New Drug Approvals

Home » Uncategorized » Solifenacin, солифенацин , سوليفيناسين , 索利那新 , コハク酸ソリフェナシン

Solifenacin, солифенацин , سوليفيناسين , 索利那新 , コハク酸ソリフェナシン

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

PAYPAL DONATIONS

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Blog Stats

  • 1,302,568 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,773 other followers

add to any

Share

Solifenacin Structural Formulae V.1.svg

SOLIFENACIN, YM-905

MF C23H26O2, a molecular weigt  362.4647

CAS 242478-37-1

солифенацин [Russian]
سوليفيناسين [Arabic]
索利那新 [Chinese]

242478-37-1 (Solifenacin )
242478-38-2 (Solifenacin Succinate)

Image result for 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:

Figure imgf000002_0001

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]

Side effects

Main article: Anticholinergic

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]

Interactions

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]

Pharmacology

Mechanism of action

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]

Pharmacokinetics

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 Nglucuronide, 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]

Chemistry

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]

Image result for Solifenacin

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:

Figure imgf000004_0001

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:

Figure imgf000004_0002

Scheme 3

History

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]

Society and culture

Economics

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:

VESIcare (solifenacin succinate) Structural Formula Illustration

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

str0

 

PAPER

An Improved Process for the Preparation of Highly Pure Solifenacin Succinate via Resolution through Diastereomeric Crystallisation

Chemical Research and Development, APL Research Center, Aurobindo Pharma Ltd., Survey No. 71 & 72, Indrakaran (V), Sangareddy (M), Medak Dist-502329, Andhra Pradesh, India
Department of Engineering Chemistry, A. U. College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India
Org. Process Res. Dev., 2014, 18 (8), pp 934–940
*E-mail: pauldouglas12@gmail.com. Tel.: +91-9347098430.
Abstract Image

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.

Image result for solifenacin succinate

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].

[1860-5397-9-265-6]
Figure 6: Structures of solifenacin (2.57) and muscarine (2.58).

Image result for solifenacin succinate

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].

The enantioselective synthesis of the tetrahydroisoquinoline fragment is achieved via an asymmetric addition of phenylethylzinc to the imine N-oxide 2.66 yielding the corresponding 3,4-dihydroisoquinoline-N-hydroxide 2.68. Further reductive cleavage of the hydroxylamine moiety followed by activation with 4-nitrophenyl chloroformate [79] yields the intermediate 2.69. In the last step of the sequence the addition of (R)-quinuclidinol generates solifenacin (2.57).

  1. 76 Broadley, K. J.; Kelly, D. R. Molecules 2001, 6, 142–193.
    Return to citation in text:
  2. 77  Daeniker, H. U.; Grob, C. A. Org. Synth. 1964, 44. doi:10.1002/0471264180.os044.30
    Return to citation in text:
  3. 78  Arai, N.; Akashi, M.; Sugizaki, S.; Ooka, H.; Inoue, T.; Ohkuma, T. Org. Lett. 2010, 12, 3380–3383. doi:10.1021/ol101200z
    Return to citation in text:

str0 str2 str3

str0

 str0 str2 str3

PATENT

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.

Figure imgb0001

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

Figure imgb0002

A specific method for producing Solifenacin or its HCl salt is also disclosed, as depicted by the following scheme (Scheme-1).

Figure imgb0003

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,

Figure imgb0004

Figure imgb0005

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%
This document discloses production of Solifenacin hydrochloride and oxalate-containing composition, respectively in reference examples 2 and 4. It states that the hydrochloride and oxalate salts were also not possible to prepare in pure form and only the succinate salt was obtained in a pure form. It also states that the hydrochloride and oxalate containing composition contains the impurities A and B above (A and B both are chiral impurities), at 0.85% or more and 0.50% or more compared to Solifenacin, respectively, even after salt formation and crystallization steps. Thus, there exists a need to prepare both the HCl and oxalate salts as well as other pharmaceutically acceptable salts of Solifenacin in a form that is chemically and chirally pure, is solid and can be handled on an industrial scale. There also exists a need to prepare chemically pure Solifenacin base.
EP 1726304 more specifically discloses the method of preparation of the Solifenacin using an alkoxide base, which makes the process commercially viable. Compared to the process described in US 6,017,927 , instead of using sodium hydride having disadvantages like combustion risk and contamination of mineral oil, this method uses an alkoxide base, which overcomes these drawbacks. This document discloses the presence of certain alkylated impurities, which may be present in the Solifenacin base and salts upto 1% concentration.
EP 1757604 discloses four different processes for the preparation of Solifenacin base and the succinate salts.
WO 2008011462 discloses processes for the preparation of Solifenacin base using sodium hydride, and also discloses crystalline form of Solifenacin base and crystalline form of Solifenacin hydrochloride. The salt is prepared as an intermediate step to obtain the succinate salt of Solifenacin in a chemically pure form (purity by HPLC: 99.74%). Nothing is stated about the purity of either the succinate salt or the HCl salt obtained through this process.

