FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR PREPARATION OF
DARIFENACIN HYDROBROMIDE"
Emcure Pharmaceuticals Limited,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Darifenacin hydrobromide having impurity level conforming to regulatory specifications. The invention specifically relates to the minimization of associated impurities during the preparation and isolation of Darifenacin, obtained by condensation reaction of 3-(S)-{+)-(l-carbamoyl-l,l-diphenylmethyl) pyrrolidine or its salt with 5-(2-bromoethyl)-2,3-dihydrobenzofuran.
BACKGROUND OF THE INVENTION
Darifenacin, chemically known as (S)-l-[2-(2,3-dihydro-5-benzofuran)ethyl]-a,a-diphenyl-3-pyrrolidineacetamide is a selective muscarinic M3 receptor antagonist, which exhibits its therapeutic action by blocking the M3 muscarinic acetylcholine receptor; primarily responsible for bladder muscle contractions. Darifenacin hydrobromide (la), originally developed by Pfizer is the active ingredient of pharmaceutical formulations for oral treatment of urinary incontinence, which are available under various brand names such as Enablex, Emselex, Darken etc.

US 5,096,890 discloses various routes for synthesis of Darifenacin. The first route relates to the reaction of 3-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine with 5-(2-bromoethyl)-2,3-dihydrobenzofuran using acetonitrile as a solvent, in presence of potassium carbonate to give 3-( 1 -carbamoyl-1,1 -diphenylmethyl)-1 -[2-(2,3-dihydrobenzofuran-5-yl)ethyl] pyrrolidine. The reactant, 5-(2-bromoemyl)-2,3-dihydrobenzofuran is synthesized by bromination of 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran, which in turn, is obtained by the reduction of (2,3-dihydrobenzofuran-5-yl)acetic acid with lithium aluminium hydride. The other intermediate, 3-(1-carbamoyl-l,l-diphenylmethyl)pyrrolidine is obtained by reaction of N,0-ditosylated pyrrolidine with diphenyl acetonitrile in presence of sodium

hydride, followed by detosylation with hydrobromic acid and hydrolysis of the nitrile group using concentrated sulfuric acid.
The second route involves reaction of 3-(l -carbamoyl-1,1 -diphenylmethyl)pyrrolidine with 5-chloroacetyl-2,3-dihydrobenzofuran, followed by reduction of the carbonyl group with Pd/C. The third route relates to the reaction of 5-(2-bromoethyl) benzo [2,3-b]furan with 3-(1-carbamoyl-l,l-diphenylmethyl)pyrrolidine, followed by hydrogenation of the double bond in the benzofuran moiety using palladium on carbon as catalyst.
However, Darifenacin free base thus obtained by the above routes was found to have low purity and therefore required extensive purification by column chromatography before conversion to its hydrobromide salt utilizing acetone and aqueous hydrobromic acid. The requirement of chromatographic purification technique is quite tedious and cumbersome on a commercial scale and hence these methods are found to be industrially unviable.
US 7,442,806 discloses another method involving reaction of (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile hydrobromide with 5-(2-bromoethyl)-2,3-dihydrobenzofuran in presence of potassium carbonate and water, followed by treatment with hydrobromic acid to yield (S)2-{1 - [2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl} -2,2-acetonitrile hydrobromide. The nitrile functional group was then hydrolyzed using potassium hydroxide in tertiary amyl alcohol and was then further treated with hydrobromic acid to yield Darifenacin hydrobromide. (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile hydrobromide was synthesized by a route comprising reaction of 3-(S)-(+)-hydroxypyrrolidine with tosyl chloride in presence of a base and a phase transfer catalyst, followed by treatment of the N,0-ditosylated derivative with diphenyl acetonitrile, and subsequent deprotection of the tosyl group with hydrobromic acid.
WO 2007/076159, US 2010/0317871, WO2003/080599, WO2011/070419 also disclose various methods for preparation and purification of Darifenacin hydrobromide in which the associated impurities formed during the condensation reaction of 3-(l-carbamoyl-1,1-diphenylmethyl)pyrrolidine with 5-(2-bromoethyl)-2,3-dihydrobenzofuran in presence of a base are minimized by an additional step of purification. Procedures disclosed in these

references include methods such as chromatographic purifications or successive crystallizations in order to obtain Darifenacin hydrobromide of desired purity. Such techniques, which are tedious and laborious and involve utilization of high volumes of solvents, render the synthetic methods industrially unviable. One of the impurities, which is encountered invariably during the preparation of Darifenacin hydrobromide is (S)-3-(2-amino-2-oxo-l,l-diphenylethyl)-l,l-bis(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-l-pyrrolidinium bromide of formula (II). However, prior art methods reported so far do not disclose an effective and practical method to control or minimize this impurity below regulatory limits.

