Title of Invention	IMPROVED PROCESSES FOR THE PREPARATION SOLIFENACIN
Abstract	The present invention describes novel and improved processes for the preparation of 1-Phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 3-quinuclidinyl ester of general formula (Ia), in either racemic or optically active (1S,3'R) or (1S,3'S) or (1R,3'S) or (1R,3'R) forms and their pharmaceutically acceptable salts using novel intermediates of formula (II) and (VI) in either racemic ot optically active (S) or (R) forms.

Title of Invention

IMPROVED PROCESSES FOR THE PREPARATION SOLIFENACIN

Abstract

The present invention describes novel and improved processes for the preparation of 1-Phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 3-quinuclidinyl ester of general formula (Ia), in either racemic or optically active (1S,3'R) or (1S,3'S) or (1R,3'S) or (1R,3'R) forms and their pharmaceutically acceptable salts using novel intermediates of formula (II) and (VI) in either racemic ot optically active (S) or (R) forms.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENT RULES, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION "IMPROVED PROCESSES FOR THE PREPARATION OF SOLIFENACIN" We, CADILA HEALTHCARE LIMITED, of Zydus Research Centre, "Zydus Tower", Satellite Cross Roads, Gandhinagar-Sarkhej Highway, Ahmedabad - 380015, Gujarat, India; The following specification describes the invention: 1 ZRC-PD-31-Prov Field of invention: The present invention describes novel and improved processes for the preparation of Solifenacin base and also Solifenacin succinate from the base prepared according to the process of the present invention. BACKGROUND ART l(S)-Phenyl-l, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid 3(R)-quinuclidinyl ester [(3R)-azabicyclo[2.2.2]oct-3-yl-(lS)-l-phenyl-3,4-dihydroisoquinoline-2-(lH)- carboxylate] is known as Solifenacin, also known as YM-905 (in its free base form) and YM-67905 (in its succinate form). Succinate form is available in market under the trade name, Vesicare. Solifenacin succinate is a urinary antispasmodic of the anticholinergic class. It is used in the treatment of overactive bladder with urge incontinence and acts as a selective antagonist to the M (3) receptor. [Chilman-Blair, Kim et.al., Drugs Of Today, 40(4):343-353, 2004]. Solifenacin (I) Solifenacin's (C23H26N2O2). molecular weight is 362.5. 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 drug Solifenacin was first disclosed in US. Patent No. 6,017,927 by Yamanouchi Pharmaceuticals. Disclosed therein are compounds whose general formula is: (0 m(R)—Y -(CH2)„ }ji II O A specific method for producing Solifenacin or a salt thereof is disclosed here, depicted by the following scheme (Scheme-1). 2 ZRC-PD-31-Prov Scheme 1 In this document, a method of preparation of Solifenacin base and some of its salts are described but as per EP 1414965, there are issues related to obtaining Solifenacin in pure form, both chiral as well as chemical, and the above mentioned application do not provide any suggestion for the purification of salt. WO 05075474 (Astellas pharma), describes preparation of a composition containing Solifenacin or a salt thereof in high degree of optical purity for medicinal use. This application describes the preparation of the succinate salt and a process for improving the chiral & chemical purity of the base by converting into the succinate salt. WO 05087231 and WO 05105795 more specifically disclose about the method of preparation of the solifenacin using a lower alkoxide base, which made the process commercially viable. Compared to the process in US 6,017,927, instead of using sodium hydride having disadvantages like combustion risk and contamination of mineral oil, this method uses an alkoxide base which overcomes these drawbacks. The scheme is depicted below. NaOR1 Solifenacin W However, the main disadvantage here was additional impurity (X) obtained due to the new alkoxide base used and the subsequent purification processes to be employed if the impurity limit exceeded 1%. There are a few principal processes for synthesizing Solifenacin known in the prior art. Most of them use the following key intermediates or their derivatives as starting materials. H%, (R)-(-)-Quinuclidinol (S)-l -Phenyl-1,2,3,4-tetrahydroisoquinoline (A) (B) 3 ZRC-PD-31-Prov US. Patent No. 6,017,927 describes a process using this two intermediates (A) and (B) as shown in above scheme 1, of