WO 2008062282 discloses a process for the preparation of Solifenacin, which is shown below. (Scheme 6).

Figure imgb0006
WO 2008077357 application covers process for preparing Solifenacin using non-nucleophilic base. Reaction of crude Solifenacin base with L-tartaric acid provides crystalline Solifenacin hydrogen tartrate salt, which is then transformed to optically pure base as well as other salts (succinate).
WO2008019055 application discloses process for optical resolution of 1-phenyl-1,2,3,4-tetra hydroisoquinoline, which is one of the key intermediate of Solifenacin.
WO2008019103 discloses amorphous and crystalline forms of Solifenacin base as well as process for preparation of the same. In this document they have disclosed form B1 of Solifenacin base prepared by slurring amorphous Solifenacin base in DIPE solvent.
WO2008013851 discloses amorphous and crystalline forms-I and II of Solifenacin succinate as well as process for preparation of the same.
WO2008120080 disclosed a process wherein 3(R)-quinuclidinol is activated by reaction with bis [1H-1,2,4-triazol-1-yl]-methanone, and the solution obtained is reacted with 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline to give Solifenacin.
US 20080114029 discloses new polymorphic form of I(S)-phenyl-1,2,3,4-tetrahydroisoquinoline, a key intermediate for the preparation of Solifenacin base.
Though several processes for preparing both the Solifenacin base as well as hydrochloride and oxalate salts are known, very little is said about the chemical purity of any of them. Most of the processes describe the necessity of formation of the succinate salts for improving the chemical purity. Therefore, there is a need to develop a safe modified process for preparing Solifenacin (free base) which give better yields and improved purity. There also is a requirement to prepare such other new salts of Solifenacin, which not only is chemically and chirally pure but also have superior pharmaceutical properties over one or more of the known salts of Solifenacin. We herein disclose an improved process for preparing Solifenacin base in a pure form (chemically and chirally) and also chemically and chirally pure hydrochloride, oxalate, succinate, gentisate, citrate, hydrobromide, sulphate, nitrate, phosphate, maleate, methane sulphonate, ethane sulphonate, benzene sulphonate, tosylate, α- ketoglutarate, glutarate, nicotinate, malate, 1,5-naphthalene disulfonate and ascorbate salts of Solifenacin. In a preferred embodiment, these salts have atleast 98% purity and may be used to prepare the pure Solifenacin base from the impure base through the intermediate formation of any of these salts. Additionally, several of these salts have superior pharmaceutical properties over one or more known salts of Solifenacin.

Image result for Solifenacin

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.

% Chemical purity 96.87 %
% Chiral purity by HPLC – 98.83 %.

CLIP

Image result for Solifenacin

https://www.researchgate.net/figure/235670427_fig2_Figure-6-Scheme5-Synthesis-of-the-chiral-drug-solifenacin

PATENT

WO2014067219A1.

 

PATENT

https://www.google.com/patents/EP2406257A1?cl=enhttps://www.google.com/patents/EP2406257A1?cl=en

Image result for Solifenacin

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;

Figure imgf000003_0003

Solifeπacin and its pharmaceutically acceptable salts are first reported in US Patent No. 6,017,927 (927′), which disclosed two’ synthetic routes “Route-A and Route-B” for the preparation of (I RS, 3’RS)- Solifenacin and (I S, 3’RS)-Solifenacin as shown in Scheme- 1 :

Figure imgf000004_0001

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.

Figure imgf000005_0001

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.

Figure imgf000005_0002

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:

