An Improved Process for the Preparation of Solifenacin and Its Pharmaceutically Acceptable Salts Thereof
Field of the Invention:
The present invention relates to an improved process for the preparation of solifenacin and its pharmaceutically acceptable salts thereof especially succinate. Solifenacin succinate is chemically known as (lS)-3,4-dihydro-l-phenyl-2(lH)-isoquinoline-carboxylic acid (3R)-l-azabicyclo-[2.2.2]oct-3-yl ester succinate, which is represented by formula-1. Solifenacin succinate is represented by formula-la.

Solifenacin succinate is a urinary antispasmodic, acting as a selective antagonist to the M (3)-receptor. It is used as treatment of symptoms of overactive bladder, such as urinary urgency and increased urinary frequency, as may occur in patients with overactive bladder syndrome (OAB), as reviewed in Chilman-Blair, Kim et al., Drugs of Today, 40(4):343-353(2004). Its crystalline powder is white to pale yellowish-white and is freely soluble at room temperature in water, glacial acetic acid, DMSO, and methanol.
The commercial tablet is marketed under the trade name VESICARE®. As VESICARE®, it was approved by the FDA for once daily treatment of OAB and is prescribed as 5 mg and 10 mg tablets. The drug was developed by Yamanouchi Pharmaceutical Co. Ltd. and disclosed in US Patent No. 6,017,927 and its continuation, US Patent No. 6,174,896.
Background of the Invention:
US Patent No. 6,017,927 discloses solifenacin and its pharmaceutically acceptable salts, and a process for the preparation of solifenacin and its salts. European

patent No. 1714965 describes compositions containing solifenacin succinate with less impurities and a process for its preparation. European patent No. 1726304 describes solifenacin or its salts having high purity. Processes for the preparation of solifenacin have also been described in Drugs of the Future,24(8) 871-874, (1999) and Journal of Medicinal Chemistry, 2005, 48, 6597-6606.
There are two principal ways for synthesizing solifenacin disclosed in the art. The overall synthesis as reported by Mealy ,N., et al. in Drugs of the Future,24(S) 871-874, (1999) is depicted in scheme-1.

US Patent No. 6,017,927 discloses another process for the preparation of solifenacin wherein 3-quinuclidinyl chloro formate monohydrochloride is admixed with


The methods described in the art use sodium hydride for the condensation of (R)-3-quinuclidinyl fragment with (lS)-l-pheny-l,2,3,4-tetrahydroisoquinoline fragment. Also in one process the separation of isomeric impurities is carried out in the final stages; hence there is a greater probability for the isomeric impurities being present in the final product.
The present synthesis of solifenacin involves the condensation of stereo specific starting materials i.e. (R)-3-quinuclidinol fragment with (IS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline fragment, which prevents the formation of byproducts. The use of inorganic bases like sodium hydroxide, potassium hydroxide and the like control the side reactions thereby increasing the purity and yield of the final product.
The process of the present invention has advantages of improved yield and increased productivity which affords a significantly greater weight of solifenacin and its pharmaceutically acceptable salts. The process is also industrially scaleable, and cost effective.
Brief Description of the Invention:
This invention relates to an improved process for the preparation of solifenacin and its pharmaceutically acceptable salts thereof especially succinate comprising of; Reacting (R)-3-quinuclidinol, compound of formula-6 with (S)-ethyl-l-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate compound of formula-9 in presence of an inorganic base in a suitable solvent, followed by treatment with succinic acid to provide solifenacin succinate, compound of formula-la

Advantages of the Present Invention:
• Prior art processes have disclosed the use of sodium hydride in the condensation
step in the final stage, which is difficult to handle and highly pyrophoric.
• Avoids the use of strong bases such as sodium hydride, which prevents side
reactions and helps to control the formation of byproducts.
• The process use of optically pure intermediates, hence avoids the resolution in the
final stages, which leads to improvement in the yield and purity of the final
products.
• Easy to scale up to industrial level.
Brief Description of the Drawings:
Figure-1: Illustrates the powder X-ray diffraction pattern of crystalline solifenacin
succinate Figure-2: Illustrates the IR spectrum of crystalline solifenacin succinate Figure-3: Illustrates the DSC of crystalline solifenacin succinate
Detailed Description of the Invention:
This invention relates to an improved process for the preparation of solifenacin and its pharmaceutically acceptable salts thereof especially succinate comprises of reacting (R)-3-quinuclidinol, compound of formula-6


in presence of an inorganic base in a suitable solvent, distilling off the solvent and dissolving the condensed solid in acetone and treatment with succinic acid to provide solifenacin succinate, compound of formula-la followed by purification of solifenacin succinate in a suitable solvent like methanol, ethanol, acetone, ethyl acetate and mixtures thereof to provide crystalline solifenacin succinate, which is characterized by the PXRD pattern, IR spectrum and DSC thermo gram as shown in Figure-1, Figure-2 and Figure-3 respectively.
(R)-3-quinuclidinol, compound of formula-6 is condensed with (S)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate, compound of formula-9 in presence of inorganic base selected from a group which includes but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, preferably sodium hydroxide. The suitable solvent used in the condensation is selected from a group consisting of aromatic hydrocarbon solvents like benzene, toluene, xylene, chlorobenzene and the like; or halogenated solvents such as dichloromethane, chloroform, ethylene dichloride and the like; and their mixtures thereof; preferably toluene.
The condensed product was dissolved in acetone followed by treatment with succinic acid to provide solifenacin succinate, compound of formula-la.
The processes reported in prior art the condensation is carried out using strong base like sodium hydride or metal alkoxides, which are difficult to handle, pyrophoric and not utilizable in a large scale process. Apart from that when practiced in the laboratory, these reagents led to side reactions leading to the formation of byproducts, hence decreasing the purity of the final product. The use of sodium hydroxide or potassium hydroxide minimized the side reactions as well as the formation of the

byproducts. This provided an added advantage, that the purity of the product increased
minimizing the workup procedure, and making it easier for scale up to an industrial level.
The substrates for the condensation reaction (R)-3-quinuclidinol, compound of
formula-6 and (S)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinolinecarboxylate
compound of formula-9,were prepared by the conventional methods disclosed in art. The preparation is illustrated in scheme-3.


HPLC Analysis of Related Substances:
Apparatus : A liquid chromatogram is equipped with UV-Detector.
Column : Symmetry shield RP18,250 X 4.6 mm, 5 um.
Flow rate : 1.0 ml /min
Wave length : 210 nm
Temperature : 27°C
Load : 10^1
Run time : 65 min
Diluents : Buffer for diluent: acetonitrile in the ratio 70:30 v/v
(Buffer for diluent preparation: Dissolve 1.36 gram (0.01 m) of KH2PO4 in
1000 ml of water, to this add 1 ml of triethyl amine).
Sample concentration : 1 mg/ml
Elution : gradient
Mobile phase-A : Buffer
Mobil phase B : acetonitrile: water (800:200) v/v
Buffer preparation : 0.01M of KH2P04 in water, pH=3.5 with H3PO4.
Gradient : Time Mobile phase-A Mobile phase-B
0.1 70 30
3.0 70 30
35.0 25 75
55.0 25 75
65.0 70 30
Isomer Content by chiral HPLC
Apparatus : A liquid chromatograph is equipped with variable
Wavelength UV detector
Column : Chiralpak AD-H, 250 X 4.6 mm, 5 micron
Flow rate : LI.0ml ./min
Wavelength : 220 nm
Temperature : 17°C
Load : 20 ul