Thus, there still exists a need for a convenient, industrially viable process for preparation of Darifenacin hydrobromide which results in a product having impurity levels complying to regulatory norms.
The present inventors have tried out several methods for controlling the said impurity (II) and it was an unexpected finding that with the use of cyclopentyl methyl ether as a solvent, the impurity (II) could be controlled during the condensation reaction and also minimized significantly during the isolation of Darifenacin free base.
OBJECT OF THE INVENTION
An objective of the present invention is to provide a convenient, industrially scalable process for synthesis of Darifenacin hydrobromide which avoids use of chromatographic separations or successive crystallizations to get rid of the impurities generated during the preparation of Darifenacin hydrobromide

Another object of the invention is to provide a method for preparing pure Darifenacin hydrobromide involving control on the formation of impurity of formula (II), generated during the reaction of diphenylmethyl pyrrolidine derivative of formula (IX) with bromoethyl dihydrobenzofuran of formula (X) and which is further minimized during isolation.
SUMMARY OF THE INVENTION
The present invention relates to a novel and scalable process for preparation of (S)-l-[2-(2,3-dihydro-5-benzofuran)ethyl]-a,a-diphenyl-3-pyrrolidineacetamide hydrobromide (la) having desired purity by overcoming the problems faced in the prior art.
An aspect of the invention relates to a process for the preparation of Darifenacin hydrobromide (la), comprising reaction of 3-(S)-(+)-(l-carbamoyl-1,1 -diphenylmethyl) pyrrolidine of formula (IX) or its acid addition salt (IXa) with 5-(2-bromoethyl)-2,3 dihydrobenzofuran of formula (X) in a mixture of cyclopentyl methyl ether and water, and in presence of potassium carbonate, filtering the reaction mixture and isolating Darifenacin of formula (I), which is then further treated with hydrobromic acid in acetone to yield Darifenacin hydrobromide (la) of desired purity.
These objectives of the present invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
During the experimentation aimed at optimization of the process for preparation of Darifenacin hydrobromide, the present inventors observed that various impurities were formed during the condensation reaction of 3-(l-carbamoyl-l,l-diphenylmethyl) pyrrolidine or its salt (IX or IXa) with 5-(2-bromoethyl)-2,3-dihydrobenzofuran (X) in presence of a base such as potassium carbonate. Formation of these impurities in the final stage of syntfiesis hampered the overall yield and also necessitated elaborate purification, which contributed significantly to the increase in process time and incurred costs.

Rigorous experimentation was then carried out with a focus on the condensation reaction between 3-( 1-carbamoyl-1,1-diphenylmethyl) pyrrolidine or its salt (DC or IXa) with 5-(2-bromoethyl)-2,3-dihydrobenzoruran (X), to pave a control on the formation of such impurities by studying the effect of base, solves and reaction conditions.
The inventors unexpectedly found that when cyclopentyl methyl ether was employed as a solvent, the reaction yielded Darifenacin hydrobromide having substantially low level of associated impurities. It was surprisingly observed that the reaction proceeded at a relatively facile rate and yet the undesired supstitution on the pyrrolidine ring leading to formation of impurity of formula (II) was under control. Further, it was also observed that the impurity (II) separated as a sticky solid during filtration of the reaction mixture. As a consequence, Darifenacin hydrobromide with substantially reduced impurity levels wherein the impurities were within regulatory limits was obtained in good yield, without involving any elaborate separation or purification procedure.
The inventors also found that impurity formation depended on the solvent utilized for the reaction. It was observed that when other solvents such as acetonitrile, methanol, methyl tertiary butyl ether, 1,2-dimethoxyethane, toluene, methyl ethyl ketone etc. were used for the final condensation reaction, either the reaction was too slow or impurity formation was significantly more.
When acetonitrile was used as a solvent, although the condensation reaction proceeded with a significant rate, it was associated with remarkably high percentage of impurity (II) while in case of methyl tertiary butyl ether as a solvent; the desired reaction proceeded at a very slow rate. The use of methanol resulted in the reaction becoming slow and impurity formation was more in comparison with acetonitrile.


Scheme 1: Method embodied in the present invention for the preparation of Darifenacin hydrobromide (la)
In an embodiment, the tartrate salt of 3-(l-carbamoyl-l,l-diphenylmethyl) pyrrolidine of formula (IXa) was treated with 5-(2 bromoethyl)-2,3-dihydrobenzofuran of formula (X) in presence of a base and an organic solvent, optionally, in presence of water.
The base was selected from the group comprising of organic or inorganic bases such as triethylamine, aniline, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate etc., but preferably potassium carbonate.
The solvent was selected from the group comprising of acetonitrile, methanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, methyl tertiary butyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane. The solvent was preferably cyclopentyl methyl ether.
The reaction was carried out in the temperature range of 60 to 85 C and completion of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was filtered to separate the sticky impurity, which had separated out and the organic layer was concentrated to give Darifenacin base.
In case of solvents like cyclopentyl methyl ether, the impurity, (S)-3-(2-amino-2-oxo-l,l-diphenylethyl)-1,1 -bis(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-1 -pyrrolidinium bromide of

formula (II) was substantially reduced to 5% with complete conversion of the starting material to the final product. Thus, the condensation reaction took place with a good balance between reaction speed and control on undesired substitutions leading to impurities. Furthermore, when cyclopentyl methyl ether was utilized as solvent, the impurity of formula (II) separated out as a sticky mass and was easily removed during filtration. The resulting organic layer having impurity of formula (II) within regulatory limits was concentrated to give Darifenacin base.
For solvents like meuianol, the extent of formation of impurity (II) exceeded 10% and which was difficult to minimize substantially or remove during the subsequent conversion of Darifenacin into its hydrobromide salt.

Scheme 2: Method embodied in the present invention for the preparation of compound (IX)
Darifenacin base, obtained after the condensation reaction was mixed with acetone and treated with 48 % aqueous hydrobromic acid to give the hydrobromide salt, which was then subsequently isolated from butanol to give Darifenacin hydrobromide (la) having the desired purity, wherein the impurity levels conformed to regulatory specifications. Compound (IX) and compound (X), the reactants employed in the condensation reaction, were synthesized as follows (Scheme-2).

(S)-3-Hydroxypyrrolidine hydrochloride of formula (III) was treated with di-tertiary butyl dicarbonate (Boc anhydride) in presence of aqueous sodium bicarbonate solution in the temperature range of 20 to 40°C. After completion of the reaction as monitored by TLC; the reaction mass was extracted with ethyl acetate. Separation and concentration of the organic layer gave N-Boc-(S)-3-hydroxypyrrolidine of formula (IV) as viscous oil. Treatment of compound (IV) with p-toluenesulfonyl chloride and aqueous sodium hydroxide in tetrahydrofuran as solvent at 20 to 40°C gave N-Boc-3-tosyloxy pyrrolidine of formula (V). It is pertinent to note that as compared to prior art, the reaction was carried out without using any phase transfer catalyst. This ensured saving on the cost of expensive phase transfer catalysts, and also eliminated the time and energy required for separation and recycle of the used catalyst, creating a favorable impact on the reaction economics.
When the reaction was complete, as monitored by TLC, the compound of formula (V) was isolated by adding water to the reaction mass, followed by extraction with ethyl acetate and separation and concentration of the organic layer.
The compound (V) was treated with diphenyl acetonitrile of formula (VI) in presence of a
base and a solvent or mixture of solvents in a temperature range of 45 to 75°C to yield (S)-
2,2-diphenyl-2-[(l-tertiarybutyloxycarbonyl)-3-pyrrolidinil] acetonitrile of formula (VII).
After the reaction was complete, the reaction mixture was concentrated, and the residue
was mixed with water and extracted with ethyl acetate. Concentration of the organic layer
gave compound (VII).
The base was selected from alkali metal alkoxides such as sodium tertiary butoxide, and
potassium tertiary butoxide.
The solvent was selected from a group comprising dimethyl formamide, dimethyl
acetamide, dimethyl sulfoxide, dioxane and tetrahydrofuran.
Compound (VII) on treatment with a strong acid such as hydrochloric or sulfuric acid in
presence of an organic solvent selected from methanol and ethanol gave (S)-2,2-diphenyl-
2-(3-pyrrolidinyl)acetonitrile of formula (VIII), which on further treatment with
concentrated sulfuric acid yielded 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine
(IX). Treatment of compound (IX) with tartaric acid yielded the tartrate salt of formula
(IXa).


5-(2-haloethyl)-2,3-dihydrobenzofuran of formula (X) was prepared by the process disclosed in Scheme-3.
Scheme 3: Method embodied in the present invention for the preparation of compound (X)
2,3-Dihydrobenzofuran (Xa) was treated with acetyl chloride in presence of anhydrous aluminium chloride to yield 5-acetyl-2,3-dihydrobenzofuran (Xb), which on halogenation with N-chlorosuccinimide or N-bromosuccinimide in methanol as solvent and in presence of p-toluene sulfonic acid and water gave 5-(2-haloacetyl)-2,3-dihydrobenzofuran (Xc), which on reduction with sodium borohydride in presence of anhydrous aluminium chloride in solvent tetrahydrofuran yielded 5-(2-haloethyl)-2,3-dihydrobenzofuran of formula (X).
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.
EXAMPLES
Example 1: Synthesis of Darifenacin hydrobromide (la)
The tartrate salt of 3 -(S)-(+)-(l -Carbamoyl- 1,1-diphenylmethyl) pyrrolidine ((IXa;
300gms) was added to a stirred mixture of water (900 ml) and cyclopentyl methyl ether
(1200ml) followed by addition of potassium carbonate (404.55gms) and 5-(2-bromoethyl)-
2,3-dihydrobenzofuran (185.77gms). The reaction mixture was heated at 70 to 75°C till
completion of reaction, as monitored by HPLC and filtered to remove the sticky mass. The
organic layer after separation and concentration yielded crude Darifenacin (I). Addition of

HBr (48%, 117.3 ml) at 0 to 5°C to the solution of crude Darifenacin in acetone (2400 ml), followed by stirring at 25 to 30°C yielded Darifenacin hydrobromide. Further treatment of the obtained solid in solvent butanol (2100 ml) in presence of hydrobromic acid yielded pure Darifenacin hydrobromide (la). Yield: 240 g Purity: NLT 99.5%
Example 2: Synthesis of 3-(S)-(+)-(l-carbamoyI-l,l-diphenylmethyl) pyrrolidine (IX) Diphenyl acetonitrile (124.5g) was added to a mixture of tetrahydrofuran (600 ml) and dimethyl formamide (200 ml). The mixture was cooled to 0 to 5°C and potassium tertiary butoxide (101.2 g) was gradually added to it. N-Boc-3-(S)-suifonyIoxy-pyrroIidine, (V, 200 g) dissolved in a mixture of tetrahydrofuran (240 ml) and dimethylformamide (160 ml) was then added to the reaction mass and the reaction mixture was heated at 55 to 60°C till completion of the reaction as monitored by HPLC. When the reaction was complete, the reaction mass was concentrated and water was added to the residue. Extraction of the reaction mixture with ethyl acetate, followed by separation of the organic layer and concentration yielded (S)-2,2-diphenyl-2-[N-Boc-3-pyrrolidinyl]-acetonitrile (VII). Concentrated hydrochloric acid (185 ml) was added to the mixture of (S)-2,2-diphenyl-2-[N-Boc-3-pyrrolidinyl]-acetonitrile (VII) dissolved in methanol (600 ml) and stirred at 25 to 30°C till completion of the reaction as monitored by TLC. The reaction mixture was concentrated and the residue was diluted with water. The pH of the reaction mass was adjusted to 9-10 using sodium carbonate. Extraction of the reaction mass with ethyl acetate, followed by separation and distillation of the organic layer led to (S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile (VIII). Concentrated sulfuric acid (342 ml) was carefully added to compound (VIII) followed by careful addition of water (34.2 ml).The reaction mixture was then heated to 90-95°C till completion of the reaction, as monitored by TLC. Water was added to the reaction mass carefully, followed by pH adjustment to 9-10 by addition of aqueous sodium hydroxide. The reaction mixture was extracted with ethyl acetate and the organic layer concentrated to give 3 -(S)-(+)-(l -carbamoyl- 1,1-diphenylmethyl) pyrrolidine (IX).
Yield: 97 g Purity: 99%