which the quinuclidinol reactant is available commercially. Another process is reported by Mealy, N., et al. in Drugs of Future, 24(8): 871-874(1999) is depicted below (scheme 2) which also includes a process for preparing the intermediates (A) and (B). Tartaric acid Scheme 2 WO 2007/076116 (Teva) application discloses another process of preparation using different intermediates shown below. (Scheme 3). ORX 3-Quinuclidinol 4 ZRC-PD-31-Prov Hence, there is a need in the art for improved process for preparing solifenacin and its salts with better yields and improved purity, especially, to reduce the alkylated impurities, chiral impurities and to get overall chemical purity. Objects of the invention: The object of the present invention is to provide an improved process for the preparation of Solifenacin. It is yet another object of the invention to provide a process for preparing Solifenacin using the novel intermediate (S)-l -Phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonitrile of the formula (II). It is yet another object of the invention to provide a process to obtain Solifenacin base in high chiral and chemical purity. It is yet another object of the invention to provide a process for preparing pharmaceutically acceptable salts of Solifenacin base in high chemical & chiral purity by converting the chirally pure Solifenacin base to its corresponding salts. Detailed description: Accordingly, the present invention provides a process for the preparation of Solifenacin of the formula (I) and its salts using a novel intermediate (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonitrile of the formula (II), ^^Y ~"CN (ID A second aspect of the present invention is a process for the preparation of Solifenacin (I) and its salts according to Scheme 4 5 ZRC-PD-31-Prov NH V NH ^ (Vlllb) (Scheme 4) a) reacting either (S), (R )or (S/R) 1 -phenyl-1,2,3,4-tetrahydroisoquinoline of formula (III) with cyanogen halides, preferably bromide, in a suitable solvent(s) in presence of a suitable base to afford the compound of a formula (II) with retention of configuration. b). reacting the compound of the formula (II) in acidic or basic condition with either (S/R) or (S) or (R) 3-Quinuclidinol (IV) to afford the imino ester of the formula (V) with retention of configuration. Alternatively, the reaction may proceed through the intermediate formation of an imidoyl halide (VIA) or imino ester (VIB) and reacting it with either (S/R) or (S) or (R) 3-Quinuclidinol (IV) to afford the imino ester comound of the formula (V) with retention of configuration; c) optionally, resolving the compound of formula (V) to get the compound of formula (I) in a chirally pure form d). hydrolysis of the imino ester compound of formula (V) to afford Solifenacin base (I) in racemic or chirally pure form; e) optionally, resolution of the racemic base to obtain chirally and chemically pure Solifenacin base (I). Alternatively, the imino ester (V) may be obtained by reacting 3-Quinuclidinol of formula (IV) in either (S/R) or (S) or (R) form with a suitable Cyanogen halide, preferably bromide, in a suitable solvent(s) in the presence of a suitable base to afford the novel compound of a 6 ZRC-PD-31-Prov formula (VII) which is further reacted in acidic or basic condition with either (S/R) or (R) or (S) 1-phenyl-1,2,3,4-tetrahydroisoquinoline (III) to afford the imino ester of the formula (V), with retention of configuration. Alternatively, the reaction may proceed through the intermediate formation of an imidoyl halide (VIIIA) or imino ester (VIIIB) and reacting it with either (S/R) or (S) or (R) l-phenyl-l,2,3,4-tetrahydroisoquinoline (III) to afford the imino ester compound of the formula (V) with retention of configuration. The process is further described by the following non-limiting examples, which provides the preferred mode of carrying out the process of the present invention. It is to be appreciated that several alterations, modifications, optimizations of the processes described herein are well within the scope of a person skilled in the art and such alterations, modifications, optimizations etc. should be construed to be within the scope of the present inventive concept as is disclosed anywhere in the specification. Example 1 Preparation of (R/S)-l-phenyl-l,2,3,4-tetrahydro-isoquinoline-2-carbonitrile To a dry, 1.0 L round bottom flask was charged (R/S)-l-phenyl-1,2,3,4-tetrahydroisoquinoline (28g) and