FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
AN IMPROVED PROCESS FOR THE PREPARATION OF DARIFENACIN OR SALTS THEREOF
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMAI - 400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

IMPROVED PROCESS FOR THE PREPARATION FOR DARIFENACIN OR SALTS THEREOF
TECHNICAL FIELD
The present invention relates to an improved process for the preparation of Darifenacin or salts thereof via selective N-alkylation of the 3-(S)-(+) - (1-carbamoyl-1, 1-diphenyl methyl)-pyrrolidine L-(+) tartrate with 5-(2-bromoethyl)-2, 3-dihydrobenzofuran.
BACKGROUND OF THE INVENTION
Darifenacin, chemically known as (S)-2-{l-[2-(2, 3-dihydrobenzofuran-5-yl) ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide is a selective muscarinic M3 receptor antagonist works by selectively blocking an important receptor involved in the control of bladder muscle contraction and used for the treatment of overactive bladder. It has a chemical structure as shown below (formula I)

Darifenacin is marketed under the trade name ENABLEX® as its hydrobromide salt and chemically known as (S)-2-{l-[2-(2, 3-dihydrobenzofuran-5-yl) ethyI]-3-pyrrolidinyl}-2, 2-diphenylacetamide hydrobromide shown as formula II.


US 5096890 (Cross, Peter E, et al; Mar., 1992) describes Darifenacin and its pharmaceutically acceptable salts. The '890 patent also describes several methods for the preparation of Darifenacin. One of the disclosed process involves reaction of 3-(S)-(-) -(1-carbamoyl-1, 1-diphenyl methyl) pyrrolidine and 5-(2-bromoethyl)-2, 3-dihydrobenzofuran), anhydrous potassium carbonate in acetonitrile. After the reaction was over, the crude Darifenacin was obtained by dichloromethane extraction from aqueous solution. The crude darifenacin thus obtained was purified by column chromatography and it was further re-crystallized from diisopropyl ether. The yield obtained after re-crystallization is very low and the process also involves the use of column chromatography. The process described is difficult to apply at commercial scale. The 3-(S)-(-) - (1-carbamoyl-l, 1-diphenyl methyl) pyrrolidine used in the process was obtained by treating its tartrate salt with aqueous sodium hydroxide and extracting with dichloromethane. The dichloromethane solution was evaporated under vacuum and a foam type compound was obtained, which is very difficult to handle at commercial scale. However, in the '890 patent, the 3-(S)-(+) - (1-carbamoyl-l, 1-diphenyl methyl)-pyrrolidine- L-(+) tartrate is first converted into its free base as mentioned above by treating it with base and extracting with dichloromethane. Also, as described above, the free base obtained by distillation of the dichloromethane, and during this distillation lots of foam is generated which is difficult to handle. On this ground, to avoid the problem of the distillation and getting foam formation, in the present invention it was found that the 3-(S)-(+)- (1-carbamoyl-l, 1-diphenyl methyl)-pyrrolidine- L-(+) tartrate and 5-(2-bromoethyl)-2,3-dihydrobenzofuran can be directly N-alkylated. Thus, the present invention provides the process which reduces the number of reaction steps as well as free off the problem of foaming of the compound during distillation.