Figure imgf000010_0001
Figure imgf000012_0001

3-Quinuclidinol χ= halogen,

R=alkyl

Figure imgf000012_0002

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

PATENT

1. WO9620194A1 / US6017927A.

2. J. Med. Chem. 200548, 6597-6606.

3. WO2007076116A2.

PAPER

str0

str2
str3
High-performance liquidchromatography (HPLC)
An in house LC Isogradient method was devel- oped for the separation of all possible stereoisomers ofsolifenacinsuccenate. Waters make HPLC system equipped with 515 pump and UV detector was used for betterseparation and quantification of impurities. Used for the preparation of mobile phase wasin the ratio of n-Hexane:Isopropyl alcohol:Ethanol:Diethylamine (85:7.5:7.5:0.02), particle 5 µmsize,Chiraipak AD-H,250X4.6mm column was used with a time 60min isogradient programcolumn overtemperature was 25 º C and column eluent was monitored by UV detector at 215nm. This LC method was able to separate all the process-related chiralsubstanceswith good resolution. An in house LC Isogradient method was developed for the separation of N-oxide impurity and solifenacin succenate. SHIMADZUmake HPLCsystem equipped with 436 pump and UV detector was used for betterseparation and quantification ofimpurities. Used for the preparation of mobile phase wasin the buffer (1.36 gm of potassium dihydrogen ortho- phosphate in 1000ml water containing 1.0 ml of tri- ethylamine), particle5 µm size,kromasil 100- 5C8 ,250X4.6mm columnwas used with a time 30min isogradient program.column overtemperature was 30 ºC and column eluent was monitored byUV detector at 210nm. This LC method was able to separate N- oxide and solifenacinwith good resolution.
REFERENCES FOR ABOVE
[1] R.F.Majewski, K.N.Camphell, S.Dykstra, R.Covington, J.C.Simms; Anticholinergic agents. Esters of 4-alkyl-(or 4- polymethylene)amino-2- butynols, J.Med.Chem., 8, 719-720 (1965).
[2] K.E.Andersson; Current concepts in the treatment
of disorders of micturition, Drugs, 35, 477-494
(1988). [3] I.Masatoshi; Process for producing solifenacin or
its salts, EP 1757604 A1, (2007). [4] P. Jprdo, S. Laura, M. Ester, A. Ignasi, B.Jordi, An
improved process for the synthesis of solifenacin, WO 2008/062282A2, 2008. [5] R.Naito, Y.Yenetoku, Y.Okamoto, A.Toyoshima, K.Ikeda, M.Takeuchi; Synthesis and antimuscarinic
properties of quinuclidin-3-yl 1,2,3,4-
tetrahydroisoquinoline-2-carboxylate derivatives as
novel muscarinic receptor antagonists, J.Med.Chem., 48, 6597-6606 (2005)
PATENT

WO2010103529A1.

 PAPER
PATENT
WO2013147458A1.

 

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
PATENT CITATIONS
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

References

 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.

Solifenacin
Solifenacin Structural Formulae V.1.svg
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
Pregnancy
category

AU: B3

US: C (Risk not ruled out)

Routes of
administration
Oral
Legal status
Legal status

UK: POM (Prescription only)

US: ℞-only

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 Yes
ChemSpider 135771 
UNII A8910SQJ1U Yes
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]

Title: Solifenacin
CAS Registry Number: 242478-37-1
CAS Name: (1S)-3,4-Dihydro-1-phenyl-2(1H)-isoquinolinecarboxylic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester
Additional Names: (1S,3¢R)-3¢quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate
Molecular Formula: C23H26N2O2
Molecular Weight: 362.46
Percent Composition: C 76.21%, H 7.23%, N 7.73%, O 8.83%
Literature References: Muscarinic M3 receptor antagoinst. Prepn: M. Takeuchi et al., WO 9620194; eidem, US 6017927 (1996, 2000 both to Yamanouchi). Receptor binding studies: K. Ikeda et al., Arch. Pharmacol. 366, 97 (2002); selectivity profile: A. Ohtake et al., Eur. J. Pharmacol. 492, 243 (2004). Clinical study in overactive bladder: C. R. Chapple et al., Br. J. Urol. 93, 303 (2004); F. Habb et al., Eur. Urol. 47, 376 (2005). Clinical comparison with tolterodine: C. R. Chapple et al., ibid. 48, 464 (2005). Review of efficacy and tolerability studies: S. Brunton, L. Kuritzky, Curr. Med. Res. Opin. 21, 71-80 (2005); of clinical development: C. K. Payne, Drugs 66, 175-190 (2006).
Properties: Yellow oil.
Derivative Type: Succinate
CAS Registry Number: 242478-38-2
Manufacturers’ Codes: YM-905
Trademarks: Vesicare (Yamanouchi)
Molecular Formula: C23H26N2O2.C4H6O4
Molecular Weight: 480.55
Percent Composition: C 67.48%, H 6.71%, N 5.83%, O 19.98%
Properties: White to slightly yellowish crystals, mp ~145°. Freely sol in acetic acid, water, methanol, dimethylsulfoxide.
Melting point: mp ~145°
Therap-Cat: In treatment of urinary incontinence.
Keywords: Antimuscarinic.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Paypal Donate

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,773 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

View Full Profile →

TWITTER

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: