FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
IMPROVED PROCESS FOR THE PREPARATION OF SOLIFENACIN SUCCINATE
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road,
Near Dinesh Hall,
Ahmadabad 380 009.
Gujarat, India
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
This invention relates to an improved process for the preparation of solifenacin succinate.
BACKGROUND OF THE INVENTION
1(S), 3(R)-1-azabicyclo[2.2.2]-oct-3-yl-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarbo-xylate succinate known as solifenacin under the International Non-Proprietary Name is marketed as a succinate salt. Solifenacin is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Solifenacin base can be represented by (1), and was disclosed in U.S. Pat. No. 6,017,927 (the '927 patent).

The '927 patent discloses two preparation methods for the preparation of solifenacin. The first preparation method as depicted in scheme 1 includes condensation of ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (2; R = Et) with 3-quinuclidinol (3). The second preparation method includes condensation of 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (4) with 3(R)-quinuclidinyl chloroformate (5).
It has been observed that the condensation between ethyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (2; R = Et) with 3-quinuclidinol (3) requires presence of a very strong base like sodium hydride. Sodium hydride requires storage under inert atmosphere and is a flammable material. Hence it is not a base of choice in any chemical process.

Even after the use of a very strong base like sodium hydride the reaction takes two days to complete.
It has also been observed that during the condensation reaction 1 (S)-phenyl-1,2,3,4-tetrahydroisoquinoline (4) is generated in the reaction mixture as impurity in an amount of 15-25 %. As this impurity is difficult to remove, the product i.e. solifenacin base isolated from the reaction mixture also contains 1 (S)-phenyl-1,2,3,4-tetrahydroisoquinoline (4) as impurity.

For the above mentioned reasons, the condensation reaction is not industrially feasible. Hence, there remains a need in the art to modify the reaction in such a way that it becomes industrially feasible.
It has been surprisingly observed that use of a phase transfer catalyst in the condensation reaction of alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinoline-

carboxylate (2) with 3(R)-quinuclidinol (3) not only improves the rate of reaction but also allows the use of a base which is a less hazardous than sodium hydride.
It has also been surprisingly observed that when a mixture of toluene and sulpholane is used as the solvent in the condensation reaction, the rate of reaction is drastically enhanced allowing the reaction to complete in a very short time and also allows the use of a base which is less hazardous than sodium hydride.
It has also been surprisingly observed that addition of acetic anhydride or acetyl chloride into the reaction mixture of alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (2) and 3(R)-quinuclidinol (3) results in a more pure solifenacin base (1).
SUMMARY OF THE INVENTION
In one embodiment the specification discloses a process for the preparation of solifenacin base (1) comprising the steps of
(i) providing a solution of alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinoline-carboxylate (2) and 3(R)-quinuclidinol (3) in a suitable solvent;
(ii) adding a base and a phase transfer catalyst to the above solution of step
(i);
(iii) refluxing the suspension of step (ii) for sufficient time to complete the
reaction; (iv) isolating solifenacin base from the reaction.
In another embodiment the specification discloses a process for the preparation of solifenacin base (1) comprising the steps of
(i) providing a solution of alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinoline-carboxylate (2) and 3(R)-quinuclidinol (3) in a mixture of toluene and sulfolane; (ii) adding a base to the above solution of step (i);

(iii) refluxing the suspension of step (ii) for sufficient time to complete the
reaction; (iv) isolating solifenacin base from the reaction. In yet another embodiment the specification discloses a process for the preparation of solifenacin base (1) comprising the steps of
(i) providing a solution of alkyl 1(S)-phenyl-1>2,3,4-tetrahydro-2-isoquinoline-
carboxylate (2) and 3(R)-quinuclidinol (3) in a suitable solvent; (ii) adding a base and a phase transfer catalyst to the above solution of step
(i); (iii) refluxing the suspension of step (ii) for sufficient time to complete the
reaction; (iv) adding acetic anhydride or acetyl chloride in the reaction mixture; (v) stirring the reaction mixture; (vi) isolating solifenacin base from the reaction-
In still another embodiment the specification discloses a process for the preparation of solifenacin base (1) comprising the steps of
(i) providing a solution of 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (4) in toluene under inert atmosphere;
(ii) adding triethylamine to the solution of step 0);
(iii) cooling the reaction mixture of step (ii);
(iv) adding alkyl chloroformate and toluene solution to the above reaction mixture of step (iii);
(v) stirring the reaction mixture of step (iv) at room temperature;
(vi) quenching the reaction mixture with water;
(vii) isolating the organic layer;
(viii) optionally mixing sulfolane to the organic layer of step (vii);
(ix) dissolving 3(R)-quinuclidinol (3) in the above solution;
(x) adding a base and a phase transfer catalyst to the above solution of step (ix);
(xi) refluxing the suspension of step (x);

