Claims:1. A process for the preparation of Solifenacin succinate of formula (I)

Formula (I)
comprising the steps of:
(a) reacting racemic (RS)-ethyl 1-phenyl-1, 2, 3, 4-tetrahydro-2-isoquinolinecarboxylate of formula (II)

Formula (II)
with racemic (RS)-3-quinuclidinol of formula (III)

Formula (III)
in the presence of a base in an organic solvent to obtain racemic Solifenacin base;
(b) preparing a reaction mixture of racemic Solifenacin base of step (a) and succinic acid;
(c) stirring and filtering the reaction mixture of step (b) to obtain residue from filtrate;
(d) preparing a reaction mixture of the residue of step (c) and L-tartaric acid to obtain Solifenacin tartrate;
(e) preparing an aqueous solution of a base then adding Solifenacin tartrate of step (d) followed by water-immiscible organic solvent;
(f) stirring and separating organic layer from step (e) and concentrating it to obtain a residue; and
(g) dissolving the residue of step (f) in an organic solvent and treating with succinic acid to obtain Solifenacin succinate of Formula I
2. The process of claim 1, wherein the organic solvent used in step (a) is selected from a group comprising of dimethylformamide (DMF), toluene, hexane, cyclohexane or mixtures thereof.
3. The process of claim 1, wherein the succinic acid used in step (b) is 0.3 to 1 molar equivalent with respective to racemic Solifenacin base.
4. The process of claim 1, wherein the L-tartaric acid used in step (d) is 0.5 to 2 molar equivalents with respective to Solifenacin base.
5. The process of claim 1, wherein the succinic acid used in step (b) is 0.6 molar equivalent with respective to racemic Solifenacin base.
6. The process of claim 1, wherein the L-tartaric acid used in step (d) is 1 molar equivalent with respective to Solifenacin base.
7. The process of claim 1, wherein the base used in step (a) and step (e) is selected from a group comprising of potassium carbonate, sodium carbonate, ammonium hydroxide, sodium hydroxide and potassium hydroxide
8. The process of claim 1 optionally comprises a step of purifying Solifenacin tartrate of step (d) in an organic solvent.
9. The process of claim 8, wherein the organic solvent is selected from a group comprising of isopropyl alcohol, methyl alcohol, ethyl alcohol, propyl alcohol or mixtures thereof.
10. The process of claim 1, wherein the succinic acid used in step (g) is 0.7 to 1 molar equivalent with respective to Solifenacin base.
11. The process of claim 1, wherein the succinic acid used in step (g) is 0.85 molar equivalent with respective to Solifenacin base.
12. The process of claim 1, wherein the organic solvent used in step (g) is selected from a group comprising of acetone, methyl alcohol, ethyl alcohol, isopropyl alcohol, methyl acetate, ethyl acetate or mixtures thereof.
13. Solifenacin succinate substantially separated from its corresponding (1R, 3S), (1R, 3R) and (1S, 3S) isomers.
14. Solifenacin succinate as obtained by process of claim 1. , Description:Field of the Invention
The present invention relates to the field of process chemistry. More particularly, the present invention relates to an improved process for the preparation of Solifenacin succinate.

Background of the Invention
Solifenacin succinate (I), chemically (1S)-3, 4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylic acid (3R)-1-azabicyclo [2.2.2] oct-3-yl ester succinate, was disclosed in U.S. Patent No. 6,017,927 (the ‘927 patent). It is a potent muscarinic M3 receptor antagonist and has greater affinity for the M3 receptor than other known muscarinic receptors. It is commercially available under the brand name Vesicare® and has been approved for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and urinary frequency.

Formula (I)

The molecular structure of Solifenacin has two chiral centers at C1 and C3 positions, and hence exits as four stereoisomers namely, (1S, 3R)-isomer, (1R, 3S)-isomer, (1S, 3S)-isomer and (1R, 3R)-isomer. Out of four stereoisomers, (1S, 3R)-isomer is therapeutically active whereas the other stereoisomers are undesired isomers. As per pharmacopeial requirements, content of undesired isomers is to be limited to not more than 0.15% each in Solifenacin succinate.

There are several processes documented in prior art for synthesis of Solifenacin succinate. The ‘927 patent discloses a process, wherein (RS)-ethyl 1-phenyl-1, 2, 3, 4-tetrahydro-2-isoquinolinecarboxylate is reacted with racemic (RS) 3-quinuclidinol to give Solifenacin as a mixture of (1S, 3R)-isomer, (1S, 3S)-isomer, (1R, 3R)-isomer and (1R, 3S)-isomer.

