PF-06273340

N-(5-(2-amino-7-(1-hydroxy-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl)-2-(5-chloropyridin-2-yl)acetamide

CAS 1402438-74-7
Chemical Formula: C23H22ClN7O3
Molecular Weight: 479.925

• Originator Pfizer
• ClassAnalgesics; Small molecules
• Mechanism of ActionUndefined mechanism

• 06 Oct 2014 Pfizer plans a phase I trial in Pain (In volunteers) in the Netherlands (NCT02260947)
• 07 Aug 2014 Discontinued – Phase-I for Pain (In volunteers) in Belgium (PO)
• 07 Aug 2014 Discontinued – Phase-I for Pain (In volunteers) in Singapore (PO)

PF-06273340 is a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor with an excellent LipE profile (IC50 value: Trk-A = 6 nM; Trk-B = 4 nM; Trk-C = 3 nM). PF-06273340 has low metabolic turnover in HLM and hHep is a good substrate for efflux transporters P-gp (ER = 35.7) and BCRP (ER = 4.0) and has moderate passive permeability (RRCK Papp = 5.4 × 10−6 cm s−1). PF-06273340 is well-tolerated was selected as a candidate for clinical development.

Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases activated by neurotrophins. Trks play important roles in pain sensation as well as tumour cell growth and survival signaling. Thus, inhibitors of Trk receptor kinases might provide targeted treatments for conditions such as pain and cancer. Recent developments in this field have been reviewed by Wang et al in Expert Opin. Ther.

Patents (2009) 19(3): 305-319 and an extract is reproduced below.

“1.1 Trk receptors

As one of the largest family of proteins encoded by the human genome, protein kinases are the central regulators of signal transduction as well as control of various complex cell processes. Receptor tyrosine kinases (RTKs) are a subfamily of protein kinases (up to 100 members) bound to the cell membrane that specifically act on the tyrosine residues of proteins. One small group within this subfamily is the Trk kinases, with three highly homologous isoforms: TrkA, TrkB, and TrkC. All three isofonns are activated by high affinity growth factors named neurotrophins (NT): i) nerve growth factor (NGF), which activates TrkA; ii) brain-derived neurotrophic factor (BDNF) and NT-4/5, which activate TrkB; and iii) NT-3, which activates TrkC. The binding of neurotrophins to the extracellular domain of Trks causes the Trk kinase to autophosphorylate at several intracellular tyrosine sites and triggers downstream signal transduction pathways. Trks and neurotrophins are well known for their effects on neuronal growth and survival.

1.2 Trks and cancer

Originally isolated from neuronal tissues, Trks were thought to mainly affect the maintenance and survival of neuronal cells. However, in the past 20 years, increasing evidence has suggested that Trks play key roles in malignant transformation, chemotaxis, metastasis, and survival signaling in human tumors. The association between Trks and cancer focused on prostate cancer in earlier years and the topic has been reviewed. For example, it was reported that malignant prostate epithelial cells secrete a series of neurotrophins and at least one Trks. In pancreatic cancer, it was proposed that paracrine and/or autocrine neurotrophin-Trk interactions may influence the invasive behavior of the cancer. TrkB was also reported to be overexpressed in metastatic human pancreatic cancer cells. Recently, there have been a number of new findings in other cancer settings. For example, a translocation leads to expression of a fusion protein derived from the W-terminus of the ETV9 transcription factor and the C-terminal kinase domain of TrkC. The resulting ETV6-TrkC fusions are oncogenic in vitro and appear causative in secretory breast carcinoma and some acute myelogenous leukemias (AML). Constitutively active TrkA fusions occurred in a subset of papillary thyroid cancers and colon carcinomas. In neuroblastoma, TrkB expression was reported to be a strong predictor of aggressive tumor growth and poor prognosis, and TrkB overexpression was also associated with increased resistance to chemotherapy in neuroblastoma tumor cells in vitro. One report showed that a novel splice variant of TrkA called TrkAIII signaled in the absence of neurotrophins through the inositol phosphate-AKT pathway in a subset of neuroblastoma. Also, mutational analysis of the tyrosine kinome revealed that Trk mutations occurred in colorectal and lung cancers. In summary, Trks have been linked to a variety of human cancers, and discovering a Trk inhibitor and testing it clinically might provide further insight to the biological and medical hypothesis of treating cancer with targeted therapies.

1.3 Trks and pain

Besides the newly developed association with cancer, Trks are also being recognized as an important mediator of pain sensation. Congenital insensitivity to pain with anhidrosis (CIPA) is a disorder of the peripheral nerves (and normally innervated sweat glands) that prevents the patient from either being able to adequately perceive painful stimuli or to sweat. TrkA defects have been shown to cause CIPA in various ethnic groups.

Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and opiates have low efficacy and/or side effects (e.g., gastrointestinal/renal and psychotropic side effects, respectively) against neuropathic pain and therefore development of novel pain treatments is highly desired. It has been recognized that NGF levels are elevated in response to chronic pain, injury and inflammation and the administration of exogenous NGF increases pain hypersensitivity. In addition, inhibition of NGF function with either anti- NGF antibodies or non-selective small molecule Trk inhibitors has been shown to have effects on pain in animal models. It appears that a selective Trk inhibitor (inhibiting at least NGF’s target, the TrkA receptor) might provide clinical benefit for the treatment of pain. Excellent earlier reviews have covered targeting NGF/BDNF for the treatment of pain so this review will only focus on small molecule Trk kinase inhibitors claimed against cancer and pain. However, it is notable that the NGF antibody tanezumab was very recently reported to show good efficacy in a Phase II trial against osteoarthritic knee pain.”

International Patent Application publication number WO2009/012283 refers to various fluorophenyl compounds as Trk inhibitors; International Patent Application publication numbers WO2009/152087, WO2008/080015 and WO2008/08001 and WO2009/152083 refer to various fused pyrroles as kinase modulators; International Patent Application publication numbers WO2009/143024 and WO2009/143018 refer to various pyrrolo[2,3-d]pyrimidines substituted as Trk inhibitors; International Patent Application publication numbers WO2004/056830 and WO2005/1 16035 describe various 4-amino-pyrrolo[2,3- d]pyrimidines as Trk inhibitors. International Patent Application publication number WO201 1/133637 describes various pyrrolo[2,3-d]pyrimidines and pyrrolo[2,3-b]pyridines as inhibitors of various kinases.

US provisional application US61/471758 was filed 5^th April 2012 and the whole contents of that application in it’s entirety are herewith included by reference thereto.

Thus Trk inhibitors have a wide variety of potential medical uses. There is a need to provide new Trk inhibitors that are good drug candidates. In particular, compounds should preferably bind potently to the Trk receptors in a selective manner compared to other receptors, whilst showing little affinity for other receptors, including other kinase and / or GPC receptors, and show functional activity as Trk receptor antagonists. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated. They should preferably be e.g. well absorbed from the gastrointestinal tract, and / or be injectable directly into the bloodstream, muscle, or subcutaneously, and / or be metabolically stable and possess favourable pharmacokinetic properties.

Among the aims of this invention are to provide orally-active, efficacious, compounds and salts which can be used as active drug substances, particularly Trk antagonists, i.e. that block the intracellular kinase activity of the Trk, e.g. TrkA (NGF) receptor. Other desirable features include good HLM/hepatocyte stability, oral bioavailability, metabolic stability, absorption, selectivity over other types of kinase, dofetilide selectivity. Preferable compounds and salts will show a lack of CYP inhibition/induction, and be CNS- sparing.

N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(5-chloropyridin-2-yl)acetamide

Scheme 1. Synthesis of 14^a

^aReagents and conditions:

(i) NIS, MeCN, 12 °C to rt, 1 h, 82%;

(ii) BrMe₂CO₂Me, KI, Cs₂CO₃, DMF, 60°C, 19 h, 92%;

(iii) LiOH, THF/H₂O, 60 °C, 3 h, 90%;

(iv) DIBAL-H, THF, 0 °C, 1.5 h, 56%;

(v) TBMS-Cl, imidazole, DMF, 0 °C to rt, 16 h, 96%;

(vi) benzophenone imine, Pd₂(dba)₃, K₃PO₄, DME, 50 °C, 17 h, 51%;

(vii) 20, i-PrMgCl, THF, 0 °C, then 22, THF, 0 °C to rt, 16 h, 66%;

(viii) 2,4-dimethoxybenzylamine, DMAP, 1,4-dioxane, reflux, 2 d, then citric acid, THF, rt, 5 h, 78%;

(viiii) 2-(5-chloropyridin-2-yl)acetic acid, T₃P, Et₃N, THF, rt, 2 h, then TFA, 50°C, 3 h, then K₂CO₃, MeOH, rt, 16 h, 48%.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.64 (s, 6H), 3.90 (d, J = 5.5, 2H), 3.95 (s, 2H), 5.05 (dd, J = 5.7, 5.5, 1H), 6.54 (br s, 2H), 7.49 (d, J = 8.4, 1H), 7.69 (s, 1H), 7.92 (dd, J = 8.3, 2.4, 1H), 8.40 (m, 1H), 8.56 (d, J = 2.5, 1H), 8.64 (d, J = 1.8, 1H), 8.94 (d, J = 2.2, 1H), 8.96 (s, 1H), 10.71 (s, 1H). HPLC (6 min, acid) R_t 1.26 min; UV 220 nM 100% purity; LC-MS (ES^–) m/z 478 (M – H⁺); HRMS (ES⁺) m/z 480.15468 (M + H⁺).