PCT application No WO 2007076159 (Merli V., et al July, 2007) describes preparation of Darifenacin via reacting 5-(2-chloroethyl)-2, 3-dihydrobezofuran (DBF-EtCl) and 3-(S)-(-) - (1-carbamoyl-1, 1-diphenyl methyl) pyrrolidine tartrate in aqueous potassium carbonate under refluxing condition. After reaction is over, it was extracted with n-butanol. Further vacuum distillation was performed to remove water and again n-butanol and acetic anhydride was added. The process disclosed involves lots of operation and n-butanol for extraction which has some solubility of Water and hence required further distillation. As it involves lots of operation, the through put of the process will be very low.
WO2008126106 (Reddy S. et al, October 2008) als0 describes the process for the preparation of Darifenacin hydrobromide. According to the disclosed process, first the 3-(S)-(-) - (1-carbamoyl-l, 1-diphenyl methyl) pyrrolidine tartrate was converted into free base by using aqueous hydroxide and extracts with toluene. The free base thus obtained was reacted with 5-(2-bromoethyl)-2, 3-dihydrobenzofuran by using potassium hydroxide in acetonitrile. The said reaction requires more reaction time i.e. 18 hrs for completion.
Another PCT application No WO2009/125430 A2 (Tyagi, et al Oct., 2009) also describes the process for the preparation of Darifenacin free base and its hydrobromide salt. In this patent, 3-(S)-(-) - (1-carbamoyl-l, 1-diphenyl methyl) pyrrolidine tartrate was reacted with 5-(2-bromoethyl)-2, 3-dihydrobenzofuran by Using potassium hydroxide in acetonitrile and tetrahydrofuran. The potassium hydroxide being a strong base generates impurities in the reaction.
US2009/0306406 Al (Nuria S.M., et al Dec, 2009) describes process for the preparation of Darifenacin wherein the 3-(S)-(-) - (1-carbamoyl-l, 1-diphenyl methyl) pyrrolidine tartrate was reacted with 5-(2-bromoethyl)-2, 3-dihydrobenzofuran under phase transfer condition by using toluene, potassium hydroxide and pha.se transfer catalyst. The reaction was refluxed at 100°C and stirred for 16.0 hrs. The high temperature reaction indicates that phase transfer conditions are not effective for this reaction.

The PCT application WO2010/032225 (Bhanu M. N., et al Mar. 2010) also disclose the preparation of crude Darifenacin hydrobromide, wherein the 3-(S)-(-) - (1 -carbamoyl-1, 1-diphenyl methyl) pyrrolidine tartrate was reacted with 5-(2-bromoethyl)-2, 3-dihydrobenzofbran in aqueous potassium carbonate and reaction was run at higher temperature. The work-up procedure employed is very lengthy and requires lots of operation.
Thus in view of the above cited prior art and mentioned drawbacks, there exist a need to develop an efficient, cost effective and high through-put process for preparation of Darifenacin.
OBJECT OF THE INVENTION
The object of the present invention is to provide an efficient process for the synthesis of Darifenacin or salts thereof.
Another object of present invention is to provide a process with increased through-put at industrial scale and is also cost effective.
Still another object of the present invention is to provide Darifenacin or salts thereof with improved purity.
Yet another object of the present invention is to provide an industrially scalable process for the preparation of Darifenacin or its salts
SUMMARY OF THE INVENTION:
The present invention relates to an improved process for the preparation of (S)-2-{l-[2-(2, 3-dihydrobenzofuran-5-yl) ethyl]-3-pyrrolidinyl}-2, 2-diphenylacetamide known as Darifenacin (formula I) and salts thereof, wherein the said process involves the steps of


a)
a) selective N-alkylation of 3-(S)-(+) - (1-carbamoyl-l, 1-diphenyl methyl pyrrolidine- L- (+) - tartrate with 5-(2-bromoethyl)-2, 3-dihydrobenzofuran in presence of base, solvent and alkali metal or transition metal halide catalyst;
b) treating darifenacin free base of step a) with an acid in an organic solvent to form Darifenacin salt; and
c) purification of Darifenacin salt of step b) from a mixture of an organic solvent and water.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, efficient and high through-put process for the preparation of (S)-2-{l-[2-(2, 3-dihydrobenzofuran-5-yl) ethyl]-3-pyrrolidinyl}-2, 2-diphenylacetamide known as Darifenacin or salts thereof.
The process according to present invention involves the steps of selective N-alkylation of the 3-(S)-(+) - (1-carbamoyl-l, l-diphenylmethyl)-pyrrolidine L-(+) tartrate with 5-(2-bromoethyl)-2, 3-dihydrobenzofuran in presence of base, solvent and alkali metal or transition metal halide catalyst; treating Darifenacin with inorganic acid to obtain its salt; and purification of the salt from the mixture of an organic solvent and water to obtain pure Darifenacin salt.
In the synthesis of Darifenacin hydrobromide the key raw materials used are 3-(S)-(+)-(1 -carbamoyl-1,1-diphenyl methyl)-pyrrolidine- L-(+) tartrate and 5-(2-bromoethyl)-2,3-dihydrobenzofuran which can be prepared by the method reported in the literature for example as in US patent no.5,096,890.

The process according to present invention, wherein the N-alkylation of 3-(S)-(+) - (1-carbamoyl-1, 1-diphenylmethyl)-pyrrolidine L-(+) tartrate with 5-(2-bromoethyl)-2, 3-dihydrobenzofuran is carried out in presence of base, solvent and alkali metal or transition metal halide catalyst.
The said catalyst used in the N-alkylation step is the one which activates the leaving groups of the alkylating reagents for selective and efficient N-alkylation to obtain Darifenacin. The catalyst which can be used in said N-alkylation reaction comprises of iodide or bromide salt of alkali metals or transition metals such as sodium iodide, sodium bromide, potassium iodide, potassium bromide, copper iodide and copper bromide; preferably they are potassium iodide, sodium iodide or copper iodide.
The bases which can be used in the said alkylation reaction comprises of carbonates of alkali and alkaline metals. Preferably the said bases are sodium carbonate and potassium carbonate; more preferably the base is powdered potassium carbonate.
Further the N-alkylation reaction is carried out in the presence of solvents, which comprises of hydrocarbons, ketones, esters and nitriles. The hydrocarbon solvents are chlorinated hydrocarbon solvents, and they comprises of dichloromethane, dichloroethane and monochlorobenzene. The ketonic solvents, which can be used are comprised of acetone, methyl ethyl ketone and methyl isobutyl ketone. The nitriles, which can be used as solvents are comprised of acetonitrile, propionitrile and butyronitrile. The most preferred solvent for the said N-alkylation reaction is acetonitrile.
The said N-alkylation reaction according to the process of the present invention can be performed at room temperature to reflux temperature of the solvents; preferably at 50 -60°C.
The progress of the reaction can be monitored by TLC or HPLC. After reaction is over it was worked up by adding water and the product formed can be isolated with water immiscible solvents such as dichloromethane.

The crude product obtained after distillation of the solvent used can be as such taken for the preparation of its salt.
The Darifenacin free base thus obtained can be converted into its salt by treating the Darifenacin free base with an inorganic or organic acid in presence of an organic solvent.
The said acids used in the salt formation reaction according to present invention are selected from the group of hydrobrornic acid, hydrochloric acid, hydroiodic acid, tartaric acid; preferably the acid is hydrobrornic acid.
The organic solvent used in said Darifenacin salt formation step according to present invention comprises of ketone; preferably it is acetone. The salt formation reaction can be conducted at 0°C to room temperature, most preferably at 25 - 30°C.
The crude Darifenacin salt obtained in step b) of the process according to the present invention can be purified from a mixture of an organic solvent and water. The said organic solvents used in the purification of Darifenacine salt prepared according to the process of the present invention comprises of acetone, tert-butanol and tetrahydrofuran.
The ratio of water used in combination with the said organic solvent varies from 5.0% to 50.0% of the solvent, preferably 6-10% of water is used with respect to amount of solvent.
The purified Darifenacin salt, preferably Darifenacin Hydrobromide can be obtained by filtration and washing. The Darifenacin hydrobromide obtained via said purification process according to the present invention has purity of greater than 99%, preferably greater than 99.77%, more preferably greater than 99.88%.
Darifenacin hydrobromide obtained according to process of the present invention, wherein the purity of Darifenacin hydrobromide meets the criteria of purity described in ICH guideline in which any individual impurity is not more than 0,1% by HPLC.
The process according to present invention is represented in Scheme 1.

Scheme 1

Although the invention has been described with reference to0 specific embodiments, this description is not meant to be construed in a limiting sense, various modifications of the disclosed embodiments, as well as alternate embodiments of the said invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as defined herein above and as exemplified and claimed herein below.
Examples

The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims
Preparation of Darifenacin hydrobromide Example I:
Charge 100 gm (0.232 mole) 3-(S)-(+) - (1-carbamoyl-l, 1-diphenyl methyl) -pyrrolidine- L- (+) - tartrate, 1.0 lit. Acetonitrile, 58.03 gm (0.255 mole) 5-(2-bromoethyl)-2, 3-dihydrobenzofuran, 128.43 gm (0.929 mole) powdered potassium carbonate and 100 mg potassium iodide ( KI) at room temperature under stirring in a four neck round bottom flask fitted with overhead stirrer in a water bath. Heat the reaction mixture up-to 60°C and maintained for 2-3 hrs. The progress of the reaction was monitored by hplc. After completion of the reaction acetonitrile was distilled off under vacuum at 55-60°C up-to stirrable reaction mass. Cool the reaction mass to room temperature and 500 ml water and 500ml dichloromethane was added at room temperature. The organic layer was separated and the aqueous layer was extracted again with 200 ml dichloromethane. Combined both organic layers and washed with 200 ml water. Dry organic layer over sodium sulphate and concentrated under vacuum completely to get oil. Dissolve the oil in 400 ml acetone at room temperature and add 22.9 ml (0.418 mole) 48 % aqueous HBr drop-wise at 25-30°C.Stir the reaction mass for 2 hrs. The precipitated solid was filtered and washed with 200 ml acetone to obtain 90 gm of Darifenacin hydrobromide.
Example II:
Charge 10 gm (0.023 mole) 3-(S)-(+) - (1-carbamoyl-l, 1-diphenyl methyl) pyrrolidine-L- (+) - tartrate, 100 ml Acetonitrile, 6.33 gm (0.0278 mole) 5-(2-bromoethyI)-2, 3-dihydrobenzofuran, 12.84gm (0.092 mole) powdered potassium carbonate, 10 mg (0.1 %) Nal at room temperature under stirring in a four neck round bottom flask fitted with overhead stirrer in a water bath. Heat the reaction mixture up-to 60°C and maintained 2-3 hrs. The progress of the reaction was monitored by hplc. After completion of the reaction acetonitrile was distilled off under vacuum at 55-60°C up-to stirrable reaction mass. Cool the reaction mass to room temperature and 100 ml water and 100ml dichloromethane was

added at room temperature. The organic layer was separated and the aqueous layer was extracted again with 20 ml dichloromethane. Combined both organic layers and washed with 20 ml water. Dry organic layer over sodium sulphate and concentrated under vacuum completely to get oil. Dissolve the oil in 50 ml acetone at room temperature and add 2.25 ml (0.0418 mole) 48 % aqueous HBr drop-wise at 25-30°C.Stir the reaction mass for 2 hrs. The precipitated solid was filtered and washed with 20 ml acetone to obtain 8.5 gm of Darifenacin hydrobromide.
Example III:
Charge 10 gm (0.023 mole) 3-(S)-(+) - (1-carbamoyl-1, 1-diphenyl methyl) pyrrolidine-L- (+) - tartrate, 100 ml Acetonitrile, 6.33 gm (0.0278 mole) 5-(2-bromoethyl)-2, 3-dihydrobenzofuran, 12.84gm (0.092 mole) powdered potassium carbonate, 10 mg (0.1 %) Cul at room temperature under stirring in a four neck round bottom flask fitted with overhead stirrer in a water bath. Heat the reaction mixture up-to 60 C and maintained 2-3 hrs. The progress of the reaction was monitored by hplc. After completion of the reaction acetonitrile was distilled off under vacuum at 55-60°C up-to stirrable reaction mass. Cool the reaction mass to room temperature and 100 ml water and 100ml dichloromethane was added at room temperature. The organic layer was separated and the aqueous layer was extracted again with 20 ml dichloromethane. Combined both organic layers and washed with 20 ml water. Dry organic layer over sodium sulphate and concentrated under vacuum completely to get oil. Dissolve the oil in 50 ml acetone at room temperature and add 2.25 ml (0.0418 mole) 48 % aqueous HBr drop-wise at 25-30°C.Stir the reaction mass for 2 hrs. The precipitated solid was filtered and washed with 20 ml acetone to obtain 8.43 gm of Darifenacin hydrobromide.
Purification of darifenacin hydrobromide
Example-1:
Charged 3.0 gm Darifenacin hydrobromide, 30 ml acetone, and 4.5 ml water at room temperature in a four neck flask fitted with overhead stirrer in a water bath. Heated the

reaction mass to reflux temperature and maintained for 1.0 hr. to get clear solution. The solution was cooled to room temperature and then to 5-10°C and maintained for 30 min., the solid obtained was filtered and washed with 3.0 ml Acetone. 2.0 gm pure Darifenacin hydrobromide obtained.
Example- II:
Charged 10 gm Darifenacin hydrobromide, 50 ml THF, and 5.0 ml water at room temperature in a four neck flask fitted with overhead stirrer in a water bath. The reaction mass was heated to reflux temperature and maintained for 1.0 hr. to get clear solution. The solution was cooled to room temperature and then to 5-10 C and maintained for 30 min. The solid obtained was filtered and washed with 10 ml THF. 7.0 gm pure Darifenacin hydrobromide obtained.
Example III
Charged 5.0 gm Darifenacin hydrobromide, 50 ml tert-butanol, and 5.0 ml water at room temperature in a four neck flask fitted with overhead stirrer in a water bath. The reaction mass was heated to reflux temperature and maintained for 1.0 hr. to get clear solution. The solution was cooled to room temperature and maintained for 30 min. The solid obtained was filtered and washed with 3.0 ml tert-butanol. 4.6 gm pure Darifenacin hydrobromide obtained.
Claims:
1. An improved process for the preparation of Darifenacin of formula (I) or salt thereof wherein the process comprises of


(I)
a) selective N-alkylation of 3-(S)-(+) - (1-carbamoyl-1, 1-diphenyl methyl pyrrolidine- L- (+) - tartrate with 5-(2-bromoethyl)-2, 3-dihydrobenzofuran in presence of base, solvent and alkali metal or transition metal halide catalyst;
b) treating darifenacin free base of step a) with an acid in an organic solvent to form Darifenacin salt; and
c) purification of Darifenacin salt of step b) from a mixture of an organic solvent and water.

2. A process according to claim 1 a) wherein the alkali or transition metal halide catalysts comprises of potassium iodide, potassium bromide, sodium iodide, sodium bromide, copper iodide or copper bromide preferably sodium iodide, potassium iodide or copper iodide.
3. A process of claim la) wherein solvents comprises of chlorinated hydrocarbon, ketones or nitriles.
4. The process according to claim 3, wherein the chlorinated hydrocarbons comprises of dichloromethane, dichloroethane and monochlorobenzene; the ketones comprises of acetone, methyl ethyl ketone, methyl isobutyl ketone and nitriles comprises of acetonitrile, propionitrile and butyronitrile preferably nitrile solvent and more preferably acetonitrile.
5. A process according to claim 1 a) wherein the base is an inorganic base comprises of alkali and alkaline metal carbonates.

6. A process according to claim 5, wherein inorganic base is sodium carbonate or potassium carbonate, preferably powdered potassium carbonate.
7. A process according to claim 1 b) wherein the acids comprises of hydrobromic acid , hydrochloric acid, hydroiodic acid, tartaric acid preferably hydrobromic acid.
8. A process according to claim 1 b) wherein the said organic solvents which can be used are ketones, preferably acetone.
9. A process according to claim 1 b) wherein the darifenacin salt is darifenacin hydrobromide.
10. A process according to claim 1 c) wherein the aqueous organic solvents comprises of acetone, tert-butanol or tetrahydrofuran, preferably acetone in combination with water.
11. Darifenacin hydrobromide obtained according to process as claimed in Claim 1 wherein the impurity is not more than 0.1% by HPLC.
12. An improved process according to any of the preceding claims substantially as herein described with reference to the examples.