FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Solifenacin or a salt thereof, more particularly the present invention relates to an economically viable and industrially advantageous process for the preparation of highly pure Solifenacin or a salt thereof.

BACKGROUND OF THE INVENTION

Solifenacin salt of formula I, particularly Solifenacin succinate, acts as a muscarinic M3-receptor antagonist and is used for symptomatic treatment of urgent incontinence and/or increased frequency of urinating and urgency of urinating in patients with a hyperactive urinary bladder. Solifenacin is chemically known as (lS,3 ' ?)-quinuclidin-3 '-yl-l -phenyl-l ,2,3,4-tetrahydro isoquinoline-2-carboxylate. Commercially, Solifenacin succinate is available under the trade name Vesicare ^® .

Formula I

EP 0 801 067 discloses a process for the preparation of Solifenacin, a racemic mixture or biologically active pure isomer (\S,3 'R) thereof. The patent discloses the reaction of quinuclidinol and l-phenyl-l,2,3,4-tetrahydroisoquinoline carbamoyl derivative in the presence of sodium hydride. Further, the patent discloses the condensation of 1-phenyl-l , 2,3,4- tetrahydroisoquinoline and an activated quinuclidinol derivative, such as the chloroformate or the carbonate derivative in the presence of pyridine. The obtained racemic compounds are resolved by chiral high-pressure liquid chromatography. The main disadvantage of the process is the use of column chromatography for the purification of Solifenacin base and long reaction times, which render the process industrially unsuitable.

EP 1 879 867 discloses the preparation of Solifenacin by condensing (S)- 1-phenyl-l, 2,3, 4-tetra hydroisoquinoline and a haloalkyl haloformate in the presence of a first base to yield a haloalkyl- 1,2,3,4-tetrahydroisoquinoline carbamate, which is subsequently converted to Solifenacin. In an alternative process of the application, (i?)-3-quinuclidinol is condensed with a haloalkyl haloformate in the presence of a base to obtain haloalkyl-quinuclidylcarbonate which is converted to Solifenacin. The reaction procedure is tedious while its cost-efficiency is hampered by the need to use two different bases for the two stages of the condensation.

EP 1 757 604 discloses the reaction of (5)- 1-phenyl-l , 2, 3, 4-tetrahydroisoquinoline with leaving groups such as 1 H-imidazole-l-yl, 2,5-dioxopyrrolidin-l-yloxy , 3 -methyl- lH-imidazol-3 -ium-1- yl or chloro and further condensation with (J?)-3-quinuclidinol in the presence of sodium hydride as a base and a mixture of toluene and dimethylformamide or toluene alone as a reaction medium. The condensation reaction involves use of hazardous sodium hydride and use of column chromatography for the purification of an intermediate ethyl (/?)-quinuclidin-3-yl carbonate, so handling of the reaction is difficult and time consuming; further, the leaving groups used are costly. Purity and yield of Solifenacin thus obtained is not reported in the application. WO 2010/103529 discloses a process for preparing Solifenacin by reacting (i?)-3-quinuclidinol with bis(aryl) carbonate to form aryl carbonate substituted (i?)-3-quinuclidinol, which was further condensed with (15)- 1 -phenyl- 1 , 2,3, 4-tetrahydroisoquinoline to provide Solifenacin. The major disadvantage of this process is its low yield and the formation of undesired isomers which requires additional purification steps.

WO 2008/120080 discloses a process for the preparation of Solifenacin by reacting (i?)-3- quinuclidinol and l ,l -carbonyl-di-(l ,2,4-triazole) in an organic solvent, followed by condensation with (1 S)- 1 -phenyl- 1 , 2,3, 4-tetrahydroisoquinoline in the presence of triethylamine to provide Solifenacin. The reagents used, i.e. l , l -carbonyl-di-(l ,2,4-triazole), are costly. It is apparent that large volumes of solvents are required and reaction is carried out at reflux temperature.

According to one embodiment of Indian application 2668/MUM/2008, reaction of aryl/heteroaryl substituted heteroaryl carbonate or chloroformate with ( IS)- 1 -phenyl- 1 ,2,3, 4- tetrahydroisoquinoline in the presence of a base is described which is further reacted with (i?)-3- quinuclidinol in the presence of a base to obtain Solifenacin base. In another embodiment, reaction of aryl/heteroaryl/substituted heteroaryl carbonate or chloroformate with (/?)-3- quinuclidinol in the presence of a base which is further reacted with (lS)-l -phenyl-l ,2,3,4- tetrahydroisoquinoline in the presence of a base to obtain Solifenacin base. The disadvantage of these processes is that the key intermediates are obtained in low yield and purity which ultimately leads to a costly final product.

It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, byproducts of the reaction, products of side reactions or degradation products. Impurities in an active pharmaceutical ingredient (API) may arise from degradation of the API itself or during the preparation of the API, they are undesirable and may be harmful. Furthermore, it is required to control the levels of these impurities in the finished dosage forms and to ensure that the impurity is present in the lowest possible levels, even if structural determination is not possible.

The above described methods for the preparation of Solifenacin base or salts thereof involve long reaction time, hazardous reagents and distillation of solvents at high temperature which leads to higher impurity formation and increased production cost. Hence there is a need to develop an efficient process with high yield, safe to handle and appropriate for industrial use.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide an improved process for the preparation of Solifenacin or a salt thereof, which overcomes the deficiencies of the prior art processes and results to a cost effective industrial production without compromising the yield and quality of the product.

Another object of the present invention is to provide an improved method for the preparation of Solifenacin or a salt thereof by providing novel intermediate compounds and further selecting the appropriate reactants, catalysts, solvent systems and conditions used to afford the products in high yield and purity.

Yet another object of the present invention is to provide substantially pure Solifenacin or a salt thereof substantially free of unwanted isomers. In accordance with the above objects of the present invention, a process for the preparation of compound of formula I is provided,

.Salt Formula I

comprising the following steps:

a) reacting compound of formula II

Formula II

a compound of formula III in a suitable solvent;

Formula III

wherein R represents one of the following

to f ormula B

wherein R and R'are as defined above, provided that R' is not and alkyl;

b) treating a compound of formula A or a compound of formula B, optionally obtained in situ, with compound of

Formula IV

c) optionally isolating Solifenacin free base; and/or d) optionally converting to a Solifenacin salt.

According to the present invention certain impurities are formed during the synthesis of Solifenacin or its salts, which are persistent impurities in the final stage and have not been previously disclosed. Hence these impurities need to be strictly controlled. Among impurities X, Y and Z described, impurities X and Y are novel and thus form part of the present invention.

An object of the present invention is to provide an isolated impurity, l-({[(lS)-l-phenyl-3,4- dihydroisoquinolin-2(lH)-yl]carbonyl}oxy)pyrrolidine-2,5-dio ne (impurity X) having the following structural formula:

Impurity X

Yet another object of the present invention is to provide impurity X as an impurity of Solifenacin or salts thereof.

Yet another object of the present invention is to provide a process for synthesizing and isolating impurity X.

Yet another object of the present invention is to provide an isolated impurity bis[(lS)-l-phenyl- 1,2,3,4-tetrahydro isoquinolin-2-yl]methanone (impurity Y), having the following structural formula:

Impurity Y

Still another object of the present invention is to provide impurity Y as an impurity of Solifenacin or salts thereof.

Yet another object of the present invention is to provide a process for the synthesizing and isolating impurity Y.

Isomeric impurity ( 1 ,3i?)-3-[[( 1 '-phenyl- 1 ',2 ^, ,3',4'-tetrahydro-2 ' -isoquinolyl)carbonyl]oxy] quinuclidine 1 -oxide (impurity Z ) has been disclosed in EP 0 801 067 and characterized.

Impurity Z

Still another object of the present invention is to provide highly pure Solifenacin or salts thereof substantially free of impurity X, impurity Y and impurity Z.

Yet another object of the present invention is to provide a pharmaceutical composition comprising Solifenacin or salt thereof substantially free of impurity X, impurity Y and impurity Z and one or more pharmaceutically acceptable excipients. In another aspect of the present invention, a pharmaceutical composition is provided, comprising Solifenacin or salt thereof prepared by the process disclosed herein and one or more pharmaceutically acceptable excipients.

Further, another aspect of the present invention is to provide novel compound of general formula A which is a useful intermediate in the preparation of Solifenacin succinate.

Formula A

wherein R represents one of the following:

The present invention provides advantages such as high yield and purity, no use of hazardous base like sodium hydride or sodium ethoxide which have handling difficulties in industrial scale, all reactions are carried out at room temperature, it is an easily scalable process and no racemization occurs at any of the stereocenters.

Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG.1 : Illustrates an XRPD pattern of Solifenacin succinate.

FIG.2: Illustrates a DSC thermogram of Solifenacin succinate.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the present invention, unless otherwise stated, the term "ambient temperature" means 20-40°C, preferably 20-35°C. The term "reflux temperature" means boiling temperature of the solvent used.

According to the present invention, the process for preparing Solifenacin or salts thereof comprises the following stages:

Stage Ϊ) Preparation of Solifenacin free base

The reaction of compound of formula II with compound of formula III, wherein R and R' are as defined above is carried out in a solvent selected from polar aprotic solvents such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate and non polar solvents such as toluene, cyclohexane or mixtures thereof, preferably acetonitrile. The reaction mixture is stirred at ambient temperature for about 3-6 hours, preferably about 3-4 hours, more preferably until completion of the reaction. The completion of the reaction is monitored by any suitable technique such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) or gas chromatography. A compound of formula A or compound of formula B may be optionally isolated by conventional techniques such as acid-base treatment, extraction with solvent, column chromatography and crystallization or used directly in the next step.

A solution of compound of formula IV in a suitable solvent selected from polar aprotic solvents such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate and non polar solvents such as toluene, cyclohexane or mixtures thereof, preferably acetonitrile, is added to the solution or residue obtained in the previous step and stirred overnight at ambient temperature until completion of the reaction. The reaction mixture is then concentrated at reduced pressure. A solvent is added to the obtained residue selected from polar aprotic solvents such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate and non polar solvents such as toluene, cyclohexane or mixtures thereof, preferably toluene. An acid is added to the solution, selected from hydrochloric acid, sulphuric acid and hydrobromic acid, preferably hydrochloric acid. The mixture is stirred for about 0.5 -3 hours, followed by phase separation. The aqueous layer is basified using an inorganic base such as such as sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide or an organic base such as liquor ammonia, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo[4.3.0]non-5- ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), triethyl amine (TEA), or diisoproyl amine. Preferred base is potassium carbonate. The basified aqueous layer is extracted with a suitable solvent such as polar aprotic solvents such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate and non polar solvents such as toluene, cyclohexane or mixtures thereof, preferably ethyl acetate. The organic layer is washed with water to remove inorganic impurities. The organic solvent is distilled off from the obtained organic layer to provide a residue of Solifenacin free base.

Solifenacin free base can be optionally isolated from the residue according to conventional methods to provide pure Solifenacin free base having chromatographic purity more than 90% and chiral purity more than 95%, preferably more than 98%, most preferably more than 99%.

Stage II: Preparation of Solifenacin acid salt

The acid used in this stage for the salt formation of Solifenacin free base may be an inorganic acid or an organic acid. Said inorganic acids include hydrochloric acid and hydrobromic acid and organic acids include succinic acid, oxalic acid and tartaric acid, preferably succinic acid. The solvents used in this stage include polar protic solvents water, methanol, ethanol, isopropyl alcohol, butanol or polar aprotic solvent such as ethylacetate, acetone or mixtures thereof; preferably a mixture of ethylacetate and ethanol is used.

The solvent or mixture of solvents and the acid used are added to the residue of Solifenacin free base. Thus obtained reaction mixture is heated to the reflux temperature of the solvent for about 0.5 to 1 hour. After completion of the reaction the compound of formula I is isolated by conventional techniques such as acid-base treatment, extraction with solvent, column chromatography and crystallization. Preferably the solution is cooled to room temperature, about 20-35°C. The crystals are collected by filtration, washed with an organic solvent and dried in a hot air oven to obtain pure Solifenacin salt, preferably Solifenacin succinate of formula I. According to another aspect of the present invention, an isolated impurity is provided, 1-({[(1S)- l-phenyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl} oxy) pyrrolidine-2,5-dione (impurity X).

Impurity X has been synthesized, isolated and identified by IR spectroscopy, mass spectroscopy, Ή NMR spectroscopy and ¹³ C NMR spectroscopy consistent with the assigned structure.

According to the present invention, impurity X is formed during the synthesis of Solifenacin or salts thereof.

According to the another embodiment, impurity X can be prepared by reacting N,N- disuccinimidyl carbonate in a solvent with (15)- 1 -phenyl- 1, 2,3, 4-tetrahydroisoquinoline at suitable temperature with stirring. The solvent of reaction mixture is distilled under reduced pressure; the residue is extracted in a suitable solvent or mixture of solvents and washed with water at ambient temperature. Impurity X is isolated by conventional techniques such as evaporation, acid-base treatment, column chromatography and/or crystallization.

According to another embodiment isolated impurity bis[(15)-l-phenyl-l,2,3,4-tetrahydro isoquinolin-2-yl]methanone is provided (impurity Y).

Impurity Y has been synthesized, isolated and identified by IR spectroscopy, mass spectroscopy, Ή NMR spectroscopy and ¹³ C NMR spectroscopy consistent with the assigned structure. According to the present invention, impurity Y is formed during the synthesis of Solifenacin or salts thereof.

According to another embodiment, impurity Y can be prepared by treating (1S)-1 -phenyl - 1,2,3, 4-tetrahydroisoquinoline with triphosgene in the presence of a base and in a suitable solvent. Impurity Y is isolated by conventional techniques such as evaporation, acid-base treatment, column chromatography and/or crystallization.

Impurity Z has been synthesized, isolated and identified by IR spectroscopy, mass spectroscopy and 1H NMR spectroscopy consistent with the assigned structure.

Impurity Z is formed as an impurity during the synthesis of Solifenacin or salts thereof of the present invention.

According to another embodiment, impurity Z can be prepared by treating Solifenacin with an oxidizing agent such as m-chloroperbenzoic acid in the presence of a base and in a suitable solvent. Impurity Z may be isolated by conventional techniques such as evaporation, acid-base treatment, column chromatography and/or crystallization.

In another aspect, highly pure solifenacin or salts thereof prepared by the process of the present invention comprises one or more of impurity X, impurity Y and impurity Z, in an amount of about 0.01 area-% to about 0.1 area-% each, specifically in an amount of about 0.01 area-% to about 0.05 area-% each, as measured by HPLC.

As used herein, highly pure Solifenacin or salts thereof substantially free of impurity X, impurity Y and impurity Z refers to Solifenacin or salts thereof comprising impurity X, impurity Y and impurity Z, in an amount of less than about 0.1 area-% each as measured by HPLC. In another embodiment, highly pure Solifenacin or salt thereof disclosed herein has a total purity of greater than about 99.5%, preferably greater than about 99.8%, more preferably greater than about 99.9%, and most preferably greater than about 99.95% as measured by HPLC.

Further encompassed herein is the use of highly pure Solifenacin or salt thereof substantially free of impurity X, impurity Y and impurity Z for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier. Said specific pharmaceutical composition is selected from a solid dosage form and/or an oral suspension.

In a further embodiment, a pharmaceutical composition comprising Solifenacin or salt thereof prepared by the process disclosed herein is provided with one or more pharmaceutically acceptable excipients; pharmaceutical composition is preferably selected from a solid dosage form and/or an oral suspension.

The process for the preparation of Solifenacin succinate according to the present invention will be described in detail with reference to the following examples, which are provided by way of illustration only and should not be construed as a limit to the scope of the invention in any manner.

EXAMPLES

Preparation of Solifenacin succinate:

Example 1

To a stirred solution of (i?)-3-quinuclidinol (1 1.5 mmol, 1.46 g) in acetonitrile (50 ml) at ambient temperature, Ν,Ν ^' -disuccinimidyl carbonate (14.4 mmol, 3.69 g) was added. The resulting mixture was stirred at ambient temperature for 4 hours. The solution of ( 15)- 1 -Phenyl- 1 , 2, 3, 4- tetrahydroisoquinoline (9.6 mmol, 2.0 g, Chromatographic purity: 99.93%, Chiral purity: 98.65%) in acetonitrile (25 ml) was added in reaction mass and then stirred overnight. The reaction mixture was concentrated at reduced pressure. The residue was then diluted with toluene (10 ml) and IN hydrochloric acid (20 ml) was added therein. The reaction mixture was stirred and the phases were separated. Separated aqueous layer was basified with a 20% sodium carbonate (20 ml) solution, followed by extraction with ethyl acetate (20 ml). The aqueous layer was re-extracted with ethyl acetate (10 ml). Combined the organic layer and washed with water (10 ml), the solvent therein was distilled off. To the resulting residue (i.e. Solifenacin free base: Chromatographic purity: 91.03%, Chiral purity: 99.03%) ethyl acetate (20 ml), ethanol (3.5 ml) and succinic acid (1.09 g) were added, the reaction mixture was heated to reflux followed by cooling at room temperature, and formed crystals were collected by filtration, which were then washed with ethyl acetate (3 ml) twice and dried in a hot air oven to obtain 3.9 g of Solifenacin succinate. Yield: 1.95 w/w, % yield: 85%, Chromatographic purity: 99.46%, Chiral purity: 99.93%.

Example 2

To a stirred solution of Ν,Ν ^' -disuccinimidyl carbonate (143 mmol, 36.8 g) in acetonitrile (60 ml) at ambient temperature (/?)-3-quinuclidinol (1 10 mmol, 14 g) was added. The resulting mixture was stirred at ambient temperature for 4 hours. ( \S)-\ -Phenyl- 1 , 2, 3, 4-tetrahydroisoquinoline (95.6 mmol , 20 g, Chromatographic purity: 99.99%, Chiral purity: 99.0%) was added to the reaction mass and stirred at 25-35°C until completion of reaction. The reaction mass was concentrated at reduced pressure. The residue was then diluted with toluene (100 ml) and IN hydrochloric acid (200 ml) was added therein. The reaction mixture was stirred and the phases were separated. Separated aqueous layer was basified with potassium carbonate to pH 9- 10, followed by extraction with ethyl acetate (100 ml). The aqueous layer was re-extracted with ethyl acetate (40 ml). The organic layers of ethyl acetate were combined, washed with water (60 ml) and the solvents were distilled off. To the resulting residue (i.e. Solifenacin free base: Chromatographic purity: 97.99%) ethyl acetate (200 ml), ethanol (35 ml) and succinic acid (10.9 g) were added, the reaction mixture was heated to reflux followed by cooling at 5°C, and the formed crystals were collected by filtration, which were then washed with ethyl acetate (30 ml) twice and dried in hot air oven to obtain 40.8 g of Solifenacin succinate. Yield: 2.04 w/w, % yield: 89%, Chromatographic purity: 99.89%, Chiral purity: 99.9%. Example 3

To a stirred solution of ( ?)-3-quinuclidinol (1 1.5 mmol, 1.46 g) in acetonitrile (50 ml), at 30- 35°C bis(l ,3-dioxoisoindolin-2-yl) carbonate (14.3 mmol, 5.05 g) was added. The resulting mixture was stirred at 30-35°C for 4-6 hours. The solution of ( 1 S)- 1 -phenyl- 1 , 2, 3, 4-tetrahydro isoquinoline (9.6 mmol , 2.0 g) in acetonitrile (25 ml) was added to the reaction mass and the reaction mass was stirred until completion of the reaction. Solifenacin succinate was isolated as described in example 1.

X-ray powder diffraction pattern of Solifenacin succinate gives characteristic peaks having significant reflections expressed as 20 ±0.2 values and % intensity as given in the table below.

The crystalline form of Solifenacin succinate is further characterized an endotherm at about 146.6°C by DSC. Example 4: Preparation of l-({[(lS)-l-phenyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl} oxy) pyrrolidine-2,5-dione (Impurity X)

Acetonitrile (45 ml) and Ν,Ν-disuucinimidyl carbonate (9.18 g) were charged into a round bottom flask and cooled to 20°C, followed by addition of (5)- 1 -phenyl- 1,2,3, 4- tetrahydroisoquinoline (5.0 g) at below 30°C. The solution was stirred for 120 minutes followed by distillation under reduced pressure below 55°C.The residue was extracted in ethyl acetate (50 ml) and water (50 ml). The aqueous layer was separated and re-extracted with ethyl acetate (30 ml). Ethyl acetate layer was washed twice with water (20 ml x 2) at ambient temperature. The organic layer was separated and distilled under reduced pressure below 55°C. Degassed for 120 minutes under reduced pressure below 55°C to obtain l-({[(lS)-l-phenyl-3,4- dihydroisoquinolin-2(lH)-yl]carbonyl} oxy) pyrrolidine-2,5-dione (6.55 g). (Yield: 78%, Purity by HPLC 99.69%). IR (cm ^"1 ): 3522, 3084, 2935, 2893, 1757, 1765, 1425, 1213, 1085, 746; Ή NMR (DMSO-d6, δ ppm): 2.81 (s, 4H), 2.86-3.03 (m, 2H), 3.37-3.95 (m, 2H), 6.26-6.42 (m, 1H), 7.16-7.37 (m, 9H); ¹³ C NMR (DMSO-d ₆ , ppm): 171, 151 , 141, 134.8, 134.6, 134.4, 129.4, 129.2, 129, 128.6, 128.3, 128.2, 128, 126.9, 126.8, 59, 40, 28, 26, 25.7;MS: m/z: 373 (M+23). Example 5: Preparation of bis[(l S - 1 -phenyl- 1, 2,3, 4-tetrahydro isoquinolin-2-yl]methanone (Impurity Y)

Dichloromethane (125 ml), potassium carbonate (33.03 g) and (S)-l -Phenyl- 1 ,2,3,4- tetrahydroisoquinoline (25.0 g) were charged into a round bottom flask, and cooled to 5°C followed by slow addition of a solution of triphosgene (6.38 g) in dichloromethane (125 ml) at below 10°C and then stirred overnight at ambient temperature. The reaction mass was quenched with water (125 ml). The organic layer was separated and aqueous layer was re-extracted with dichloromethane (100 ml). Both organic layers were combined and washed with water (100 ml). The solvent was distilled off and degassed for 30 minutes under reduced pressure below 55°C to obtained crude bis[( IS)- 1 -phenyl- 1,2,3,4-tetrahydro isoquinolin-2-yl] methanone (25.3 g). Purified by column chromatography using cyclohexane and ethyl acetate to obtain bis[(lS)-l- phenyl- 1,2,3, 4-tetrahydro isoquinolin-2-yl] methanone( 17.94 g). (Yield: 33.7%, Purity by HPLC: 98.54%). IR (cm ^"1 ): 3057, 3026, 2993, 2956, 2835, 1645, 1415; 1H NMR (CDC1 ₃ , S ppm): 2.82-2.98 (m, 4H), 3.28-3.35 (m, 2H), 3.67-3.733 (m, 2H), 6.22 (s, 2H), 7.01-7.31 (m, 18H); ¹³ C NMR (CDC1 ₃ , ppm): 163, 143, 135, 134, 128.8, 128.7, 128.6, 128.3, 127.2, 126.8, 126.1, 59, 41, 29; MS: m/z: 445 (M+l).

Example 6: Preparation of (rS,3/?)-3-[[(r-phenyl-r,2',3',4'-tetrahydro-2'-isoquinolyl) carbonyl] oxy] quinuclidine 1 -oxide (Impurity Z)

Dichloromethane (200 ml), sodium bicarbonate (5.16 g) and (lS,3 ^' i?)-quinuclidin-3 ^' -yl 1- phenyl-l,2,3,4-tetrahydro isoquinoline-2-carboxylate (19.0 g) were charged into a round bottom flask and cooled to 5°C, followed by the slow addition of m-chloroperbenzoic acid (14.10 g) at below 10°C and stirring for 60 minutes at ambient temperature. The reaction mass was quenched with water (250 ml).The organic layer was separated and washed with a solution of sodium thiosulphate (25.0 g) in water (250 ml) followed by fresh water (75 ml). The solvent was distilled off and degassed for 30 minutes under reduced pressure below 55°C to obtained crude (l£,3 'i?)-l '-oxido quinuclidin-3 '-yl 1 -phenyl- l ,2,3,4-tetrahydroisoquinoline-2-carboxylate (19.85 g). Purified by column chromatography using ethyl acetate and methanol to obtain pure (1 'S,3i?)-3 - [[( 1 '-phenyl- 1 ',2 ^* ,3 ',4'-tetrahydro-2 ' -isoquinolyl)carbonyl]oxy] quinuclidine 1 -oxide (16.5 g). (Yield: 83%, Purity by HPLC 99.13%). Ή NMR (CDCI3, δ ppm): 1.85-2.15 (m, 3H), 2.15-2.35 (m, 2H), 2.75-2.90 (m, 1H), 2.90-2.95 (m, 1 H), 3.20-3.50 (m, 6H), 3.70-3.80 (m, 1 H), 3.85-4.10 (m, 1H), 5.14 (brs, 1H), 6.14, 6.43 (brsx2, 1H), 7.05-7.40 (m, 9H). IR (cm ^*1 ): 2966, 2937, 2879, 1695, 1689, 1425; MS: m/z: 379 (M+l).

While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the scope thereof, as defined in the appended claims.