(xii) adding acetic anhydride or acetyl chloride in the reaction mixture;
(xiii) stirring the reaction mixture;
(xiv) isolating solifenacin base from the reaction. In another embodiment the solifenacin base (1) can be further converted to any acid addition salt by any method known in the art. Preferably, solifenacin base (1} is converted to solifenacin succinate by methods known in the art.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment the specification discloses a process for the preparation of solifenacin base (1) comprising the steps of
(i) providing a solution of alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinoline-carboxylate (2) and 3(R)-quinuclidinol (3) in a suitable solvent;
(ii) adding a base and a phase transfer catalyst to the above solution of step
(i);
(iii) refluxing the suspension of step (ii) sufficient time to complete the
reaction; (iv) isolating solifenacin base from the reaction.
The process comprises dissolving alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinoline-carboxylate (2) and 3(R)-quinuclidinol (3) in a suitable solvent. The alkyl group is selected from a group consisting of methyl and ethyl. A suitable base and catalytic amount of a phase transfer catalyst is added to the above solution and the reaction mixture is heated to reflux for sufficient time to complete the reaction. The reaction mixture is then quenched with water and the pH is adjusted to 1-2 by the addition of 1 N HCI. The aqueous layer is separated and is made alkaline to pH by the addition of 10 % sodium carbonate solution. The aqueous solution is then extracted with ethyl acetate and the organic layer is evaporated to get solifenacin base as oil.

The solvent for this reaction may be selected from a group of aromatic and aliphatic hydrocarbon solvent like benzene, toluene, xylene, cyclohexane; ether solvent like tetrahydrofuran, dioxane, dimethoxyethane; dimethylformamide; dimethylsulphoxide; dimethylacetamide; sulfolane and mixture thereof.
The base is selected from a metal hydroxide, metal alkoxide and mixture thereof. The metal hydroxide base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, and mixture thereof. The most preferred metal hydroxide is sodium hydroxide. The metal alkoxide base is selected.from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium 'tert-butoxide, potassium tert-butoxide and mixture thereof. The most preferred metal alkoxide base is sodium methoxide. The quantity of base that is to be added to the reaction is found to be 1.0 to 3.0 equivalent compared to 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinoline-carboxylate (2).
The phase transfer catalyst may be any phase transfer catalyst known in the art. Preferably phase transfer catalyst is selected from a group consisting of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride, tetrabutyl ammonium hydrogen sulphate, methyl trioctyl ammonium chloride and mixture thereof. The most preferred phase transfer catalyst is tetrabutyl ammonium bromide.
It has been observed that the reaction takes about 15-24 hours for completion. It has been a dramatic improvement from the process described in the '927 patent in which the reaction takes two days to complete.
In another embodiment the specification discloses a process for the preparation of solifenacin base (1) comprising the steps of
(i) providing a solution of alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinoline-carboxylate (2) and 3(R)-quinuclidinol (3) in a mixture of toluene and sulfolane; (ii) adding a base to the above solution of step (i);

(iii) refluxing the suspension of step (ii) for sufficient time to complete the reaction;
(iv) isolating solifenacin base from the reaction. The process comprising of dissolving alkyl 1 (S)-phenyl-1,2,3,4-tetrahydro-2-isoquinoline-carboxylate (2) and 3(R)-quinuclidinol (3) in a mixture of toluene and sulfolane. The ratio of toluene and sulfolane may vary from 1:20 to 20:1. A suitable base is added to the above solution and refluxed for sufficient time to complete the reaction. The base is selected from a metal hydroxide, metal alkoxide and mixture thereof. The preferred bases for the reaction are sodium hydroxide and sodium methoxide. The reaction mixture is then quenched with water and the pH is adjusted to 1-2 by the addition of 1 N HCI. The aqueous layer is separated and is made alkaline to pH by the addition of 10 % sodium carbonate solution. The aqueous solution is then extracted with ethyl acetate and the organic layer is evaporated to get solifenacin base (1) as oil.
It has been observed that the reaction only takes 12-15 hours to complete when a mixture of toluene and sulfolane is used as the. solvent for this condensation reaction. This is a very significant improvement when compared to the reaction time (2 days) reported in the '927 patent. Also this process allows the use of a milder base than sodium hydride as disclosed in the '927 patent.
In yet another embodiment the specification discloses a process for the preparation of solifenacin base (1) comprising the steps of
(i) providing a solution of alkyl 1(S)-phenyl-1,2,3,4--tetrahydro-2-isoquinoline-carboxylate (2) and 3(R)-quinuclidinol (3) in a suitable solvent;
(ii) adding a base and a phase transfer catalyst to the above solution of step
(i);
(iii) refluxing the suspension of step (ii) for sufficient time to complete the
reaction; (iv) adding acetic anhydride or acetyl chloride in the reaction mixture; (v) stirring the reaction mixture;

(vi) isolating the product.
It has been observed that the condensation reaction between alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (2) with 3(R)-quinuclidinol (3) generates 1-phenyl-1,2,3,4-tetrahydroisoquinoline (4) in the reaction mixture as impurity in an amount of 15-25 %. It has been observed that the impurity can not be removed by normal acid-base treatment as expected. Hence the product i.e. solifenacin base (1) isolated from the reaction mixture also contains 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (4) as impurity in an amount of 15-25 %.
The reaction between alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (2) and 3(R)-quinuclidinol (3) is carried out as described above. After the reaction is over, the reaction mixture is cooled to room temperature and acetic anhydride or acetyl chloride is added to the reaction mixture and stirred for 2-3 hours in order to convert 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (4) into its acetyl derivative (6).

The reaction mixture is quenched with water and acidified to pH 1-2 by addition of 1 N HCI. The aqueous layer is separated and basified to pH 8.5 by the addition of 10 % potassium carbonate solution. The organic layer is separated and washed with water and distilled to obtain pure solifenacin base (1).
Table 1 shows that when the condensation reaction between alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (2) with 3(R)-quinuclidinol (3) is worked up without the treatment of acetic anhydride or acetyl chloride, the isolated product, solifenacin base (1) contains more than 16.5 % of 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (4) as impurity. But when the above mentioned condensation

reaction is treated with acetic anhydride or acetyl chloride as described above, the said impurity level in the isolated product is less than 2 %.

Condition Impurity during reaction Impurity in solifenacin base by
monitoring by HPLC (%) HPLC (%)
Without 16.90 16.69
addition of
acetylating
agent
Addition of 21.20 1.76
acetylating
agent
In yet another embodiment the specification discloses a process for the preparation of solifenacin base (1) comprising the steps of
(i) providing a solution of 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (4) in toluene under inert atmosphere;
(ii) adding triethylamine to the solution of step (i);
(iii) cooling the reaction mixture of step (ii);
(iv) adding alkyl chloroformate and toluene solution to the above reaction mixture of step (iii);
(v) stirring the reaction mixture of step (iv);
(vi) quenching the reaction mixture with water;
(vii) isolating the organic layer;
(viii) optionally mixing sulfolane to the organic layer of step (vii);
(ix) dissolving 3(R)-quinuclidinol (3) in the above solution;
(x) adding a base and a phase transfer catalyst to the above solution (ix);
(xi) refluxing the suspension of step (x);
(xii) adding acetic anhydride or acetyl chloride in the reaction mixture;

(xiii) stirring the reaction mixture;
(xiv) isolating solifenacin base (1) from the reaction.
The process comprises dissolving 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (4) (1.0 equivalent) in toluene under inert atmosphere. The inert atmosphere is created in the reaction vessel by bubbling an inert gas like nitrogen, argon and the like. Triethylamine is added to the solution and the solution is cooled to 0-5 °C. Ethyl chloroformate is dissolved separately in toluene and the solution is added to the above cooled solution over a period of 15 minutes drop wise. The reaction mixture is stirred for 2 hours at room temperature. Water is added to the reaction mixture in order to quench the reaction. It was observed that there is no need to isolate and/or purify the product, alkyl 1(S)-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (2). The organic layer can be directly taken ahead for the next step i.e. the condensation reaction with 3(R)-quinuclidinol (3). The organic layer is separated and optionally mixed with sulfolane. To this solution, 3(R)-quinuclidinol (3) is dissolved and the condensation reaction is carried out as described above to obtain solifenacin base (1).
In still another embodiment the solifenacin base (1) prepared by a method as described above can be further converted to any acid addition salt by any method known in the art. Preferably, solifenacin base (1) prepared by a method as described above is.converted to solifenacin succinate by any method known in the art.
The starting materials, 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (4) and 3{R)-quinuclidinol (3) are prepared as per the processes known in the art.
The method of preparation of solifenacin base (1) and solifenacin succinate as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:

EXAMPLE 1
Preparation of ethyl 1