Example 3: Synthesis of 5-(2-chIoroetbyl)-2,3-dihydrobenzofuran (X)
2,3-Dihydrobenzofuran (Xa; 200g) was gradually added to a stirred mixture of anhydrous aluminium chloride (233 g) and dichloromethane (1000 ml) at -10 to 0°C, followed by careful addition of acetyl chloride ( 156.8g). The reaction mixture was stirred at -10 to 0 C till completion of the reaction. The reaction mass was then added to aqueous hydrochloric acid with stirring and extracted with dichloromethane. Concentration of the organic layer gave 5-acetyl-2,3 dihydrobenzofuran (Xb), which was then isolated by addition of cyclohexane (1200 ml).
Para toluene sulfonic acid hydrate (93.8 g) was added in small portions to a mixture of 5-acetyl-2,3-dihydrobenzofuran (200 g) in methanol (1000 ml) and the reaction mass was stirred at 25-30°C, followed by gradual addition of N-chlorosuccinimide (181.2g). The reaction was continued at 30-35°C till completion, as monitored by TLC. The reaction mass was then quenched with 10% aqueous solution of sodium carbonate, and concentrated. The resultant mass was mixed with water and extracted with ethyl acetate. Separation of the organic layer and subsequent concentration gave 5-(2-chloroacetyl)-2,3-dihydrobenzofuran of formula (Xc), which was isolated by addition of cyclohexane (1000ml).
5-(2-Chloroacetyl)-2,3-dihydrobenzofuran (Xc; lOOg) was mixed with tetrahydrofuran (600ml) and the mixture was cooled to 5-10°C. Sodium borohydride (86.6g) was added to the mixture in small portions and the reaction mass was stirred at 5-10°C. Anhydrous aluminium chloride (169.5 g) was then added to the reaction mass in small portions, the temperature of the reaction mixture was raised to 55-60°C and the reaction was continued at same temperature. After completion of the reaction as monitored by HPLC, the reaction mixture was quenched with aqueous hydrochloric acid and concentrated to yield a residue, which was extracted with toluene. Separation and concentration of the toluene layer gave 5-(2-chloroethyl)-2,3-dihydrobenzofuran of formula (X). Yield: 75 g Purity: 99%

We claim,
1) An improved process for the preparation of Darifenacin hydrobromide (la)
comprising,
i) reaction of 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl) pyrrolidine of formula (DC) or its acid addition salt (IXa) with 5-(2-bromoethyl)-2,3-dihydrobenzofuran of formula (X) in an organic solvent, optionally in presence of water and in presence of potassium carbonate at a temperature of 60-80°C,
ii) cooling the reaction mixture and filtering
iii) concentrating the organic layer, dissolving the residue containing Darifenacin (I) in acetone and treating with hydrobromic acid.
2) A process according to claim 1, wherein the organic solvent is selected from the group comprising of acetonitrile, methanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, methyl ethyl ketone, methyl tertiary butyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane or a mixture thereof.
3) A process according to claim 1 and 2, wherein the solvent is preferably cyclopentyl methyl ether.
4) A process according to claim 1, wherein the reaction temperature is 70-75°C.
5) An improved process for the preparation of Darifenacin hydrobromide (la) comprising,
i) reaction of 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl) pyrrolidine of formula (DC) or its acid addition salt (IXa) with 5-(2-bromoethyl)-2,3-dihydrobenzofuran of formula (X) in cyclopentyl methyl ether, optionally in presence of water and in presence of potassium carbonate at a temperature of 70-75 C,
ii) cooling the reaction mixture and filtering
iii) concentrating the organic layer, dissolving the residue containing Darifenacin (I) in acetone and treating with hydrobromic acid