Elution : isocratic
Run time : 60 minutes
Diluent : ethanol
Mobile phase : A mixture of 870 volumes of n-hexane, 130 volumes of
2-propanol and 1 volume of diethyl aniline Sample concentration : lOmg/ml
Analysis of particle size distribution of Solifeancin succinate;
A Malvern laser diffraction instrument was used to characterize the particle size
distribution of solifenacin succinate.
Instrument model : Malvern Mastersizer 2000
Dispersant name : light liquid paraffin
Instrument parameters:
i) Material RI: 1.600
ii) Dispersant RI: 1.468
iii) Analysis model: general purpose
iv) Sensitivity: Normal

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Reference example-1:
Preparation of (lS)-3,4-dihydro-l-phenyl-2(lH)-isoquinolinecarboxylic acid-(3R)-
l-azabicyclo-[2.2.2]oct-3-yl ester succinate(solifenacin succinate)
A mixture of 20 grams of (R)-3-quinuclidinol and 15 grams of (lS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate in 150 ml of toluene was refluxed azeotropically for 2 hrs using dean stark apparatus to remove water from the solvent. The reaction mixture was cooled under atmosphere of nitrogen to 25°C, 0.36 grams of sodium hydride was added to it and further refluxed for 18 hrs. The reaction mixture was cooled to 25°C and quenched with saturated sodium chloride solution. The aqueous and organic layers were separated. The organic layer was extracted with 20% hydrochloric acid solution. The extracted solution was neutralized with saturated sodium carbonate solution and then extracted it with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate layer was treated with activated carbon, stirred for 15 min and filtered through hyflow bed. The solvent was distilled off under reduced pressure to provide a residue. The residue was dissolved in 100 ml of acetone and 5.5 grams of succinic acid was added to it. The reaction mixture was heated to 55°C and stirred for 15 min, it was further cooled to 25°C and stirred for 45 min. The reaction mixture was finally cooled to 0-5°C and stirred for 1 hr. The solid precipitated was filtered, washed with acetone and dried at 50°C to provide the title compound. Yield: 17 grams.

Reference example-2:
Preparation of (lS)-3,4-dihydro-l-phenyI-2(lH)-isoquinolinecarboxylic acid-(3R)-
l-azabicyclo-[2.2.2]oct-3-yl ester succinate.(solifenacin succinate)
A mixture of 20 grams of (R)-3-quinuclidinol and 15 grams of (IS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate in 150 ml of toluene was refluxed azeotropically for 2hrs using dean stark apparatus to remove water from the solvent. The reaction mixture was cooled under atmosphere of nitrogen to 25°C; 2.87 grams sodium methoxide was added to it and further refluxed for 18 hrs. The reaction mixture was cooled to 25°C and quenched with saturated sodium chloride solution. The aqueous and organic layers were separated. The organic layer was extracted with 20% hydrochloric acid solution. The extracted solution was neutralized with saturated sodium carbonate solution and then extracted it with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate layer was treated with activated carbon, stirred for 15 min and filtered through hyflow bed. The solvent was distilled off under reduced pressure to provide a residue. The residue was dissolved in 100 ml of acetone and 5.5 grams of succinic acid was added to it. The reaction mixture was heated to 55°C and stirred for 15 min; it was further cooled to 25°C and stirred for 45 min. The reaction mixture was finally cooled to 0-5°C and stirred for 1 hr. The solid precipitated was filtered, washed with acetone and dried at 50°C to provide the title compound. Yield: 16.5 grams.
Example-1:
Preparation of (lS)-3,4-dihydro-l-phenyl-2(lH)-isoquinolinecarboxylic acid (3R)-
l-azabicyclo-[2.2.2]oct-3-yl ester succinate (solifenacin succinate)
A mixture of 20 grams of (R)-3-quinuclidinol and 15 grams of (lS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate in 150 ml of toluene was refluxed azeotropically for 2hrs using dean stark apparatus to remove water from the solvent. The reaction mixture was cooled under atmosphere of nitrogen to 25°C, 2.56 grams of sodium hydroxide was added to it and further refluxed for 18 hrs. The reaction mixture was cooled to 25°C and quenched with saturated sodium chloride solution. The aqueous and