SYNTHESIS

WO-2012137089-A1

https://www.google.com/patents/WO2012137089A1?cl=enhttps://www.google.com/patents/WO2012137089A1?cl=en

MARK ANDREWS

Sharanjeet Kaur Bagal,

Karl Gibson

Kiyoyuki OMOTO

Thomas Ryckmans,

Example 46: N-(5-{[2-Amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5- yl]carbonyl}pyridin-3-yl)-2-(5-chloropyridin-2-yl)acetamide

(5-Chloropyridin-2-yl)acetic acid (26.1 g, 152 mmol) (see Preparation 90) was added to (5-aminopyridin- 3-yl){7-(2-{[ferf-butyl(dimethyl)silyl]oxy}-1 , 1-dimethylethyl)-2-[(2,4-dimethoxybenzyl)ami

d]pyrimidin-5-yl}methanone (75.0 g, 130 mmol ) (see Preparation 51 ), 1-propylphosphonic acid cyclic anhydride (187 mL, 317 mmol, 50% solution in EtOAc) and triethylamine (61.9 mL, 444 mmol ) in THF (423 mL). The mixture was stirred at 25°C for 2 hours then saturated aqueous sodium bicarbonate (400 mL) was added and the organic layer was separated. The aqueous phase was extracted with EtOAc (400 mL) and all organic phases were combined and dried over sodium sulfate then evaporated in vacuo. The residue brown solid was dissolved in trifluoroacetic acid (300 mL) and the solution was stirred at 50°C for 3 hours then evaporated in vacuo. Methanol (1800 mL) was added to the residue and the mixture was filtered. The filtrate was evaporated in vacuo and azeotroped with ethanol (3 x 200 mL).

Potassium carbonate (87.7 g, mmol) was added to the crude trifluoroacetamide in methanol (300 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water (2000 mL) and filtered. The solid was washed with water (200 mL) then triturated with ethanol (2 x 200 mL at room temperature then 380 mL at 50°C) to afford the title compound as a yellow solid in 48% yield, 29.9 g. H NMR (400 MHz, DMSO-c/6) δ: 1.64 (s, 6H), 3.90 (d, 2H), 3.95 (s, 2H), 5.05 (t, 1 H), 6.54 (br s, 2H), 7.49 (d, 1 H), 7.69 (s, 1 H), 7.92 (dd, 1 H), 8.40 (m, 1 H), 8.56 (m, 1 H), 8.64 (d, 1 H), 8.94 (d, 1 H), 8.96 (s, 1 H), 10.71 (s, 1 H); LCMS (System 3): R_t = 9.92 min; m/z 480 [M+H]⁺.

PAPER

The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

Sarah E. Skerratt

MARK ANDREWS

Abstract

The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially “druggable” point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.

ADDITIONAL INFORMATION

The aqueous solubility of PF-06273340 is 131 μM, much improved over previous analogues, it is highly kinase-selective (Gini score of 0.92) and has no measurable activity at the hERG channel. PF-06273340 was profiled in a series of in vitro safety assays, showing little cytotoxicity in THLE or HepG2 cell lines (IC50 > 42 μM and >300 μM, respectively) and was evaluated for broader pharmacological activity in a panel of receptors, ion channels, and enzymes. In this broad panel, all IC50/Ki values were >10 μM except for COX-1 (IC50 = 2.7 μM) and dopamine transporter assays (Ki = 5.2 μM) and PDEs 4D, 5A, 7B, 8B, and 11 (54−89% inhibition at 10 μM). PF-06273340 was screened in the Invitrogen wide kinase panel of 309 kinases, and all were inhibited by <40% when tested at 1 μM except the following: MUSK (IC50 53 nM), FLT-3 (IC50 395 nM), IRAK1 (IC50 2.5 μM), MKK (90% @ 1 μM), and DDR1 (60% @ 1 μM).

REFERENCES

1: Skerratt SE, Andrews MD, Bagal SK, Bilsland J, Brown D, Bungay PJ, Cole S,
Gibson KR, Jones R, Morao I, Nedderman A, Omoto K, Robinson C, Ryckmans T,
Skinner K, Stupple PA, Waldron G. The Discovery of a Potent, Selective and
Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of
Pain. J Med Chem. 2016 Oct 21. [Epub ahead of print] PubMed PMID: 27766865.

Gareth Waldron

(-)-32 as an off-white solid.
Analytical data
LCMS 418 [M+H]+1
H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.61 (dd,J = 11.2, 2.0 Hz, 1H), 6.49-6.38 (m, 2H), 6.33 (s, 1H), 5.61 (m, 1H), 4.88 (s, 2H), 4.20(t, J = 4.3 Hz, 2H), 3.35-3.18 (m, 6H).
Optical rotation [α]D20 -38.5° (c = 0.107, DMSO)

PAPER

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ

Son Pham

Associate Director, Medicinal Chemistry at Medivation

Roopa Rai

Sr. Director, Medicinal Chemistry at Medivation

 

Brahmam Pujala

Senior Research Scientist at Integral Biosciences

Abstract

The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.

Monali Banerjee

Director, R&D

Ms. Banerjee has more than 10 years of research experience, during which she has held positions of increasing responsibility. Her past organizations include TCG Lifesciences (Chembiotek) and Sphaera Pharma. Ms. Banerjee is a versatile scientist with a deep understanding of the fundamental issues that underlie various aspects of drug discovery. At Curadev, she has been responsible for target selection, patent analysis, pharmacophore design, assay development, ADME/PK and in vivo and in vitro pharmacology. Ms. Banerjee holds a Masters in Biochemistry and a Bachelors in Chemistry both from Kolkata University.

Nidhi Adlaka & Neha Munjal are developing a bioprocess for butanediol. Over the next few decades, chemical routes of manufacture will gradually be replaced by more environment friendly biological methods.

Read more at:
http://economictimes.indiatimes.com/articleshow/47276311.cms?utm_source=contentofinterest&utm_medium=text&utm_campaign=cppst

Dr. Arjun Surya, CSO, Curadev enthralling participants with anecdotes of his entrepreneurial jrney in drugdiscovery

Manish Tandon

Co-founder Curadev Pharma Pvt Ltd

//////////////B-cell,  BCR,  BTK,  inhibitor,  p110δ,  PI3K,  pyrazolopyrimidine, Novel Dual Inhibitors, BTK , PI3Kδ, Medivation, Integral BioSciences,  Curadev, Fundación Ciencia y Vida, Departamento de Ciencias Biológicas,

Valdetamid (Valdetamide)

Structural formula

UV – spectrum

Conditions : Concentration – 50 mg / 100 ml
The solvent designation schedule	methanol	Water	0.1 M HCl	0.1M NaOH
maximum absorption	–	–	–	–
	–	–	–	–
ε	–	–	–	–

IR – spectrum

Wavelength (μm)
Wave number (cm -1 )

Range
10 largest peaks:
Peak	53	55	57	67	69	81	112	126	127	140
Value	152	848	115	141	929	156	286	999	338	238

References

• UV and IR Spectra. H.-W. Dibbern, RM Muller, E. Wirbitzki, 2002 ECV

• NIST / EPA / NIH Mass Spectral Library 2008

• Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman.Academic Press, 2000.

• Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

Brief background information

Salt	ATC	Formula	MM	CAS
–	N05C	C 9 H 17 NO	155.24 g / mol	512-48-1

Using

• hypnotic

Classes substance

• Amides

Synthesis Way

Synthesis of a)

Trade names

A country	Tradename	Manufacturer
Germany	Arantxa	Hoechst
	Betadorm-H	Woelm
	insomnia	ICN
	Nokturetten	Starke
	New Dolestan	Much
Ukraine	no	no

Formulations

• dragees 50 mg;

• 300 mg Tablets

References

• DRP 473 329 (IG Farben; appl 1925.).

• DRP 616 876 (IG Farben; appl 1930.).

• DRP 622 875 (IG Farben; appl 1931.).

• GB 253,950 (IG Farben; appl 1926;.. D-prior 1925).

