JP2015521635A - Method for preparing solifenacin or a salt thereof - Google Patents

Abstract

The present invention relates to an improved process for the preparation of solifenacin of the formula I or a salt thereof, more particularly the invention relates to an economically viable and industrially useful high-purity solifenacin of the formula I or a salt thereof. It relates to an advantageous preparation method.

Description

  The present invention relates to an improved method for preparing solifenacin or a salt thereof, and more particularly, the present invention relates to an economically viable and industrially advantageous method for preparing high-purity solifenacin or a salt thereof.

Solifenacin salt of formula I, especially solifenacin succinate acts as muscarinic M ₃ receptor antagonist, is used in the symptomatic treatment of increasing and urination urgency of urge incontinence and / or urination frequency in overactive bladder patients. Solifenacin is chemically known as (1S, 3′R) -quinuclidin-3′-yl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate. Commercially, solifenacin succinate is available under the trade name Vesicare®.

  EP-A-081067 discloses a process for the preparation of solifenacin, a racemic mixture or the biologically active and pure isomer (1S, 3'R) thereof. The patent discloses the reaction of quinuclidinol with 1-phenyl-1,2,3,4-tetrahydroisoquinolinecarbamoyl derivatives in the presence of sodium hydride. Furthermore, the patent discloses the condensation of 1-phenyl-1,2,3,4-tetrahydroisoquinoline with activated quinuclidinol derivatives such as chloroformate or carbonate derivatives in the presence of pyridine. The resulting racemate is separated by chiral high pressure liquid chromatography. The main drawbacks of the method are the use of column chromatography for the purification of solifenacin base and the long reaction time, which makes the process industrially unsuitable.

  EP 1 879 867 discloses the condensation of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline and haloalkyl haloformates in the presence of a first base to form haloalkyl-1,2,3. Disclosed is the preparation of solifenacin by obtaining 1,4-tetrahydroisoquinoline carbamate, which is then converted to solifenacin. In another method of the application, (R) -3-quinuclidinol is condensed with a haloalkyl haloformate in the presence of a base to give a haloalkyl-quinuclidyl carbonate, which is converted to solifenacin. While the reaction procedure is tedious, its cost efficiency is hampered by the need to use two different bases for the two-step condensation.

  EP 1757604 is, for example, 1H-imidazol-1-yl, 2,5-dioxopyrrolidin-1-yloxy, 3-methyl-1H-imidazol-3-ium-1-yl or chloro. Reaction of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline with various leaving groups and presence of sodium hydride as base and a mixture of toluene and dimethylformamide as reaction medium or toluene alone Further condensation with (R) -3-quinuclidinol is disclosed below. The condensation reaction requires the use of hazardous sodium hydride and the use of column chromatography for the purification of the intermediate ethyl carbonate (R) -quinuclidin-3-yl, making the reaction difficult to handle. In addition, it is time consuming; and the cost of the leaving group used is high. The purity and yield of solifenacin thus obtained is not reported in that application.

  WO 2010/103529 reacts (R) -3-quinuclidinol with bis (aryl) carbonate to form an aryl carbonate substituted (R) -3-quinuclidinol, which is referred to as (1S) -1-phenyl- Disclosed is a method for preparing solifenacin by further condensing with 1,2,3,4-tetrahydroisoquinoline to obtain solifenacin. The main drawback of this process is its low yield and the production of unwanted isomers that require additional purification steps.

  WO 2008/120080 reacts (R) -3-quinuclidinol with 1,1-carbonyl-di- (1,2,4-triazole) in an organic solvent and then in the presence of triethylamine (1S ) Disclosed is a method for preparing solifenacin by condensation with 1-phenyl-1,2,3,4-tetrahydroisoquinoline. The reagent used, ie 1,1-carbonyl-di- (1,2,4-triazole), is expensive. Obviously, a large amount of solvent is required and the reaction is carried out at reflux temperature.

  According to one embodiment of Indian Application No. 2668 / MUM / 2008, aryl / heteroaryl / substituted hetero with (1S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline in the presence of a base Reactions of aryl carbonates or chloroformates are described, which are further reacted with (R) -3-quinuclidinol in the presence of a base to give solifenacin base. In another embodiment, after reaction of aryl / heteroaryl / substituted heteroaryl carbonate or chloroformate with (R) -3-quinuclidinol in the presence of a base, (1S) -1-phenyl is further added in the presence of a base. Reaction with -1,2,3,4-tetrahydroisoquinoline gives the solifenacin base. The disadvantage of these methods is that important intermediates are obtained in low yield and purity, which ultimately leads to expensive end products.

  It is known that synthetic compounds can contain exogenous compounds or impurities resulting from their synthesis or degradation. Impurities can be unreacted starting materials, reaction byproducts, side reaction products or degradation products. Impurities in the active pharmaceutical ingredient (API) can arise from degradation of the API itself or during the preparation of the API, which can be undesirable and harmful. Furthermore, it is necessary to control the amount of these impurities in the finished dosage form to ensure that the impurities are present at the lowest possible level, even if structure determination is not possible.

  The above process for preparing solifenacin base or salts thereof involves long reaction times, dangerous reagents, and distillation of the solvent at high temperatures leading to the formation of more impurities and increased manufacturing costs. Therefore, there is a need to develop an efficient method that is high in yield, safe to handle and suitable for industrial applications.

  Thus, the present invention provides an improved method of preparing solifenacin or a salt thereof that eliminates the disadvantages of conventional methods and enables cost-effective industrial production without compromising product yield and quality. It is an object of the invention.

  Another object of the present invention is to provide a novel intermediate compound and to select the appropriate reactants, catalysts, solvent systems and conditions used to obtain a product in high yield and purity of solifenacin or a salt thereof. It is to provide an improved preparation method.

  Yet another object of the present invention is to provide substantially pure solifenacin or a salt thereof substantially free of undesirable isomers.

According to the above object of the invention, the formula I
A method for preparing a compound of
a) Formula II in a suitable solvent
A compound of formula III
(Where R is the following:
R ′ represents one of the following:
Or a compound of formula B or a compound of formula B
(In the above formula, R and R ′ are as defined above, provided that R ′ is
And not alkyl)
The step of generating
b) A compound of formula A or a compound of formula B which may be obtained in situ is of formula IV
Treating with a compound of:
c) optionally separating solifenacin free base; and / or d) optionally converting to solifenacin salt is provided.

  According to the present invention, certain impurities are produced during the synthesis of solifenacin or its salts and become residual impurities in the final stage, which have not been disclosed so far. Therefore, it is necessary to strictly control these impurities. Of the impurities X, Y and Z described, impurities X and Y are novel and thus form part of the present invention.

The object of the present invention is the following structural formula:
Isolated impurity 1-({[(1S) -1-phenyl-3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} oxy) pyrrolidine-2,5-dione (impurity X) having It is to be.

Still another object of the present invention is to provide an impurity X as an impurity of solifenacin or a salt thereof.
Yet another object of the present invention is to provide a method for synthesizing and separating impurities X.

Yet another object of the invention is the following structural formula:
To provide isolated impurity bis [(1S) -1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl-] methanone (impurity Y) having

Still another object of the present invention is to provide an impurity Y as an impurity of solifenacin or a salt thereof.
Yet another object of the present invention is to provide a method for synthesizing and separating impurities Y.

Isomeric impurity (1 ′S, 3R) -3-[[(1′-phenyl-1 ′, 2 ′, 3 ′, 4′-tetrahydro-2′-isoquinolyl) carbonyl] oxy] quinuclidine 1-oxide (impurity Z) is disclosed and characterized in EP-A-081067.

Still another object of the present invention is to provide a high-purity solifenacin or a salt thereof substantially free of impurities X, Y and Z.
Yet another object of the present invention is to provide a pharmaceutical composition comprising solifenacin or a salt thereof substantially free of impurities X, Y and Z and one or more pharmaceutically acceptable excipients. It is to be.

  In another aspect of the present invention, there is provided a pharmaceutical composition comprising solifenacin or a salt thereof prepared by the methods disclosed herein and one or more pharmaceutically acceptable excipients.

Furthermore, another aspect of the present invention is a compound of general formula A which is a useful intermediate in the preparation of solifenacin succinate.
(Where R is the following:
A novel compound).