dichloro methane (280 mL) at room temperature (RT). To the clear solution triethyl amine (TEA, 28 mL) was added. It was cooled to -5 to 0 °C and Cyanogen bromide (20g) was added into the reaction mixture in small portions at -5 to 0 °C. It was stirred for 1-3 h at -5 to 0 °C. The solution was diluted with dichloromethane (280 mL) and it was transferred into a separating funnel. It was washed with water, dilute acetic acid and water. Organic layer was collected and dried over anhyd. Sodium sulfate. It was concentrated under reduced pressure to obtain (R/S)-l-phenyl-l,2,3,4-tetrahydro-isoquinoline-2-carbonitrile. (31.1 g, % Y-99.3 %) Example 2 Preparation of l-Phenyl-l,2,3,4-tetrahydro-lH-isoquinoline-2-carboximidic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester To a dry, 50 mL round bottom flask was charged l-aza-bicyclo[2.2.2]octan-3-ol (0.55 g) and THF (5 mL) at RT. It was cooled to 10 to 20 °C. To the clear solution 55 % NaH (0.190 g) was added at 10 to 20 °C. After 30-50 min., (R/S)-l-phenyl-1,2,3,4-tetrahydro-isoquinoline-2-carbonitrile (l.0g) was added at 10 to 20 °C. It was heated and stirred for 3 h at reflux temperature. Reaction mixture was poured into water (10 mL). It was extracted with Ethyl acetate. The extract was washed with water. Organic layer was collected and dried over sodium sulfate. It was concentrated under reduced pressure to obtain crude 1-phenyl-1,2,3,4- 7 ZRC-PD-31-Prov tetrahydro-isoquinoline-2-carboximidic acid l-aza-bicyclo[2.2.2]oct-3-yl ester (1.2 g) . The crude product was purified by column chromatography on neutral alumina (CHCI3: MeOH, 95:5) to give pure product. (0.285 g, % Y- 18 %) Example 3 Preparation of l-aza-bicyclo[2.2.2]oct-3-yl l-Phenyl-l,2,3,4-tetrahydro-lH-isoquinoline- 2-carboxylate To a 25 mL round bottom flask was charged 1 -phenyl-1,2,3,4-tetrahydro-isoquinoline-2-carboximidic acid l-aza-bicyclo[2.2.2]oct-3-yl ester (0.250 g), aq. HC1 and methanol (2.5 mL) at RT. It was stirred for 48 h at RT. Distilled out solvent at reduced pressure. Semi-solid mass was dissolved in 10 mL water. It was basified with 20 % aq. NaOH. It was transferred into a separating funnel. It was extracted with ethyl acetate. The extract was washed with water. Organic layer was collected and dried over sodium sulfate. It was concentrated under reduced pressure to obtain l-aza-bicyclo[2.2.2]oct-3-yl 1-Phenyl-l,2,3,4-tetrahydro-lH-isoquinoline-2-carboxylate (0.190 g). Following the general processes described above, chirally pure forms of compound of formula (V) were prepared by starting with corresponding chiral starting materials. Example 4 Preparation of (R/S)-3-cyanato-quinuclidine To a dry, 1.0 L round bottom flask was charged (R/S)-3-quinuclidinol (2g) and toluene (10 mL) at RT. To the clear solution 55 % NaH (0.6 g) was added. It was stirred at RT. After 30 min., reaction mixture was cooled to 0-5 °C and Cyanogen bromide (1.53g) was added into it in small portions at 0 to 5 °C. It was stirred for 24 h at RT. It was diluted with 20 mL toluene and poured into 20 mL cold water. The solution was transferred into a separating funnel and the organic layer was collected. It was washed with water. Organic layer was collected and dried over anhyd. Sodium sulfate. It was concentrated under reduced pressure to obtain (R/S)-3-cyanato-quinuclidine. (0.3 g, % Y-12.5%) Example 5 Preparation of l-Phenyl-l,2,3»4-tetrahydro-lH-isoquinoline-2-carboximidic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester To a dry, 50 mL round bottom flask was charged (R/S)-3-cyanato-quinuclidine (0.25 g) and THF (5 mL) at RT. It was cooled to 10 to 20 °C. To the clear solution 55 % NaH (0.070 g) was added at 10 to 20 °C. After 30 min. (R/S)-l-phenyl-1,2,3,4-tetrahydro- isoquinoline (0.340g) was added at 10 to 20 °C. It was heated and stirred for 3 h at reflux temperature. Reaction mixture was poured into water and extracted with Ethyl acetate. The extract was washed with water. Org. layer was collected and dried over sodium sulfate. It was 8 ZRC-PD-31-Prov concentrated under reduced pressure to obtain crude 1 -phenyl- 1,2,3,4-tetrahydro-isoquinoline-2-carboximidic acid l-aza-bicyclo[2.2.2]oct-3-yl ester (0.55 g) . The crude product was purified by column chromatography on neutral alumina (CHCI3: MeOH, 95:5) to give pure product. (0.105 g, % Y- 17.7 %) The Solifenacin base obtained may be further converted to the succinate salt by techniques known in the art. 9

Full Text

FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"IMPROVED PROCESSES FOR THE PREPARATION OF
SOLIFENACIN"
We, CADILA HEALTHCARE LIMITED, of Zydus Research Centre, "Zydus Tower", Satellite Cross Roads, Gandhinagar-Sarkhej Highway, Ahmedabad - 380015, Gujarat, India;
The following specification describes the invention:
1

ZRC-PD-31-Prov
Field of invention:
The present invention describes novel and improved processes for the preparation of Solifenacin base and also Solifenacin succinate from the base prepared according to the process of the present invention.
BACKGROUND ART
l(S)-Phenyl-l, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid 3(R)-quinuclidinyl
ester [(3R)-azabicyclo[2.2.2]oct-3-yl-(lS)-l-phenyl-3,4-dihydroisoquinoline-2-(lH)-
carboxylate] is known as Solifenacin, also known as YM-905 (in its free base form) and YM-67905 (in its succinate form). Succinate form is available in market under the trade name, Vesicare. Solifenacin succinate is a urinary antispasmodic of the anticholinergic class. It is used in the treatment of overactive bladder with urge incontinence and acts as a selective antagonist to the M (3) receptor. [Chilman-Blair, Kim et.al., Drugs Of Today, 40(4):343-353, 2004].

Solifenacin

(I)
Solifenacin's (C23H26N2O2). molecular weight is 362.5. 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 drug Solifenacin was first disclosed in US. Patent No. 6,017,927 by Yamanouchi Pharmaceuticals. Disclosed therein are compounds whose general formula is:
(0
m(R)—Y
-(CH2)„ }ji II
O
A specific method for producing Solifenacin or a salt thereof is disclosed here, depicted by the following scheme (Scheme-1).
2

ZRC-PD-31-Prov
Scheme 1
In this document, a method of preparation of Solifenacin base and some of its salts are described but as per EP 1414965, there are issues related to obtaining Solifenacin in pure form, both chiral as well as chemical, and the above mentioned application do not provide any suggestion for the purification of salt.
WO 05075474 (Astellas pharma), describes preparation of a composition containing Solifenacin or a salt thereof in high degree of optical purity for medicinal use. This application describes the preparation of the succinate salt and a process for improving the chiral & chemical purity of the base by converting into the succinate salt.
WO 05087231 and WO 05105795 more specifically disclose about the method of preparation of the solifenacin using a lower alkoxide base, which made the process commercially viable. Compared to the process in US 6,017,927, instead of using sodium hydride having disadvantages like combustion risk and contamination of mineral oil, this method uses an alkoxide base which overcomes these drawbacks. The scheme is depicted below.

NaOR1
Solifenacin W
However, the main disadvantage here was additional impurity (X) obtained due to the new alkoxide base used and the subsequent purification processes to be employed if the impurity limit exceeded 1%.
There are a few principal processes for synthesizing Solifenacin known in the prior art. Most of them use the following key intermediates or their derivatives as starting materials.

H%,

(R)-(-)-Quinuclidinol (S)-l -Phenyl-1,2,3,4-tetrahydroisoquinoline
(A) (B)
3

ZRC-PD-31-Prov
US. Patent No. 6,017,927 describes a process using this two intermediates (A) and (B) as shown in above scheme 1, of which the quinuclidinol reactant is available commercially. Another process is reported by Mealy, N., et al. in Drugs of Future, 24(8): 871-874(1999) is depicted below (scheme 2) which also includes a process for preparing the intermediates (A) and (B).

Tartaric acid

Scheme 2
WO 2007/076116 (Teva) application discloses another process of preparation using different intermediates shown below. (Scheme 3).

ORX
3-Quinuclidinol

4

ZRC-PD-31-Prov
Hence, there is a need in the art for improved process for preparing solifenacin and its salts with better yields and improved purity, especially, to reduce the alkylated impurities, chiral impurities and to get overall chemical purity.
Objects of the invention:
The object of the present invention is to provide an improved process for the preparation of Solifenacin.
It is yet another object of the invention to provide a process for preparing Solifenacin using the novel intermediate (S)-l -Phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonitrile of the formula (II).
It is yet another object of the invention to provide a process to obtain Solifenacin base in high chiral and chemical purity.
It is yet another object of the invention to provide a process for preparing pharmaceutically acceptable salts of Solifenacin base in high chemical & chiral purity by converting the chirally pure Solifenacin base to its corresponding salts.
Detailed description:
Accordingly, the present invention provides a process for the preparation of Solifenacin of the formula (I) and its salts using a novel intermediate (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonitrile of the formula (II),
^^Y ~"CN (ID
A second aspect of the present invention is a process for the preparation of Solifenacin (I) and its salts according to Scheme 4
5