1H NMR PREDICT

13C NMR PREDICT

Acetylcholine Chloride

2-acetyloxyethyl(trimethyl)azanium;chloride

60-31-1

Acetylcholine chloride is obtained as white or off-white hygroscopic crystals, or as a crystalline powder. The salt is odorless, or nearly odorless, and is a very deliquescent powder. Acetylcholine bromide is obtained as deliquescent crystals, or as a white crystalline powder. The substance is hydrolyzed by hot water and alkali

Chemistry

History

Laboratory Synthesis Of Acetylcholine chloride

Acetylcholine
IUPAC name	2-Acetoxy-N,N,N-trimethylethanaminium
Abbreviation	ACh
Sources	motor neurons, parasympathetic nervous system, brain
Targets	skeletal muscles, brain, many other organs
Receptors	nicotinic, muscarinic
Agonists	nicotine, muscarine, cholinesterase inhibitors
Antagonists	tubocurarine, atropine
Precursor	choline, acetyl-CoA
Synthesizing enzyme	choline acetyltransferase
Metabolizing enzyme	acetylcholinesterase
Database links
CAS Number	51-84-3
PubChem	CID: 187
IUPHAR/BPS	294
DrugBank	EXPT00412
ChemSpider	182
KEGG	C01996

1H NMR PREDICT

13 C NMR PREDICT

/////////CC(=O)OCC[N+](C)(C)C.[Cl-]

Doxercalciferol

• Molecular FormulaC₂₈H₄₄O₂
• Average mass412.648

Doxercalciferol (1α-hydroxyvitamin D2) is a commercially approved vitamin D derivative used to treat chronic kidney disease (CKD) patients whose kidneys cannot metabolically introduce a hydroxyl group at C1. A new process for the production of doxercalciferol from ergocalciferol was developed using a continuous photoisomerization of a known vitamin D intermediate as the key step, thus circumventing the limitations of batch photoisomerization processes. Doxercalciferol is produced in an overall yield of about 10% from ergocalciferol.

Doxercalciferol

1H NMR (CDCl3) δ 6.40 (d, 1H, J = 11.2), 6.04 (d, 1H, J = 11.2), 5.35 (s, 1H), 5.15–5.29 (m, 2H), 5.03 (s, 1H), 4.45 (dd, 1H, J = 7.3, 4.0), 4.21–4.31 (m, 1H), 2.81–2.90 (m, 1H), 2.62 (d, 1H, J = 13.3), 2.34 (dd, 1H, J = 13.3, 6.5), 1.83–2.11(m, 6H), 1.42–1.79 (m, 7H), 1.21–1.40 (m, 3H), 1.04 (d, 3H, J = 6.6), 0.94 (d, 3H, J = 6.8), 0.86 (t, 6H, J = 7.3), 0.58 (s, 3H) ppm.

References

Doxercalciferol

Names
IUPAC name (1S,3R,5Z,7E,22E)-9,10-Secoergosta-5,7,10,22-tetraene-1,3-diol
Other names 1-Hydroxyergocalciferol; 1-Hydroxyvitamin D2; 1α-Hydroxyergocalciferol; 1α-Hydroxyvitamin D2; Hectorol; TSA 840
Identifiers
CAS Number	54573-75-0
3D model (Jmol)	Interactive image
ChEMBL	ChEMBL1200810
ChemSpider	4444554
DrugBank	DB06410
ECHA InfoCard	100.170.997
IUPHAR/BPS	2790
PubChem	5281107
UNII	3DIZ9LF5Y9
InChI[show]
SMILES[show]
Properties
Chemical formula	C28H44O2
Molar mass	412.66 g·mol−1
Pharmacology
ATC code	H05BX03 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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ADRAFINIL

2-((diphenylmethyl)sulfinyl)-acetohydroxamicaci;2-((diphenylmethyl)sulfinyl)-n-hydroxy-acetamid;2-((diphenylmethyl)sulfinyl)-n-hydroxyacetamide;2-(benzhydrylsulfinyl)acetohydroxamicacid;ADRAFINIL;2-[(DIPHENYLMETHYL)SULFINYL]ACETOHYDROXAMIC ACID;CRL 40028;OLMIFON

• CAS 63547-13-7
• MF:C15H15NO3S
• MW:289.35
• EINECS:264-303-1

WATCH THIS POST AS DETAILS LIKE SYNTHESIS ARE UPDATED………….

Adrafinil is touted mainly for its stimulant properties and ability to provide alertness and wakefulness.

• Stay up late/stay awake during normal sleeping hours: Adrafinil may be helpful for night workers who need a kick-start adapting their body’s natural circadian rhythm of wakefulness in the daytime and sleepiness in the evening to their job needs. This can also make it helpful for periodic late-night study sessions. Adrafinil is best taken in the afternoon or evening for nighttime wakefulness.
• Boost energy, alertness, and focus during the day time: Adrafinil can also be used as an energy-boost during waking hours.
• CONTACT SKYPE CATHERINESSPC WICKR

Adrafinil (INN) (brand name Olmifon)^[2] is a discontinued wakefulness-promoting agent (or eugeroic) that was formerly used inFrance to promote vigilance (alertness), attention, wakefulness, mood, and other parameters, particularly in the elderly.^[3][4] It was also used off-label by individuals who wished to avoid fatigue, such as night workers or others who needed to stay awake and alert for long periods of time. Additionally, “adrafinil is known to a larger nonscientific audience, where it is considered to be a nootropic agent.”^[3] Adrafinil is a prodrug; it is primarily metabolized in vivo to modafinil, resulting in very similar pharmacological effects.^[3] Unlike modafinil, however, it takes time for the metabolite to accumulate to active levels in the bloodstream. Effects usually are apparent within 45–60 minutes when taken orally on an empty stomach. Adrafinil was marketed in France under the trade name Olmifon^[2] until September 2011 when it was voluntarily discontinued.^[4]

Pharmacology

Pharmacodynamics

Because α₁-adrenergic receptor antagonists were found to block effects of adrafinil and modafinil in animals, “most investigators assume[d] that adrafinil and modafinil both serve as α₁-adrenergic receptor agonists.”^[3] However, adrafinil and modafinil have not been found to bind to the α₁-adrenergic receptor and they lack peripheral sympathomimetic side effects associated with activation of this receptor;^[5] hence, the evidence in support of this hypothesis is weak, and other mechanisms are probable.^[3] Modafinil was subsequently screened at a variety of targets in 2009 and was found to act as a weak, atypical blocker of the dopamine transporter(and hence as a dopamine reuptake inhibitor), and this action may explain some or all of its pharmacological effects.^[6][7][8] Relative to adrafinil, modafinil possesses greater specificity in its action, lacking or having a reduced incidence of many of the common side effects of the former (including stomach pain, skin irritation, anxiety, and elevated liver enzymes with prolonged use).^[9][10][11] There is a case report of two patients that adrafinil may increase interest in sex.^[3] A case report of adrafinil-induced orofacial dyskinesia exists.^[12][13] Reports of this side effect also exist for modafinil.^[12]

Pharmacokinetics

In addition to modafinil, adrafinil also produces modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056) as metabolites, which form from metabolic modification of modafinil.

History

Adrafinil was discovered in 1974 by two chemists working for the French pharmaceutical company Laboratoires Lafon who were screening compounds in search of analgesics.^[14] Pharmacological studies of adrafinil instead revealed psychostimulant-like effects such as hyperactivity and wakefulness in animals.^[14] The substance was first tested in humans, specifically for the treatment of narcolepsy, in 1977–1978.^[14] Introduced by Lafon (now Cephalon), it reached the market in France in 1984,^[4] and for the treatment of narcolepsy in 1985.^[14][15] In 1976, two years after the discovery of adrafinil, modafinil, its active metabolite, was discovered.^[14] Modafinil appeared to be more potent than adrafinil in animal studies, and was selected for further clinical development, with both adrafinil and modafinil eventually reaching the market.^[14] Modafinil was first approved in France in 1994, and then in the United States in 1998.^[15] Lafon was acquired by Cephalon in 2001.^[16] As of September 2011, Cephalon has discontinued Olmifon, its adrafinil product, while modafinil continues to be marketed.^[4]

Society and culture

Regulation

Athletic doping

Adrafinil and its active metabolite modafinil were added to the list of substances prohibited for athletic competition according to World Anti-Doping Agency in 2004.^[17]

New Zealand

In 2005 a Medical Classification Committee in New Zealand recommended to MEDSAFE NZ that adrafinil be classified as a prescription medicine due to risks of it being used as a party drug. At that time adrafinil was not scheduled in New Zealand.^[18]

Research

In a clinical trial with clomipramine and placebo as active comparators, adrafinil showed efficacy in the treatment of depression.^[3] In contrast to clomipramine however, adrafinil was well-tolerated, and showed greater improvement in psychomotor retardation in comparison.^[3] As such, “further investigations of the antidepressive effects of adrafinil are warranted.”^[3]

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SYNTHESIS

Adrafinil (CAS NO.63547-13-7) was discovered in the late 1970s by scientists working with the French pharmaceutical company Group Lafon. First offered in France in 1986 as an experimental treatment for narcolepsy, Lafon later developed modafinil, the primary metabolite of adrafinil. Modafinil possesses greater selective alpha-1 adrenergic activity than adrafinil without the side effects of stomach pain, skin irritations, feelings of tension, and increases in liver enzyme levels.
It is important to monitor the liver of an individual using adrafinil. It can cause liver damage in some instances.

