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DOI: 10.1039/C6GC02396G, http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC02396G?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract
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BRD2879
BRD-K56962879-001-01-5
CAS 1304750-47-7
Chemical Formula: C30H38FN3O5S
Molecular Weight: 571.7084
3-cyclohexyl-1-(((4R,5R)-8-((3-fluorophenyl)ethynyl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-1-methylurea
3-cyclohexyl-1-[[(4R,5R)-8-[2-(3-fluorophenyl)ethynyl]-2-[(2S)-1-hydroxypropan-2-yl]-4-methyl-1,1-dioxo-4,5-dihydro-3H-6,1$l^{6},2-benzoxathiazocin-5-yl]methyl]-1-methylurea
BRD2879 is a potent and cell-active inhibitor of IDH1-R132H with a markedly different structure from previously reported probes with (IC50 = 50 nM for inhibiting IDH1-R132H enzyme). BRD2879 represents a new structural class of mutant IDH1 inhibitors that, with optimization, may prove useful in the study of this enzyme and its role in cancer
The Eli and Edythe L. Broad Institute of MIT and Harvard (/ˈbroʊd/), often referred to as the Broad Institute, is a biomedical and genomic research center located in Cambridge, Massachusetts, United States. The institute is independently governed and supported as a 501(c)(3) nonprofit research organization under the name Broad Institute Inc.,[1][2] and is partners with Massachusetts Institute of Technology, Harvard University, and the five Harvard teaching hospitals.
PAPER
Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC50 = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties.
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1H NMR (300 MHz, CDCl3, 27 °C) δ 7.88 (d, J = 8.3 Hz, 1H), 7.39-7.27 (m, 3H), 7.22-7.14 (m, 2H), 7.12-7.03 (m, 1H), 4.57 (td, J = 9.5, 2.5 Hz, 1H), 4.35-4.23 (m, 2H), 3.97-3.78 (m, 2H), 3.74-3.60 (m, 2H), 3.51 (ddd, J = 12.3, 9.9, 4.0 Hz, 1H), 3.40 (dd, J = 15.8, 5.1 Hz, 1H), 3.18 (dd, J = 9.9, 2.9 Hz, 1H), 3.12 (dd, J = 14.4, 2.6 Hz, 1H), 2.66 (s, 3H), 2.30-2.16 (m, 1H), 2.06 (d, J = 12.2 Hz, 1H), 1.96 (d, J = 12.1 Hz, 1H), 1.69-1.58 (m,1H), 1.58-1.45 (m, 2H), 1.23 (d, J = 6.8 Hz, 3H), 1.40-0.97 (m, 5H), 0.94 (d, J = 7.0 Hz, 3H).
13C NMR (75 MHz, CDCl3, 27 °C) δ 164.20, 160.92, 157.74, 154.80, 134.60, 130.26, 130.15, 129.56, 128.62, 127.82, 127.77, 127.68, 126.90, 124.27, 118.81, 118.50, 116.63, 116.35, 91.32, 88.40, 85.60, 64.86, 58.03, 51.64, 49.88, 48.51, 36.73, 34.51, 34.35, 34.31, 25.72, 25.28, 25.23, 15.76, 15.05.
HRMS (ESI) calc’d for C30H38FN3O5S [M+H]+ : 572.2589. Found: 572.2588.
1H NMR PREDICT
13C NMR PREDICT
Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1
Jason M. Law, Sebastian C. Stark, Ke Liu, Norah E. Liang, Mahmud M. Hussain, Matthias Leiendecker, Daisuke Ito, Oscar Verho, Andrew M. Stern, Stephen E. Johnston, Yan-Ling Zhang, Gavin P. Dunn, Alykhan F. Shamji, and Stuart L. Schreiber
Publication Date (Web): August 18, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.6b00264
FC1=CC(C#CC2=CC(O[C@@H](CN(C(NC3CCCCC3)=O)C)[C@H](C)CN([C@@H](C)CO)S4(=O)=O)=C4C=C2)=CC=C1
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PF 610655, PF-00610355; PF-610,355
PF-610355 (also known as PF-00610355 or PF-610,355) is an inhalable[1] ultra-long-acting β2 adrenoreceptor agonist[2] (ultra-LABA) that was investigated as a treatment of asthma and COPD by Pfizer.[3] It utilizes a sulfonamide agonist headgroup, that confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties minimized systemic exposure following inhalation and reduced systemically-mediated adverse events.[4] Its in vivo duration on action confirmed its potential for once-daily use in humans.[5]
The investigation and development of PF-610355 were discontinued in 2011,[6] likely for strategic and regulatory reasons.[7]
PF-610355). Mp 197−199 °C.
1 H NMR (600 MHz, d6-DMSO) δ 0.89 (s, 3H), 0.91 (s, 3H), 2.54 (s, 2H), 2.59−2.68 (m, 2H), 2.89 (s, 3H), 3.44 (s, 2H), 4.31 (d, 2H), 4.42 (dd, 1H), 6.80−8.83 (m, 3H), 6.97−7.02 (m, 2H), 7.08−7.12 (m, 3H), 7.16 (t, 1H), 7.19 (d, 1H), 7.30 (t, 1H), 7.37−7.41 (m, 4H), and 8.50 (t, 1H).
13C NMR (151 MHz, d6-DMSO) δ 26.39, 26.64, 39.85, 42.22, 42.48, 46.36, 50.15, 52.71, 72.00, 115.14, 115.70, 123.76, 124.02, 124.29, 124.38, 124.76, 125.23, 126.49, 127.57, 127.63, 128.40, 128.71, 130.82, 131.13, 135.38, 135.73, 138.43, 139.94, 140.20, 149.76, 157.11, and 170.28.
HRMS (ESI): calcd (M + H)+ 618.2632, found 618.2641. Found: C, 65.70%; H, 6.33%; N, 6.71%; S, 5.24%. C34H39N3O6S·0.17H2O requires C, 65.78%; H, 6.39%; N, 6.77%; S, 5.16%
PAPER
PF-610355 is a novel inhaled β-2 adrenoreceptor agonist. Process development of the final intermediate and the API are discussed with emphasis on the control of physical properties and subsequent isolations. This includes development of a constant volume distillation and evaluation of Nutsche filtration, agitated filter drying, and centrifugation to prevent particle attrition. The optimized process employed to manufacture 100 kg of the API is described.
PAPER
Optimization of the Manufacturing Route to PF-610355 (1): Synthesis of Intermediate 5
Tertiary carbinamine 5 is an isolated intermediate in the synthesis of a novel, inhaled β-2 adrenoreceptor agonist PF-610355. Process development for the key amide-formation and Ritter reactions, together with reaction understanding studies are discussed in context of the synthesis of 5. The optimized process employed to manufacture 140 kg of 5 is described, and was shown to have superior metrics to the preliminary commercial route.
. PMID 23323609.. PMID 21232045. |
|
| Systematic (IUPAC) name | |
|---|---|
|
N-[(4′-Hydroxy-3-biphenylyl)methyl]-2-[3-(2-{[(2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl]amino}-2-methylpropyl)phenyl]acetamide
|
|
| Clinical data | |
| Routes of administration |
Inhalation |
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | 862541-45-5 |
| ATC code | None |
| PubChem | CID 11505444 |
| ChemSpider | 9680243  |
| UNII | ZH5SMU97AJ |
| ChEMBL | CHEMBL1240967 |
| Chemical data | |
| Formula | C34H39N3O6S |
| Molar mass | 617.76 g·mol−1 |
///////////PF 610355
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Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India
Recent Advances in Drug Development
SOLIFENACIN, YM-905
MF C23H26O2, a molecular weigt 362.4647
CAS 242478-37-1
242478-37-1 (Solifenacin )
242478-38-2 (Solifenacin Succinate)
Solifenacin succinate, YM-67905
コハク酸ソリフェナシン
| Molecular Formula: | C11H19NO7S |
| Formula Weight: | 480.56 |
CAS 242478-38-2
Usage Muscarinic M3 receptor antagoinst. Used in treatment of urinary incontinence.
Usage sedative
Usage Solifenacin succinate is a urinary antispasmodic of the antimuscarinic class.
(3R)-l-azabicyclo[2.2.2]oct-3-yl-(lS)-l-phenyl-3,4-dihydroisoquinoline-2-(lH)- carboxylate ((S)-phenyl-l?2,3,4-tetrahydroisoquinoline-2-carboxylic acid 3(R)-quinuclidinyl ester) is known as solifenacin, also known as YM-905 (in its free base form) and YM-67905 (in its succinate form). Solifenacin has the molecular formula C23H26O2, a molecular weight of 362.4647, and the following chemical structure:
C23H26N2O2 Exact Mass: 362.1994
MoI. Wt.: 362.4647 m/e: 362.1994 (100.0%), 363.2028 (25.6%), 364.2061 (3.1%) C, 76.21; H, 7.23; N, 7.73; O, 8.83
Solifenacin succinate is a urinary antispasmodic, acting as a selective antagonist to the M(3)-receptor. It is used as treatment of symptoms of overactive bladder, such as urinary urgency and increased urinary frequency, as may occur in patients with overactive bladder syndrome (OAB), as reviewed in Chilman-Blair, Kim et at., Drugs of Today, 40(4):343 – 353 (2004). Its crystalline powder is white to pale yellowish-white and is freely soluble at room temperature in water, glacial acetic acid, DMSO, and methanol. The commercial tablet is marketed under the trade name VESICAJRE®. As VESICARE®, it was approved by the FDA for once daily treatment of OAB and is prescribed as 5 mg and 10 mg tablets.
The drug was developed by Yamanouchi Pharmaceutical Co. Ltd. and disclosed in US. Patent No. 6,017,927 and its continuation, US. Patent No. 6,174,896.
Solifenacin succinate was first approved by the European Medicines Agency (EMA) on June 8, 2004, then approved by U.S. Food and Drug Administration (FDA) on Nov 19, 2004, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on April 20, 2006. It was developed and marketed as Vesicare® by Astellas.
Solifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle and stimulation of salivary secretion. By preventing the binding of acetylcholine to these receptors, solifenacin reduces smooth muscle tone in the bladder, allowing the bladder to retain larger volumes of urine and reducing the number of micturition, urgency and incontinence episodes. It is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.
Vesicare® is available as tablet for oral use, containing 5 or 10 mg of Solifenacin succinate. The recommended dose is 5 mg once daily. If the 5 mg dose is well tolerated, the dose may be increased to 10 mg once daily.
(1S)-3,4-dihydro-1-phenyl-2-(1H)-isoquinolinecarboxylic acid (3R)-1- azabicyclo[2.2.2]oct-3-yl ester. succinate (Solifenacin succinate) (1)
Solifenacin succinate (1) as white crystalline powder. (104.50 g, 87% w/w yield based on in-put).
Chromatographic purity: 99.94 % (by HPLC). Chiral purity: 99.94% (by chiral HPLC). (1S, 3’S)- Diastereomer content: 0.06% (by chiral HPLC).
Mp 145-146 °C.
[α]D 25 (c=1, in Water): + 40.6°.
IR (KBr) (cm-1): 3282, 3024, 3007, 2964, 2937, 2881, 2607, 1722, 1685, 1579, 1491, 1227, 761, 751.
HRMS: m/z = 363.2071 [M + H] + . 1H NMR (DMSO-d6): δ 1.50 – 1.81 (m, 4H), 2.07 (m, 1H), 2.36 (s, 4H), 2.56 – 3.30 (m, 8H), 3.41 & 3.85 (2m, 2H), 4.79 (m, 1H), 6.27 (brs, 1H), 7.20 – 7.32 (m, 9H), 11.79 (brs, 2H).
13C NMR (DMSO-d6): δ 18.3 (CH2), 22.3 (CH2), 24.6 (CH), 27.7 (CH2), 30.2 (2xCH2), 38.9 (CH2), 45.1 (CH2), 46.0 (CH2), 54.1 (CH2), 57.3, 70.2, 126.2 (CH), 127.1 (CH), 127.2 (2xCH), 128.1 (CH), 128.4 (2xCH), 128.7 (CH), 134.7, 135.4, 154.3, 174.5.
Solifenacin (INN, trade name Vesicare) is a medicine of the antimuscarinic class and was developed for treating contraction of overactive bladder[1] with associated problems such as increased urination frequency and urge incontinence.[2] It is manufactured and marketed by Astellas, GlaxoSmithKline[3] and Teva Pharmaceutical Industries.
Solifenacin is contraindicated for people with urinary retention, gastric retention, uncontrolled or poorly controlled closed-angle glaucoma, severe liver disease (Child-Pugh class C),[4] and hemodialysis.[2]
Long QT syndrome is not a contraindication although solifenacin, like tolterodine and darifenacin, binds to hERG channels of the heart and may prolong the QT interval. This mechanism appears to be seldom clinically relevant.[5]
The most common side effects of solifenacin are dry mouth, blurred vision, and constipation. As all anticholinergics, solifenacin may rarely cause hyperthermia due to decreased perspiration.[4]
Solifenacin is metabolized in the liver by the cytochrome P450 enzyme CYP3A4. When administered concomitantly with drugs that inhibit CYP3A4, such as ketoconazole, the metabolism of solifenacin is impaired, leading to an increase in its concentration in the body and a reduction in its excretion.[4]
As stated above, solifenacin may also prolong the QT interval. Therefore, administering it concomitantly with drugs which also have this effect, such as moxifloxacin or pimozide, can theoretically increase the risk of arrhythmia.[3]
Solifenacin is a competitive cholinergic receptor antagonist, selective for the M3 receptor subtype. The binding of acetylcholine to these receptors, particularly M3, plays a critical role in the contraction of smooth muscle. By preventing the binding of acetylcholine to these receptors, solifenacin reduces smooth muscle tone in the bladder, allowing the bladder to retain larger volumes of urine and reducing the number of micturition, urgency and incontinence episodes. Because of a long elimination half life, a once-a-day dose can offer 24-hour control of the urinary bladder smooth muscle tone.[2]
Peak plasma concentrations are reached 3 to 8 hours after absorption from the gut. In the bloodstream, 98% of the substance are bound to plasma proteins, mainly acidic ones. Metabolism is mediated by the liver enzyme CYP3A4 and possibly others. There is one known active metabolite, 4R-hydroxysolifenacin, and three inactive ones, the N–glucuronide, the N-oxide and the 4R-hydroxy-N-oxide. The elimination half-life is 45 to 68 hours. 69% of the substance, both in its original form and as metabolites, are excreted renally and 23% via the feces.[2]
Atropine for comparison
Like other anticholinergics, solifenacin is an ester of a carboxylic acid containing (at least) an aromatic ring with an alcohol containing a nitrogen atom. While in the prototype anticholinergic atropine the alcohol is tropine, solifenacin has another bicycle, quinuclidinyl alcohol.
The substance is a basic yellow oil, while the form used in tablets, solifenacin succinate, consists of white to slightly yellowish crystals.[6]
Scheme 1 wherein the quinuclidinol reactant is available commercially. The overall synthesis as reported by Mealy, N., et al. in Drugs of the Future, 24 (8): 871-874 (1999) is depicted in Scheme 2:
Scheme 2
U.S. Patent No. 6,017,927 discloses another process for the preparation of solifenacin, wherein 3-quinuclidinyl chloroformate monohydrochloride is admixed with ( IR)-I -phenyl- 1,2,3,4-tetrahydroisoquinoline to obtain solifenacin, as seen below in Scheme 3:
Scheme 3
The compound was studied using animal models by the Yamanouchi Pharmaceutical Co., Ltd. of Tokyo, Japan. It was known as YM905 when under study in the early 2000s.[7]
A 2006 cost-effectiveness study found that 5 mg solifenacin had the lowest cost and highest effectiveness among anticholinergic drugs used to treat overactive bladder in the United States, with an average medical cost per successfully treated patient of $6863 per year.[8]
Chemically, solifenacin succinate is butanedioic acid, compounded with (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)iso-quinolinecarboxylate (1:1) having an empirical formula of C23H26N2O2•C4H6O4, and a molecular weight of 480.55. The structural formula of solifenacin succinate is:
|
Solifenacin succinate is a white to pale-yellowish-white crystal or crystalline powder. It is freely soluble at room temperature in water, glacial acetic acid, dimethyl sulfoxide, and methanol. Each VESIcare tablet contains 5 or 10 mg of solifenacin succinate and is formulated for oral administration. In addition to the active ingredient solifenacin succinate, each VESIcare tablet also contains the following inert ingredients: lactose monohydrate, corn starch, hypromellose 2910, magnesium stearate, talc, polyethylene glycol 8000 and titanium dioxide with yellow ferric oxide (5 mg VESIcare tablet) or red ferric oxide (10 mg VESIcare tablet).