ZRC-PD-31-Prov

NH V NH ^
(Vlllb)
(Scheme 4)
a) reacting either (S), (R )or (S/R) 1 -phenyl-1,2,3,4-tetrahydroisoquinoline of formula (III)
with cyanogen halides, preferably bromide, in a suitable solvent(s) in presence of a suitable
base to afford the compound of a formula (II) with retention of configuration.
b). reacting the compound of the formula (II) in acidic or basic condition with either (S/R) or
(S) or (R) 3-Quinuclidinol (IV) to afford the imino ester of the formula (V) with retention of
configuration.
Alternatively, the reaction may proceed through the intermediate formation of an imidoyl halide (VIA) or imino ester (VIB) and reacting it with either (S/R) or (S) or (R) 3-Quinuclidinol (IV) to afford the imino ester comound of the formula (V) with retention of configuration;
c) optionally, resolving the compound of formula (V) to get the compound of formula (I) in a chirally pure form
d). hydrolysis of the imino ester compound of formula (V) to afford Solifenacin base (I) in racemic or chirally pure form;
e) optionally, resolution of the racemic base to obtain chirally and chemically pure Solifenacin base (I).
Alternatively, the imino ester (V) may be obtained by reacting 3-Quinuclidinol of formula (IV) in either (S/R) or (S) or (R) form with a suitable Cyanogen halide, preferably bromide, in a suitable solvent(s) in the presence of a suitable base to afford the novel compound of a
6

ZRC-PD-31-Prov
formula (VII) which is further reacted in acidic or basic condition with either (S/R) or (R) or (S) 1-phenyl-1,2,3,4-tetrahydroisoquinoline (III) to afford the imino ester of the formula (V), with retention of configuration.
Alternatively, the reaction may proceed through the intermediate formation of an imidoyl halide (VIIIA) or imino ester (VIIIB) and reacting it with either (S/R) or (S) or (R) l-phenyl-l,2,3,4-tetrahydroisoquinoline (III) to afford the imino ester compound of the formula (V) with retention of configuration.
The process is further described by the following non-limiting examples, which provides the preferred mode of carrying out the process of the present invention. It is to be appreciated that several alterations, modifications, optimizations of the processes described herein are well within the scope of a person skilled in the art and such alterations, modifications, optimizations etc. should be construed to be within the scope of the present inventive concept as is disclosed anywhere in the specification.
Example 1
Preparation of (R/S)-l-phenyl-l,2,3,4-tetrahydro-isoquinoline-2-carbonitrile
To a dry, 1.0 L round bottom flask was charged (R/S)-l-phenyl-1,2,3,4-tetrahydroisoquinoline (28g) and dichloro methane (280 mL) at room temperature (RT). To the clear solution triethyl amine (TEA, 28 mL) was added. It was cooled to -5 to 0 °C and Cyanogen bromide (20g) was added into the reaction mixture in small portions at -5 to 0 °C. It was stirred for 1-3 h at -5 to 0 °C. The solution was diluted with dichloromethane (280 mL) and it was transferred into a separating funnel. It was washed with water, dilute acetic acid and water. Organic layer was collected and dried over anhyd. Sodium sulfate. It was concentrated under reduced pressure to obtain (R/S)-l-phenyl-l,2,3,4-tetrahydro-isoquinoline-2-carbonitrile. (31.1 g, % Y-99.3 %)
Example 2
Preparation of l-Phenyl-l,2,3,4-tetrahydro-lH-isoquinoline-2-carboximidic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester
To a dry, 50 mL round bottom flask was charged l-aza-bicyclo[2.2.2]octan-3-ol (0.55 g) and THF (5 mL) at RT. It was cooled to 10 to 20 °C. To the clear solution 55 % NaH (0.190 g) was added at 10 to 20 °C. After 30-50 min., (R/S)-l-phenyl-1,2,3,4-tetrahydro-isoquinoline-2-carbonitrile (l.0g) was added at 10 to 20 °C. It was heated and stirred for 3 h at reflux temperature. Reaction mixture was poured into water (10 mL). It was extracted with Ethyl acetate. The extract was washed with water. Organic layer was collected and dried over sodium sulfate. It was concentrated under reduced pressure to obtain crude 1-phenyl-1,2,3,4-
7