The Adrafinil with CAS registry number of 63547-13-7 is also known as 2-[(Diphenylmethyl)sulfinyl]-N-hydroxyacetamide. The IUPAC name is 2-Benzhydrylsulfinyl-N-hydroxyacetamide. It belongs to product categories of Aromatics Compounds; Aromatics; Intermediates & Fine Chemicals; Pharmaceuticals; Sulfur & Selenium Compounds. This chemical is a light pink solid and its EINECS registry number is 264-303-1. In addition, the formula is C₁₅H₁₅NO₃S and the molecular weight is 289.35. This chemical is harmful if swallowed.

Physical properties about Adrafinil are: (1)ACD/LogP: 1.596; (2)ACD/LogD (pH 5.5): 1.60; (3)ACD/LogD (pH 7.4): 1.53; (4)ACD/BCF (pH 5.5): 9.60; (5)ACD/BCF (pH 7.4): 8.34; (6)ACD/KOC (pH 5.5): 175.52; (7)ACD/KOC (pH 7.4): 152.63; (8)#H bond acceptors: 4; (9)#H bond donors: 2; (10)#Freely Rotating Bonds: 6; (11)Index of Refraction: 1.653; (12)Molar Refractivity: 78.858 cm³; (13)Molar Volume: 215.542 cm³; (14)Polarizability: 31.262 10-24cm³; (15)Surface Tension: 67.25 dyne/cm; (16)Density: 1.342 g/cm³

Preparation of Adrafinil: it is prepared by reaction of diphenyl methyl bromide with thiourea. This reaction needs reagent NaOH. After reacting with chloroacetic acid, hydrochloric acid amine and hydrogen peroxide, the product is obtained. The yield is about 73%.

Uses of Adrafinil: it is used as non-amphetamine-type psychostimulant and can wake up and raise awareness. For the elderly arousal disorder and depressive symptoms in symptomatic treatment.

Benzhydrylsulphinyl-acetohydroxamic Acid (Adrafinil)¹

1 US Pat 4,066,686

Diphenylmethanethiol

15.2 g (0.2 mol) of thiourea and 150 ml of demineralized water are introduced into a 500 ml three-neck flask equipped with a central mechanical stirrer, and with a dropping funnel and a condenser on the (respective) side-necks.The temperature of the reaction mixture is brought to 50°and 49.4g (0.2 mol) of bromodiphenyl- methane are added all at once whilst continuing the heating. After refluxing for about 5 minutes, the solution, which has become limpid, is cooled to 20°C and 200 ml of 2.5 N NaOH are then added dropwise whilst maintaining the said temperature. The temperature is then again kept at the reflex for 30 minutes after which, when the mixture has returned to ordinary temperature (15-25°C), the aqueous solution is acidified with 45 ml of concentrated hydrochloric acid. The supernatant oil is extracted with 250 ml of diethyl ether and the organic phase is washed with 4×80 ml of water and then dried over magnesium sulphate. 39 g of crude diphenylmethane-thiol are thus obtained. Yield 97.5%.

Benzhydryl-thioacetic acid

10 g (0.05 mol) of diphenylmethane-thiol and 2g (0.05 mol) of NaOH dissolved in 60 ml of demineralised water are introduced successively into a 250 ml flask equipped with a magnetic stirrer and a reflux condenser. The reactants are left in contact for 10 minutes whilst stirring, and a solution consisting of 7g (0.075 mol) of chloroacetic acid, 3g (0.075 mol) of NaOH pellets and 60 ml of demineralized water is then added all at once. The aqueous solution is gently warmed to about 50°C for 15 minutes, washed with 50 ml of ether, decanted and acidified with concentrated hydrochloric acid. after filtration, 10.2g of benzhydryl-thioacetic acid are thus obtained. Melting point 129-130°C. Yield 79%.

Ethyl benzhydryl-thioacetate

The following reaction mixture is heated under reflux for 7 hours: 10.2 g (0.0395 mol) of benzhydryl-thioacetic acid, 100 ml of anhydrous ethanol and 2 ml of sulphuric acid. When heating has been completed, the ethanol isevaporated in vacuo; the oily residue is taken up in 100 ml of ethyl ether and the organic solution is then washed with water, with an aqueous sodium carbonate solution and then with water until the wash waters have a neutral pH. After drying over sodium sulphate, the solvent is evaporated. 10.5g of ethyl benzhydryl- thioacetate are thus obtained. Yield 93%.

Benzhydryl-thioacetohydroxamic acid

The following three solutions are prepared:

1. Ethyl Benzhydryl-thioacetate 10.8 g (0.0378 mol) in 40 ml methanol
2. Hydroxylamine hydrochloride 5.25 g (0.0756 mol) in 40 ml methanol
3. Potassium Hydroxide pellets 7.3 g (0.0134 mol) in 40 ml methanol

The solutions are heated, if necessary, until they become limpid, and when the temperatures have again fallen to below 40°C, the solution of potassium hydroxide in methanol is poured into the solution of hydroxylamine hydrochloride in alcohol. Finally, at a temperature of about 5° to 10°C, the solution of ethyl benzhydryl- thioacetate is added in its turn. After leaving the reactants in contact for 10 minutes, the sodium chloride is filtered off the limpid solution obtained is kept for about 15 hours at ordinary temperature. The methanol is then evaporated under reduced pressure, the residual oil is taken up in 100 ml of water and the aqueous solution is acidified with 3 N hydrochloric acid. The hydroxamic acid which has crystallized is filtered off, washed with water and then dried. 9.1 g of product are obtained. Yield = 87.5%. Melting point 118-120°C.

Adrafinil (CRL 40,028)

10.4g (0.038 mol) of benzhydryl-thioacetohydroxamic acid are oxidized at 40°C, over the course of 2 hours, by means of 3.8 ml (0.038 mol) of hydrogen peroxide of 110 volumes strength (33%), in 100 ml of acetic acid.

When the oxidation has ended, the acetic acid is evaporated under reduced pressure and the residual oil is taken up in 60 ml of ethyl acetate. The product which has crystallized is filtered off and then purified by recrystallisation from a 3:2 (by volume) mixture of ethyl acetate and isopropyl alcohol.

8g (73%) of Adrafinil, mp 159-160°C, are thus obtained. H₂O Solubility

CLIP

Figure 2: GC/MS extracted ion chromatogram (a) and mass spectrum (b) of derivatized adrafinil in the electron ionization mode (monitoring the m/z 167, 165 and 152 ions; all the four peaks are derivatised adrafinil products).

Figure 4: LC/ESI-MS full scan chromatogram of adrafinil and its metabolites (a) (modafinil acid RT 3.8 min, adrafinil RT 4.0 min, modafinil RT 4.1 min), and LC/ESI-MS full scan mass spectra of modafinil acid (b), adrafinil (c), and (d) modafinil. (b, c and d showing the similar ions at m/z 167, 165, 152 together with the appropriate sodium and potassium adducts).

NMR

1H NMR PREDICT

13C NMR PREDICT

Patent

https://www.google.com/patents/US6180678 below

FIG. 1 shows the structure of adrafinil and its metabolites.

FIG. 2 shows the chemical synthesis of adrafinil.

//////////////

References

External links

• “SID 184744 – PubChem Substance Summary“. PubChem Project. National Center for Biotechnology Information. Retrieved 7 December 2005.
• “Adrafinil – Bank of Automated Data on Drugs“. Bank of Automated Data on Drugs. VIDAL. Archived from the original on 5 October 2008. Retrieved 4 October 2008.
• Milgram, Norton W.; Callahan, Heather; Siwak, Christina (September 1992). “Adrafinil: A Novel Vigilance Promoting Agent” (PDF). CNS Drug Reviews. 5 (3): 193–212.doi:10.1111/j.1527-3458.1999.tb00100.x.
• Thobois, S. P.; Xie, J.; Mollion, H.; Benatru, I.; Broussolle, E. (August 2004). “Adrafinil-induced orofacial dyskinesia”. Movement Disorders. 19 (8): 965–966.doi:10.1002/mds.20154. PMID 15300665.

Adrafinil

Clinical data
Trade names	Olmifon
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	N06BX17 (WHO)
Legal status
Legal status	US: Unscheduled
Pharmacokinetic data
Bioavailability	80%
Metabolism	75% (Liver)
Metabolites	Modafinil
Biological half-life	1 hour (T1/2 is 12–15 hours for modafinil)[1]
Excretion	Kidney
Identifiers
Systematic (IUPAC) name: (±)-2-Benzhydrylsulfinylethanehydroxamic acid
Synonyms	CRL-40028
CAS Number	63547-13-7
PubChem (CID)	3033226
DrugBank	DB08925
ChemSpider	2297976
UNII	BI81Z4542G
KEGG	D07348
ChEMBL	CHEMBL93077
Chemical and physical data
Formula	C15H15NO3S
Molar mass	289.351 g/mol
3D model (Jmol)	Interactive image

////////////ADRAFINIL

• O=S(C(c1ccccc1)c2ccccc2)CC(=O)NO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

+91 9323115463

GLENMARK SCIENTIST ,  INDIA
web link

Personal website

BRAND ANTHONYCRASTO

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Dr. Anthony Melvin Crasto Principal Scientist, Glenmark Pharma +919323115463 | amcrasto@gmail.com | https://newdrugapprovals.wordpress.com | India

http://pubs.acs.org/doi/suppl/10.1021/op300056k

Preparation of 1-(2-Methoxyphenoxy)-2,3-epoxypropane 4.

To a stirring solution of 2-methoxy phenol 2 (10 kg, 80.55 mol) and water (40 L) at about 30 °C was added sodium hydroxide (1.61 kg, 40.25 mol) and water (10 L). After stirring for 30−45 min, epichlorohydrin 3 (22.35 kg, 241.62 mol) was added and stirred for 10−12 h at 25−35 °C. Layers were separated, and water (40 L) was added to the organic layer (bottom layer) containing product. Sodium hydroxide solution (3.22 kg, 80.5 mol) and water (10 L) were added at 27 °C and stirred for 5−6 h at 27 °C.

The bottom product layer was separated and washed with sodium hydroxide solution (3.0 kg 75 mol) and water (30 L). Excess epichlorohydrin (3) was recovered by distillation of the product layer at below 90 °C under vacuum (650−700 mmHg) to give 13.65 kg (94%) of title compound with 98.3% purity by HPLC, 0.2% of 2- methoxy phenol 2, 0.1% of epichlorohydrin 3, 0.1% of chlorohydrin 11, 0.3% of dimer 12 and 0.3% of dihydroxy 13.

1 H NMR (400 MHz, CDCl3, δ) 6.8−7.0 (m, 4H), 4.3 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 3.8 (dd, J = 5.6 Hz, 5.3 Hz, 1H), 3.7 (s, 3H), 3.2−3.4 (m, 1H), 2.8 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 2.7 (dd, J = 5.6 Hz, 5.3 Hz, 1H);

IR (KBr, cm−1 ) 2935 (C−H, aliphatic), 1594 and 1509 (CC, aromatic), 1258 and 1231 (C−O−C, aralkyl ether), 1125 and 1025 (C−O−C, epoxide);

MS (m/z) 181 (M+ + H).

Compound Details

CAS 2210-74-4

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

CREDIT……….http://www.molbase.com/en/synthesis_2210-74-4-moldata-95563.html

RakeshwarBandichhor

DR REDDYS LABORATORIES

An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers

By: Laura I. Mosquera-Giraldo and Lynne S. Taylor Imagine spending billions of dollars in the discovery of a new drug, and then realizing that it is impractical to administer it orally because it cannot reach the systemic circulation and achieve a therapeutic effect. This is the case for many emerging drugs that are insoluble in water, […]

via Designing Polymers for Amorphous Solid Dispersions — AAPS Blog

lumefantrine

2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylidene]-9H-fluoren-4-yl]ethan-1-ol

UNII F38R0JR742
CAS number 82186-77-4
Weight Average: 528.94
Monoisotopic: 527.154947772
Chemical Formula C30H32Cl3NO

Lumefantrine (or benflumetol) is an antimalarial drug. It is only used in combination with artemether. The term “co-artemether” is sometimes used to describe this combination.^[1] Lumefantrine has a much longer half-life compared to artemether and so is therefore thought to clear any residual parasites that remain after combination treatment.^[2]

Lumefantrine, along with pyronaridine and naphtoquine, were synthesized in course of the Project 523 antimalaria drug research initiated in 1967; these compounds are all used in combination antimalaria therapies.^[3][4][5]

Lumefantrine is an antimalarial drug chemically known as 2-(dibutylamino)-1-[(9Z)-2, 7-dichloro-9-(4- chlorobenzylidene)-9H-floren-4-yl] ethanol, which is used in the prevention and treatment of Malaria in worm blooded animals. Lumefantrine is using the combination of β-Artemether in the treatment of Malaria

http://derpharmachemica.com/vol8-iss3/DPC-2016-8-3-91-100.pdf

REFERENCES

[1] Ulrich Beutler, C Peter.; Fuenfschilling.; and Andreas, Steinkemper.; Novartis Pharma AG; Chemical and Analytical Development: CH-4002 Basel, Switzerland, Organic Process Research & Development 2007, 11, 341- 345.

[2] Boehm, M. Fuenfschilling.; Krieger, P. C.; Kuesters, E. M.; Struber, F.; Org. Process Res. DeV. 2007, 11, 336- 340.

[3] (a) Rao, D. R.; Kankan, R. N.; Phull, M. S.; Patent Application CN 1009-3724 20060424, 2005. (b) Deng, R.; Zhong, J.; Zhao, D.; Wang, J.; Yaoxue, X. 2000, 35 (1), 22. (c) Allmendinger, Th.; Wernsdorfer, W. H. PCT WO 99/67197.

[4] Perrumattam, J.; Shao, Ch.; Confer, W. L. Synthesis 1994, 1181.

[5] Fuenfschilling, P. C.; Hoehn P.; Mutz J.-P. Organic Process Res. Dev. 2007, 11, 13.

[6] Di Nunno, L.; Scilimati, A. Tetrahedron 1988, 44, 3639.

[7] Pharmacopeial Forum, Vol. 36(2) [Mar.-Apr. 2010]

Preparation of 2-(dibutylamino)-1-[(9Z)-2, 7-dichloro-9-(4-chlorobenzylidene)-9H-floren-4-yl] ethanol (Lumefantrine) 1.

To a stirred solution of NaOH (1.97 g 0.0492 mol) in methanol (100 ml) there was added 1-(2, 7- dichloro-9 H-fluren-4-yl)-2-(dibutyl amino) ethanol (10 g, 0.0246 mol) and para chloro benzaldehyde (5.24 g 0.0372). The suspension obtained was stirred at reflux temperature till the absence of starting material by TLC. After confirming the product formation reaction mixture was cooled to room temperature and further stirred at same temperature for overnight. The precipitated solids were filtered and washed with methanol and dried under vacuum at 50°C to get desired compound.  (Purity by HPLC: 99%).

IR (cm-1): 3408, 3092, 2953, 2928, 2870, 2840, 1634, 1589, 1487, 1465, 1443, 1400, 1365, 1308, 1268, 1241, 1207, 1173, 1156, 1085, 1071, 1014, 980, 933, 874, 839, 815, 806, 770;

1H NMR (CDCl3, δ ppm): 7.75 (d, 1H, CH, J 1.5 Hz), 7.68 (d, 1H, CH, J 1.5 Hz), 7.60-7.63 (m, 1H, CH), 7.32-7.35 (dd, 1H, CH, J 1.7,8.3 Hz), 7.45-7.50 (m, 1H, CH), 5.35-5.39 (dd, 1H, CH, J 3.0,9.9 Hz), 2.41-2.74 (m, 1H, CH2Ha), 2.86-2.92 (m, 1H, CH2Hb), 2.41-2.74 (m, 4H, CH2), 1.25-1.56 (m, 8H, CH2), 0.97 (t, 1H, CH, J 7.2 Hz), 7.60-7.63 (m, 1H, CH), 7.45-7.50 (m, 4H, CH), 4.54 (broad, 1H, OH),

13C NMR (CDCl3, δ ppm): 138.2, 141.5, 120.6, 133.2, 126.3, 135.0, 135.0, 136.4, 123.9, 128.3, 132.8, 123.0, 139.8, 65.5, 60.0, 53.5, 29.1, 20.6, 14.0, 127.6, 134.7, 130.5, 129.1, 133.2;

MS: m/z: 528 [M+H]+ ; Analysis calcd. for C30H32Cl3NO: C, 68.12; H, 6.10; N, 2.65% Found: C, 68.38; H, 6.14; N, 2.63 %.

CLIP

One-dimensional 1H NMR spectrum of B) a lumefantrine standard,

A CLIP

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532012000100010&lng=en&nrm=iso

CLIP

A simple and precise method for quantitative analysis of lumefantrine …

 

References

Lumefantrine

Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a609024
Routes of administration	Oral
ATC code	P01BF01 (WHO) (combination with artemether)
Legal status
Legal status	US: C
Identifiers
IUPAC name[show]
CAS Number	82186-77-4
PubChem (CID)	6437380
DrugBank	DB06708
ChemSpider	4941944
UNII	F38R0JR742
KEGG	D03821
ChEBI	CHEBI:156095
ChEMBL	CHEMBL38827
Chemical and physical data
Formula	C30H32Cl3NO
Molar mass	528.939 g/mol
3D model (Jmol)	Interactive image

///////////lumefantrine

CCCCN(CCCC)CC(O)C1=C2C(=CC(Cl)=C1)\C(=C/C1=CC=C(Cl)C=C1)C1=C2C=CC(Cl)=C1

MODANAFIL

Patent EP0966962 and Patent US2002043207.

Modafinil (INN,^[6] USAN, BAN, JAN) is a wakefulness-promoting agent (or eugeroic) used for treatment of disorders such as narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.^[7] It has also seen widespread off-label use as a purported cognition-enhancing agent. In English-speaking countries it is sold under the brand names Alertec, Modavigil, and Provigil. In the United States modafinil is classified as a schedule IV controlled substance and restricted in availability and usage, due to concerns about possible addiction potential. In most other countries it is a prescription drug but not otherwise legally restricted.

Although the mechanism of action of modafinil was initially unknown, it now appears that the drug acts as a selective, relatively weak, atypical dopamine reuptake inhibitor. However, it appears that other additional mechanisms may also be at play.

History

Modafinil was originally developed in France by neurophysiologist and emeritus experimental medicine professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide,^[77] and has similar activity to the parent drug but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil.

In 1998, modafinil was approved by the U.S. Food and Drug Administration^[78] for the treatment of narcolepsy and in 2003 for shift work sleep disorder and obstructive sleep apnea/hypopnea^[79] even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil.^[80]

It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who originally leased the rights from Lafon, but eventually purchased the company in 2001.

Cephalon began to market the R-enantiomer armodafinil of modafinil in the U.S. in 2007. After protracted patent litigation and negotiations (see below), generic versions of modafinil became available in the U.S. in 2012.

That’s how it went…

2-benzhydryl-sulfanylacetamide.

Diphenylbromomethane (4,95g = 0.02 moles) and thiourea (1,52g=0.02moles) were refluxed in 20mls water for 30mins. As the synth from Rh’s says, a clear solution must have been formed in 5 mins, but in the end we still had a lot of oil at the bottom (the reasion to blame was old, semidecomposed diphenylbromomethane – when we opened the can, it emitted HBr). We were too lazy to separate the oil , so 2.5g (0.04moles) KOH in 15mls water was added straight and the reflux continued for 30 more mins. A disgusting stench filled the lab.

Thus obtained solution of potassium salt of diphenylmercaptane was cooled to 50-60 C and 1.9g (0.02moles) of chloroacetamide was added thereto. The mixtr was left to its own devices for 2hours – the precipitated oil crystallized. The xtals were filtered, washed thrice w/water, thrice w/ether (removing all benzhydrol). After drying there was obtained 1.9g (37%) of  finely divided crystals with mp of 111 C.

With fresh diphenylbromomethane this will give not less than 80% – otherwise I’ll bee a reddish (this is an idiom which I am again unable to translate).

Modafinil

Into the solution of 3.6g benzhydrylsulfanylacetamide (0.014moles) in 15mls of GAA there was added 3mls (~0.03moles) 30% hydrogene peroxide. The mixture was left at RT (15 Ñ in our case, better not to heat above) for 20 hrs. Then into the solution there was added 30mls aqua, scratching the walls with a glass rod. After 1 hr the precipitate was filtered, washed w/water twice, then w/ether and dried. Yield – 2,3g (61%), mp – 158-159 C. After some time the mother liquor yielded some more product but we were too lazy to work it up.

PATENT
Patent US2002183552

This is a part of the experimental section:

Preparation of isothiouronium Salt (IV).

Diphenylmethanol (130 g, 0.7 mole) and thiourea (65 g, 0.85 mole) are added in 0.5 L reactor charging with water (325 ml). The mixture is heated to 95°C. (an emulsion is obtained) and 48% HBr (260 gr. 3.22 mole, 4.6 equivalents) is then added gradually during 0.5 hour. The mixture is heated under reflux {106-107°C) for 0.5 hour and cooled to 80-85°C. At this temperature, the mixture is seeded with several crystals of the product and the mixture is stirred at that temperature for 0.5 hour and then cooled to 25°C. The colorless crystals are collected by filtration, washed with water (200 ml) yielding about 240 gr. of wet crude isothiouronium salt.

Preparation of diphenylmethylthioacetamide.

A 2 L reactor was charged with diphenylmethylisothiouronium bromide crude wet obtained (240 gr.) and water {700 mL) under nitrogen. The suspension was heated to 60°C and 46% aqueous NaOH solution (98 ml, 1.68 mole, 2.4 eq.) was added. The reaction mixture was heated to 85°C and stirred until all the solid was dissolved. Then, it was cooled to 60°C and chloroacetamide (80 g, O.84 mole, 1.2 eq.) was added in five portions hour at 60-70°C during one hour. The suspension is stirred at 70°C for 4-5 hours. The mixture was filtered while warm and the cake was washed with hot water (250 ml). Diphenylmethylthioacetamide crude wet is obtained [220 gr., HPLC assay: 78%, HPLC purity: 95%, yield: 95% (from diphenylmethanol.)]

20 gr. of the product was recrystallized twice from ethyl acetate, dried in vacuo to give 15 gr. of pure title compound.

Preparation of Modafinil.

A 1.0 L reactor was charged with diphenylmethylthioacetamide crude wet (220 gr.) obtained above and glacial acetic acid (610 mL). The mixture was heated to 40°C and stirred until full dissolution is achieved. 5.8% H2O2 solution (500g, 1.2 eq) was added dropwise during 0.5 hours at 40-45°C. The reaction mixture was stirred at 40-45°C for 4 hours. Then sodium metabisulfite (18.3g) in 610 mL water was added in order to quench the unreacted H2O2 and the suspension was stirred for 0.5 hours. Then the reaction mixture was cooled to 15°C and filtered. The cake was washed with water (610 mL) and dried on air to obtain crude wet Modafinil (205 g). Reslurry in refluxing ethyl acetate, followed by recrystallization from methanol:water (4:1) solution afforded pure Modafinil [125 g, HPLC assay: 99.9%, HPLC purity: 99.9%, yield: 67% (from diphenylmethanol)].

CLIP

Anti-Narcoleptic Agent Modafinil and Its Sulfone: A Novel
Facile Synthesis and Potential Anti-Epileptic Activity
Nithiananda Chatterjie, James P. Stables, Hsin Wang, and George J. Alexander
Neurochemical Research, Vol. 29, No. 8, August 2004 (© 2004), pp. 1481–1486

Abstract:

We report a facile procedure to synthesize racemic modafinil (diphenylmethylsulfinylacetamide), which is now being used in pharmacotherapy, and its achiral oxidized derivative (diphenylmethylsulfonyl acetamide). Modafinil is of interest more than for its potential anti-narcoleptic activity. It has also been reported to have neuroprotective properties and may potentially be effective in the enhancement of vigilance and cognitive performance. Finally, it may also protect from subclinical seizures that have been implicated as causative factors in autistic spectrum disorders and other neurodegenerative conditions. This agent can now be synthesized simply and in larger amounts than previously, making it more readily available for testing in various research modalities. The described procedure also lends itself to production of several other amides of potential interest. We are currently in the process of synthesizing and testing several new derivatives in this series. The anticonvulsant properties of modafinil and its sulfone derivative have not previously been extensively described in the literature. It may be of interest to note that the oxidized derivative of modafinil is also nontoxic and almost as effective as an anticonvulsant as the parent.

Experimental

Diphenylmethylthioacetic Acid (3)
Benzhydryl bromide (14.78 gm, 0.059 mole) was dissolved in 75 ml of acetone in a 250-ml round-bottomed flask. To this solution was added dropwise sodium mercaptoacetate (6.59 g, 0.058 mole) in about 60 ml of H2O; the mixture was stirred under N2 for 2 h at room temperature and was thereafter warmed at about 60–70°C for 1 h. The reaction mixture was evaporated to dryness and taken up in CH2Cl2 and saturated aqueous NaHCO3. The organic extract was rejected, and the aqueous phase was treated with acid to pH 2 and chilled. Suction filtration gave the 6.9 g of the acid (3, 46%), mp 125°C. Rf  0.2. Recrystallization from MeOH/H2O gave mp 126–128°C.

Diphenylmethylthioacetamide (4)
Diphenylmethylthioacetic acid (19.5 g, 0.076 mole)
in 114 ml of dry benzene was taken in a 250-ml roundbottomed
flask attached to a reflux condenser, under N2 gas. To this was added thionyl chloride (19.5 ml, 0.097 mole) with a dropping funnel. The mixture was stirred at room temperature with a magnetic stirrer and refluxed for 1 h. Thereafter, the mixture was evaporated under low pressure to give a yellow oil that was taken up in about 100 ml of CH2Cl2 and filtered to yield a clear orange solution. This was chilled in ice water and added slowly to an ice-cold solution of concentrated NH4OH in H2O (40:40 ml). The ensuing mixture was stirred for 1 h and shaken well in a separatory funnel. The organic layer was dried (Na2SO4) and evaporated to dryness to give 14.39 g (54%) of the amide (4), mp 108–109°C (lit2 110°C). Rf  0.8. Recrystallization from CH3OH/H2O gave mp 109–110°C.

Diphenylmethylsulfinylacetamide (modafinil, 1)
Diphenylthioacetamide (3.46 g, 0.013 mole) was  taken in glacial acetic acid (14 ml) with stirring; to this was added 1.34 ml of 30% H2O2 with chilling in ice water. The mixture was left in the refrigerator for 4 h and thereafter worked up by treating it with 70 ml of ice-cold water. The precipitated material was filtered under suction and washed with ice-cold water to give 1.5 g of white crystals (43%), mp 159–160°C. Rf  0.6. Recrystallization from hot MeOH gave mp 161–162°C

Diphenylmethylsufonylacetamide (2)
Diphenylmethylthioacetamide (2.5 g, 0.009 mole) (reg. No. 118779-53-6) was dissolved in about 12 ml of glacial acetic acid and 3 ml of 30% H2O2 and set aside overnight (16 h or more). The next day, the mixture was diluted with 100 ml of H2O and set aside to cool in the refrigerator. Upon filtration and drying, 2.1 g (80%) of 2 was obtained as a white powder. Rf  0.89. The melting  point of sample after recrystallization from absolute EtOH was 195–197°C.

One aspect of our preparation of modafinil needs further mention. When diphenylmethylthioacetamide (4) is being oxidized by H2O2, care must be taken to keep the reaction mixture cool, and workup should be done in a timely manner. Allowing the reaction to go to 24 h or longer at room temperature results in the formation of the sulfone (2). The paper by Mu et al. (3) does not discuss this possibility. In our hands, the procedure stated therein led to the higher melting sulfone and not the modafinil. Our NMR data for the newly prepared modafinil preparation are in consonance with the data of the patented commercial product. It should be noted that the methylene protons in modafinil are geminally
coupled and appear as a pair of doublets. This is due to the fact that the adjacent sulfoxide moiety is chiral, and therefore the methylene protons adjacent to it wind up being diastereotopic with different chemical shifts and coupling. In the sulfone 2, the methylene protons appear as a singlet due to the fact that the adjacent sulfone moiety is achiral, thus making the two protons equivalent. Modafinil 1 is, however, an equal mixture of enantiomers, as in the reported patent and publication (2,3).

RESULTS
The chemical pathway leading to modafinil may be
represented in Scheme 1.

see pdf for further information and references,

CLIP

Synthesis and determination of the absolute configuration of the enantiomers of modafinil
Thomas Prisinzano^a, John Podobinski^a, Kevin Tidgewell^a, Min Luo^a and Dale Swenson^b
Tetrahedron: Asymmetry 15(6), 1053-1058 (2004) (../rhodium/pdf /modafinil.enantiomers.pdf)
DOI:10.1016/j.tetasy.2004.01.039

^a Division of Medicinal & Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242-1112, USA
^b Department of Chemistry, The University of Iowa, Iowa City, Iowa 52242, USA

Abstract
The asymmetric synthesis of both enantiomers of modafinil, a unique CNS stimulant with a reduced abuse liability, is described. This approach effectively prepares modafinil on a multigram scale in several steps from benzhydrol. The described synthetic route has also been used to produce the more water soluble analogue, adrafinil. X-ray crystallographic analysis on (-)-(diphenylmethanesulfinyl)acetic acid has determined the absolute configuration to be R.

Graphical Abstract

Stereochemistry Abstract

(S)-(+)-(Diphenylmethanesulfinyl)acetic acid
C₁₅H₁₄O₃S

[alpha]D²² + 40.2 (c=1.11, MeOH)
Source of chirality: resolution via diastereomeric salt formation with (R)-(+)-alpha-methylbenzylamine
Absolute configuration: S CLIP

http://www.wmich.edu/cas/experts/docs/2011posters/modafinil.pdf

Narcolepsy is a debilitating neurological disorder which is characterized by chronic sleepiness and is marked to be disorganization of sleep and wake patterns. Every six out of ten thousand people in Western Europe and North America are affected by this disorder. Modafinil (Provigil®) is approved by the Food and Drug Administration for the treatment of narcolepsy. It is commonly used in opposition to Ritalin®, however Ritalin® has an associated dependency issue. Modafinil, a central nervous system stimulant, has reported to have little abuse potential. Modafinil has the ability to act like wake-promoting sympathomimetic agents which includes amphetamine. At relevant pharmacological concentrations modafinil lacks binding ability to receptors for sleep/wake regulation, which includes the ones used for norepinephrine and serotonin. The precise mechanism of action of modafinil is unknown and is presently being researched. Modafinil contains a chiral sulfoxide moiety but is prescribed as a racemate. In collaboration with faculty from the Psychology department at Western Michigan University we were to synthesize modafinil for behavioral studies with animals. Therefore a large scale of pure modafinil was synthesized.

The tetrahedral sulfur atom acts as a chiral center (being surrounded by two dissimilar carbon atoms, an oxygen atom and an electron lone pair (Figure 1). Unlike most analogous trisubstituted amines that undergo umbrella-like inversion at the nitrogen atom, sulfoxides are configurationally stable.

The initial target of this synthesis was to prepare the 2-(diphenylmethylthio)acetamide (1) (Scheme I). The reaction of benzyhydral chloride and thiourea are reacted with potassium iodide, water, heat, 30% sodium hydroxide, 2-chloroacetamide and triethylamine. The procedure required the 2-(diphenylmethylthio) acetamide (1) to be recrystallized to remove any impurities with methanol:water solution 60:40 . After recrystallization (Figure 2) the ¹H NMR spectrum of the synthesized 2-(diphenylmethylthio)acetamide (1) provides evidence that the recrystallization did not purify the compound. In addition recrystallization significantly reduced the percent yield from 78.3-79.2% to 56%. If the compound were pure it would only show peaks at the following locations (ppm): 3.05 (s, 2H), 5.18 (s, 1H), 6.53 (s, 1H), 7.21-7.44(m, 10H).

In preparing (±) modafinil (2) the procedure used acetic acid and hydrogen peroxide to form peracetic acid to react with 2-(diphenylmethylthio)acetamide (1) to form (±) modafinil (2) . The summation of experimentations of Scheme II eventually lead us to use of commercially available peracetic acid to obtain a more pure molecule of (±) modafinil (2). Over oxidation of the sulfone product can be seen if occurs at the peak (ppm):3.7-3.8 in a¹H NMR spectrum of (±) modafinil (2) .

To produce pure 2-(diphenylmethylthio)acetamide (1) elimination of the recrystallization step and 2-(diphenylmethylthio)acetamide (1) was then purified via column chromatography using dichloromethane:ether 80:20 as an eluent with the stationary phase (silica gel). After testing several of the fractions from the column using thin layer chromatography the fractions where able to be identified that contained 2- (diphenylmethylthio)acetamide (1). Once 2-(diphenylmethylthio)acetamide (1) was isolated it was oxidized with peracetic acid. The oxidation process was extended to three hours due to lack of desired product (±) modafinil (Figure 1).

With the procedure we used and modified through experimentation a new procedure was developed that increased the percent yield from 56% to 78.3-79.2%. We encountered a few problems that lead to the removal of the recrystallization step and the use of column chromatography was performed to purify 2-(diphenylmethylthio)acetamide (1) . Over- oxidation could have occurred but would have showed up at 3.7-3.8 (ppm), this did not occur in our experiment. The peak at 1.5 (ppm) is a water peak that was not fully removed during the rotovep procedure. After a precise and confident procedure was perfected then we were able to upscale the reaction and sythesize12gs of pure (±) modafinil.

FROM EROWID………

Benzhydrylsulphinylacetamide (Modafinil)²

Benzhydrylthioacetyl chloride

19.5g (0.076 mol) of benzhydrylthioacetic acid in 114 ml of benzene are placed in a three-necked flask provided with a condenser and a dropping funnel. The mixture is heated and 19 ml of thionyl chloride are added drop by drop. Once the addition is complete, the reflux is continued for about 1 hour, cooling and filtering are carried out and the benzene and the excess thionyl chloride and then evaporated. In this way, a clear orange oil is obtained.

Benzhydrylthioacetamide

35 ml of ammonia in 40 ml of water are introduced into a three-necked flask provided with a condenser and a dropping funnel and the benzhydrylthioacetyl chloride dissolved in about 100 ml of methylene chloride is added drop by drop. Once the addition is complete, the organic phase is washed with a dilute solution of soda and dried over Na₂SO₄, the solvent is evaporated and the residue is taken up in diisopropyl ether; in this way, the benzhydrylthioacetamide is crystallized. 16.8 g of product (yield 86%) are obtained. M.p. 110°C.

Modafinil (CRL 40,476)

14.39 g (0.056 mol) of benzhydrylthioacetamide are placed in a balloon flask and 60 ml of acetic acid and 5.6 ml of H₂O₂ (about 110 volumes, 33%) are added. The mixture is left in contact for one night at 40°C. and about 200 ml of water are then added; the CRL 40476 crystallizes. By recrystallization from methanol, 11.2 g of benzhydrylsulphinylacetamide are obtained. Yield: 73%. M.p. 164-66°C.

High-yield Synthesis of Modafinil from Benzhydrol⁵

A recent patent⁵ describes a very easy two-step route to the Modafinil precursor diphenylmethanethioacetamide from benzhydrol (diphenylmethanol) in 90% yield and with 95% purity. A 200g batch is made in a 2000 mL vessel using water as reaction medium and ethyl acetate for recrystallization of the product.

Diphenylmethylbromide is prepared in situ from benzhydrol and react it with thiourea in a one-pot reaction to form the corresponding isothiouronium salt. The crude salt is then reacted with chloroacetamide (by generating the thiolate cation in situ), and after filtration and washing, diphenylmethylthioacetamide is isolated in excellent yield and good purity. After oxidation of the thioacetamide with hydrogen peroxide, followed by recrystallization, the overall yield of Modafinil is 67% from the benzhydrol.

(Chimimanie’s Voice:) The synthesis works just as great without the nitrogen inert atmosphere (most patents do not use it at all), step two is only a hydrolysis of the thiouronium salt to the thiolate. You just have to put the salt, NaOH and heat till you got a homogenous solution, with no more solid material floating around. The following chloroacetamide S_N2 reaction is a breeze too. Sometime a blue solution can bee obtained, it is nothing to worry about. In the final step, you just have to filter off the solid which did not dissolve when the crude thioacetamide is put in the GAA/H₂O₂, bee4 crashing the soluble one with water.
Do not forget to slurry the modafinil in EtOAc and then recrystallize it from aqueous MeOH, as the crystalline shape of modafinil is important for the kinetic and quality of effects, at least according to the patents EP0966962 and US2002043207.

Experimental

Preparation of isothiouronium Salt (IV)

Diphenylmethanol (130 g, 0.7 mole) and thiourea (65 g, 0.85 mole) are added in 0.5 L reactor charging with water (325 ml). The mixture is heated to 95°C. (an emulsion is obtained) and 48% HBr (260 gr. 3.22 mole, 4.6 equivalents) is then added gradually during 0.5 hour. The mixture is heated under reflux (106-107°C) for 0.5 hour and cooled to 80-85°C. At this temperature, the mixture is seeded with several crystals of the product and the mixture is stirred at that temperature for 0.5 hour and then cooled to 25°C. The colorless crystals are collected by filtration, washed with water (200 ml) yielding about 240 gr. of wet crude isothiouronium salt.

(Antoncho’s Voice:) Assholium successfully made Modafinil by this method, but there turned out to be a mistake in the original patent text – In the preparation of IV, the quantity of HBr stated here is excessive and leads to complete hydrolysis of the initially formed isothiouronium salt. The acid should bee added until the reaction mixture turns completely clear (about half as much as the patent says) – a sort of titration. Further addition will result in precipitation of heavy stinky oil, benzhydrylmethanethiol.

Preparation of diphenylmethylthioacetamide

A 2 L reactor was charged with diphenylmethylisothiouronium bromide crude wet obtained (240 gr.) and water (700 mL) under nitrogen. The suspension was heated to 60°C and 46% aqueous NaOH solution (98 ml, 1.68 mole, 2.4 eq.) was added. The reaction mixture was heated to 85°C and stirred until all the solid was dissolved. Then, it was cooled to 60°C and chloroacetamide (80 g, 0.84 mole, 1.2 eq.) was added in five portions hour at 60-70°C during one hour. The suspension is stirred at 70°C for 4-5 hours. The mixture was filtered while warm and the cake was washed with hot water (250 ml). Diphenylmethylthioacetamide crude wet is obtained [220 gr., HPLC assay: 78%, HPLC purity: 95%, yield: 95% from diphenylmethanol]. 20g of the product was recrystallized twice from ethyl acetate, dried in vacuo to give 15g of pure title compound.

Preparation of Modafinil

A 1.0 L reactor was charged with diphenylmethylthioacetamide crude wet (220 gr.) obtained above and glacial acetic acid (610 mL). The mixture was heated to 40°C and stirred until full dissolution is achieved. 5.8% H₂O₂ solution (500g, 1.2 eq) was added dropwise during 0.5 hours at 40-45°C. The reaction mixture was stirred at 40-45°C for 4 hours. Then sodium metabisulfite (18.3g) in 610 mL water was added in order to quench the unreacted H₂O₂ and the suspension was stirred for 0.5 hours. Then the reaction mixture was cooled to 15°C and filtered. The cake was washed with water (610 mL) and dried on air to obtain crude wet Modafinil (205 g). Reslurry in refluxing ethyl acetate, followed by recrystallization from methanol:water (4:1) solution afforded pure Modafinil [125 g, HPLC assay: 99.9%, HPLC purity: 99.9%, yield: 67% (from diphenylmethanol)].

Modafinil

(R)-(−)-modafinil (armodafinil; top) (S)-(+)-modafinil (bottom)
Clinical data
Trade names	Provigil, others (see below)
AHFS/Drugs.com	Monograph
MedlinePlus	a602016
License data	US FDA: Modafinil
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Dependence liability	Psychological: Very low[1] Physical: Negligible[1]
Addiction liability	Very low to low[2]
Routes of administration	Oral (tablets)
ATC code	N06BA07 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: Schedule F UK: POM (Prescription only) US: Schedule IV
Pharmacokinetic data
Bioavailability	Not determined due to the aqueous insolubility
Protein binding	62%
Metabolism	Hepatic (primarily via amide hydrolysis;[3] CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 involved [4]
Biological half-life	15 hours (R-enantiomer), 4 hours (S-enantiomer)[5]
Excretion	Urine (80%)
Identifiers
IUPAC name[show]
Synonyms	CRL-40476; Diphenylmethylsulfinylacetamide
CAS Number	68693-11-8
PubChem (CID)	4236
IUPHAR/BPS	7555
DrugBank	DB00745
ChemSpider	4088
UNII	R3UK8X3U3D
KEGG	D01832
ChEBI	CHEBI:31859
ChEMBL	CHEMBL1373
ECHA InfoCard	100.168.719
Chemical and physical data
Formula	C15H15NO2S
Molar mass	273.35 g/mol
3D model (Jmol)	Interactive image

Atul Kumar

Professor, Academy of Scientific and Innovative Research (AcSIR)/ Senior Principal Scientist at CSIR-CDRI

Central Drug Research Institute

Medicinal and Process Chemistry Division (CDRI)

Lucknow, Uttar Pradesh, India

Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide, MOD) is a key psychostimulant drug used for the treatment of narcolepsy and other sleep disorders that has a very low addiction liability. Recently, MOD has been clinically investigated for the treatment of cocaine addiction and used by astronauts in long-term space missions. We have developed a synthetic strategy for “smart drug” Modafinil. An efficient atom and step economic (EASE) synthesis has been carried out by the direct reaction of benzhydrol and 2-mercaptoacetamide using the recyclable heterogeneous catalyst Nafion-H along with post-sulfoxidation. This protocol exhibits improved sustainability credentials. We have also developed a superior pre-sulfoxidation approach for the synthesis of Modafinil.

Dr. Atul Kumar

Senior Principal Scientist

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