Paper
http://shodhganga.inflibnet.ac.in/bitstream/10603/71060/10/10_chapter%202.pdf
PAPER
An improved process for the preparation of solifenacin succinate (1) involving resolution through diastereomeric crystallization is described. (1S)-IQL derivative (5) is esterified to form (1S)-ethoxycarbonyl IQL derivative (6) which is condensed with (RS)-3-quinuclidinol (7) to form a solifenacin diastereomeric mixture (8); this is subjected to resolution through diastereomeric crystallization to produce solifenacin succinate (1), which is used for the treatment of an overactive bladder.
CLIP
http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-265
The piperidine scaffold also features in a recently discovered pharmaceutical, namely solifenacin (2.57, Vesicare), a competitive antagonist of the muscarinic acetylcholine receptor used in the treatment of an overactive bladder. This species was co-developed by Astellas and GSK scientists and consists of a chiral hydroisoquinoline linked to a (R)-quinuclidinol unit through a carbamate linkage (Figure 6). Upon protonation the tertiary amine of the quinuclidine is expected to resemble the ammonium substructure of muscarine (2.58) [76].
This molecule can be prepared by direct coupling of the (R)-quinuclidinol and tetrahydroisoquinoline carbamate partner (Scheme 28). The (R)-quinuclidinol (2.59) itself can be accessed from quinuclidone (2.60), and is most conveniently prepared by alkylation of ethyl isonicotinate (2.61) with ethyl bromoacetate (2.62) followed by full reduction of the pyridine ring therefore yielding the corresponding piperidine 2.63. A base-mediated Dieckmann cyclisation and Krapcho decarboxylation [77] then furnishes 2.60. Traditionally, the reduction of 2.60 to prepare 2.59 can be carried out under fairly mild hydrogenation conditions that ultimately produce racemic quinuclidinol. However, an improved approach makes use of a Noyori-type asymmetric reduction employing a BINAP ligated RuCl2 and a chiral diamine to yield the desired (R)-quinuclidine in high yield and enantioselectivity [78].
https://www.google.com/patents/EP2489666A2?cl=enhttps://www.google.com/patents/EP2489666A2?cl=en
Solifenacin {1(S)-Phenyl-1,2,3,4-tetrahydroisoquinolin-2-carboxylic acid 3(R)-quinuclidinyl ester or [(3R)-1-azabicyclo[2.2.2]oct-3-yl-(1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate]}, also known as YM-905 (in its free base form) has the following structure.
Molecular formula of Solifenacin is C23H26N2O2 and its molecular weight is 362.5. Solifenacin and its salts are used as therapeutic agents for Pollakiuria and incontinence of urine due to hyperactive bladder, not as agents for curing hyperactive bladder itself but as therapeutic agents for suppressing the symptoms thereof.
The drug Solifenacin was first disclosed in US. Patent NoS. 6,017,927and 6,174,896 (CIP of US 6017927 ) (Yamanouchi Pharmaceuticals). Disclosed therein are compounds with the following general formula
A specific method for producing Solifenacin or its HCl salt is also disclosed, as depicted by the following scheme (Scheme-1).
In the reference cited above, the method of preparation of the Solifenacin base using sodium hydride and subsequent conversion of the base to the HCl salt is described, but no data is given for the purity of either the Solifenacin base or the salt. Solifenacin hydrochloride is disclosed particularly in Example-8 of the same patent and crystallization is carried out in a mixture of acetonitrile and diethyl ether. The melting point reported is 212-214 °C. This patent also discloses 3-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate mono oxalate (Example 1) which is the oxalate salt of racemic Solifenacin (M.P. 122-124 °C). The crystallization of the racemate oxalate salt is carried out in a mixture of isopropanol and isopropyl ether.
Polymorphism, the occurrence of different solid state forms, is a property of many molecules and molecular complexes. A single molecular entity may give rise to a variety of solid state forms having distinct crystal structures and physical properties such as melting point, powder X-ray diffraction pattern, infrared (IR) absorption fingerprint and different physicochemical properties. One solid state form may give rise to several polymorphic forms, which are different from one another in all the above properties.
Subsequently, a process for preparation of Solifenacin base and its salts, wherein succinate salt was obtained in high degree of optical purity for medicinal use, was described in EP 1714965 by Astellas Pharma. This document stated that the free base of Solifenacin has the following impurities,
The concentration of the impurities present in the base were as follows:
| Compound A | 4.51% |
| Compound B | 2.33% |
| Compound C | 0.14% |
| Compound D | 0.32% |
| Compound E | 1.07% |
WO 2008062282 discloses a process for the preparation of Solifenacin, which is shown below. (Scheme 6).
Example 1Preparation of (+)-(1S,3’R)-quinuclidin-3′-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Solifenacin)
To the cooled solution of freshly prepared sodium methoxide (1.8 g), (R)-3-quinuclidinol HCl (6.4 g) was added under N2 atmosphere. It was stirred at 5-30 °C for 30 min to 1 hrs. Distilled out the solvent at reduced pressure. To the semi-solid mass dry toluene was added. Reaction mixture was heated to reflux temp. and stirred for 1-3 h. During this process, traces of water and methanol were removed azeotropically by using Dean-Stark apparatus and was cooled to 60-70 °C. (S)- Ethyl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-caboxylate (10 g) dissolved in dry toluene and dry DMF were added. It was again heated to reflux temperature and stirred for 5-25 h while distilling off solvent to remove ethanol at intervals with addition of fresh quantity of dry solvent. It was cooled to room temperature.
Workup:
To the reaction mixture water and toluene were added. It was stirred for 10-15 min. and transferred into a separating funnel. Organic layer was collected. The product was extracted with 20 % aqueous HCl solution. It was basified with 40 % aqueous K2CO3 solution at 15-20 °C. The product was extracted with ethyl acetate. Both the extracts were combined and washed with brine solution. Organic layer was collected and dried over anhydrous sodium sulfate and solvent was distilled out at reduced pressure.
(+)-(1S,3’R)-quinuclidin-3′-yl-1-phenyl-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate (Solifenacin) (6.6 g , 51 % yield) was obtained.
https://www.google.com/patents/EP2406257A1?cl=enhttps://www.google.com/patents/EP2406257A1?cl=en
Solifenacin succinate is the international common denomination for butanedioic acid compounded with (l S)-(3R)-l-azabicyclo[2.2.2]oct-3-yl-3,4-dihydro-l-phenyl-2(lH)-isoquinolinecarboxylate (1 : 1), having an empirical formula Of C2SH2ON2O2 .C4H6O4 and the structure is represented in formula VI given below;
Scheme 1 : Reported synthetic schemes in US’ 927
Both the routes have several drawbacks such as; a) Use of hazardous and pyrophoric reagent, NaH, in the process which is very difficult to handle and thus makes the process unsafe to handle at industrial level. The use of strong agent NaH also leads to racemization of the products and thus suffers to provide enantiomerically pure Solifencin; b) Use of ethylchloroformate to prepare ethyl carboxylate derivative in route A which is lachrymatory in nature; c) Ethylcarboxylate derivative produces ethanol as a by-product during trans-esterification reaction in the subsequent reaction that interferes in nucleophilic attack against Solifenacin in the presence of a base and hence it is necessary to remove ethanol from the reaction mixture in the form of azeotrope with toluene or the like simultaneously while carrying out the reaction, so as to control the reaction; d) Use of column chromatography for the purification of Solifenacin base, which makes the process industrially not feasible; f) The reaction requires longer time for the completion and hence turn around time of the batch in production makes it less attractive. International Patent Application No WO2005/075474 disclosed another synthetic route for the preparation of Solifenacin and Solifenacin succinate as shown in Scheme-2.
Scheme 2
The above route does not overcome the problems associated with the process disclosed in 927′ as the process described in this scheme also uses ethylchloroformate in the first step and produces ethanol as a by-product in the second step.
Yet another International Patent application no W02005/105795A1 discloses an improved process for preparing Solifenacin as represented in Scheme-3, wherein leaving group (Lv) can be lH-imidazole-1-yl, 2,5-dioxopyrrolidin-l-yloxy, 3-methyl-l H-imidazol-3-ium- l-yl or chloro and further condensation is carried out in the presence of sodium hydride as a base and a mixture of toluene and dimethylformamide or toluene alone as a reaction medium. The process described herein represents few draw backs such as, use of hazardous sodium hydride, use of chromatographic purifications, and use of moisture sensitive leaving groups (Lv) and hence handling of the reaction is difficult. Further the leaving groups used are expensive and thus making the process uneconomic.
Scheme 3 Hence, there is need of efficient process for producing Solifenacin and its succinate salt which is safe to handle, industrially feasible, and economically viable.
Example 1
PREPARATION OF SOLIFENACIN SUCCINATE OF FORMULA (VI);
To a stirred solution of (3R)-quinuclidin-3-ol (25 gm) in dimethylformamide (175 ml) was added bis-(4- dinitrophenyl) carbonate (83.83 gm) with stirring at 25-3O0C under nitrogen atmosphere. The reaction mass was stirred at 25-300C for 2r3. hours. Upon completion of this reaction by HPLC, ( IS)-I -phenyl- 1,2,3,4-tetrahydroisoquinoline (41.0 gm) was added to resultant brown colored reaction solution and further stirred at 25-3O0C for 3-4 hrs. After completion of the reaction (monitored by HPLC), the reaction solution was diluted with water (250 ml) and the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid. The resulting reaction solution was extracted with diisopropylether (300ml X 2) to separate the nitro-phenol.
The aqueous layer was then extracted with dichloromethane (300 ml) and dichloromethane layer was separated and diluted with 200 ml water. The pH of the biphasic mixture was adjusted to 9-10 with ammonium hydroxide and organic layer was separated, washed with water (200 ml X 2), and concentrated under vacuum to yield 57.0 gm (79%) of compound I as a syrup having HPLC purity of 98.8% and Chiral purity of 99.9%: Compound (I) was further dissolved in acetone (400 ml) and contacted with succinic acid (18.58 gm) at 25-300C. and stirred for 30 min. Precipitated solid was filtered, washed with acetone (57 ml), and dried under vacuum to yield 53.0 gm solifenacin succinate of formula (VI) as a white crystalline solid; HPLC purity 99.93%; Chiral purity : 99.98%;
The ether layer comprising nitro-phenol was subjected to vacuum distillation to recover diisopropylether and nitro-phenol.
Example 2
PREPARATION OF SOLIFENACIN SUCCINATE OF FORMULA (VI);
To a stirred solution of (3R)-quinuclidin-3-ol (5 gm) in dry pyridine (30 ml) was added bis-(4- dinitrophenyl) carbonate (17.5 gm) with stirring at 25-3O0C under nitrogen atmosphere. The reaction mass was stirred at 25-300C for 2-3 hours. Upon completion of the reaction by HPLC, ( IS)-I -phenyl – 1,2,3,4-tetrahydroisoquinoline (7.5 gm) was added to resultant brown colored reaction solution and further stirred at 25-3O0C for 3-4 hrs. After completion of the reaction (monitored by HPLC), the reaction solution was diluted with water (100 ml) and the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid. The resulting reaction solution was extracted with diisopropylether (60 ml X 2) to separate the nitro-phenol.
The aqueous layer was then extracted with dichloromethane (60 ml), and dichloromethane layer was separated and diluted with 40 ml of water. The pH of the biphasic mixture was adjusted to 9-10 with ammonium hydroxide and organic layer was separated, washed with water (40 ml X 2), and concentrated under vacuum to yield 10.0 gm (70.8%) of solifenacin of formula (I) as a syrup having HPLC purity of 97.9% and Chiral purity of 99.96%: Compound (I) was further dissolved in acetone (70 ml) and contacted with succinic acid (3.25 gm) at 25-300C. and stirred for 30 min. Precipitated solid was filtered, washed with acetone (10 ml), and dried under vacuum to yield 8.5.0 gm solifenacin succinate of formula (VI) as a white crystalline solid; HPLC purity 99.78%; Chiral purity : 99.96%;
Example 3
PREPARATION OF SOLIFENACIN SUCCINATE OF FORMULA (VI):
(3/?)-quinuclidin-3-ol (1.0 gm) of was dissolved in tetrahydrofuran (15 ml) and dry pyridine (1.0 ml) with stirring. Bis-(4-dinitrophenyl) carbonate (3.82 gm) was added to the above solution at 25-300C. After completion of the reaction, (lS)-l-phenyl-l,2,3,4-tetrahydroisoquinoline (1.5 gm) was added to the resulting brown reaction solution and then stirred till completion of the reaction. Upon completion of the reaction, the reaction solution was diluted with water (20 ml) and the pH of the solution was adjusted to 1 -2 using concentrated hydrochloric acid. The resulting solution was extracted with diisopropylether (12.0 ml X 2) to separate the nitro-phenol.
The aqueous layer was separated and further extracted with dichloromethane (12 ml X 2). The dichloromethane layer was diluted with water (8 ml) and pH of the resulting mixture was adjusted to 9-10 using ammonium hydroxide solution. The aqueous layer was separated from organic layer, washed with water (8 ml x 2) and concentrated to yield 1.5 gm (53.5%) solifenacin of Formula (I) having HPLC purity 96.47% ; chiral purity 99.10%; Compound (I) was dissolved in acetone (10.5 ml) and treated with 0.48 gm succinic acid at 25-300C, and stirred for 30 minutes. The precipitated solid was filtered, washed with 1.0 ml acetone, and solid dried under vacuum yield 1.4 gm of compound VI having HPLC purity 99.86%; chiral purity: 99.93%.
Example 4
PREPARATION OF (3^-l-AZABICYCLO[2.2.21OCT-3-YL4-NITROPHENYL CARBONATE
OF FORMULA (TV);
To a stirred solution of (3i?)-quinuclidin-3-ol (1.0 gm) in dichloromethane (10 ml) was added Bis-(4- dinitrophenyl) carbonate (2.87 gm) at 25-300C and the resulting brown solution was stirred at ambient temperature till the completion of reaction by HPLC. Dichloromethane was distilled off to get the residue that was diluted with water (10 ml) and was added concentrated hydrochloric acid till pH of the mixture is I to 2. The acidic solution was extracted with di-isopropylether (10 ml X 2) to separate out the nitro- phenol. The aqueous layer was then extracted with dichloromethane (20 ml) to separate the compound of formula (IV). The dicloromethane layer- comprising the compound of formula (IV) was further mixed with water (10ml) and pH was adjusted to 9-10 with ammonium hydroxide. The organic layer was then separated, washed with water, dried over sodium sulphate, and concentrated under vacuum to yield (3R)-I- azabicyclo[2.2.2]oct-3-yl4-nitrophenyl carbonate of formula (IV) as a syrup with around 46% yield (1.07 gm); HPLC purity: 87.27% by HPLC.
Example 5
PREPARATION OF SOLIFENACIN SUCCINATE OF FORMULA (VI)
To a stirred solution of (3R)-l-azabicyclo[2.2.2]oct-3-yl4-nitrophenyl carbonate (1.0 gm) of formula (IV) obtained as per Example 4 in pyridine (5 ml), (lS)-l-phenyl-l,2,3,4-tetrahydroisoquinoline (0.78 gm) was added and the resulting brown solution was stirred for 6 hrs. After completion of the reaction the solvent was distilled off and the residue obtained was diluted with 10 ml water, the pH of the resulting solution was adjusted to 1-2 using the concentrated hydrochloric acid and extracted with di-isopropylether (10 ml X 2) to separate out the nitro-phenol.
The aqueous layer was separated and further extracted with dichloromethane (20 ml) and obtained dichloromethane layer was mixed with water (10 ml) and pH of the resulting mixture was adjusted to 9- 10 using ammonium hydroxide. Layers were separated, the organic layer was washed with water, dried over sodium sulphate, and concentrated in vacuum to yield the 1.07 gm (89.43%) of compound solifenacin of formula (I) having HPLC purity 97.08% purity
Example 6
PREPARATION OF SOLIFENACIN SUCCINATE OF FORMULA (VD.
To a stirred solution of (3R)-quinuclidin-3-ol (Formula II, 100 gm) in dimethylformamide (400 ml), bis- (4-dinitrophenyl) carbonate (Formula III, 285.04 gm) was added with stirring at 25-30°C under nitrogen atmosphere. The reaction mass was stirred at 25-30°C for 2-3 hours. After completion of the reaction which was monitored by TLC, ( IS)-I -phenyl- 1, 2,3, 4-tetrahydroisoquinoline (Formula V, 171.44 gm) was added to the resultant brown colored reaction solution. The reaction mixture was further stirred at 25- 3O0C for 3-4 hrs. After completion of the reaction (by HPLC), the reaction solution was diluted with water (1000 ml) and the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid. The resulting reaction solution was extracted with diisopropylether (1000ml X 2) to separate the nitro-phenol. The aqueous layer was then mixed with dichloromethane (1000ml), the content was stirred, and dichloromethane layer was separated. Aqueous layer was re-extracted with dichloromethane (l OOOml).The combined dichloromethane was distilled off completely to obtain the residue. The residue was dissolved in water (1000 ml) and toluene (1000 ml) was added and the pH of the biphasic mixture was adjusted to 9-10 with ammonium hydroxide. The mixture was stirred and toluene layer was separated and aqueous layer was re-extracted with toluene (1000 ml). The combined toluene layer were washed with water (1000 ml) followed by solution of 0.5% sodium hydroxide (1000 ml X 2) and further washed with water (1000 ml). The toluene layer was distilled off completely to obtain the residue which was further dissolved in acetone (800 ml) and toluene 1080 ml). The solution was treated with Succininc acid (88.0 gm) and the mixture obtained was heated at 55-600C for 30 min. The mixture was further cooled to 10-150C, maintained for 60 min and filtered. The product was dried to afford Solifenacin Succinate (Formula VI) as white crystalline solid. Yield of the compound VI270 gm. HPLC purity : 99.85%: Chiral Purity: 99.99%
Example 7
Purification process for Solifenacin Succinate:
The wet material obtained from the example 6 was purified to improve chiral and chemical purity.. The wet material (270 gm) was dissolved in a mixture of water (700 ml) and toluene (700 ml) and stirred for 15 min. The pH of resulting mixture was adjusted to 9-10 using aqueous ammonia, stirred for 15-20 min and separated organic and aqueous layer. Aqueous layer was re-extracted with toluene (700 ml) and combined with the separated organic layer. The combined organic layer was washed with water (700 ml x 2) and distilled off completely to obtain the thick residue. The residue was dissolved in acetone (1600 ml), decolorized with activated charcoal, and treated with succininc acid (75.0 gm). The contents were heated at 55-600C for 30 mih, cooled to 10-15°C, and maintained for 60 min. The crystalline solid obtained was filtered, and dried under vacuum (650-700 mm/Hg to afford Solifenaicn Succinate (Formula VI) as white crystalline solid. Yield: 250 gm (66.6%); HPLC purity: 99.95% and Chiral purity: 100.0%
PAPER
Org. Lett. 2010, 12, 2690-2693.
PATENT
https://www.google.com/patents/WO2007076116A2?cl=en
Scheme 4:
3-Quinuclidinol χ= halogen,
R=alkyl
Scheme 5
EXAMPLES Example 1 : Preparation of solifenacin succinate
A solution of (S)-l-phenyl-l,2,3,4-tetrahydroisoquinoline (C15H15N) (16g), toluene (80ml), and diisopropylethylamine (DIPEA, 13.5g) was cooled to 0°C. Chloroethylchloro formate (C3H4CbO2) (CECF, 13.0gr) was added dropwise, keeping the temperature between 0°-20°C. After stirring at room temperature for 1.5 hours, the mixture was filtered.
The filtrate was added to solution of (R)-quinuclidin-3-ol (C7Hi3NO) (11.6g) in toluene (80ml), DMF (16ml), and NaH (60%, 5.5g) at 80°C during 1 hour, and stirred at 95°-100°C for 17 hours. The mixture was cooled to room temperature, and THF (small amount) was added. A saturated NaCl solution (300ml) was added, and the phases were separated. The organic phase was acidified with 10% HCl solution, and the phases were separated. The aqueous phase was basified with K2CO3solution and extracted with ethyl acetate (EtOAc). The organic phase was filtered and evaporated to obtain solifenacin (SLF) (21.25g). The residue was dissolved in ethanol (EtOH) (100ml) and succinic acid (7.Og) was added. Seeding with SLF-succinate was performed, and the mixture was stirred at RT for 16 hours. The product was isolated by vacuum filtration, washed with EtOH (3x20ml), and dried in vacuum oven at 50° over night to obtain SLF-succinate (10.46g).
Example 2: Preparation of solifenacin succinate
Chloroethylchloroformate (CECF, 13.Og) is added dropwise to solution of (R)- quinuclidin-3-ol (11.6g) and diisopropylethylamine (DIPEA, 13.5g) in THF (150ml), keeping the temperature between 0°-20°C. The mixture is stirred at room temperature for several hours. Then (S)-l-phenyl-l,2,3,4-tetrahydroisoquinoline (16g) is added and the solution is stirred at room temperature for another 16 hours. The solution is diluted with EtOAc (350ml) and washed with a saturated NaCl solution (300ml). The organic phase is acidified with 10% HCl solution, and the phases are separated. The aqueous phase is basified with K.2CO3 solution and extracted with EtOAc. The organic phase is filtered and evaporated to obtain SLF. The residue is dissolved in EtOH (100ml), and succinic acid (7.Og) is added. Seeding with SLF-succinate is performed, and the mixture is stirred at RT for 16 hours. The product is isolated by vacuum filtration, washed with EtOH (3x20ml), and dried in vacuum oven at 50° over night to obtain SLF-succinate. Example 3: Preparation of solifenacin succinate
Chloroethylchloroformate (CECF, 13.Og) is added dropwise to solution of (R)- quinuclidin-3-ol (11.6g) and diisopropylethylamine (DIPEA, 13.5g) in Toluene (150ml), keeping the temperature between 0°-20°C. The mixture is stirred at room temperature for several hours and filtrated. Then (S)-l-phenyl-l,2,3,4-tetrahydroisoquinoline (16g) is added followed by addition of sodium hydride (60%, 5.5g) and the mixture is stirred at reflux for another 16 hours. The solution is diluted with EtOAc (350ml) and washed with a saturated NaCl solution (300ml). The organic phase is acidified with 10% HCl solution, and the phases are separated. The aqueous phase is basified with K2CO3 solution and extracted with EtOAc. The organic phase is filtered and evaporated to obtain SLF. The residue is dissolved in EtOH (100ml), and succinic acid (7.Og) is added. Seeding with SLF-succinate is performed, and the mixture is stirred at RT for 16 hours. The product is isolated by vacuum filtration, washed with EtOH (3x20ml), and dried in vacuum oven at 50° over night to obtain SLF-succinate.
CLIP
1. WO9620194A1 / US6017927A.
2. J. Med. Chem. 2005, 48, 6597-6606.
3. WO2007076116A2.
WO2010103529A1.
| Cited Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| WO2007076116A2 * | Dec 21, 2006 | Jul 5, 2007 | Teva Pharmaceutical Industries Ltd. | Intermediates for preparing solifenacin |
| Reference | ||
|---|---|---|
| 1 | * | See also references of WO2010103529A1 |
| Cited Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| EP0801067A1 * | Dec 27, 1995 | Oct 15, 1997 | Yamanouchi Pharmaceutical Co. Ltd. | Novel quinuclidine derivatives and medicinal composition thereof |
| EP1714965A1 * | Feb 7, 2005 | Oct 25, 2006 | Astellas Pharma Inc. | Composition containing solifenacin succinate |
| EP1726304A1 * | Mar 11, 2005 | Nov 29, 2006 | Astellas Pharma Inc. | Solifenacin-containing composition |
| EP1757604A1 * | Apr 25, 2005 | Feb 28, 2007 | Astellas Pharma Inc. | Process for producing solifenacin or its salt |
| Reference | ||
|---|---|---|
| 1 | * | MEALY N ET AL: “YM-53705 (AS MONOHYDROCHLORIDE) 1(S)-PHENYL-1,2,3,4-TETRAHYDROISOQUIN OLINE-2-CARBOXYLIC AID 3(R)- QUINUCLIDINYL ESTER MONOSUCCINATE” DRUGS OF THE FUTURE, BARCELONA, ES, vol. 24, no. 8, 1999, pages 871-874, XP001061585 ISSN: 0377-8282 cited in the application |
| 2 | * | NAITO ET AL: “Synthesis and Antimuscarinic Properties of Quinuclidin-3-yl 1,2,3,4-Tetrahydroisoquinoline-2-carboxyla te Derivatives as Novel Muscarinic Receptor Antagonists” J.MED.CHEM., vol. 48, 20 October 2005 (2005-10-20), pages 6597-6606, XP002435582 |
| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| WO2008013851A2 * | Jul 24, 2007 | Jan 31, 2008 | Teva Pharmaceutical Industries Ltd. | Processes for preparing polymorphic forms of solifenacin succinate |
| WO2008013851A3 * | Jul 24, 2007 | Dec 24, 2008 | Mili Abramov | Processes for preparing polymorphic forms of solifenacin succinate |
| WO2009087664A1 * | Dec 2, 2008 | Jul 16, 2009 | Cadila Healthcare Limited | Process for preparing chemically and chirally pure solifenacin base and its salts |
| WO2010012459A2 * | Jul 29, 2009 | Feb 4, 2010 | Krka, D.D., Novo Mesto | A process for the preparation of solifenacin salts and their inclusion into pharmaceutical dosage forms |
| WO2010012459A3 * | Jul 29, 2009 | Aug 5, 2010 | Krka, D.D., Novo Mesto | A process for the preparation of solifenacin salts and their inclusion into pharmaceutical dosage forms |
| WO2012175119A1 | Jun 22, 2011 | Dec 27, 2012 | Isochem | Process for the preparation of solifenacin and salts thereof |
| CN102887894A * | Jul 18, 2011 | Jan 23, 2013 | 天津市医药集团技术发展有限公司 | Crystal form of solifenacin succinate and preparation method thereof |
| EP2406257A1 * | Aug 31, 2009 | Jan 18, 2012 | Megafine Pharma (P) Ltd. | A new method for the preparation of solifenacin and new intermediate thereof |
| EP2406257A4 * | Aug 31, 2009 | Nov 14, 2012 | Megafine Pharma P Ltd | A new method for the preparation of solifenacin and new intermediate thereof |
| EP2489666A2 * | Dec 2, 2008 | Aug 22, 2012 | Cadila Healthcare Limited | Chemically and chirally pure solifenacin base and its salts |
| EP3067353A1 | Jul 29, 2009 | Sep 14, 2016 | KRKA, D.D., Novo Mesto | A process for the preparation of solifenacin salts and their inclusion into pharmaceutical dosage forms |
| US9399624 | Apr 17, 2015 | Jul 26, 2016 | Shanghai Jingxin Biomedical Co., Ltd. | Process for preparing (1S)-1-phenyl-3,4-dihydro-2(1H)-isoquinoline-carboxylate |
Goldman, Lee (2011). Goldman’s Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. p. 343. ISBN 1437727883.
Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 8659–62. ISBN 978-3-85200-181-4.
Drugs.com: Monograph on Vesicare.
Lexi-Comp (December 2009). “Solifenacin”. The Merck Manual Professional. Retrieved 10 June 2011.
“Vesicare 5mg & 10mg film-coated tablets”. eMC. Retrieved 13 December 2015.
The Merck Index. An Encyclopaedia of Chemicals, Drugs and Biologicals (14 ed.). 2006. p. 1494. ISBN 978-0-911910-00-1.
Kobayashi, S.; et al. (July 2001). “Effects of YM905, a Novel Muscarinic M3-Receptor Antagonist, on Experimental Models of Bowel Dysfunction In Vivo”. Jpn. J. Pharmacol. 86 (3): 281–288. PMID 11488427.
Ko Y, Malone DC, Armstrong EP (Dec 2006). “Pharmacoeconomic evaluation of antimuscarinic agents for the treatment of overactive bladder”. Pharmacotherapy. 26(12): 1694–702. doi:10.1592/phco.26.12.1694. PMID 17125433.
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
1-azabicyclo[2.2.2]oct-3-yl (1R)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate
|
|
| Clinical data | |
| Trade names | Vesicare |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a605019 |
| License data |
US FDA: Solifenacin |
| Pregnancy category |
|
| Routes of administration |
Oral |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 90% |
| Protein binding | 98% |
| Metabolism | CYP3A4 |
| Metabolites | Glucuronide, N-oxide, others |
| Biological half-life | 45 to 68 hours |
| Excretion | Renal (69.2%) and fecal (22.5%) |
| Identifiers | |
| CAS Number | 242478-37-1  |
| ATC code | G04BD08 (WHO) |
| PubChem | CID 154059 |
| IUPHAR/BPS | 7483 |
| DrugBank | DB01591 |
| ChemSpider | 135771 |
| UNII | A8910SQJ1U |
| KEGG | DG00481 |
| ChEMBL | CHEMBL1734 |
| Synonyms | YM905 |
| Chemical data | |
| Formula | C23H26N2O2 |
| Molar mass | 362.465 g/mol |
////////солифенацин , سوليفيناسين , 索利那新 , Solifenacin, YM 67905, YM 905 , コハク酸ソリフェナシン
コハク酸ソリフェナシン
Solifenacin Succinate
C23H26N2O2▪C4H6O4 : 480.55
[242478-38-2]
(DS003, BMS-599793)
Cas 676489-50-2
| Molecular Formula: | C27H22N6O3 |
|---|---|
| Molecular Weight: | 478.512 g/mol |
2-[1-[2-(4-methoxy-7-pyrazin-2-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxo-acetyl]-4-piperidylidene]-2-phenyl-acetonitrile;
2-[1-[2-(4-methoxy-7-pyrazin-2-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl]piperidin-4-ylidene]-2-phenylacetonitrile;
Piperidine, 4-(cyanophenylmethylene)-1-[2-(4-methoxy-7-pyrazinyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-;
US 20040063744 , US 20040186292, WO 2009114313
| Inventors | Andrew S. Thompson, Hua Cheng, Stanislaw Pikul |
| Applicant | International Partnership For Microbicides |
2-(1-(2-(4-methoxy-7-(pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanoyl)piperidin-4- ylidene)-2-phenylethanenitrile
1 (DS003, BMS-599793) is a small molecule entry inhibitor that interferes with HIV infection by binding to the gp120 protein.1 The International Partnership for Microbicides (IPM) licensed 1 from Bristol-Myers Squibb (BMS) with the goal to develop it as a topical microbicide for use in resource-poor countries. Microbicides are vaginal dosage forms of potent inhibitors of HIV that women can use to prevent sexual transmission of HIV from male partners.
1 (a) Maddon, P. J.; Dalgleish, A. G.; McDougal, J. S.; Clapham, P. R.; Weiss, R. A.; Axel. R. Cell 1986, 47, 333-348. (b) McDougal, J. S.; Kennedy, M. S.; Sligh, J. M.; Cort, S. P.; Mawle, A.; Nicholson, J. K. Science 1986, 231, 382-385. (c) Moore, J. P.; Jameson, B. A.; Weiss, R. A.; Sattentau, Q. J. in Viral fusion mechanisms. ed. J. Bentz, CRC Press, Boca Raton, Fla. 1993, p. 233-289.
The discovery and development of new therapeutic strategies against HIV has extended and improved the quality of life of infected patients. Thus far, 30 antiretroviral drugs have been approved by the Food and Drug Administration to treat individuals infected with HFV. These drugs fall into three major classes: reverse transcriptase inhibitors, protease inhibitors, and entry inhibitors, including fusion inhibitors. Unfortunately, currently available therapies have several limitations.
For example, as HIV reproduces itself, different strains of the virus emerge, some of which are resistant to antiretroviral drugs. Therefore, doctors recommend patients infected with HIV take a combination of antiretroviral drugs known as highly active antiretroviral therapy (HAART). This strategy, which typically combines at least three effective antiretroviral drugs from at least two different classes, has been shown to effectively suppress the virus when used properly.
Patients taking antiretroviral drugs, however, often have low adherence to complicated drug regimens. The currently recommended HAART regimen involves taking several antiretroviral drugs each day, some of which may require fasting and cause unpleasant side effects such as nausea and vomiting. In addition, antiretroviral drugs may cause more serious medical problems, including metabolic changes such as abnormal fat distribution, abnormal lipid and glucose metabolism, and bone loss. Additional problems associated with current therapies include drug-drug interactions, toxicity, poor tolerability, inconvenient dosing frequency, and food interactions, Thus, simpler, less toxic, and more effective drag regimens would be beneficial.
Entry inhibitors represent the newest generation of antivirals for the treatment of HIV. These inhibitors may prove beneficial for the growing number of HIV-infected individuals who have developed resistance to the currently available reverse transcriptase inhibitors and protease inhibitors. These compounds act by interfering with attachment of HIV gpl20 to either the CD4 T cell receptor or the CCR5/CXCR4, thereby blocking entry of the vims into the host cell (Biia «t al, J, Antinύcrβb, Chemother. 57(4):619 (2006)). Maraviroc and enfuvirtide are currently the only entry inhibitors that have been approved by the Food and Drug Administration (FDA). Thus, new entry inhibitors and efficient and effective methods for synthesizing them are needed in the art.
2-(1-(2-(4-methoxy-7-(pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanoyl)piperidin-4- ylidene)-2-phenylethanenitrile (1, laboratory scale process). A flask was charged with acid 11 (9.29 g, 31.2 mmol), DIPEA (12.9 mL, 78 mmol), 4 (7.18 g, 36.3 mmol) and DMF (95 mL) subsequently. HATU (13.66 g, 35.9 mmol) was added to the reaction mixture over 10 minutes, which was accompanied by increase of internal temperature from 19 0C to 27 0C. After the reaction mixture was stirred at 25 0C for 3.5 h the HPLC analysis showed complete disappearance of acid 11. Ethanol (950 mL) was added and the resulting suspension was heated at reflux for 1 h. The mixture was then cooled to 25 0C and 1 was isolated by filtration and washed with ethanol (50 mL). The material was dried under vaccum at 50 0C to afford 10.58 g (71% yield) of 1 as a colorless solid.
1H NMR (300 MHz, CDCl3) 2.58-2.65 (m, 2H), 2.91-2.99 (m, 2H), 3.48-3.51(m, 1H), 3.68-3.78 (m, 2H), 3.95-3.99 (m, 1H), 4.11 (s, 3H), 7.27-7.46 (m, 5H), 8.16 (d, J = 5.1 Hz, 1H), 8.21-8.25 (m, 1H), 8.60 (s, 2H), 9.82 (d, J = 3.9 Hz, 1H), 11.75(br s, 1H).
LCMS: m/e 479.3 (M+H)+. Analysis by ICP-MS showed 16 ppm Pd, 79 ppm Fe, 102 ppm Zn. This material was found to be a mixture of two polymorphs: Form 1 and Form 2.
kilo-lab scale process including polymorph conversion
1 (84% yield) and 99.6% purity by HPLC. This material was a pure Form 1 polymorph.
1H NMR (400 MHz, CDCl3) 2.61 (t, J = 5.8 Hz, 1H), 2.65 (t, J = 5.9 Hz, 1H), 2.94 (t, J = 5.8 Hz, 1H), 2.99 (t, J = 5.9 Hz, 1H), 3.51 (t, J = 5.8 Hz, 1H), 3.72 (t, J = 5.8 Hz, 1H), 3.78 (t, J = 6.0 Hz, 1H), 3.98 (t, J = 6.0 Hz, 1H), 4.12, 4.12 (two s, 3H), 7.29-7.47 (m, 5H), 8.16, 8.18 (two s, 1H), 8.23, 8.25 (two d, J = 3.1 Hz, 1H), 8.60-8.63 (m, 2H), 9.83, 9.84 (two d, J = 1.4 Hz, 1H), 11.76, 11.78 (two br s, 1H);
13H NMR (100 MHz, CDCl3) 30.3, 31.0, 33.7, 34.3, 41.7, 42.0, 46.0, 46.3, 56.8, 111.4, 115.0 (2C), 117.7 (2C), 120.9, 124.2, 128.9 (2C), 129.0, 129.1 (2C), 131.9, 132.6 (2C), 133.9 (2C), 136.6, 142.2, 143.4, 143.7 (2C), 151.1, 151.3, 154.8, 166.4, 166.5, 185.6
Anal. Calcd for C27H22N6O3: C, 67.77; H, 4.63; N, 17.56. Found: C, 67.84; H, 4.64; N, 17.56.
1H NMRPREDICT
13C NMR PREDICT
Patent
https://www.google.com/patents/WO2009114313A2?cl=en
EXAMPLES
10 Example 1: Synthesis of Iodopyrazine (1) from Chloropyrazine
NaI, HOAc, H2SO4, MeCN, f N reflux,4-6h, ca. 58% f Υ
A reaction mixture of chloropyrazine (7.5 ml, 83 mmol), NaI (30.3 g, 202 15 mmol), HOAc (9.6 ml, 168 mmol) and H2SO4(0.5 ml) in MeCN (105 ml) was heated at reflux for 4.5 hours. The solvent was removed and water (120 ml) was added. After the solution was basified with saturated NaHCO3, it was extracted with dichloromethane (DCM) (2 x 125 ml). The DCM layers were combined, washed with saturated Na2S2O3, brine and dried. The removal of solvent gave crude iodopyrazine as an oil (12.33 g, 20 71%). Analysis by 1H NMR showed there was less than about 10 mol% of chloropyrazine in the oil. Another batch of chloropyrazine (50 g, 437 mmol) was also converted into crude iodopyrazine (about 65 g) by the same procedure. These two batches of crude iodopyrazine were combined and distillation of the crude iodopyrazine under reduced pressure (about 0.75 torr, bp 47°C) gave pure compound 64 g (60%). 25
1H-NMR (CDCl3, 300MHz) 8.40 (dd, /=1.8, 2.4Hz, IH), 8.51 (d, /=2.4Hz,lH), 8.87 (d, /=1.5Hz,lH).
Example 2: Synthesis of Coupled Azaindole (3) from Iodopyrazine (1)
O Q C4H3IN2 = 205.98 C12H10N4O = 226.23 To a solution of iodopyrazine 1 (45.8 g, 0.222 mol) in tetrahydrofuran (THF) (460 ml) at -18°C, BuMgCl (2 M in THF, 108 ml, 216 mmol) was added dropwise via an addition funnel over 20 minutes. The internal temperature of the resulting suspension was raised to -1O0C after addition. The mixture was stirred for another 40 minutes during which time the internal temperature dropped to -180C. Then, ZnCl2 (0.5 M in THF, 220 mmol) was added via addition funnel over 15 minutes. The NaCl-ice bath was removed after addition and the mixture was warmed up to room temperature over 2 hours and was stirred at room temperature for another 0.5 hours. Chloroazaindole 2 (12.95 g, 71 mmol) and PdCl2(dppf)2 (5.8 g, 7.1 mmol) were added into the mixture and mixture heated at 58°C for 6 hours, then stirred at room temperature overnight. Analysis by HPLC showed >20:l ratio of product to starting material.
The reaction was quenched with NH4Cl (36 N aqueous, 25 ml) and the resulting inorganic salt was filtered off and washed with THF. The filtrate was concentrated to about 200 ml and IL of dichloromethane was added. The solution was washed with brine (3×500 ml) and dried (Na2SO4). The solution was concentrated and the residue was absorbed onto silica gel (25 g), then put on top of a silica gel (105 g) column and eluted with hexanes and EtOAc(hexanes:EtOAc=3:l to 0:1). Removal of the solvent gave crude coupled azaindole 3 which was then heated in refluxing EtOAc (350 ml) for about 0.5 hours. After an insoluble sparkling dark red solid was filtered off, and EtOAc was removed, a brown solid (14.86 g) was obtained, which was then dissolved in a refluxing solution of hexanes (40 ml) and EtOAc (120 ml). The resulting solution was cooled to room temperature and the product isolated by filtration to give a brown solid 3 (9.56 g, >99% pure by HPLC, 60% yield).
1H NMR (DMSO-d6, 300 MHz) (δ, ppm): 4.02(s, 3H), 6.63-6.65(m, IH), 7.56(t, / = 2.7Hz, IH), 8.04(s, IH), 8.64(d, / = 2.7Hz, IH), 8.74-8.75(m, IH), 9.62(d, / = 1.5Hz, IH), 11.78 (br, s, IH); LCMS: m/e 227 (M+H)+.
Analysis by ICP-MS showed
Example 3: Synthesis of Acylated Azaindole (4) from Coupled Azaindole (3)
C12H10N4O = 226.23 C15H12N4O4 = 312.28
3 4
To a solution of dichloromethane and nitromethane (4:1, 200 ml) in a 500 ml 3- neck flask cooled with ice-water bath, was added AlCl3 (22.3g, 168 mmoles) in portions. Then, 3 (4.75 g, 21.0 mmol) was added into the solution in portions. The internal temperature was raised from 1°C to 60C then back tol°C. ClCOCO2Me (3.9ml, 41.1 mmoles) was added into the solution dropwise using a syringe in over about 5 minutes. The resulting homogeneous solution was stirred at 00C for 10 minutes and then put in the cold room (about 00C ) for 15 hours without stirring. Analysis by HPLC after 15 hours showed that the ratio of 3:4:5 was 0:92:3. The reaction solution was then poured into cold 25% aqueous NH4OAc solution (500 ml) in portions. The organic layer was separated and the aqueous layer was extracted with DCM (300 ml, then 2×150 ml). The combined organic layers were washed with brine (2×300 ml) and dried (Na2SO4). Removal of solvent in vacuo gave ester 4 as a solid (4.85 g, 74%).
Analysis by ICP-MS showed
Example 4: Synthesis of Acylated Azaindole (5) from Acylated Azaindole (4)
C15H12N4O4 = 312.28 C14H10N4O4 = 298.25 4 5
To suspension of ester 4 (10.00 g, 32.1 mmol) in methanol (150 ml), K2CO3 (1
M, 150 ml, 150 mmol) was added. After the reaction mixture was stirred at room temperature for 1 hour methanol was removed in vacuo. The remaining reaction mixture was diluted with water to 1.2 L and washed with MTBE (2×400 ml). The aqueous phase was acidified with HCl (2 M, 185 ml, 370 mmol) to pH=l. The acid 5 (a grey solid) thus formed was filtered off and dried (9.29 g, 97% yield).
Analysis by ICP-MS showed
Example 5: Synthesis of Nitrile 6 from l-Boc-4-piperidone
1 ) NaHMDS, THF,
2) TFA, 3)NaHCO3,
Boc-N >=O 4) HCI . HHCCII
6
NaHMDS (2 M in THF, 8.6 ml, 17.2 mmol) was added into a solution of 1-Boc- 4-piperidone (3.0 g, 14.4 mmol) and benzyl cyanide (2.0 ml, 17.2 mmol) in THF (60 ml) at room temperature. The reaction mixture was heated at 50-600C (oil bath) until benzyl cyanide was consumed (as monitored by HPLC). The reaction was quenched by the addition of methanol (12 ml), and the solvent was removed in vacuo. TFA (30 ml, 402 mmol) was added to the residue and the resulting mixture was stirred at room temperature overnight. Most of the TFA was removed in vacuo and saturated NaHCO3 (100 ml) was added. The mixture was extracted with EtOAc (80 ml, 3×30 ml). The organic layers were combined and washed with brine, and dried (Na2SO4). After removal of the EtOAc, the remaining residue was dissolved in DCM (20 ml). The DCM solution was added dropwise to HCl (0.5 M in ether, 40 ml of 2M diluted to 160 ml with ether) at room temperature to form the hydrochloride salt of nitrile 6. The hydrochloride salt of nitrile 6 was then filtered off and was washed with ether (3×10 ml), and dried to afford 2.75 g of a yellow solid (81% yield).
xample 6: Synthesis of DS003 from Acylated Azaindole 5 and Nitrile 6
5 DS003
A 2 L flask was charged with acid 5 (9.29 g, 31.2 mmol), DIPEA (12.9 ml, 78 mmol), nitrile 6 (7.18 g, 36.3 mmol) and DMF (95 ml) subsequently. HATU (13.66 g, 35.9 mmol) was added the reaction mixture in portions over 10 minutes. The internal temperature rose to 27°C from 19°C. After the reaction mixture was stirred at room temperature for 3.5 hours, analysis by HPLC showed that the starting material was completely consumed. Ethanol (950 ml) was added and the resulting suspension was heated at reflux for lhour. The mixture was then cooled to room temperature and
DS003 was isolated by filtration and washed with ethanol (50 ml). The material was dried on a rotovap at 40-500C then by using an oil pump at room temperature to afford 10.58 g of DS003 (71% yield, >99% purity by HPLC).
1H NMR (CDCl3, 300 MHz) (δ, ppm): 2.58-2.65 (m, 2H), 2.91-2.99 (m, 2H), 3.48- 3.51(m, IH), 3.68-3.78 (m, 2H), 3.95-3.99 (m, IH), 4.11 (s, 3H), 7.27-7.46 (m, 5H), 8.16 (d, J = 5.1Hz, IH), 8.21-8.25 (m, IH), 8.60 (s, 2H), 9.82 (d, J = 3.9 Hz, IH), 11.75 (br, IH); LCMS: m/e 479.3 (M+H)+.
Analysis by ICP-MS showed
Paper
Synthetic Process Development of BMS-599793 Including Azaindole Negishi Coupling on Kilogram Scale
A new approach to the synthesis of 1 (DS003, BMS-599793), a small-molecule HIV entry inhibitor, is described. The initial medical chemistry route has been modified by rearranging the sequence of synthetic steps followed by replacement of the Suzuki coupling step by the Negishi conditions. Acylation of the resulting azaindole 7 under the Friedel–Crafts conditions is studied using monoesters of chlorooxalic acid in the presence of aluminum chloride. Polymorphism of 1is also investigated to develop conditions suitable for preparation of the desired Form 1 of the target compound. The new route is further optimized and scaled up to establish a new process that is applied to the synthesis of kilogram quantites of the target active pharmaceutical ingredient.
| Patent ID | Date | Patent Title |
|---|---|---|
| US7915283 | 2011-03-29 | INDOLE, AZAINDOLE AND RELATED HETEROCYCLIC 4-ALKENYL PIPERIDINE AMIDES |
| US7348337 | 2008-03-25 | Indole, azaindole and related heterocyclic 4-alkenyl piperidine amides |
////////BMS-599793, BMS 599793
O=C(C(=O)c3cnc2c3c(OC)cnc2c1cnccn1)N4CC/C(CC4)=C(\C#N)c5ccccc5
or
COC1=CN=C(C2=C1C(=CN2)C(=O)C(=O)N3CCC(=C(C#N)C4=CC=CC=C4)CC3)C5=NC=CN=C5
| Molecular Formula: | C57H60N10O12S2 |
|---|---|
| Molecular Weight: | 1141.285 g/mol |
4-tert-butyl-N-[6-[[5-[[6-[(4-tert-butylphenyl)sulfonylamino]-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]oxymethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]benzenesulfonamide
N,N′-(6,6′-(2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis- (methylene)bis(oxy)bis(5-(2-methoxy phenoxy)-2,2′-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide)
Mp: 72−74 °C.
1 H NMR (400 MHz, CDCl3): δ 1.25 (6H, s), 1.29 (18H, s), 3.84−3.90 (4H, m), 4.27−4.31 (2H, m), 6.84−6.87 (3H, t), 6.97−7.00 (2H, dd), 7.09−7.13 (3H, t), 7.43−7.45 (10H, m), 9.0−9.01 (4H, d), 8.43 (2H, br s);
13C NMR (100 MHz, CDCl3): δ 25.88, 30.02, 34.10, 55.01, 61.53, 77.36, 108.43, 111.4, 118.73, 120.4, 124.09, 124.34, 126.67, 127.38, 128.35, 135.30, 138.25, 144.74, 148.62, 150.99, 156.07, 156.71, 160.56;
MS: m/z 1142.2 (M + H);
Elem. Anal: Found: C 59.87, H 5.20, N 12.38; Calcd for C57H60N10O12S2: C 59.99, H 5.30, N 12.27
A new and efficient synthetic process for the synthesis of an endothelin receptor antagonist, bosentan monohydrate, involves the coupling of p–tert-butyl-N-(6-chloro-5-(2-methoxy phenoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide (7) with (2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (14) as a key step. This new process provides desired bosentan monohydrate (1) with better quality and yields. Our new methodology consists of technical innovations/improvements which totally eliminate the probability for the formation of critical impurities such as pyrimidinone 8, dimer impurity 9, and N-alkylated impurity 13 in the final drug substance.
1H NMR PREDICT
13 C NMR PREDICT
Org. Process Res. Dev., 2013, 17 (8), pp 1021–1026
DOI: 10.1021/op400100s
/////////////
CC1(OC(C(O1)COC2=NC(=NC(=C2OC3=CC=CC=C3OC)NS(=O)(=O)C4=CC=C(C=C4)C(C)(C)C)C5=NC=CC=N5)COC6=NC(=NC(=C6OC7=CC=CC=C7OC)NS(=O)(=O)C8=CC=C(C=C8)C(C)(C)C)C9=NC=CC=N9)C
The transamination-chemistry-based process for sitagliptin is a through-process, which challenges the crystallization of the active pharmaceutical ingredient (API) in a batch stream composed of multiple components. Risk-assessment-based design of experiment (DoE) studies of particle size distribution (PSD) and crystallization showed that the final API PSD strongly depends on the seeding-point temperature, which in turn relies on…
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