ZRC-PD-31-Prov
tetrahydro-isoquinoline-2-carboximidic acid l-aza-bicyclo[2.2.2]oct-3-yl ester (1.2 g) . The
crude product was purified by column chromatography on neutral alumina (CHCI3: MeOH,
95:5) to give pure product. (0.285 g, % Y- 18 %)
Example 3
Preparation of l-aza-bicyclo[2.2.2]oct-3-yl l-Phenyl-l,2,3,4-tetrahydro-lH-isoquinoline-
2-carboxylate
To a 25 mL round bottom flask was charged 1 -phenyl-1,2,3,4-tetrahydro-isoquinoline-2-carboximidic acid l-aza-bicyclo[2.2.2]oct-3-yl ester (0.250 g), aq. HC1 and methanol (2.5 mL) at RT. It was stirred for 48 h at RT. Distilled out solvent at reduced pressure. Semi-solid mass was dissolved in 10 mL water. It was basified with 20 % aq. NaOH. It was transferred into a separating funnel. It was extracted with ethyl acetate. The extract was washed with water. Organic layer was collected and dried over sodium sulfate. It was concentrated under reduced pressure to obtain l-aza-bicyclo[2.2.2]oct-3-yl 1-Phenyl-l,2,3,4-tetrahydro-lH-isoquinoline-2-carboxylate (0.190 g).
Following the general processes described above, chirally pure forms of compound of formula (V) were prepared by starting with corresponding chiral starting materials.
Example 4
Preparation of (R/S)-3-cyanato-quinuclidine
To a dry, 1.0 L round bottom flask was charged (R/S)-3-quinuclidinol (2g) and toluene (10 mL) at RT. To the clear solution 55 % NaH (0.6 g) was added. It was stirred at RT. After 30 min., reaction mixture was cooled to 0-5 °C and Cyanogen bromide (1.53g) was added into it in small portions at 0 to 5 °C. It was stirred for 24 h at RT. It was diluted with 20 mL toluene and poured into 20 mL cold water. The solution was transferred into a separating funnel and the organic layer was collected. It was washed with water. Organic layer was collected and dried over anhyd. Sodium sulfate. It was concentrated under reduced pressure to obtain (R/S)-3-cyanato-quinuclidine. (0.3 g, % Y-12.5%)
Example 5
Preparation of l-Phenyl-l,2,3»4-tetrahydro-lH-isoquinoline-2-carboximidic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester
To a dry, 50 mL round bottom flask was charged (R/S)-3-cyanato-quinuclidine (0.25
g) and THF (5 mL) at RT. It was cooled to 10 to 20 °C. To the clear solution 55 % NaH
(0.070 g) was added at 10 to 20 °C. After 30 min. (R/S)-l-phenyl-1,2,3,4-tetrahydro-
isoquinoline (0.340g) was added at 10 to 20 °C. It was heated and stirred for 3 h at reflux
temperature. Reaction mixture was poured into water and extracted with Ethyl acetate. The
extract was washed with water. Org. layer was collected and dried over sodium sulfate. It was
8

ZRC-PD-31-Prov
concentrated under reduced pressure to obtain crude 1 -phenyl- 1,2,3,4-tetrahydro-isoquinoline-2-carboximidic acid l-aza-bicyclo[2.2.2]oct-3-yl ester (0.55 g) . The crude product was purified by column chromatography on neutral alumina (CHCI3: MeOH, 95:5) to give pure product. (0.105 g, % Y- 17.7 %)
The Solifenacin base obtained may be further converted to the succinate salt by techniques known in the art.

9

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Patent Number

252218

Indian Patent Application Number

1597/MUM/2007

PG Journal Number

18/2012

Publication Date

04-May-2012

Grant Date

02-May-2012

Date of Filing

21-Aug-2007

Name of Patentee

CADILA HEALTHCARE LIMITED

Applicant Address

ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD.

Inventors:

#	Inventor's Name	Inventor's Address
1	PATEL, PANKAJ R.	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD 380 015.
2	PANDEY, BIPIN	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD 380 015.
3	DAVE, MAYANK G.	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD 380 015.
4	KOTHARI, HIMANSHU M.	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD 380 015.

PCT International Classification Number

C07D453/02; C07D453/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA