Dark Chocolate improves vision with 2 hours Contrast sensitivity and visual acuity were significantly higher 2 hours after consumption of a dark chocolate bar compared with a milk chocolate bar, but the duration of these effects and their influence in real-world performance await further testing. Rabin JC, Karunathilake N, Patrizi K. Effects of Milk vs […]
via Dark Chocolate improves vision with 2 hours — ClinicalNews.Org
Transient receptor potential (TRPM) is a family of non-selective cation channels that are widely expressed in mammalian cells. TRP channels are composed of six transmembrane domains and the family consists of eight different channels, TRPM1–TRPM8. TRPM7 is compromised of an ion channel moiety essential for the ion channel function, which serves to increase intracellular calcium […]
via Mibefradil, a new class of compound to study TRPM7 channel function — Sussex Drug Discovery Centre
Rigel Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) approved Tavalisse (fostamatinib disodium hexahydrate) for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Tavalisse is an oral spleen tyrosine kinase (SYK) inhibitor that targets the underlying autoimmune cause of the…
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.8b00565
Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinl Chemistry Letters, Elsevier Publications. Congratulation Sir !
Click here for details. https://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry-letters
The research interests of his group lie in issues related to application of oriented organic synthesis, in particular total synthesis of biologically active natural products, medicinal chemistry and crop protection. This team has been credited with having accomplished total synthesis of more than 25 natural products with impressive biological activities. “Some of our recent achievements include identification of potential leads, like antibiotic compound based on hunanamycin natural product for treating food infections, anti-diabetic molecule in collaboration with an industry partner and anti-TB compound using a strategy called ‘re-purposing of a drug scaffold’,” said Reddy.
A total of two awardees out of four were from CSIR institutes. In addition to Reddy, Rajan Shankarnarayanan, CSIR – CCMB, Hyderabad (basic sciences), also was conferred with the award. Vikram Mathews, CMC, Vellore (medical research) and Prof Ashish Suri, AIIMS, New Delhi (clinical research), were the others to receive the awards.
With more than 80 scientific publications and 35 patents, Reddy is one of the most prominent scientists in the city and has already been honoured with the Shanti Swarup Bhatnagar prize in chemical sciences. Reddy is also a nominated member of the scientific body of Indian Pharmacopoeia, government of India and was elected as a fellow of the Telangana and Maharashtra Academies of Sciences in addition to the National Academy of Sciences, India (NASI).
| The U.S. Food and Drug Administration today expanded the approval of Xeljanz (tofacitinib) to include adults with moderately to severely active ulcerative colitis. Xeljanz is the first oral medication approved for chronic use in this indication. Other FDA-approved treatments for the chronic treatment of moderately to severely active ulcerative colitis must be administered through an intravenous infusion or subcutaneous injection. |
May 30, 2018
The U.S. Food and Drug Administration today expanded the approval of Xeljanz (tofacitinib) to include adults with moderately to severely active ulcerative colitis. Xeljanz is the first oral medication approved for chronic use in this indication. Other FDA-approved treatments for the chronic treatment of moderately to severely active ulcerative colitis must be administered through an intravenous infusion or subcutaneous injection.
“New treatments are needed for patients with moderately to severely active ulcerative colitis,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research. “Today’s approval provides an alternative therapy for a debilitating disease with limited treatment options.”
Ulcerative colitis is a chronic, inflammatory bowel disease affecting the colon. Patients experience recurrent flares of abdominal pain and bloody diarrhea. Other symptoms include fatigue, weight loss and fever. More than 900,000 patients are affected in the U.S., many of them experiencing moderately to severely active ulcerative colitis, and there is currently no cure.
The efficacy of Xeljanz for the treatment of moderately to severely active ulcerative colitis was demonstrated in three controlled clinical trials. This included two 8-week placebo-controlled trials that demonstrated that 10 mg of Xeljanz given twice daily induces remission in 17 to 18 percent of patients by week eight. In a placebo-controlled trial among patients who achieved a clinical response by week eight, Xeljanz, at a 5 mg or 10 mg dose given twice daily, was effective in inducing remission by week 52 in 34 percent and 41 percent of patients, respectively. Among patients who achieved remission after 8 weeks of treatment, 35 percent and 47 percent achieved sustained corticosteroid-free remission when treated with 5 mg and 10 mg, respectively.
The safety of chronic use of Xeljanz for ulcerative colitis was studied in the 52-week placebo- controlled trial. Additional supportive safety information was collected from patients who received treatment in an open-label long-term study.
The most common adverse events associated with Xeljanz treatment for ulcerative colitis were diarrhea, elevated cholesterol levels, headache, herpes zoster (shingles), increased blood creatine phosphokinase, nasopharyngitis (common cold), rash and upper respiratory tract infection.
Less common serious adverse events included malignancy and serious infections such as opportunistic infections. Xeljanz has a boxed warning for serious infections and malignancy. Patients treated with Xeljanz are at increased risk for developing serious infections that may lead to hospitalization or death. Lymphoma and other malignancies have been observed in patients treated with Xeljanz.
Use of Xeljanz in combination with biological therapies for ulcerative colitis or with potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended.
Xeljanz, made by Pfizer Labs, was previously approved in 2012 for rheumatoid arthritis and in 2017 for psoriatic arthritis.
/////////////Xeljanz, tofacitinib, pfizer, fda 2017, psoriatic arthritis, ulcerative colitis
TRAIL, a member of the TNF family of ligands, causes caspase-dependent apoptosis through activation of its receptors, death receptor 4 and DR5.ONC201 was originally identified as a small molecule that inhibits both Akt and ERK, resulting in dephosphorylation of Foxo3a and thereby induces TRAIL transcription.Recently, two independent groups, Wafik El Deiry at Fox Chase and…
via ONC201 disrupts mitochondrial function and kills breast cancer cells, reveals study — Med-Chemist
Doxepin
1668-19-5
1229-29-4 (hydrochloride), 4698-39-9 ((E)-isomer); 25127-31-5 ((Z)-isomer)
Launched – 1964
| Doxepin Hydrochloride | 3U9A0FE9N5 | 1229-29-4 |
NSC-108160
P-3693A
SO-101
Aponal
Quitaxon
Silenor
Sinequan
Sinquan
Xepin
Zonalon
USP32/pub/data/v32270/usp32nf27s0_m28110
N,N-Dimethyldibenz[b,e]oxepin-D11(6H),
-propylamine hydrochloride 
[1229-29-4; 4698-39-9 ((E)-isomer); 25127-31-5 ((Z)-isomer)].
SINEQUAN® (doxepin hydrochloride) is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C19H21NO•HCl having a molecular weight of 316. It is a white crystalline solid readily soluble in water, lower alcohols and chloroform.
Inert ingredients for the capsule formulations are: hard gelatin capsules (which may contain Blue 1, Red 3, Red 40, Yellow 10, and other inert ingredients); magnesium stearate; sodium lauryl sulfate; starch.
Inert ingredients for the oral concentrate formulation are: glycerin; methylparaben; peppermint oil; propylparaben; water.
SINEQUAN (doxepin HCl) is a dibenzoxepin derivative and is the first of a family of tricyclic psychotherapeutic agents. Specifically, it is an isomeric mixture of: 1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-, hydrochloride.
 |
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.
Synthesis Reference
Luigi Schioppi, Brian Talmadge Dorsey, Michael Skinner, John Carter, Robert Mansbach, Philip Jochelson, Roberta L. Rogowski, Cara Casseday, Meredith Perry, Bryan Knox, “LOW-DOSE DOXEPIN FORMULATIONS AND METHODS OF MAKING AND USING THE SAME.” U.S. Patent US20090074862, issued March 19, 2009.
DOI: 10.1007/BF00904459
DOI: 10.1007/BF00901313 US 3420851
DE 1232161
SYN 2
Synth Commun 1989, 19(19): 3349, US 3438981
Condensation of dibenzo-oxepinone (I) with 3-(dimethylamino)propylmagnesium chloride (II), followed by a dehydration of the resultant tertiary alcohol with hot HCl gives the target 3-(dimethylamino)propylidene derivative.
SYN 3
Chlorination of 2-(phenoxymethyl)benzoic acid (I) with SOCl2 at 50 °C gives 2-(phenoxymethyl)benzoyl chloride (II), which undergoes cyclization in the presence of FeCl3 in toluene to furnish dibenzo[b,e]oxepin-11-one (III)
Grignard reaction of intermediate (III) with tert-butyl 3-chloropropyl ether (IV) using Mg in refluxing THF or Et2O provides 11-(3-tert-butoxypropyl)-6,11-dihydrodibenzo[b,e]oxepin-11-ol (V), which upon elimination by means of HCl in refluxing EtOH affords alkene (VI).
Treatment of tert-butyl ether (VI) with SOCl2 in refluxing toluene gives 11-(3-chloropropylidene)-6,11-dihydrodibenzo[b,e]oxepine (VII), which is then coupled with dimethylamine (VIII) in the presence of Ni(OAc)2, PPh3 and K2CO3 in DMF or in EtOH at 100 °C to furnish doxepin (VII) .
Finally, treatment of tertiary amine (VII) with HCl at 140 °C yields the target doxepin hydrochloride .
US 2014309437, CN 102924424
Doxepin is a tricyclic antidepressant (TCA) used as a pill to treat major depressive disorder, anxiety disorders, chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia).[8][7][9] As a cream it is used for short term treatment of itchiness due to atopic dermatitis or lichen simplex chronicus.[10]
At doses used to treat depression, doxepin appears to inhibit the reuptake of serotonin and norepinephrine and to have antihistamine, adrenergic and serotonin receptor antagonistic, and anticholinergic activities; at low doses used to treat insomnia it appears to be selective for the histamine H1 receptor.[11]
It was introduced under the brand names Quitaxon and Aponal by Boehringer, which discovered it, and as Sinequan by Pfizer,[12] and has subsequently been marketed under many other names worldwide.[2]
Doxepin is used as a pill to treat major depressive disorder, anxiety disorders, chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia).[8][7][9] As a cream it is used for short term treatment of itchiness to due atopic dermatitis or lichen simplex chronicus.[10]
In 2016 the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with drugs; doxepin was among those recommended for short term help maintaining sleep, on the basis of weak evidence.[13][14] The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar.[13] A 2015 AHRQ review of treatments for insomnia had similar findings.[15]
A 2010 review found that topical doxepin is useful to treat itchiness.[16]
A 2010 review of treatments for chronic hives found that doxepin had been superseded by better drugs but was still sometimes useful as a second line treatment.[17]
Doxepin is a tricyclic compound, specifically a dibenzoxepin, and possesses three rings fused together with a side chain attached in its chemical structure.[38] It is the only TCA with a dibenzoxepin ring system to have been marketed.[64] Doxepin is a tertiary amine TCA, with its side chain–demethylated metabolite nordoxepin being a secondary amine.[40][41] Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and trimipramine.[65][66] Doxepin is a mixture of (E) and (Z) stereoisomers (the latter being known as cidoxepin or cis-doxepin) and is used commercially in a ratio of approximately 85:15.[3][67] The chemical name of doxepin is (E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine[38][68] and its free base form has a chemical formula of C19H21NO with a molecular weight of 279.376 g/mol.[68] The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely.[3][69] The CAS Registry Number of the free base is 1668-19-5 and of the hydrochloride is 1229-29-4.[3][69]
clip
https://www.sciencedirect.com/science/article/pii/S0040402007016079
Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969.[38] It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.[44][69]
Doxepin is the generic name of the drug in English and German and its INN and BAN, while doxepin hydrochloride is its USAN, USP, BANM, and JAN.[3][69][70][2] Its generic name in Spanish and Italian and its DCIT are doxepina, in French and its DCF are doxépine, and in Latin is doxepinum.[2]
The cis or (Z) stereoisomer of doxepin is known as cidoxepin, and this is its INN while cidoxepin hydrochloride is its USAN.[3]
It was introduced under the brand names Quitaxon and Aponal by Boehringer and as Sinequan by Pfizer.[12]
As of October 2017, doxepin is marketed under many brand names worldwide: Adnor, Anten, Antidoxe, Colian, Dofu, Doneurin, Dospin, Doxal, Doxepini, Doxesom, Doxiderm, Flake, Gilex, Ichderm, Li Ke Ning, Mareen, Noctaderm, Oxpin, Patoderm, Prudoxin, Qualiquan, Quitaxon, Sagalon, Silenor, Sinepin, Sinequan, Sinequan, Sinquan, and Zonalon.[2] It is also marketed as a combination drug with levomenthol under the brand name Doxure.[2]
The oral formulations of doxepin are FDA-approved for the treatment of depression and sleep-maintenance insomnia and its topical formulations are FDA-approved the short-term management for some itchy skin conditions.[71] Whereas in Australia and the United Kingdom, the only licensed indication(s) is/are in the treatment of major depression and pruritus in eczema, respectively.[20][72]
As of 2017 there was no good evidence that topical doxepin was useful to treat localized neuropathic pain.[73] Cidoxepin is under development by Elorac, Inc. for the treatment of chronic urticaria (hives).[74] As of 2017, it is in phase II clinical trials for this indication.[74] The drug was also under investigation for the treatment of allergic rhinitis, atopic dermatitis, and contact dermatitis, but development for these indications was discontinued.[74]
Doxepin was under development by Winston Pharmaceuticals in an intranasal formulation for the treatment of headache.[75] As of August 2015, it was in phase II clinical trials for this indication.[75]
PATENT
https://patents.google.com/patent/US9486437B2/en
Doxepin:
Doxepin HCl is a tricyclic compound currently approved and available for treatment of depression and anxiety. Doxepin has the following structure:
For all compounds disclosed herein, unless otherwise indicated, where a carbon-carbon double bond is depicted, both the cis and trans stereoisomers, as well as mixtures thereof are encompassed.
Doxepin belongs to a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds, and is currently approved and prescribed for use as an antidepressant to treat depression and anxiety. Doxepin has a well-established safety profile, having been prescribed for over 35 years.
Doxepin, unlike most FDA approved products for the treatment of insomnia, is not a Schedule IV controlled substance. U.S. Pat. Nos. 5,502,047 and 6,211,229, the entire contents of which are incorporated herein by reference, describe the use of doxepin for the treatment chronic and non-chronic (e.g., transient/short term) insomnias at dosages far below those used to treat depression.
It is contemplated that doxepin for use in the methods described herein can be obtained from any suitable source or made by any suitable method. As mentioned, doxepin is approved and available in higher doses (75-300 milligrams) for the treatment of depression and anxiety. Doxepin HCl is available commercially and may be obtained in capsule form from a number of sources. Doxepin is marketed under the commercial name SINEQUAN® and in generic form, and can be obtained in the United States generally from pharmacies in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg dosage, and in liquid concentrate form at 10 mg/mL. Doxepin HCl can be obtained from Plantex Ltd. Chemical Industries (Hakadar Street, Industrial Zone, P.O. Box 160, Netanya 42101, Israel), Sifavitor S.p.A. (Via Livelli 1—Frazione, Mairano, Italy), or from Dipharma S.p.A. (20021 Baranzate di Bollate, Milano, Italy). Also, doxepin is commercially available from PharmacyRx (NZ) (2820 1st Avenue, Castlegar, B.C., Canada) in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg. Furthermore, Doxepin HCl is available in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg and in a 10 mg/ml liquid concentrate from CVS Online Pharmacy Store (CVS.com).
Also, doxepin can be prepared according to the method described in U.S. Pat. No. 3,438,981, which is incorporated herein by reference in its entirety. It should be noted and understood that although many of the embodiments described herein specifically refer to “doxepin,” other doxepin-related compounds can also be used, including, for example, pharmaceutically acceptable salts, prodrugs, metabolites, in-situ salts of doxepin formed after administration, and solid state forms, including polymorphs and hydrates.
Metabolites:
In addition, doxepin metabolites can be prepared and used. By way of illustration, some examples of metabolites of doxepin can include, but are not limited to, desmethyldoxepin, hydroxydoxepin, hydroxyl-N-desmethyldoxepin, doxepin N-oxide, N-acetyl-N-desmethyldoxepin, N-desmethyl-N-formyldoxepin, quaternary ammonium-linked glucuronide, 2-O-glucuronyldoxepin, didesmethyldoxepin, 3-O-glucuronyldoxepin, or N-acetyldidesmethyldoxepin. The metabolites of doxepin can be obtained or made by any suitable method, including the methods described above for doxepin.
Desmethyldoxepin has the following structure:
Desmethyldoxepin is commercially available as a forensic standard. For example, it can be obtained from Cambridge Isotope Laboratories, Inc. (50 Frontage Road, Andover, Mass.). Desmethyldoxepin for use in the methods discussed herein can be prepared by any suitable procedure. For example, desmethyldoxepin can be prepared from 3-methylaminopropyl triphenylphosphonium bromide hydrobromide and 6,11-dihydrodibenz(b,e)oxepin-11-one according to the method taught in U.S. Pat. No. 3,509,175, which is incorporated herein by reference in its entirety.
Hydroxydoxepin has the following structure:
2-Hydroxydoxepin can be prepared by any suitable method, including as taught by Shu et al. (Drug Metabolism and Disposition (1990) 18:735-741), which is incorporated herein by reference in its entirety.
Hydroxyl-N-desmethyldoxepin has the following structure:
2-Hydroxy-N-desmethyldoxepin can be prepared any suitable method.
Doxepin N-oxide has the following structure:
Doxepin N-oxide can be prepared by any suitable method. For example, doxepin N-oxide can be prepared as taught by Hobbs (Biochem Pharmacol (1969) 18:1941-1954), which is hereby incorporated by reference in its entirety.
N-acetyl-N-desmethyldoxepin has the following structure:
N-acetyl-N-desmethyldoxepin can be prepared by any suitable means. For example, (E)-N-acetyl-N-desmethyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164), hereby incorporated by reference in its entirety.
N-desmethyl-N-formyldoxepin has the following structure:
N-desmethyl-N-formyldoxepin can be prepared by any suitable means. For example, (E)-N-desmethyl-N-formyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164), hereby incorporated by reference in its entirety.
N-acetyldidesmethyldoxepin has the following structure:
N-acetyldidesmethyldoxepin can be prepared by any suitable means. For example, (E)-N-acetyldidesmethyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164), hereby incorporated by reference in its entirety.
Didesmethyldoxepin has the following structure:
Didesmethyldoxepin can be prepared by any suitable means. For example, (Z)- and (E)-didesmethyldoxepin have been isolated from plasma and cerebrospinal fluid of depressed patients taking doxepin, as taught by Deuschle et al. (Psychopharmacology (1997) 131:19-22), hereby incorporated by reference in its entirety.
3-O-glucuronyldoxepin has the following structure:
3-O-glucuronyldoxepin can be prepared by any suitable means. For example, (E)-3-O-glucuronyldoxepin has been isolated from the bile of rats given doxepin, as described by Shu et al. (Drug Metabolism and Disposition (1990) 18:1096-1099), hereby incorporated by reference in its entirety.
2-O-glucuronyldoxepin has the following structure:
2-O-glucuronyldoxepin can be prepared by any suitable means. For example, (E)-2-O-glucuronyldoxepin has been isolated from the bile of rats given doxepin, and also in the urine of humans given doxepin, as described by Shu et al. (Drug Metabolism and Disposition (1990) 18:1096-1099), hereby incorporated by reference in its entirety.
Quaternary ammonium-linked glucuronide of doxepin (doxepin N+-glucuronide) has the following structure:
N+-glucuronide can be obtained by any suitable means. For example, doxepin N+-glucuronide can be prepared as taught by Luo et al. (Drug Metabolism and Disposition, (1991) 19:722-724), hereby incorporated by reference in its entirety.
PATENT
https://patents.google.com/patent/CN105330638A/en
doxepin hydrochloride, the chemical name is N, N- dimethyl-3-dibenzo (b, e) _ oxepin -11 (6H) -1-propanamine salt subunit cistron iso the mixture body configuration. CAS Number 1229-29-4 thereof, of the formula
[0003]
[0004] Doxepin hydrochloride is a drug for the treatment of depression and anxiety neurosis that act to inhibit the central nervous system serotonin and norepinephrine reuptake, such that these two synaptic cleft neurotransmitter concentration increased and antidepressant effect, but also has anti-anxiety and sedative effects. Doxepin hydrochloride oral absorption, bioavailability of 13-45%, half-life (Shu 1/2) is 8-12 hours, to apparent volume of distribution (1) ^ 9-33171.Primarily metabolized in the liver to active metabolites thereof demethylation.Metabolite excretion from the kidney, elderly patients decline of metabolism and excretion ability of this product
[0005] Chinese Patent CN102924486A discloses a method for preparing a hydrochloride of doxepin. The method comprises the coupling reaction CN, i.e., the use of Ni (0Α〇) 2 / ΡΡ1 ^ φ to the amine-based compound. Although Ni catalyst the reaction step (OAc) 2 is more readily available and inexpensive, but the low yield of this step, and low product purity.
SUMMARY
[0006] Accordingly, the present invention provides a method of o-toluic acid synthesized multi doxepin hydrochloride, the higher the yield and purity of the obtained product was purified by this method.
[0007] – o-methylbenzoate method for the synthesis of doxepin hydrochloride, comprising the steps of:
[0008] (1) o-methylbenzoic acid with N- halosuccinimide benzylation halogenation reaction occurs in an acetonitrile solvent in the light conditions, to give o-halo-methylbenzoic acid (Compound J), the following reaction formula,
[0009]
[0010] (2) Compound J celite load cesium fluoride intramolecular substitution reaction, to give phthalide (Compound H) in an acetonitrile solvent and as a catalyst, the following reaction formula,
[0011]
[0012] (3) The phenol compound J with sodium methoxide in an alcohol solvent substitution reaction, to give a compound I, the following reaction formula,
[0013]
[0014] (4) The cyclization reaction of Compound I in a solvent in the catalytic DMS0 anhydrous aluminum chloride to give 6, 11-dihydro-dibenzo [b, e] oxepin -11- one (compound A), the following reaction formula,
[0015]
[0016] (5) 6, 11-dihydro-dibenzo [b, e] oxepin-11-one (Compound A) and 3-chloropropyl alkyl tert-butyl ether (compound B) is added magnesium powder and with THF and / or a nucleophilic addition of anhydrous diethyl ether under the conditions of the reaction solvent to give the hydroxy compound (compound C), the following reaction formula,
[0017]
[0018] (6) heating elimination reaction to give an olefin compound (Compound D) in a strong base in an alcoholic solvent to the hydroxy compound, the following reaction formula,
[0019]
[0020] (7) to the olefinic compound in the nucleophilic substitution reaction of a hydrogen halide acid, to give halide (Compound E), the following reaction formula,
[0022] wherein the compound E X is a C1, Br, or a a I;
[0023] (8) the halide with dimethylamine in a solvent under an organic lithium compound is added in ether to nucleophilic substitution reaction to yield doxepin (Compound F.), The following reaction formula,
[0024]
[0025] (9) the doxepin neutralization reaction with hydrochloric acid to give sulfasalazine (Compound G), the following reaction formula,
Example 1
[0043] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 10 ° C, under stirring for 4h. A known separation method, separation of o-bromomethyl-benzoic acid. This compound is named J.
[0044] placed in a 20L reaction container, Compound J, diatomaceous earth in an amount of 0.05 to load cesium fluoride (compound J as a mass basis), acetonitrile in an amount of 2.5 (in Compound J 1 is a mass basis), and the temperature was adjusted to 30 ° C, with stirring under reflux for 20h adjustment. Then, a known means for separating the reaction phthalide.
After [0045] placed in a 20L reaction vessel phthalide, 3 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), the reaction solution temperature adjusted to 50 ° C, was added dropwise start phenol was 1.05 mass (in mass was 1 meter phthalide), dropwise over lh. After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.
[0046] The above compound I, in an amount of 10% anhydrous aluminum chloride (mass of Compound I was 100% basis), the amount of DMS0 3 (mass basis Compound I 1) into a reaction vessel , the temperature was adjusted to 95 ° C. The reaction time is to be 12h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.
[0047] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.1-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2 times the mass 6, 11-dihydro-dibenzo [b, e] oxepin-11-one magnesium in , taking all of fifths THF (5 to 6 times by mass, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) and heated to 35 ° C and allowed to react. After the reaction started, the remaining 3/5 of THF was added dropwise.Was added dropwise to the system to be completed into hydrogen, reflux. After a total reaction 5h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.
[0048] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 1.5 times the mass of hydroxy compound class of sodium hydroxide (concentration l〇wt mass%), was heated to 65 ° C, 2h elimination reaction after the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.
[0049] placed in a 20L reaction vessel of the olefin compound, in an aqueous solution plus 1 times the mass of the olefinic compound hydrochloride (concentration of 5wt%), and heated to 50 ° C, so that a nucleophilic substitution reaction . The reaction time is to be after 4h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.
[0050] placed in a 20L reaction vessel above halide, 0.1 times the mass of methyl lithium halides to 2 times the mass of the halide in diethyl ether, heated to 40 ° C, so that the nucleophilic substitution reaction. The reaction time is to be after 5h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.
[0051] 20L is placed in a pressure reactor above doxepin, 1.05 times the mass of material in the doxepin hydrochloride (concentration of 30wt%), the control pressure to 3 ~ 4MPa, and heated to 130 ° C , and among the responses. Time after to be reacted for 20 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 37.9%, measured by HPLC obtaining 99.2% purity.
[0052] Example 2
[0053] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 20 ° C, under stirring for 2h. A known separation method, separation of o-toluic acid halide.
[0054] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.
After [0055] phthalide placed in 20L reaction vessel, an amount of sodium methoxide in 10 ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 60 ° C, was added dropwise start phenol was 1.15 mass (in mass was 1 meter phthalide), dropwise over lh.After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.
[0056] The above compound I, in an amount of 40% anhydrous aluminum chloride (mass of Compound I was 100% basis), in an amount of DMS0 8 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 105 ° C. The reaction time is to be for 6h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.
[0057] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.5-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.4 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 40 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, reflux. When the total reaction 2h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.
[0058] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 5 times the mass of hydroxy compound class of sodium hydroxide (concentration of 70wt%), was heated to 80 ° C, the reaction was stopped after the elimination reaction LH, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.
[0059] placed in a 20L reaction vessel of the olefin compound, in an aqueous solution of 2 times the mass of the olefinic compound added hydrobromic acid (concentration of 30wt%), and heated to 60 ° C, so that nucleophilic Substitution reaction. The reaction time is to be after the 1. 5h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.
[0060] placed in a 20L reaction vessel above halide, 0.8 times the mass of phenyl lithium halide to 8 times the mass of the halide in diethyl ether, heated to 50 ° C, so that the nucleophilic substitution reaction. The reaction time is to be after 2h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.
[0061] 20L is placed in a pressure reactor above doxepin, 1.2 times the mass of material in the doxepin hydrochloride (concentration of 38wt%), the control pressure to 3 ~ 4MPa, and heated to 150 ° C , and among the responses. Time after to be reacted for 16 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 39.7%, measured by HPLC obtaining 99.4% purity.
[0062] Example 3
[0063] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, under stirring for 3h. A known separation method, separation of o-bromomethyl-benzoic acid.
[0064] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.
After [0065] phthalide placed in 20L reaction vessel, an amount of sodium methoxide in ethanol solvent 6 (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start phenol was 1.10 mass (in mass was 1 meter phthalide), dropwise over lh.After the dropwise addition, the reaction temperature after 3. 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.
[0066] Anhydrous aluminum above compound I, in an amount of 25% of the chloride (compound I mass is 100% basis), in an amount of DMS0 6. 5 (in compound I is a mass basis) into the reaction vessel temperature is adjusted to 100 ° C. The reaction time is to be 9h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.
[0067] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.3-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.2 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 38 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, refluxed for 2h. After a total reaction 3. 5h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.
[0068] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 3-hydroxysteroid times the mass of the compound of sodium hydroxide (concentration of 40wt%), and heated to 75 ° C, 1. 5h the reaction stopped after elimination the reaction was cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.
[0069] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 18wt%), was heated to 55 ° C, so nucleophilic substitution reaction. The reaction time is to be after 2h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.
[0070] placed in a 20L reaction vessel above halide, 0.4 times the mass of the halide in n-butyllithium, in diethyl ether five times the mass of halide and heated to 45 ° C, so that a nucleophilic substitution reaction . The reaction time is to be 3. After 5h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.
[0071] 20L is placed in a pressure reactor above doxepin, 1.12 times the mass of material in the doxepin hydrochloride (concentration of 34wt%), the control pressure to 3 ~ 4MPa, and heated to 140 ° C , and among the responses. Time after to be reacted for 18 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 40.2%, measured by HPLC obtaining 99.5% purity.
[0072] Example 4
[0073] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, under stirring for 4h. A known separation method, separation of o-toluic acid halide.
[0074] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.
After [0075] phthalide placed in 20L reaction vessel, 5 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start phenol was 1.15 mass (in mass was 1 meter phthalide), dropwise over lh.After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.
[0076] The above compound I, in an amount of 25% anhydrous aluminum chloride (mass of Compound I was 100% basis), in an amount of DMS0 8 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 100 ° C. The reaction time is to be 12h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.
[0077] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.3-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.4 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 40 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, reflux. When the total reaction 2h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.
[0078] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 5 times the mass of hydroxy compound class of sodium hydroxide (concentration of 70wt%), was heated to 80 ° C, the reaction was stopped after the elimination reaction LH, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.
[0079] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 30wt%), and heated to 60 ° C, so nucleophilic substitution reaction. The reaction time is to be after the 1. 5h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.
[0080] placed in a 20L reaction vessel above halide, 0.8 times in mass n-butyl lithium halide, eight times the mass of the halide in diethyl ether, heated to 50 ° C, so that a nucleophilic substitution reaction . The reaction time is to be after 2h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.
[0081] 20L is placed in a pressure reactor above doxepin, 1.2 times the mass of material in the doxepin hydrochloride (concentration of 38wt%), the control pressure to 3 ~ 4MPa, and heated to 150 ° C , and among the responses. Time after to be reacted for 16 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 41.6%, measured by HPLC obtaining 99.7% purity.
[0082] Example 5
[0083] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, the reaction 2. 5h under stirring. A known separation method, separation of o-bromomethyl-benzoic acid.
[0084] placed in a 20L reaction vessel o-bromomethyl benzoic acid, diatomaceous earth in an amount of load of cesium fluoride 0.05 ~ 0.15 (in mass Compound J is 1 meter), in an amount of 2. 5-8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.
After [0085] phthalide placed in 20L reaction vessel, 5 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start was 1.08 mass of phenol (mass was phthalide 1 meter), dropwise over lh.After the dropwise addition, the reaction temperature after 3h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.
[0086] Anhydrous aluminum above compound I, in an amount of 25% of the chloride (compound I mass is 100% basis), in an amount of DMS0 5 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 100 ° C.The reaction time is to be 8h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.
[0087] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.2-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.2 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 38 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, reflux. When the total reaction 2h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.
[0088] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 2 times the mass of hydroxy compound class of sodium hydroxide (concentration of 40wt%), was heated to 70 ° C, the reaction was stopped after the elimination reaction 2h, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.
[0089] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 15wt%), and heated to 50 ° C, so nucleophilic substitution reaction. The reaction time is to be after 4h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.
[0090] placed in a 20L reaction vessel above halide, 0.4 times the mass of the halide in n-butyl lithium, 2 to 8 times the mass of the halide in diethyl ether, heated to 45 ° C, so that nucleophilic Substitution reaction. The reaction time is to be after 3h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.
[0091] 20L is placed in a pressure reactor above doxepin, 1.12 times the mass of material in the doxepin hydrochloride (mass concentration 37. 6wt%), the control pressure to 3 ~ 4MPa, heated to 140 ° C, allowing the reaction among. Time after to be reacted for 20 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 43.9%, measured by HPLC obtaining 99.9% purity.
PATENTS
|
|
 |
|
| Clinical data | |
|---|---|
| Trade names | Sinequan, many others[2] |
| Synonyms | NSC-108160[3] |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682390 |
| License data | |
| Pregnancy category |
|
| Routes of administration |
By mouth, topical, intravenous, intramuscular injection[1] |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 13–45% (mean 29%)[5][6] |
| Protein binding | 76%[7] |
| Metabolism | Hepatic (CYP2D6, CYP2C19)[4][5] |
| Metabolites | Nordoxepin, glucuronide conjugates[4] |
| Elimination half-life | Doxepin: 8–24 hours (mean 17 hours)[7] Nordoxepin: 31 hours[7] |
| Excretion | Urine: ~50%[4][5] Feces: minor[5] |
| Identifiers | |
| CAS Number |
|
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C19H21NO |
| Molar mass | 279.376 g/mol |
| 3D model (JSmol) | |
//////////////Doxepin, ドキセピン , NSC-108160 , P-3693A , SO-101
[H]C(CCN(C)C)=C1C2=CC=CC=C2COC2=CC=CC=C12
C19H21NO·HCl 315.84
Identification—
Related compounds—
Chromatographic system (see Chromatography 
621
)— The liquid chromatograph is equipped with a 215-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L1. The flow rate is about 1 mL per minute. The column temperature is maintained at 30
. Chromatograph about 20 µL of the Standard solution, and record the peak areas as directed for Procedure: the resolution, R, between doxepin related compound A and doxepin related compound C is not less than 1.5; the resolution between doxepin related compound C and doxepin related compound B is not less than 1.5; and the signal-to-noise ratio for all the peaks is not less than 10. [NOTE—Use the approximate relative retention times given in Table 1 for the purpose of peak identification. The doxepin related compound C peak will be the largest peak in the Standard solution chromatogram.]
| Name | Relative Retention Time (RRT) |
Limit (%) |
| Doxepin related compound A | 0.48 | 0.10 |
| Doxepin related compound C | 0.55 | 0.20 |
| Doxepin related compound B | 0.63 | 0.10 |
| Doxepin hydrochloride | 1.0 | — |
| Unknown impurity | — | 0.10 each |
Procedure— Inject a volume (about 20 µL) of the Test solution into the chromatograph, record the chromatogram for up to 2.2 times the retention time of doxepin, and measure the peak responses. Calculate the percentage of each individual doxepin related compound in the portion of Doxepin Hydrochloride taken by the formula:
in which rU is the individual peak response for each doxepin related compound obtained from the Test solution; rS is the response of the corresponding peak in theStandard solution; CS is the concentration, in mg per mL, of each doxepin related compound in the Standard solution; and CT is the concentration, in mg per mL, of Doxepin Hydrochloride in the Test solution. The related substance limits are listed in Table 1. [NOTE—Discard any peak with a relative retention time less than 0.25. This method is not intended to resolve the E- and Z-isomers of doxepin hydrochloride. Minor variations in the mobile phase composition could result in a shoulder in the trailing edge of doxepin. In cases where there may be separation, both the E- and Z-isomers should be used in the appropriate calculations.] Use the response of the doxepin peak obtained from the Standard solution and the concentration of doxepin hydrochloride in the Standard solution to calculate the percentage of unknown individual impurities.
Assay—
Procedure— Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of C19H21NO·HCl in the portion of Doxepin Hydrochloride taken by the formula:
in which C is the concentration, in µg per mL, of USP Doxepin Hydrochloride RS in the Standard preparation, and rU(Z) and rU(E) are the respective peak responses of the (Z)- and (E)-isomers obtained from the Assay preparation, and rS(Z) and rS(E) are the respective peak responses of the (Z)- and (E)-isomers obtained from the Standard preparation. Calculate the percentage of the (Z)-isomer in the Assay preparation taken by the formula:
in which WS is the weight, in mg, of USP Doxepin Hydrochloride RS in the Standard preparation, WT is the weight, in mg, in the portion of Doxepin Hydrochloride taken, and PZ is the labeled percentage of (Z)-isomer in USP Doxepin Hydrochloride RS. Similarly calculate the percentage of (E)-isomer in the Assay preparationtaken by the formula:
in which PE is the labeled percentage of (E)-isomer in USP Doxepin Hydrochloride RS.
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
| Monograph | Ravi Ravichandran, Ph.D. Senior Scientist 1-301-816-8330 |
(MDPP05) Monograph Development-Psychiatrics and Psychoactives |
| Reference Standards | Lili Wang, Technical Services Scientist 1-301-816-8129 RSTech@usp.org |
Pharmacopeial Forum: Volume No. 32(2) Page 330
Chromatographic Column—
Penciclovir
Cas 39809-25-1
97845-62-0 (Na salt)
Launched – 1996 PERRIGO, Herpes labialis
BRL-39123; penciclovir; BRL 39123A; penciclovir sodium; Denavir; Vectavir; Euraxvir; Fenivir
Penciclovir was approved for medical use in 1996.[2]
Developed and launched by SmithKline Beecham (SB; now GlaxoSmithKline) and now marketed in the US by Prestium Pharma and ex-US by Novartis, penciclovir (Vectavir; Fenivir; Denavir; Euraxvir) is a 1% topical cream indicated for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age and older
APPROVALS
THE US
In September 1996, the compound was approved by the US FDA for cold sore treatment , and was launched in the US in 1997.
EUROPE
In December 1995, SB filed for European approvals of the drug . In 1997, the drug was approved in Belgium Iceland Denmark Norway Ireland . In January 2003, the drug was launched in Sweden . In May 2007, the drug was launched in Portugal .
JAPAN
In December 1995, SB filed for Japanese approval of the drug .
CHINA
In September 1999, the compound was approved in China
FDA
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020629s016lbl.pdf
Chemically, penciclovir is known as 9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine. Its molecular formula is C10H15N5O3; its molecular weight is 253.26. It is a synthetic acyclic guanine derivative
Penciclovir is a white to pale yellow solid. At 20°C it has a solubility of 0.2 mg/mL in methanol, 1.3 mg/mL in propylene glycol, and 1.7 mg/mL in water. In aqueous buffer (pH 2) the solubility is 10.0 mg/mL. Penciclovir is not hygroscopic. Its partition coefficient in n-octanol/water at pH 7.5 is 0.024 (logP = -1.62).
In herpes labialis, the duration of healing, pain and detectable virus is reduced by up to one day,[3] compared with the total duration of 2–3 weeks of disease presentation.
Penciclovir is inactive in its initial form. Within a virally infected cell a viral thymidine kinase adds a phosphate group to the penciclovir molecule; this is the rate-limiting step in the activation of penciclovir. Cellular (human) kinases then add two more phosphate groups, producing the active penciclovir triphosphate. This activated form inhibits viral DNA polymerase, thus impairing the ability of the virus to replicate within the cell.
The selectivity of penciclovir may be attributed to two factors. First, cellular thymidine kinases phosphorylate the parent form significantly less rapidly than does the viral thymidine kinase, so the active triphosphate is present at much higher concentrations in virally infected cells than in uninfected cells. Second, the activated drug binds to viral DNA polymerase with a much higher affinity than to human DNA polymerases. As a result, penciclovir exhibits negligible cytotoxicity to healthy cells.
The structure and mode of action of penciclovir are very similar to that of other nucleoside analogues, such as the more widely used aciclovir. A difference between aciclovir and penciclovir is that the active triphosphate form of penciclovir persists within the cell for a much longer time than the activated form of aciclovir, so the concentration within the cell of penciclovir will be higher given equivalent cellular doses.
SYN
Choudary, B.M.; Geen, G.R.; Grinter, T.J.; MacBeath, F.S.; Parratt, M.J.
Influence of remote structure upon regioselectivity in the N-alkylation of 2-amino-6-chloropurine: Application to the synthesis of penciclovir
Nucleosides Nucleotides 1994, 13(4): 979
PATENT
US 6573378
PATENT
CN 102070636
PAPER
https://www.tandfonline.com/doi/abs/10.1081/SCC-120026312?journalCode=lsyc20Selective and Practical Synthesis of Penciclovir
PAPER
| Journal of Zhejiang University SCIENCE A 2013 Vol.14 No.10 P.760-766 |
Accelerated effect on Mitsunobu reaction via bis-N-tert-butoxycarbonylation protection of 2-amino-6-chloropurine and its application in a novel synthesis of penciclovir
| Author(s): Li-yan Dai, Qiu-long Shi, Jing Zhang, Xiao-zhong Wang, Ying-qi Chen | ||
| Affiliation(s): . Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China | ||
| Corresponding email(s): dailiyan@zju.edu.cn | ||
| Key Words: 2-amino-6-chloropurine, Mitsunobu reaction, bis-Boc protection, Penciclovir (PCV) | ||
To synthesize 3 and 4, 2-amino-6-chloropurine (ACP) is commonly used as a starting material, coupling with alkyl halide side chains (Geen et al., 1990; Geen et al., 1992; Kim et al., 1998; Brand et al., 1999; Toyokuni et al., 2003). However, considering its isomerization at N7 and N9 positions under acidic or alkaline conditions, the most challengeable issue is the selectivity of a N-alkylation at the N7 or N9 position of ACP. Normally, alkylation takes place at the N9 position as well as at the N7 position of the purine moiety, and the N9/N7 ratio is usually less than 6:1 (Kim et al., 1998). Accordingly, to improve this ratio, several approaches have been reported, mainly involving changing the structure of the side chains (Geen et al., 1992) and modification of the ACP (Brand et al., 1999). For example, as reported by Zheng et al. (2004) (Fig. 2), a side chain 6 was synthesized and separated readily at 0 °C. After coupling 6 with 2-amino-6-chloropurine 7, the ratio of the product 9-isomer purine (8a) and the 7-isomer purine (8b) could reach about 10:1. However, the reaction temperature must be strictly controlled as 6 decomposes easily even at room temperature and then an extra careful column chromatography separation procedure would be required to obtain pure 8a. Thus, finding a more practical and efficient method, which could avoid the formation of N7-alkylated compound and shorten the synthetic steps to obtain ACP, becomes attractive.
The Mitsunobu reaction might be an alternative (potential) approach (Mitsunobu, 1981; Swamy et al., 2009). This reaction has become a very popular chemical transformation due to its mildness, occurring under essentially neutral conditions, and its stereospecificity, proceeding with complete Walden inversion of stereochemistry (Mitsunobu, 1981). Moreover, it permits C-O, C-S, C-N, or C-C bonds formed by the condensation of an acidic component with a primary or a secondary alcohol. Actually, some literature has already reported successful Mitsunobu coupling of ACP and adenine with allylic and benzylic alcohol, showing a good N9 selectivity (Yang et al., 2005; Kitade et al., 2006; Yin et al., 2006). However, a poor to modest yield (20%–50%) and a limited substrate scope were observed. In order to improve these yields, Lu et al. (2007) developed a modified Mitsunobu method to couple purine with alcohols in a higher temperature (70 °C), along with two rounds of the Mitsunobu reaction; yet its long reaction procedure and poor atom economy weaken its potential. The poor solubility of ACP or its derivatives in THF, the preferred solvent for Mitsunobu reactions, is likely the primary reason for these defects being observed.
A possible process to improve the solubility of ACP is to make use of the tert-butoxycarbonyl group (Boc), which can serve as the protection of the exocylic amino groups functionality and increase the lipophilicity of the base portion of the purine. Another advantage of the Boc protection group is that its acidolytic removal is less sensitive to steric factors and can also be removed under neutral conditions (Hwu et al., 1996; Siro et al., 1998). In contrast, a few studies have recently been reported that apply the Boc group in the protection of nucleobase (Sikchi and Hultin, 2006; Porcheddu et al., 2008). As described by Porcheddu et al. (2008), solubility of nucleobases, including guanine, was increased in some organic solvents after protected by Boc groups. In addition, some results in our previous study (Yang et al., 2011) demonstrated a very good improvement in coupling purine derivatives under Mitsunobu conditions. Thus, it could be safer to presume that protecting amino groups of ACP with Boc would be an ideal way for its application in the synthesis of PCV 3 and offer similar results as shown under Mitsunobu conditions.
In this study, we firstly synthesized a bis-Boc protected ACP, namely, bis-Boc-2-amino-6-chloropurine 9 (Fig. 3) and investigated its solubility in several different Mitsunobu solvents, then coupling bis-Boc-2-amino-6-chloropurine 9 with a large scope of alcohols confirmed its good reactivity for a Mitsunobu reaction and successfully developed a new and efficient method for the preparation of PCV using Mitsunobu coupling reaction as the key step.
To a 250 ml N2-flushed flask with dry THF (100 ml), equipped with a magnetic stir bar, 2-amino-6-chloropurine (2.0 g, 11.8 mmol) and DMAP (0.14 g, 1.18 mmol) were added. Boc2O (10.3 g, 47.2 mmol) was added to the stirred suspension under an N2atmosphere, then the reaction mixture was stirred for 6 h at room temperature (TLC analysis indicated the disappearance of 2-mino-6-chloropurine). The excess amount of THF was removed, and the crude product was dissolved in AcOEt (400 ml), washed with HCl aqueous (2 mol/L, 1×30 ml) and brine (2×50 ml), dried with Na2SO4 and concentrated in vacuo to give a white solid (5.2 g, 94.5%). mp 51–52 °C; 1H NMR (500 MHz, CDCl3): δ=1.47 (s, 18H, C(CH3)3), 1.69 (s, 9H, C(CH3)3), 8.58 (s, 1H, CH); 13C NMR (125 MHz, CDCl3) δ=153.8, 152.0, 151.8, 150.6, 145.5, 144.7, 130.8, 88.0, 83.9, 28.0.
2. Bis-Boc-2-amino-6-chloropurine (9)
A solution of the white solid obtained above (14 g, 30 mmol) in MeOH (400 ml) was added to saturated NaHCO3 aqueous (200 ml), then the turbid solution was stirred at 55 °C for 2 h, at which point clean conversion to bis-Boc protected adenine was observed by TLC. After evaporation of MeOH, the residue mixture was cooled, added 5 mol/L hydrochloric acid to get pH=7 (approximate). A large amount of white solid formed, the reaction mixture was filtrated and then dried under a vacuum to give a white solid 9 (10.5 g, 95.5%). mp 101.3–103.3 °C; 1H NMR (500 MHz, CDCl3): δ=1.50 (s, 18H, C(CH3)3), 8.41 (s, 1H, CH); 13C NMR (125 MHz, CDCl3) δ=153.5, 151.9, 151.6, 151.3, 145.6, 128.5, 82.7, 28.5.
2.3. 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxane (5)
2-hydroxymethyl-1,4-butanediol 11 (8.10 g, 67.4 mmol) and 2,2-dimethoxypropane (13 ml, 105.7 mmol) were dissolved in dry THF (20 ml). The mixture was stirred and p-toluenesulfonic acid monohydrate (0.64 g, 3.4 mmol) was added, the clear solution was stirred at room temperature for 12 h, triethylamine (10 ml) was added to quench the reaction, and the solution was stirred for 30 min. Then solvents were removed to leave a colorless liquid, the residue was subject to column chromatography on silica gel eluted with 2:1 EtOAc/hexane to give a colorless liquid 5 (6.2 g, 61.5%), R f=0.46 (2:1 EtOAc/hexane). 1H NMR (500 MHz, CDCl3): δ=3.99 (dd, 2H, Heq. J 1=11.80 Hz, J 2=4.45 Hz, CH2); 3.80 (t, 2H, J=6.71 Hz, CH2), 3.34 (dd, 2H, Hax. J 1=11.80 Hz, J 2=8.11 Hz, CH2), 1.90–1.98 (m, 2H, CH and OH), 1.62 (q, 2H, J=6.85 Hz, CH2 ); 13C NMR (125 MHz, CDCl3): δ=100.5, 69.8, 60.4, 31.9, 30.3, 21.2.
2.4. Bis-Boc-2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl] purine (12)
Bis-Boc-2-amino-6-chloropurine 9 (1.0 equivalent) was added to a solution of the side chain 5 (1.1 equivalent) and phosphine reagent (1.1 equivalent) in anhydrous THF under N2 atmosphere at 0 °C, the resulting solution was treated with di-p-nitrobenzyl azocarboxylate (DNAD) (1.1 equivalent) dropwise and the reaction mixture was continued at room temperature for 8 h, then the solvent was evaporated and the residue dissolved in cyclohexane. The triphenylphosphane oxide precipitated and was filtered off and then the filtrate evaporated under reduced pressure. The product was purified by a column chromatography on silica gel to obtain the pure products as a white solid. mp>280 °C (dec); 1H NMR (500 MHz, CDCl3): δ=8.36 (s, 1H, CH), 4.02 (t, 2H, J=7.23 Hz, CH2), 3.79 (dd, 2H, Heq. J 1=11.57 Hz, J 2=4.46 Hz, CH2), 3.56 (dd, 2H, Hax. J 1=11.57 Hz, J 2=8.77 Hz, CH2), 1.67 (q, 2H, J=7.22 Hz, CH2), 1.53–1.61 (m, 1H, CH), 1.47 (s, 18H, C(CH3)3), 1.39 (s, 3H, CH3), 1.36 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3): δ=154.3, 151.7, 151.5, 151.1, 128.0, 104.8, 81.7, 71.5, 50.8, 33.7, 28.6, 26.2, 25.7.
2.5. 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl) ethyl]purine (8a)
A mixture of compound 12 (2.56 g, 5.0 mmol), 2,6-dimethyl pyridine (1.18 ml, 10 mmol) and dry DCM (20 ml) was stirred at 0 °C, then TBTMS-OTf was added dropwise; after the addition, the reaction mixture was stirred at room temperature until TLC showed that compound 12 had completely disappeared. Then 30 ml saturated ammonium chloride solution was added, separated the organic layer, extracted with DCM (2×20 ml), combined and washed by saturated NaCl (2×40 ml), dried with anhydrous sodium sulfate and evaporated to give a white solid (1.21 g, 78%). mp 125–126 °C; 1H NMR (500 MHz, CDCl3): δ=8.07 (s, 1H, CH) , 6.99 (s, 2H, NH2), 4.12 (t, 2H, J=7.31 Hz, CH2), 3.82 (dd, 2H, 4′-Heq, J 1=11.79 Hz, J 2=4.50 Hz, CH2), 3.53 (dd, 2H, 4′-Hax, J 1=11.79 Hz, J 2=8.80 Hz, CH2), 1.74 (q, 2H, J=7.30 Hz, CH2), 1.53–1.65 (m, 1H, CH), 1.36 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3): δ=159.94, 150.31, 150.26, 141.84, 132.11, 100.52, 68.14, 52.90, 31.32, 26.84, 26.05.
2.6. 9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine (PCV 3)
Compound 12 (5.12 g, 10 mmol) was dissolved in THF (20 ml) hydrochloric acid (2 mol/L, 20 ml). The mixture was stirred for 2 h at 70 °C, and then slowly warmed to reflux for 2 h. After evaporation of the THF under reduced vacuum, 10% aqueous NaOH solution was added to neutralize the residual liquid, and a large amount of off-white solid formed, filtered, washed with acetone and then water, and dried under vacuum to give an off-white solid 3 (2.07 g, 82%). mp 274.6–276.9 °C.
Mole fraction solubility x of bis-Boc-2-amino-6-chloropurine 9 in different Mitsunobu solvents
| T (K) (±0.05 K) | Solubility x a (%)
|
|||
| THFb | DCMb | Methylbenzeneb | Acetonitrileb | |
| 273.15 | 0.1141 | 0.0493 | 0.0213 | 0.0150 |
| 278.15 | 0.1191 | 0.0552 | 0.0253 | 0.0178 |
| 283.15 | 0.1251 | 0.0613 | 0.0303 | 0.0210 |
| 288.15 | 0.1299 | 0.0664 | 0.0349 | 0.0244 |
| 293.15 | 0.1352 | 0.0734 | 0.0405 | 0.0288 |
| 298.15 | 0.1399 | 0.0809 | 0.0470 | 0.0347 |
| 303.15 | 0.1463 | 0.0894 | 0.0544 | 0.0417 |
| 308.15 | 0.1523 | 0.0983 | 0.0634 | 0.0501 |
| 313.15 | 0.1581 | 0.1081 | 0.0734 | 0.0617 |
b: all the solvents were further purified by distillation in dry agent (Na/benzophenone) and the sample bis-boc-2-amino-6-chloropurine 9 was dried in vacuum for over 2 d
As shown in Table 1, THF, which is the most common solvent in Mitsunobu reaction, has great solubility for bis-Boc-2-amino-6-chloropurine 9. Afterwards, the best solvent THF was taken for coupling 9 with a number of alcohols under normal Mitsunobu conditions to investigate its reactivity. The results were illustrated in Table 2. We clearly learned that bis-Boc-2-amino-6-chloropurine 9, as an excellent nucleophilic precursor, was able to react with a large number of alcohols, including primary alcohol, secondary alcohol, allyl alcohol, benzyl alcohol, etc., with high N9 selectivity and yields. Moreover, tert-Butyl alcohol still could not react with a protected purine as in the previous study (Yang et al., 2011), owing to its steric hindrance in tertiary carbon.
Investigation of the reactivity of bis-Boc-2-amino-6-chloropurine 9 with different alcohols
| Entry | Alcohol | Product | Isolated yield (%) |
| 1 | 10a | 90.2 | |
| 2 | 10b | 86.6 | |
| 3 | 10c | 83.3 | |
| 4 | 10d | 84.8 | |
| 5 | 10e | 86.4 | |
| 6 | 10f | 81.2 | |
| 7 | 10g | 81.5 | |
| 8 | 10h | 80.7 | |
| 9 | 10i | 0 |
Our next objective was the synthesis of PCV. As was expected, bis-Boc-2-amino-6-chloropurine 9 combined with the side chain 5(1.1 equivalent) under normal Mitsunobu conditions successfully obtained the desired N9-alkylated compound 12 in 92% yield without the undesired N7 alkylation by-product being formed. Importantly, the reaction conditions were significantly milder than those reported in recent studies (Geen et al., 1990; 1992; Kim et al., 1998; Brand et al., 1999; Toyokuni et al., 2003), requiring only 1.1 equivalent of each of the alcohol, PPh3 and DNAD, and proceeding to completion within 60 min at room temperature. This is mainly due to the enhanced solubility of the compound 9 as mentioned above. By process c in Fig. 4, compound 8a was obtained under neutral conditions. It is 1H and 13C NMR spectra further indicated that no 7-isomer purine (8b) was formed. Subsequently, we could obtain PCV 3 in an acid condition as procedure e; or directly starting from 12, where hydrolytic dechlorination and deprotection step(s) were accomplished in one pot under mild acid conditions (2mol/L, hydrochloric acid in THF at room temperature) to afford the target PCV 3 in 80%–85% yield (process d). The overall yield of PCV from 11 was 44.5% higher than that in previous study (16%) (Zheng et al., 2004).
EP 0141927; ES 8602791; ES 8603887; ES 8603888; JP 1994293764; US 5075445
This compound has been obtained by two similar ways: 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (IX), which is finally converted into penciclovir by hydrlysis with 2N HCl.
References
|
|
| Clinical data | |
|---|---|
| Pronunciation | /ˌpɛnˈsaɪkloʊˌvɪər/[1] |
| Trade names | Denavir |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a697027 |
| Pregnancy category |
|
| Routes of administration |
Topical |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 1.5% (oral), negligible (topical) |
| Protein binding | <20% |
| Metabolism | Viral thymidine kinase |
| Elimination half-life | 2.2–2.3 hours |
| Excretion | Renal |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| ECHA InfoCard | 100.189.687  |
| Chemical and physical data | |
| Formula | C10H15N5O3 |
| Molar mass | 253.258 g/mol |
| 3D model (JSmol) | |
/////////////Penciclovir, BRL-39123, BRL 39123A, penciclovir sodium, Denavir, Vectavir, Euraxvir, Fenivir,
C1=NC2=C(N1CCC(CO)CO)NC(=NC2=O)N
june 5, 2018
Release
As part of the U.S. Food and Drug Administration and the U.S. Department of Agriculture’s ongoing effort…
View original post 899 more words
Chenodeoxycholic acid
Chenodiol
|
Chenodeoxycholate;
Chenodeoxycholic acid; 3alpha,7alpha-Dihydroxy-5beta-cholanic acid; Chenodiol |
Synthesis ReferenceHenry Francis Frost, Fritz Fabian, Christopher James Sharpe, William Arthur Jones, “Process for preparing chenodeoxycholic acid.” U.S. Patent US4022806, issued October, 1974. US4022806
First ref
Chenodeoxycholic acid (also known as chenodesoxycholic acid, chenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. It occurs as a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165–167 °C. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the main bile acids produced by the liver.[1]
It was first isolated from the bile of the domestic goose, which gives it the “cheno” portion of its name (Greek: χήν = goose).[2]
Chenodeoxycholic acid and cholic acid are the two primary bile acids in humans. Some other mammals have muricholic acid or deoxycholic acid rather than chenodeoxycholic acid.[1]
Chenodeoxycholic acid is synthesized in the liver from cholesterol by a process which involves several enzymatic steps.[1] Like other bile acids, it can be conjugated in the liver with taurine or glycine, forming taurochenodeoxycholate or glycochenodeoxycholate. Conjugation results in a lower pKa. This means the conjugated bile acids are ionized at the usual pH in the intestine and will stay in the gastrointestinal tract until reaching the ileum where most will be reabsorbed. Bile acids form micelles which facilitate lipid digestion. After absorption, they are taken up by the liver and resecreted, so undergoing an enterohepatic circulation. Unabsorbed chenodeoxycholic acid can be metabolised by bacteria in the colon to form the secondary bile acid known as lithocholic acid.
Chenodeoxycholic acid is the most potent natural bile acid at stimulating the nuclear bile acid receptor, farnesoid X receptor (FXR).[3]The transcription of many genes is activated by FXR.
Indication
Chenodiol is indicated for patients with radiolucent stones in well-opacifying gallbladders, in whom selective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age. Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.
Associated Conditions
Pharmacodynamics
It acts by reducing levels of cholesterol in the bile, helping gallstones that are made predominantly of cholesterol to dissolve. Chenodeoxycholic acid is ineffective with stones of a high calcium or bile acid content.
Mechanism of action
Chenodiol suppresses hepatic synthesis of both cholesterol and cholic acid, gradually replacing the latter and its metabolite, deoxycholic acid in an expanded bile acid pool. These actions contribute to biliary cholesterol desaturation and gradual dissolution of radiolucent cholesterol gallstones in the presence of a gall-bladder visualized by oral cholecystography. Bile acids may also bind the the bile acid receptor (FXR) which regulates the synthesis and transport of bile acids.
EMA
On 16 December 2014, orphan designation (EU/3/14/1406) was granted by the European Commission to Sigma-Tau Pharma Ltd, United Kingdom, for chenodeoxycholic acid for the treatment of inborn errors in primary bile acid synthesis.
The sponsorship was transferred to sigma-tau Arzneimittel GmbH, Germany, in May 2015.
Chenodeoxycholic acid has been authorised in the EU as Chenodeoxycholic acid sigma-tau since 10 April 2017.
The name of the product changed to Chenodeoxycholic acid Leadiant in May 2017.
The sponsorship was transferred to Leadiant GmbH, Germany, in June 2017.
On 16 February 2017, the Committee for Orphan Medicinal Products (COMP) concluded its review of the designation EU/3/14/1406 for Chenodeoxycholic acid sigma-tau (chenodeoxycholic acid) as an orphan medicinal product for the treatment of inborn errors in primary bile acid synthesis. The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other methods of treatment. As other methods of treatment are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with inborn errors in primary bile acid synthesis. The COMP recommended that the orphan designation of the medicine be maintained1.
1 The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation similar products with the same therapeutic indication cannot be placed on the market.
http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2015/02/WC500183233.pdf
Chenodeoxycholic acid has been used as medical therapy to dissolve gallstones.[4]
Chenodeoxycholic acid can be used in the treatment of cerebrotendineous xanthomatosis.[5]
The Australian biotechnology company Giaconda has tested a treatment for Hepatitis C infection that combines chenodeoxycholic acid with bezafibrate.[6]
As diarrhea is a complication of chenodeoxycholic acid therapy, it has also been used to treat constipation.[7][8]
In supramolecular chemistry, molecular tweezers based on a chenodeoxycholic acid scaffold is a urea receptor that can contain anionsin its binding pocket in order of affinity: H2PO4− (dihydrogen phosphate) > Cl− > Br− > I− reflecting their basicities (tetrabutylammonium counter ion).[9]
PAPER
Improved Chemical Synthesis, X-Ray Crystallographic Analysis, and NMR Characterization of (22R)-/(22S)-Hydroxy Epimers of Bile Acids
Lipids (2014), 49, (11), 1169-1180.
A Practical and Eco-friendly Synthesis of Oxo-bile Acids
By Han, Young Taek and Yun, HwayoungFrom Organic Preparations and Procedures International, 48(1), 55-61; 2016
DOI:10.1080/00304948.2016.1127101
General Procedure
An aqueous solution of 0.2 M NaBrO3 (1.5 equiv. per hydroxy group) was added dropwise to a slurry of bile acid (1 equiv.) and ceric ammonium nitrate (0.05 equiv.) in 20% aqueous acetonitrile (0.2 M) at 80°C over 20 min. The bile acid slowly dissolved in a few minutes, and then the color of the reaction mixture changed to orange. The reaction mixture was stirred at the same temperature and the progress of the reaction was monitored by TLC on silica gel (1:20 MeOH-CH2Cl2) until disappearance of the starting material and partially oxidized intermediates. It was then cooled in an ice bath and quenched with aqueous Na2S2O3 solution. Water was added slowly to the resulting white suspension until no more oxo-bile acid precipitated. The white solid was collected, washed with water until the filtrate was colorless, and then dried in vacuo at 50°C. Methyl 3,7α-Diacetoxy-12-oxo-5β-cholanoate(3),21 was obtained in 92% yield (275 mg) as a white solid from 300 mg (0.590 mmol) of 2 via the general procedure. mp. 176-178°C, lit.22 mp. 178-179°C, IR (thin film, neat): 2947 (m), 2873 (s), 1736 (w), 1706 (w), 1436 (s), 1365 (m) cm-1; 1H-NMR (400 MHz, CDCl3): δ 4.96 (m, 1H, 7-CH), 4.55 (m, 1H, 3-CH), 3.64 (s, 3H), 2.49 (t, 1H, J = 12.6 Hz), 2.41-0.80 (m, 23H), 2.01 (s, 3H), 2.00 (s, 3H), 1.01 (s, 3H, 18-CH3), 1.00 (s, 3H, 19-CH3), 0.83 (d, 3H, J = 6.6 Hz, 21-CH3); 13C-NMR (CDCl3, 100 MHz): δ 214.0 (12-C), 174.6 (24-C), 170.7 (C = O), 170.2 (C = O), 73.5 (3-C), 70.5 (7-C), 57.1 (13-C), 53.1 (14-C), 51.5 (CH3O), 46.3 (17-C), 40.5 (5-C), 37.9 (11-C), 37.8 (4-C), 37.6 (8-C), 35.54 (9-C), 35.52 (20-C), 34.9 (1-C), 34.5 (10-C), 31.3 (6-C), 31.2 (22-C), 30.4 (23-C), 27.4 (16-C), 26.5 (2-C), 23.8 (15-C), 22.1 (19-C), 21.51 (CH3CO2), 21.46 (CH3CO2), 18.6 (21-C), 11.5 (18-C); LR-MS (FABC) m/z 505 (M+H +). HR-MS (FABC): Calcd for C29H45O7 (M+H +): 505.3165. Found 505.3161.
next step
R:KOH, R:N2H4
NOTE STARTING IS BILE ACID AS BELOW
Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-
PAPER
https://pubs.acs.org/doi/pdf/10.1021/jo01091a623
Journal of Organic Chemistry
Volume24
Pages1367-8
Journal
1959
DOI:10.1021/jo01091a623
Chenodeoxycholic acid (V). Five hundred mg. of the above ester IV was hydrolyzed with 80 ml. of ethanolic 5% potassium hydroxide for 4 hr. After partial concentration of the volume and addition of water, the reaction product was acidified with hydrochloric acid. The resulting precipitate was collected, dried, and crystallized from ethyl acetate. A quantitative crop (400 mg.) of prisms melting at 143- 145° were obtained. Recrystallization from the same solvent yielded a product of m.p. 145-146°, [ ]2 +10.7° (dioxane). Anal. Caled, for C24H40O4: C, 73.43; H, 10.27. Found: C, 73.49; H, 10.31.
NOTE I IS BILE ACID
Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-
PATENT
https://patents.google.com/patent/CN102060902A/en
chenodeoxycholic acid (3 α, 7 α – dihydroxy _5 β – cholestane-24-oic acid) Chenodeoxycholic Ac id (referred to as CDCA), clinically used to correct dissolving cholesterol calculi and bile saturation drugs, the main function is to reduce the cholesterol in the bile saturation, large doses can inhibit the synthesis of cholesterol CDCA and increasing bile gallstone patients cholesterol level in a non-saturated, thereby preventing the formation of cholesterol gallstones of cholesterol and promote stone dissolve and fall off. It also has significant anti-asthmatic, anti-inflammatory, antitussive and expectorant effects.
[0003] Synthesis of chenodeoxycholic acid or ursodeoxycholic acid (3 α, 7β_ -5β_ dihydroxy-cholestane-24-oic acid, ursodeoxycholic Acid, referred UDCA), a key intermediate. Ursodeoxycholic acid is the main active ingredient of precious Chinese medicine bear bile, used in a variety of clinical hepatobiliary disease and dyspepsia. Currently we bear bile resources are scarce, mainly used synthetic chemical ursodeoxycholic acid as a clinical treatment. Therefore, the preparation of chenodeoxycholic acid is also important for the preparation of ursodeoxycholic acid.
[0004] CDCA mainly come from poultry or livestock bile extraction. Traditional extraction process complicated operation, low yield, (pharmaceutical industry, 1987,18 (9), 416; Chinese Journal of Biochemical Pharmaceutics, 1996,17 (1), 17; Applied Technology, 1998, (4), 9; CN1850846A ) can not meet the needs of modern industry. Chemical synthesis of chenodeoxycholic acid have also been reported (Japanese Journal of Chemistry 1955,76 (3), 297 -J Org Chem 1982,47 (2): 2331; Journal of Biochemical Pharmaceutics 1987,1,6 -, Tap Chi Duoc ^ oc2004 , 44 (1), 11; CN1869043A), but lower yield widespread pollution major problem, especially in the oxidation reaction is often used to expensive, and polluting agents.Therefore, to reduce pollution, reduce environmental hazards, streamline operations, improve yield, reduce costs, important for the synthesis of chenodeoxycholic acid.
n particular by the following steps:
(1) Preparation of cholate: bile acid in alcohol, concentrated hydrochloric acid as catalyst, at reflux, cooling and crystallization, filtration, and washed with methanol.
[0008] (2) Preparation of 3α, 7α- diacetyl hydroxy -12α- cholate: bile acid ester was dissolved in dichloromethane and triethylamine was added with stirring acetic anhydride and the catalyst N, N- dimethyl pyridine, methylene chloride was distilled off, poured into water, filtered to give 3α, 7α- diacetyl -12 α – hydroxy cholate.
[0009] (3) 3α, 7α- diacetyl -12– Preparation oxo chenodeoxycholic acid ester: Take 3 α, 7 α – diacetyl -12 α – hydroxy cholate dissolved in ethyl acetate and methanol, bromide and tetrabutylammonium bromide as catalyst, and acetic acid was added dropwise under stirring hypochlorite, the organic solvent was distilled off and filtered, to give 12-oxo-3,7-diacetyl Chenodeoxy cholate.
[0010] (4) i2 – Preparation oxo chenodeoxycholic acid: 3,7-diacetyl-12-oxo-chenodeoxycholic acid ester added ethanol – sodium hydroxide solution, at reflux.PH adjusted with hydrochloric acid value of the reaction system acidic, ethanol was distilled off, and filtered to give 12- oxo crude chenodeoxycholic acid, fine recrystallization.
[0011] Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid, ethylene glycol and solid sodium hydroxide, hydrated corpus, refluxed for 2 hours, gradually warming evaporated partially hydrated corpus, continue to heat up to 150 ° C, continued to reflux, cooled to room temperature, poured into water, adjusting the PH with hydrochloric acid, the white precipitate was filtered, washed with water to give crude chenodeoxycholic acid, recrystallization
Azusa mouth
M ο not mesh
[0012] Step (1): cholic acid to alcohol weight to volume ratio of 1: 2 ~ 5, the volume ratio of concentrated hydrochloric acid to alcohol is 10 wide: 100, 5-5 hours reflux time was 0.5.
[0013] Step (2): cholate: acetic anhydride molar ratio = 1: 2 ~ 5, the reaction temperature, time; Tl2O hours; cholate was added per mole of N, N- dimethylpyridine wide 5g.
[0014] Step (; 3): The hypochlorite is sodium hypochlorite or calcium hypochlorite; bromide is sodium bromide, potassium bromide and the like.
[0015] Step (4): recrystallization from a solvent with an alcohol such: as methanol or ethanol.
[0016] Step (5): recrystallization solvent is a water-miscible organic solvents, such as: methanol, ethanol, acetonitrile, acetone and the like.
[0017] Step (cholate was used ¾ of methyl cholate, ethyl cholate, cholic acid or cholic acid propyl ester; Step (3) used as 3 [alpha], 7 α – diacetyl -12 α – hydroxy cholate as 3 α, 7 α – diacetyl -12 α – hydroxy methyl cholate, 3 α, 7α- diacetyl -12 α – hydroxy bile acid ethyl ester, 3 α, 7α- diacetyl yl -12 α – hydroxy acid or ester 3α, 7α- diacetyl -12 α – hydroxy acid ester.
[0018] The invention has the advantages: in cholic acid as raw materials, and the choice of bromide tetrabutylammonium bromide as catalyst, in a non-polluting oxidizing agent is hypochlorite, Intermediate 3 α, 7 α – Diacetyl _12_ oxo chenodeoxycholic acid ester yield of 90% or more, thereby improving the yield of the final product of chenodeoxycholic acid, 99% yield, low cost and no pollution, very convenient for industrial production. detailed description
[0019] The present invention will be better described, for example is as follows:
(1) Preparation of methyl cholate: bile acid 5. lg, 15ml of anhydrous methanol, heating the whole solution. Refluxed for 3 hours, was added 0. 4ml concentrated hydrochloric acid, the reaction was stopped after 30min, after slow cooling, and filtered to give methyl cholate 5. 05g, 95% yield. 1HNMR (CDCl3):. Δ 0. 70 (s, 3H, 18- CH3), 0.90 (s, 3H, 19- CH3), 0.98 (d, 3H, 21-CH3), 3 50 (m, 1H, 3 β -H), 3. 67 (s, 3H, OCH3), 3. 87 (s, 1H, 7 β -H), 3. 99 (s, 1H, 12 β -H).
[0020] (2) Preparation of 3α, 7α- methyl cholate diacetyl-hydroxy -12α-: bile acid methyl ester 4. 71g (Ilmmol) IOOml was placed in a flask, was added methylene chloride 30ml, triethylamine 3 . Chiu 1, stirred at room temperature, was added dropwise acetic anhydride 2. 7ml (28. 6mmo 1), followed by addition of 20mg N, N- dimethylpyridine catalyst, the reaction time of 7 hours, methylene chloride was distilled off, into the water, filtered to give a white solid. The crude product was recrystallized from methanol to give white crystals 4. 05g, yield 67.2%. 1H NMR (CDCl3) δ: 4.90 (m, 1H, 7 β -H), 4. 59 (s, 1H, 3 β -H), 4 01 (s, 1H, 12 β -H), 3 67.. (s, 3Η, OCH3), 2. 08 (s, 3Η, CH3CO), 2. 02 (s, 3Η, CH3CO), 0. 98 (s, 3Η, 21-CH3), 0. 93 (s, 3Η , 19-CH3), 0.69 (s, 3Η, 18_CH3).
[0021] (3) 3α, 7α – 12-oxo-diacetyl chenodeoxycholic acid methyl ester prepared: Take 3 α, 7 α – diacetyl -12 α- hydroxy methyl cholate 1.917 g ( 3. 79mmol) was placed in a 50ml round bottom flask, 12ml of ethyl acetate was added, 5ml methanol, stirring at room temperature, was added 0. 25g 0. Ig of potassium bromide and tetrabutylammonium bromide. Was added dropwise a solution of acetic acid and 6g of sodium hypochlorite (7%) (5.62mmol), for 10 hours. Methanol was distilled off under reduced pressure and ethyl acetate, filtered, washed with water, and dried to give crude 1.915g, 1.75g as a white solid after recrystallization from methanol, yield 91.2%. 1H bandit R (CDCl3) δ:.. 4. 99 (d, 1H, 7 β-H), 4 60 (m, 1H, 3 β-H), 3 67 (s, 3H, OCH3), 2. 07 (s, 6H, CH3CO), 1. 03 (s, 6H, I8-CH3 and 19-CH3), 0. 82 (d, 3H, 21-CH3) ο
[0022] (4) 12- oxo chenodeoxycholic acid Preparation: Take 3 α, 7 α – diacetyl _12_ oxo chenodeoxycholic acid methyl ester 1. 56g, was dissolved in 30ml 95% ethanol was added 3. 2g of sodium hydroxide, heated at reflux for 5 hours. PH adjusted with hydrochloric acid value of the reaction system, most of the ethanol was distilled off, filtered, washed with water, and dried to give a white solid 12- oxo-1 crude chenodeoxycholic acid, recrystallized from methanol ^ g 1. 25g, yield rate of 96%. Tun bandit R (CDCl3) δ:. 3.96 (d, 1H, 7 β-H), 3 47 (m, 1H, 3 β-H), 1.03 (s, 3H, 19_CH3), 0.89 (s, 3H, 18_CH3 ), 0 · 70 (d, 3 H, 21_CH3).
[0023] Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid 0. 9g, 15ml ethylene glycol was added solid sodium hydroxide and 1. 5g, 15ml hydrated corpus (80%) , 120 ° C reflux for 2 hours, change return device is a distillation apparatus, was gradually warmed evaporated amount hydrated corpus, continue to heat up to 150 ° C, continuing reflux for 4h, cooled to room temperature, poured into water, adjusted with HCl of PH3, white precipitated, was filtered cake was washed with water, and dried to give crude chenodeoxycholic acid 0. 92g, recrystallized from methanol to give 0. 86g, 99 (s, 1H, C00H).
Paper
https://pubs.acs.org/doi/abs/10.1021/ja01168a045
The Preparation of Chenodeoxycholic Acid and Its Glycine and Taurine Conjugates.Hofmann, Alan F.
Chenodeoxycholic acid (3α, 7α- -5β- dihydroxy-cholestane acid) Chenodeoxycholic Acid (referred to as CDCA), a medicine for treating gallstones. 1848 first discovered in goose bile, 1924, known as the CDCA. By reducing cholesterol absorption, synthesis, the bile cholesterol decreased, thereby suppressing cholesterol gallstone formation and promote dissolution, and can reduce cholesterol saturation.
Chenodeoxycholic acid addition pharmaceutically itself, but also as the preparation of ursodeoxycholic acid (3α, 7β- -5β- dihydroxy bile acid, abbreviated UDCA) starting material. Ursodeoxycholic acid is the main active ingredient contained bile valuable medicine, in clinical treatment of various gastrointestinal diseases and bladder diseases. But the limited sources of bear bile medicine, and contrary to the principles of animal protection. So, dwindling source of natural bear bile, can not meet the medical requirements. Therefore, the preparation of chenodeoxycholic acid is also of great significance for further preparation of ursodeoxycholic acid.
CDCA bile extracted mainly from poultry or animal bile extraction methods in the past as it involves toxic chemicals (animal biological pharmacy, 1981, People’s Medical Publishing House, P259; pharmaceutical industry, 1987,18 (2): 75-76; ) or unsafe to use a large amount of organic solvent (Chinese Journal of biochemical Pharmaceutics, 1996,17 (1): 17; application technology, 1998,4: 9-10; US Patent, 3,965,131; US Patent, 4,331,607; USPatent, 4,163,017), can not be meet the requirements of modern industry, CDCA and low purity prepared costly.
PATENT
https://patents.google.com/patent/WO2007069814A1/en
Chenodeoxycholic acid is generally contained in bile of cow, swine, bear, or poultry such as chicken or goose, as well as in bile of human. Chenodeoxycholic acid is used as starting material for the preparation of ursodeoxycholic acid which is effective to alleviate biliary system diseases, hyperlipidemia, cholelithiasis, and chronic liver diseases, and a typical process for preparing ursodeoxycholic acid known in the art is as follows.
A typical process for preparing chenodeoxycholic acid comprises the steps of: esterifying cholic acid (3α,7α,12θ!-trihydroxy cholic acid) with methyl; protecting the hydroxyl group of 3α and Ia position by acetylating them with anhydrous acetic acid; oxidizing the hydroxyl group of 12α position to carbonyl group by using chromic acid, and then removing the carbonyl group by Wolff-kichner reduction reaction; hydrolyzing and deprotecting the obtained product to yield chenodeoxycholic acid. The above process requires the reaction to be maintained at a high temperature of more than 200 °C , and the supply of raw material may be interrupted by bovine spongiform encephalopathy, etc. Bile ,of poultry contains chenodeoxycholic acid, lithocholic acid, and a small amount of cholic acid. Thus, the process for separating chenodeoxycholic acid from poultry is well known in the art, but is not economically reasonable due to the supply decrease of raw material and low yield [see, Windhaus et al, I Physiol. Chem., 140, 177-185 (1924)].
US Patent No. 4,186,143 disclosed a process for purely separating and purifying chenodeoxycholic acid from chenodeoxycholic acid mixture derived from natural swine bile. This process comprises the major steps of: pre-treatment to remove 3ohydroxy-6- oxo-5/3-cholic acid by saponification of bile; esterification of bile acid; acetylation of bile acid ester; removal of intermediate product by using non-polar organic solvent; crystallization of acetylated ester of formula I; deprotection; and production of the compound of formula I by using crystallization in organic solvent. However, this patent does not describe HPLC content for acetylated ester of formula I, and the purity of the final product is very low since the specific rotatory power is [ofo25 +13.8° (c=l, CHCl3), and the melting point is 119-121 °C [STD: [α]D 25 +15.2°(c=l, CHCl3), melting point 127- 129 “C]. Also, the crystallization for purifying the final product requires a very long time (i.e., 16-48 hours), and the entire process is complex as eight (8) steps. Thus, when purifying the compound of formula I by using the above process, the yield of the final product becomes low, and the reaction time is as long as 12 days. Therefore, the process is not economically reasonable.
Step 6: Deprotection and crystallization of chenodeoxycholic acid
To 220ml of water were added 24.5g of chenodeoxycholic acid-diacetate-ester and 29.5g of sodium hydroxide, and then the solution was stirred with reflux for 4 hours. To the solution was added 370ml of water. The solution’s pH is adjusted to 2.0-3.0 by using 59ml of hydrochloric acid. Then, the solution was stirred at 35-45 °C for 1 hour, and then filtered. The filtered material was washed with 24.5ml of water and dried in vacuum at 70 °C to obtain 19.5g of pure chenodeoxycholic acid, m.p.: 160-161 °C, [α]o25 +13.0°(c=l, CHCl3).
Step 8: Production of the compound of formula I
The reaction solution was extracted by using ethyl acetate, and aqueous layer was discarded therefrom. Ethyl acetate layer in the solution was washed with 6% saline, and the solution was distilled to about 90ml. This solution was cooled, kept cool for one day after adding 90ml of hexane, and filtered. Thus filtered material was washed with 20ml of hexane, and dried in vacuum at 60 °C to produce 12.7g of chenodeoxycholic acid. m.p. 142-1450C; [α]D 25 +13.0°(c=l, CHCl3). INDUSTRIAL APPLICABILITY The present invention can purify chenodeoxycholic acid of formula I from swine bile solid in high yield and purity. Also, the present invention is suitable for industrial purification by reducing the purification time.
PATENT
https://patents.google.com/patent/CN102060902A/en
chenodeoxycholic acid (3 α, 7 α – dihydroxy _5 β – cholestane-24-oic acid) Chenodeoxycholic Ac id (referred to as CDCA), clinically used to correct dissolving cholesterol calculi and bile saturation drugs, the main function is to reduce the cholesterol in the bile saturation, large doses can inhibit the synthesis of cholesterol CDCA and increasing bile gallstone patients cholesterol level in a non-saturated, thereby preventing the formation of cholesterol gallstones of cholesterol and promote stone dissolve and fall off. It also has significant anti-asthmatic, anti-inflammatory, antitussive and expectorant effects.
[0003] Synthesis of chenodeoxycholic acid or ursodeoxycholic acid (3 α, 7β_ -5β_ dihydroxy-cholestane-24-oic acid, ursodeoxycholic Acid, referred UDCA), a key intermediate. Ursodeoxycholic acid is the main active ingredient of precious Chinese medicine bear bile, used in a variety of clinical hepatobiliary disease and dyspepsia. Currently we bear bile resources are scarce, mainly used synthetic chemical ursodeoxycholic acid as a clinical treatment. Therefore, the preparation of chenodeoxycholic acid is also important for the preparation of ursodeoxycholic acid.
[0004] CDCA mainly come from poultry or livestock bile extraction. Traditional extraction process complicated operation, low yield, (pharmaceutical industry, 1987,18 (9), 416; Chinese Journal of Biochemical Pharmaceutics, 1996,17 (1), 17; Applied Technology, 1998, (4), 9; CN1850846A ) can not meet the needs of modern industry. Chemical synthesis of chenodeoxycholic acid have also been reported (Japanese Journal of Chemistry 1955,76 (3), 297 -J Org Chem 1982,47 (2): 2331; Journal of Biochemical Pharmaceutics 1987,1,6 -, Tap Chi Duoc ^ oc2004 , 44 (1), 11; CN1869043A), but lower yield widespread pollution major problem, especially in the oxidation reaction is often used to expensive, and polluting agents.Therefore, to reduce pollution, reduce environmental hazards, streamline operations, improve yield, reduce costs, important for the synthesis of chenodeoxycholic acid.
Preparation of chenodeoxycholic acid.
[0007]
Cholic acid esters prepared by (1) Weigh 50 g of cholic acid, dissolved in 150 ml of anhydrous methanol was added 5 ml of concentrated hydrochloric acid was refluxed for 30 minutes, cooled slowly into the freezer, the available capacity methyl cholate It was 95%.
(2) hydroxy -12α- diacetyl – Preparation of methyl cholate methyl cholate weighed 50 g, was dissolved in 100 ml of pyridine was purified, dissolved completely, 100 ml of acetic anhydride was stirred at room temperature for 3 to 4 hours, poured into 500 ml of water, a white precipitate in the refrigerator, filtered the next day, diacetyl -12α- available hydroxy – methyl cholate, yield 40%.
(3) 3α, 7α–diacetoxy-12-oxo – Preparation of methyl cholanic acid prepared above was weighed 25 g of crude product, dissolved in 250 ml of acetone, filtered to remove insolubles, the stirring conditions , the Jones reagent was slowly added, at room temperature for 30 minutes, filtered, water was added to the filtrate precipitated white precipitate was filtered available 3α, 7α–diacetoxy-12-oxo – methyl-cholanic acid. The yield was 100%.
(4) 12- oxo – Preparation of chenodeoxycholic acid in ethanol 10% – sodium hydroxide solution and saponified for 1 hour at room temperature, the solution was acidified, poured into water to give 12- oxo – chenodeoxycholic acid , 100% yield.Recrystallized in absolute ethanol.
Preparation of chenodeoxycholic acid (5) was weighed 12- oxo – chenodeoxycholic acid, 20 grams, was added 300 ml of ethylene glycol and 30 g of solid sodium hydroxide and 300 ml of hydrazine hydrate (85%), 100 ℃ refluxed for 2 hours, warming gradually raised to 130. ℃, generated by hydrazine hydrate was distilled off, continue to heat up to 185 ~ 190 ℃, continued reflux for 4 hours, cooled to a lower temperature, poured into water and heat, PH adjusted with hydrochloric acid (20%) 3, a white precipitate was filtered cake was washed with water to give chenodeoxycholic acid.
(6) Purification of chenodeoxycholic acid obtained weighed amount of chenodeoxycholic acid, dissolved with a small amount of ethanol, was impregnated on a silica gel column petroleum ether, liquid flow linear velocity by column chromatography 1 ~ 5cm / control points, with petroleum ether: acetone = 2, begins to elute, detected by TLC chromatography therebetween, Junichi appearance of spots to be chenodeoxycholic acid appears to start collecting the eluate until no Chenodeoxy acid spots, distillation under reduced pressure and dried to give pure higher chenodeoxycholic acid.
PATENTS
|
|
 |
|
| Names | |
|---|---|
| IUPAC names
chenodiol
OR 3α,7α-dihydroxy-5β-cholanic acid OR 5β-cholanic acid-3α,7α-diol OR (R)-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid |
|
| Identifiers | |
|
3D model (JSmol)
|
|
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| DrugBank | |
| ECHA InfoCard | 100.006.803 |
| EC Number | 207-481-8 |
| KEGG | |
|
PubChem CID
|
|
| UNII | |
| Properties | |
| C24H40O4 | |
| Molar mass | 392.57 g/mol |
| Melting point | 165 to 167 °C (329 to 333 °F; 438 to 440 K) |
| Pharmacology | |
| A05AA01 (WHO) | |
| License data | |
|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|
|
 verify (what is   ?) |
|
| Infobox references | |
////////////////////Chenodeoxycholic acid, ケノデオキシコール酸 , orphan designation
[H][C@@]1(CC[C@@]2([H])[C@]3([H])[C@H](O)C[C@]4([H])C[C@H](O)CC[C@]4(C)[C@@]3([H])CC[C@]12C)[C@H](C)CCC(O)=O
| Chemical Names: | Alatrofloxacin mesylate; UNII-2IXX802851; 146961-77-5; Alatrofloxacin mesylate [USAN]; 157605-25-9; 2IXX802851 |
|---|---|
| Molecular Formula: | C27H29F3N6O8S |
| Molecular Weight: | 654.618 g/mol |
| CAS No. | 146961-76-4 (Alatrofloxacin ); 157605-25-9 (Alatrofloxacin Mesylate); |
| Chemical Name | (1α, 5α, 6α)-L-alanyl-N-[3-[6-carboxy-8-(2,4-difluorophenyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridine-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-L-alaninamide, monomethanesulfonate |
Research Code：CP-116517-27; CP-116517, Trade Name：Trovan I.V.® MOA：Quinolone antibiotic Indication：Life- or limb-threatening infections caused by susceptible strains Status：Withdrawn Company：Pfizer (Originator)
Alatrofloxacin (Trovan IV) is a fluoroquinolone antibiotic developed by Pfizer, delivered as a mesylate salt.[1]
Trovafloxacin and alatrofloxacin were both withdrawn from the U.S. market in 2001
Alatrofloxacin mesylate was first approved by the U.S. Food and Drug Administration (FDA) on Dec 18, 1997. It was developed and marketed as Trovan I.V. ® by Pfizer in the US.
Alatrofloxacin mesylate is a fluoronaphthyridone related to the fluoroquinolones with in vitro activity against a wide range of gram-negative and gram-positive aerobic and anaerobic microorganisms. The bactericidal action of alatrofloxacin results from inhibition of DNA gyrase and topoisomerase IV. Trovan I.V.® is indicated for the treatment of patients initiating therapy in in-patient health care facilities (i.e., hospitals and long term nursing care facilities) with serious, life- or limb-threatening infections caused by susceptible strains of the designated microorganisms in the conditions listed below.
Trovan I.V.® is available as injection solution for intravenous use, containing 7.86 mg/ml of Alatrofloxacin mesylate. The recommended starting dose is 200 mg or 300 mg administered intravenously.
Alatrofloxacin mesylate was withdrawn from the U.S. market in 2001.
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 27317-69-7 | C11H20N2O5 | N–tert-butoxycarbonyl-l-alanyl-l-alanine | L-Alanine, N-[(1,1-dimethylethoxy)carbonyl]-L-alanyl- |
| 186772-86-1 | C33H37F3N6O7 | N-[(1,1-dimethylethoxy)carbonyl]-l-alanyl-N-[(1α,5α,6α)-3-[8-(2,4-difluorophenyl)-6-(ethoxycarbonyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-l-alaninamide | L-Alaninamide, N-[(1,1-dimethylethoxy)carbonyl]-L-alanyl-N-[(1α,5α,6α)-3-[8-(2,4-difluorophenyl)-6-(ethoxycarbonyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]- |
| 171176-56-0 | C22H19F3N4O3 | ethyl (1α,5α,6α)-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate | 1,8-Naphthyridine-3-carboxylic acid, 7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-, ethyl ester, (1α,5α,6α)- |
| 134575-66-9 | C27H27F3N4O5 | ethyl (1α,5α,6α)-1-(2,4-difluorophenyl)-7-[6-[[(1,1-dimethylethoxy)carbonyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate | 1,8-Naphthyridine-3-carboxylic acid, 1-(2,4-difluorophenyl)-7-[6-[[(1,1-dimethylethoxy)carbonyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-6-fluoro-1,4-dihydro-4-oxo-, ethyl ester, (1α,5α,6α)- |
| 75-75-2 | CH4O3S | methanesulfonic acid | Methanesulfonic acid |
| Country | Trade Name | Vendor | Annotation |
|---|---|---|---|
| D | TROVAN | Pfizer | wfm |
| F | Turvel | Pfizer | wfm |
| GB | Turvel | Pfizer | wfm |
| I | Turvel | Pfizer | wfm |
| USA | Trovan | Pfizer | wfm |
(wfm = withdrawn from market)
References
“Center for Drug Evaluation and Research – Application Number: 020759/020760 – Chemistry Review(s)” (PDF). Food and Drug Administration. Retrieved 29 August 2014.
 |
|
| Clinical data | |
|---|---|
| AHFS/Drugs.com | Micromedex Detailed Consumer Information |
| MedlinePlus | a605016 |
| Pregnancy category |
|
| Routes of administration |
Intravenous |
| ATC code |
|
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | N/A |
| Protein binding | 76% (trovafloxacin) |
| Metabolism | Quickly hydrolyzed to trovafloxacin |
| Elimination half-life | 9 to 12 hours (trovafloxacin) |
| Excretion | Fecal and renal(trovafloxacin) |
| Identifiers | |
| CAS Number | |
| ChemSpider | |
| UNII | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C26H25F3N6O5 |
| Molar mass | 558.509 g/mol |
| 3D model (JSmol) | |
/////////////////
RG7604,Taselisib
GDC-0032, GDC0032;GDC 0032, RO5537381
Taselisib (GDC-0032) is an experimental cancer drug in development by Roche. It is a small molecule inhibitor targeting phosphoinositide 3-kinase subtype PIK3CA.[1]
Taselisib is in phase III with Roche , clinical trials for treatment of metastatic breast cancer and non-small cell lung cancer.[2]
Taselisib is a phosphatidylinositol 3-kinase (PI3Kalpha) inhibitor in phase III clinical studies at Roche for the treatment of postmenopausal women with histologically or cytologically confirmed locally advanced or metastatic estrogen-receptor positive (ER+) breast cancer.
Taselisib is an orally bioavailable inhibitor of the class I phosphatidylinositol 3-kinase (PI3K) alpha isoform (PIK3CA), with potential antineoplastic activity. Taselisib selectively inhibits PIK3CA and its mutant forms in the PI3K/Akt/mTOR pathway, which may result in tumor cell apoptosis and growth inhibition in PIK3CA-expressing tumor cells. By specifically targeting class I PI3K alpha, this agent may be more efficacious and less toxic than pan PI3K inhibitors. Dysregulation of the PI3K/Akt/mTOR pathway is frequently found in solid tumors and causes increased tumor cell growth, survival, and resistance to both chemotherapy and radiotherapy. PIK3CA, which encodes the p110-alpha catalytic subunit of the class I PI3K, is mutated in a variety of cancer cell types and plays a key role in cancer cell growth and invasion.
PRODUCT PATENT
WO 2011036280
https://encrypted.google.com/patents/WO2011036280A1?cl=en
Discovery of 2-(3-(2-(1-Isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (GDC-0032): A -sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity
J Med Chem 2013, 56(11): 4597
Condensation of 4-bromo-2-hydroxybenzaldehyde with glyoxal in the presence of NH3 in MeOH gives 5-bromo-2-(1H-imidazol-2-yl)phenol
Which upon annulation with 1,2-dibromoethane in the presence of Cs2CO3 in DMF at 90 °C yields 9-bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine .
Iodination of oxazepine with NIS in DMF provides 9-bromo-2,3-diiodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine,
Which upon mono-deiodination by means of EtMgBr in THF at -15 °C affords 9-bromo-2-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine .
Amidation of iodide with CO in the presence of PdCl2(PPh3)2 and HMDS in DMF at 70 °C produces the intermediate,
Which upon reaction with N,N-dimethylacetamide dimethyl acetal in the presence of DME at 65 °C furnishes intermediate . Intramolecular cyclization of this compound with isopropylamine hydrochloride in AcOH generates triazole derivative,
Which upon Suzuki coupling with dioxaborolane derivative in the presence of Pd(PPh3)4 and KOAc in CH3CN/H2O at 120 °C yields the target compound Taselisib.
| In vitro | DMSO | 70 mg/mL warmed (151.99 mM) |
|---|---|---|
| Water | Insoluble | |
| Ethanol | Insoluble warmed |
| Description | Taselisib (GDC 0032) is a potent, next-generation β isoform-sparing PI3K inhibitor targeting PI3Kα/δ/γ with Ki of 0.29 nM/0.12 nM/0.97nM, >10 fold selective over PI3Kβ. | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Features | A beta isoform-sparing PI3K inhibitor. | ||||||||||||||||
| Targets |
|
||||||||||||||||
| In vitro | GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3Kα, δ, and γ isoforms, with 30 fold less inhibition of the PI3K β isoform relative to the PI3Kα isoform. Preclinical data show that GDC-0032 has increased activity against PI3Kα isoform (PIK3CA) mutant and HER2-amplified cancer cell lines. GDC-0032 inhibits MCF7-neo/HER2 cells proliferation with IC50 of 2.5 nM. [1] | ||||||||||||||||
| Cell Data |
|
||||||||||||||||
| In vivo | GDC-0032 pharmacokinetics is approximately dose proportional and time independent with a mean t1/2 of 40 hours. The combination of GDC-0032 enhances activity of fulvestrant resulting in tumor regressions and tumor growth delay (91% tumor growth inhibition (TGI)). In addition, the combination of GDC-0032 with tamoxifen enhances the efficacy of tamoxifen in vivo (102%TGI for GDC-0032). [1] |
The invention relates to methods of making the PI3K inhibitor I (GDC-0032), named as 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanamide, having the structure:
and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.
Another aspect of the invention includes novel intermediates useful for preparing GDC- 0032 and having the structures:
The following Schemes 1-15 illustrate the chemical reactions, processes, methodology for the synthesis of GDC-0032, Formula I, and certain intermediates and reagents. Scheme 1:
Scheme 1 shows the synthesis of intermediate isopropylhydrazine hydrochloride 4 from Boc-hydrazine 1. Condensation of 1 with acetone and magnesium sulfate gave Boc-hydrazone, tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (Example 1). Palladium-catalyzed hydrogenation of 2 in acetic acid and methanol gave Boc-isopropyl-hydrazine 3 (Example 2) which was treated in situ with hydrogen chloride gas to give 4 (Example 3).
Alternatively, the double bond of 2 can be reduced with a hydride reagent such as sodium cyanoborohydride (Example 2).
Scheme 2:
Scheme 2 shows the synthesis of l-isopropyl-3-methyl-lH-l,2,4-triazole 7 from methyl acetimidate hydrochloride 5 and isopropylhydrazine hydrochloride 4. Reaction of 5 and 4 in triethylamine and methanol followed by cyclization of condensation product, N’- isopropylacetohydrazonamide 6 (Example 4) with triethyl orthoformate (triethoxymethane) gave 7 (Example 5). Alternatively, 4 and acetamidine can be reacted to give 6.
Or, 4 can be reacted with acetonitrile and an acid to form the corresponding salt of 6. Scheme 3:
0 K2C03, H20, MTBE w
Scheme 3 shows the synthesis of intermediate, 2-chloro-N-methoxy-N-methylacetamide 10. Reaction of 2-chloroacetyl chloride 8 and Ν,Ο-dimethylhydroxylamine hydrochloride 9 in aqueous potassium carbonate and methyl, tert-butyl ether (MTBE) gave 10 (Example 6).
Scheme 4:
Scheme 4 shows the synthesis of intermediate 4-bromo-2-fluorobenzimidamide hydrochloride 12 formed by reaction of 4-bromo-2-fluorobenzonitrile 11 with lithium hexamethyldisilazide (LiHMDS) in tetrahydrofuran (Example 7). Alternatively, 11 is treated with hydrogen chloride in an alcohol, such as ethanol, to form the imidate, ethyl 4-bromo-2- fluorobenzimidate hydrochloride, followed by ammonia in an alcohol, such as ethanol, to form 12 (Example 7).
Scheme 5:
Scheme 5 shows the synthesis of 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l,2,4-triazole V from l-isopropyl-3-methyl-lH-l,2,4-triazole 7.
Deprotonation of 7 with n-butyllithium and acylation with 2-chloro-N-methoxy-N- methylacetamide 10 gave intermediate 2-chloro-l-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)ethanone 13 (Example 8). Cyclization of 13 with 4-bromo-2-fluorobenzimidamide hydrochloride 12 and potassium hydrogen carbonate in water and THF (tetrahydrofuran) formed the imidazole V (Example 9).