The present invention provides advantages such as high yield and purity, does not use dangerous bases such as sodium hydride or sodium ethoxide that are difficult to handle on an industrial scale, and all reactions are carried out at room temperature, The process is easy to scale up and racemization does not occur at any stereocenter.
Other objects and advantages of the present invention will become apparent to those skilled in the art in light of the following detailed description.

2 shows the XRPD pattern of solifenacin succinate. 2 shows a DSC thermogram of solifenacin succinate.

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

According to the present invention, the process for preparing solifenacin or a salt thereof comprises the following steps:
Step I) Preparation of Solifenacin Free Base Reaction of a compound of formula II with a compound of formula III, wherein R and R are as defined above, is carried out with a polar aprotic solvent such as dichloromethane, acetonitrile, It is carried out in a solvent selected from dimethylformamide, tetrahydrofuran, ethyl acetate, and nonpolar 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. The compound of formula A or the compound of formula B is optionally separated by conventional techniques such as acid-base treatment, solvent extraction, column chromatography and crystallization, or directly in the next step. Can be used.

  Solutions of compounds of formula IV in a suitable solvent selected from polar aprotic solvents such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate, and nonpolar 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 the reaction is complete. The reaction mixture is then concentrated under reduced pressure. A nonpolar solvent such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate, and a nonpolar solvent such as toluene, cyclohexane or mixtures thereof, preferably toluene, are added to the resulting residue. . An acid selected from hydrochloric acid, sulfuric acid, hydrobromic acid, preferably hydrochloric acid is added to the solution. The mixture is stirred for about 0.5-3 hours, followed by phase separation. The aqueous layer may be an inorganic base such as sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, or an organic base such as ammonia solution, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), triethylamine (TEA), or diisopropylamine Be sexualized. A preferred base is potassium carbonate. The basified aqueous layer is formed with a suitable solvent, such as a polar aprotic solvent such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate, and a nonpolar solvent such as toluene, cyclohexane or mixtures thereof, preferably ethyl acetate. Extracted. The organic layer is washed with water to remove inorganic impurities. The organic solvent is distilled off from the resulting organic layer to obtain a solifenacin free base residue.

  Solifenacin free base can optionally be separated from the residue according to common methods, with chromatographic purity exceeding 90% and exceeding 95%, preferably exceeding 98%, most preferably exceeding 99% Pure solifenacin free base with chiral purity is obtained.

Stage II: Preparation of Solifenacin Salt The acid used at this stage for salt formation of solifenacin free base may be an inorganic acid or an organic acid. The inorganic acid includes hydrochloric acid and hydrobromic acid, and the organic acid includes succinic acid, oxalic acid, and tartaric acid, preferably succinic acid. Solvents used at this stage include polar protic solvents such as water, methanol, ethanol, isopropyl alcohol, butanol, or polar aprotic solvents such as ethyl acetate, acetone or mixtures thereof, preferably with ethyl acetate. A mixture of ethanol is used.

  The solvent or solvent mixture and acid used are added to the solifenacin free base residue. The reaction mixture thus obtained is heated to the reflux temperature of the solvent for about 0.5 to 1 hour. After completion of the reaction, the compounds of formula I are separated by conventional techniques such as acid-base treatment, solvent extraction, column chromatography and crystallization. Preferably, the solution is cooled to room temperature, ie 20-35 ° C. The crystals are collected by filtration, washed with an organic solvent and dried in a hot air oven to give a pure solifenacin salt, preferably solifenacin succinate of formula I.

According to another aspect of the present invention, isolated impurity 1-({[(1S) -1-phenyl-3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} oxy) pyrrolidine-2,5 -Dione (impurity X) is provided.
Impurity X was synthesized, isolated, and identified as consistent with the assigned structure by IR spectroscopy, mass spectrometry, ¹ H NMR spectroscopy and ¹³ C NMR spectroscopy.

According to the invention, impurity X is generated during the synthesis of solifenacin or a salt thereof.
According to another embodiment, the impurity X comprises N, N-disuccinimidyl carbonate in a solvent at a suitable temperature with stirring at (1S) -1-phenyl-1,2,3,4-tetrahydro It can be prepared by reacting with isoquinoline. The solvent of the reaction mixture is distilled under reduced pressure; the residue is extracted with a suitable solvent or solvent mixture and washed with water at ambient temperature. Impurity X is separated by conventional techniques such as evaporation, acid-base treatment, column chromatography and / or crystallization.

