg
Ranitidine-A-3D-balls.png
Systematic (IUPAC) name
N-(2-[(5-[(dimethylamino)methyl]furan-2-yl)methylthio]ethyl)-N’-methyl-2-nitroethene-1,1-diamine
Clinical data
Pronunciation /rəˈnɪtdn/
Trade names Zantac, others
AHFS/Drugs.com Monograph
MedlinePlus a601106
License data
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Routes of
administration
Oral, IV
Legal status
Legal status
Pharmacokinetic data
Bioavailability 39 to 88%
Protein binding 15%
Metabolism Hepatic: FMOs, including FMO3; other enzymes
Biological half-life 2–3 hours
Excretion 30–70% Renal
Identifiers
CAS Number 66357-35-5 Yes
ATC code A02BA02 (WHO)
A02BA07 (WHO) (ranitidine bismuth citrate)
PubChem CID 3001055
IUPHAR/BPS 1234
DrugBank DB00863 Yes
ChemSpider 4863 
UNII 884KT10YB7 Yes
KEGG D00422 Yes
ChEBI CHEBI:8776 
ChEMBL CHEMBL1790041 
Synonyms Dimethyl [(5-{[(2-{[1-(methylamino)-
2-nitroethenyl]amino}ethyl)sulfanyl]
methyl}furan-2-yl)methyl]amine
Chemical data
Formula C13H22N4O3S
Molar mass 314.4 g/mol

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