The ‘927 patent also discloses another variant process, wherein (1S)-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline is reacted with racemic (RS)-3-quinuclidinyl chloroformate mono-hydrochloride to produce Solifenacin Base as a mixture of (1S, 3R)-isomer and (1S, 3S)–isomer. However, the ‘927 patent is silent about the separation of (1S, 3R)-isomer of Solifenacin from the stereoisomeric mixture of Solifenacin.

Condensation of (RS)-ethyl 1-phenyl-1, 2, 3, 4-tetrahydro-2-isoquinolinecarboxylate with chirally pure (R)-3-quinuclidinol is taught in U.S. Patent No. 7,829,715 to obtain Solifenacin base, which is converted into Solifenacin succinate by treating with succinic acid in solvent mixture containing ethyl alcohol and ethyl acetate.

Another U.S. Patent No. 8,772,491 suggests condensation of chirally pure (S)-ethyl 1-phenyl-1, 2, 3, 4-tetrahydro-2-isoquinolinecarboxylate with racemic (RS)-3-quinuclidinol to obtain Solifenacin base, which is converted into Solifenacin succinate by treating with succinic acid in solvent mixture of ethyl alcohol and ethyl acetate.

European Patent No. 2 094 693 discloses condensation of chirally pure (S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate with chirally pure (R)-3-quinuclidinol to get Solifenacin base followed by its conversion to Solifenacin succinate in multiple steps.

A process for the preparation of racemic Solifenacin base by condensation of racemic (RS)-ethyl 1-phenyl-1, 2, 3, 4-tetrahydro-2-isoquinolinecarboxylate and racemic (RS)-3-quinuclidinol is disclosed in the Indian Patent Application No. 2668/MUM/2008. However, the application is silent about the separation of (1S, 3R)-isomer of Solifenacin from the stereoisomeric mixture of Solifenacin base.

All the aforementioned prior art involves either use of optically pure ethyl 1-phenyl-1, 2, 3, 4-tetrahydro-2-isoquinolinecarboxylate or use of optically pure 3-quinuclidinol, which not only are expensive starting materials but also prone to racemization under acidic or basic reaction conditions used during the synthesis, making it difficult to manage on industrial scale. Hence, there is a need to provide a simple and cost effective process for Solifenacin succinate.

The present invention is directed towards the process for preparing Solifenacin succinate by reacting racemic (RS)-ethyl 1-phenyl-1, 2, 3, 4-tetrahydro -2-isoquinolinecarboxylate and racemic (RS)-3-quinuclidinol followed by isolation of optically pure Solifenacin succinate having more than 99% purity.

Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of Solifenacin succinate of formula (I)

Formula (I)
comprising the steps of:
(a) reacting racemic (RS)-ethyl 1-phenyl-1, 2, 3, 4-tetrahydro-2-isoquinoline carboxylate of formula (II)

Formula (II)
with racemic (RS)-3-quinuclidinol of formula (III)

Formula (III)
in presence of base in an organic solvent to obtain racemic Solifenacin base;
(b) preparing a reaction mixture of racemic Solifenacin base of step (a) and succinic acid;
(c) stirring and filtering the reaction mixture of step (b) to obtain residue from filtrate;
(d) preparing a reaction mixture of the residue of step (c) and L-tartaric acid to obtain Solifenacin tartrate;
(e) preparing an aqueous solution of a base then adding Solifenacin tartrate of step (d) followed by a water-immiscible organic solvent;
(f) stirring and separating organic layer from step (e) and concentrating to obtain a residue; and
(g) dissolving the residue of step (f) in an organic solvent and treating with succinic acid to obtain Solifenacin succinate of formula (I).
In another embodiment, the present invention relates to an improved process for the preparation of Solifenacin succinate without using expensive optically pure starting materials.

Detailed Description of the Invention
The present invention provides a process for the preparation of Solifenacin succinate of formula (I).

Formula (I)

The process comprises, reacting racemic (RS)-ethyl 1-phenyl-1, 2, 3, 4-tetrahydro -2-isoquinoline carboxylate of formula (II)

Formula (II)
with racemic (RS)-3-quinuclidinol of formula (III)

Formula (III)
in presence of base in an organic solvent to obtain racemic Solifenacin base and isolating the optically pure Solifenacin succinate of formula (I).

Separating (1S, 3R)-isomer from a mixture of stereoisomers has not been reported so far. The present inventors have meticulously worked and synthesized steps to isolate (1S, 3R)-isomer in more than 99% purity by HPLC with other undesired isomers at level of less than 0.15% by Chiral HPLC.

In the first step of the process racemic Solifenacin base is obtained by reaction of racemic (RS)-ethyl 1-phenyl-1, 2, 3, 4-tetrahydro-2-isoquinoline carboxylate (II) with racemic (RS)-3-quinuclidinol (III) in presence of base selected from group comprising of potassium carbonate, sodium carbonate, ammonium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide and potassium hydroxide in a solvent selected from group comprising of dimethyl formamide (DMF), toluene, hexane, cyclohexane or mixtures thereof. The reaction is carried out at a temperature 35°C to 115°C for a period of about 10-30 hours. After completion, the reaction is worked up. The work up involves following operations.

The reaction mass is cooled to about 0°C to 30°C followed by addition of aqueous hydrochloric acid (HCl). The aqueous acidic layer is separated and treated with suitable base selected from a group comprising of potassium carbonate, sodium carbonate, ammonium hydroxide, sodium hydroxide and potassium hydroxide. Ethyl acetate is added to the aqueous layer under stirring. Ethyl acetate layer is separated and it is concentrated under vacuum to give racemic Solifenacin base containing 23.71% (1S, 3R)-isomer, 23.09% (1R, 3S)-isomer, 24.44% (1S, 3S)-isomer and 24.85% (1R, 3R)-isomer by Chiral HPLC.

In the second step of the process of the present invention racemic Solifenacin base of step one, is treated with succinic acid in an organic solvent selected from group comprising of isopropyl alcohol, methyl alcohol, ethyl alcohol, ethyl acetate or mixtures thereof at a temperature 25°C to 30°C for a period of 10 to 30 hours. In the preferred aspect of present invention succinic acid is used in 0.3 to 1 molar equivalent with respect to racemic Solifenacin base. More preferably succinic acid can be used in 0.6 molar equivalent with respect to racemic Solifenacin base.

The precipitated solid is filtered and washed with ethyl acetate. The filtrate is treated with aqueous solution of suitable base selected from a group comprising of potassium carbonate, sodium carbonate, ammonium hydroxide, sodium hydroxide and potassium hydroxide. Layers are separated. Organic layer is evaporated under vacuum to give residue containing 38.97% (1S, 3R)-isomer, 34.49% (1R, 3S)-isomer, 7.50% (1S, 3S)-isomer and 7.76% (1R, 3R)-isomer by Chiral HPLC. Preferably the residue is treated with 0.5 to 2 molar equivalent of L-tartaric acid with respect to Solifenacin base. More preferably L-tartaric acid can be used in 1 molar equivalent with respect to Solifenacin base. The treatment is carried out in the presence of organic solvent selected from group comprising of isopropyl alcohol, methyl alcohol, ethyl alcohol, Propyl alcohol or mixtures thereof at temperature 25°C to 30°C for 10-30 hours to get precipitate of tartrate salt. The precipitated tartrate salt is isolated by filtration. The filtered solid is optionally purified by stirring in organic solvent selected from group comprising of isopropyl alcohol, methyl alcohol, ethyl alcohol, propyl alcohol or mixtures thereof to get purified tartrate salt containing 95.98% (1S, 3R)-isomer, 2.08% (1R, 3S)-isomer, 0.24% (1S, 3S)- isomer and 0.26% (1R, 3R)-isomer by Chiral HPLC.

In the third step, tartrate salt is converted in to free base by treating with aqueous solution of a base selected from a group comprising of potassium carbonate, sodium carbonate, ammonium hydroxide, sodium hydroxide or potassium hydroxide in an organic solvent selected from ethyl acetate, methylene dichloride, toluene or mixtures thereof. Organic Layer is separated and it is evaporated under vacuum to obtain the residue. The residue is dissolved in a solvent selected from a group comprising of acetone, methyl alcohol, ethyl alcohol, isopropyl alcohol, methyl acetate, ethyl acetate or mixtures thereof. In the preferred aspect of the present invention the resulting solution is treated with 0.7 to 1 molar equivalent of succinic acid with respect to Solifenacin base. More preferably succinic acid can be used in 0.85 molar equivalents with respect to Solifenacin base. The treatment is done at temperature 25°C to 30°C for 10-30 hours. The precipitated Solifenacin succinate is isolated by filtration. Chiral HPLC analysis showed 99.59% of desired (1S, 3R)-isomer, 0.13% (1R, 3S)-isomer, 0.13% (1S, 3S)-isomer and 0.07% (1R, 3R)-isomer.