According to another embodiment, isolated impurity bis [(1S) -1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl] methanone (impurity Y) is provided.
Impurity Y was synthesized, isolated, and identified as consistent with the assigned structure by IR spectroscopy, mass spectrometry, ¹ H NMR spectroscopy and ¹³ C NMR spectroscopy.

According to the invention, impurity Y is generated during the synthesis of solifenacin or a salt thereof.
According to another embodiment, impurity Y is prepared by treating (1S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline with triphosgene in a suitable solvent in the presence of a base. Can do. Impurity Y is separated by conventional techniques such as evaporation, acid-base treatment, column chromatography and / or crystallization.

Impurity Z was synthesized, isolated, and identified by IR spectroscopy, mass spectrometry and ¹ H NMR spectroscopy as being consistent with the assigned structure.
Impurity Z is generated as an impurity during the synthesis of solifenacin or a salt 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 a suitable solvent in the presence of a base. Impurity Z can be separated by conventional techniques such as evaporation, acid-base treatment, column chromatography and / or crystallization.

In another aspect, the high purity solifenacin or salt thereof prepared by the method of the present invention is each in an amount of about 0.01 area% to about 0.1 area%, particularly about 0, respectively, as measured by HPLC. One or more of impurities X, Y, and Z are included in an amount of .01 area% to about 0.05 area%.
As used herein, high-purity solifenacin or a salt thereof substantially free of impurities X, Y and Z is an impurity less than about 0.1 area% each as measured by HPLC. It means solifenacin or a salt thereof containing X, impurity Y and impurity Z.

  In another embodiment, the high purity solifenacin or salt thereof disclosed herein is greater than about 99.5%, preferably greater than about 99.8%, more preferably about 99.99, as measured by HPLC. It has a total purity exceeding 9%, most preferably exceeding 99.95%.

  Also included herein is the use of high purity solifenacin or salt substantially free of impurities X, Y and Z for the manufacture of a pharmaceutical composition with a pharmaceutically acceptable carrier. It is in. The specific pharmaceutical composition is selected from solid dosage forms and / or oral suspensions.

  In a further embodiment, a pharmaceutical composition containing solifenacin or a salt thereof prepared by the methods disclosed herein includes one or more pharmaceutically acceptable excipients; The product is preferably selected from solid dosage forms and / or oral suspensions.

  The method of preparation of solifenacin succinate according to the present invention will be described in detail with reference to the following examples which are provided for illustration only and should not be construed as limiting the scope of the invention in any way.

Preparation of solifenacin succinate:
Example 1
To a stirred solution of (R) -3-quinuclidinol (11.5 mmol, 1.46 g) in acetonitrile (50 ml) at ambient temperature is added N, N′-disuccinimidyl carbonate (14.4 mmol, 3.69 g). added. The resulting mixture was stirred at ambient temperature for 4 hours. (1S) -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 to the reaction mass and stirred overnight. The reaction mixture was concentrated under reduced pressure. The residue was then diluted with toluene (10 ml) and 1N hydrochloric acid (20 ml) was added thereto. The reaction mixture was stirred and the phases were separated. The separated aqueous layer was basified with 20% sodium carbonate (20 ml) solution and extracted with ethyl acetate (20 ml). The aqueous layer was re-extracted with ethyl acetate (10 ml). The organic layers were combined and washed with water (10 ml), and the solvent therein was distilled off. The resulting residue (ie, solifenacin free base: chromatographic purity: 91.03%, chiral purity: 99.03%) was added to ethyl acetate (20 ml), ethanol (3.5 ml) and succinic acid (1.09 g). ) And the reaction mixture is heated to reflux, then cooled at room temperature, and the resulting crystals are collected by filtration, then washed twice with ethyl acetate (3 ml), dried in a hot air oven, and 3. 9 g of solifenacin succinate was obtained. Yield: 1.95 w / w,% yield: 85%, chromatographic purity: 99.46%, chiral purity: 99.93%.

Example 2
(R) -3-Quinuclidinol (110 mmol, 14 g) was added to a stirred solution of N, N′-disuccinimidyl carbonate (143 mmol, 36.8 g) in acetonitrile (60 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 4 hours. (1S) -1-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, 25 Stir at −35 ° C. until the reaction is complete. The reaction mass was concentrated under reduced pressure. The residue was then diluted with toluene (100 ml) and 1N hydrochloric acid (200 ml) was added therein. The reaction mixture was stirred and the phases were separated. The separated aqueous layer was basified to pH 9-10 with potassium carbonate and extracted with ethyl acetate (100 ml). The aqueous layer was re-extracted with ethyl acetate (40 ml). The organic layers of ethyl acetate were combined and washed with water (60 ml), and the solvent was distilled off. Ethyl acetate (200 ml), ethanol (35 ml) and succinic acid (10.9 g) are added to the resulting residue (ie, solifenacin free base: chromatographic purity: 99.99%) and the reaction mixture is heated to reflux. After cooling to 5 ° C., the resulting crystals were collected by filtration, then washed twice with ethyl acetate (30 ml) and dried in a hot air oven to give 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 (R) -3-quinuclidinol (11.5 mmol, 1.46 g) in acetonitrile (50 ml) at 30-35 ° C. was added bis (1,3-dioxoisoindoline-2-yl) carbonate (14 .3 mmol, 5.05 g) was added. The resulting mixture was stirred at 30-35 ° C. for 4-6 hours. A solution of (1S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline (9.6 mmol, 2.0 g) in acetonitrile (25 ml) was added to the reaction mass and the reaction mass was stirred until the reaction was complete. . Solifenacin succinate was isolated as described in Example 1.
The X-ray powder diffraction pattern of solifenacin succinate gives a characteristic peak with significant reflection expressed as 2θ ± 0.2 values and% intensity given in the table below.
The crystalline form of solifenacin succinate is further characterized as endothermic at about 146.6 ° C. by DSC.

Example 4: Preparation of 1-({[(1S) -1-phenyl-3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} oxy) pyrrolidine-2,5-dione (impurity X) acetonitrile ( 45 ml) and N, N-disuccinimidyl carbonate (9.18 g) in a round bottom flask, cooled to 20 ° C. and then (S) -1-phenyl-1,2,3,4 below 30 ° C. -Tetrahydroisoquinoline (5.0 g) was added. The solution was stirred for 120 minutes and then distilled under reduced pressure below 55 ° C. The residue was extracted with ethyl acetate (50 ml) and water (50 ml). The aqueous layer was separated and re-extracted with ethyl acetate (30 ml). The ethyl acetate layer was washed twice with water (20 ml × 2) at ambient temperature. The organic layer was separated and distilled under reduced pressure below 55 ° C. Degas for 120 minutes under reduced pressure at <55 ° C. to give 1-({[(1S) -1-phenyl-3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} oxy) pyrrolidine-2,5 -Dione (6.55 g) was obtained. (Yield: 78%, purity 99.69% by HPLC). IR (cm ^-1 ): 3522, 3084, 2935, 2893, 1757, 1765, 1425, 1213, 1085, 746; ¹ H NMR (DMSO-d ₆ , 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 [(1S) -1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl] methanone (impurity Y) Dichloromethane (125 ml), potassium carbonate (33.03 g) and ( S) -1-Phenyl-1,2,3,4-tetrahydroisoquinoline (25.0 g) was placed in a round bottom flask, cooled to 5 ° C., and then triphosgene (6. 38 g) solution was added slowly and then stirred overnight at ambient temperature. The reaction mass was quenched with water (125 ml). The organic layer was separated and the 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, degassed under reduced pressure at less than 55 ° C. for 30 minutes, and crude bis [(1S) -1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl] methanone (25.3 g). ) Purification by column chromatography using cyclohexane and ethyl acetate gave bis [(1S) -1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl] -methanone (17.94 g). (Yield: 33.7%, purity by HPLC: 98.54%). IR (cm ^-1 ): 3057, 3026, 2993, 2956, 2835, 1645, 1415; ¹ H NMR (CDCl ₃ , δ 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 (CDCl 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 + 1).

Example 6: (1 ′S, 3R) -3-[[(1′-Phenyl-1 ′, 2 ′, 3 ′, 4′-tetrahydro-2′-isoquinolyl) carbonyl] oxy] quinuclidine 1-oxide ( Preparation of Impurity Z) Dichloromethane (200 ml), sodium bicarbonate (5.16 g) and 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (1S, 3′R) -quinuclidine-3 ′ -Ile (19.0 g) was placed in a round bottom flask and cooled to 5 ° C., then m-chloroperbenzoic acid (14.10 g) was slowly added below 10 ° C. and stirred 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 thiosulfate (25.0 g) in water (250 ml) followed by fresh water (75 ml). The solvent was distilled off, degassed under reduced pressure at less than 55 ° C. for 30 minutes, and crude 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (1S, 3′R) -1′- Oxidoquinuclidin-3′-yl (19.85 g) was obtained. Purification by column chromatography using ethyl acetate and methanol gave pure (1 ′S, 3R) -3-[[(1′-phenyl-1 ′, 2 ′, 3 ′, 4′-tetrahydro-2 '-Isoquinolyl) carbonyl] oxy] quinuclidine 1-oxide (16.5 g) was obtained. (Yield: 83%, purity 99.13% by HPLC). ¹ H NMR (CDCl ₃ , 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, 1H), 3.20-3.50 (m, 6H), 3.70-3.80 (m, 1H), 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 + 1).

  While the invention has been described in terms of particular embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made in the invention without departing from the scope set forth in the appended claims. Will.

Claims (14)

Formula I
A method for preparing a compound of
a) Formula II
A compound of formula III
(Where R is the following:
R ′ represents one of the following:
Or a compound of formula B or a compound of formula B
(In the above formula, R and R ′ are as defined above, provided that R ′ is
Or not alkyl)
The step of generating
b) A compound of formula A or a compound of formula B which may be obtained in situ is of formula IV
Treating with a compound of:
c) optionally separating solifenacin free base; and d) optionally converting solifenacin free base to a solifenacin salt.   The reaction of the compound of formula II with the compound of formula III is carried out in a polar aprotic solvent or a nonpolar solvent, such as a solvent selected from acetonitrile, dichloromethane, toluene, dimethylformamide, tetrahydrofuran or mixtures thereof. Item 2. The method according to Item 1.   Treatment of the compound of formula A or the compound of formula B with the compound of formula IV is selected from polar aprotic or nonpolar solvents such as acetonitrile, dichloromethane, toluene, ethyl acetate, dimethylformamide, tetrahydrofuran or mixtures thereof. The process according to claim 1, which is carried out in a solvent.   The process according to claim 1, wherein the acid used to obtain the solifenacin salt is selected from inorganic acids such as hydrochloric acid and hydrobromic acid or organic acids such as succinic acid, oxalic acid and tartaric acid. Formula A obtained by the process of claim 1 wherein R has the meaning as described above.
Compound.   1-({[(1S) -1-phenyl-3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} oxy) pyrrolidine-2,5 in an amount of less than 0.1 area% as measured by HPLC -Solifenacin or a salt thereof containing dione (impurity X).   Solifenacin containing bis [(1S) -1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl-] methanone (impurity Y) in an amount of less than 0.1 area% as measured by HPLC or its salt.   (1 ′S, 3R) -3-[[(1′-phenyl-1 ′, 2 ′, 3 ′, 4′-tetrahydro-2′-isoquinolyl) in an amount of less than 0.1 area% as determined by HPLC ) Carbonyl] oxy] quinuclidine 1-oxide (impurity Z), solifenacin or a salt thereof.   Solifenacin or a salt thereof having a purity of greater than 99%, comprising at least one of impurity X, impurity Y or impurity Z, each in an amount of less than about 0.2 area% as measured by HPLC.   12. Solifenacin or a salt thereof according to any one of claims 8 to 11 having a total purity of about 99% to about 99.99% as measured by HPLC. Isolated impurity 1-({[(1S) -1-phenyl-3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} oxy) pyrrolidine-2,5-dione.
Isolated impurity bis [(1S) -1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl] methanone.
  A pharmaceutical composition comprising solifenacin or a salt thereof substantially free of impurities X, Y and Z and one or more pharmaceutically acceptable excipients.   A pharmaceutical composition comprising solifenacin or a salt thereof prepared by the method disclosed herein and one or more pharmaceutically acceptable excipients.