organic layers were separated. The organic layer was extracted with 20% hydrochloric acid solution. The extracted solution was neutralized with saturated sodium carbonate solution and then extracted it with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate layer was treated with activated carbon, stirred for 15 min and filtered through hyflow bed. The solvent was distilled off under reduced pressure to provide a residue. The residue was dissolved in 100 ml of acetone and 5.5 grams of succinic acid was added to it. The reaction mixture was heated to 55°C and stirred for 15 min, it was further cooled to 25°C and stirred for 45 min. The reaction mixture was finally cooled to 0-5 °C and stirred for 1 hr. The solid precipitated was filtered, washed with acetone and dried at 50°C to provide the title compound. Yield: 16.9 grams.
Purity by HPLC 99.51%; Isomer content by chiral HPLC 99.42%,other isomer 0.57%.
Example-2:
Preparation of (lS)-3,4-dihydro-l-phenyI-2(lH)-isoquinolinecarboxylic acid (3R)-
l-azabicydo-[2.2.2]oct-3-yl ester succinate (solifenacin succinate)
A mixture of 13.2 grams of (R)-3-quinuclidinol and 10 grams of (lS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate in 100 ml of toluene was refluxed azeotropically for 2hrs using dean stark apparatus to remove water from the solvent. The reaction mixture was cooled under atmosphere of nitrogen to 25°C, 4 grams of potassium hydroxide was added to it and further refluxed for 18 hrs. The reaction mixture was cooled to 25 °C and quenched with saturated sodium chloride solution. The aqueous and organic layers were separated. The organic layer was extracted with 20% hydrochloric acid solution. The extracted solution was neutralized with saturated sodium carbonate solution and then extracted it with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate layer was treated with activated carbon, stirred for 15 min and filtered through hyflow bed. The solvent was distilled off under reduced pressure to provide a residue. The residue was dissolved in 100 ml of acetone and 5.5 grams of succinic acid was added to it. The reaction mixture

was heated to 55°C and stirred for 15 min, it was further cooled to 25°C and stirred for 45 min. The reaction mixture was finally cooled to 0-5 °C and stirred for 1 hour. The solid precipitated was filtered, washed with acetone and dried at 50°C to provide the title compound. Yield: 12 grams.
Example-3:
Preparation of (lS)-3,4-dihydro-l-phenyI-2(lH)-isoquinolinecarboxylic acid (3R)-
l-azabicyc!o-[2.2.2]oct-3-yl ester (solifenacin).
A mixture of 13.2 grams of (R)-3-quinuclidinol and 10 grams of (lS)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate in 100 ml of toluene was refluxed azeotropically for 2hrs using dean stark apparatus to remove water from the solvent. The reaction mixture was cooled under atmosphere of nitrogen to 25°C, 4.0 grams of potassium hydroxide was added to it and further refluxed for 18 hrs. The reaction mixture was cooled to 25°C and quenched with saturated sodium chloride solution. The aqueous and organic layers were separated. The organic layer was extracted with 20% hydrochloric acid solution. The extracted solution was neutralized with saturated sodium carbonate solution and then extracted it with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Distilled of the solvent to obtain the title compound. Yield: 11.5 grams. MR: 82-89°C
Example-4:
Purification of (lS)-3,4-dihydro-l-phenyl-2(lH)-isoquinolinecarboxylic acid (3R)-
l-azabicyclo-[2.2.2]oct-3-yl ester succinate.(solifenacin succinate)
A mixture of 47 grams of solifenacin succcinate, 40ml of methanol and 200ml of ethyl acetate was heated to reflux to get a clear solution. The reaction mixture was filtered through a hyflow bed and cooled to 25 °C and stirred for 2hrs. The solid precipitated was filtered, washed with ethyl acetate and dried at 50°C to provide crystalline solifenacin succinate.