Scheme 6:
Scheme 6 shows the synthesis of 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III from V. Alkylation of the imidazole nitrogen of V with a 2-hydroxyethylation reagent such as, l,3-dioxolan-2-one, gave 2-(2-(4- bromo-2-fluorophenyl)-4-( 1 -isopropyl-3-methyl- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H-imidazol- 1 – yl)ethanol 14 (Example 10). Cyclization of 14 with an aqueous basic reagent, such as methyltributylammonium chloride in aqueous potassium hydroxide, gave III, which can be cystallized from ethanol and water (Example 11). Scheme 7:
IV
Scheme 7 shows the synthesis of ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2-methylpropanoate IV starting from 2-bromo-2-methylpropanoic acid 15. Alkylation of pyrazole with 15 gave 2- methyl-2-(lH-pyrazol-l-yl)propanoic acid 16 (Example 12). Esterification of 16 with sulfuric acid in ethanol gave ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17 (Example 13).
Regiospecific bromination of 17 with N-bromosuccinimide (NBS) gave IV (Example 14). Alternatively, 16 was treated in situ with a brominating reagent such as l,3-dibromo-5,5- dimethylhydantoin (DBDMH) to give 2-(4-bromo-lH-pyrazol-l-yl)-2-methylpropanoic acid which was esterified to give IV, where R is ethyl. Other esters can also be prepared, such as methyl, iso-propyl, or any alkyl, benzyl or aryl ester.
Scheme 8:
Scheme 8 shows an alternative synthesis of ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2- methylpropanoate IV starting from ethyl 2-bromo-2-methylpropanoate 18. Alkylation of pyrazole with 18 in the presence of a base such as sodium tert-butyloxide or cesium carbonate gave a mixture of ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17 and ethyl 2-methyl-3-(lH- pyrazol-l-yl)propanoate 19. Bromination of the mixture with l,3-dibromo-5,5- dimethylimidazolidine-2,4-dione (DBDMH) gave a mixture containing IV, ethyl 3-(4-bromo- lH-pyrazol-l-yl)-2-methylpropanoate 20, and 4-bromo-lH-pyrazole 21 which was treated with a strong base under anhydrous conditions, such as lithium hexamethyldisilazide in tetrahydrofuran. Acidification with hydrochloric acid gave IV.
Scheme 9:
Pd(O) catalyst
KOAc, EtOH
Scheme 9 shows the synthesis of 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)- 5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanamide, GDC-0032, 1 from ethyl 2-(4-bromo- 1 H-pyrazol- 1 -yl)-2-methylpropanoate IV (CAS Registry Number: 1040377-17-0, WO 2008/088881) and 9-bromo-2-(l-isopropyl-3-methyl-lH- 1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III (CAS Registry Number: 1282514-63-9, US 2012/0245144, US 8242104). Other esters besides ethyl can also be used which can be hydrolyzed with aqueous base, such as methyl, iso-propyl, or any alkyl, benzyl or aryl ester. In a one-pot Miyaura Borylation /Suzuki, Buchwald system, ethyl 2-(4-bromo-lH- pyrazol-l-yl)-2-methylpropanoate IV is reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(l,3,2- dioxaborolane), CAS Reg. No. 73183-34-3, also referred to as B2Pin2, and a palladium catalyst such as XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, CAS Reg. No. 564483- 18-7), with a salt such as potassium acetate, in a solvent such as ethanol, at about 75 °C to form the intermediate ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)propanoate 22 (Example 15, CAS Registry Number: 1201657-32-0, US 8242104, US 8263633, WO 2009/150240).
XPhos ligandIntermediate 22 can be isolated or reacted in situ (one pot) with III to form 23.
A variety of low valent, Pd(II) and Pd(0) palladium catalysts can be used during the Suzuki coupling step to form 23 (Example 16) from 22 and III, including PdCl2(PPh3)2, Pd(t- Bu)3, PdCl2 dppf CH2C12, Pd(PPh3)4, Pd(OAc)/PPh3, Cl2Pd[(Pet3)]2, Pd(DIPHOS)2, Cl2Pd(Bipy), [PdCl(Ph2PCH2PPh2)]2, Cl2Pd[P(o-tol)3]2, Pd2(dba)3/P(o-tol)3, Pd2(dba)/P(furyl)3,
Cl2Pd[P(furyl)3]2, Cl2Pd(PMePh2)2, Cl2Pd[P(4-F-Ph)3]2, Cl2Pd[P(C6F6)3]2, Cl2Pd[P(2-COOH- Ph)(Ph)2]2, Cl2Pd[P(4-COOH-Ph)(Ph)2]2, and encapsulated catalysts Pd EnCat
30, Pd EnCat TPP30, and Pd(II)EnCat BINAP30 (US 2004/0254066).
The ester group of 23 is saponified with an aqueous basic reagent such as lithium hydroxide, to give 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoic acid II (Example 17). Intermediate 23 can be isolated or further reacted in situ with the aqueous basic reagent to form II. The carboxylic acid group of II is activated with an acyl activating reagent such as di(lH-imidazol-l-yl)methanone (carbonyl diimidazole, CDI) or Ν,Ν,Ν’,Ν’-tetramethyl- 0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (HATU), and then reacted with an alcoholic ammonia reagent, such as ammonia dissolved in methanol, ethanol, or isopropanol, aqueous ammonium hydroxide, aqueous ammonium chloride, or ammonia dissolved in THF, to give I (Example 18).
A variety of solid adsorbent palladium scavengers can be used to remove palladium after the Suzuki coupling step to form compound I. Exemplary embodiments of palladium scavengers include FLORISIL®, SILIABOND®Thiol, and SILIABOND® Thiourea. Other palladium scavengers include silica gel, controlled-pore glass (TosoHaas), and derivatized low crosslinked polystyrene QUADRAPURE AEA, QUADRAPURE IMDAZ, QUADRAPURE MPA, QUADRAPURE TU (Reaxa Ltd., Sigma-Aldrich Chemical Co.).
Scheme 10 shows the synthesis of 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III from 4-bromo-2-fluorobenzonitrile 11. Addition of hydroxylamine to the nitrile of 11 gave 4-bromo-2-fluoro-N-hydroxybenzimidamide 24. Michael addition of 24 to ethyl propiolate gave ethyl 3-(4-bromo-2- fluorobenzimidamidooxy)acrylate 25. Heating 25 in a high-boiling solvent such as toluene, xylene, ethylbenzene, or diphenyl oxide gave cyclized imidazole, ethyl 2-(4-bromo-2- fluorophenyl)-lH-imidazole-4-carboxylate 26, along with by-product pyrimidine, 2-(4-bromo-2- fluorophenyl)pyrimidin-4-ol. Alternatively, 25 can be cyclized to 26 with catalytic Lewis acids such as Cu(I) or Cu(II) salts. Alkylation of 26 with a 2-hydroxyethylation reagent, such as 1,3- dioxolan-2-one, in a base, such as N-methylimidazole or cesium carbonate, gave ethyl 2-(4- bromo-2-fluorophenyl)-l-(2-hydroxyethyl)-lH-imidazole-4-carboxylate 27. Ring-cyclization of 27 with an aqueous basic reagent, such as potassium hydroxide, lithium hydroxide, and methyl tributylammonium hydrochloride, gave 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepine-2-carboxylic acid 28. Addition of acetamidine to 28 with triphenylphosphine gave 9-bromo-N-(l-iminoethyl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2- carboxamide 29. Ring-cyclization of 29 with isopropylhydrazine hydrochloride 4 in acetic acid gave 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepine III.
Alternatively, 28 can be reacted with N’-isopropylacetohydrazonamide 6 to give III (Scheme 12).
Scheme 11 :
Scheme 11 shows the synthesis of 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l ,2,4-triazole V from 4-bromo-2-fluorobenzimidamide hydrochloride 12. 3-Chloro-2-oxopropanoic acid and 12 are reacted with base to give 2-(4-bromo-2-fluorophenyl)- lH-imidazole-4-carboxylic acid 30. Alternatively, 3-bromo-2-oxopropanoic acid can be reacted with 12 to give 30. Reaction of 30 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU (N,N,N’,N’-tetramethyl-0-(lH-benzotriazol-l-yl)uronium hexafluorophosphate, O- (Benzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, CAS Ref. No. 94790- 37-1) in DMF gives intermediate, 2-(4-bromo-2-fluorophenyl)-N-(l-(2- isopropylhydrazinyl)ethylidene)-lH-imidazole-4-carboxamide 31 which need not be isolated and cyclizes upon heating to give V.
Alternatively, 5-(2-(4-chloro-2-fluorophenyl)-lH-imidazol-4-yl)-l-isopropyl-3-methyl- lH-l,2,4-triazole 44, the chloro version of V, can be prepared from 4-chloro-2-fluorobenzonitrile 38 (Scheme 15) Scheme 12:
Scheme 12 shows an alternative synthesis of 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III from 4-bromo-2- fluorobenzonitrile 11. Alkylation of 11 with tert-butyl 2-hydroxyethylcarbamate gives tert-butyl 2-(5-bromo-2-cyanophenoxy)ethylcarbamate 32. Cyclization of 32 under acidic conditions, such as hydrochloric acid in ethanol, gives 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33. It will be noted that 33 has an alternative tautomeric form where the double bond is inside the oxazepine ring. Formation of the imidazole ring occurs by reaction of 3-bromo-2- oxopropanoic acid (X = Br, R = OH), or other 3-halo-2-oxopropanoic acid or ester (R = alkyl), and 33 to give 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28. Coupling of 28 with N’-isopropylacetohydrazonamide 6 and a coupling reagent such as HBTU, HATU or CDI in DMF gives intermediate, 9-bromo-N-(l-(2-isopropylhydrazinyl)ethylidene)- 5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxamide 34, which need not be isolated and forms 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III upon heating.
Alternatively, N’-isopropylacetohydrazonamide 6 is used as monohydrochloride salt, which has to be set free under the reaction conditions with an appropriate base, such as K2CO3. Scheme 13:
Scheme 13 shows an alternative synthesis of 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin- 5(2H)-imine 33 from 4-bromo-2-fluorobenzonitrile 11. Reaction of 11 with sodium methoxide in methanol gives methyl 4-bromo-2-fluorobenzimidate 35. Alkylation of 35 with 2- aminoethanol gives 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzimidamide 36, followed by cyclization to 33.
Scheme 14:
37
11
Scheme 14 shows another alternative synthesis of 8-bromo-3,4- dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33 from 4-bromo-2-fluorobenzonitrile 11. Reaction of 11 with 2-aminoethanol and potassium tert-butoxide displaces fluorine to give 2-(2- aminoethoxy)-4-bromobenzonitrile hydrochloride 37. Ring closure of 37 with
trimethylaluminum gave 33. Alternatively, other trialkylaluminum reagents can be used, or magnesium alkoxide reagents such as magnesium ethoxide (magnesium bisethoxide, CAS Reg. No. 2414-98-4) to cyclize 37 to 33.
Scheme 15 shows the synthesis of 5-(2-(4-chloro-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l,2,4-triazole 44 from 4-chloro-2-fluorobenzonitrile 38. Addition of hydroxylamine to the nitrile of 38 gave 4-chloro-2-fluoro-N-hydroxybenzimidamide 39.
Michael addition of 39 to ethyl propiolate gave ethyl 3-(4-chloro-2- fluorobenzimidamidooxy)acrylate 40. Heating 40 in diphenyl oxide gave cyclized imidazole, ethyl 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylate 41. Saponification of the ester of 41 with aqueous sodium hydroxide in tetrahydrofuran gave 2-(4-chloro-2-fluorophenyl)-lH- imidazole-4-carboxylic acid 42. Reaction of 42 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-chloro-2-fluorophenyl)-N-(l-(2- isopropylhydrazinyl)ethylidene)-lH-imidazole-4-carboxamide 43 which cyclizes upon heating to give 44.
EXAMPLES
Example 1 tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2
To a solution of tert-butyl hydrazinecarboxylate 1 (CAS Reg. No. 870-46-2) (25.1 g, 0.190 mol) in acetone (185 mL) was added the magnesium sulfate (6 g) and 12 drops acetic acid (Wu et al (2012) Jour. Med. Chem. 55(6):2724-2736; WO 2007/056170; Zawadzki et al (2003) Polish Jour. Chem. 77(3):315-319). The mixture was heated to reflux for 2.5 h and cooled to rt and filtered. The filtrate was concentrated to give tert-butyl 2-(propan-2- ylidene)hydrazinecarboxylate 2 (CAS Reg. No. 16689-34-2) as an off-white solid (32 g, 98%) (used in the next step without further purification). LC-MS [M+H]+ = 172.9, RT = 2.11 min. 1H NMR 300 MHz (CDC13) d 7.35 (br s, 1H, NH), 2.04 (s, 3H), 1.82 (s, 3H), 1.54 (s, 9H); 13C NMR 300 MHz (CDC13) d 152.9, 149.7, 80.7, 28.1, 25.3, 15.9. Example 2 tert-butyl 2-isopropylhydrazinecarboxylate 3
tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2- isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).
Alternatively, tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (0.51 g, 3.0 mmol) was dissolved in 20 mL of THF, treated with NaB¾CN (0.19 g, 3.0 mmol) and a few mg of bromocresol green, followed by a solution of p-toluenesulfonic acid (0.57 g, 3.0 mmol) in 1.5 mL of THF which was added dropwise over approximately 1 h to maintain the reaction pH between 3.5-5.0. After stirring at room temperature for an additional hour, the solvent was removed by rotary evaporation, and the residue was partitioned between EtOAc (30 mL) and brine. The organic phase was extracted with sat. NaHCC>3, 20 mL and brine, evaporated to a residue and dissolved in 10 mL of ethanol. The ethanolic solution was treated with 3.6 mL of 1M NaOH solution (3.6 mmol) and left to stir at rt for 30 min. The solvent was removed by rotary evaporation and the residue was taken up into ethyl acetate and extracted with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography using 5 % MeOH in DCM as eluent to collect tert-butyl 2- isopropylhydrazinecarboxylate 3 (0.4 g, 77 % yield): mp = 47-49 °C; Rf = 0.44 (5 % MeOH in DCM); IH NMR 300 MHz (CDC13) d 6.03 (s, N-H, IH), 3.92 (s, N-H, IH), 3.14 (m, IH), 1.46 (s, 9H), 1.02 (d, 6H, J = 6 Hz); 13C NMR 300 MHz (CDC13) d 157.2, 80.8, 51.2, 28.7, 21.0.
Example 3 isopropylhydrazine hydrochloride 4
tert-butyl 2-isopropylhydrazinecarboxylate 3 was treated with hydrochloric acid to remove the Boc protecting group and give 4 (CAS Reg. No. 16726-41-3).
Example 4 N’-isopropylacetohydrazonamide 6
Methyl acetimidate hydrochloride 5 (CAS Reg. No. 14777-27-6), isopropylhydrazine hydrochloride 4, and triethylamine were reacted in methanol to give 6 (CAS Reg. No. 73479-06- 8).
Example 5 l-isopropyl-3 -methyl- lH-l,2,4-triazole 7
N’-isopropylacetohydrazonamide 6 was treated with triethylorthoformate in ethanol, followed by triethylamine and tetrahydrofuran to give 7 (CAS Reg. No. 1401305-30-3). Example 6 2-chloro-N-methoxy-N-methylacetamide 10
To a solution of 21.2 kg potassium carbonate K2CO3 (153.7 mol, 3.0 eq) in 30 L H20 was added, Ν,Ο-dimethylhydroxylamine 9 (CAS Reg. No. 1117-97-1) (5.0 kg, 51.3 mol, 1.0 eq) at 15-20 °C. The reaction was stirred at rt for 30min and 30 L methyl tert-butyl ether (TBME) was added. After stirred for 30min, the mixture was cooled to 5°C, and 11.6 kg of 2-Chloroacetyl chloride 8 (CAS Reg. No. 79-04-9 (102.7 mol, 2.0 eq) were added slowly. The reaction was stirred at rt overnight. Organics were separated from aqueous, and aqueous was extracted with TBME (30 L). The combined organics were washed with H20 (50 L), brine (50 L) and dried over Na2S04. Filtered and concentrated under vacuum afforded 5.1 kg of 2-chloro-N-methoxy- N-methylacetamide 10 (CAS Reg. No. 67442-07-3) as a white solid.
Example 7 4-bromo-2-fluorobenzimidamide hydrochloride 12
To 35.0 L of lithium hexamethyldisilazide LiHMDS (35.0 mol, 1.4 eq, 1.0 M in THF) under N2 was added a THF solution of 4-Bromo-2-fluorobenzonitrile 11 (CAS Reg. No. 105942- 08-3) (5.0 kg in 10 L THF) at 10 °C, the mixture was stirred at rt for 3h. Cooled to -20°C and 8.3 L of HCl-EtOH (6.6 M) were added. The mixture was stirred at -10 °C for additional lh, filtered. The wet cake was washed with EA (10 L) and H20 (6 L). Drying in vacuo yielded 5.8 kg 4- bromo-2-fluorobenzimidamide hydrochloride 12 (CAS Reg. No. 1187927-25-8) as an off-white solid.
Alternatively, to a 200-L vessel was charged 4-bromo-2-fluorobenzonitrile 11 (10 kg, 50.00 mol, 1.00 equiv) and ethanol (100 L) followed by purging 40 kg Hydrogen chloride (g) at – 10 °C with stirring (Scheme 4). The resulting solution was allowed to react for an additional 36 h at 10 °C. The reaction progress was monitored by TLC until 11 was consumed completely. The resulting mixture was concentrated under vacuum while maintaining the temperature below 60 °C. The volume was concentrated to 10-15 L before 60 L MTBE was added to precipitate the product. The precipitates were collected by filtration to afford in 12 k g of ethyl 4-bromo-2- fluorobenzimidate hydrochloride 12 as a white solid. (Yield: 85%). 1H NMR δ 7.88-7.67 (m), 4.89 (br s), 4.68 (q), 3.33 (m), 1.61 (t). MS M+l: 245.9, 248.0.
To a 200L vessel, was charged ethyl 4-bromo-2-fluorobenzimidate hydrochloride (12.5 k g, 44mol, 1.00 equiv, 99%) and ethanol (125 L) followed by purging NH3 (g) at -5 °C for 12 h. The resulting solution was stirred at 30 °C for an additional 24 h. The reaction progress was monitored by TLC until SM was consumed completely. The precipitates were filtered and the filtrate was concentrated under vacuum. The product was precipitated and collected by filtration to afford 6.1 kg (54.5%) of 4-bromo-2-fluorobenzamidine hydrochloride 12 as a white solid. 1H NMR δ 9.60 (br), 7.91-7.64 (m), 3.40 (s), 2.50 (m). MS M+l: 216.9, 219.9.
Example 8 2-chloro-l-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)ethanone 13
To a 10L four necked flask was charged l-Isopropyl-3-methyl-lH-l,2,4-triazole 7 (400 g) in THF (2.5 L). The resulting solution was cooled to -40 °C and 2.5 M n-butyllithium BuLi in n- hexanes (1.41 L) was added while keeping the internal temp, below -20°C. The resulting yellow suspension was stirred at -40°C for 1 hour before being transferred. To a 20L flask was charged 2-chloro-N-methoxy-N-methylacetamide 10 (485 g) in THF (4 L). The resulting solution was cooled to -40 °C at which point a white suspension was obtained, and to this was added the solution of lithiated triazole 7 keeping the internal temp, below -20°C. At this point a yellow orange solution was obtained which was stirred at – 30°C for lhour. Propionic acid (520 mL) was added keeping the internal temp, below -20°C. The resulting off-white to yellowish suspension was warmed to -5 °C over 30 minutes. Citric acid (200 g) in water (0.8 L) was added and after stirring for 5 minutes a clear biphasic mixture was obtained. At this point stirring was stopped and the bottom aqueous layer was removed. The organic phase was washed with 20w% K3PO4 solution (1 L), 20w% K2HP04 solution (2 L), and 20w% NaCl solution (1 L). The organics was reduced to ca 4L via distillation under vacuum to afford 2-chloro-l-(l-isopropyl-3- methyl-lH-l,2,4-triazol-5-yl)ethanone 13 as a dark amber liquid which was used “as is” in the next step.
Example 9 5-(2-(4-bromo-2-fluorophenyl)- lH-imidazol-4-yl)-l -isopropyl-3-methyl- lH-l,2,4-triazole V
To a 10 L four- neck flask were charged with THF (5.6 L), 4-bromo-2- fluorobenzimidamide hydrochloride 12 (567 g), KHCO3 (567 g) and water (1.15 L). The resulting white suspension was heated to 60°C over 2 hours. At this point a hazy solution was obtained to which was added a solution of 2-Chloro-l-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)ethanone 13 in THF (2 L). This solution was stirred at 60-65 °C for 24 hours. Then the aqueous bottom layer was removed. The organic layer was concentrated under vacuum. The residue was slurried in a mixture of MIBK (1.25 L) and toluene (0.7 L), and the precipitated product was filtered giving 552 g of 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l,2,4-triazole V (98.0% purity, 254 nm) as a brown solid Example 10 2-(2-(4-bromo-2-fluorophenyl)-4-(l-isopropyl-3-methyl-lH-l,2,4-triazol- 5-yl)- 1 H-imidazol- 1 -yl)ethanol 14
5-(2-(4-Bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l-isopropyl-3-methyl-lH- 1,2,4- triazole V (2.75 kg, 7.55 mol) was added to a solution of 3-dioxolan-2-one (ethylene carbonate, 3.99 kg, 45.3 mol) inN-methylimidazole (12 L) at 50 °C. The suspension was heated at 80°C for 7 h until the reaction was judged complete by HPLC. The solution of 14 was cooled to 35 °C and used directly in the subsequent cyclization.
Example 11 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepine III
To a solution of 2-(2-(4-Bromo-2-fluorophenyl)-4-(l-isopropyl-3-methyl-lH-l,2,4- triazol-5-yl)-l H-imidazol- l-yl)ethanol (7.55 mmol) 14 inN-methylimidazole(12 L) at 35 °C was added methyl tributylammonium chloride (115 g, 0.453 mol), toluene (27.5 L) and 35% potassium hydroxide solution (10.6 kg, 25 mol in 22 L of water). The biphasic solution was stirred vigorously at 65 °C for 18 h when it was judged complete by HPLC. Stirring was stopped but heating was continued and the bottom aqueous layer was removed. Added isopropyl acetate (13.8 L) and the organic phase was washed twice with water (13.8 L and 27.5 L). The solvent was removed via vacuum distillation and after 30 L had been removed, isopropanol (67.6 L) was added. Vacuum distillation was resumed until an additional 30 L of solvent had been removed. Added additional isopropanol (28.8 L) and continued vacuum distillation until the volume was reduced by 42 L. Added isopropanol (4L) and the temperature was increased to >50 °C. Added water (28 L) such that the internal temperature was maintained above 50 °C, then heated to 75 °C to obtain a clear solution. The mixture was allowed to cool slowly and the product crystallized out of solution. The resulting suspension was cooled to 0 °C, held for 1 h then filtered and the cake was washed with water (5.5 L). The cake was dried at 45 °C under a nitrogen sweep to give III as a tan solid (3.30 kg, 71.6 wt %, 80.6% yield).
Example 12 2-methyl-2-(lH-pyrazol-l-yl)propanoic acid 16
2-Bromo-2-methylpropanoic acid 15 and pyrazole were reacted in triethylamine and 2- methyltetrahydrofuran to give 16.
Example 13 ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17
2-Methyl-2-(lH-pyrazol-l-yl)propanoic acid 16 was treated with sulfuric acid in ethanol to give 17. Alternatively, pyrazole (10 g, 147 mmol, 1.0 eq.) was dissolved in DMF (500 ml) at room temperature (Scheme 8). 2-Bromoisobutyrate 18 (22 ml, 147 mmol, 1.0 eq.), cesium carbonate CS2CO3 (53 g, 162 mmol, 1.1 eq) and catalytic sodium iodide Nal (2.2 g, 15 mmol, 0.1, eq) were added to the mixture that was then heated to 60 °C for 24 hr. Reaction was followed by 1H NMR and pyrazole was not detected after 24 hr. The reaction mixture was quenched with a saturated solution of NaHCC>3 (200 ml) and ethyl acetate EtOAc (150 ml) was added and organics were separated from aqueous. Organics were dried over Na2S04, filtered and concentrated under vacuum to afford an oil which was purified by flash chromatography to give 17.
Example 14 Ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2-methylpropanoate IV
Method A: Ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17 was reacted with N- bromosuccinimide (NBS) in 2-methyltetrahydrofuran to give IV (CAS Reg. No. 1040377-17-0).
Method B: Ethyl 2-bromo-2-methylpropanoate 18 and pyrazole were reacted with sodium tert-butoxide in dimethylformamide (DMF) to give a mixture of ethyl 2-methyl-2-(lH- pyrazol-l-yl)propanoate 17 and ethyl 2-methyl-3-(lH-pyrazol-l-yl)propanoate 19 which was treated with l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione to give a mixture of IV, ethyl 3- (4-bromo-lH-pyrazol-l-yl)-2-methylpropanoate 20, and 4-bromo-lH-pyrazole 21. The mixture was treated with a catalytic amount of lithium hexamethyldisilazide in tetrahydrofuran followed by acidification with hydrochloric acid to give IV.
Example 15 ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)propanoate 22
To a 50 L glass reactor was charged ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2- methylpropanoate IV (1.00 kg, 3.85 mol, 1.00 equiv), potassium acetate, KOAc (0.47 kg, 4.79 mol 1.25 equiv), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(l,3,2-dioxaborolane),
bis(pinacolato)diboron, B2Pin2 (1.22 kg, 4.79 mol, 1.25 equiv) and ethanol (10 L, 10 vol) and the mixture was stirred until a clear solution was obtained. The solution was vacuum/degassed 3x with nitrogen. To this mixture was charged XPhos ligand (0.023 kg, 0.048 mol, 1.0 mol ) and the Pd precatalyst (0.018 kg, 0.022 mol, 0.5 mol ) resulting in a homogeneous orange solution. The solution was vacuum/degassed once with nitrogen. The internal temperature of the reaction was set to 75 °C and the reaction was sampled every 30 min once the set temperature was reached and was monitored by LC (IPC method: XTerra MS Boronic). After 5 h, conversion to 22 (CAS Reg. No. 1201657-32-0) was almost complete, with 1.3% IV remaining. Example 16 ethyl 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoate 23
Ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)propanoate 22 and 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III were reacted under Suzuki conditions with palladium catalyst, in isopropanol and aqueous phosphate buffer to give 23.
A 1M solution of K3PO4 (1.60 kg in 7.6 L of water, 7.54 mol, 2.00 equiv) was charged to the above reaction mixture from Example 15, followed by the addition of a solution of III in THF (1.33 kg in 5.0 L, 3.43 mol, 0.90 equiv) over 2 min. The reaction mixture was warmed to 75 °C (internal temperature) over 45 min and stirred for 13 h at 75 °C, then analyzed by HPLC (III not detected) showing the formation of 23.
Example 17 2-(4-(2-( 1 -isopropyl-3-methyl- 1 H- 1 ,2,4-triazol-5-yl)-5 ,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoic acid II
Ethyl 2-(4-(2-(l -isopropyl-3 -methyl- 1 H- 1 ,2,4-triazol-5-yl)-5 ,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanoate 23 was treated with aqueous lithium hydroxide to give II.
The ester saponification reaction was initiated with the addition of 3.5 M aqueous LiOH (0.74 kg in 5.0 L, 17.64 mol, 5 equiv) to the reaction mixture from Example 16 and allowed to warm to 75 °C. The mixture was sampled every 30 min (IPC method: XTerra MS Boronic) and the saponification was complete after 4.5 h (with less than 0.3% 23 remaining). The reaction mixture was concentrated via distillation to approximately half volume (starting vol = 37 L; final vol = 19 L) to remove EtOH and THF, resulting in tan-brown slurry. Water (5 L, 5 vol) was charged to the mixture and then distilled (starting vol = 25 L; final vol = 21 L). The temperature was set at 60 °C (jacket control) and then charged with isopropyl acetate, IP Ac (4 L, 4 vol). The biphasic mixture was stirred a minimum of 5 min and then the layers allowed to separate for a minimum of 5 min. The bottom aqueous layer was removed into a clean carboy and the organics were collected into a second carboy. The extraction process was repeated a total of four times, until the organic layer was visibly clear. The aqueous mixture was transferred back to the reactor and then cooled to 15 °C. A 6 M solution of HC1 (6.4 L, 38.40 mol, 10 equiv) was charged slowly until a final pH = 1 was obtained. The heterogeneous mixture was then filtered. The resulting solids were washed twice with 5 L (2 x 5 vol) of water. The filter was then heated to 80 °C and the vacuum set to -10 Psi (with nitrogen bleed) and the solids were dried for 24 h (KF = 2.0 % H20) to give 1.54 kg (95% corrected yield) of II as a white solid; 98% wt, 97.3 % pure.
Example 18 2-(4-(2-( 1 -isopropyl-3-methyl- 1 H- 1 ,2,4-triazol-5-yl)-5 ,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- lH-pyrazol- 1 -yl)-2-methylpropanamide I (GDC-0032)
2-(4-(2-(l-Isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanoic acid II was treated with di(lH- imidazol-l-yl)methanone (carbonyldiimidazole, CDI) in tetrahydrofuran followed by methanolic ammonia to give crude I.
Solid II (1.44 kg, 3.12 mol, 1.00 equiv) was transferred into a 20 L bottle and then THF
(10 L, 7 vol) was charged. The slurry was transferred under reduced pressure into a second 50 L reactor and additional THF (5 L, 3 vol) was added for the rinse. The internal temperature of the slurry was set to 22 °C and Γ1 -carbonyldiimidazole, CDI (0.76 Kg, 5.12 mol, 1.50 equiv) was charged to the mixture and a clear solution was observed after 5 min. The reaction mixture was sampled every 30 min and analyzed by HPLC (IPC: XTerra MS Boronic method) which showed almost complete conversion to the acyl-imidazole intermediate and 1.2% remaining II after 30 min. An additional portion of CDI (0.07 kg, 0.15 mol, 0.14 equiv) was added, and the reaction mixture was stirred for 1 h and then analyzed by HPLC (IPC: XTerra MS Boronic method) which showed 0.8% remaining II.
Into a second 50-L reactor, was added NH3/MeOH (1.5 L, 10.5 mol, 3.37 equiv) and THF
(5 L, 3 vol). The acyl-imidazole intermediate was transferred to a second reactor under reduced pressure (transfer time -10 min). The internal temperature was then set to 45 °C and the volume of solvent was distilled down from 35 L to 12 L. Water (6 L, 4 vol) was then added to the mixture that was further distilled from 18 L to 11 L. Finally, another portion of water (6 L, 4 vol) was added and the solvents were distilled one last time from 17 L to 14 L, until no more THF was coming out. The reaction was then cooled down to 10 °C (internal temperature). The white slurry was filtered and the filter cake was washed with water (2 x 6 L, 2 x 4 vol). The solids were then dried at 80 °C (jacket temp) in the Aurora filter for 24 h (KF = 1.5 % H20) under vacuum to give 1.25 kg crude I, GDC-0032 (84% corrected yield, 96% wt, 97.3 % pure by HPLC) as a white solid.
A slurry of crude I (1.15 kg, 2.50 moles) in MeOH (6 L, 5 vol) was prepared and then charged to a 50 L glass reactor. Additional MeOH (24 L, 21 vol) was added to the mixture, which was then heated to 65 °C. A homogenous mixture was obtained. Si-thiol (Silicycle, Inc., 0.23 kg, 20% wt) was added to the solution via the addition port and the mixture was stirred for 3 hours. It was then filtered warm via the Aurora filter (jacket temperature = 60 °C, polish filtered and transferred directly into a second 50 L reactor with reduced pressure. The solution was then heated back to 65 °C internal temperature (IT). The homogeneous solution was cooled down to 54 °C and I seeds (12 g, 1 % wt) in MeOH (50 mL) were added with reduced pressure applied to the reactor. The mixture was then cooled down to 20 °C over 16 hours. The solids were then filtered via the Aurora filter and dried at 80 °C for 72 hours to give 921 g, 80% yield of I as a methanoate solvate (form A by XRPD,) and transferred to a pre-weighed charge-point bag.
In an isolator, the solids were slurred in IP Ac (8 L, 7 vol) and transferred to a clean 10 L reactor. The mixture was stirred for 1 h at 60 °C (IT). The solids were then filtered via the Aurora system and dried at 80 °C (jacket) for 96 h. A sample of I was removed and analyzed by GC (IP Ac = 1 %). To attempt more efficient drying, the API was transferred to two glass trays in an isolator and sealed with a drying bag before being dried in a vacuum oven set at 100 °C for 16 h. GC (IPC: Q12690V2) showed 1 % solvent was still present. The process afforded 760 g (68% corrected yield, 68% wt, 99.9 % purity by LC) of a white solid (form B by XRPD).
Crude I (340.7 g) was charged to a 2-1 . 1 1 DPI · bottle and slurried with 0.81 ,
isoamylalcohol (I A A). The slurry was transferred to a 20 L reactor and diluted with 6.7 L round- bottom flask (22 vol total). The white slurry was heated until a solution was observed (internal temperature rose to 118 °C and then cooled to 109 °C). The solution was polish filtered (0.2 μ .Μ filter). A flask was equipped with overhead stirring and the filtrate was slurried in isoamyl alcohol (344 ml ., 21 vol). The mixture was warmed to 95 °C (internal) until the solids dissolved. A slurry of charcoal (10 wt%, 0.16g) and silicycle thiol (10 wt%, 0.16g) in isoamyl alcohol (1 vol, 1 6 ml . ) was charged and the mixture was stirred at 90-95 °C for 1 h and then filtered (over Celite® pad). The clear amber colored solution was cooled to 73 °C (seeding temp range = 70 ±5 °C) and a GDC-0032 I seed (10 wt%, 0.16g) was added. The temperature of the heating mantle was turned off and the mixture was allowed to cool to room temperature overnight with stirrin (200 rpni). After 17 hr, the white solids were filtered starting with slow gravity filtration and then vacuum was applied. The solids were suction dried for 20 min with mixing until a free flowing powder was obtained. ( “rude weight prior to oven drying = 16 g. The solids were oven- dried at 100 °C for 24 h and then sampled for testing. Drying continued at 100 °C for another 24 hr. I l l NMR (DMSO d6) δ 8.38 (t), 8.01 (s), 7.87 (s), 7.44, 7.46 (d), 7.36 (s), 7.18 (br s), 6.81
(br s), 5.82 (m), 3.99 (s), 2.50 (s), 2.26 (s), 1.75 (s), 1.48, 1.46 (d).
Purified 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- lH-pyrazol- 1 -yl)-2-methylpropanamide I (GDC-0032) was dry granulation formulated in tablet form by the roller compaction method (He et al (2007) Jour, of Pharm. Sci., 96(5):1342-1355) with excipients including lactose, microcrystalline cellulose (AVICEL® PH 01, FMC BioPolymer, 50 μΜ particle),
croscarmellose sodium (Ac-Di-Sol®, FMC BioPolymer), and magnesium stearate.
Example 19 4-bromo-2-fluoro-N-hydroxybenzimidamide 24
To a solution of 4-Bromo-2-fluorobenzonitrile 11 (800 g, 4 mol, 1 eq), hydroxylamine hydrochloride (695 g, 10 mol, 2.5 eq) in MeOH (2 L, 2.5 vol) was added Et3N (485 g, 4.8 mol, 1.2 eq), then the mixture was stirred at 60 °C for 40 min and checked by HPLC (no nitrile remaining). Reaction was then quenched by H20 (30 L), and lots of off-white solid was separated out, and then filtered, the filter cake was washed with water (10 L x 2) and 1350 g wet 4-bromo-2-fluoro-N-hydroxybenzimidamide 24 was obtained with 96% purity.
Example 20 ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25
To a solution of 4-Bromo-2-fluoro-N-hydroxybenzimidamide 24 (800 g, 3.43 mol, 1 eq) and Amberlyst® A21 (20 wt%, 160 g) in PhMe (12 L, 15 vol) was added ethyl propiolate (471 g, 4.8 mol, 1.4 eq) at 10 °C. The reaction was stirred at 50 °C overnight and checked by LC-MS (ca 14A% of starting material 24 was left). Reaction was then filtered and the filtrate was concentrated under vacuum, and 1015 g ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25 was obtained as a yellow oil with 84.9% LC purity (yield: 89%).
Example 21 ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylate 26
A solution of ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25 (300 g, 0.91 mol, 1 eq) in diphenyl oxide (900 mL, 3 vol) was stirred at 190 °C under N2 for 1 h and checked by LC-MS (no 25 remaining). Cooled the mixture to rt and TBME (600 mL, 2 vol of 25) was added, and then PE (1.8 L, 6 vol of 25) was dropwise added to separate out solids. The mixture was stirred at rt for 20 min, and filtered to give 160 g wet cake. The wet cake was washed with PE (1 L) and dried to afford 120 g ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylate 26 with 92% LC purity as brown solids. Example 22 ethyl 2-(4-bromo-2-fluorophenyl)- 1 -(2-hydroxyethyl)- 1 H-imidazole-4- carboxylate 27
Ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylate 26 and l,3-dioxolan-2- one and N-methylimidazole were reacted to give 27.
Example 23 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28
Ethyl 2-(4-bromo-2-fluorophenyl)-l -(2-hydroxyethyl)- lH-imidazole-4-carboxylate 27, potassium hydroxide and methyl tributylammonium hydrochloride were reacted at 65 °C, cooled, and concentrated. The mixture was dissolved in ethanol and water to crystallize 28.
Example 24 9-bromo-N-(l-iminoethyl)-5,6-dihydrobenzo[f]imidazo[l,2- d] [ 1 ,4]oxazepine-2-carboxamide 29
9-Bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28, triphenylphosphine, and acetamidine were reacted to give 29.
Example 25 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III
9-Bromo-N-( 1 -iminoethyl)-5 ,6-dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepine-2- carboxamide 29 was reacted with isopropylhydrazine hydrochloride 4 in acetic acid to give III.
Example 26 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 30
3-Chloro-2-oxopropanoic acid and 4-bromo-2-fluorobenzimidamide hydrochloride 12 are reacted with base to give 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 30.
Alternatively, to a solution of ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4- carboxylate 26 (1350 g, 4.3 mol) in THF (8.1 L, 6 vol) and H20 (4 L, 3 vol) was added NaOH (520 g, 13 mol, 3 eq), and the reaction was stirred at 65 °C for 48 h till it completed (checked by LC-MS). Adjust the mixture with 2 M HC1 to pH = 5, and product was separated out as a yellow solid, filtered to give 2.2 kg wet cake, the wet cake was washed with H20 (1.5 L), DCM (1.5 L x 3), PE (1 L), and dried to afford 970 g pure 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4- carboxylic acid 30 (Scheme 10). Example 27 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l-isopropyl-3-methyl- lH-l,2,4-triazole V
Reaction of 30 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-bromo-2-fluorophenyl)-N-(l-(2-isopropylhydrazinyl)ethylidene)- lH-imidazole-4-carboxamide 31 which cyclizes upon heating to give V.
Example 28 tert-butyl 2-hydroxyethylcarbamate gives tert-butyl 2-(5-bromo-2- cyanophenoxy)ethylcarbamate 32
Alkylation of 4-bromo-2-fluorobenzonitrile 11 with tert-butyl 2-hydroxyethylcarbamate gives 32.
Example 29 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33
Cyclization of tert-butyl 2-hydroxyethylcarbamate gives tert-butyl 2-(5-bromo-2- cyanophenoxy)ethylcarbamate 32 under acidic conditions, such as hydrochloric acid in ethanol, gives 33.
Example 30 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28
Reaction of 3-bromo-2-oxopropanoic acid and 8-bromo-3,4- dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33 gives 28 (CAS Reg. No. 1282516-74-8).
Example 31 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepine III
Coupling of 28 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU in
DMF gives intermediate, 9-bromo-N-(l-(2-isopropylhydrazinyl)ethylidene)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxamide 34, which forms III upon heating.
Example 32 methyl 4-bromo-2-fluorobenzimidate 35
Reaction of 4-bromo-2-fluorobenzonitrile 11 with sodium methoxide in methanol gives 35.
Example 33 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33
Alkylation of methyl 4-bromo-2-fluorobenzimidate 35 with 2-aminoethanol gives 4- bromo-2-fluoro-N-(2-hydroxyethyl)benzimidamide 36, followed by cyclization to 33 (Scheme 13). Alternatively, reaction of 11 with 2- aminoethanol and potassium tert-butoxide displaces fluorine to give 2-(2-aminoethoxy)-4-bromobenzonitrile hydrochloride 37. Ring closure of 37 with trimethylaluminum gave 33 (Scheme 14). A solution of 11 (10 g, 50 mmol) and 2- aminoethanol (3.1 mL, 50.8 mmol) in 2-methyltetrahydrofuran (80 mL) was cooled to 0 °C and a solution of 1M potassium tert-butoxide in tetrahydrofuran (55 mL, 55 mmol) was slowly added while maintaining the solution temperature below 5 °C. The reaction was stirred at 0 °C for 30 min until judged complete by HPLC at which point it was warmed to 25 °C. A solution of 0.5M HC1 in isopropanol (100 mL, 50 mmol) was added and the desired HC1 salt 3 crystallized directly from the solution. The solid was collected by filtration and dried under vacuum with a nitrogen bleed to give 2-(2-aminoethoxy)-4-bromobenzonitrile hydrochloride 37 as a white solid. (12.1 g, 87 % yield).
To a flask was charged 37 (9.00 g, 32.4 mmol) and toluene (90.0 ml). The suspension was cooled to 0 °C and was added trimethylaluminum (1.8 equiv., 58.4 mmol, 2M in toluene) drop-wise over 30 minutes. The suspension was then stirred at room temperature for 1 h and then warmed to 100 °C. After 5 h, the solution was cooled to 0 °C and quenched with aqueous NaOH (2N, 90.0 ml). The suspension was extracted with EtOAc (4 x 90 ml) and the combined extracts were dried over then filtered through Celite®. The solution was concentrated and the residue triturated with EtOAc to afford 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33 (6.26 g, 26.0 mmol, 80% yield) as white crystalline solid.
Example 34 4-chloro-2-fluoro-N-hydroxybenzimidamide 39
To a solution of 4-chloro-2-fluorobenzonitrile 38 (400 g, 2.58 mol, 1.0 eq),
hydroxylamine hydrochloride (448 g, 6.45 mol, 2.5 eq) in MeOH (1 L, 2.5 vol) was added Et3N (313 g, 3.1 mol, 1.2 eq), then the mixture was stirred at 60 °C for 40 min and checked by HPLC (no nitrile remaining). Reaction was then quenched by H20 (10 L), and lots of off-white solid was separated out, and then filtered, the filter cake was washed with water (10 L x 2) and 378 g 4-chloro-2-fluoro-N-hydroxybenzimidamide 39 was obtained with 93% purity (Scheme 15).
Example 35 ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40
To a solution of 4-chloro-2-fluoro-N-hydroxybenzimidamide 39 (378 g, 2 mol, 1.0 eq) and Amberlyst® A21 (20 wt%, 75.6 g) in toluene PhMe (5.6 L, 15 vol) was added ethyl propiolate (275 g, 2.8 mol, 1.4 eq) at 30 °C. The reaction was stirred at 30 °C overnight and checked by LC-MS. Reaction was then filtered and the filtrate was concentrated under vacuum, and 550 g ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40 was obtained as a yellow oil with 83% LC purity (Scheme 15).
Example 36 ethyl 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylate 41
A solution of ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40 (550 g, 1.9 mol, 1.0 eq, 83% LC purity) in diphenyl oxide (1.65 L, 3 vol) was stirred at 190 °C under N2 for 1 h and checked by LC-MS (no 40 remaining). Cooled the mixture to rt and PE (10 L) was added dropwise. The mixture was stirred at rt for 20 min, and filtered to give 400 g wet cake, after purified by chromatography on silica gel (PE / EA=1 / 5) to get 175 g pure ethyl 2-(4-chloro-2- fluorophenyl)-lH-imidazole-4-carboxylate 41 with 98% LC purity (Scheme 15).
Example 37 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 42
To a solution of ethyl 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylate 41 (175 g, 4.3 mol) in THF (1 L, 6 vol) and H20 (500 mL, 3 vol) was added NaOH (78 g, 1.95 mol, 3.0 eq), and the reaction was stirred at 65 °C for 48 h till it completed (checked by LC-MS). Adjust the mixture with 2 N HC1 to pH = 5, and product was separated out as a yellow solid, filtered to give 210 g wet cake, the wet cake was washed with H20 (300 mL), DCM (3 x 300 mL), PE (500 mL), and dried to afford 110 g pure 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 42 (CAS Reg. No. 1260649-87-3) (Scheme 15 ). I l l NMR (DMSO d6) δ: 12.8 (br s), 8.0, 7.9 (br s), 7.46, 7.4 (m).
PATENT
US 2014275523
SYNTHESIS
Taselisib_药物数据_原料药API_CCIS-CHEM化学平台科研物资一站式采购平台 …
CLIP
http://www.ccis-chem.com/goods.php?id=194272
Taselisib是罗氏集团及其下属公司Genentech和Chugai研发，目前治疗绝经后妇女雌激素受体阳性（ER +）乳腺癌和非小细胞肺癌（NSCLC）的三期临床研究均在进行中。
基本信息更新时间：2016-02-01
化学信息更新时间：2015-08-27
| 分子量 | 460.53 | |||||||||||||
| 分子式 | C24H28N8O2 | |||||||||||||
| CAS号 | 1282512-48-4 (Taselisib); | |||||||||||||
| 化学名称 | 1H-Pyrazole-1-acetamide, 4-[5,6-dihydro-2-[3-methyl-1-(1-methylethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-d][1,4]benzoxazepin-9-yl]-a,a-dimethyl- | |||||||||||||
| Fudosteine药品（游离态）参数: | ||||||||||||||
|
||||||||||||||
化学合成路线及相关杂质更新时间：2015-12-15
参考文献：J. Med. Chem. 2013, 56, 4597−4610
参考文献：WO2014140073A1
PAPER
J Med Chem 2013, 56(11): 4597
Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.
2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (11l)
the invention relates to polymorph forms of the PI3K inhibitor I (taselisib, GDC-0032, RG7604, CAS Reg. No. 1282512-48-4, Genentech, Inc.), named as 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide, having the structure:
and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.
References
|
|
| Clinical data | |
|---|---|
| ATC code |
|
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C24H28N8O2 |
| Molar mass | 460.54 g·mol−1 |
| 3D model (JSmol) | |
This compound and its uses are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.
Taselisib, an investigational PI3K inhibitor, is currently in clinical development based on its potential selectivity for the PI3Kα isoform.1,2 Preclinical data have shown that taselisib induced growth inhibition in PI3Kα-mutant cell lines.1 Taselisib continues to be investigated in ongoing clinical studies.
1Taselisib is an investigational PI3K inhibitor currently being studied for its potential to selectively inhibit the PI3Kα isoform.1,2
2Taselisib is designed to bind to the ATP-binding pocket of PI3Kα to potentially prevent subsequent downstream signaling.1
3In preclinical studies, taselisib induced growth inhibition in PI3Kα-mutant xenograft mouse models.1 Taselisib continues to be investigated in ongoing clinical studies.
//////////////////RG7604, Taselisib, PHASE 3, metastatic breast cancer, non-small cell lung cancer, RO5537381, Roche
CC1=NN(C(=N1)C2=CN3CCOC4=C(C3=N2)C=CC(=C4)C5=CN(N=C5)C(C)(C)C(=O)N)C(C)C
| Molecular Formula: | C16H14FN3O |
|---|---|
| Molecular Weight: | 283.306 g/mol |
6-amino-2-(fluoromethyl)-3-(2-methylphenyl)quinazolin-4-one
HQ 495, C033541, QA-3735, UNII:CO4U2C8ORZ
Afloqualone; 56287-74-2; Arofuto; Aroft; Afloqualon; Afloqualone [INN:JAN]
Afloqualone (Arofuto) is a quinazolinone family GABAergic drug and is an analogue of methaqualone developed in the 1970s by a team at Tanabe Seiyaku.[1] It has sedative and muscle-relaxant effects resulting from its agonist activity at the β subtype of the GABAareceptor ,[2] and has had some clinical use, although it causes photosensitization as a side-effect that can cause skin problems such as dermatitis.[3]
PATENT
CN 106496145
PATENT
CN 106496144
https://patents.google.com/patent/CN106496144A/en
Example 1:
[0027] A-fluoro-quinolin-one process, comprising the steps of:
[0028] A. To the hydrogenation apparatus 10g 6- nitro-2- (fluoromethyl) -3- (2-methylphenyl) -4- (3H) -1,3- phthalazinone , 150ml acid content of 0.1 ~ 0.4N n-butanol solution of acetic acid, lg palladium ruthenium bimetallic catalyst, hydrogen pressure 0.02 ~ 0.4MPa, reaction temperature of 25-50 ° C, after 1 hour, filtered to give the filtrate ;
[0029] B. washed catalyst with ethanol, at normal temperature, under reduced pressure to obtain a solution ⑴;
[0030] C. was added to the filtrate and the solution ⑴ water, 0.1N sodium hydroxide solution was added, the pH adjusted to 10.2 to 11.0, and stirred at 50-60 ° C 0.5 h, cooled to room temperature and filtered to give the crude fluoro-quinolin-one;
[0031] D.-fluoro-quinolin per gram of the recrystallization solvent was added 5 ~ 15ml crude ketone, wherein the recrystallization solvent is a volume ratio of 1: 1: 0.2 in a solution of isopropanol (m), a solution of acid butyl ester (II ) and water mixture; crystallized at room temperature, filtered to give a fluorine methaqualone.
[0032] Example 2:
[0033] A-fluoro-quinolin-one process, comprising the steps of:
[0034] A. hydrogenation apparatus added to 20g 6- nitro _2_ (fluoromethyl) -3- (2_-methylphenyl) -4- (3-1,3-phthalazinone buckle, acid content of the acid-containing 240ml 0.1 ~ 0.4N ethanol solution of hydrochloric acid, lg palladium ruthenium bimetallic catalyst, hydrogen pressure 0.02 ~ 0.4MPa, reaction temperature of 25-50 ° C. after 0.5 hours the reaction was filtered to obtain filtrate;
[0035] B. washed catalyst with ethanol, at normal temperature, under reduced pressure to obtain a solution ⑴;
[0036] C. was added to the filtrate and the solution ⑴ water, 0.1N sodium hydroxide solution was added, the pH adjusted to 10.2 to 11.0, and stirred at 50-60 ° C 1 hour, cooled to room temperature and filtered to give the crude fluoro-quinolin-one;
[0037] D.-fluoro-quinolin added per gram of crude ketone was recrystallized from 5 ~ 15ml of the solvent, wherein the recrystallization solvent is a volume ratio of 1: o.2: methanol solution of i (m), an ethyl acetate solution (II ) and water mixture; crystallized at room temperature, filtered to give a fluorine methaqualone.
[0038] Example 3:
[0039] – quinolin-fluoro-one kind of process, comprising the steps of:
[0040] A. Add 5g 6- nitro apparatus _2_ hydride (fluoromethyl) -3- (2-methylphenyl) -4- (3-1,3-Perot phthalazinone, 80ml methanol containing an acid in an amount of 0.1 ~ 0.4N solution of sulfuric acid, lg palladium ruthenium bimetallic catalyst, hydrogen pressure 0.02 ~ 0.4MPa, reaction temperature of 25-50 ° C. after 1.5 hours the reaction was filtered to obtain filtrate;
[0041] B. the catalyst was washed with ethanol, normal temperature under reduced pressure to obtain a solution (the I);
[0042] C. was added to the filtrate and the solution (I) water, 0.1N sodium hydroxide solution was added, the pH adjusted to 10.2 to 11.0, and stirred at 50-60 ° C 1 hour, cooled to room temperature and filtered to give fluoro-quinolin-one Crude;
[0043] D. methaqualone fluorine per gram of crude product were added 5 ~ 15ml recrystallization solvent, wherein the recrystallization solvent is a volume ratio of 1: 0.2: 0.2 ethanol solution (m), carboxylic acid butyl ester (II) and water mixture; crystallization at room temperature, and filtered to give fluoro-quinolin-one.
PAPER
6-Amino-2-(fluoromethyl)-3-(2-methylphenyl)quinazolin-4(3H)-one
Acta Crystallographica, Section E: Structure Reports Online (2007), 63, (7), o3109
http://scripts.iucr.org/cgi-bin/paper?S1600536807026670
PAPER
Synthesis of the metabolites of afloqualone and related compounds
Chemical & pharmaceutical bulletin (1983), 31, (4), 1158-65.
Seven main metabolites (3-9) of afloqualone (1, 6-amino-2-fluoromethyl-3-(o-tolyl)-4 (3H)-quinazolinone and related 4 (3H)-quinazolinone derivatives were synthesized. The metabolites 4 and 5 containing a sulfur atom were prepared by the reaction of 6-acetamido-2-chloromethyl-3-(o-tolyl)-4 (3H)-quinazolinone (11) with NaSCH3 followed by oxidation with H2O2. Reaction of 11 and N-acetyl-L-cysteine gave the mercapturic acid-conjugated metabolite 6. Condensation of 2-fluoroacetamido-5-nitrobenzoic acid (19) and 2-amino-benzyl alcohol (20) with dicyclohexylcarbodiimide (DCC) in the presence of 1-hydroxy-benzotriazole afforded 2-fluoromethyl-3-(o-hydroxymethylphenyl)-6-nitro-4 (3H)-quinazolinone (21), which was converted to the metabolites 7 and 8. Treatment of the 2-bromomethyl-4 (3H)-quinazolinone (24) with AgBF4-H2O in dimethylsulfoxide (DMSO) gave the 2-hydroxymethyl metabolite 9. None of the main metabolites (2-9) showed significant central nervous system depressant activity
https://www.jstage.jst.go.jp/article/cpb1958/31/4/31_4_1158/_article
|
|
| Clinical data | |
|---|---|
| AHFS/Drugs.com | International Drug Names |
| ATC code |
|
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C16H14FN3O |
| Molar mass | 283.3 |
| 3D model (JSmol) | |
//////////////Afloqualone, HQ 495, アフロクアロン , C033541, QA-3735, UNII:CO4U2C8ORZ, 4831
CC1=CC=CC=C1N2C(=NC3=C(C2=O)C=C(C=C3)N)CF
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 108-24-7 | C4H6O3 | acetic anhydride | Acetic acid, anhydride |
| 69123-71-3 | C7H5ClN2O3 | 2-amino-5-nitrobenzoyl chloride | Benzoyl chloride, 2-amino-5-nitro- |
| 23076-31-5 | C14H13N3O3 | N-(2-amino-5-nitrobenzoyl)-o-toluidine | Benzamide, 2-amino-N-(2-methylphenyl)-5-nitro- |
| 56287-72-0 | C16H14FN3O4 | 2-[(fluoroacetyl)amino]-N-(2-methylphenyl)-5-nitrobenzamide | Benzamide, 2-[(fluoroacetyl)amino]-N-(2-methylphenyl)-5-nitro- |
| 359-06-8 | C2H2ClFO | fluoroacetyl chloride | Acetyl chloride, fluoro- |
| 56287-73-1 | C16H12FN3O3 | 2-(fluoromethyl)-3-(2-methylphenyl)-6-nitro-4(3H)-quinazolinone | 4(3H)-Quinazolinone, 2-(fluoromethyl)-3-(2-methylphenyl)-6-nitro- |
| 616-79-5 | C7H6N2O4 | 5-nitroanthranilic acid | Benzoic acid, 2-amino-5-nitro- |
| 95-53-4 | C7H9N | o-toluidine | Benzenamine, 2-methyl- |
| Country | Trade Name | Vendor | Annotation |
|---|---|---|---|
| J | Aflomus | Hishiyama | |
| Airomate | SawaiNippon Chemiphar | ||
| Arofuto | Tanabe |
| CAS: | 81403-68-1 HCL SALT |
Alfuzosin (INN, provided as the hydrochloride salt) is a pharmaceutical drug of the α1 blocker class. As an antagonist of the α1adrenergic receptor, it works by relaxing the muscles in the prostate and bladder neck, making it easier to urinate. It is thus used to treat benign prostatic hyperplasia (BPH).[1]
Alfuzosin is marketed in the United States by Sanofi Aventis under the brand name Uroxatral and elsewhere under the tradenames Xat, Xatral, Prostetrol and Alfural. Alfuzosin was approved by the U.S. FDA for treatment of BPH in June 2003.
The most common side effects are dizziness (due to postural hypotension), upper respiratory tract infection, headache, fatigue, and abdominal disturbances. Side effects include stomach pain, heartburn, and congested nose.[2] Adverse effects of alfuzosin are similar to that of tamsulosin with the exception of retrograde ejaculation.[3]
Alfuzosin should be used with caution in patients with severe renal insufficiency, and should not be prescribed to patients with a known history of QT prolongation who are taking medications known to prolong the QT interval.
Alfuzosin contains a stereocenter and is therefore chiral. There are two enantiomeric forms, (R)-alfuzosin and (S)-alfuzosin. The drug is used as a racemate, (RS)-alfuzosin, a 1: 1 mixture of the (R)- and (S)-forms.[4]
| Enantiomers of alfuzosin | |
|---|---|
 CAS number: 123739-69-5 |
 CAS number.: 123739-70-8 |
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 23680-84-4 | C10H10ClN3O2 | 4-amino-2-chloro-6,7-dimethoxyquinazoline | 4-Quinazolinamine, 2-chloro-6,7-dimethoxy- |
| 5004-88-6 | C9H12N2O3 | 2-amino-4,5-dimethoxybenzamide | Benzamide, 2-amino-4,5-dimethoxy- |
| 541-41-3 | C3H5ClO2 | chloroformic acid ethyl ester | Carbonochloridic acid, ethyl ester |
| 72104-44-0 | C9H14N2O2 | 2-cyano-N-methyl-N-tetrahydrofuroylethylamine | 2-Furancarboxamide, N-(2-cyanoethyl)tetrahydro-N-methyl- |
| 27631-29-4 | C10H8Cl2N2O2 | 2,4-dichloro-6,7-dimethoxyquinazoline | Quinazoline, 2,4-dichloro-6,7-dimethoxy- |
| 28888-44-0 | C10H10N2O4 | 2,4-dihydroxy-6,7-dimethoxyquinazoline | 2,4(1H,3H)-Quinazolinedione, 6,7-dimethoxy- |
| 20357-25-9 | C9H9NO5 | 4,5-dimethoxy-2-nitrobenzaldehyde | Benzaldehyde, 4,5-dimethoxy-2-nitro- |
| 4959-60-8 | C9H10N2O5 | 4,5-dimethoxy-2-nitrobenzamide | Benzamide, 4,5-dimethoxy-2-nitro- |
| 28888-44-0 | C10H10N2O4 | 6,7-dimethoxyquinazoline-2,4-dione | 2,4(1H,3H)-Quinazolinedione, 6,7-dimethoxy- |
| 541-41-3 | C3H5ClO2 | ethyl chloroformate | Carbonochloridic acid, ethyl ester |
| 693-05-0 | C4H8N2 | 3-(methylamino)propanenitrile | Propanenitrile, 3-(methylamino)- |
| 81403-67-0 | C9H18N2O2 | N1-methyl-N2-tetrahydrofuroyltrimethylenediamine | 2-Furancarboxamide, tetrahydro-N-[3-(methylamino)propyl]- |
| 16874-33-2 | C5H8O3 | (±)-tetrahydrofuran-2-carboxylic acid | 2-Furancarboxylic acid, tetrahydro- |
| 167391-50-6 | C8H12O5 | tetrahydro-2-furancarboxylic acid anhydride with ethyl hydrogen carbonate | 2-Furancarboxylic acid, tetrahydro-, anhydride with ethyl hydrogen carbonate |
| 57-13-6 | CH4N2O | urea | Urea |
| 120-14-9 | C9H10O3 | veratraldehyde | Benzaldehyde, 3,4-dimethoxy- |
| Country | Trade Name | Vendor | Annotation |
|---|---|---|---|
| D | Alfunar | Apogepha | |
| Alfusin | TAD Pharma | ||
| Urion | Sanofi-Aventis | ||
| Uroxatral | Sanofi-Aventis | ||
| F | Urion | Zambon | |
| Xatral | Sanofi-Aventis | ||
| GB | Xatral | Sanofi-Aventis | |
| I | Mittoval | Sanofi-Aventis | |
| Xatral | Sanofi-Aventis |
SYN
Mathias Scheer, “Alfuzosin tablets and synthesis.” U.S. Patent US20060062845, issued March 23, 2006.
Syn, DOI: 10.1021/jm00151a003 NB: (WO2009001369)
FTIR spectrum of alfuzosin hydrochloride
CLIP
C19H27N5O4·HCl 425.91
Identification—
pH 791: between 4.0 and 5.5
Optical rotation 781: 
0.10 to +0.10
Related compounds—
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a detector set at 254 nm and a 4.6-mm × 15-cm column that contains 5-µm packing L1. The flow rate is about 1.5 mL per minute. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the peak-to-valley ratio is at least 5. [NOTE—The peak-to-valley ratio is determined as the ratio of the height above the baseline of the impurity A peak to the height above the baseline of the lowest point of the curve separating this impurity peak from the peak due to alfuzosin.]
Procedure— Separately inject equal volumes (about 10 µL) of the Reference solution and the Test solution, record the chromatograms, and measure the peak responses. Calculate the percentage of each impurity in the portion of Alfuzosin Hydrochloride taken by the formula:
in which 100 is the percentage conversion factor; rU is the peak response for any impurity obtained from the Test solution; 1000 is the dilution factor; and rS is the peak response for alfuzosin obtained from the Reference solution: the limits are as shown in the accompanying table. Disregard any peak with an area less than 0.05%.
| Compound | Relative Retention Time |
Limit (%) |
| Alfuzosin | 1.0 | — |
| Impurity A1 | 1.2 | * |
| Impurity D2 | 0.5 | 0.20 |
| Any individual unspecified impurity | — | 0.10 |
| Total impurities | — | 0.30 |
|
1 N-[3-[(4-Amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino]propyl]furan-2-carboxamide.
2 N-(4-Amino-6,7-dimethoxyquinazolin-2-yl)-N-methylpropane-1,3-diamine.
* Impurity A, a component of USP Alfuzosin System Suitability Mixture RS, is not a specified impurity.
|
||
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
| Monograph | Daniel K. Bempong, Ph.D. Senior Scientist 1-301-816-8143 |
(MDPS05) Monograph Development-Pulmonary and Steroids |
| Reference Standards | Lili Wang, Technical Services Scientist 1-301-816-8129 RSTech@usp.org |
Pharmacopeial Forum: Volume No. 34(1) Page 69
Chromatographic Column—
 |
|
| Clinical data | |
|---|---|
| Pronunciation | /ælˈfjuːzoʊsɪn/ al-FEW-zoh-sin |
| Trade names | Uroxatral, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a64002 |
| Pregnancy category |
|
| Routes of administration |
By mouth (tablets) |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 49% |
| Protein binding | 82–90% |
| Metabolism | Liver (CYP3A4-mediated) |
| Elimination half-life | 10 hours |
| Excretion | Feces (69%) and Urine (24%) |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| ECHA InfoCard | 100.108.671 |
| Chemical and physical data | |
| Formula | C19H27N5O4 |
| Molar mass | 389.46 g·mol−1 |
| 3D model (JSmol) | |
/////////////////塩酸アルフゾシン, Uroxatral, alfuzosin
COC1=C(OC)C=C2C(N)=NC(=NC2=C1)N(C)CCCNC(=O)C1CCCO1
OPC-12759
OPC-12759E
OPC-759
Rebamipide, an amino acid derivative of 2-(1H)-quinolinone, is used for mucosal protection, healing of gastroduodenal ulcers, and treatment of gastritis. It works by enhancing mucosal defense, scavenging free radicals, and temporarily activating genes encoding cyclooxygenase-2.
Rebamipide is used in a number of Asian countries including Japan (marketed as Mucosta), South Korea, China[1] and India (where it is marketed under the trade name Rebagen). It is also approved in Russia under the brand name Rebagit.[2] It is not approved by the Food and Drug Administration for use in the United States.
Studies have shown that rebamipide can fight the damaging effects of NSAIDs on the GIT mucosa, and more recently, the small intestine.[citation needed] It has also been studied for the treatment of Behçet’s disease.[3] It was shown to successfully treat pouchitis in a single-N study after first-line therapies for the condition were unsuccessful.[4] Some studies have shown effectiveness in presbyacusis(age-related hearing loss).[citation needed]
It has also been shown to alleviate signs and symptoms of dry eyes in a randomised controlled trial although this is not yet widely available clinically.[5]
SYN
Rebamipide (CAS NO.: 111911-87-6), with its systematic name of 4-Quinolinepropanic acid, alpha-((4-chlorobenzoyl)amino)-1,2-dihydro-2-oxo-, (+-)-, could be produced through many synthetic methods.
Following is one of the reaction routes:
4-(Bromomethyl)quinolin-2(1H)-one (I) could react with hot phosphorus oxychloride to produce a mixture of 4-(bromomethyl)-2-chloroquinoline (II) and 2-chloro-4-(chloromethyl)quinoline (III), and then the mixture without separation is ondensed with 2(S)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (IVs) in the presence of butyllithium in hexane, affording (-)-2-chloro-4-[6(S)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(R)-yl methyl]quinoline (Vr). The hydrolysis of (Vr) with HCl produces 3-(2-chloroquinolin-4-yl)-(R)-alanine methyl ester (VIr), which is treated with HCl and propylene oxide to afford 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(R)-alanine (VIIr). At last, this compound is acylated with 4-chlorobenzoyl chloride (VIII) by means of K2CO3in acetone, affording (R)-OPC-12759.
Figure 2 The synthetic route of Rebamipide.
DE 3324034; US 4578381 ABOVE
The condensation of 4-(bromomethyl)quinolin-2(1H)-one (I) with diethyl acetamidomalonate (II) by means of sodium ethoxide in refluxing ethanol gives ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4yl)propionate (III), which is submitted to a decarboxylative hydrolysis with refluxing 20% HCl yielding 3-(2-oxo-1,2-dihydroquinolin-4yl)alanine (IV). Finaily this compound is acylated with 4-chlorobenzoyl chloride by means of K2CO3 in acetone water.
SYN
Chem Pharm Bull 1991,39(11),2906 ABOVE
The synthesis of (R)- and (S)-isomers of OPC-12759 has been described: These optical isomers can be obtained in three different ways: 1) The reaction of 4-(bromomethyl)quinolin-2(1H)-one (I) with hot phosphorus oxychloride gives a mixture of 4-(bromomethyl)-2-chloroquinoline (II) and 2-chloro-4-(chloromethyl)quinoline (III), which, without separation, is condensed with 2(S)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (IVs) by means of butyllithium in hexane, yielding (-)-2-chloro-4-[6(S)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(R)-yl methyl]quinoline (Vr). The hydrolysis of (Vr) with HCl affords 3-(2-chloroquinolin-4-yl)-(R)-alanine methyl ester (VIr), which is treated with HCl and propylene oxide to give 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(R)-alanine (VIIr). Finally, this compound is acylated with 4-chlorobenzoyl chloride (VIII) by means of K2CO3 in acetone, affording (R)-OPC-12759.
SYN
3) The methylation of 3-(2-oxo-1,2-dihydroquinolin-4-yl)-(R,S)-alanine (IX) with SOCl2 and methanol yields the corresponding methyl ester (X), which is submitted to optical resolution with D-(-)-mandelic acid, affording adducts (XII) and (XIII). The hydrolytic treatment of (XII) and (XIII) with HCl and propylene oxide finally yields isomers (VIIr) and (VIIs), already obtained. Racemic OPC-12759 can also be resolved into its optical isomers by treatment with brucine and fractionated crystallization.
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 39098-85-6 | C4H5ClO2 | acetoacetyl chloride | Butanoyl chloride, 3-oxo- |
| 62-53-3 | C6H7N | aniline | Benzenamine |
| 4876-10-2 | C10H8BrNO | 4-(bromomethyl)-2(1H)-quinolinone | 2(1H)-Quinolinone, 4-(bromomethyl)- |
| 128-08-5 | C4H4BrNO2 | N-bromosuccinimide | 2,5-Pyrrolidinedione, 1-bromo- |
| 122-01-0 | C7H4Cl2O | 4-chlorobenzoyl chloride | Benzoyl chloride, 4-chloro- |
| 1068-90-2 | C9H15NO5 | diethyl acetamidomalonate | Propanedioic acid, (acetylamino)-, diethyl ester |
| 4900-38-3 | C19H22N2O6 | ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate | Propanedioic acid, (acetylamino)[(1,2-dihydro-2-oxo-4-quinolinyl)methyl]-, diethyl ester |
| 5162-90-3 | C12H12N2O3 | 3-(2-oxo-1,2-dihydroquinolin-4-yl)alanine | 4-Quinolinepropanoic acid, α-amino-1,2-dihydro-2-oxo- |
| 102-01-2 | C10H11NO2 | 3-oxo-N-phenylbutanamide | Butanamide, 3-oxo-N-phenyl- |
| Country | Trade Name | Vendor | Annotation |
|---|---|---|---|
| J | Mucosta | Otsuka |
PAPER
https://pubs.acs.org/doi/10.1021/acs.oprd.7b00382#
Rebamipide (1) is a superior drug compared to existing drugs for use in healing of peptic ulcers, gastrointestinal bleeding, and dyspepsia. It is also useful as an ophthalmic drug for the treatment of dry eye syndrome. Process intensification for its synthesis was achieved by (i) averting uncontrollable frothing using Krapcho decarboxylation instead of conventional acid hydrolysis, where uncontrollable frothing became chaotic, (ii) minimizing organic waste generation by using a single organic solvent, and (iii) avoiding anti-foaming agents (n-octanol, acetophenone) and acetic acid. With these trifling modifications, the overall yield of active pharmaceutical ingredient (API) was ≥83% with excellent purity (≥99.89%), and the process meets the metrics of “green” chemistry with an E-factor = 11.5. The developed hassle-free commercial process is viable for multi-kilogram synthesis of Rebamipide (1) as the key step, Krapcho decarboxylation is safe to run at 130–140 °C in DMSO, and it was proved to be effective by differential scanning calorimetry thermal screening studies. The characterization data of intermediates, process-related impurities, and API are reported. The carryover and process-related impurities were controlled efficiently. The present work can enhance the scope and worldwide adoptability of Rebamipide (1), which is currently limited to Asian countries.
https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00382/suppl_file/op7b00382_si_001.pdf
|
|
| Clinical data | |
|---|---|
| Trade names | Mucosta (JP), Rebagen (KR,CN, IN), Rebagit (RU) |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration |
Oral (tablets) |
| ATC code | |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C19H15ClN2O4 |
| Molar mass | 370.786 g/mol |
| 3D model (JSmol) | |
/////////Rebamipide, UNII:LR583V32ZR, ребамипид , ريباميبيد ,瑞巴派特 , OPC-12759 , OPC-12759E , OPC-759 , OPC 12759 , OPC 12759E , OPC 759 , OTSUKA, JAPAN 1990
OC(=O)C(CC1=CC(O)=NC2=CC=CC=C12)NC(=O)C1=CC=C(Cl)C=C1
New ICH Guidelines:
*ICH Q13* on Continuous Manufacturing &
*ICH Q14* on ATP – QbD (Analytical target profile and quality by design)
New ICH Guidelines: ICH Q13 on Conti Manufacturing and ICH Q14 on AQbD
In a press release from 22 June the International Council for Harmonisation (ICH) has announced that they will prepare new topics for the future. The Assembly agreed to begin working on two new topics for ICH harmonisation:
Analytical Procedure Development and Revision of Q2(R1) Analytical Validation (Q2(R2)/Q14)
and
Continuous Manufacturing (Q13)
The long anticipated revision of ICH Q2(R1) “Guideline on Validation of Analytical Procedures: Text and Methodology” has been approved and the work plan is scheduled to commence in Q3 2018. It is intended that the new guidelines will be consistent with ICH Q8(R2), Q9, Q10, Q11 and Q12 .
The AQbD approach is very important to collect information in order…
View original post 154 more words
BMS-986169
CAS 1801151-08-5 Related CAS : 1801151-09-6 1801151-08-5
Chemical Formula: C23H27FN2O2
Molecular Weight: 382.4794
Elemental Analysis: C, 72.23; H, 7.12; F, 4.97; N, 7.32; O, 8.37
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
(3R)-3-[(3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl]-1-[(4-methylphenyl)methyl]pyrrolidin-2-one
BMS-986169 is a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder. BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 μM) and had negligible activity in an assay panel containing 40 additional pharmacological targets.
Chemical structures of BMS-986169 and the phosphate prodrug BMS-986163.
PAPER
Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug
This paper describes the efficient scale-up synthesis of the potent negative allosteric glutamate N2B (GluN2B) inhibitor 1 (BMS-986169), which relies upon a stereospecific SN2 alkylation strategy and a robust process for the preparation of its phosphate prodrug 28 (BMS-986163) from parent 1 using POCl3. A deoxyfluorination reaction employing bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce a fluorine substituent. The optimized routes have been demonstrated to provide APIs suitable for toxicological studies in vivo.
https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00120/suppl_file/op8b00120_si_001.pdf
PAPER
https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.8b00080
BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder
There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.
(S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-
methylbenzyl)pyrrolidin-2-one (compound 23) and (R)-3-((3S,4S)-3-fluoro-4-(4-
hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169, compound
5)……https://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.8b00080/suppl_file/ml8b00080_si_001.pdf
Analytical data for BMS-986169 (compound 5): LCMS (C23H27FN2O2, MW 382.2, ESAPI),
observed 383.2 m/z (M+H)+; []D20 = +6.09 (c = 1.15, MeOH); Anal. Calcd for
C23H27FN2O2 (382.21): C, 72.22; H, 7.12; N, 7.32. Found: C, 72.26; H, 7.05; N, 7.31; HRMS
(ESI) Calcd for C23H27N2O2, 383.2118. Found, 383.2129;
13C NMR (126 MHz, chloroformd)
172.4, 155.0, 137.5, 133.0, 132.8, 129.4, 128.6, 128.2, 115.6, 91.6 (d, J=173.5 Hz),
65.0, 54.5 (d, J=25.4 Hz), 48.3, 47.7 (d, J=17.3 Hz), 46.7, 43.6, 31.5, 21.1, 19.2;(500 MHz, chloroform-d) 7.23 – 7.11 (m, 5H), 6.92 (d, J=8.5 Hz, 2H), 6.18 (br. s., 1H),
4.79 – 4.55 (m, 1H), 4.57 – 4.33 (m, 2H), 3.72 (t, J=8.7 Hz, 1H), 3.46 – 3.30 (m, 1H), 3.30 –
3.09 (m, 2H), 2.82 (d, J=8.5 Hz, 1H), 2.73 – 2.56 (m, 2H), 2.49 (d, J=2.5 Hz, 1H), 2.36 (s,
3H), 2.21 – 1.98 (m, 2H), 1.87 (br. s., 2H). The corresponding 1H NMR spectrum for
compound 5 is shown below
1H NMR
https://patents.google.com/patent/US9221796B2/und
InventorDalton KingLorin A. Thompson, IIIJianliang ShiSrinivasan ThangathirupathyJayakumar Sankara WarrierImadul IslamJohn E. Macor
Current Assignee Bristol-Myers Squibb Co
https://patents.google.com/patent/WO2015105772A1/und
N-Methyl-D-aspartate (NMDA) receptors are ion channels which are gated by the binding of glutamate, an excitatory neurotransmitter in the central nervous system. They are thought to play a key role in the development of a number of neurological diseases, including depression, neuropathic pain, Alzheimer’s disease, and Parkinson’s disease. Functional NMDA receptors are tetrameric structures primarily composed of two NRl and two NR2 subunits. The NR2 subunit is further subdivided into four individual subtypes: NR2A, NR2B, NR2C, and NR2D, which are differentially distributed throughout the brain. Antagonists or allosteric modulators of NMDA receptors, in particular NR2B subunit-containing channels, have been investigated as therapeutic agents for the treatment of major depressive disorder (G. Sanacora, 2008, Nature Rev. Drug Disc. 7: 426-437).
The NR2B receptor contains additional ligand binding sites in additon to that for glutamate. Non-selective NMDA antagonists such as Ketamine are pore blockers, interfering with the transport of Ca++ through the channel. Ketamine has demonstrated rapid and enduring antidepressant properties in human clinical trials as an i.v. drug. Additionally, efficacy was maintained with repeated, intermittent infusions of Ketamine (Zarate et al., 2006, Arch. Gen. Psychiatry 63: 856-864). This class of drugs, though, has limited therapeutic value because of its CNS side effects, including dissociative effects.
An allosteric, non-competitive binding site has also been identified in the N-terminal domain of NR2B. Agents which bind selectively at this site, such as
Traxoprodil, exhibited a sustained antidepressant response and improved side effect profile in human clinical trials as an i.v. drug (Preskorn et al., 2008, J. Clin.
PsychopharmacoL, 28: 631-637, and F. S. Menniti, et al, 1998, CNS Drug Reviews, 4, 4, 307-322). However, development of drugs from this class has been hindered by low bioavailability, poor pharmacokinetics, and lack of selectivity against other pharmacological targets including the hERG ion channel. Blockade of the hERG ion channel can lead to cardiac arrythmias, including the potentially fatal Torsades de pointe, thus selectivity against this channel is critical. Thus, in the treatment of major depressive disorder, there remains an unmet clinical need for the development of effective NR2B-selective negative allosteric modulators which have a favorable tolerability profile.
NR2B receptor antagonists have been disclosed in PCT publication WO 2009/006437.
The invention provides technical advantages, for example, the compounds are novel and are ligands for the NR2B receptor and may be useful for the treatment of various disorders of the central nervous system. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
Synthetic Scheme 1
The l-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V may be reacted with (4-oxy-phenyl)cyclic amines VI in the presence of base to produce protected products VII, which may be subjected to cleavage conditions appropriate for the protecting group (PGi) to generate final products I, which may be separated into individual enantiomers/diastereomers I*, as shown in synthetic scheme 2.
Synthetic Scheme 2
I I*
Compounds la may be prepared by condensing l-phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V with substituted 4(4-oxyphenyl)piperidines Vllla-c to generate protected intermediates IX, which may be subjected to cleavage conditions appropriate for the protecting group (PGi) to generate final products la, which may be separated into individual enantiomers/diastereomers la*, as shown in synthetic scheme 3.
Synthetic Scheme 3
The 4(4-oxyphenyl)piperidines Vllla-c may be synthesized in turn by a sequence starting with a protected tetrahydropiperidine X, which can be hydroxylated via hydroboration/oxidation to give the protected hydroxypiperidine XI, which may be either directly transformed into the protected fluoropiperidine XII by treatment with DAST or oxidized into the protected 3-oxopiperidine XIII, which may be further transformed into protected 3,3-difluoropiperidines XIV via treatment with DAST. XI, XII, and XIV may be transformed into Villa, Vlllb, and VIIIc, respectively, by employing cleaving conditions appropriate for the protecting group (PG2), as shown in synthetic scheme 3 a.
S nthetic scheme 3 a
Chiral
Cleavage Individual enantiomers/
G2P-N diastereomers
separation
conditions
OH 
Villa*
Villa
XI
Chiral
Cleavage Individual enantiomers/
HN
G2P-N diastereomers
%_\J> PQ separation
PG1 conditions
R F
F Vlllb*
Vlllb
XII
Chiral
Individual enantiomers/
G2P- diastereomers separation
Vlllc*
For tetrahydropyridines X which are not commercially available may be synthesized by coupling protected bromophenols XV with protected unsaturated
piperidineboronic acids XVI, as shown in synthetic scheme 4a.
Synthetic scheme 4a:
For tetrahydropyridines X which are not commercially available may be synthesized by adding the anion generated from protected bromophenols XV to a protected 4-piperidinone XVII to yield 4-phenyl-4-piperidinol XVIII, which may be dehydrated under acid conditions to yield the desired X, as shown in synthetic scheme 4b.
Synthetic scheme 4b:
l-Phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V may be condensed with isolated individual enantiomers VIIIa-c*, which results in diastereomers 1- phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones IX*, which may be deprotected and separated to give final products la*, as shown in scheme 5.
Alternatively, the backbone scaffold may be synthesized by condensing 1- phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V with hydroxypiperidines Villa to yield the protected 3-fluoropiperidines IXa, which may themselves be converted to the protected 3-fluoropiperidines IXb or oxidized to the ketones XIX, which may be converted to the 3,3-difluoropiperidines Ixc, as shown in scheme 6. The final compounds can then be isolated after the deprotection of IXa-c.
Scheme 6
Example 46, P-1 Example 46, P-2
(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one.
Example 46, P-3 Example 46, P-4
Step A. (±)-rel-(3S,4S)- 1 -benzyl-4-(4-methoxyphenyl)piperidin-3-ol.
To a suspension of sodium tetrahydroborate (2.7 g, 72 mmol) in THF (200 mL) at 0 °C under a nitrogen atmosphere was added dropwise boron trifluoride etherate (8.8 mL, 70 mmol) and the resulting mixture was stirred for 30 minutes. Then 1-benzyl- 4-(4-methoxyphenyl)-l,2,3,6-tetrahydropyridine (10 g, 36 mmol, from S. Halazy et al WO 97/28140 (8/7/97)) dissolved in 100 mL of tetrahydrofuran was added. The mixture was allowed to warm to rt and stirred for 2 h. The reaction was then quenched by the dropwise addition of 100 mL of water. Next were added
sequentially 100 mL of ethanol, 100 mL of a 10% aqueous sodium hydroxide solution, and 30%> hydrogen peroxide (18 mL, 180 mmol) and the mixture was stirred at reflux temperature overnight. The reaction mixture was then allowed to cool, diluted with saturated aqueous ammonium chloride (200 mL), and extracted with ethyl acetate (500 mL). The organic layer was dried over Na2S04, filtered, and evaporated under reduced pressure to give (±)-rel-(3S,4S)- 1 -benzyl-4-(4-methoxyphenyl)piperidin-3-ol (8.5 g, 24.6 mmol, 69%> yield) which was used without further purification. LCMS (Method K) RT 1.99 min; m/z 298.0 (M+H+).
Step B. (±)-re -(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol.
To a solution of (±)-re/-(35′,45)-l-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (9 g, 30 mmol) in methanol (150 mL) was added 10 % Pd/C (4.8 g) and the reaction mixture was stirred overnight under a hydrogen atmosphere. The catalyst was then removed by filtration through Celite and the solvent was evaporated under reduced pressure to give (±)-re/-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 24.6 mmol, 81% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-de) δ ppm 7.10 – 7.15 (m, 2 H) 6.80 – 6.86 (m, 2 H) 4.30 (d, J=5.27 Hz, 1 H) 3.37 – 3.43 (m, 1 H) 3.04 (dd, J=11.58, 4.36 Hz, 1 H) 2.86 (d, J=12.17 Hz, 1 H) 2.43 (td, J=12.09, 2.67 Hz, 1 H) 2.22 – 2.35 (m, 2 H) 1.57 – 1.63 (m, 1 H) 1.43 – 1.54 (m, 1 H).
To a solution of (±)-re/-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (4.5 g, 21.7 mmol) in DCM (150 mL) at -10°C under nitrogen was added a 1 M solution of boron tribromide in DCM (109 mL, 109 mmol). The reaction mixture was allowed to warm to rt, stired for 2 h, and then rechilled to 0 °C and quenched by the addition of a saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layer was washed with 250 mL of DCM and then to it was added 200 mL 10% aqueous NaOH, followed by 9.5 g (43.5 mmol) of di-t-butyl dicarbonate and the resulting mixture was stirred for an additional 2 h. The mixture was then extracted with 200 mL ethyl acetate and the organic layer was separated, dried over Na2S04,filtered, and evaporated under reduced pressure to (±)-re/-(35′,45)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-l-carboxylate (6.5 g, 12 mmol, 56 % yield) which was used without further purification. LCMS (Method K) RT 2.33 min, m/z 282 (M+H+ -2 t-butyl), 370; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.27 (d, J=8.66 Hz, 2 H) 7.08 (d, J=8.66 Hz, 2 H) 4.85 (d, J=5.65 Hz, 1 H) 4.13 (d, J=8.41 Hz, 1 H) 3.97 (d, J=10.48 Hz, 1 H) 3.45 (tt, J=10.27, 5.19 Hz, 1 H) 1.67 (d, J=3.39 Hz, 1 H) 1.50 – 1.59 (m, 1 H) 1.49 (s, 11 H).
Step D. (±)-re/-(35′,45)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate.
To a solution of (±)-re/-(35′,45)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-l-carboxylate (6.5 g, 16.5 mmol) in 100 mL of methanol was added 11.42 g of potassium carbonate (83 mmol) and the reaction mixture was stirred at rt for 5 h. The organic solvent was removed under reduced pressure and the residue was partitioned between IN HC1 (300 mL) and ethyl acetate (300 mL). The layers were separated and the organic layer was dried over Na2S04 and evaporated under reduced pressure to give (±)-re/-(35′,45)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate (5 g, 15 mmol, 92 % yield) which was used without further purification. LCMS (method F) RT 1.85 min, m/z 238 (M+H+ – 1-butyl), 279 (M+H+ – t-butyl+CH3CN), 1H NMR (400 MHz, DMSO-d6) δ ppm 7.01 (d, J=8.53 Hz, 2 H) 6.66 (d, J=8.53 Hz, 2 H) 4.70 (d, J=5.02 Hz, 1 H) 4.09 (br. s., 1 H) 3.94 (d, J=11.55 Hz, 1 H) 3.35 – 3.41 (m, 1 H) 2.66 – 2.77 (m, 1 H) 2.29 – 2.39 (m, 1 H) 1.63 (dd, J=13.30, 3.26 Hz, 1 H) 1.44 – 1.52 (m, 1 H) 1.42 (s, 9 H).
Step E. (3S,4S)-tert-Butyl 3 -hydroxy-4-(4-hydroxyphenyl)piperidine-l -carboxylate and (3R, -tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate.
E-1 E-2
(±)-rel-(3S,4S)-tert-Butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine- 1 -carboxylate (5 g, 17 mmol, from step D) was subjected to chiral SFC separation (method C-5) to yield enantiomers E-1 (1.9 g, 6.48 mmol, 38.0 % yield) and E-2 (2.4 g, 8.18 mmol, 48.0 % yield). Data for E-1 : chiral HPLC (method A5 ) retention time 3.42 min. Data for E-2: chiral HPLC (method A5) retention time 4.2 min.
Step F. (3R,4R)-tert-Butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-l-carboxylate.
A mixture of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate (620 mg, 2.1 mmol, E-2 from step E), potassium carbonate (584 mg, 4.2 mmol), and benzyl bromide (0.25 mL, 2.1 mmol) in DMF (5 mL) was stirred at rt for 16 h. The solvent was removed by evaporation and the residue was treated with 50 mL of water. The aqueous mixture was then extracted 4 times with 50 mL of chloroform. The combined organic phases were dried over anhydous Na2S04, filtered, and evaporated to yield 750 mg of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-l -carboxylate which was used without further purification. LCMS (method F) RT 2.28 min, m/z = 310 (M+H+ – t-butyl -water), 328 (M+H+ -t-butyl).
Step G. (3i?,4i?)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride.
A mixture of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (750 mg, 2 mmol), dioxane (4 mL) and 4.9 mL of 4 M HCI in dioxane was stirred at rt for 2h. The reaction was then evaporated to dryness to yield 550 mg of (3i?,4i?)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride which was used without further purification. LCMS (method J) RT 0.70 min, m/z 284 (M+H+).
Step H. 3-((3i?,4i?)-4-(4-(Benzyloxy)phenyl)-3-hydroxypiperidin-l -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one .
A mixture of 3-bromo-l-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 220 mg, 0.82 mmol), (3i?,4i?)-4-(4-(benzyloxy)phenyl)piperidin-3-ol hydrochloride (262 mg, 0.82 mmol, from step G) and triethylamine (11 mL, 8.2 mmol) was stirred at 60 °C for lh, 80 °C for 1 h, 100 °C for 1 h and 120 °C for 1 h. The reaction mixture was then allowed to cool, diluted with 40 mL of water and extracted four times with 50 mL of chloroform. The combined organic layers were washed with 60 mL brine, dried over anhydrous sodium sulfate, filtered, and evaporated to yield 382 mg of 3-((3 ?,4i?)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one which was used without further purification. LCMS (method J) (main component of a mixture) RT 2.23 min, m/z 471 (M+H+).
Step I. 3-((3R, 4R)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one .
A solution of 3-(-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) in DCM (5 mL) cooled to 0 °C was treated dropwise with DAST (0.32 mL, 2.4 mmol) over 3 min. The reaction mixture was then allowed to warm to rt and was stirred for 2 h. The reaction was then quenched with 50 mL of 10% aqueous sodium bicarbonate solution and extracted 4 times with 40 mL of DCM. The combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield 382 mg of 3-((3i?,4i?)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one as a mixture of two diastereomers and rearrangement products which was used without further purification. LCMS (method J) (main component of a mixture) RT 0.9 min, m/z 473 (M+H+).
Step J. 3-((3i?,4i?)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)-l -(4-methylbenzyl)pyrrolidin-2-one .
A mixture of 3-((Ji?,4i?)-(4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) and methanol (4 mL) was flushed with nitrogen, followed by the addition of 172 mg of 10% Pd/C. Then the mixture was stirred at rt overnight under 25-99 psi hydrogen pressure. The reaction was then transferred to a 100 mL autoclave and stirred at 7 kg/cm2 hydrogen pressure for 4 days. The catalyst was removed by filtration through Celite and the solvent was evaporated off. The crude product was subjected to HPLC purification (method B) to yield 77.3 mg 3-((Ji?,4i?)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair) LCMS (method Q) RT 1.15 min, m/z 383.0 (M+H+).
Step K. (5)-3-((3i?,4i?)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl>
methylbenzyl)pyrrolidin-2-one and (i?)-3-((3i?,4i?)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one.
The diastereomeric mixture from step J was separated by SFC method C-7 to yield homochiral Examples 46 P-l (29.3 mg) and P-2 (32.8 mg). Data for P-l (S)-3-((3R, 4R)-3 -fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2 (M+H+), 405.2 (M+Na+); HPLC (method B) RT 8.24 min (98.8% AP); HPLC (method C) RT 6.52 min (99.1% AP); Chiral HPLC (method C-6) RT 4.1 min; 1H NMR (400 MHz, methanol-d4) δ ppm 1.76 – 1.86 (m, 2 H) 2.07 (d, J=8.53 Hz, 1 H) 2.13 – 2.21 (m, 1 H) 2.34 (s, 3 H) 2.43 (s, 0 H) 2.55 – 2.60 (m, 1 H) 2.65 – 2.70 (m, 1 H) 2.75 (br. s., 1 H) 3.20 – 3.30 (m, 2 H) 3.38 – 3.45 (m, 1 H) 3.70 (t, J=8.78 Hz, 1 H) 4.44 (t, J=79.81 Hz, 3 H) 4.63 – 4.71 (m, 1 H) 6.70 – 6.80 (m, 2 H) 7.07 – 7.15 (m, 2 H) 7.07 – 7.12 (m, 1 H) 7.13 – 7.22 (m, 4 H); 19F NMR δ ppm -184.171. Data for P-2: (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2 (M+H+), 405.2 (M+Na+); HPLC (method B) RT 8.29 min (99.7% AP); HPLC (method C) RT 6.52 min (99.8% AP); Chiral HPLC (method C-6) RT 6.92 min; 1H NMR (400 MHz, methanol-d4) δ ppm 1.80 – 1.90 (m, 2 H) 2.07 (d, J=8.03 Hz, 1 H) 2.19 (s, 1 H) 2.34 (s, 3 H) 2.41 – 2.48 (m, 1 H) 2.66 (d, J=4.52 Hz, 2 H) 2.95 – 3.03 (m, 1 H) 3.10 – 3.18 (m, 1 H) 3.20 – 3.30 (m, 2 H) 3.68 – 3.78 (m, 1 H) 4.38 (s, 1 H) 4.51 (d, J=14.56 Hz, 2 H) 6.70 – 6.80 (m, 2 H) 7.05 – 7.13 (m, 2 H) 7.13 – 7.22 (m, 4 H); 19F NMR δ ppm -184.311.
(3S,4S)-tert-Butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-l-carboxylate.
To a solution of (3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate (400 mg, 1.36 mmol, the first eluting enantiomer E-l from step E) in DCM (5 mL) cooled to 0 °C was added dropwise DAST (0.54 mL, 4.1 mmol) over 10 min. The mixture was allowed to warm up to rt and was stirred for 2h. The reaction was slowly quenched with 50 mL of a 10%> aqueous sodium bicarbonate solution and extracted four times with 50 mL of DCM. The combined organic layerss were washed with 75 mL of brine, dried, and concentrated under vacuum to yield 390 mg of {3S,4S)-tert-bvXy\ 3-fluoro-4-(4-hydroxyphenyl)piperidine-l-
carboxylate which was used without further purification. LCMS (Method Q) RT 0.92 min, m z 240.1(M+H+).
Step M. 4-((3S’,4S)-3-Fluoropi ridin-4-yl)phenol hydrochloride.
A mixture of (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-l-carboxylate (390 mg, 1.3 mmol) and 4M HC1 in dioxane (3.3 mL, 13.2 mmol) in dioxane (4 mL) was stirred at rt for 2 hr. It was then concentrated to dryness, washed with 10 mL of 5% DCM/diethyl ether mixture and the solid was isolated by filtration. Yield: 260 mg of 4-((J£4S)-3-fluoropiperidin-4-yl)phenol hydrochloride; LCMS
(method Q) RT 0.46 min, mz 196.1(M+H+) 1H NMR (400 MHz, DMSO-d6) δ = 9.57 (br. s., 4 H), 8.92 – 8.68 (m, 1 H), 7.14 (d, J= 8.5 Hz, 1 H), 7.06 (d, J= 8.5 Hz, 2 H), 6.82 – 6.73 (m, 2 H), 5.07 – 4.85 (m, 1 H), 3.77 – 3.36 (m, 9 H), 3.32 – 3.22 (m, 2 H), 3.13 – 2.85 (m, 5 H), 2.06 – 1.88 (m, H).
Step N. 3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one.
A mixture of 3-bromo-l-(4-methylbenzyl)pyrrolidin-2-one (200 mg, 0.75 mmol), triethylamine (0.52 mL, 3.7 mmol) and 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride (173 mg, 0.75 mmol) in DMF (3 mL) was heated to 120 °C in a microwave reactor for 1.5 h. The mixture was allowed to cool and was then mixed with 60 mL water and extracted 5 times with 40 mL of DCM. The combined organic extracts were washed with 80 mL of brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give 265 mg of 3-((3 4S)-3-fluoro-4-(4-hydroxy-phenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one as a mixture of 2 diastereoisomers. LCMS (method P) RT 0.92 min m/z 383.4 (M+H+).
Step O. (5)-3-((3lS,45)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one and (i?)-3-((35,,45)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one.
A portion of the diasteromer mixture from step N (130 mg) was subjected to chiral purification via SFC (method C-7) to give homochiral Examples 46 P-3 (37.7 mg) and P-4 (60.7 mg). Data for P-3 (S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT = 2.10 min, m/z 383.2 (M+H+); HPLC (Method C) RT 6.54 min, (Method D) RT 8.20 min; chiral HPLC (method C-6) RT 3.42 min;1H NMR (400 MHz, methanol-d4) δ ppm 1.76 – 1.86 (m, 2 H) 2.06 (d, J=8.53 Hz, 1 H) 2.10 – 2.21 (m, 1 H) 2.34 (s, 3 H) 2.40 – 2.48 (m, 1 H) 2.53 – 2.60 (m, 1 H) 2.61 – 2.70 (m, 2 H) 2.95 -3.01 (m, 1 H) 3.01 (s, 2 H) 3.10 – 3.16 (m, 1 H) 3.18 – 3.28 (m, 2 H) 3.72 (s, 1 H) 4.35 – 4.41 (m, 1 H) 4.46 – 4.70 (m, 2 H) 6.72 – 6.80 (m, 2 H) 7.05 – 7.23 (m, 6 H). Data for P-4 (R)-3-((3S,4S)-3-fiuoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT 2.11 min, m/z 383.2 (M+H+);; HPLC (Method C) RT 6.50 min, (Method D) RT 8.21 min; chiral HPLC (method C-6) RT 6.31 min; 1H NMR (400 MHz, methanol-d4) δ ppm 1.81 (dd, J=7.28, 2.76 Hz, 2 H) 2.06 (d, J=9.04 Hz, 2 H) 2.33 (s, 3 H) 2.43 (s, 1 H) 2.55 (br s, 1 H) 2.66 (d, J=40.16 Hz, 2 H) 2.75 – 2.80 (m, 1 H) 2.96 – 3.10 (m, 2 H) 3.20 – 3.28 (m, 2 H) 3.41 (d, J=5.52 Hz, 1 H) 3.66 – 3.75 (m, 1 H) 4.31 – 4.41 (m, 1 H) 4.46 – 4.71 (m, 2 H) 6.76 (d, J=8.53 Hz, 2 H) 7.05 – 7.23 (m, 6 H).
Example 48 (Peak 1, Peak 2, Peak 3, Peak 4)
(S)-l-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-l- yl)pyrrolidin-2-one, (S)-l-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4- methoxyphenyl)piperidin-l-yl)pyrrolidin-2-one, (R)-l-(4-fluorobenzyl)-3-((3S,4S)-3- hydroxy-4-(4-methoxyphenyl)piperidin-l-yl)pyrrolidin-2-one, and (R)-l-(4- fluorobenzyl)-3-((3RAR)-3-hydroxy-4-(4-methoxyphenyl)piperidin-l-yl)pyrrolidin-2- one
Step A. (±)-re/-l-(4-Fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4- methoxyphenyl)piperidin- 1 -yl)pyrrolidin-2-one.
To a solution of 3-bromo-l-(4-fluorobenzyl)pyrrolidin-2-one (Intermediate 1, 300 mg, 1.1 mmol) and trans-4-(4-methoxyphenyl)piperidin-3-ol (from Example 46, step B, 240 mg, 1.16 mmol) in acetonitrile (10 mL) was added triethylamine (560 mg, 5.5 mmol) and the mixture was heated at 120 °C in a microwave reactor for 1 h. The reaction mixture was then diluted with water and extracted with 100 mL of ethyl acetate. The organic layer was dried over Na2S04, filtered, and evaporated under reduced pressure to give (±)-re/-l-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4- methoxyphenyl)piperidin-l-yl)pyrrolidin-2-one (450 mg, 0.7 mmol) as a mixture of four diastereomers which was used without further purification. LCMS (Method S) RT 1.89 min, m/z 399.1 (M+H+).
Step B. (±)-re/-3-((3lS,45)-3-Fluoro-4-(4-methoxyphenyl)piperidin- 1 -yl)- 1 -(4-fluorobenzyl)pyrrolidin-2-one.
To a solution of l-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)piperidin-l-yl)pyrrolidin-2-one from step B (2.5 g, 6.3 mmol) in 50 mL DCM was added DAST (4.1 mL, 31 mmol) and the reaction was stirred at ambient temperature for 1 h. The reaction was then quenched with a sat.bicarbonate solution (200 mL) and the mixture was extracted with 200 mL of DCM. The organic layer was dried over Na2S04, filtered, and evaporated under reduced pressure. The residue was purified via silica gel chromatography eluting with 28% ethyl acetate in hexane to give (±)-re/-3-((35′,45)-3-fluoro-4-(4-methoxyphenyl)piperidin-l-yl)-l-(4-fluorobenzyl)pyrrolidin-2-one (900 mg, 1.6 mmol) as a mixture of four
diastereomers. LCMS (method P) RT 0.89 min, m/z 401.2 (M+H+).
Step C. 3-((3lS,45)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-fluorobenzyl)pyrrolidin-2-one.
To a solution of (tra/?5-3-fluoro-4-(4-methoxyphenyl)piperidin-l-yl)-l-(4-fluorobenzyl)pyrrolidin-2-one (700 mg, 1.75 mmol) in 50 mL of DCM at 0 °C was added BBr3(0.3 mL, 3.5 mmol). The reaction mixture was allowed to warm up to room temperature over 1 h. The mixture was then diluted with a sat. bicarbonate solution and extracted with 200 mL of DCM. The organic layer was dried over Na2S04, filtered, and evaporated under reduced pressure.
The residue was purified by preparative HPLC(method A) to yield 120 mg of 3-((35′,45)-3-fluoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-fluorobenzyl)pyrrolidin-2-one as a mixture of four diastereomers. LCMS (method N) RT 1.45 min, m/z 387.0 (M+H+).
Step D. (S)- 1 -(4-fluorobenzyl)-3-((35′,45)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1 -yl)pyrrolidin-2-one, (S)- 1 -(4-fluorobenzyl)-3-((3i?,4i?)-3-hydroxy-4-(4-methoxyphenyl)piperidin-l-yl)pyrrolidin-2-one, (i?)-l-(4-fluorobenzyl)-3-((35′,45)-3-hydroxy-4-(4-methoxyphenyl)piperidin- 1 -yl)pyrrolidin-2-one, and (R)- 1 -(4-fluorobenzyl)-3-((3i?,4i?)-3-hydroxy-4-(4-methoxyphenyl)piperidin-l-yl)pyrrolidin-2-one.
The diastereomeric mixture from step C was separated via chiral SFC (method F) into the 4 homochiral diastereomers, Example 48 P-1, P-2, P-3, and P-4. Data for P-1 (S)- 1 -(4-fluorobenzyl)-3-((35′,45)-3-hydroxy-4-(4-methoxyphenyl)piperidin- 1 -yl)pyrrolidin-2-one: Chiral SFC (Method F) RT 3.32 min, 100% AP; HPLC (Method A) RT 6.53 min, 96.0%AP, (Method B) RT 6.7 min, 96.3 %AP; LCMS (Method F) RT 2.02 min, m/z 387.0 (M+H+); 1H NMR (400 MHz, methanol-^) δ ppm 7.32 (dd, J=8.78, 5.27 Hz, 2 H) 7.07 – 7.14 (m, 4 H) 6.76 (d, J=8.53 Hz, 2 H) 4.41 – 4.56 (m, 2 H) 3.74 (t, J=8.78 Hz, 1 H) 3.23 – 3.31 (m, 2 H) 3.10 – 3.17 (m, 1 H) 3.01 (d, J=11.04 Hz, 1 H) 2.88 (d, J=7.03 Hz, 1 H) 2.66 (td, J=10.04, 4.52 Hz, 1 H) 2.57 (dd, J=10.54, 6.53 Hz, 1 H) 2.40 – 2.49 (m, 1 H) 2.16 – 2.25 (m, 1 H) 2.03 – 2.13 (m, 1 H) 1.80 -1.88 (m, 2 H). Data for P-2 (5)-l-(4-fluorobenzyl)-3-((3i?,4i?)-3-hydroxy-4-(4-methoxyphenyl)piperidin-l-yl)pyrrolidin-2-one: Chiral SFC (Method F) RT 4.15 min, 99.7% AP; HPLC (Method A) RT 6.52 min, 98.1%AP, (Method B) RT 6.92 min, 98.6 %AP; LCMS (Method F) RT 2.03 min, m/z 387.0 (M+H+);1H NMR (400 MHz, methanol-^) δ ppm 7.29 – 7.34 (m, 2 H) 7.07 – 7.14 (m, 4 H) 6.76 (d, J=9.04 Hz, 2 H) 3.71 (t, J=8.78 Hz, 1 H) 3.39 – 3.45 (m, 1 H) 3.24 – 3.31 (m, 2 H) 2.74 -2.80 (m, 1 H) 2.64 – 2.72 (m, 1 H) 2.57 (dd, J=10.54, 6.02 Hz, 1 H) 2.43 (td, J=10.04, 5.02 Hz, 1 H) 2.15 – 2.25 (m, 1 H) 2.05 – 2.14 (m, 1 H) 1.77 – 1.85 (m, 2 H). Data for P-3 (i?)-l-(4-fluorobenzyl)-3-((35′,45)-3-hydroxy-4-(4-methoxyphenyl)piperidin-l-yl)pyrrolidin-2-one: Chiral SFC (Method F) RT 4.56 min, 97.4% AP; HPLC (Method A) RT 6.53 min, 96.0%AP, (Method B) RT 6.94 min, 96.4 %AP; LCMS (Method F) RT 2.02 min, m/z 387.0 (M+H+); 1H NMR (400 MHz, methanol-^) δ ppm 7.29 -7.34 (m, 2 H) 7.07 – 7.13 (m, 4 H) 6.74 – 6.78 (m, 2 H) 4.40 – 4.55 (m, 2 H) 3.71 (t, J=9.04 Hz, 1 H) 3.38 – 3.45 (m, 1 H) 3.23 – 3.31 (m, 2 H) 2.76 (br. s., 1 H) 2.64 -2.72 (m, 1 H) 2.57 (dd, J=10.54, 6.02 Hz, 1 H) 2.43 (td, J=10.04, 5.02 Hz, 1 H) 2.16 – 2.25 (m, 1 H) 2.05 – 2.14 (m, 1 H) 1.77 – 1.87 (m, 2 H). Data for P-4 (R)-\-(4- fluorobenzyl)-3-((3i?,4i?)-3-hydroxy-4-(4-methoxyphenyl)piperidin-l-yl)pyrrolidin-2-one: Chiral SFC (Method F) RT 5.57 min, 99.9% AP; HPLC (Method A) RT 6.55 min, 99.9%AP, (Method B) RT 6.90 min, 99.9 %AP; LCMS (Method F) RT 2.03 min, m/z 387.0 (M+H+); 1H NMR (400 MHz, methanol-^) δ ppm 7.32 (dd, J=8.78, 5.27 Hz, 2 H) 7.07 – 7.14 (m, 4 H) 6.76 (d, J=8.53 Hz, 2 H) 4.41 – 4.56 (m, 3 H) 3.74 (t, J=8.53 Hz, 1 H) 3.24 – 3.32 (m, 2 H) 3.10 – 3.17 (m, 1 H) 2.66 (td, J=9.91, 4.77 Hz, 1 H) 2.57 (dd, J=10.54, 6.53 Hz, 1 H) 2.41 – 2.49 (m, 1 H) 2.16 – 2.24 (m, 1 H) 2.04 – 2.12 (m, 1 H) 1.80 – 1.88 (m, 2 H).
Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.
1: Bristow LJ, Gulia J, Weed MR, Srikumar BN, Li YW, Graef JD, Naidu PS, Sanmathi
C, Aher J, Bastia T, Paschapur M, Kalidindi N, Kumar KV, Molski T, Pieschl R,
Fernandes A, Brown JM, Sivarao DV, Newberry K, Bookbinder M, Polino J, Keavy D,
Newton A, Shields E, Simmermacher J, Kempson J, Li J, Zhang H, Mathur A, Kallem
RR, Sinha M, Ramarao M, Vikramadithyan RK, Thangathirupathy S, Warrier J, Islam
I, Bronson JJ, Olson RE, Macor JE, Albright CF, King D, Thompson LA, Marcin LR,
Sinz M. Preclinical Characterization of
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrr
olidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate
2B Receptor Negative Allosteric Modulator with Potential in Major Depressive
Disorder. J Pharmacol Exp Ther. 2017 Dec;363(3):377-393. doi:
10.1124/jpet.117.242784. Epub 2017 Sep 27. PubMed PMID: 28954811.
2. BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder
Lawrence R. Marcin, Jayakumar Warrier, Srinivasan Thangathirupathy, Jianliang Shi, George N. Karageorge, Bradley C. Pearce, Alicia Ng, Hyunsoo Park, James Kempson, Jianqing Li, Huiping Zhang, Arvind Mathur, Aliphedi B. Reddy, G. Nagaraju, Gopikishan Tonukunuru, Grandhi V. R. K. M. Gupta, Manjunatha Kamble, Raju Mannoori, Srinivas Cheruku, Srinivas Jogi, Jyoti Gulia, Tanmaya Bastia, Charulatha Sanmathi, Jayant Aher, Rajareddy Kallem, Bettadapura N. Srikumar, Kumar Kuchibhotla Vijaya, Pattipati S. Naidu, Mahesh Paschapur, Narasimharaju Kalidindi, Reeba Vikramadithyan, Manjunath Ramarao, Rex Denton, Thaddeus Molski, Eric Shields, Murali Subramanian, Xiaoliang Zhuo, Michelle Nophsker, Jean Simmermacher, Michael Sinz, Charlie Albright, Linda J. Bristow, Imadul Islam, Joanne J. Bronson, Richard E. Olson, Dalton King, Lorin A. Thompson, and John E. Macor
Publication Date (Web): April 13, 2018 (Letter)
DOI: 10.1021/acsmedchemlett.8b00080
| Patent ID | Patent Title | Submitted Date | Granted Date |
|---|---|---|---|
| US9221796 | Selective NR2B antagonists |
2015-01-05
|
2015-12-29
|
//////////////////BMS-986169, BMS-986169, BMS 986169, BMS986169
O=C1N(CC2=CC=C(C)C=C2)CC[C@H]1N3C[C@@H](F)[C@H](C4=CC=C(O)C=C4)CC3
CH4630808, CH-4630808, NA-808
(2S)-2-[(E,2S)-1-[[(1S)-2-(4-but-2-ynoxyphenyl)-1-carboxyethyl]amino]-1,11-dioxooctadec-3-en-2-yl]-2-hydroxybutanedioic acid
| Molecular Formula: | C35H49NO10 |
|---|---|
| Molecular Weight: | 643.774 g/mol |
Cas 827034-92-4 DOUBLE BOND E, SP ROT (-)
CAS 744208-75-1 E Z NOT DEFINED
Chugai Pharmaceutical (Originator)
Trisodium Der ,CAS 1799542-36-1, SP ROT (-), MW 709.7097, MF C35 H46 N O10 . 3 Na, Trisodium (2S)-2-[(2S,3E)-1-([(1S)-2-[4-(but-2-yn-1-yloxy)phenyl]-1-carboxylatoethyl]amino)-1,11-dioxooctadec-3-en-2-yl]-2-hydroxybutanedioate
SIMILAR
PAPER
https://www.sciencedirect.com/science/article/pii/S0960894X12013741
Bioorganic & Medicinal Chemistry Letters
Scheme 3. Reagents and conditions: (a) TBDPSCl, imidazole, DMF, rt; (b) n-BuLi, (CH2O)n, THF; (c) Red-Al, 0 C, then I2, THF 40 C; (d) DHP, PPTS, DCM, rt; (e) n-BuLi, (CH2O)n, THF, 78 C to 0 C; (f) TBDPSCl, imidazole, DMF, rt; (g) PPTS, EtOH. 28.6% over 7 steps; (h) L-(+)-DET, Ti(Oi-Pr)4, TBHP, DCM, 97%, >95% ee; (i) Terminal alkyne 7 in Scheme 2, Cp2ZrClH, MeMgCl, CuI, THF, 20 C, 91% yield⁄ ; (j) 2,2-dimethoxypropane, PPTS, DCM, 85% yield⁄ ; (k) TBAF, AcOH, THF, 89% yield⁄ ; (l) oxalyl chloride, DMSO, triethylamine, DCM, 78 C; (m) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH-H2O; (n) N,N-dimethylformamide di-tert-butyl acetal, 58% yield in 3 steps⁄ ; (o) 80% AcOH, THF, rt, 90% yield⁄ ; (p) Jones reagent, aqueous acetone, 10 C, 80% yield⁄ ; (q) the corresponding amine, HATU, Hunig base, 85% yield⁄ ; (r) TFA, anisole, DCM, 90% yield⁄ ; (s) H2-Pd/C, EtOH, 80%; (t) NaBH4, THF, MeOH, 93% yield. ⁄ yields when n = 5 and R1 = n-C7H15.
Paper
Development of a Kilogram-Scale Synthesis of a Novel Anti-HCV Agent, CH4930808
CH4630808 corrected
Herein, we report the kilogram-scale synthesis of CH4930808 (1) CH 4630808 CORRECTED, a novel anti-hepatitis C virus agent. While pursuing improved productivity using many through-process strategies, we conducted scrupulous impurity control. Finally, we successfully developed a practical and scalable process for the synthesis of (1·1.5Na·2.5H2O), by which we prepared 3.28 kg of the active pharmaceutical ingredient for clinical studies
https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00383/suppl_file/op7b00383_si_001.pdf
1H-NMR and 13C-NMR spectra of compound 5·HCl S 3– S 4
1H-NMR spectra of compound 1·1.5 Na·2.5 H2O S 5
13C-NMR spectra compound 1·1.5 Na·2.5 H2O S 6
1H-COSY spectra of compound 1·1.5 Na·2.5 H2O S 7 – S 8
DEPT spectra of compound 1·1.5 Na·2.5 H2O S 9 – S 10
HMBC spectra of compound 1·1.5 Na·2.5 H2O S 11 – S 17
MASS
PATENT
WO 2004071503
WO 2005005372
WO 2006016657
WO 2006088071
WO 2007000994
WO 2007132882
WO 2009154248
WO 2014027696
PAPER
Angewandte Chemie, International Edition (2012), 51(17), 4218-4222, S4218/1-S4218/77.
Bioorganic & Medicinal Chemistry Letters (2013), 23(1), 336-339
PAPER
Organic & Biomolecular Chemistry (2017), 15(31), 6632-6639.
http://pubs.rsc.org/en/Content/ArticleLanding/2017/OB/C7OB01608E#!divAbstract
10.1039/C7OB01608E
The viridiofungin analogue NA808 was synthesized by the stereoselective Ireland–Claisen rearrangement of dienylmethyl ester, regioselective bromolactonization of β-divinylpropanoic acid and retro-bromolactonization.
The number of people infected with hepatitis C virus (HCV) is estimated at 1 to 200 million people worldwide, and over 2 million people in Japan. Approximately 50% of these patients migrate to chronic hepatitis, of which approximately 20% become liver cirrhosis, liver cancer after more than 30 years after infection. About 90% of liver cancer is said to be hepatitis C cause. In Japan, more than 20,000 patients die every year from liver cancer associated with HCV infection.
HCV was discovered in 1989 as a major causative virus of non-A non-B hepatitis after transfusion. HCV is an enveloped RNA virus whose genome
It consists of single-stranded (+) RNA and is classified as a genus Hepacivirus of Flaviviridae.
Since HCV avoids the immune mechanism of the host due to a cause which is still unclear, persistent infection is often established even when infected with an adult with developed immune mechanism, progresses to chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, surgery It is also known that many patients have liver cancer recurrence due to inflammation that continues to occur in non-cancerous areas.
Therefore, establishment of an effective therapy for hepatitis C is desired, and among them, apart from coping therapy that suppresses inflammation by anti-inflammatory agents, development of a drug that reduces or eradicates HCV in the affected liver It is strongly desired.
Interferon treatment is currently known as the only effective treatment for HCV elimination. However, the number of patients with interferon effective is about one third of all patients. In particular, interferon response to HCV genotype 1 b is very low. Therefore, development of anti-HCV drugs that can replace or be used in combination with interferon is strongly desired.
In recent years, Ribavirin (1 – 3 – D – lipofuranosyl – 1 H – 1, 2, 4 – triazole – 3 – carboxamide) is commercially available as a therapeutic agent for hepatitis C by combining with interferon, Is still low, further new treatment for hepatitis C is desired. In addition, attempts have been made to eliminate viruses by enhancing the immune system of patients, such as interferon agonists, interleukin-12 agonists, etc. However, no effective drug has yet been found.
Since the HCV gene has been cloned, molecular biological analysis of the mechanism and function of viral genes, functions of proteins of each virus and the like has been accompanied by rapid development of forces, replication of virus in host cells, persistent infection, pathogenesis The mechanism such as sexuality has not been sufficiently elucidated, and at the present time, an HCV infection experiment system using reliable cultured cells has not been constructed. Conventionally, when evaluating anti-HCV drugs, alternative alternative virus method using other closely related viruses had to be used.
In recent years, however, it became possible to observe in vitro HCV replication using the nonstructural region part of HCV, so that anti-HCV drugs could be easily evaluated by the replicon assay method (Non-Patent Document 1). The mechanism of H CV RN A replication in this system is believed to be identical to the replication of the full-length HCV RNA genome infected with hepatocytes. Therefore, this system can be said to be a cell-based approach system useful for identifying compounds that inhibit the replication of HCV.
The compounds claimed in this patent are compounds that inhibit the replication of HCV found by the replicon astrocyte method. These inhibitors are considered highly likely to be therapeutic agents for HCV.
Non-Patent Document 1
B. Roman et al., Science (Science), 1999, 285, 110 – 113
Example 14
– 1 (Step 1 1)
According to the method described in the literature (J. Org. Chem. 1989, 45, 5522, BE Marron, et al)
TBDPSO.
a on
Of compound a (7.0 1 g) was synthesized, and anhydrous ethyl ether of this compound a
(700 ml) was cooled to 0 ° C. and bis (2-methoxyethoxy) aluminum hydride (414 mmol, 218 ml, 70% toluene solution) was added slowly. Five minutes after adding the reagent, the ice bath was removed and stirring was continued for 1 hour at room temperature. The reaction solution was cooled to 0 ° C and anhydrous ethyl acetate (1 9.8 ml, 203 mmol) was added slowly. After stirring at the same temperature for 10 minutes, it was cooled to 1 78 ° C., and iodine (76.1 g,
300 thigh 0 1) was added. The temperature was gradually raised to room temperature over 2 hours to complete the reaction. To the reaction solution was added aqueous sodium bisulfite solution, and ethyl acetate was added. The reaction solution was filtered with suction through celite, the organic layer was separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (100 g) as a light brown oily substance. The obtained crude product was directly used for the next reaction.
Physicochemical properties of compound b
Molecular weight 466
FAB-MS (positive mode, matrix m-NBA) 467 (M + H + ).
Chemical shift value of X H-NMR (in heavy chloroform) δ:
J = 6 Hz), 3.80 (2H, t, J = 6 Hz), 4.18 (2H, t, J = 5 Hz), 2.73 (2H, t, J = 6 Hz), 1.49 Hz, 5.91 (1 H, t, J = 5 Hz), 7.35 – 7.46 (6 H, m), 7.65 – 7.69 (4 H, m)
1 -2 (Step 1 – 2)
TBDPS
Dichloro port methane solution of compound b obtained in the above reaction (300 ml) was cooled to 0 ° C, dihydropyran (22. 7 ml, 248删0 plus 1). Pyridinium paratoluenesulfonic acid (260 mg, 1 mol) was added to this solution. After 1 hour sodium bicarbonate water was added to stop the reaction. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound c (108 g) thus obtained was directly used for the next reaction.
Physicochemical properties of compound c
Molecular weight 550
FAB-MS (positive mode, matrix m-NBA) 551 (M + H + )
Chemical shift value of 1 H – NMR (in heavy mouth formium) δ:
3.46-3.58 (2H, m), 3.76 (2H, t, J = 6 Hz), 3.82 (2H, t, J = 6 Hz), 1.04 (9H, s), 1.49-1.91 J = 13, 6 Hz), 4.65 (1 H, t, J = 3 Hz), 5.91 (1 H, t (s)), 4.93 (1 H, m), 4.06 (1 H, dd, J = 13, 6 Hz) , J = 5 Hz) 7.35 – 7.43 (6 H, m), 7.65 – 7.69 (4 H, m)
1-3 (Step 1- 3)
The crude compound c (4. 73 g) was dissolved in anhydrous ethyl ether (30 ml) and cooled to 1 78 ° C. Tert-butyllithium (1 7. 2 mol, 1 0.7 ml, 1.6 N pentane solution) was added slowly. After stirring at the same temperature for 1 hour, paraformaldehyde (1 8.9 mraol, 570 mg) was added and the mixture was warmed to 0 ° C. for 30 minutes at the same temperature and stirred for 1 hour. An aqueous solution of salthyanmonium was added to stop the reaction, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with a small amount of ethyl acetate and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product obtained by concentration under reduced pressure was purified by column chromatography (silica gel, hexane-ethyl acetate 9: 1 to 4: 1) to give compound d (1. 635 g) as a colorless oily substance.
Physicochemical properties of compound d
Molecular weight 454
FAB-MS (positive mode, matrix m-NBA) 455 (M + H + )
^ – NMR (chemical shift value in heavy chloroform) δ:
J = 6 Hz), 3.03 (1 H, t, J = 6 Hz), 3.47 – 3.58 (2 H, m), 3.75 – 3.92 (2 H, (3 H, m), 4.08 – 4.26 (4 H, m), 4.68 (1 H, t, 3 Hz),
5.53 (1 H, t, J = 7 Hz) 7.35 – 7.47 (6 H, m), 7.64 – 7.68 (4 H, m)
1 -4 (Step 1 – 4)
An anhydrous N, N-dimethylformamide solution (2 ml) of the compound d (34 mg, 0. 76 mmol) and imidazole (71 mg, 1.14 mmol) was cooled to 0 ° C and tert- Chlorosilane (0: 2 ml, 0. 76 mmol) was capped and stirred for 2 hours. An ammonium chloride aqueous solution was added to stop the reaction, and the mixture was extracted with hexane. The organic layer was washed with water twice, followed by saturated brine and dried over anhydrous sodium sulfate. And concentrated under reduced pressure to obtain crude compound e (554 mg) as a colorless oily substance.
Physicochemical properties of compound e
FAB-MS (positive mode, matrix m-NBA) 715 (M + Na + )
Chemical shift value of ‘1 H-NMR (in heavy mouth formium) δ:
(4H, m), 1.00 J = 7 Hz), 5.43 (1 H, t, J = 7 Hz), 7.29 – 7.48 (12 H, m), 4.00 – 4.09 (1 H, m), 4.14 , 7.57 – 7.78 (8 H, m)
1-5 (Step 1- 5)
f
Pyridinium paratoluenesulfonic acid (9 O mg, 0.36 mmol) was added to an ethanol solution (6 ml) of the compound e (1. 16 g, 1. 67 mmol), and the mixture was stirred at 60 ° C. for 3.5 hours. After cooling the solution to room temperature, a saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate 20: 1) to give compound f (825 mg, 81%) as a colorless oily substance.
Physicochemical properties of compound f
Molecular weight 608
FAB-MS (positive mode, matrix m-NBA) 631 (M + Na + )
^ – NMR (chemical shift value in heavy chloroform) δ:
(2H, t, J = 7 Hz), 3.75 (2H, t, J = 7 Hz), 3.90 (2H, t, J = 7 Hz), 1.01 (9H, s), 1.01 , 7.59-7.47 (12 H m), 7.57-7.75 (8 H, m), 4.14 (2 H, s), 5 47 (1 H, t, J =
1-6 (Step 1-6)
9
The round bottom flask containing the rotor was heated and dried under reduced pressure and then purged with nitrogen, and anhydrous
Dichloromethane (60 ml) was added and cooled to _20 ° C. Titanium tetraisopropoxide (2.3 3 ml, 7.8 8 mmol), L 1 (+) – Jetyl tartrate (1.6 2 ml, 9. 4 6 min. 0 1) was added successively, and after stirring for 15 minutes, compound f (4.80 g, 7. 88 mmol) in dichloromethane (30 ml), and the mixture was stirred for 15 minutes. Cool to _ 25 ° C and add tert-butyl hydroperoxide (5. 25 ml,
15. 8 mmol, 3 N dichloromethane solution) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at 20 ° C. for 2 hours, dimethylsulfide (1.1 ml) was added, and the mixture was further stirred at the same temperature for 1 hour. A 10% aqueous solution of tartaric acid was added to the reaction solution and the mixture was stirred for 30 minutes, and then stirred at room temperature for 1 hour. The organic layer was separated, the aqueous layer was extracted with a small amount of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained was concentrated under reduced pressure, and purified by force RAM chromatography (silica gel, hexane / monoacetic acid ethyl 9: 1). Compound g (4. 78 g, 97%) was obtained as a colorless oily substance. The asymmetric yield (> 95% ee) was determined by NMR analysis of the corresponding MT PA ester.
Physicochemical properties of compound g
Molecular weight 624
F AB-MS (positive mode, matrix m-NBA) 647 (M + Na + )
– Chemical shift value of NMR (in heavy chloroform) δ:
J = 14, 7 Hz), 2.23 (1 H, dt, J = 14, 1 H), 1.02 (9 H, s), 1.03 (9 H, s), 1.72 (6H, m), 7.32-7.45 (12H, m), 7.60- 7.65 (8H, m), 6.5 Hz), 3.17 (1H, dd, J = 6, 5 Hz), 3.55-3.79
1 – 7 (Step 1 – 7)
To a solution (100 ml) of the compound α (10. 45 g, 37.2 mmol) produced in the step 2-3 of Production Example 1 described below in an anhydrous tetrahydrofuran solution (100 ml) under a nitrogen atmosphere was added biscyclopentadienylzirconium hydride chloride (10. lg, 37.2 mol) was added at room temperature and stirred for 30 minutes. The resulting solution was cooled to 1780C and methyl magnesium chloride (24.7 ml, 74 mmol, 3 N tetrahydrofuran
Furan solution), and the mixture was stirred for 5 minutes. Monovalent copper iodide (500 mg, 7.2 mM) was added to this solution and the temperature was gradually raised to _ 30 ° C. An anhydrous tetrahydrofuran solution (70 ml) of the compound g (4. 49 g) was added over 20 minutes, and after completion of the dropwise addition, the mixture was stirred at 25 ° C. overnight. The saturated ammonium chloride aqueous solution was slowly added, the reaction was stopped, and the temperature was gradually raised to room temperature. The mixture was stirred at room temperature for 10 hours and the resulting white solid was filtered off through celite. The celite was washed thoroughly with ethyl acetate and the organic layer was separated. The aqueous layer was extracted with a small amount of ethyl acetate and the combined organic layer was washed with saturated aqueous ammonium chloride solution and then dried over anhydrous sodium sulfate. Concentrated under reduced pressure and the obtained crude product was purified by column chromatography (silica gel, hexyl acetate
20: 1 to 9: 1) to give compound h (5. 96 g, 91%) as a pale yellow oily substance.
Physicochemical properties of compound h
Molecular weight 907
F AB – MS (negative mode, matrix πι – Α Β A) 906 (Μ – Η + )
Chemical shift value of 1 H-NMR (in heavy chloroform) δ:
0.88 (3H, t, 
0.99 (9H, s), 1.04 (9H, s), 1.18-1.63 (22H, m), 1.78-2.01 (4H, m), 2.44-2.57 (1H, m), 3.00 (1H, t, J = 6 Hz), 3.59-3.92 (10H, m), 4.28 (1H, s), 5.37-5.55 (2H, m), 7.29-7.65 (20H, m)
1-8 (Step 1-8)
Compound h (5.30 g, 5.84 dragon ol) was dissolved in dichloromethane (200 ml) and 2, 2-dimethoxypropane (150 ml), pyridinium paratoluenesulfonic acid (15 mg, 0.058 mmol) was added , And the mixture was stirred at room temperature overnight. The reaction was quenched by adding saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane-ethyl acetate 20: 1). Compound i (4. 69 g, 86%) was obtained as a pale yellow oily substance.
Physicochemical properties of Compound i
Molecular weight 947
F AB-MS (negative mode, matrix m-NBA) 946 (M – H + )
Chemical shift value of 1 H – NMR (in heavy mouth formium) δ:
(1 H, m), 0.88 (3H, t, J = 6 Hz), 1.02 (9H, s), 1.05 (9H, s), 1.14-1.63 (28H, m), 1. 2.16 (2H, m), 7.28 – 7.47 (12H, m), 7.61 – 7.69 (1H, d, J = 10 Hz), 3.64-3.86 (6H, m 3.92 (s, 4H), 5.36-5.42 8 H, m) 1 – 9 (Step 1 – 9)
A tetrahydrofuran solution (50 ml) of the compound i (4. 39 g, 4. 64 mmol) was cooled to 0 ° C., tetrabutylammonium fluoride (10. 2 ml, 10, 2 difficulty, 1 M tetrahydrofuran solution) and Acetic acid (0. 53 ml, 9. 27 mmol) was added. The temperature was gradually raised to room temperature and stirred for 2 days. A saturated ammonium chloride aqueous solution was added and the mixture was extracted twice with dichloromethane. The combined organic layer was washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, hexane-ethyl acetate 9: 1 to 3: 2) to obtain the compound〗 (1. 73 g, 81%) Was obtained as a pale yellow oily substance.
Physicochemical properties of compound j
Molecular weight 470
F AB-MS (positive mode, matrix m-NBA) 493 (M + Na + )
Chemical shift value of X H-NMR (in heavy chloroform) δ:
2.73 (1H, dt, J = 6, 10 Hz), 2.95 (3H, t, J = 6 Hz), 1.17-1.73 (26H, m), 1.91-2.16 (4H, m), 2.4 J = 15, 7 Hz (1 H, dt, J = 15 Hz), 3.48 (1 H, d, J = 1 Hz), 3.63-4.01 (m, 10 H), 5.15 )
1-10 (Step 1- 10)
Under an atmosphere of nitrogen, a solution of oxalyl chloride (0. 575 ml, 6. 6 mol) in anhydrous dichloromethane (17 ml) was cooled to 178 ° C. and dimethyl sulfoxide
(0. 9 36 ml, 1 3 2 minol) in dichloromethane (1 ml) was added dropwise and the mixture was stirred for 15 minutes. Dichloromethane solution (5 ml) of compound j (388 mg, 0. 824 aura) was slowly added dropwise. The mixture was stirred at the same temperature for 1 hour, then terethylamine (3 ml, 21.4fflmol) was added and the mixture was stirred for 30 minutes. The cooling bath was removed and a low-boiling compound was removed by blowing a nitrogen gas stream to the solution, followed by drying under reduced pressure. Jether ether (15 ml) was added to the residue, and insoluble matter was filtered off and concentrated. After this operation was carried out twice, the obtained residue was immediately used for the next reaction.
The crude dialdehyde was dissolved in 2-methyl-2-propanol (24 ml) and 2-methyl-2-butene (6 ml) and cooled to about 5 to 7 ° C. To this solution was added sodium chlorite (745 mg, 8. 24 mmol) and sodium dihydrogenphosphate
(745 mg, 6. 2 l mmol) in water (7. 45 ml) was slowly added dropwise. After 2 hours the mixture was cooled to 0 ° C. and aqueous sodium hydrogenphosphate solution was added to adjust PH to approximately 5. The mixture was extracted three times with dichloromethane, and the combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure afforded a pale yellow oily residue which was immediately used for the next reaction without further purification.
The crude dicarboxylic acid was dissolved in N, N-dimethylformamide di tert-butylacetal (4. 5 ml) and stirred at 70 ° C. for 1 hour. The low boiling point compound was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate 20: 1) to give compound k (340 mg, 60%) as a pale yellow oily substance.
Physicochemical properties of compound k
Molecular weight 6 10
FAB-MS (positive mode, matrix m-NBA) (M + H + ) 611, (M + Na + ) 633
^ – NMR (chemical shift value in heavy chloroform) δ:
(2H, ABq, J = 15, 18 Hz), 2.93 (1 H, q, J = 6 Hz), 1.18 J = 7 Hz), 3.82-3.88 (2H, m), 3.92 (4H, s), 5.51-5.69 (2H, m)
1- 11 (Step 1 – 1 1)
Compound k (34 mg, 0. 556 mmol) was dissolved in tetrahydrofuran (1 ml), 80% acetic acid aqueous solution (10 ml) was added, and the mixture was stirred at room temperature for 3.5 hours. The mixture was slowly added into a saturated aqueous solution of sodium bicarbonate to neutralize acetic acid and then extracted twice with ethyl acetate. Drying over anhydrous sodium sulfate, followed by filtration and concentration under reduced pressure to give compound t
(290 mg, 99%) as a pale yellow oil.
Physicochemical properties of compound f
Molecular weight 526
FAB – MS (positive mode, matrix m – NBA) (M + H + ) 527,
(M + Na + ) 549
Chemical shift value of iH-NMR (in heavy chloroform) δ:
(2H, Q 
, 2.25-2.41 (5H, m), 1.99 (1H, d, J = 7 Hz), 2.04 (1H, d (1H, t, 7 Hz), 1.18- 1.68 (36H, ra), 2.01 J = 7 Hz), 5.58 (1 H, dt, J = 16, 6 Hz), 3.62 (3H, m), 3.99 (1H, s), 5.42
1-12 (Step 1 – 12)
Acetone (45 ml) was cooled to 0 ° C. and Jyones reagent (0.48 ml, 0.9 mmol, 1.8 9 N) was added. An acetone solution (3 ml) of the compound (216 mg, 0, 41) was slowly added dropwise to this mixture. Stirring at the same temperature for 1 hour
After stirring, the reaction was stopped by adding an aqueous sodium bisulfite solution until the yellow color of the reaction disappeared and a dark green precipitate appeared. A saturated saline solution (20 ml) was added thereto, and the mixture was extracted twice with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane monomethanol 50: 1 to 20: 1) to give compound m (198 mg, 89%) as a pale yellow oily substance.
Physicochemical properties of compound m
Molecular weight 541
ESI (L CZMS positive mode) (M + H + ) 542
Chemical shift value of 1 H – NMR (in heavy mouth formium) δ:
J = 8 Hz), 2.70 (1 H, t, J = 6 Hz), 1.16 – 1.67 (36 H, m), 1.99 (2 H, J = 15, 5 Hz), 2.68 (1 H, d, J = 9 Hz), 3.28 )
1 – 13 (Step 1 – 13)
A solution of the compound m (6. 4 mg, 0.12 mmol), a solution of (S) -4- (2-butynyloxy) phenylalanine t-butyl ester hydrochloride (4.6 mg, 0.114 mmol) in N, N-dimethylformamide lml) was cooled to 110 ° C and N, N-diisopropylethylamine (0 ° 5 ml, 0.026 mmol), O- (7-azobenzotriazole 1- 1, N, N, N ‘, N’ – tetramethyluronium hexafluorophosphate (7.0 mg, 0.17 mmol) was added sequentially. The temperature was raised to room temperature with stirring and stirred overnight. An aqueous ammonium chloride solution was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and then with saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by thin layer silica gel thin layer chromatography (hexane / ethyl acetate 7: 3) to obtain compound n
(8. 4 mg, 88%) as a colorless solid.
Physicochemical properties of compound n
^ – NMR (chemical shift value in heavy chloroform) δ:
J = 1.9 Hz), 1.90-2.03 (2H, m), 2.29 – 2.43 (4H, t, J = 6.9 Hz), 1 .12-1.68 (45H, m), 1.85 (3H, m), 4.22 (1 H, s), 4.57 – 4.74 (3H, d, J = 16.5 Hz) J = 8.6 Hz), 7.01 (1 H, d, J = 8.6 Hz), 5.46 (1 H, dd J = 9.2, 15.2 Hz), 5.64 (1 H, dt, J = 6.6, 15.2 Hz) 7.9 Hz), 7.13 (2H, d, J – 8.6 Hz)
1-14 (Step 1 – 14)
Dichloromethane solution (3 ml) of compound n (8.4 mg) was cooled to 0 ° C and anisanol (0.01 ml) and trifluoroacetic acid (1 ml) were sequentially added. Slowly warmed to room temperature and stirred overnight. After concentrating the reaction solution under reduced pressure and azeotropically twice with benzene, the residue was purified with megabond-1-butanediol (500 mg, Parian) (dichloromethane-methanol = 20: 1) to obtain Compound 21 (5. 3 mg, 80% As a colorless solid.
Physicochemical properties of compound 21 ‘
Molecular weight 643
ESI (LC / MS positive mode) 644 (M + H +)
Chemical shift value of 1 H – NMR (in methanol d – 4) δ:
0.90 (3 H, t, J = 7 Hz), 1.19 – 1.38 (1 m), 1.42 – 1.60 (cm), 1.82 (3 H, t,
J = 2 Hz), 2.8 – 2.98 (2 H, m), 3.09 – 3.23 (2 H, m), 2.8 (2H, d, J = 9 Hz) 7 7.13 (2H, d, J = 9 Hz), 4.53 – 4.67 (3H, m), 5.39-5.61 (2H, m), 6.83
References
Discovery of NA808: A novel host targeting anti-HCV agent
237th Am Chem Soc (ACS) Natl Meet (March 22-26, Salt Lake City) 2009, Abst MEDI 14
///////////////CH4630808, CH 4630808, NA 808
CCCCCCCC(=O)CCCCCCC=CC(C(=O)NC(CC1=CC=C(C=C1)O)C(=O)O)C(CC(=O)O)(C(=O)O)O
TITLE COMPD
O=C(O)[C@](O)(CC(=O)O)[C@H](\C=C\CCCCCCC(=O)CCCCCCC)C(=O)N[C@@H](Cc1ccc(OCC#CC)cc1)C(=O)O
CAS 6217-54-5
WeightAverage: 328.4883
Chemical FormulaC22H32O2
4,7,10,13,16,19-Docosahexaenoic acid, (4Z,7Z,10Z,13Z,16Z,19Z)-
| Doconexent sodium | 295P7EPT4C | 81926-93-4 | |
A mixture of fish oil and primrose oil, doconexent is used as a high-docosahexaenoic acid (DHA) supplement. DHA is a 22 carbon chain with 6 cis double bonds with anti-inflammatory effects. It can be biosythesized from alpha-linolenic acid or commercially manufactured from microalgae. It is an omega-3 fatty acid and primary structural component of the human brain, cerebral cortex, skin, and retina thus plays an important role in their development and function. The amino-phospholipid DHA is found at a high concentration across several brain subcellular fractions, including nerve terminals, microsomes, synaptic vesicles, and synaptosomal plasma membranes
Synthesis , By Farmer, Ernest H.; Van den Heuvel, Frantz A., From Journal of the Chemical Society (1938), 427-30.
ALSO
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk (breast milk), fish oil, or algae oil.[1]
DHA’s structure is a carboxylic acid (-oic acid) with a 22-carbon chain (docosa- derives from the Ancient Greek for 22) and six (hexa-) cis double bonds (-en-);[2] with the first double bond located at the third carbon from the omega end.[3] Its trivial name is cervonic acid, its systematic name is all-cis-docosa-4,7,10,13,16,19-hexa-enoic acid, and its shorthand name is 22:6(n−3) in the nomenclature of fatty acids.
Most of the DHA in fish and multi-cellular organisms with access to cold-water oceanic foods originates from photosynthetic and heterotrophic microalgae, and becomes increasingly concentrated in organisms the further they are up the food chain. DHA is also commercially manufactured from microalgae: Crypthecodinium cohnii and another of the genus Schizochytrium.[4] DHA manufactured using microalgae is vegetarian.[5]
In strict herbivores, DHA is manufactured internally from α-linolenic acid, a shorter omega-3 fatty acid manufactured by plants (and also occurring in animal products as obtained from plants), while omnivores and carnivores primarily obtain DHA from their diet.[6] Limited amounts of eicosapentaenoic and docosapentaenoic acids are possible products of α-linolenic acid metabolism in young women[7] and men.[6] DHA in breast milk is important for the developing infant.[8] Rates of DHA production in women are 15% higher than in men.[9]
DHA is a major fatty acid in brain phospholipids and the retina. While the potential roles of DHA in the mechanisms of Alzheimer’s disease are under active research,[10] studies of fish oil supplements, which contain DHA, have failed to support claims of preventing cardiovascular diseases.[11][12][13]
DHA is the most abundant omega-3 fatty acid in the brain and retina. DHA comprises 40% of the polyunsaturated fatty acids (PUFAs) in the brain and 60% of the PUFAs in the retina. Fifty percent of the weight of a neuron‘s plasma membraneis composed of DHA.[14]
DHA modulates the carrier-mediated transport of choline, glycine, and taurine, the function of delayed rectifier potassium channels, and the response of rhodopsin contained in the synaptic vesicles, among many other functions.[15]
DHA deficiency is associated with cognitive decline.[16] Phosphatidylserine (PS) controls apoptosis, and low DHA levels lower neural cell PS and increase neural cell death.[17] DHA levels are reduced in the brain tissue of severely depressed patients.[18][19]
In humans, DHA is either obtained from the diet or may be converted in small amounts from eicosapentaenoic acid (EPA, 20:5, ω-3) via docosapentaenoic acid (DPA, 22:5 ω-3) as an intermediate.[7][6] This synthesis had been thought to occur through an elongation step followed by the action of Δ4-desaturase.[6] It is now considered more likely that DHA is biosynthesized via a C24 intermediate followed by beta oxidation in peroxisomes. Thus, EPA is twice elongated, yielding 24:5 ω-3, then desaturated to 24:6 ω-3, then shortened to DHA (22:6 ω-3) via beta oxidation. This pathway is known as Sprecher’s shunt.[20][21]
In organisms such as microalgae, mosses and fungi, biosynthesis of DHA usually occurs as a series of desaturation and elongation reactions, catalyzed by the sequential action of desaturase and elongase enzymes. A common pathway in these organisms involves:
DHA can be metabolized into DHA-derived specialized pro-resolving mediators (SPMs), DHA epoxides, electrophilic oxo-derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids, among others.[23]
The enzyme CYP2C9 metabolizes DHA to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]).[24]
While one human trial of 402 subjects lasting 18 months concluded that DHA did not slow decline of mental function in elderly people with mild to moderate Alzheimer’s disease,[25] a similar trial of 485 subjects lasting 6 months concluded that algal DHA of 900 mg per day taken decreased heart rate and improved memory and learning in healthy, older adults with mild memory complaints.[26]
In another early-stage study, higher DHA levels in middle-aged adults was related to better performance on tests of nonverbal reasoning and mental flexibility, working memory, and vocabulary.[27]
One study found that the use of DHA-rich fish oil capsules did not reduce postpartum depression in mothers or improve cognitive and language development in their offspring during early childhood.[28] Another systematic review found that DHA had no significant benefits in improving visual field in individuals with retinitis pigmentosa.[29] A 2017 pilot study found that fish oil supplementation reduced the depression symptoms emphasizing the importance of the target DHA levels.[30]
It has been recommended to eat foods which are high in omega-3 fatty acids for women who want to become pregnant or when nursing.[31] A working group from the International Society for the Study of Fatty Acids and Lipids recommended 300 mg/day of DHA for pregnant and lactating women, whereas the average consumption was between 45 mg and 115 mg per day of the women in the study, similar to a Canadian study.[32] Despite these recommendations, recent evidence from a trial of pregnant women randomized to receive supplementation with 800 mg/day of DHA versus placebo, showed that the supplement had no impact on the cognitive abilities of their children at up to seven years follow-up.[33]
In one preliminary study, men who took DHA supplements for 6–12 weeks had lower blood markers of inflammation.[34]
Algae-based DHA supplements
Ordinary types of cooked salmon contain 500–1500 mg DHA and 300–1000 mg EPA per 100 grams.[35] Additional rich seafood sources of DHA include caviar (3400 mg per 100 grams), anchovies (1292 mg per 100 grams), mackerel (1195 mg per 100 grams), and cooked herring(1105 mg per 100 grams).[35] Brains from mammals are also a good direct source, with beef brain, for example, containing approximately 855 mg of DHA per 100 grams in a serving.[36]
In the early 1980s, NASA sponsored scientific research on a plant-based food source that could generate oxygen and nutrition on long-duration space flights. Certain species of marine algae produced rich nutrients, leading to the development of an algae-based, vegetable-like oil that contains two polyunsaturated fatty acids, DHA and arachidonic acid,[37] present in some health supplements.
DHA is widely used as a food supplement. It was first used primarily in infant formulas.[38] In 2004, the US Food and Drug Administration endorsed qualified health claims for DHA.[39]
Some manufactured DHA is a vegetarian product extracted from algae, and it competes on the market with fish oil that contains DHA and other omega-3s such as EPA. Both fish oil and DHA are odorless and tasteless after processing as a food additive.[40]
Vegetarian diets typically contain limited amounts of DHA, and vegan diets typically contain no DHA.[41] In preliminary research, algae-based supplements increased DHA levels.[42]While there is little evidence of adverse health or cognitive effects due to DHA deficiency in adult vegetarians or vegans, breast milk levels remain a concern for supplying adequate DHA to the developing fetus.[41]
Fish oil is widely sold in capsules containing a mixture of omega-3 fatty acids, including EPA and DHA. Oxidized fish oil in supplement capsules may contain lower levels of EPA and DHA.[43][44]
An abundance of DHA in seafood has been suggested as being helpful in the development of a large brain,[45] though other researchers claim a terrestrial diet could also have provided the necessary DHA.[46]
Patent
CN 106190872
https://patents.google.com/patent/CN106190872A/zh
PATENT
WO 2017038860
https://patents.google.com/patent/WO2017038860A1/en
[Example 1]
The raw EPA ethyl ester 1 of Comparative Example 1 containing EPA 96.7%, except for changing the temperature of the alkaline hydrolysis in 6 ° C., in the same manner as in Comparative Example 1 was alkaline hydrolysis.
That is, the starting EPA ethyl ester 1 2.50 g, ethanol 6.25 mL (4.92 g, 14.11 equivalents relative fatty acid), water 1.00 mL, 48 wt% sodium hydroxide aqueous solution 0.76 g ( 1.20 equivalents of base) was added a sample solution 3 was prepared against fatty acids. In sample liquid 3, moisture 1.40 g, i.e., was 10.27 equivalents relative fatty acid. The sample liquid 3, stirred for 24 hours 6 ° C., was subjected to hydrolysis treatment. Confirmed the completion of the reaction of the hydrolysis treatment, returned to the sample liquid 3 after treatment at room temperature, after transferred to a separatory funnel, and hexane was added 3.13 mL, purified water 2.50mL the sample liquid 3. When further adding 2.25g of hydrochloric acid, the sample solution 3 was separated into two layers of hexane and aqueous layers. The pH of the aqueous layer was 1.0.
The sample liquid 3 was stirred, then the mixture was allowed to stand, after removing the aqueous layer from the sample liquid 3, was further stirred with purified water 3.75mL the sample liquid 3 after removal. Hydrochloric acid was added small amount to adjust the pH of the aqueous layer to 1.0. Thereafter, the aluminum plate was washed with the same amount of purified water as rinsing liquid. Rinsing liquid is recovered after washing with water was repeatedly washed with water until neutral pH 6.0 ~ 7.0. The hexane layer was recovered from the sample liquid 3 after washing with water, the recovered hexane layer, the hexane was removed with an evaporator and vacuum, the EPA3 a composition containing free EPA was obtained 2.14 g.
Against EPA3, it was evaluated in the same manner as EPA1. The results are shown in Table 1 and Table 4.
The recovery was 93.8%. The resulting Gardner color of EPA3 is 2-, AnV 1.3, ethyl ester (EE) content 2790Ppm, conjugated diene acid content was 0.47%. Conjugated unsaturated fatty acids other than the conjugated diene acid was not detected. These physical property values are shown in Table 1. Note that the conjugated unsaturated fatty acids, only the conjugated diene acid shown in Table 1.
PATENT
WO-2018120574
Process for production of docosahexaenoic acid (DHA), by microbial fermentation of Schizochytrium limacinum . Discloses use of DHA for treating cardiovascular diseases, infertility or neurological diseases. See CN106635405 , claiming method for separating DHA from powder DHA grease by supercritical extraction method. Kingdomway lists that it produces DHA by microorganism fermentation.
The current commercial sources of DHA are mainly fish oil and microalgae. DHA extracted from traditional deep-sea fish oil is unstable due to the variety, season and geographical location of fish, and the content of cholesterol and other unsaturated fatty acids is high. The difference in length and degree of unsaturation of fatty acid chains is large, resulting in limited production and content of DHA. It is not high, it is difficult to separate and purify, and the cost is high. With the growing shortage of fish oil raw materials, it is difficult to achieve the widespread use of DHA, a high value-added product in the food and pharmaceutical industries. The production of DHA by microbial fermentation can overcome the defects of traditional fish oil extraction, can be used for mass production of DHA, continuously meet people’s needs, has broad application prospects, and has attracted the attention of scholars at home and abroad. The microbial fermentation method uses fermented microorganisms such as fungi and microalgae to produce DHA-containing algal oil, and refined to obtain essential oil with high DHA content. DHA-producing strains approved by the Ministry of Health include Schizochytrium sp., Ulkenia amoeboida, and Crypthecodinium cohnii.
The market share of DHA produced by microbial fermentation is increasing rapidly year by year. There is a trend to replace DHA of fish oil, improve the production technology and quality of microalgae DHA, and the prospect of entering the microalgae DHA market is broad.
The publication No. CN103882072A discloses a method for producing docosahexaenoic acid by using Schizochytrium, and the highest yield disclosed is a cell dry weight of 61.2 g/L, a DHA content of 55.07%, and a DHA yield of 22.17 g. /L. The publication No. CN101812484A discloses a method for fermenting DHA by high-density culture of Schizochytrium, which discloses a dry cell weight of 120-150 g/L and a DHA yield of 26-30 g/L, which is also reported. The highest production level of DHA produced by Schizochytrium sp. Although the DHA productivity has been greatly improved compared with the previous research, the industrial production of docosahexaenoic acid by using microalgae greatly reduces the production cost, increases the unit yield, and enables the method of microbial fermentation to produce DHA. Promotion and popularization are still far from enough.
There are three main methods for extracting DHA from the fermentation liquid of Schizochytrium, one is centrifugation, the other is organic solvent extraction, and the third is supercritical extraction. Centrifugation, such as the publication No. CN101817738B, discloses a method for extracting DHA from algae and fungal cells by separating the microalgae or fungal fermentation broth after fermentation by a separation system, and adjusting the pH of the sludge with an acid. 2.0-4.0, then control the temperature of the slime at 10 °C-20 °C, add anti-oxidant in the slime, and then carry out high-pressure homogenization and breaking through the high-pressure homogenizer; add the broken mud to the water, stir and feed The liquid was separated by a three-phase separator to obtain DHA grease. The invention adopts physical wall breaking and physical extraction methods, has simple process, high cell breakage, low temperature treatment of bacteria sludge and antioxidant treatment, can effectively protect the biological activity of algae and fungal cells, and the product is green and non-toxic. Residue. However, the quality of the oil layer after centrifugation of the invention is poor. In addition to the oil, it also contains impurities such as water, medium components and cell debris, which is not conducive to subsequent refining. In addition, the wastewater layer after centrifugation contains a large amount of slag and has a high COD. Difficult to handle or process is extremely costly. The organic solvent extraction method, such as the publication No. CN101824363B, discloses a method for extracting docosahexaenoic acid oil: the fermentation liquid containing docosahexaenoic acid is subjected to enzymatic breaking, and then an organic solvent is used first. The first stage water is divided, the cells are enriched, and the organic solvent is used for secondary extraction to obtain a crude oil. The method is simple in operation and low in equipment investment, but the method uses organic solvent for extraction, and the final product may have solvent residue, and the extraction process has safety hazards such as flammability and explosion. The supercritical extraction method, as disclosed in the publication No. CN102181320B, discloses a method for extracting bio-fermented DHA algae oil, comprising the following steps: a) drying the solid matter obtained by solid-liquid separation of the microalgae fermentation liquid to obtain a dried bacterial cell; b) extracting the dried cells with supercritical carbon dioxide as an extractant to obtain a carbon dioxide fluid; c) separating the carbon dioxide fluid under reduced pressure to obtain DHA algae oil. Experiments show that the DHA content of DHA algae oil obtained by the method provided by the invention is more than 40%, the extraction yield is only 85.23%, and the need to add ethanol as the extracting agent has certain safety risks and supercritical. The equipment is expensive and the extraction yield is not high.
In the prior art, the refining of DHA hair oil is mostly carried out by chemical refining technology, and the DHA hair oil is degummed, alkali refining, decolorized and deodorized to obtain DHA essential oil. Inevitably, there are some problems in the process technology. For example, in order to achieve the requirement of controlling low acid value, alkali refining usually adds excessive alkali, and some triglycerides are inevitably saponified; high COD wastewater produced by alkali refining will pollute the environment; Alkali refining requires high temperature treatment for a long time, which is easy to cause the product’s peroxide value and anisidine value to increase; the deodorization temperature is high, and the long time is easy to produce trans fatty acids.
PATENT
CN106635405
https://patents.google.com/patent/CN106635405A/zh
PATENT
WO2012153345
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012153345
PAPER
NMR
Organic Chemistry 2014 vol. 2014 21 pg. 4548 – 4561
Patent
WO 2015162265
| 1 H NMR (500 MHz; CDCI3) δΗ 5.43-5.30 (m, 12H, CH=CH), 2.85-2.80 (m, 10H, CH2 bis-allylic), 2.42-2.40 (m, 4H, CH2-C=0, CH2 allylic), 2.07 (quint, J = 7.5 Hz, 2H, CH2 allylic), 0.98 (t, J = 7.5 Hz, 3H, CH3) |
REFERENCE
 |
|||
|
|||
| Names | |||
|---|---|---|---|
| IUPAC name
(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid
|
|||
| Other names | |||
| Identifiers | |||
|
3D model (JSmol)
|
|||
| ChEBI | |||
| ChEMBL | |||
| ChemSpider | |||
| ECHA InfoCard | 100.118.398 | ||
|
PubChem CID
|
|||
| UNII | |||
| Properties | |||
| C22H32O2 | |||
| Molar mass | 328.488 g/mol | ||
| Density | 0.943 g/cm3 | ||
| Melting point | −44 °C (−47 °F; 229 K) | ||
| Boiling point | 446.7 °C (836.1 °F; 719.8 K) | ||
|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|
|||
///////////Docosahexaenoic acid (22:6(n-3)), ZAD9OKH9JC, доконексен, دوكونيكسانت , 二十二碳六烯酸 , Doconexent, 6217-54-5, cervonic acid, DHA, doconexent, 81926-93-4
CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O
|
6
|
MW: 644.9746 |
|
7
|
MW: 328.4928 |
|
8
|
MW: 328.4928 |
|
9
|
MW: 909.3808 |
|
MW: 328.493 |
|
|
2
|
MW: 328.4928 |
|
3
|
MW: 328.493 |
|
4
|
MW: 350.4749 |
|
5
|
MW: 328.493 |
| Molecular Formula: | C10H20CaN2O8S2 |
|---|---|
| Molecular Weight: | 400.474 g/mol |
3-acetamidopropane-1-sulfonic acid
| INGREDIENT | UNII | CAS | fre form
Cas 77337-76-9 181.21 C5H11NO4S |
|---|---|---|---|
| Acamprosate Calcium | 59375N1D0U | 77337-73-6 |
Acamprosate, sold under the brand name Campral, is a medication used along with counselling to treat alcohol dependence.[1][2]
Acamprosate, also known by the brand name Campral, is a drug used for treating alcohol dependence. Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutaminergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated. Reports indicate that acamprosate only works with a combination of attending support groups and abstinence from alcohol. Certain serious side effects include allergic reactions, irregular heartbeats, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence. Acamprosate should not be taken by people with kidney problems or allergies to the drug.
Acamprosate is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal.[3] When used alone, acamprosate is not an effective therapy for alcoholism in most individuals;[4] however, studies have found that acamprosate works best when used in combination with psychosocial support since it facilitates a reduction in alcohol consumption as well as full abstinence.[2][5][6]
Serious side effects include allergic reactions, abnormal heart rhythms, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence.[7] Diarrhea is the most common side-effect.[8] Acamprosate should not be taken by people with kidney problems or allergies to the drug.[9]
Until it became a generic in the United States, Campral was manufactured and marketed in the United States by Forest Laboratories, while Merck KGaA markets it outside the US.
Medical uses
Acamprosate is useful when used along with counselling in the treatment of alcohol dependence.[2] Over three to twelve months it increases the number of people who do not drink at all and the number of days without alcohol.[2] It appears to work as well as naltrexone.[2]
Acamprosate is primarily removed by the kidneys and should not be given to people with severely impaired kidneys (creatinine clearance less than 30 mL/min). A dose reduction is suggested in those with moderately impaired kidneys (creatinine clearancebetween 30 mL/min and 50 mL/min).[1][10] It is also contraindicated in those who have a strong allergic reaction to acamprosate calcium or any of its components.[10]
The US label carries warnings about increased of suicidal behavior, major depressive disorder, and kidney failure.[1]
Adverse effects that caused people to stop taking the drug in clinical trials included diarrhea, nausea, depression, and anxiety.[1]
Other frequent adverse effects include headache, stomach pain, back pain, muscle pain, joint pain, chest pain, infections, flu-like symptoms, chills, heart palpitations, high blood pressure, fainting, vomiting, upset stomach, constipation, increased appetite, weight gain, edema, sleepiness, decreased sex drive, impotence, forgetfulness, abnormal thinking, abnormal vision, distorted sense of taste, tremors, runny nose, coughing, difficulty breathing, sore throat, bronchitis, and rashes.[1]
Acamprosate calcium
The pharmacodynamics of acamprosate is complex and not fully understood;[11][12][13] however, it is believed to act as an NMDA receptor antagonist and positive allosteric modulator of GABAA receptors.[12][13]
Ethanol and benzodiazepines act on the central nervous system by binding to the GABAA receptor, increasing the effects of the inhibitory neurotransmitter GABA (i.e., they act as positive allosteric modulators at these receptors).[12][4] In chronic alcohol abuse, one of the main mechanisms of tolerance is attributed to GABAA receptors becoming downregulated (i.e. these receptors become less sensitive to GABA).[4] When alcohol is no longer consumed, these down-regulated GABAA receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect, leading to physical withdrawal symptoms;[4] since GABA normally inhibits neural firing, GABAA receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer inhibitory postsynaptic potentialsoccur through GABAA receptors), leading to neuronal over-excitation (i.e., more action potentials in the postsynaptic neuron). One of acamprosate’s mechanisms of action is the enhancement of GABA signaling at GABAA receptors via positive allosteric receptor modulation.[12][13] It has been purported to open the chloride ion channel in a novel way as it does not require GABA as a cofactor, making it less liable for dependence than benzodiazepines. Acamprosate has been successfully used to control tinnitus, hyperacusis, ear pain and inner ear pressure during alcohol use due to spasms of the tensor tympani muscle.[medical citation needed]
In addition, alcohol also inhibits the activity of N-methyl-D-aspartate receptors (NMDARs).[14][15] Chronic alcohol consumption leads to the overproduction (upregulation) of these receptors. Thereafter, sudden alcohol abstinence causes the excessive numbers of NMDARs to be more active than normal and to contribute to the symptoms of delirium tremensand excitotoxic neuronal death.[16] Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs.[17] Acamprosate reduces this glutamate surge.[18] The drug also protects cultured cells from excitotoxicity induced by ethanol withdrawal[19] and from glutamate exposure combined with ethanol withdrawal.[20]
Acamprosate was developed by Lipha, a subsidiary of Merck KGaA.[21] and was approved for marketing in Europe in 1989.[citation needed]
In October 2001 Forest Laboratories acquired the rights to market the drug in the US.[21][22]
It was approved by the FDA in July 2004.[23]
The first generic versions of acamprosate were launched in the US in 2013.[24]
As of 2015 acamprosate was in development by Confluence Pharmaceuticals as a potential treatment for fragile X syndrome. The drug was granted orphan status for this use by the FDA in 2013 and by the EMA in 2014.[25]
“Acamprosate” is the INN and BAN for this substance. “Acamprosate calcium” is the USAN and JAN. It is also technically known as N-acetylhomotaurine or as calcium acetylhomotaurinate.
It is sold under the brand name Campral.[1]
In addition to its apparent ability to help patients refrain from drinking, some evidence suggests that acamprosate is neuroprotective (that is, it protects neurons from damage and death caused by the effects of alcohol withdrawal, and possibly other causes of neurotoxicity).[18][26]
It has been hypothesized that long-term ethanol exposure alters the expression or activity of specific GABAA receptor subunits in discrete brain regions. Regardless of the underlying mechanism, ethanol-induced decreases in GABAA receptor sensitivity are believed to contribute to ethanol tolerance, and also may mediate some aspects of physical dependence on ethanol. … Detoxification from ethanol typically involves the administration of benzodiazepines such as chlordiazepoxide, which exhibit cross-dependence with ethanol at GABAA receptors (Chapters 5 and 15). A dose that will prevent the physical symptoms associated with withdrawal from ethanol, including tachycardia, hypertension, tremor, agitation, and seizures, is given and is slowly tapered. Benzodiazepines are used because they are less reinforcing than ethanol among alcoholics. Moreover, the tapered use of a benzodiazepine with a long half-life makes the emergence of withdrawal symptoms less likely than direct withdrawal from ethanol. … Unfortunately, acamprosate is not adequately effective for most alcoholics.
Due to the complex nature of this drug’s MMOA, and a paucity of well defined target affinity data, we do not map to a primary drug target in this instance.
Acamprosate is a NMDA glutamate receptor antagonist and a positive allosteric modulator of GABAA receptors.
Marketed formulations contain acamprosate calcium
Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutaminergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated. … The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely understood. Chronic alcohol exposure is hypothesized to alter the normal balance between neuronal excitation and inhibition. in vitro and in vivostudies in animals have provided evidence to suggest acamprosate may interact with glutamate and GABA neurotransmitter systems centrally, and has led to the hypothesis that acamprosate restores this balance. It seems to inhibit NMDA receptors while activating GABA receptors.
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 3687-18-1 | C3H9NO3S | 3-aminopropane-1-sulfonic acid | 1-Propanesulfonic acid, 3-amino- |
| 156-87-6 | C3H9NO | 3-amino-1-propanol | 1-Propanol, 3-amino- |
| Country | Trade Name | Vendor | Annotation |
|---|---|---|---|
| D | Campral | Merck | |
| F | Aotal | Merck Lipha | |
| GB | Campral EC | Merck Serono | |
| USA | Campral | Forest |
 |
|
 |
|
| Clinical data | |
|---|---|
| Trade names | Campral EC |
| Synonyms | N-Acetyl homotaurine, Acamprosate calcium (JAN JP), Acamprosate calcium (USANUS) |
| Pregnancy category |
|
| Routes of administration |
Oral [1] |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 11%[1] |
| Protein binding | Negligible[1] |
| Metabolism | Nil[1] |
| Elimination half-life | 20 h to 33 h[1] |
| Excretion | Renal[1] |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| ECHA InfoCard | 100.071.495 |
| Chemical and physical data | |
| Formula | C5H11NO4S |
| Molar mass | 181.211 g/mol |
| 3D model (JSmol) | |
| (what is this?) (verify) |
|
////////////////Acamprosate calcium, アカンプロセート
CC(=O)NCCCS(O)(=O)=O
CC(=O)NCCCS(=O)(=O)[O-].CC(=O)NCCCS(=O)(=O)[O-].[Ca+2]