Hereinafter, the invention is explained in details in the following examples, which are provided by the way of illustration only and therefore should not be construed to limit the scope of the invention in any way.

Example 1
Preparation of (1S)-3, 4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylic acid (3R)-1-azabicyclo [2.2.2] oct-3-yl ester (racemic Solifenacin base)

To a stirred solution of dimethylformamide (9 L) and racemic (RS)-3- quinuclidinol (6.5 Kg) is added sodium methoxide (4.1 Kg) and stirred for 15 min. The reaction mixture is heated to 40°C to 50C. Toluene (60 L) is added to the reaction mixture. Temperature of the reaction mixture is raised to 110C. Solution of racemic (RS)-ethyl-1-phenyl-1, 2, 3, 4-tetrahydro-2-isoquinolinecarboxylate (7.2 Kg) in toluene
(20 L) is charged to reaction mixture at 110C. Reaction temperature is maintained at 110 to 115C for 15 hours. The reaction mixture is cooled to 25°C to 30C. Reaction mixture is quenched in water (50 L). Organic layer is separated out from the aqueous layer. To the organic layer is charged aqueous hydrochloric acid (HCl) (40 L) under stirring. Aqueous layer separated. Potassium carbonate is charged to aqueous layer at temperature 25°C to 30C. Aqueous layer is extracted with ethyl acetate (40 L). Ethyl acetate layer is concentrated under vacuum to furnish racemic Solifenacin base as liquid (7.3 Kg) containing 23.71% (1S, 3R)-isomer, 23.09% (1R, 3S)-isomer, 24.44 % (1S, 3S)-isomer, and 24.85 % (1R, 3R)-isomer by Chiral HPLC.

Example 2
Preparation of tartrate salt of (1S)-3, 4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylic acid (3R)-1-azabicyclo [2.2.2] oct-3-yl ester (Solifenacin tartrate)

To 7.3 Kg racemic Solifenacin base obtained in Example 1 is added ethyl acetate (14 L), ethyl alcohol (0.86 L) and succinic acid (1.42 Kg). The reaction mixture is stirred for 15 hours at temperature 25°C to 30C. The precipitated solid is filtered and washed with ethyl acetate 7 L. The mother liquor is treated with aqueous solution of potassium carbonate followed by separation and concentration of ethyl acetate layer under vacuum to get residue. To the residue is added Isopropyl alcohol (3 L), methyl alcohol (3 L) and L-tartaric acid 1.5 Kg. The reaction mixture is stirred for 15 hours at temperature 25°C to 30C. The isolated solid is filtered. The wet cake is suspended in 2 L methyl alcohol and stirred for 2 hours at temperature 25°C to 30C. Solid is filtered and dried under vacuum to give 1.2 Kg Solifenacin tartrate containing 95.98% (1S, 3R)-isomer, 2.08 % (1R, 3S)-isomer, 0.24 % (1S, 3S)-isomer, and 0.26 % (1R, 3R)-isomer by Chiral HPLC.

Example 3
Preparation of (1S) - 3, 4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylic acid (3R)-1-azabicyclo [2.2.2] oct-3-yl ester succinate (Solifenacin succinate)

To Solifenacin tartrate (0.35 Kg) is added aqueous solution of potassium carbonate (0.4 L) and ethyl acetate (1.5 L) stirred, settled and separate out ethyl acetate layer. Separated ethyl acetate layer is concentrated under vacuum to obtain residue. Residue is dissolved in ethyl acetate (1 L) and ethyl alcohol (0.05 L) and further treated with succinic acid (0.068 Kg). The reaction mixture is stirred overnight at temperature 25°C to 30C. Solid was separated out by filtration and dried under vacuum to furnish (0.25 Kg) Solifenacin succinate (I) containing 99.59 % (1S, 3R)-isomer, 0.13 % (1R, 3S)-isomer, 0.13 % (1S, 3S)-isomer, and 0.07 % (1R, 3R)-isomer by Chiral HPLC.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.