Yield: 34 grams.
Particle size distribution: D (0.1):22.21um; D (0.5):49.41um; D (0.9):94.71um;
D (mean):54.28um.
Example-5:
Purification of (lS)-3,4-dihydro-l-phenyl-2(lH)-isoquinolinecarboxyIic acid (3R)-
l-azabicyclo-[2.2.2]oct-3-yl ester succinate.(solifenacin succinate)
A mixture of 10 grams of solifenacin succcinate, 10 ml of ethanol and 40 ml of ethyl acetate was heated to reflux to get a clear solution. The reaction mixture was filtered through a hyflow bed and cooled to 25°C and stirred for 2 hrs. The solid precipitated was filtered, washed with ethyl acetate and dried at 50°C to provide crystalline solifenacin succinate. Yield: 7.3 grams.
Purity by HPLC 99.94%; Isomer content by chiral HPLC 99.95%, other isomer 0.05%. Particle size distribution: D (0.1):16.037um; D (0.5):41.80um; D (0.9): 103.01 um; D(mean); 53.50 µm.

We Claim:
1. An improved process for the preparation of solifenacin compound of formula-1,

Which comprises of reacting (R)-3-quinuclidinol compound of formula-6

Formula-6 with (S)-ethyl-l -phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate compound of formula-9
in presence of a suitable inorganic base in a suitable solvent to provide solifenacin, compound of formula-1.
2. An improved process for the preparation of solifenacin succinate compound of
formula-1a,
Formula-la Which comprises of the following steps; a) reacting the (R)-3-quinuclidinol compound of formula-6


in presence of a suitable inorganic base in a suitable solvent to provide solifenacin,
b) which on in-situ reaction with a succinic acid in a suitable solvent to provide
solifenacin succinate compound of formula-la,
c) purifying the solifenacin succinate compound of formula-la in a suitable solvent
to provide the pure solifenacin succinate.
3. The process according to any of the preceding claims, wherein the inorganic base
used is selected from a group selected from hydroxides of alkali and alkaline earth
metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the
like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and
the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium
bicarbonate and the like.
4. The process according to claim 1 and claim 2, wherein the inorganic base used is
hydroxides of alkali and alkaline earth metals like lithium hydroxide, sodium
hydroxide, potassium hydroxide.

5. The process according to claim 1 and claim 2, wherein the inorganic base used is
carbonates and bicarbonate of alkali metals selected from sodium carbonate,
potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
6. The process according to claim-1 and step a) of claim-2, wherein the suitable solvent
is selected from a group consisting of aromatic hydrocarbon solvents like benzene,
toluene, xylene, chlorobenzene and the like; halogenated solvents such as
dichloromethane, chloroform, ethylene dichloride and the like; and their mixtures
thereof.
7. The process according to step b) and c) of claim 2, wherein the suitable solvent used
is selected from methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone or
mixtures thereof.

with (S)-ethyl-l-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate compound of formula-9


in presence of sodium hydroxide in toluene to provide solifenacin compound of formula-1.
9. An improved process for the preparation of solifenacin succinate compound of formula-1a,
Which comprises of the following steps;
a) Reacting the (R)-3-quinuclidinol, compound of formula-6

Formula-6 with (S)-ethyl-l-phenyl-l,2,3,4-tetrahydro-2-isoquinoline carboxylate compound of formula-9
in presence of sodium hydroxide in toluene to provide solifenacin,
b) which on in-situ reaction with a succinic acid in acetone to provide solifenacin
succinate compound of formula-la,

c) purifying the solifenacin succinate obtained from step-b) in a mixture of methanol and ethyl acetate to provide pure solifenacin succinate compound of formula-la.
10. The process according to claim 9, where in the solifenacin succinate prepared is having a mean particle size in the range of 30-80 µm and D (0.9) in the range of 70-130 µm.