Title of Invention	A METHOD FOR THE PREPARATION OF SOLIFENACIN
Abstract	A new method for the preparation of solifenacin by reacting quinuclidin-3-ol and bis (p-nitro phenyl) carbonate to form (3/0-l-azabicycIo["2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV); and treating (3/?)-l-azabicyclo[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV) with (hS")-l-phenyl-1, 2, 3. 4-tetrahydroisoquinoline in an inert atmosphere to form a Solifenacin base which is converted into its pharmaceutical!)" acceptable salts. The invention also provide new compound. (3/?)-l-azabicyclo[2.2.2]oct-3-yl 4-nilrophenyl carbonate, which is used as an intermediate for the preparation of Solifenacin base and a process for the preparation thereof.

Title of Invention

A METHOD FOR THE PREPARATION OF SOLIFENACIN

Abstract

A new method for the preparation of solifenacin by reacting quinuclidin-3-ol and bis (p-nitro phenyl) carbonate to form (3/0-l-azabicycIo["2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV); and treating (3/?)-l-azabicyclo[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV) with (hS")-l-phenyl-1, 2, 3. 4-tetrahydroisoquinoline in an inert atmosphere to form a Solifenacin base which is converted into its pharmaceutical!)" acceptable salts. The invention also provide new compound. (3/?)-l-azabicyclo[2.2.2]oct-3-yl 4-nilrophenyl carbonate, which is used as an intermediate for the preparation of Solifenacin base and a process for the preparation thereof.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 oft 970) As amended by the Patents (Amendment) Act, 2005 & The Patents Rules, 2003 As amended by the Patents (Amendment) Rules, 2005 COMPLETE SPECIFICATION (Sec section (0 and rule 13) TITLE OF THE INVENTION A NEW METHOD FOR THE PREPARATION OK SOL1FENACIN AND NEW INTERMEDIATE THEREOF. APPLICANTS Name Nationality Address Megafinc Pharma(P) Ltd. Indian Company 4,h Floor. SKTilNA. 55. Maharshi Karve Road. Marine Lines. Mumbai - 400 002. Maharashtra. India. PREAMBLE I O THE DESCRIPTION ["he following specification particularly describes the nature of this invention and the manner in which it is to be performed: TECHNICAL FIELD: The present invention relates to a new method for the preparation of Solifenacin of formula (I): and its pharmaceuticallv acceptable salts. The present invention also relates lo (3/0-1-azabicyclo \|2.2.2\|ocl-3-y) 4-nitrophenyl carbonate o! formula (IV); which is used as an intermediate for the preparation of Solifenaein. The present invention also relates to a process for the preparation of the compound of formula (IV). BACKGROUND OK THE INVENTION: Solifenaein Succinate is commercially marketed as pharmaceutical)}' active substance indicated for the treatment of overactive bladder with symptoms of urinary incontinence, urgency and high urinary frequency. Solifenaein succinate is acting as a selective antagonist to the M (3)-reecptor. The chemical name of the Solifenaein is {)S)-(3R)-]-a/abieylo \|2.2.2\| Oct-3-yl-3.4-dihydro-]-pheny]-2(1 11)-isoc]uinolinc carboxylate of formula (I); ") Formula 1 Solifenacin succinate is the inlcrnaiional common denomination for bulancdioic acid compounded with (lS)-pR)-l-a/abicyclo \|2.2.2\|oct-3-yl-3.4-dihydro-l-phcnyl-2(ll l)-isoquinolinecarboxylaie (1:1). having an empirical formula ofC23H26N2O2 .C4UO4 and the structure represented in Ibrmuia VI given below; Formula (VI) Solifenacin and its pharmaceutical!}' acceptable salts arc first reporlcd in US Patent No. 6.017.927 (927"). which disclosed two synthetic routes "Route-A and Roulc-B" for the preparation of (IRS. 3'RS)-So]ifenacin und (IS. 3RS)-Solifcnacin as shown in Scheme-1; .3 Both (he routes have several drawbacks such as: a) Use of very hazardous and pyrophoric reagent. Nail, in fhe process which is very diflieuh to handle and thus makes the process unsafe to handle at industrial level. b) Use of ethyichloroformate to prepare ethylcarboxylate derivative in route A which is lachrymatory in nature. c) Hthylcarboxylatc derivative produces elhanol as a by-product during trans-esterifiealion reaction in the subsequcn! reaction that interferes in nuclcophilic attack against Solilenacin in the presence of a base and hence it is necessary to remove elhanol from the reaction mixture in the form of a/.eotrope with toluene or the like simultaneously while carrying out the reaction, so as lo control the reaction. d) Use of column chromatography for the purification of solifenacin base, which makes the process industrially not feasible. 0 The reaction requires longer lime for the completion cuid hence turn around lime of ihe batch in production makes it less attractive. 4 International Patent Application No WO2005/075474 disclosed another synthetic route for the preparation of Solifenacin and Solifenaein Succinate as shown in Sebeme-2. Solifenacin succinate 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 ehlylchlorofomrate in the first step and produces ethanol as a by-product in the second step. Yet another International Patent application no W02005/I05795AI discloses an improved process for preparing Solifenacin as represented in Schemc-3. wherein leaving group (l.v) can be II i-imida/ole-1-yl. 2.5-dioxopyrrolidin-l-yloxy. 3-methyl-lH-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 dimethyUonnamide or toluene alone as a reaction medium. The process described herein represents few draw backs such as. use ofha/.ardous sodium hydride, use of chromatographic purifications, and use of moisture sensitive leaving groups (l.v) and hence handling of the reaction is difficult, further the leaving groups used are expensive and thus making [he process uneconomic. n Hence, there is need of efficient process for producing solifenacin and ils succinate sail which is sale io handle, industrially Feasible, and economically viable. OBJECTS OF THE PRESENT INVENTION: An object of the present invention is to provide a new method for the preparation of Solifenacin and / or its salts, wherein the process is economical, simple, efficient, cost-effective and easy io cam' out. Another object of the invention is to provide the new method for the preparation of Solifenacin and /or its salts with high yields and substantially pure and l"rec from impurities and thus making the process efficient. Yet another object of the invention is to provide the new method for the preparation of Solifenacin and / or its salts in a single pot where in isolation of intermediates by nitrations arc avoided to reduce exposure of the production executive to the chemicals and to reduce the turn around time of the total time cycle per batch. Another object of the invention is to provide the new method for the preparation of Solifenacin and / or its salts which avoids hazardous and costly reagents or chemicals and involves simple work-up thus making the process simple and cost-effective. 6 Yet another object of the invention is lo provide the new method for the preparation of Solifenacin and / or its salts in which nitro-phenoi is a by-product which is easily separable and recoverable from the reaction mixture by vacuum distillation and giving monitory benefits to the process. Yet another object of the invention is to provide a new compound. (3/0-l-a/abicyclo\|2.2.2\|oct-3-yl 4-nitrophcnyl carbonate, of formula (IV). which is used as intermediate for the production of Solifenacin. Yet another object of the invention is to provide a process for the preparation of (3/0-1 -azabicyclo J2.2.2] ocl-3-yl 4-nilrophenyl carbonate compound of formula (IV) which is used as an intermcdiale for the production of Solifenacin. DETAILED DESCRIPTION OK THE INVENTION The present invention provides a novel method for efficiently preparing Solifenacin and/or one of its pharmaceuiically acceptable salts. According to the process of present invention, solifenacin is obtained by using milder reaction conditions and without the need for laborious operations such as chromatographic purifications or solvent distillations, and hazardous chemicals. The process for making the compound (1) involves two chemical reactions. Accordingly, it will be described as a two-step process. While the steps are normally run separately, that is consecutively, the process may nonetheless be conveniently performed in a one pot arrangement as well. e.g. as a one pot process with out isolation of the intermediate product According to the invention, there is provided a new method for the preparation of Solifenacin ol' formula (I); the method comprises: a. reacting (R)-c\|uinuclidm-3-ol of formula (II) and bis(p-nitrophcnyl)carbonate of formula (III) to form (3/?)-l-azabieyclo\|2.2.2\|oct-3-yl 4-nitrophcnyl carbonate of formula (IV); and 7 b. treating the reaction mixture comprising (3/0-l-a/.abicyclo\|2.2.2]oct-3-yl 4-nitropheny' carbonate of the formula (IV) of step (a) with (iS)-Uphenyl-I. 2. 3. 4-tctrahydroisoquinoline ol formula (V) to obtain (3R)-3-\|{LS)-l-phenyl-1.2.3.4-tctrahydro isoquinolinylcarhonyloxy\|-l-a/.abicyclo)2.2.2 [octane (Solifenaein) of formula (I). Step (a) of the above method comprises reacting (R)-quinuclidin-3-ol formula (II) and bisfp-nitrophenyl)carbonate of formula (111) in an organic solvent and in an inert atmosphere at temperature of- 40 to IO0°C. Step (a) may also be carried out in the presence of suitable base. Preferably, step (a) is carried out temperature of 0 to 30°C. more preferably. 25 to 30°C. The organic solvents used in the above reaction of step (a) is selected from the group consisting of a C1-C10 ether, a C5-C8 cyclic ether. C2-H) aliphatic ester. C2-C8 aliphatic amides. sulfoxide. C5-CS cyclic amines. C5-C10 aliphatic amines. C1-C8 chlorinated hydrocarbon, and mixtures of thereof: preferably, the solvent is selected from dimethyl fonnamide. N-methylpyrolidone. N'.N- 8 dimethylacetamide. dimethyl sulfoxide, chlorinated hydrocarbon, pyridine, and mixtures therco]; more preferably, the solvent is dimethylformamidc. The reaction time of step (a) is invariably depends on the lemperaiure condition used to carry out the step (a). The reaction time increases with decrease in temperature. The course of the reaction is monitored by a suitable analytical method, for instance by 11 PLC and/or by TLC. and ihc second step of the reaction process does not start until the first reaction step is essentially completed- i.e. more than 95%. preferably more than 98% of the starting materia) has been converted /consumed which requires around 2-3 hours at 25-30°C. 'The above mentioned step (b) comprises treating the reaction mixture comprising (3tf)-l-azabicyclo\|2.2,2\|oct-3-y] 4-nilrophcnyl carbonate of formula (IV) of step (a) with (1S)-1-phenyl-1. 2, 3. 4-teirabydroisoquinolinc of formula (V) in an organic solvent and in an men atmosphere at temperature of- 20 to 50°C to obtain (3JV)-3-\|(l.V)-l-phcnyl-L2.3.4-tetrahydro isoquinolinylcarbony-loxy]-l-azabicyclo\|2.2.2\|oclane fSolifenacin) of formula (1). The process of step (b) typically comprise adding (IS)-1-phenyl-1. 2. 3. 4-teirahydroisoquino!ine of formula (V) to the reaction mixture of step fa) in portion wise or at once, as such or dissolved in ihe organic solvent. Step (b) proceeds while stirring the reaction mixture. Step (b) is carried out preferably al temperature of 0 and 30°C: most preferably 25 to 30°C. Step (b) of the method is monitored by a suitable analytical process, for instances by I (PLC and/or by TLC. The above mentioned method further / optionally comprises A. isolating (37()-'-3/abicyclo\|2.2.2\|oct-3-yl-4-nitrophenyl carbonate of formula (IV) from (he reaction mixture obtained in step (a) by a.separating out the nitro-phenol from the reaction mixture obtained from step (a) by distilling out the organic solvent under vacuum from the reaction mass of step (a) to get residue. 9 adding water to the residue, adjusting the pH of the resultant mixture to I to 2 using an acid, preferably hydrochloric acid; extracting the reaction mass with a water immiscible organic solvent to separate out nitro-phenol: b.isolating the compound o!" formula (IV) by extracting the aqueous layer obtained from step (a) with a water immiscible organic solvent to separate the compound of formula {IVj. diluting the organic layer comprising the compound of formula (IV) with water, adjusting pi 1 of the resulting mixture to 9 to 13. preferably between 9 to 10 using base, separating the organic layer, washed with water, and then concentrated to yield compound of formula (iV) as a syrup. B. using the compound of formula (IV) in step (b) to obtain the compound of formula (I). The method of the invention further comprises isolalion of (3/0-3-l(l-3-l-phenyl-1.2.3.4-tcl!'ahYdro-2-)soquim.l]iny]carbonyJoxy\|-]-azabicyclol2.2.2loctane of formula (1) bv a. Separating nitro-phcnoJ from the reaction mass obtained from s\cp (b): by adding water to the reaction mass obtained from step (b) followed by adjusting pH to 1-2 by using acid, preferably hydrochloric acid, adding water immiscible organic solvent to the reaction mass followed by mixing the reaction mass, separating out ihc water immiscible organic layer comprising nitre-phenol and aqueous layer comprising hydrochloride salt of (3/i)-3-\|( \S)-\ -phenyl-1.2.3.4-letrahydro-2-isoquinoliny! carbony!oxy\|-l-azabicyclo\|2.2.2 [octane of formula (I); and b. isolating (3R)-3-[( LS)1 -phenyl- L2.3.44etrahydro-2-isoquinolinyJcarbonyloxy\|-1-azabicyc]o \|2.2.2loctane of the formula (I) by extracting the hydrochloride salt of compound oi' formula (]) in a water immiscible organic solvent from the aqueous layer obtained from the above mentioned step (a), adding water to the organic layer followed by adjusting the pH of the solution to 9 to 13 by adding base followed by separating aqueous layer and organic layer comprising (3/R)-3-[( l.S) I-phenyl-1.2.3.4-tetrahydro-2- isoquinohnylcarbonyloxy\|-l-.abicyclo 12.2.21 octane of formula (I): washing the organic layer with water and concentrating the organic layer to yield compound of (he formula (1) as syrup /oil. 10 The water immiscible organic solvent used in the separation of p-nitro phenol is selected to essentially separate die by-product nitro phenol from the reaction mixture. The organic solvent comprises, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like: ethers such as diethyl ether, diisopropylcther. melhyl-/tert-butylether and the like: hydrocarbons such as toluene, xylene, heptane, pentane. cyclohexane and the like: and mixtures of thereof: preferably, the solvent is selected from ethers, more preferably, diisopropylelhcr. The above mentioned method further comprises isolation of nilro phenol as potential by-product by distilling out ether from the ether layer comprising niiro-phenol obtained in the above mentioned step fa). The water immiscible organic solvent used for the extraction of solifenaein hydrochloride selected from, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like: ethers such as diethyl ether, diisopropylcther. methyl-/tert-butylether and the like: hydrocarbons such as toluene, xylene, heptane, pentane. cyclohexane and the like: chlorinated hydrocarbons such as dichloromethanc. dichlorethanc. chloroform, and the like, and mixtures of thereof: preferably, said solvent is selected from hydrocarbons, or chlorinated hydrocarbons : more preferably dichloromethanc. Preferably, the pH of the solution of step (b) is adjusted to 9 to 13. The pll adjustment in step (b) is carried out using base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium hydroxide and the like, preferably ammonium hydroxide. The above mentioned method further comprises converting a Solifenaein base of the compound o\' formula (I) into its pharmaceutically acceptable salts. The compound of the formula (J) as oil / syrup is dissolved in an organic solvent and treated with the suitable acid selected from organic acids or inorganic acids to get salt. The acid can be hydrobromic acid or succinic acid: preferably succinic acid. According to the present invention, the method for producing the Solifenaein Succinate of formula (VI) comprises: dissolving the Solifenaein of formula (1) obtained in step (b) in a organic solvent and 11 then treating the same with succinine acid cither in solid form or in dissolved form using the organic solvent, the reaction mixture is healed to dissolve the contents, cooled and the product precipitated is isolated by filtration which is further dried under vacuum to yield the Sotifenacin Succinalc of formula (V!). The organic solvent is selected from ketones such as acetone, ethyl methyl ketone, methylisobulylkcione: esters such as ethyl acetate, isopropyl acetate, isobuiyl acetate and the like: alcohols such as methanol, ethanol. isopropanol. butanol. lerl-butanol and like: ethers such as diethylethcr. diisopropylelher. mclhy]-/e/7-bmylethcr and the like: hydrocarbons such as toluene, xylene, heptane, pematne. eyclohexane and the like: and mixtures of thereof. Preferably, said solvent is selected from alcohols or ketones or mixtures thereof, more preferably said solvent is ethanol or acetone or mixtures thereof. According to the invention. Solifencin base of formula (1) and Solifcnaien Succinalc salt of formula (VI) is having yield of 81 % and 76.1 % respectively and purity of 98.0% and 99.93% respectively by HPLC (High performance liquid chromatography). The chiral purity of Solifenacin base of formula (I) and its Succinate salt of the formula (V[) is 99.8% and 99.9% respeclivcly by HP1.C using chiral column. The process of the present invention provides the Solifenaicin Succinate in highly pure form and free from potential known and unknown impurities. 12 According to the invention, there is provided a new compound (3tf)-l-azabicyclo\|2.2.2]ocl-3-yl 4-nitrophenyl carbonate of formula (IV); as an intermediate of Solifenacin. According to the invention, there is provided a process for the preparation of new compound, (jJiy l-azabicyclo[2.2.2\|oct-3-yl 4-nitrophenyl carbonate of formula (IV); as an intermediate of Soiifenacin, the process comprises; a. reacting (R)-quinuclidin-3-ol of formula (U) and bis (p-nitro phenyl) carbonate of formula (III) to form (3J?)-l-azabicycIo[2.2.2]oct-3-yI 4-nilrophenyl carbonate of formula (IV): and b. isolating the compound of the formula (IV) from the reaction mass ol~ step (a). 13 The step (a) comprises reacting (R)-quinuclidino-oi formula (II) and bis(p-nitrophenyl)carbonate of formula (111) in an organic solvent and in an inert atmosphere at temperature of- 40 to I0()°C. The step (a) may also be carried out in the presence of suitable base. Preferably, step (a) is carried out temperature of 0 to 30°C more preferably. 25 to 30°C. The organic solvents used in the above reaction of step (a) is selected from the group consisting of a CI-CIO ether, a C5-C8 cyclic ether, C2-10 aliphatic ester. C2-C8 aliphatic amides, sulfoxide, C5-C8 cyclic amines, C5-C10 aliphatic amines. C1-C8 chlorinated hydrocarbon, and mixtures of thereof; preferably, the solvent is selected from dimethylformamide. N-methylpyroIidone, N,N-dimethylacetamide, dimethyl sulfoxide, chlorinated hydrocarbon, pyridine, and mixtures thereof; more preferably, the solvent is dimelhylformamide or dichloromethane or pyridine; most preferably the solvent is dichloromethane. The reaction time of step (a) is inversely proportional to the temperature condition used to carry out step (a). The reaction time increases with decrease in temperature. Step (a) of the reaction is monitored by a suitable analytical method, for instance by HP1X and/or by TLC and is allowed to complete the reaction more than 95%. preferably more than 98% which requires around 2-3 hours at 25-30°C. The compound of formula (IV) is isolated from the reaction mixture obtained from step (a) by a. separating out the nitro-phenol from the reaction mixture obtained from step (a) by distilling out the organic solvent under vacuum from the reaction mass of step (a) to get residue, adding water to the residue, adjusting the pH of the resultant mixture to 1 to 2 using an acid, preferably hydrochloric acid; extracting the reaction mass with a water immiscible organic solvent to separate out nitro-phenol; b. isolating the compound of formula (IV) by extracting the aqueous layer obtained from step (a) with a water immiscible organic solvent to separate the compound of formula (IV). diluting the 14 organic layer comprising the compound of formula (IV) with water, adjusting pH of the resulting mixture to 9 to 13, preferably between 9 to 10 using base, separating the organic layer, washed with water, and then concentrated to yield compound of Formula (IV) as a syrup. The organic solvent used for the separation of nitro-phenol is selected from esters such as ethyl acetate, isopropyl acetate, isobutyi acetate and the like; ethers such as diethyl ether, diisopropylether. methyI-/e/7-butylether and the like; hydrocarbons such as toluene, xylene, heptane, penlanc. cyclohexane and the like; and mixtures of thereof; preferably, said solvent is selected from ethers such as diisopropylether. The process further comprises distilling out the solvent from the ether layer comprising nitro-phenol obtained from step (a) to obtain nitro-phenol. The organic solvent used for the extracting the compound of formula (IV) is selected from, esters such as ethyl acetate, isopropyl acetate, isobutyi acetate and (he like; ethers such as diethyl ether, diisopropylether. methyl-/t77-butyiethcr and the like; hydrocarbons such as toluene, xylene, heptane, pentane, cyclohexane and the like; chlorinated hydrocarbons such as dichloromethanc. dichiorethane, chloroform, and the like, and mixtures of thereof; preferably, said solvent is selected from chlorinated hydrocarbons such as dichloromethanc The base used to adjust the pH is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium hydroxide and the like, more preferably the base used for the pH adjustment is ammonium hydroxide. The isolated intermediate (IV) from step (a) is used for the preparation of solifenacin of formula (I). Quinuclidin-3-oi of formula (II) and l-pheny(-I,2,3,4-tetrahydroisoquinoiine of formula (V) used in the above mentioned method may be either (R)-enantiomer. (S)-enantioj-ncr or racemate depend upon the isomer of solifenacin need to be prepared and are shown below. 15 Achieving the desired stereochemistry of the solifenacin depends upon the selection of suitable isomers of starting materials such as quinuclidin-3-ol of formula (II) and 1-phenyl-l, 2. 3. 4-tetrahydroisoquinoline of formula (V). (3R)- quinuclidin-3-ol of formula (11) and (1 S)-l-phenyl-1. 2. 3, 4-tetrahydroisoquinoline of formula (V) is used to obtain (IS. 3R)-Solifenacin that is used for pharmaceutical purpose. The use of other isomers will lead to the formation of corresponding enanliomers of solifenacin such as, (1R, 3S)-solifenacin of Formula (la), (1R. 3R)-solifenacin of formula (lb), and (IS. 3S)-solifenacin of Formula (ic), According to the invention. Solifenacin or its pharmaceutically acceptable salt obtained is highly pure and having purity of minimum of 99.90% by HPLC. Further Solifenacin or its pharmaeeuticaily acceptable salt obtained is substantially free from impurities Thus the new method of the invention provides the method for the preparation of solifenacin and / or its salts by which yield of Solifenacin and its succinate salt obtained is 81 % and 76.1 % respectively in less time without sacrificing purity of 98.0% and 99.93% respectively thus making the process efficient. At the same time, chiral purity of Solifencin base of formula (1) and its succinate salt of the formula (VI) is achieved as 99.8 % and 99.9% respectively. The new method eliminates column chromatography and reduces reaction time. Workup of the reaction is simple as compared to the prior art. This method also avoids hazardous and costly reagents. Thus the process is simple and cost-effective. The method of the invention provides nitro-phenol as a by-product which is easily separable from the reaction mixture by vacuum distillation and giving monitory benefits. The following experimental example is illustrative of the invention but not limitative of the scope thereof Example 1 PREPARATION OK SOLIFENACIN SUCCINATE OF FORMULA (VI); To a stirred solution of (3/()-quinuclidin-3-ol (25 gm) in dimethylformamidc (175 ml) was added bis-(4-dinitropheny]) carbonate (83.83 gm) with stirring at 25-30°C under nitrogen atmosphere. The reaction mass was stirred at 25-30°C for 2-3 hours. Upon completion of this reaction by HPLC, (15)-1-phenyl-1.2,3,4-lelrahydroisoquinoline (41.0 gm) was added to resultant brown colored reaction solution and further stirred at 25-30QC 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 (he nitro-phenol. The aqueous layer was then extracted with dichloromelhane (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 17 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 1 as a syrup having HPLC purity of 98.8% and Chiral purity of 99.9%: Compound (1) was further dissolved in acetone (400 ml) and contacted with succinic acid (18.58 gm) at 25-30°C. 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 (3tf)-quinuclidin-3-ol (5 gm) in dry pyridine (30 ml) was added bis-(4-dinitrophenyl) carbonate (17.5 gm) with stirring at 25-30°C under nitrogen atmosphere. The reaction mass was stirred at 25-30°C for 2-3 hours. Upon completion of the reaction by HPLC, (LS>1-phenyl-l,2,3.4-tetrahydroisoquinoline (7.5 gm) was added to resultant brown colored reaction solution and further stirred at 25-30°C for 3-4 firs. 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 (1) was further dissolved in acetone (70 ml) and contacted with succinic acid (3.25 gm) at 25-30°C. and stirred for 30 min. Precipitated solid was filtered, washed with acetone (10 ml), and dried under vacuum to yield 8.5.0 18 gm solifenacin succinate of formula (VI) as a white crystalline solid; HPLC purity 99.78%; Chiral purity : 99.96%; The ether layer comprising nitro-phenol was subjected to vacuum distillation to recover diisopropylether and nitro-phenol. 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 25-30°C. After completion of the reaction, (l»S)-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 (1) was dissolved in acetone (10.5 ml) and treated with 0.48 gm succinic acid at 25-30°C, 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 V] having HPLC purity 99.86%; chiral purity: 99.93%. The ether layer comprising nitro-phenol was subjected to vacuum distillation to recover diisopropylether and nitro-phenol. 19 Example 4 PREPARATION OF (3R)-l-AZABICYCLO\|2.2.2\|OCT-3-YL4-MTRQ}1HKNY], CARBONATE OF FORMULA (IV); To a stirred solution of (3fl)-quinuclidin-3-oI (1.0 gm) in dichloromelhane (10 ml) was added Bis-(4-dinitrophenyl) carbonate (2.87 gm) at 25-30°C and the resulting brown solution was stirred at ambient temperature till the completion of reaction by HPLC. Dichloromelhane 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 1 to 2. The acidic solution was extracted with di-isopropyielher (10 ml X 2) to separate out the nitro-phenol. The aqueous layer was then extracted with dichloromelhane (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 (3J?)-l-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. The ether layer comprising nitro-phenol was subjected to vacuum distillation lo recover diisopropylether and nitro-phenol. Example 5 PREPARATION OF SOLIFENACIN SUCCINATE OF FORMULA fVI) To a stirred solution of (3/?)-l-azabicyclo[2.2.2]oct-3-yl4-nitrophenyl carbonate (1.0 gm) offormula (IV) obtained as per Example 4 in pyridine (5 mi), (\S)-\-phenyl-1,2.3.4-letrahydroisoquinoline (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 pf 1 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. 20 k The aqueous layer was separated and further extracted with dichloromelhane (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 (1) having HPLC purity 97.08% purity The ether layer comprising nitro-phenol was subjected to vacuum distillation to recover diisopropylether and nitro-phenol. We claim: 1, A new method for (he preparation of (R)-3-[( IS1)- 1 -phenyl-1.2,3,4-tetrahydro-2-isoquinolinylcarbonyloxy]-l-azabicyclo[2.2.2]octane, Solifenacin. of the formula (1); Formula I the method comprises: a. reacting (R)-quinuclidiji-3-ol of formula (II) and bis (p-nitro phenyl), carbonate of the formula (III) to form (3R)-l-azabicyclo[2.2.21oct-3-yl-4-nitrophenyl carbonate of the formula (IV); and b. treating the reaction mixture comprising (3tf)-1-azabicyclo[2.2.2]oct-3-yl 4-nilrophenyl carbonate of the formula (IV) obtained in step (a) with (15)-!-phenyl-1. 2, 3, 4-tetrahydroisoquinoline of formula (V) to form a (3^y3-{(lS)-l-pheny\~l.2J.4-tetrahydro-2-isoquinolinylcarbonyloxyj-l-azabicyclo[2.2.2]ociane of the formula (I). 2. The method as claimed in claim I, wherein the step (a) comprises reacting (R)-quinuclidin-3-ol formula (II) and bis(p-nitrophenyl)carbonate of formula (III) in an organic solvent and in an inert atmosphere at temperature of- 40 to 100°C. 3. The method as claimed in claim 1. further/ optionally comprises a. Isolating(3/0-l-azabicyclo[2.2.2]ocl-3-yl4-nitrophenyl carbonate of formula (IV) from the reaction mixture obtained in step (a) of claim 1 ; and b. Reacting (3/f)-l-azabicyclo[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV) with (liS)-l-phenyl-1, 2, 3, 4-tetrahydroisoquinoline of formula (V) to form a (3R)-3-[(LS')-l- phenyl-l,2.3,4-tetrahydro-2-isoquino]inyIcarbonyloxy]-l-azabicyclo[2.2.2]octane of formula (I). 4. The method as claimed in claims 1 and 3. wherein the step (b) comprises treating the reaction mixture comprising (3tf)-l-azabicyc[o[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV) obtained in step (a) with (lS)-l-phenyl-l. 2, 3, 4-letrahydroisoquinoline of formula (V) in an organic solvent and in an inert atmosphere at temperature of-20 and 50°C to obtain QR)-3-\|'(1S)-1-phenyl-1,2.3,4-tctrahydro isoquinolinylcarbony- loxy]-l-azabicyclo[2.2.2]octane (Solifenacin) of formula (I). 5. The method as claimed in claims 1 to 3. wherein the organic solvents used in step (a) is selected from the group consisting of a C1-C10 ether, a C5-C8 cyclic ether. C2-10 aliphatic esler, C2-C8 aliphatic amides, sulfoxide, C5-C8 cyclic amines. C5-C10 aliphatic amines. Cl-C8 chlorinated hydrocarbon, and mixtures of thereof. 6. The method as claimed in claim 5. wherein the organic solvent is selected from dimethylformamide, N-methylpyrolidone, N,N-dimethylacetamide: dimethyl sulfoxide, chlorinated hydrocarbon, pyridine, and mixtures thereof. 7. The method as claimed in claim 3, wherein isolation of (3/0-I-azabicyclo[2.2.2]oct-3-yl4-nilrophenyl carbonate of formula (IV) of step (a) comprises (a) separating out the nitro-phenol from the reaction mixture obtained from step (a) by distilling out the organic solvent under vacuum from the reaction mass of step (a) to gel residue, adding the water to the residue, adjusting the pH of the resultant mixture to I io 2 using an acid, extracting the reaction mass with a water immiscible organic solvent to separate out nitro-phenol; and 23 (b) isolating the compound of formula fJV) by extracting the aqueous layer obtained from step (a) with a water immiscible organic solvent to separate the compound of formula (IV), diluting the organic layer comprising the compound of formula (IV) with water. adjusting pH of the resulting mixture to 9 to 13, separating the organic layer, washed with water, and then concentrated to yield compound of Formula (IV) as a syrup. 8. The method as claimed in claims 1 to 4 further comprises isolation of (3/^)-3-[(US')-l-phenyl- 1.2,3,4-tetrahydro-2-isoquinolinylcarbonyloxy]-l-azabicyclo-[2.2.2]ociane of formula (I) by a. Separating nitro-phenol from the reaction mass obtained from step (b); by adding water to the reaction mass obtained from step (b) followed by adjusting pi I to 1-2 by using acid, preferably hydrochloric acid, adding water immiscible organic solvent to the reaction mass followed by mixing the reaction mass, separating out the water immiscible organic layer comprising nitro-phenol and aqueous layer comprising hydrochloride salt of (3R)-3-[( l.S)-l -phenyl-1.2,3,4-tetrahydro-2-isoquinolinylcarbonyloxy]-l-azabicyclo[2.2.2]octane of formula (I); and b. isolating (3y^)-3-[(KS')-l-phenyl-l,2,3.4-tetrahydro-2-isoquinolinylcarbonyloxy]-l.- azabicyclo \|2.2.2]octane of formula (1); by extracting the hydrochloride salt of compound of formula (1) in a water immiscible organic solvent from the aqueous layer obtained from the above mentioned step (a), adding water to the organic layer followed by adjusting the pi 1 of the solution to 9 to 13 by adding base followed by separating aqueous layer and organic layer comprising QR)-3-\( \S}-\ -phenyl- lJ2,3.4-tetrahydro-2-isoquinolinylcarbonyloxyj-l-azabicyclo [2.2.2] octane compound of formula (1); washing the organic layer with water and concentrating the organic layer to yield compound of the formula (1) as syrup /oil. 9. The method as claimed in claims 7 and 8, wherein the organic solvent used in the separation of p-nitro phenol is selected from esters such as ethyl acetate, isopropyl acetate, isobuty! acetate and the like; ethers such as diethyl ether, diisopropylether. melhyl-/e/7-butylether and the like; hydrocarbons such as toluene, xylene; heptane, pentane. cyclohexane and the like; and mixtures of thereof. 10. The method as claimed in claims 7 and 8, further comprises distilling out the solvent from the ether layer comprising nitro-phenol obtained from step (a) to obtain nitrophenol. 24 4. A new compound (3/^)-l-azabicyclo[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV); as an intermediate of Solifenacin. 25 11. The method as claimed in claim 7, wherein the organic solvent used for the extracting the compound of formula (IV) is selected from, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, diisopropylether. methyl-te/v-butylether and the like; hydrocarbons such as toluene, xylene, heptane, pentane, cyclohexanc and the like; chlorinated hydrocarbons such as dichloromethane. dichlorethane, chloroform. and the like, and mixtures of thereof. 12. The method as claimed in claim 8, wherein the water immiscible organic solvent used for the extraction of Solifenacin hydrochloride in step (b) is selected from, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like: ethers such as diethyl ether, diisopropylether, methyl-/e/7-butylether and the like; hydrocarbons such as toluene, xylene, heptane, pentane, cyclohexane and the like; chlorinated hydrocarbons such as dichloromethane, dichlorethane, chloroform, and the like, and mixtures of thereof. 13. The method as claimed in any one of preceding claims further comprises converting a solifenacin base into its succinate salt of formula (VI); 15. A process for the preparation of new compound. (3/?)-l-azabicyclo['2.2.2\|oct-3-yl 4-nitrophenyl carbonate, of formula (IV); as an intermediate of Solifenacin, the process comprises; a. reacting (R)-quinuclidin-o-ol of formula (II) and bis (p-nitro phenyl) carbonate of formula (III) to form (3/?)-I-azabicyclo[2.2.2]ocl-3-yl 4-nitrophenyl carbonate of formula (IV): and b. isolating the compound of the formula (IV) from the reaction mass of step (a). 16. The process as claimed in claim 15, wherein the step (a) comprises reacting (R)-quinuclidin-3-ol formula (II) and bis(p-nitrophenyl)carbonate of formula (III) in an organic solvent and in an inert atmosphere at temperature of- 40 to 100°C. 17. The process as claimed in claims 15 to 16 wherein the organic solvent is selected from the group consisting of a C1-C10 ether, a C5-C8 cyclic ether, C2-10 aliphatic ester,C2-C8 aliphatic amides, sulfoxide, C5-C8 cyclic amines, C5-C10 aliphatic amines, C1-C8 chlorinated hydrocarbon , and mixtures of thereof. 26 18. The process as claimed in claims 17. wherein said solvent is selected from diisopropyielhcr. methyl tert-butyl ether, letrahydrofuran. ethyl acetate, acetonilrile. dimetbylformamide. dimethyl sulfoxide, chloroform, pyridine, dichloromethane and mixtures thereof 19. The process as claimed in claims 15 to 16 further comprises isolation of (3/0-1-azabicyclo[2.2.2]oct-3-yl4-nitrophenyl carbonate of formula (IV) by (c) separating out the nitro-pheno! from the reaction mixture obtained from step (a) by distilling out the organic solvent under vacuum from the reaction mass of step (a) (o get residue, adding water to the residue, adjusting the pH of the resultant mixture to 1 to 2 using an acid, preferably hydrochloric acid; extracting the reaction mass with a water immiscible organic solvent to separate out nitro-phenol; and (d) isolating the compound of formula (IV) by extracting the aqueous layer obtained from step (a) with a water immiscible organic solvent to separate the compound of formula (IV), diluting the organic layer comprising the compound of formula (IV) with water, adjusting pH of the resulting mixture to 9 to 13, separating the organic layer, washed with water, and then concentrated to yield compound of formula (IV) as a syrup. 20. The process as claimed in claim 19, wherein the organic solvent used in the separation of p-nitro phenol is selected from esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, diisopropylether. mcthyl-/e/7-butylether and the like; hydrocarbons such as toluene, xylene, heptane, pentane, cyclohexane and the like: and mixtures of thereof. 21. The process as claimed in claim 19 further comprises distilling out the solvent from the ether layer comprising nitro-phenol obtained from step (a) to obtain nitro-phenol. 22. The process as claimed in claim 19 wherein the organic solvent used for the extracting the compound of formula (IV) is selected from, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, diisopropylether, melhyl-/m-butylether and the like: hydrocarbons such as toluene, xylene, heptane, pentane, cyclohexane and the like; chlorinated hydrocarbons such as dichloromethane. dichlorelhane. chloroform, and the like, and mixtures of thereof 23. The process as claimed in any one of the preceding claims wherein Solifenacin or its pharmaceutically acceptable salt obtained is highly pure and having purity of minimum of 99.90% by HPLC. 27 28 24. The process as claimed in any one of the preceding claims wherein Soiifenacin or it's pharmaceuticallv acceptable salt obtained is substantially free from impurities

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 oft 970) As amended by the Patents (Amendment) Act, 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules, 2005
COMPLETE SPECIFICATION
(Sec section (0 and rule 13)

TITLE OF THE INVENTION
A NEW METHOD FOR THE PREPARATION OK SOL1FENACIN AND NEW
INTERMEDIATE THEREOF.
APPLICANTS
Name
Nationality
Address
Megafinc Pharma(P) Ltd.
Indian Company
4,h Floor. SKTilNA. 55. Maharshi Karve Road. Marine Lines.
Mumbai - 400 002. Maharashtra. India.
PREAMBLE I O THE DESCRIPTION
["he following specification particularly describes the nature of this invention and the manner in which it is to be performed:

TECHNICAL FIELD:
The present invention relates to a new method for the preparation of Solifenacin of formula (I):

and its pharmaceuticallv acceptable salts.
The present invention also relates lo (3/0-1-azabicyclo |2.2.2|ocl-3-y) 4-nitrophenyl carbonate o! formula (IV);

which is used as an intermediate for the preparation of Solifenaein.
The present invention also relates to a process for the preparation of the compound of formula (IV).
BACKGROUND OK THE INVENTION:
Solifenaein Succinate is commercially marketed as pharmaceutical)}' active substance indicated for the treatment of overactive bladder with symptoms of urinary incontinence, urgency and high urinary frequency. Solifenaein succinate is acting as a selective antagonist to the M (3)-reecptor. The chemical name of the Solifenaein is {)S)-(3R)-]-a/abieylo |2.2.2| Oct-3-yl-3.4-dihydro-]-pheny]-2(1 11)-isoc]uinolinc carboxylate of formula (I);
")

Formula 1
Solifenacin succinate is the inlcrnaiional common denomination for bulancdioic acid compounded with (lS)-pR)-l-a/abicyclo |2.2.2|oct-3-yl-3.4-dihydro-l-phcnyl-2(ll l)-isoquinolinecarboxylaie (1:1). having an empirical formula ofC23H26N2O2 .C4UO4 and the structure represented in Ibrmuia VI given below;

Formula (VI)
Solifenacin and its pharmaceutical!}' acceptable salts arc first reporlcd in US Patent No. 6.017.927 (927"). which disclosed two synthetic routes "Route-A and Roulc-B" for the preparation of (IRS. 3'RS)-So]ifenacin und (IS. 3*RS)-Solifcnacin as shown in Scheme-1;
.3

Both (he routes have several drawbacks such as:
a) Use of very hazardous and pyrophoric reagent. Nail, in fhe process which is very diflieuh to
handle and thus makes the process unsafe to handle at industrial level.
b) Use of ethyichloroformate to prepare ethylcarboxylate derivative in route A which is
lachrymatory in nature.
c) Hthylcarboxylatc derivative produces elhanol as a by-product during trans-esterifiealion reaction in the subsequcn! reaction that interferes in nuclcophilic attack against Solilenacin in the presence of a base and hence it is necessary to remove elhanol from the reaction mixture in the form of a/.eotrope with toluene or the like simultaneously while carrying out the reaction, so as lo control the reaction.
d) Use of column chromatography for the purification of solifenacin base, which makes the process industrially not feasible.
0 The reaction requires longer lime for the completion cuid hence turn around lime of ihe batch in production makes it less attractive.
4

International Patent Application No WO2005/075474 disclosed another synthetic route for the preparation of Solifenacin and Solifenaein Succinate as shown in Sebeme-2.

Solifenacin succinate
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 ehlylchlorofomrate in the first step and produces ethanol as a by-product in the second step.
Yet another International Patent application no W02005/I05795AI discloses an improved process for preparing Solifenacin as represented in Schemc-3. wherein leaving group (l.v) can be II i-imida/ole-1-yl. 2.5-dioxopyrrolidin-l-yloxy. 3-methyl-lH-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 dimethyUonnamide or toluene alone as a reaction medium. The process described herein represents few draw backs such as. use ofha/.ardous sodium hydride, use of chromatographic purifications, and use of moisture sensitive leaving groups (l.v) and hence handling of the reaction is difficult, further the leaving groups used are expensive and thus making [he process uneconomic.
n

Hence, there is need of efficient process for producing solifenacin and ils succinate sail which is sale io handle, industrially Feasible, and economically viable.
OBJECTS OF THE PRESENT INVENTION:
An object of the present invention is to provide a new method for the preparation of Solifenacin and / or its salts, wherein the process is economical, simple, efficient, cost-effective and easy io cam' out.
Another object of the invention is to provide the new method for the preparation of Solifenacin and /or its salts with high yields and substantially pure and l"rec from impurities and thus making the process efficient.
Yet another object of the invention is to provide the new method for the preparation of Solifenacin and / or its salts in a single pot where in isolation of intermediates by nitrations arc avoided to reduce exposure of the production executive to the chemicals and to reduce the turn around time of the total time cycle per batch.
Another object of the invention is to provide the new method for the preparation of Solifenacin and / or its salts which avoids hazardous and costly reagents or chemicals and involves simple work-up thus making the process simple and cost-effective.
6

Yet another object of the invention is lo provide the new method for the preparation of Solifenacin and / or its salts in which nitro-phenoi is a by-product which is easily separable and recoverable from the reaction mixture by vacuum distillation and giving monitory benefits to the process.
Yet another object of the invention is to provide a new compound. (3/0-l-a/abicyclo|2.2.2|oct-3-yl 4-nitrophcnyl carbonate, of formula (IV). which is used as intermediate for the production of Solifenacin.
Yet another object of the invention is to provide a process for the preparation of (3/0-1 -azabicyclo J2.2.2] ocl-3-yl 4-nilrophenyl carbonate compound of formula (IV) which is used as an intermcdiale for the production of Solifenacin.
DETAILED DESCRIPTION OK THE INVENTION
The present invention provides a novel method for efficiently preparing Solifenacin and/or one of its pharmaceuiically acceptable salts. According to the process of present invention, solifenacin is obtained by using milder reaction conditions and without the need for laborious operations such as chromatographic purifications or solvent distillations, and hazardous chemicals.
The process for making the compound (1) involves two chemical reactions. Accordingly, it will be described as a two-step process. While the steps are normally run separately, that is consecutively, the process may nonetheless be conveniently performed in a one pot arrangement as well. e.g. as a one pot process with out isolation of the intermediate product
According to the invention, there is provided a new method for the preparation of Solifenacin ol' formula (I); the method comprises:
a. reacting (R)-c|uinuclidm-3-ol of formula (II) and bis(p-nitrophcnyl)carbonate of formula (III) to form (3/?)-l-azabieyclo|2.2.2|oct-3-yl 4-nitrophcnyl carbonate of formula (IV); and
7

b. treating the reaction mixture comprising (3/0-l-a/.abicyclo|2.2.2]oct-3-yl 4-nitropheny' carbonate of the formula (IV) of step (a) with (iS)-Uphenyl-I. 2. 3. 4-tctrahydroisoquinoline ol formula (V) to obtain (3R)-3-|{LS)-l-phenyl-1.2.3.4-tctrahydro isoquinolinylcarhonyloxy|-l-a/.abicyclo)2.2.2 [octane (Solifenaein) of formula (I).

Step (a) of the above method comprises reacting (R)-quinuclidin-3-ol formula (II) and bisfp-nitrophenyl)carbonate of formula (111) in an organic solvent and in an inert atmosphere at temperature of- 40 to IO0°C.
Step (a) may also be carried out in the presence of suitable base.
Preferably, step (a) is carried out temperature of 0 to 30°C. more preferably. 25 to 30°C.
The organic solvents used in the above reaction of step (a) is selected from the group consisting of a C1-C10 ether, a C5-C8 cyclic ether. C2-H) aliphatic ester. C2-C8 aliphatic amides. sulfoxide. C5-CS cyclic amines. C5-C10 aliphatic amines. C1-C8 chlorinated hydrocarbon, and mixtures of thereof: preferably, the solvent is selected from dimethyl fonnamide. N-methylpyrolidone. N'.N-
8

dimethylacetamide. dimethyl sulfoxide, chlorinated hydrocarbon, pyridine, and mixtures therco]; more preferably, the solvent is dimethylformamidc.
The reaction time of step (a) is invariably depends on the lemperaiure condition used to carry out the step (a). The reaction time increases with decrease in temperature.
The course of the reaction is monitored by a suitable analytical method, for instance by 11 PLC and/or by TLC. and ihc second step of the reaction process does not start until the first reaction step is essentially completed- i.e. more than 95%. preferably more than 98% of the starting materia) has been converted /consumed which requires around 2-3 hours at 25-30°C.
'The above mentioned step (b) comprises treating the reaction mixture comprising (3tf)-l-azabicyclo|2.2,2|oct-3-y] 4-nilrophcnyl carbonate of formula (IV) of step (a) with (1S)-1-phenyl-1. 2, 3. 4-teirabydroisoquinolinc of formula (V) in an organic solvent and in an men atmosphere at temperature of- 20 to 50°C to obtain (3JV)-3-|(l.V)-l-phcnyl-L2.3.4-tetrahydro isoquinolinylcarbony-loxy]-l-azabicyclo|2.2.2|oclane fSolifenacin) of formula (1).
The process of step (b) typically comprise adding (IS)-1-phenyl-1. 2. 3. 4-teirahydroisoquino!ine of formula (V) to the reaction mixture of step fa) in portion wise or at once, as such or dissolved in ihe organic solvent. Step (b) proceeds while stirring the reaction mixture.
Step (b) is carried out preferably al temperature of 0 and 30°C: most preferably 25 to 30°C.
Step (b) of the method is monitored by a suitable analytical process, for instances by I (PLC and/or by TLC.
The above mentioned method further / optionally comprises
A. isolating (37()-'-3/abicyclo|2.2.2|oct-3-yl-4-nitrophenyl carbonate of formula (IV) from (he
reaction mixture obtained in step (a) by
a.separating out the nitro-phenol from the reaction mixture obtained from step (a) by distilling out the organic solvent under vacuum from the reaction mass of step (a) to get residue.
9

adding water to the residue, adjusting the pH of the resultant mixture to I to 2 using an acid,
preferably hydrochloric acid; extracting the reaction mass with a water immiscible organic
solvent to separate out nitro-phenol:
b.isolating the compound o!" formula (IV) by extracting the aqueous layer obtained from step
(a) with a water immiscible organic solvent to separate the compound of formula {IVj.
diluting the organic layer comprising the compound of formula (IV) with water, adjusting pi 1
of the resulting mixture to 9 to 13. preferably between 9 to 10 using base, separating the
organic layer, washed with water, and then concentrated to yield compound of formula (iV)
as a syrup.
B. using the compound of formula (IV) in step (b) to obtain the compound of formula (I).
The method of the invention further comprises isolalion of (3/0-3-l(l-3-l-phenyl-1.2.3.4-tcl!'ahYdro-2-)soquim.l]iny]carbonyJoxy|-]-azabicyclol2.2.2loctane of formula (1) bv
a. Separating nitro-phcnoJ from the reaction mass obtained from s\cp (b):
by adding water to the reaction mass obtained from step (b) followed by adjusting pH to 1-2 by using acid, preferably hydrochloric acid, adding water immiscible organic solvent to the reaction mass followed by mixing the reaction mass, separating out ihc water immiscible organic layer comprising nitre-phenol and aqueous layer comprising hydrochloride salt of (3/i)-3-|( \S)-\ -phenyl-1.2.3.4-letrahydro-2-isoquinoliny! carbony!oxy|-l-azabicyclo|2.2.2 [octane of formula (I); and
b. isolating (3R)-3-[( LS)1 -phenyl- L2.3.44etrahydro-2-isoquinolinyJcarbonyloxy|-1-azabicyc]o
|2.2.2loctane of the formula (I) by extracting the hydrochloride salt of compound oi'
formula (]) in a water immiscible organic solvent from the aqueous layer obtained from
the above mentioned step (a), adding water to the organic layer followed by adjusting the
pH of the solution to 9 to 13 by adding base followed by separating aqueous layer and
organic layer comprising (3/R)-3-[( l.S) I-phenyl-1.2.3.4-tetrahydro-2-
isoquinohnylcarbonyloxy|-l-.abicyclo 12.2.21 octane of formula (I): washing the organic layer with water and concentrating the organic layer to yield compound of (he formula (1) as syrup /oil.
10

The water immiscible organic solvent used in the separation of p-nitro phenol is selected to essentially separate die by-product nitro phenol from the reaction mixture. The organic solvent comprises, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like: ethers such as diethyl ether, diisopropylcther. melhyl-/tert-butylether and the like: hydrocarbons such as toluene, xylene, heptane, pentane. cyclohexane and the like: and mixtures of thereof: preferably, the solvent is selected from ethers, more preferably, diisopropylelhcr.
The above mentioned method further comprises isolation of nilro phenol as potential by-product by distilling out ether from the ether layer comprising niiro-phenol obtained in the above mentioned step fa).
The water immiscible organic solvent used for the extraction of solifenaein hydrochloride selected from, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like: ethers such as diethyl ether, diisopropylcther. methyl-/tert-butylether and the like: hydrocarbons such as toluene, xylene, heptane, pentane. cyclohexane and the like: chlorinated hydrocarbons such as dichloromethanc. dichlorethanc. chloroform, and the like, and mixtures of thereof: preferably, said solvent is selected from hydrocarbons, or chlorinated hydrocarbons : more preferably dichloromethanc.
Preferably, the pH of the solution of step (b) is adjusted to 9 to 13. The pll adjustment in step (b) is carried out using base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium hydroxide and the like, preferably ammonium hydroxide.
The above mentioned method further comprises converting a Solifenaein base of the compound o\' formula (I) into its pharmaceutically acceptable salts. The compound of the formula (J) as oil / syrup is dissolved in an organic solvent and treated with the suitable acid selected from organic acids or inorganic acids to get salt. The acid can be hydrobromic acid or succinic acid: preferably succinic acid.
According to the present invention, the method for producing the Solifenaein Succinate of formula (VI) comprises: dissolving the Solifenaein of formula (1) obtained in step (b) in a organic solvent and
11

then treating the same with succinine acid cither in solid form or in dissolved form using the organic solvent, the reaction mixture is healed to dissolve the contents, cooled and the product precipitated is isolated by filtration which is further dried under vacuum to yield the Sotifenacin Succinalc of formula (V!).
The organic solvent is selected from ketones such as acetone, ethyl methyl ketone, methylisobulylkcione: esters such as ethyl acetate, isopropyl acetate, isobuiyl acetate and the like: alcohols such as methanol, ethanol. isopropanol. butanol. lerl-butanol and like: ethers such as diethylethcr. diisopropylelher. mclhy]-/e/7-bmylethcr and the like: hydrocarbons such as toluene, xylene, heptane, pematne. eyclohexane and the like: and mixtures of thereof. Preferably, said solvent is selected from alcohols or ketones or mixtures thereof, more preferably said solvent is ethanol or acetone or mixtures thereof.

According to the invention. Solifencin base of formula (1) and Solifcnaien Succinalc salt of formula (VI) is having yield of 81 % and 76.1 % respectively and purity of 98.0% and 99.93% respectively by HPLC (High performance liquid chromatography).
The chiral purity of Solifenacin base of formula (I) and its Succinate salt of the formula (V[) is 99.8% and 99.9% respeclivcly by HP1.C using chiral column.
The process of the present invention provides the Solifenaicin Succinate in highly pure form and free from potential known and unknown impurities.
12

According to the invention, there is provided a new compound (3tf)-l-azabicyclo|2.2.2]ocl-3-yl 4-nitrophenyl carbonate of formula (IV);

as an intermediate of Solifenacin.
According to the invention, there is provided a process for the preparation of new compound, (jJiy l-azabicyclo[2.2.2|oct-3-yl 4-nitrophenyl carbonate of formula (IV);

as an intermediate of Soiifenacin, the process comprises;
a. reacting (R)-quinuclidin-3-ol of formula (U) and bis (p-nitro phenyl) carbonate of formula (III) to form (3J?)-l-azabicycIo[2.2.2]oct-3-yI 4-nilrophenyl carbonate of formula (IV): and

b. isolating the compound of the formula (IV) from the reaction mass ol~ step (a).
13

The step (a) comprises reacting (R)-quinuclidino-oi formula (II) and bis(p-nitrophenyl)carbonate of formula (111) in an organic solvent and in an inert atmosphere at temperature of- 40 to I0()°C.
The step (a) may also be carried out in the presence of suitable base.
Preferably, step (a) is carried out temperature of 0 to 30°C more preferably. 25 to 30°C.
The organic solvents used in the above reaction of step (a) is selected from the group consisting of a CI-CIO ether, a C5-C8 cyclic ether, C2-10 aliphatic ester. C2-C8 aliphatic amides, sulfoxide, C5-C8 cyclic amines, C5-C10 aliphatic amines. C1-C8 chlorinated hydrocarbon, and mixtures of thereof; preferably, the solvent is selected from dimethylformamide. N-methylpyroIidone, N,N-dimethylacetamide, dimethyl sulfoxide, chlorinated hydrocarbon, pyridine, and mixtures thereof; more preferably, the solvent is dimelhylformamide or dichloromethane or pyridine; most preferably the solvent is dichloromethane.
The reaction time of step (a) is inversely proportional to the temperature condition used to carry out step (a). The reaction time increases with decrease in temperature.
Step (a) of the reaction is monitored by a suitable analytical method, for instance by HP1X and/or by TLC and is allowed to complete the reaction more than 95%. preferably more than 98% which requires around 2-3 hours at 25-30°C.
The compound of formula (IV) is isolated from the reaction mixture obtained from step (a) by
a. separating out the nitro-phenol from the reaction mixture obtained from step (a) by distilling
out the organic solvent under vacuum from the reaction mass of step (a) to get residue, adding water
to the residue, adjusting the pH of the resultant mixture to 1 to 2 using an acid, preferably
hydrochloric acid; extracting the reaction mass with a water immiscible organic solvent to separate
out nitro-phenol;
b. isolating the compound of formula (IV) by extracting the aqueous layer obtained from step
(a) with a water immiscible organic solvent to separate the compound of formula (IV). diluting the
14

organic layer comprising the compound of formula (IV) with water, adjusting pH of the resulting mixture to 9 to 13, preferably between 9 to 10 using base, separating the organic layer, washed with water, and then concentrated to yield compound of Formula (IV) as a syrup.
The organic solvent used for the separation of nitro-phenol is selected from esters such as ethyl acetate, isopropyl acetate, isobutyi acetate and the like; ethers such as diethyl ether, diisopropylether. methyI-/e/7-butylether and the like; hydrocarbons such as toluene, xylene, heptane, penlanc. cyclohexane and the like; and mixtures of thereof; preferably, said solvent is selected from ethers such as diisopropylether.
The process further comprises distilling out the solvent from the ether layer comprising nitro-phenol obtained from step (a) to obtain nitro-phenol.
The organic solvent used for the extracting the compound of formula (IV) is selected from, esters such as ethyl acetate, isopropyl acetate, isobutyi acetate and (he like; ethers such as diethyl ether, diisopropylether. methyl-/t77-butyiethcr and the like; hydrocarbons such as toluene, xylene, heptane, pentane, cyclohexane and the like; chlorinated hydrocarbons such as dichloromethanc. dichiorethane, chloroform, and the like, and mixtures of thereof; preferably, said solvent is selected from chlorinated hydrocarbons such as dichloromethanc
The base used to adjust the pH is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium hydroxide and the like, more preferably the base used for the pH adjustment is ammonium hydroxide.
The isolated intermediate (IV) from step (a) is used for the preparation of solifenacin of formula (I).
Quinuclidin-3-oi of formula (II) and l-pheny(-I,2,3,4-tetrahydroisoquinoiine of formula (V) used in the above mentioned method may be either (R)-enantiomer. (S)-enantioj-ncr or racemate depend upon the isomer of solifenacin need to be prepared and are shown below.
15

Achieving the desired stereochemistry of the solifenacin depends upon the selection of suitable isomers of starting materials such as quinuclidin-3-ol of formula (II) and 1-phenyl-l, 2. 3. 4-tetrahydroisoquinoline of formula (V). (3R)- quinuclidin-3-ol of formula (11) and (1 S)-l-phenyl-1. 2. 3, 4-tetrahydroisoquinoline of formula (V) is used to obtain (IS. 3R)-Solifenacin that is used for pharmaceutical purpose. The use of other isomers will lead to the formation of corresponding enanliomers of solifenacin such as, (1R, 3S)-solifenacin of Formula (la), (1R. 3R)-solifenacin of formula (lb), and (IS. 3S)-solifenacin of Formula (ic),

According to the invention. Solifenacin or its pharmaceutically acceptable salt obtained is highly pure and having purity of minimum of 99.90% by HPLC. Further Solifenacin or its pharmaeeuticaily acceptable salt obtained is substantially free from impurities
Thus the new method of the invention provides the method for the preparation of solifenacin and / or its salts by which yield of Solifenacin and its succinate salt obtained is 81 % and 76.1 % respectively in less time without sacrificing purity of 98.0% and 99.93% respectively thus making the process efficient. At the same time, chiral purity of Solifencin base of formula (1) and its succinate salt of the formula (VI) is achieved as 99.8 % and 99.9% respectively. The new method eliminates column chromatography and reduces reaction time. Workup of the reaction is simple as compared to the prior art. This method also avoids hazardous and costly reagents. Thus the process is simple and cost-effective. The method of the invention provides nitro-phenol as a by-product which is easily separable from the reaction mixture by vacuum distillation and giving monitory benefits.
The following experimental example is illustrative of the invention but not limitative of the scope thereof
Example 1
PREPARATION OK SOLIFENACIN SUCCINATE OF FORMULA (VI);
To a stirred solution of (3/(*)-quinuclidin-3-ol (25 gm) in dimethylformamidc (175 ml) was added bis-(4-dinitropheny]) carbonate (83.83 gm) with stirring at 25-30°C under nitrogen atmosphere. The reaction mass was stirred at 25-30°C for 2-3 hours. Upon completion of this reaction by HPLC, (15)-1-phenyl-1.2,3,4-lelrahydroisoquinoline (41.0 gm) was added to resultant brown colored reaction solution and further stirred at 25-30QC 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 (he nitro-phenol.
The aqueous layer was then extracted with dichloromelhane (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
17

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 1 as a syrup having HPLC purity of 98.8% and Chiral purity of 99.9%: Compound (1) was further dissolved in acetone (400 ml) and contacted with succinic acid (18.58 gm) at 25-30°C. 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 (3tf)-quinuclidin-3-ol (5 gm) in dry pyridine (30 ml) was added bis-(4-dinitrophenyl) carbonate (17.5 gm) with stirring at 25-30°C under nitrogen atmosphere. The reaction mass was stirred at 25-30°C for 2-3 hours. Upon completion of the reaction by HPLC, (LS>1-phenyl-l,2,3.4-tetrahydroisoquinoline (7.5 gm) was added to resultant brown colored reaction solution and further stirred at 25-30°C for 3-4 firs. 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 (1) was further dissolved in acetone (70 ml) and contacted with succinic acid (3.25 gm) at 25-30°C. and stirred for 30 min. Precipitated solid was filtered, washed with acetone (10 ml), and dried under vacuum to yield 8.5.0
18

gm solifenacin succinate of formula (VI) as a white crystalline solid; HPLC purity 99.78%; Chiral purity : 99.96%;
The ether layer comprising nitro-phenol was subjected to vacuum distillation to recover diisopropylether and nitro-phenol.
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 25-30°C. After completion of the reaction, (l»S)-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 (1) was dissolved in acetone (10.5 ml) and treated with 0.48 gm succinic acid at 25-30°C, 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 V] having HPLC purity 99.86%; chiral purity: 99.93%.
The ether layer comprising nitro-phenol was subjected to vacuum distillation to recover diisopropylether and nitro-phenol.
19

Example 4
PREPARATION OF (3R)-l-AZABICYCLO|2.2.2|OCT-3-YL4-MTRQ}1HKNY],
CARBONATE OF FORMULA (IV);
To a stirred solution of (3fl)-quinuclidin-3-oI (1.0 gm) in dichloromelhane (10 ml) was added Bis-(4-dinitrophenyl) carbonate (2.87 gm) at 25-30°C and the resulting brown solution was stirred at ambient temperature till the completion of reaction by HPLC. Dichloromelhane 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 1 to 2. The acidic solution was extracted with di-isopropyielher (10 ml X 2) to separate out the nitro-phenol.
The aqueous layer was then extracted with dichloromelhane (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 (3J?)-l-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.
The ether layer comprising nitro-phenol was subjected to vacuum distillation lo recover diisopropylether and nitro-phenol.
Example 5
PREPARATION OF SOLIFENACIN SUCCINATE OF FORMULA fVI)
To a stirred solution of (3/?)-l-azabicyclo[2.2.2]oct-3-yl4-nitrophenyl carbonate (1.0 gm) offormula (IV) obtained as per Example 4 in pyridine (5 mi), (\S)-\-phenyl-1,2.3.4-letrahydroisoquinoline (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 pf 1 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.
20

k

The aqueous layer was separated and further extracted with dichloromelhane (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 (1) having HPLC purity 97.08% purity
The ether layer comprising nitro-phenol was subjected to vacuum distillation to recover diisopropylether and nitro-phenol.

We claim:
1, A new method for (he preparation of (R)-3-[( IS1)- 1 -phenyl-1.2,3,4-tetrahydro-2-isoquinolinylcarbonyloxy]-l-azabicyclo[2.2.2]octane, Solifenacin. of the formula (1);

Formula I
the method comprises:
a. reacting (R)-quinuclidiji-3-ol of formula (II) and bis (p-nitro phenyl), carbonate of the
formula (III) to form (3R)-l-azabicyclo[2.2.21oct-3-yl-4-nitrophenyl carbonate of the
formula (IV); and

b. treating the reaction mixture comprising (3tf)-1-azabicyclo[2.2.2]oct-3-yl 4-nilrophenyl carbonate of the formula (IV) obtained in step (a) with (15)-!-phenyl-1. 2, 3, 4-tetrahydroisoquinoline of formula (V) to form a (3^y3-{(lS)-l-pheny\~l.2J.4-tetrahydro-2-isoquinolinylcarbonyloxyj-l-azabicyclo[2.2.2]ociane of the formula (I).

2. The method as claimed in claim I, wherein the step (a) comprises reacting (R)-quinuclidin-3-ol formula (II) and bis(p-nitrophenyl)carbonate of formula (III) in an organic solvent and in an inert atmosphere at temperature of- 40 to 100°C.
3. The method as claimed in claim 1. further/ optionally comprises
a. Isolating(3/0-l-azabicyclo[2.2.2]ocl-3-yl4-nitrophenyl carbonate of formula (IV) from
the reaction mixture obtained in step (a) of claim 1 ; and
b. Reacting (3/f)-l-azabicyclo[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV) with
(liS)-l-phenyl-1, 2, 3, 4-tetrahydroisoquinoline of formula (V) to form a (3R)-3-[(LS')-l-
phenyl-l,2.3,4-tetrahydro-2-isoquino]inyIcarbonyloxy]-l-azabicyclo[2.2.2]octane of
formula (I).
4. The method as claimed in claims 1 and 3. wherein the step (b) comprises treating the reaction mixture comprising (3tf)-l-azabicyc[o[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV) obtained in step (a) with (lS)-l-phenyl-l. 2, 3, 4-letrahydroisoquinoline of formula (V) in an organic solvent and in an inert atmosphere at temperature of-20 and 50°C to obtain QR)-3-|'(1S)-1-phenyl-1,2.3,4-tctrahydro isoquinolinylcarbony- loxy]-l-azabicyclo[2.2.2]octane (Solifenacin) of formula (I).
5. The method as claimed in claims 1 to 3. wherein the organic solvents used in step (a) is selected from the group consisting of a C1-C10 ether, a C5-C8 cyclic ether. C2-10 aliphatic esler, C2-C8 aliphatic amides, sulfoxide, C5-C8 cyclic amines. C5-C10 aliphatic amines. Cl-C8 chlorinated hydrocarbon, and mixtures of thereof.
6. The method as claimed in claim 5. wherein the organic solvent is selected from dimethylformamide, N-methylpyrolidone, N,N-dimethylacetamide: dimethyl sulfoxide, chlorinated hydrocarbon, pyridine, and mixtures thereof.
7. The method as claimed in claim 3, wherein isolation of (3/0-I-azabicyclo[2.2.2]oct-3-yl4-nilrophenyl carbonate of formula (IV) of step (a) comprises
(a) separating out the nitro-phenol from the reaction mixture obtained from step (a) by distilling out the organic solvent under vacuum from the reaction mass of step (a) to gel residue, adding the water to the residue, adjusting the pH of the resultant mixture to I io 2 using an acid, extracting the reaction mass with a water immiscible organic solvent to separate out nitro-phenol; and
23

(b) isolating the compound of formula fJV) by extracting the aqueous layer obtained from step (a) with a water immiscible organic solvent to separate the compound of formula (IV), diluting the organic layer comprising the compound of formula (IV) with water. adjusting pH of the resulting mixture to 9 to 13, separating the organic layer, washed with water, and then concentrated to yield compound of Formula (IV) as a syrup.
8. The method as claimed in claims 1 to 4 further comprises isolation of (3/^)-3-[(US')-l-phenyl-
1.2,3,4-tetrahydro-2-isoquinolinylcarbonyloxy]-l-azabicyclo-[2.2.2]ociane of formula (I) by
a. Separating nitro-phenol from the reaction mass obtained from step (b);
by adding water to the reaction mass obtained from step (b) followed by adjusting pi I to 1-2 by using acid, preferably hydrochloric acid, adding water immiscible organic solvent to the reaction mass followed by mixing the reaction mass, separating out the water immiscible organic layer comprising nitro-phenol and aqueous layer comprising hydrochloride salt of (3R)-3-[( l.S)-l -phenyl-1.2,3,4-tetrahydro-2-isoquinolinylcarbonyloxy]-l-azabicyclo[2.2.2]octane of formula (I); and
b. isolating (3y^)-3-[(KS')-l-phenyl-l,2,3.4-tetrahydro-2-isoquinolinylcarbonyloxy]-l.-
azabicyclo |2.2.2]octane of formula (1);
by extracting the hydrochloride salt of compound of formula (1) in a water immiscible organic solvent from the aqueous layer obtained from the above mentioned step (a), adding water to the organic layer followed by adjusting the pi 1 of the solution to 9 to 13 by adding base followed by separating aqueous layer and organic layer comprising QR)-3-\( \S}-\ -phenyl- lJ2,3.4-tetrahydro-2-isoquinolinylcarbonyloxyj-l-azabicyclo [2.2.2] octane compound of formula (1); washing the organic layer with water and concentrating the organic layer to yield compound of the formula (1) as syrup /oil.
9. The method as claimed in claims 7 and 8, wherein the organic solvent used in the separation of p-nitro phenol is selected from esters such as ethyl acetate, isopropyl acetate, isobuty! acetate and the like; ethers such as diethyl ether, diisopropylether. melhyl-/e/7-butylether and the like; hydrocarbons such as toluene, xylene; heptane, pentane. cyclohexane and the like; and mixtures of thereof.
10. The method as claimed in claims 7 and 8, further comprises distilling out the solvent from the ether layer comprising nitro-phenol obtained from step (a) to obtain nitrophenol.
24

4. A new compound (3/^)-l-azabicyclo[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV);
as an intermediate of Solifenacin.
25
11. The method as claimed in claim 7, wherein the organic solvent used for the extracting the compound of formula (IV) is selected from, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, diisopropylether. methyl-te/v-butylether and the like; hydrocarbons such as toluene, xylene, heptane, pentane, cyclohexanc and the like; chlorinated hydrocarbons such as dichloromethane. dichlorethane, chloroform. and the like, and mixtures of thereof.
12. The method as claimed in claim 8, wherein the water immiscible organic solvent used for the extraction of Solifenacin hydrochloride in step (b) is selected from, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like: ethers such as diethyl ether, diisopropylether, methyl-/e/7-butylether and the like; hydrocarbons such as toluene, xylene, heptane, pentane, cyclohexane and the like; chlorinated hydrocarbons such as dichloromethane, dichlorethane, chloroform, and the like, and mixtures of thereof.
13. The method as claimed in any one of preceding claims further comprises converting a solifenacin base into its succinate salt of formula (VI);

15. A process for the preparation of new compound. (3/?)-l-azabicyclo['2.2.2|oct-3-yl 4-nitrophenyl carbonate, of formula (IV);

as an intermediate of Solifenacin,
the process comprises;
a. reacting (R)-quinuclidin-o-ol of formula (II) and bis (p-nitro phenyl) carbonate of
formula (III) to form (3/?)-I-azabicyclo[2.2.2]ocl-3-yl 4-nitrophenyl carbonate of formula
(IV): and

b. isolating the compound of the formula (IV) from the reaction mass of step (a).
16. The process as claimed in claim 15, wherein the step (a) comprises reacting (R)-quinuclidin-3-ol formula (II) and bis(p-nitrophenyl)carbonate of formula (III) in an organic solvent and in an inert atmosphere at temperature of- 40 to 100°C.
17. The process as claimed in claims 15 to 16 wherein the organic solvent is selected from the group consisting of a C1-C10 ether, a C5-C8 cyclic ether, C2-10 aliphatic ester,C2-C8 aliphatic amides, sulfoxide, C5-C8 cyclic amines, C5-C10 aliphatic amines, C1-C8 chlorinated hydrocarbon , and mixtures of thereof.
26

18. The process as claimed in claims 17. wherein said solvent is selected from diisopropyielhcr. methyl tert-butyl ether, letrahydrofuran. ethyl acetate, acetonilrile. dimetbylformamide. dimethyl sulfoxide, chloroform, pyridine, dichloromethane and mixtures thereof
19. The process as claimed in claims 15 to 16 further comprises isolation of (3/0-1-azabicyclo[2.2.2]oct-3-yl4-nitrophenyl carbonate of formula (IV) by

(c) separating out the nitro-pheno! from the reaction mixture obtained from step (a) by distilling out the organic solvent under vacuum from the reaction mass of step (a) (o get residue, adding water to the residue, adjusting the pH of the resultant mixture to 1 to 2 using an acid, preferably hydrochloric acid; extracting the reaction mass with a water immiscible organic solvent to separate out nitro-phenol; and
(d) isolating the compound of formula (IV) by extracting the aqueous layer obtained from step (a) with a water immiscible organic solvent to separate the compound of formula (IV), diluting the organic layer comprising the compound of formula (IV) with water, adjusting pH of the resulting mixture to 9 to 13, separating the organic layer, washed with water, and then concentrated to yield compound of formula (IV) as a syrup.

20. The process as claimed in claim 19, wherein the organic solvent used in the separation of p-nitro phenol is selected from esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, diisopropylether. mcthyl-/e/7-butylether and the like; hydrocarbons such as toluene, xylene, heptane, pentane, cyclohexane and the like: and mixtures of thereof.
21. The process as claimed in claim 19 further comprises distilling out the solvent from the ether layer comprising nitro-phenol obtained from step (a) to obtain nitro-phenol.
22. The process as claimed in claim 19 wherein the organic solvent used for the extracting the compound of formula (IV) is selected from, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, diisopropylether, melhyl-/m-butylether and the like: hydrocarbons such as toluene, xylene, heptane, pentane, cyclohexane and the like; chlorinated hydrocarbons such as dichloromethane. dichlorelhane. chloroform, and the like, and mixtures of thereof
23. The process as claimed in any one of the preceding claims wherein Solifenacin or its pharmaceutically acceptable salt obtained is highly pure and having purity of minimum of 99.90% by HPLC.
27

28
24. The process as claimed in any one of the preceding claims wherein Soiifenacin or it's pharmaceuticallv acceptable salt obtained is substantially free from impurities

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Patent Number

269856

Indian Patent Application Number

519/MUM/2009

PG Journal Number

46/2015

Publication Date

13-Nov-2015

Grant Date

12-Nov-2015

Date of Filing

09-Mar-2009

Name of Patentee

MEGAFINE PHARMA (PVT) LTD

Applicant Address

4TH FLOOR, SETHNA 55, MAHARSHI KARVE ROAD, MARINE LINES, MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	JAGTAP KUNAL MADHAV	AT POST-TILWAN, TAL. SATANA, DIST. NASHIK-423301,
2	PANDIT BHUSHAN SUDHAKAR	FLAT NO-07, VISHWACHANDRA (D) SOCIETY, DINDORI ROAD, MHASRUL, NASIK 422004.
3	P RAGHVENDRA KUMAR	3-A, VATSLYAKUNJ APTS, RAJPAL COLONY, MAKHMALABAD NAKA, PANCHAVATI, NASHIK-422003,
4	MATHAD VIJAYAVITTHAL THIPPANNACHAR	FLAT NO. 6, RACHIT CLASSIC, KULKARNI COLONY, OFF. COLLEGE ROAD, NASHIK 422009,
5	NIPHADE NAVNATH CHINTAMAN	FLAT NO. 4, ELDORA APPARTMENTS, SAWARKAR NAGAR, GANGAPUR ROAD, NASHIK-422013,
6	MALI ANIL CHATURLAL	11A, JAIKRISHNA APARTMENTS, OLD SAIKHEDA ROAD, JAIL ROAD, NASHIK ROAD-422001,

PCT International Classification Number

C07D217/06; C07D453/02

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA