WO2008126106A2

WO2008126106A2 - Novel and improved processes for the preparation of intermediates of darifenacin, darifenacin and its pharmaceutically acceptable salts

Info

Publication number: WO2008126106A2
Application number: PCT/IN2008/000245
Authority: WO
Inventors: Manne Satyanarayana Reddy; Srinivasan Thirumalai Rajan; Karamala Rama Subba Reddy; Mummadi Venkatesh
Original assignee: Manne Satyanarayana Reddy; Srinivasan Thirumalai Rajan; Mummadi Venkatesh
Priority date: 2007-04-16
Filing date: 2008-04-15
Publication date: 2008-10-23
Also published as: WO2008126106A8; WO2008126106A3

Abstract

The present invention relates to novel and improved processes for the preparation of intermediates of darifenacin, darifenacin and its pharmaceutically acceptable salts. Darifenacin is chemically known as 3 -(S)-(-)-(l -carbamoyl- 1,1 -diphenylmethyl)-l- [2- (2,3-dihydro benzofuran-5-yl)ethyl]pyrrolidine and represented by formula (II). The invention also relates to the novel polymorphs of the pharmaceutically acceptable salts of darifenacin and the methods for their preparation.

Description

Novel and Improved Processes for the Preparation of Intermediates of Darifenacin, Darifenacin and Its Pharmaceutically Acceptable Salts.

Priority Claim: The present invention claims the priority of our earlier Indian patent application number 790/CHE/2007 filed on 16^th April 2007; Indian patent application number 2004/CHE/2007 filed on 6^th September 2007 and also an Indian patent application filed on 10^th April 2008.

Field of the Invention :

The present invention relates to novel and improved processes for the preparation of intermediates of darifenacin, darifenacin and its pharmaceutically acceptable salts.

Darifenacin is chemically known as 3-(S)-(-)-(l-carbamoyl-l,l-diphenylmethyl)-l-[2-

(2,3-dihydro benzofuran-5-yl)ethyl]pyrrolidine and represented by formula-2. The pharmaceutically acceptable salts of darifenacin are represented by formula- 1

The present invention also relates to the novel polymorphs of the pharmaceutically acceptable salts of darifenacin and the methods for their preparation.

Darifenacin is commercially available under the brand name ENABLEX®. ENABLEX is an extended-release tablet which contains 7.5 mg or 15 mg darifenacin as its hydrobromide salt. The active moiety, darifenacin is a potent muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediate functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion. They are particularly relevant to the treatment of conditions such as irritable bowel syndrome, diventricular disease, esophageal achalasia, and chronic obstructive airways disease, and urinary incontinence, treatment of bladder functional disorder, gastrointestinal hyperactivity and relaxing effect on intestinal smooth muscle cells.

Background of the Invention: US patent number 5096890 first discloses darifenacin and its pharmaceutically acceptable salts in both racemic and active forms. The pharmaceutically acceptable salts include acid addition salts, specifically the hydrochloride, hydrobromide, hydrofluoride, bisulphate, phosphate, acetate, citrate, fumarate, gluconate, maleate, succinate and tartrate salts. The said patent also disclosed different processes for the preparation of darifenacin and its pharmaceutically acceptable salts. The disclosed process comprises of reacting 3- (S)-(-)-( 1 -carbamoyl- 1 , 1 -diphenylmethyl)pyrrolidine and 5-(2-bromoethyl)benzo [2,3 - b]furan in presence of anhydrous potassium carbonate in acetonitrile to get 3 -(S)-Q-(I- carbamoyl- 1 , 1 -diphenylmethyl)- 1 - [2-(benzofuran-5-yl)ethyl]pyrrolidine compound followed by column chromatographic purification using a mixture of dichloromethane and methanol. Then the purified compound was hydrogenated using palladium on carbon in acetic acid mixture to get darifenacin followed by purifying the same through column chromatography. The purified darifenacin was further treated with hydrogen bromide to get darifenacin hydrogen bromide. The above said process involves number of column chromatographic purifications and is not suitable for commercial scale.

The same patent also discloses process for the preparation of starting material 3-

(S)-(-)-(l -carbamoyl- l,l-diphenylmethyl)pyrrolidine, which involves the usage of dangerous reagents like DEAD in the step of protection of hydroxyl with para toluene sulfonyl chloride. Hence this process is commercially not recommendable. Hence there is a need to develop a novel process which avoids the use of the above reagent.

US patent number 5096890 discloses that anhydrous darifenacin free base was obtained as foam after purification by column chromatography which was unstable and reacted with hydrobromic acid in acetone to give darifenacin hydrobromide with melting range of 229°C.

United States patent publication 2005/245597 discloses the stable hydrate form of darifenacin and process for preparing the same from darifenacin toluene solvate. The said patent also discloses that the free base is very unstable and it was difficult to produce the free base in sufficiently pure form so that it is suitable for pharmaceutical use. The present inventors provides a novel crystalline form of darifenacin base which is more stable and in highly pure form which is suitable for pharmaceutical use.

Polymorphism is the formation of a variety of crystalline forms of the same compound having distinct crystal structures and physical properties like melting points, X-ray diffraction pattern, infrared absorption pattern in fingerprint region, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. The difference in the physical properties of different crystalline forms results in some forms having distinct advantageous physical properties compared to other crystalline forms of the same compound. The discovery of new polymorphic forms of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of a pharmaceutical product. Those skilled in the art can understand that crystallization of an active pharmaceutical ingredient offers the best method for controlling important qualities like chemical quality, particle size, and polymorphic content. There is a need in the art for the preparation of new polymorphic form of darifenacin and its pharmaceutically acceptable salts.

The present invention provides novel and improved processes for the preparation of darifenacin and its pharmaceutically acceptable salts through novel intermediates and starting materials which avoid the entire prior art problems.

Brief Description of the Invention:

The first aspect of the present invention encompasses a process for the synthesis of novel oxalate salt of (S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile compound of formula-7, which comprises of the following steps; a) Reacting (R)-3-hydroxypyrrolidine hydrochloride compound of formula-3, with a chlorinating agent to provide 3-chloropyrrolidine hydrochloride compound of formula-4, b) tosylation of compound of formula-4, provides the N-tosylated-3-chloropyrrolidine compound of formula-5, c) reacting the N-tosylated-3-chloropyrrolidine compound of formula-5, with diphenyl acetonitrile in the presence of a strong base provides a condensed compound of formula-6, d) deprotection of the N-tosyl group of compound of formula-6, followed by subsequent treatment with oxalic acid, provides (S)-2,2-diphenyl-2-(3-pyrrolidinyl) acetonitrile oxalate compound of formula-7.

The second aspect of the present invention encompasses a process for the preparation of highly pure, crystalline, pharmaceutically acceptable salts of darifenacin especially darifenacin hydrobromide and darifenacin hydrochloride from the novel oxalate salt of (S)-2,2-diphenyl-2-(3-pyrrolidinyl) acetonitrile compound of formula-7. The process comprises of the following steps; a) Treating (S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile oxalate compound of formula-7 with a suitable base followed by extraction with a suitable solvent, provides the free base of compound-7, b) reaction of free base of compound-7 in-situ, with sulfuric acid to provide an amide derivative, which on treating with tartaric acid in a suitable solvent provides its tartrate salt, compound of formula-8, c) treating the tartrate salt of compound of formula-8 with a suitable base followed by extraction with a suitable solvent, provides the free base of compound-8, d) condensation of the free base of compound-8 in-situ, with 5-(2-bromoethyl)-2,3- dihydrobenzofuran of formula-9a in presence of base in a suitable solvent provides darifenacin, which on subsequent treatment with hydrochloric acid in a suitable solvent to provide darifenacin hydrochloride compound of formula- Ib. (Or) condensation of the free base of compound-8 in-situ, with 5-(2-bromoethyl)-2,3- dihydrobenzofuran of formula-9a in presence of base in a suitable solvent provides darifenacin, which on subsequent treatment with hydrobromic acid in a suitable solvent to provides darifenacin hydrobromide compound of formula- 1 a. The third aspect of the present invention is to provide a novel process for the preparation of darifenacin and its pharmaceutically acceptable salts especially hydrobromide salt compound of formula- Ia, which comprises of the following steps; a) Reacting the pyrrolidine compound of formula-5 with diphenyl ester compound of formula- 10 in presence of a strong base in a suitable solvent to provide the condensed compound of formula- 11, b) deprotection of the N-tosyl group of the condensed compound of formula- 11 to provide the diphenyl pyrrolidine compound of formula- 12 which is optionally converted into its organic acid addition salt and again converted back to compound of formula- 12 by treating with a suitable base, c) reacting the diphenyl pyrrolidine compound of formula- 12 with dihydro benzofuran compound of formula-9, in presence of a suitable aqueous alkali and/or alkaline base in a suitable solvent with or without presence of phase transfer catalyst to provide the compound of formula- 13, d) optionally converting the compound of formula- 13 into compound of formula- 14 by reacting with suitable alkali base in a suitable alcoholic solvents, followed by reacting the compound of formula- 14 with suitable chlorinating agent like thionyl chloride and an amine to provide darifenacin compound of formula-2, e) converting the compound of formula- 13 into darifenacin compound of formula-2 by treating with alcoholic ammonia in presence or absence of a suitable solvent under vapor pressure or atmospheric pressure in an autoclave, f) reacting the darifenacin compound of formula-2 with a hydrobromic acid in a ketone solvent to provide the darifenacin hydrobromide compound of formula- Ia, g) purifying the compound of formula- Ia in a suitable ketone and/or alcohol solvent to provide the pure darifenacin hydrobromide compound of formula- 1 a.

The fourth aspect of the present invention provides an improved process for the preparation of dihydrobenzofuran compound of formula-9, which comprises of the following steps; a) Reducing 2-chloro-l-(2,3-dihydrobenzofuran-5-yl)ethanone compound of formula- 18 using a mixture of trifluoroacetic acid and triethyl silane in a suitable solvent or by using a mixture of sodium borohydride in presence of sulphuric acid or trifluroacetic acid in a suitable solvent to provide the 5-(2-chloroethyl)-2,3- dihydrobenzofuran compound of formula- 19, b) treating the 5-(2-chloroethyl)-2,3-dihydrobenzofuran compound of formula- 19 with sodium halide in a suitable solvent to provide corresponding 5-(2-haloethyl)-

2,3-dihydrobenzofuran compound of forrnula-9.

The compound of formula-20 can be prepared by the ion exchange reaction using the same reagents and solvents used in the step b) of the fourth aspect of the present invention from the compound of formula- 18. The compound of formula- 18 can be reduced using the same reagents and solvents as used in step a) of the fourth aspect of the present invention to get the compound of formula-9.

The fifth aspect of the present invention is to provide a novel amorphous form of darifenacin hydrobromide compound of formula- Ia. The novel amorphous form of the present invention is characterized by the PXRD pattern and IR spectrum substantially as illustrated in figure- 1 and figure-2 respectively.

The sixth aspect of the present invention is to provide a process for the preparation of novel amorphous form of darifenacin hydrobromide compound of formula- Ia.

The seventh aspect of the present invention provides novel crystalline form-M of darifenacin hydrochloride compound of formula- Ib.

The eighth aspect of the present invention provides a novel process for the preparation of novel crystalline polymorph form-M of darifenacin hydrochloride.

The ninth aspect of the present invention is to provide a process for the purification of darifenacin hydrobromide to obtain pure crystalline darifenacin hydrobromide compound of formula- Ia characterized by its PXRD pattern, IR spectra and DSC thermogram as shown in the figure-3, figure-4 and figure-5 respectively. The purification process comprises of the following steps; a) Dissolving darifenacin hydrobromide in polar protic solvent, b) heating the solution to reflux, c) treating the solution with activated carbon, d) distilling off the solvent under reduced pressure, e) adding suitable ketone and/or alcohol solvent to the residue and refluxing for a while, f) cooling the reaction mixture to low temperature to obtain crystalline solid, g) stirring the reaction mixture at low temperature, h) separating the crystalline solid by filtration, i) drying the solid gives the pure crystalline darifenacin hydrobromide.

Advantages of the present Invention:

• Provides novel processes for the preparation of darifenacin and its pharmaceutically acceptable salts, which are simple, easy to perform at a larger scale.

• Provides a novel pyrrolidine compound as a starting material which avoids the usage of dangerous/hazardous reagents like diethyl azodicarboxylate (DEAD). • Provides pure, crystalline novel intermediates, which are useful in the preparation of darifenacin and its pharmaceutically acceptable salts with high purity and greater yields.

• Provides a novel amorphous form of darifenacin hydrobromide.

• Provides a process for purifying the darifinacin hydrobromide and purification methods for intermediates.

• Eco friendly and commercially scalable process.

Brief Description of the Drawings:

Figure-1: Illustrates the powder X-ray diffraction pattern of amorphous darifenacin hydrobromide.

Figure-2: Illustrates the IR spectrum of amorphous darifenacin hydrobromide

Figure-3: Illustrates the powder X-ray diffraction pattern of crystalline darifenacin hydrobromide.

Figure-4: Illustrates the IR spectrum of crystalline darifenacin hydrobromide. Figure-5: Illustrates the DSC of crystalline darifenacin hydrobromide.

Figure-6: Illustrates the powder X-ray diffraction pattern of crystalline form-M of darifenacin hydrochloride. Detailed description of the invention:

The first aspect of the present invention encompasses a process for the synthesis of novel oxalate salt of (S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile compound of formula-7, which comprises of the following steps; a) Reacting (R)-3-hydroxypyrrolidine hydrochloride compound of formula-3

Formula-3 with a chlorinating agent in a suitable solvent to provide 3-chloropyrrolidine compound of formula-4, b) tosylation of 3-chloropyrrolidine compound of formula-4

Formula-4 in the presence of base and a suitable solvent to provide the N-tosylated chloro pyrrolidine compound of formula-5, c) reacting the N-tosylated-3-chloropyrrolidine compound of formula-5a

Formula-5 a with diphenyl acetonitrile in the presence of a suitable base in a suitable solvent to provide a condensed compound of formula-6, d) deprotection of the N-tosyl group of compound of formula-6

Formula-6 with a suitable reagent in a suitable solvent, followed by subsequent treatment with oxalic acid, to provide (S)-2,2-diphenyl-2-(3-pyrrolidinyl) acetonitrile oxalate compound of formula-7.

Formula-7

In the ^present embodiment in step a) (R)-3-hydroxypyrrolidine hydrochloride compound of fdrmula-3 was treated with thionyl chloride, in a suitable organic solvent selected from toluene, xylene, cyclohexane, hexanes, heptanes and dichloromethane; preferably toluene to provide the compound of formula-4.

In step b) compound of formula-4 was tosylated using para toluene sulfonyl chloride in the presence of triethylamine, diisopropyl ethyl amine, pyridine, piperidine, in presence of a suitable solvent selected from a group which may include without limitation, aromatic hydrocarbon solvents like toluene, xylene, or halogenated solvents such as dichloromethane, chloroform, ethylene dichloride and the like; preferably dichloromethane to provide compound of formula-5a.

In step c) compound of formula-5a was reacted with diphenyl acetonitrile in the presence a suitable base selected from a group which include 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 potassium hydroxide to provide the condensed compound of formula-6. Suitable solvents that can be used are polar aprotic solvents like dimethyl sulfoxide, dimethyl foramide, ethyl acetate, tetrahydrofuran, etc and their mixtures thereof; preferably dimethyl formamide.

In the step d) condensed compound of formula-6 was detosylated by treating with an aqueous hydrobromic acid and phenol. The free base formed was extracted with dichloromethane, dissolved in toluene and then treated with oxalic acid taken in isopropyl alcohol provides (S)-2,2-diphenyl-2-(3-pyrrolidinyl) acetonitrile oxalate compound of formula-7.

(S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile oxalate compound of formula-7 was found to be highly pure, crystalline free flowing solid, formed in substantially high yields.

Conventionally (S)-3-hydroxypyrrolidine hydrochloride is used as a starting material but it is more costly than (R)-3-hydroxypyrrolidine hydrochloride. Hence the use of (R)-3-hydroxypyrrolidine hydrochloride as starting material which avoids the usage of DEAD and reduced the cost substantially.

The present aspect is depicted in the scheme- 1.

The second aspect of the present invention encompasses a process for the preparation of highly pure, crystalline, pharmaceutically acceptable salts of darifenacin, especially darifenacin hydrobromide and darifenacin hydrochloride. The process comprises of the following steps; a) Treating (S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile oxalate compound of formula-7 with a suitable base followed by extraction with a suitable solvent, provides the free base of compound-7, b) reaction of free base of compound-7 in-situ, with sulfuric acid to provide an amide derivative, which on treating with tartaric acid in a suitable solvent provides its tartrate salt, compound of formula-8, c) treating the tartrate salt of compound of formula-8 with a suitable base followed by extraction with a suitable solvent, provides the free base of compound-8, d) condensation of the free base of compound-8 in-situ, with 5-(2-bromoethyl)-2,3- dihydrobenzofuran of formula-9a in presence of base in a suitable solvent provides darifenacin, which on subsequent treatment with hydrochloric acid in a suitable solvent to provides the darifenacin hydrochloride compound of formula- Ib.

(Or) condensation of the free base of compound-8 in-situ, with 5-(2-bromoethyl)-2,3- dihydrobenzofuran of formula-9a in presence of base in a suitable solvent provides darifenacin, which on subsequent treatment with hydrobromic acid in a suitable solvent to provides the darifenacin hydrobromide compound of formula- Ia.

In the present embodiment the highly pure crystalline form of (S)-2,2-diphenyl-2-

(3-pyrrolidinyl)acetonitrile oxalate compound of formula-7 is used for the preparation of darifenacin and its pharmaceutically acceptable salts.

The free base of compound of formula-7 can be used directly without converting it into its oxalate salt. ^" But preparation of its oxalate salt has advantages as discussed below.

In step a) (S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile oxalate compound of formula-7 is treated with an aqueous alkali base which include 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 to provide the free base of the compound-7. The free base can be extracted with a suitable aprotic aromatic hydrocarbon solvent like benzene, toluene, xylene, and chlorobenzene etc.,. When the solvent used for the extraction was toluene it was found that the yield and purity of the free base was substantially improved, which is manifest in increased yields of the products formed in the subsequent reactions, which led to substantial increase in the overall yield of the final product. The processes disclosed in the prior art have not disclosed any data about the purity in this step. When the exemplified process of the basic patent US 5,096,890 (reference example A) was practiced in the laboratory and it was found to yield the product with a purity of less than 80 %, whereas the process adopted in the present invention yielded the product with a purity of about 99.5 % by HPLC.

In the subsequent step b) the free base of compound-7 was hydrolyzed to the amide derivative using sulfuric acid and then converted to its tartrate salt compound of formula-8. The preparation of tartrate salt affected in curtailing the impurities formed. In the step c) the tartrate salt of compound of formula-8 was converted to its free base by treating it with an aqueous base selected from a group which include 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 free base obtained was extracted in a suitable solvent which is selected from a group of aromatic hydrocarbon solvents consisting of benzene, toluene, xylene, and chlorobenzene etc.,. When the free base is preferably extracted with toluene, it was found to increase the purity and yield of the product substantially. When the exemplified process of the basic patent US 5,096,890 (reference example B) was practiced in the laboratory and it was found to yield the free base with a purity of less than 80 %, whereas the process adopted in the present invention yielded product with a purity of about 99.5

% by HPLC.

In the step d) the free base of compound of formula-8 is condensed with 5-(2- bromoethyl)-2,3-dihydrobenzofuran of formula-9a, in the presence of potassium hydroxide using acetonitrile as the solvent to provide darifenacin, which is taken in acetone and treated with hydrochloric acid to provide darifenacin hydrochloride salt, which is purified using methanol and acetone to provide the pure darifenacin hydrochloride salt, compound of formula- Ib.

When the free base of compound of formula-8 is condensed with 5-(2-bromoethyl)- 2,3-dihydrobenzofuran of formula-9a, in the presence of potassium hydroxide using acetonitrile as the solvent to provide darifenacin, which is taken in acetone and treated with hydrobromic acid to provide darifenacin hydrobromide salt, which is purified using methanol and acetone to provide highly pure, crystalline darifenacin hydrobromide salt, compound of formula- Ia. The present aspect is depicted in the scheme- 1. Scheme-1:

diphenyl acetonitrile

KOH,

DMF

The third aspect of the present invention is to provide a novel process for the preparation of darifenacin and its pharmaceutically acceptable salts especially hydrobromide salt compound of formula- Ia, which comprises of the following steps; a) Reacting the pyrrolidine compound of formula-5,

Formula-5 wherein L is a leaving group like p-toluene sulfonyloxy, chloro, bromo etc., with diphenyl ester compound of formula- 10,

Formula- 10

Where in R is H or C₁-C₄ alkyl, in presence of a strong base selected from sodium hydride, sodium tertiary butoxide, potassium tertiary butoxide, sodium methoxide, sodium hydroxide and/or alkali metal carbonates like potassium carbonate in a suitable solvent selected from toluene, xylene, cyclohexane, hexanes, acetonitrile and dimethyl sulfoxide to provide the condensed compound of formula- 11,

Formula- 11 b) detosylation of N-tosyl group the condensed compound of formula- 11 using hydrobromic acid in presence of a suitable bromine acceptor like phenol to provide the diphenyl pyrrolidine compound of formula- 12 which is optionally converted into its organic acid addition salts like tartaric acid and again converted back to compound of formula- 12 by treating with suitable base,

Formula- 12 c) reacting the diphenyl pyrrolidine compound of formula- 12 with dihydro benzofuran compound of formula-9a,

Formula-9a in presence of a suitable alkali and/or alkaline base like sodium carbonate, potassium carbonate and cesium carbonate preferably potassium carbonate in a suitable solvent selected from nitrile solvents like acetonitrile and/or non-polar solvents like toluene and/or chloro solvents like methylene chloride and/or polar solvent like water with or without presence of phase transfer catalyst selected from the group consisting tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide prefereably tetra butyl ammonium bromide to provide the compound of formula- 13,

Formula- 13 optionally converting the compound of formula- 13 into compound of formula- 14 by reacting with suitable alkali and/or alkaline base like sodium hydroxide, potassium hydroxide in a suitable alcoholic solvents like methanol, ethanol and isopropyl alcohol preferably methanol followed by reacting the compound of formula- 14 with suitable chlorinating agent like thionyl chloride and an amine like ammonia to give darifenacin or with benzyl amine or substituted benzyl amine to give corresponding benzylated darifenacin and converting the same into darifenacin compound of formula-2 by debenzylation,

Formula- 14 e) reacting the compound of formula- 13 with alcoholic ammonia or with benzyl amine or substituted benzyl amine in presence or absence of a suitable solvent under vapor pressure or atmospheric pressure in an autoclave to give darifenacin or corresponding benzylated darifenacin which on debenzylation gives darifenacin compound of formula-2 and recrystallising the darifenacin in a suitable solvents selected from ester solvents like ethyl acetate, methyl acetate, propyl acetate, and/or alcohol solvents like methanol, ethanol, isopropyl alcohol and mixtures thereof,

Formula-2 f) reacting the darifenacin compound of formula-2 with a suitable acid like hydrochloric acid, hydrobromic acid preferably hydrobromic acid in presence of ketone solvent like acetone, methyl ethyl ketone preferably acetone to provide the corresponding darifenacin hydrobromide compound of formula- Ia, g) purifying the darifenacin acid addition salt compound of formula- Ia in a suitable ketone solvents like acetone, methyl ethyl ketone, methyl isobutyl ketone and/or an alcohol solvents like methanol, ethanol, isopropyl alcohol or mixtures thereof, preferably acetone or a mixture of methanol and isopropyl alcohol.

The present aspect is depicted in the scheme-2. Scheme -2:

The fourth aspect of the present invention provides an improved process for the preparation of dihydrobenzofuran compound of formula-9, which comprises of the following steps; a) Reducing 2-chloro-l-(2,3-dihydrobenzofuran-5-yl)ethanone compound of formula- 18 using a mixture of trifluoroacetic acid and triethyl silane in a suitable solvent or by using a mixture of sodium borohydride in presence of sulphuric acid or trifluroacetic acid in a suitable solvent selected from methylene chloride, tetrahydrofuran to provide the 5-(2-chloroethyl)-2,3-dihydrobenzofuran compound of formula- 19, b) treating the 5-(2-chloroethyl)-2,3-dihydrobenzofuran compound of formula- 19 with sodium halide in a suitable solvent to provide corresponding 5-(2-haloethyl)- 2,3-dihydrobenzofuran compound of formula-9.

The compound formula-20 can be prepared by the ion exchange reaction using the same reagents and solvents used in the step b) of the fourth aspect of the present invention from the compound of formula- 18. The compound of formula-20 can be reduced using the same reagents and solvents as used in step a) of the fourth aspect of the present invention to get the compound of formula-9.

The reduction of carbonyl group of compounds of formula- 18 and formula-20 of the present invention can be performed by using borane (diborane) which is either generated in-situ by treating alkali borohydride like sodium borohydride, lithium borohydride, etc., with an suitable acid like sulfuric acid, trifluoro acetic acid etc. or by using a commercial sample. In the specific embodiment the reduction was carried out using a mixture of sodium borohydride in presence of sulphuric acid. The present aspect is depicted in the scheme-3 Scheme-3:

20 a) X = Br 9 a) X = Br 20 b) X = I 9 b) X = I Any one of the following compounds 22 to 24 may be used in place of dihydro benzofuran compound of formula-9 for the condensation reaction with the corresponding diphenyl pyrrolidne compound and the resultant compound can be converted in to darifenacin and its pharmaceutically acceptable salt by conventional methods.

wherein X is a halogen.

The sixth aspect of the present invention is to provide a process for the preparation of novel amorphous form of darifenacin hydrobromide compound of formula- 1 a, which comprises of the following steps, a) Dissolving darifenacin hydrobromide in a suitable polar protic organic solvent, b) heating the reaction mixture to reflux, c) spray drying the above obtained solution gives amorphous darifenacin hydrobromide compound of formula- 1, (Or) d) distilling off the solvent from the solution obtained in step b), to dryness, e) isolating the amorphous darifenacin hydrobromide by adding a non-polar solvent followed by filtration.

Preferably the organic solvent is a solvent which is selected from the group of C_1-5 alcohol consisting of methanol, ethanol, propanol, butanol and/or tetrahydrofuran or their mixture thereof, more preferably methanol or tetrahydrofuran. Preferably the non polar hydrocarbon solvent is a solvent selected from the group of C_6-7 aliphatic hydrocarbons consisting of n-hexane, cyclohexane, n-heptane and their mixture thereof and more preferably n-heptane. The seventh aspect of the present invention provides novel crystalline form-M of darifenacin hydrochloride compound of formula- Ib, characterized by its strong X-ray peaks at about 8.1, 9.0, 11.5, 18.2, 20.3, 22.1, 24.6 ± 0.2 degrees two theta as illustrated in figure-6.

The eighth aspect of the present invention provides a novel process for the preparation of novel crystalline polymorph form-M of darifenacin hydrochloride, which comprises of a) Dissolving the darifenacin compound of formula-2, in a suitable solvent, b) adding hydrochloric acid to the above mixture at 0- 10⁰C, c) increasing the temperature of the mixture and stirring it for certain time and cooling it to 0-10⁰C, d) filtering and drying the solid obtained to provide pure crystalline form — M of darifenacin hydrochloride.

The darifenacin compound of formula-2 used in step a) can be prepared by conventional methods or by any of the methods illustrated in the present invention. The suitable solvent used in step a) is acetone. In the step c) the reaction mixture is heated to 25-30⁰C and stirred for 10 to 15 hours, preferably for 11 to 12 hours then preferably cooled to 0-5⁰C to precipitate the solid darifenacin hydrochloride salt

The ninth aspect of the present invention is to provide a process for the purification of darifenacin hydrobromide compound of formula- Ia. The pure crystalline hydrobromide compound of formula- Ia is characterized by its PXRD pattern, IR spectrum and DSC thermo gram substantially as illustrated in figure-3, figure-4 and figure-5 respectively. The purification process for darifenacin hydrobromide comprises of the following steps; a) Dissolving darifenacin hydrobromide in polar protic solvent, b) heating the solution to reflux, c) treating the solution with activated carbon, d) distilling off the solvent under reduced pressure, e) adding suitable ketone and/or alcohol solvent to the residue and refluxing for a while, f) cooling the reaction mixture to low temperature to obtain crystalline solid, g) stirring the reaction mixture at low temperature, h) separating the crystalline solid by filtration. i) drying the solid gives the pure crystalline form of darifenacin hydrobromide compound of formula- Ia.

Preferably the polar protic organic solvent is a solvent selected from the group of C_1-5 alcohol consisting of methanol, ethanol, propanol, 2-propanol, butanol or their mixture thereof and more preferably methanol. Preferably the ketone solvent is a solvent selected from the group C_3-6 ketones consisting of acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, 2-butanone or their mixture thereof, and preferably acetone.

Darifenacin is marketed and used as its hydrobromide salt, to increase the storage time and shelf life special care and packing methods were adopted. The darifenacin hydrobromide compound of formula- Ia is packed in a white low density polythene bag and sealed, placing this primary packing into a secondary packing of low density black polythene bag with or without silica gel bags and sealed, placing the secondary packing into a triple aluminated bag with or without silica bags and sealed, enclosing this in a closed HDPE container.

The impurities which were observed in the process for the preparation of darifenacin and its pharmaceutically acceptable salts are illustrated below;

Nitrile impurity (NI) Dimer impurity -1 (DI-I) Dimer impurity -2 (DI-2) The purity of darifenacin intermediates as well as the related substances of darifenacin hydrobromide were analyzed by HPLC using the following conditions: Buffer : 0.01 M NH₄OAc +1.0 ml TEA Ph~3.0

Solvent : Acetonitrile, MeOH (50:50)

Run time : 45 min

Column : hypersil BDS C-18 250* 4.6 mm 5μm

Column temperature : 30°C Flow rate : 1.0 ml/min UV : 220nm

Injection volume: lOμl Cone : 0.5mg/ml in mobile phase

XRD analysis of pharmaceutically acceptable salts of darifenacin were carried out using SIEMENS/D-5000 X-Ray Diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min.

FI-IR spectrum of pharmaceutically acceptable salt of darifenacin were recorded on Thermo model Nicolet-380 as KBr pellet.

The thermal analysis of pharmaceutically acceptable salts of darifenacin were carried out on Waters DSC Q-IO model differential scanning calorimeter. 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 A:

Preparation of 3-(S)-(+)-(l-cyano-l,l-diphenyImethyl)pyrrolidine

A mixture containing 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l-tosylpyrrolidine (49 grams), 48% aqueous hydrobromic acid (500 ml) and phenol (50 grams) was heated under reflux for 1.25 hours then allowed to cool to room temperature. The mixture was extracted with ether (50 ml) to remove an upper layer of purple oil, then with 2:1 ether/hexane (150 ml). The aqueous layer was extracted with dichloromethane (4x100 ml), the dichloromethane extracts were combined, washed with 10% aqueous sodium hydroxide (3x50 ml), then dried (MgSO₄) and concentrated under reduced pressure to give an oil. The original ether extract was concentrated under reduced pressure to give oil which was dissolved in dichloromethane (100 ml) and washed with 10% aqueous sodium hydroxide (3x50 ml). The dichloromethane solution was dried (MgSO₄) and concentrated under reduced pressure to give oil which was combined with that obtained from the initial dichloromethane extraction. The combined oils were then dissolved in dichloromethane (200 ml) and washed with 10% aqueous sodium hydroxide solution (2x 50 ml). The dichloromethane solution was dried (MgSO₄) and concentrated reduced pressure to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product containing fractions were combined and concentrated reduced pressure to give the title compound as foam, Yield: 24.3 grams, [α]_D ²⁵ +6.0°(c 1.0, CH₂Cl₂)

Reference Example B:

Preparation of3-(S)-(-)-(l-carbamoyl-l,l-diphenylmethyl)pyrroIidine.

3-(S)-(+)-(l-Carbamoyl-l,l-diphenylmethyl)pyrrolidine-L-(+)-tartrate(0.95 grams) was dissolved in water (40 ml) and basified (pH 12) by drop wise addition of 10% aqueous sodium hydroxide. The mixture was extracted with dichloromethane (2x 50 ml), the extracts were combined, dried (Na₂SO₄), and concentrated under reduced pressure to give the title compound as a colorless foam, Yield 0.64 grams

Example 1:

Preparation of 3(+)-chloro~pyrroIidine hydrochloride:

Thionyl chloride (5 ml) was added to the solution of 3-(R)-hydroxy pyrrolidine hydrochloride (5.0 grams) in toluene at 25-30°C. The mixture was heated to 50-55⁰C and stirred for 5 hrs. The reaction mixture was cooled to 25-30°C and stirred for 12 hrs. The solid obtained was filtered, washed with 5 ml of toluene and dried under nitrogen atmosphere for 60 min at 60-65⁰C, to obtain the title compound as a white solid. Yield: 5.2 gm MR: 82-86°C; SOR (Specific Optical Rotation) = +8.1 (C=I, dichloromethane)

Example 2:

Preparation of 3-(+)-chIoro-l-(toIuene-4-sulfonyI)-pyrroIidine:

To a mixture of 3-(+)-chloro-pyrrolidine hydrochloride (5 grams), dichloromethane (50 ml) and triethylamine (7.2 grams) at 0-5⁰C, para toluene sulfonyl chloride (7.0 grams) was added with constant stirring. The mixture was stirred at 25-30⁰C for 24 hours. The reaction was quenched with water and the organic and the aqueous layers were separated. The solvent from the organic layer was distilled off under reduced pressure to obtain a solid. The crude solid was recrystallized from isopropyl alcohol to obtain the title compound as a white solid. Yield: 5.10 grams; MR: 81-84⁰C;

SOR: +21°(C=1, dichloromethane)

Example 3:

Preparation of 3-(S)-(+)-2,2-diphenyl-2-(l-tosyl -pyrrolidin-3-yI) acetonitrile: To a solution of diphenyl acetonitrile (3.0 grams) in dimethyl formamide (25 ml), potassium hydroxide (3.0 grams) was added and stirred for 2 hrs. 3-(S)-(+)-chloro-l- (toluene-4-sulfonyl)-pyrrolidine (5.0 grams) was added to the reaction mixture with constant stirring. The reaction mixture was heated to 95-100°C and stirred for 5 hrs. The temperature was reduced to 20-30⁰C, then quenched with water (250 ml) and stirred for 1 hour. The solid obtained was filtered and crystallized form methanol to obtain the title compound as a solid. Yield: 3.5 grams MR 185-188°C; SOR= +17° (C=I, dichloromethane)

Example 4: Preparation of 3(S)-(+)-2,2-diphenyl-2-(pyrrolidin-3-yl) acetonitrile oxalate:

A mixture of 3(S)-(+)-2,2-diphenyl-(l-tosyl pyrrolidin-3-yl] acetonitrile (100 grams), 48% aqueous hydrobromic acid (400 ml) and phenol (20 grams) was heated to reflux for 4 hrs. The reaction mixture was cooled to 20-30°C, dichloromethane (200 ml) was added to it and stirred for 10 min. Separated the organic and aqueous layers. The aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with 10% sodium bicarbonate solution. The solvent was distilled off under reduced pressure. Toluene (300 ml) was added to the reaction mixture and stirred for 15 min at 25-30°C. A solution of oxalic acid in isopropanol (100 ml) was added to the reaction mixture at 25-3O⁰C. The reaction mixture was cooled to 0-5⁰C and stirred for 1 hr. The solid obtained was filtered and dried. The dry solid was dissolved in isopropanol (300 ml) and heated to reflux for 45 min. The reaction mixture was cooled to 0-5⁰C and stirred for 45 min. The solid obtained was filtered and washed with isopropanol and dried to give the title compound. Yield: 72 grams. (Purity by HPLC is 99.8 %) M R: 180-185⁰C.

Example 5:

Preparation of 3(S)-(+)-2,2-diphenyl-2-(pyrrolidin-3-yl) acetonitrile:

A mixture of 3(S)-(+)-2,2-diphenyl-(l-tosyl pyrrolidin-3-yl] acetonitrile (100 grams), 48% aqueous hydrobromic acid (400 ml) and phenol (20 grams) was heated to reflux for 4 hrs. The reaction mixture was cooled to 20-30⁰C, dichloromethane

(200 ml) was added to it and stirred for 10 min. Separated the organic and aqueous layers. The aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with 10% sodium bicarbonate solution. The solvent was distilled off under reduced pressure. Toluene (300 ml) was added to the reaction mixture and stirred for 15 min at 25-3O⁰C. A solution of oxalic acid in isopropanol (100 ml) was added to the reaction mixture at 25-3O⁰C. The reaction mixture was cooled to 0-5°C and stirred for 1 hr. The solid obtained was filtered and dried. The dry solid was dissolved in isopropanol (300 ml) and heated to reflux for 45 min. The reaction mixture was cooled to 0-5°C and stirred for 45 min. The solid obtained was filtered and washed with isopropanol and dried to give a solid. Solid was taken in water (IL), 30% sodium hydroxide solution was added to adjust the pH to 12. The reaction mixture was stirred for 15 min and extracted with toluene (800 ml) at 55-60°C. The organic layer was separated, washed with water and distilled off under reduced pressure to obtain the free base. Yield: 55 grams. (Purity by HPLC 99.8%).

Example 6:

Preparation of 3-(S)-(+)-(l-carbamoyl -1,1-diphenyl methyl) pyrrolidine tartrate:

To a mixture of 3(S)-(+)-2,2-diphenyl-2-(pyrrolidin-3-yl) acetonitrile oxalate (100 grams) in water (IL), 30% sodium hydroxide solution was added to adjust the pH to 12. The reaction mixture was heated to 50-60⁰C, stirred for 15 min and extracted with toluene (800 ml). The organic layer was separated, washed with water and distilled off under reduced pressure to obtain the free base. To the free base, 95% sulfuric acid (197 ml) was added and the reaction mixture was heated to 95-100°C for 10 hrs. The reaction mixture was cooled to 25-30°C and neutralized with 30% sodium hydroxide solution. The reaction mixture was extracted with toluene. The toluene layer (850 ml) washed with water and L-(+)tartaric acid (44 grams) was added to it, stirred the reaction mixture for 45 min at 55-60⁰C, cooled it to 25-3O⁰C and further stirred for 12 hrs. Filtered the solid formed and washed with toluene and dried. Yield: 100 grams. Example 7:

Purification of 3-(S)~(+)-(l-carbamoyl -1,1-diphenyl methyl) pyrrolidine tartrate:

The 3 -(S)-(+)-(l -carbamoyl- 1,1-diphenyl methyl) pyrrolidine tartrate (110 grams) was taken in a solution of dimethyl formamide (225 ml) and isopropyl alcohol (225 ml) and heated to 80-85⁰C for 60 min. The mixture was cooled to 25-3O⁰C and stirred for 2 hrs. The solid formed was filtered and washed with isopropyl alcohol. The solid was dried to get the title compound. Yield: 100 grams. M R: 180-185⁰C; SOR: +16.5° (C=I, water)

Example 8:

Preparation of 3-(S)-(+)-(l -carbamoyl -1,1-diphenyl methyl) pyrrolidine:

To 3 -(S)-(+)-(l -carbamoyl- 1,1-diphenyl methyl) pyrrolidine tartrate (10 grams) taken in water (50 ml), a solution of aqueous sodium hydroxide was added till the pH reached 12. The reaction mixture was stirred for 20 min at 50-60⁰C, sodium chloride (15 grams) was added to it and stirred further for 20 min. The reaction mixture was extracted with toluene. The toluene layer was washed with 5% sodium chloride solution and the solvent distilled off under reduced pressure to provide the title compound. Yield: 5.6 grams (Purity by HPLC is 99.8 %)

Example 9:

Preparation of darifenacin hydrochloride:

To 3-(S)-(+)-(l-carbamoyl-l,l-diphenyl methyl) pyrrolidine tartrate (100 grams) taken in water (500 ml), a solution of aqueous sodium hydroxide was added till the pH reached 14. The reaction mixture was stirred for 20 min at 25-30⁰C, sodium chloride

(150 grams) was added to it and stirred further for 20min. The reaction mixture was heated to 55-60⁰C and extracted with toluene. The toluene layer was washed with 5% sodium chloride solution and the solvent distilled off under reduced pressure. The residue was dissolved in acetonitrile, 5-(2-bromoethyl) 2,3-dihydrobenzofuran (66 grams dissolved in 800 ml acetonitrile) and potassium hydroxide (13 grams) was added to it.

The reaction mixture was heated to 40-50⁰C and stirred for 18 hrs. The reaction mixture was cooled to 25-30°C and filtered. The acetonitrile solvent was distilled off under reduced pressure. The residue was dissolved in acetone, cooled to 0-5 °C and hydrochloric acid (36 ml) was added to it. The temperature was raised to 25-30°C and stirred for 12 hrs. The reaction mixture was cooled to 0-5° C, the solid obtained was filtered, washed with acetone and dried. It was purified using methanol and acetone to provide the title compound as a white solid. Yield: 75 grams

Example 10: Purification of darifenacin hydrochloride:

Dissolved 30 grams of darifenacin hydrochloride in 400 ml of methanol and heated the solution to reflux. Stirred the reaction mixture for 10 minutes at reflux temperature. Activated carbon 2 grams was added to the reaction mixture and stirred for 30 minutes at reflux temperature. Filtered the solution through hyflow and washed with hot methanol. Distilled off the filtrate under reduced pressure at below 60⁰C. 20 ml of acetone was added to the reaction mixture and distilled off under reduced pressure at below 60°C. Added 200 ml of acetone to the above reaction mixture. Heated the reaction mixture to reflux and stirred for 30 min. Cooled the reaction mixture to 25-30°C and stirred for 30 minutes at 25-30°C. Further cooled the reaction mixture to 0-5⁰C and stirred for 1 hour. Filtered the precipitated solid and washed with chilled acetone. Dried the solid to get pure darifenacin hydrochloride. Yield: 22 grams; (Purity by HPLC 99.7%). SOR= + 42.5 (C=I ; methylene chloride) M.R = 238-240°C

Example 11:

Preparation of darifenacin hydrobromide:

To 3 -(S)-(+)-(l -carbamoyl -1,1 diphenyl methyl) pyrrolidine tartrate (100 grams) taken in water (500 ml), a solution of aqueous sodium hydroxide was added till the pH reached 14. The reaction mixture was stirred for 20 min at 25-30°C and sodium chloride

(150 grams) was added to it and stirred for 20min. The reaction mixture was heated to

55-6O⁰C and extracted with toluene. The toluene layer was washed with 5% sodium chloride solution and the solvent distilled off under reduced pressure. The residue was dissolved in acetonitrile, 5-(2-bromoethyl)-2,3-dihydrobenzofuran (66 grams dissolved in 800 ml acetonitrile) and potassium hydroxide (13 grams) was added to it. The reaction mixture was heated to 40-50°C and stirred for 18 hrs. The reaction mixture was cooled to 25-30°C and filtered. The acetonitrile solvent was distilled off under reduced pressure. The residue was dissolved in acetone, cooled to 0-5°C and hydrobromic acid (36 ml) was added to it. The temperature was raised to 25-30°C and stirred for 12 hrs. The reaction mixture was cooled to 0-5° C, the solid obtained was filtered, washed with acetone and dried. It was purified using methanol and acetone to provide the title compound as a white solid.

Yield: 75 grams

SOR: +45 (C=I, dichloromethane)

Example 12: Purification of darifenacin hydrobromide:

Dissolved 38 grams of darifenacin hydrobromide in 400 ml of methanol and heated the solution to reflux. Stirred the reaction mixture for 10 minutes at reflux temperature. Activated carbon 2 grams was added to the reaction mixture and stirred for 30 minutes at reflux temperature. Filtered the solution through hyflow and washed with hot methanol. Distilled off the filtrate under reduced pressure at below 60°C. 20 ml of acetone was added to the reaction mixture and distilled off under reduced pressure at below 6O⁰C. Added 200 ml of acetone to the above reaction mixture. Heated the reaction mixture to reflux and stirred for 30 min. Cooled the reaction mixture to 25-3O⁰C and stirred for 30 minutes at 25-30⁰C. Further cooled the reaction mixture to 0-5⁰C and stirred for 1 hour. Filtered the precipitated solid and washed with chilled acetone. Dried the solid to get pure darifenacin hydrobromide. Yield: 27 grams; (Purity by HPLC 99.8 %).

Example 13: Preparation of 3-(S) - methyl- 2,2- diphenyl-2 -( 1-tosyl pyrrolidin -3- yl) acetate:

2,2-diphenyl acetic acid methyl ester (22.6 grams) was added to a stirred suspension of sodium hydride (4 grams of a 60% suspension in oil) in anhydrous toluene (250 ml). The mixture was heated to 55-60⁰C and stirred for 1 hour. The reaction mixture was cooled to 25-30⁰C and 3-(S)-I -tosyl-3-tosyloxypyrrolidine (39.5 grams) was added to the above mixture in portions and the mixture was heated to reflux temperature. The reaction mixture was stirred for 3 hours at reflux temperature. The reaction mixture was cooled to 25-30°C and quenched with methanol. The organic layer was washed with 5% aqueous sodium hydroxide then dried with sodium sulphate. Distilled off the toluene under reduced pressure to get solid. The obtained solid was purified by using ethyl acetate to give title compound as crystalline solid.

Yield: 25 grams; M.R: 183-186°C

Example 14:

Preparation of 3-(S)-2,2-diphenyl-2-pyrrolidin-3yl-acetic acid methyl ester :

A mixture of 3-(S)-methyl 2,2-diphenyl-2-(l-tosyl pyrrolidin-3-yl) acetate (45 grams) , 45% hydrobromic acid in acetic acid (200 ml) and phenol (45 grams) was heated to 50-55° C and stirred for 2 hours. Distilled off the acetic acid under reduced pressure at a temperature below 50°C. The obtained crude was diluted with 500 ml of methylene chloride and washed with 10% aqueous sodium hydroxide solution. The methylene chloride layer was dried over sodium sulphate and the solvent was distilled off to get the title compound as an oily residue. Yield: 22 grams

Example 15:

Preparation of (S)-2,2-diphenyl-2-{l-[2-(2,3-dihydrobenzofuran-5yl)-ethyl]- pyrrolidin-3yl} acetic acid methyl ester: A mixture of 3-(S)-2,2-diphenyl-2-pyrrolidinyl-3yl-acetic acid methyl ester

(29.5 grams), 5-(2-bromoethyl)2,3-dihydrobenzo[2,3-b]furan (22.7 grams), anhydrous potassium carbonate (27.6 grams) and acetonitrile (300 ml) was heated to reflux and stirred for 60 min. The mixture was partitioned between methylene chloride (250 ml) and 10% aqueous potassium carbonate (250 ml). The two layers were separated and the aqueous layer was extracted with methylene chloride. The organic layer was dried with sodium sulphate and distilled off the organic layer under reduced pressure followed by triturating with ethyl acetate to get the title compound. Yield: 30.5 grams Example 16:

Preparation of (S)-2,2-diphenyl-2~{l-[2-(2,3-dihydrobenzofuran-5yl)-ethyl]- pyrrolidin-3yl} acetic acid methyl ester :

A mixture of 3-(S)-2,2-diphenyl-2-pyrrolidin-3yl-acetic acid methyl ester (25 grams), 2.5 grams of tetra butyl ammonium bromide, 32.5 grams of potassium carbonate and 125 ml of water was heated to 80°C. A solution of 5-(2-bromoethyi)-2,3- dihydrobenzo[2,3-b]furan (13 grams in 125 ml of toluene) was added to the above mixture for 2 hours at 80°C. Stirred the reaction mixture for 11 hours at reflux temperature. The reaction mixture was cooled to 25-30°C and separated the organic and aqueous layer. Extracted aqueous layer twice with methylene chloride. Distilled off the organic layer completely under reduced pressure followed by triturating with ethyl acetate to get the title compound.

Yield: 28 grams

Example 17:

Preparation of darifenacin:

A mixture of (S)-2,2-diphenyl-2-{l-[2-(2,3-dihydro-benzofuran-5yl)-ethyl]- pyrrolidin-3yl} acetic acid methyl ester (25 grams) and methanolic ammonia (125 ml) was stirred for 5 hours at 45°C in an autoclave. Distilled off methanol from the reaction mixture. The obtained residue was extracted with methylene chloride followed by washing with water. The layers were separated. Distilled off the solvent from methylene chloride layer under reduced pressure to get the residue and recrystallised the same using ethyl acetate to get darifenacin as a solid. Yield: 15 grams

Example 18:

Preparation of darifenacin:

A mixture of (S)-2,2-diphenyl-2-{l-[2-(2,3-dihydro-benzofuran-5yl)-ethyl]- pyrrolidin-3yl} acetic acid methyl ester (25 grams) and methanolic ammonia (125 ml) was stirred for 7 hours at 28°C. Distilled off methanol from the reaction mixture. The obtained residue was extracted with methylene chloride followed by washing with water.

Separated the layers. Distilled off the solvent from methylene chloride layer under reduced pressure to get the residue and recrystallised the same using ethyl acetate to get darifenacin as a solid. Yield: 14 grams

Example 19:

Preparation of darifenacin hydrobromide:

A mixture of 28 grams of darifenacin and 125 ml of acetone was cooled to 0-5°C and hydrobromic acid (9 ml) was added to the above reaction mixture at 0-5 °C. Raised the temperature to 25-30°C and stirred the reaction mixture for 15 minutes at 25-30°C. Cooled the reaction mixture to 0-5⁰C and stirred for 2 hours. The precipitated solid was filtered and washed with chilled acetone. The solid was purified using acetone and methanol to get the pure darifinacin hydrobromide.

Yield: 19 grams

Purity by HPLC : 98.73%; 0.02% (RRT : 0.30); 0.42% (RRT : 0.47); 0.04% (RRT : 0.87); 0.10% (RRT : 0.89); 0.05% (RRT : 1.11); 0.10% (RRT : 1.13); 0.17% (RRT :

1.16); 0.06% (RRT : 1.26); 0.15%(RRT : 1.30); 0.04% (RRT : 1.34); 0.14% (RRT :

1.38).

Example 20: Purification of darifenacin hydrobromide:

Dissolved 38 grams of darifenacin hydrobromide in 400 ml of methanol and heated the solution to reflux. Stirred the reaction mixture for 10 minutes at reflux temperature. Activated carbon 2 grams was added to the reaction mixture and stirred for 30 minutes at reflux temperature. Filtered the solution through hyflow and washed with hot methanol. Distilled off the filtrate under reduced pressure at below 6O⁰C. 20 ml of acetone was added to the reaction mixture and distilled off under reduced pressure at below 60⁰C. Added 200 ml of acetone to the above reaction mixture. Heated the reaction mixture to reflux and stirred for 30 min. Cooled the reaction mixture to 25-3O⁰C and stirred for 30 minutes at 25-30⁰C. Further cooled the reaction mixture to 0-5⁰C and stirred for 1 hour. Filtered the precipitated solid and washed with chilled acetone. Dried the solid to get pure darifenacin hydrobromide. Thus obtained pure darifenacin hydrobromide in a crystalline form matched with PXRD, IR and DSC disclosed in figure- 3, figure-4 and figure-5 respectively. Yield: 27 grams.

Purity by HPLC 99.88%; 0.03% (RRT: 0.29); 0.07% (RRT: 0.30); 0.02% (RRT: 1.11). Particle size: D(0.1) is 3.377 μm, D(0.5) is 9.823 μm, D(0.9) is 28.069 μm, D(l.O) is 128.1 μm and mean D[4,3] is 13.894 μm. SOR: + 46.5 (1.0 % in methylene chloride)

Example 21: Purification of darifenacin hydrobromide:

Darifenacin hydrobromide (10 grams) was dissolved in 40 ml of methanol. It was treated with charcoal at reflux temperature. The solution was cooled to 50°C and filtered through celite. Isopropyl alcohol 40 ml was added to the filtrate at 45°C. The reaction mixture was cooled to 25-3O⁰C and stirred for 60 min. The reaction mixture was further cooled to 0-5°C and stirred for 2 hours. Filtered the precipitated solid and washed with a mixture of methanol and isopropyl alcohol. Thus obtained pure darifenacin hydrobromide in a crystalline form matched with PXRD, IR and DSC disclosed in figure-3, figure-4 and figure-5 respectively. Yield: 6 grams.

Example 22:

Preparation of 5-(2-chloro-ethyl)-2,3-dihydrobenzofuran:

Triethylsilane (112 grams) was added to a mixture of 2-chloro-l-(2,3- dihydrobenzofuran-5-yl)ethanone ( 100 grams) and trifluoroacetic acid (396.5 grams) at below 45°C. The reaction mixture was stirred for 7 hours at 40-45°C. The reaction mixture was cooled to -5 to 0°C and stirred for 2 hours. The solid obtained was filtered off and washed with water. Water (500 ml) was added to the wet solid obtained and stirred for 2 hours. Filtered the solid, washed it with water and dried it at 60-80°C. Dissolved the solid in dichloromethane (300 ml) and washed the organic layer with 10% sodium carbonate solution. The solvent was distilled off completely to provide the title compound as a solid. Yield: 70 grams M.R: 60-65°C Example 23:

Preparation of 5-(2-bromoethyl)-2,3-dihydrobenzofuran :

5-(2-chloroethyl)-2,3-dihydrobenzofuran (5 grams) was added to a stirred solution of sodium bromide (5.6 grams) in acetone (50 ml). The resulting suspension was heated to reflux and stirred the reaction mixture at reflux for 48 hours. The reaction mixture was filtered through hyflow and the filtrate was distilled off under reduced pressure to provide the title compound. Yield: 5 grams.

Example 24:

Preparation of 5-(2-chIoro-ethyl)-2,3-dihydrobenzofuran:

A mixture of 2-chloro-l-(2,3-dihydrobenzofuran-5-yl)ethanone (10 grams) and tetrahydrofuran (50 ml) was cooled to -5 to 0°C. Sodium borohydride (5 grams) was added to the above mixture portion wise at -5 to 0⁰C. Sulphuric acid (150 ml) was added slowly to the reaction mixture in 10 hours at -5 to 0⁰C followed by stirring for 10 hours at -5 to O⁰C. The reaction mixture was quenched with water and decanted the water. Semi solid substance was taken into water and neutralized with sodium carbonate. Filtered off the solid and dried. Suspended the dried solid in acetone (50 ml) and heated to reflux. Cooled the reaction mixture to 25-35°C. Filtered off the solid and washed with acetone and dried to get the title compound. Yield: 7 grams

Example-25:

Preparation of amorphous darifenacin hydrobromide: Darifenacin hydrobromide 5 gm was dissolved in 50 ml of methanol and heated to get a clear solution. The clear solution was then spray dried at below 50⁰C until a white amorphous powder of darifenacin was obtained. Yield: 4 grams Example 26:

Preparation of amorphous darifenacin hydrobromide:

Darifenacin hydrobromide 10 gram was dissolved in 100 ml of methanol and heated to reflux to get a clear solution. Refluxed the reaction mixture for 30 min and distilled off the methanol completely to dryness under vacuum to get the solid. Added 50 ml of n-heptane and cooled to 3O⁰C. Filtered the solid and dried. Yield: 8.2 grams. Purity by HPLC: 99.89%; 0.07 %( RRT 0.30)

Example 27:

Purification of darifenacin hydrobromide:

Darifenacin hydrobromide (50 grams) was suspended in a mixture of dimethyl formamide (75 ml) and ethyl acetate (175 ml). The reaction mixture was heated to reflux and stirred for 40 min. The reaction mixture was slowly cooled to 25-30° C and stirred for 2 hrs. The solid was filtered, washed with of dimethyl formamide and ethyl acetate and dried, to get pure darifenacin hydrobromide. . Yield: 45 grams

Example 28: Preparation of crystalline form-M of darifenacin hydrochloride

Darifenacin (10 grams) was dissolved in acetone, cooled to 0-5 °C and hydrochloric acid (36 ml) was added to it. The temperature was raised to 25-3O⁰C and stirred for 12 hrs. The reaction mixture was cooled to 0-5° C, the solid obtained was filtered, washed with acetone and dried to get the title compound as a white solid. Yield: 7.9 grams.

Claims

We Claim:

1. A process for the preparation of 3-chloropyrrolidine compound of formula-4, comprises of reacting the (R)-3-hydroxypyrrolidine hydrochloride compound of formula-3,

Formula-3 with a chlorinating agent in a suitable solvent provides 3-chloropyrrolidine compound of formula -4.

Formula-4

2. The process according to claim 1, wherein the chlorinating agent is thionylchloride.

3. The process according of claim 1, wherein the suitable solvent is selected from toluene and methylene chloride.

4. A process for the preparation of condensed compound of formula-6

Formula-6 Which comprise of the following steps, a) Tosylating the 3-chloropyrrolidine compound of formula-4,

Formula-4 in presence of organic base in a suitable solvent provides N-tosylated chloro pyrrolidine compound of formula-5a, b) reacting the N-tosylated-3-chloropyrrolidine compound of formula~5a,

Formula-5a with diphenyl acetonitrile in the presence of a suitable base in a polar aprotic solvent provides a condensed compound of formula-6.

5. The process according to step a) claim 4, wherein the organic base is selected from triethyl amine, diisopropylethylamine, pyridine, piperidine and a suitable solvent is selected from methylene chloride, chloroform, toluene and xylene or mixtures thereof.

6. The process according to step b) of claim A, wherein the suitable base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate and solvent selected from dimethylacetamide, dimethylformamide, ethylacetate, tetrahydrofuran or mixtures thereof.

7. A process for the preparation of novel oxalate salt of (S)-2,2-diphenyl-2-(3- pyrrolidinyl)acetonitrile compound of formula-7, which comprises of the following steps; a) Reacting (R)-3 -hydroxypyrrolidine hydrochloride compound of formula-3 ,

Formula-3 with thionyl chloride in toluene provides the 3-chloropyrrolidine compound of formula-4, b) tosylating the 3-chloropyrrolidine compound of formula-4,

Formula-4 in the presence of base like triethyl amine in dichloromethane provides the N-tosylated chloropyrrolidine compound of formula-5a, c) reacting the N-tosylated-3 -chloropyrrolidine compound of formula-5a,

Formula-5a with diphenyl actonitrile in the presence of potassium hydroxide in dimethyl formamide provides a condensed compound of formula-6,

Formula-6 d) deprotection of the N-tosyl group of compound of formula-6, with aqueous hydrobromic acid and phenol, followed by dissolution in toluene and subsequent treatment with oxalic acid taken in isopropanol, provides (S)-2,2-diphenyl-2-(3- pyrrolidinyl) acetonitrile oxalate compound of formula-7.

Formula-7

8. Oxalate salt of (S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile having the following structural formula.

9. Use of (S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile oxalate in the preparation of darifenacin and its pharmaceutically acceptable salts.

10. A compound of general formula-5

Formula-5

Wherein L is a leaving group such as chloro, bromo.

11. Use of compound of general formula-5 in the preparation of darifenacin and its pharmaceutically acceptable salts thereof.

12. A chloro tosyl pyrrolidine compound having the following structural formula.

13. A process for the preparation of crystalline darifenacin hydrobromide with high purity which comprises of the following steps; a) Treating (S)-2,2-diphenyl-2-(3-pyrrolidinyl) acetonitrile oxalate compound of formula-7 with suitable base followed by extraction with suitable solvent, provides the free base of compound-7, b) the free base of compound-7 on in-situ reacting with sulfuric acid to provide an amide derivative, which on treating with tartaric acid in a suitable solvent provides its tartrate salt compound of formula- 8, c) treating the tartrate salt of compound of formula-8 with a suitable base followed by extracting the free base compound of formula-8 in a suitable solvent, d) condensing the free base of compound-8 in-situ, with 5-(2-bromoethyl)-2,3- dihydrobenzofuran of formula-9a in presence potassium hydroxide, in acetonitrile provides darifenacin, which on subsequent treatment with hydrobromic acid in acetone provides darifenacin hydrobromide compound of formula- Ia.

14. A process for the preparation of crystalline darifenacin hydrochloride which comprises of the following steps; a) Treating (S)-2,2-diphenyl-2-(3-pyrrolidinyl) acetonitrile oxalate compound of formula-7 with suitable base followed by extraction with suitable solvent, provides the free base of compound-7, b) the free base of compound-7 on in-situ reacting with sulfuric acid to provide an amide derivative, which on treating with tartaric acid in a suitable solvent provides its tartrate salt compound of formula-8, c) treating the tartrate salt of compound of formula-8 with a suitable base followed by extracting the free base compound of formula-8 in a suitable solvent, d) condensing the free base of compound-8 in-situ, with 5-(2-bromoethyl)-2,3- dihydrobenzofuran of formula-9a in presence potassium hydroxide, in acetonitrile provides darifenacin, which on subsequent treatment with hydrochloric acid in acetone provides darifenacin hydrochloride compound of formula- Ib.

15. The process according to step a) and step c) of claim 13 & 14, wherein the solvent used for extraction is toluene.

16. The process according to step a) and step c) of claim 13 & 14, wherein the extraction is carried out at a temperature ranges from 20-100°C.

17. A process for the conversion of oxalate salt of (S)-2,2-diphenyl-2-(3- pyrrolidinyl)acetonitrile into its high pure free base comprising of treating it with a base, followed by extracting product formed using toluene to get the highly pure (S)- 2,2-diphenyl-2-(3 -pyrrolidinyl)acetonitrile.

18. A process for the conversion of tartrate salt of 3 -(S)-(+)-(l -carbamoyl -1,1-diphenyl methyl)pyrrolidine into its high pure free base comprising of treating it with a base followed by extracting product formed using toluene to get the highly pure 3-(S)-(+)- (1-carbamoyl -1,1-diphenyl methyl) pyrrolidine.

19. Use of toluene for the extraction of free base of (S)-2,2-diphenyl-2-(3- pyrrolidinyl)acetonitrile oxalate and 3-(S)-(+)-(l-carbamoyl-l,l-diphenyl methyl) pyrrolidine tartrate in the presence of base to get the highly pure free bases, (S)-2,2- diphenyl-2-(3-pyrrolidinyl)acetonitrile and 3-(S)-(+)-(l-carbamoyl -1,1-diphenyl methyl) pyrrolidine.

20. A process for the purification of 3 -(S)-(+)-(l -carbamoyl- 1,1-diphenyl methyl) pyrrolidine tartrate by recrystallzing it from a mixture of dimethylformarnide and isopropyl alcohol.

21. A process for the preparation of condensed compound of formula- 11,

Formula- 11

Which comprises of reacting the pyrrolidine compound of formula-5,

Formula- 10 Where in R is H or Ci-C₄ alkyl, in presence of a strong base selected from sodium hydride, sodium tertiary butoxide, potassium tertiary butoxide, sodium methoxide, sodium hydroxide and/or alkali metal carbonates like potassium carbonate in a suitable solvent selected from toluene, xylene, cyclohexane, hexanes, acetonitrile and dimethyl sulfoxide to obtain the condensed compound of formula- 11.

22. A process for the preparation of darifenacin ester compound of general formula- 13,

Formula- 13 Which comprises of reacting the diphenyl pyrrolidine compound of formula- 12

Formula- 12 with dihydro benzofuran compound of formula-9a,

Formula-9a in presence of a suitable alkali and/or alkaline base like sodium carbonate, potassium carbonate and cesium carbonate in a suitable solvent selected from nitrile solvents like acetonitrile and/or non-polar solvents like toluene and/or chloro solvents like methylene chloride and/or polar solvent like water with or without presence of phase transfer catalyst to provide the compound of formula-13.

23. The process according to claim 22, wherein the phase transfer catalyst selected from the group of tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide.

24. A process for the preparation of darifenacin and its pharmaceutically acceptable salts, which comprises of the following steps, a) converting the compound of formula- 13

Formula- 13 into compound of formula- 14 by reacting with suitable alkali and/or alkaline base like sodium hydroxide, potassium hydroxide in a suitable alcoholic solvents like methanol, ethanol and isopropyl alcohol preferably methanol followed by reacting the compound of formula- 14 with suitable chlorinating agent like thionyl chloride and an amine like ammonia to give darifenacin or with benzyl amine or substituted benzyl amine to give corresponding benzylated darifenacin and converting the same into darifenacin compound of formula-2 by debenzylation, (Or)

Formula- 14 b) by reacting the compound of formula- 13 with alcoholic ammonia or with benzyl amine or substituted benzyl amine in presence or absence of a suitable solvent under vapor pressure or atmospheric pressure in an autoclave to provide darifenacin or corresponding benzylated darifenacin which on debenzylation provides the darifenacin compound of formula-2 and recrystallising the darifenacin in a suitable solvents selected from ester solvents like ethyl acetate, methyl acetate, propyl acetate, and/or alcohol solvents like methanol, ethanol, isopropyl alcohol and mixtures thereof, and converting the pure darifenacin compound of formula-2 into its pharmaceutically acceptable salts.

25. A novel process for the preparation of darifenacin and its pharmaceutically acceptable salts comprises of the following steps; a) Reacting the pyrrolidine compound of formula-5a

Formula-5a with diphenyl methyl ester compound of formula- 1 Oa

Formula- 10a in presence of a strong base selected from sodium hydride, sodium tertiary butoxide, potassium tertiary butoxide, sodium methoxide, sodium hydroxide and/or alkali metal carbonates like potassium carbonate in a suitable solvent selected from toluene, xylene, cyclohexane, hexanes, acetonitrile and dimethyl sulfoxide provides the condensed compound of formula- 1 Ia,

Formula-l la c) deprotecting the N-tosyl group of condensed compound of formula-l la with hydrobromic acid in a suitable bromine acceptor like phenol to provide diphenyl pyrrolidine compound of formula- 12a which is optionally converted into its organic acid addition salts like tartaric acid and again converted back to compound of formula- 12a by treating with suitable base,

Formula- 12a d) reacting the diphenyl pyrrolidine compound of formula- 12a with dihydro benzofuran compound of formula-9a,

Formula-9a in presence of a suitable alkali and/or alkaline base like sodium carbonate, potassium carbonate and cesium carbonate preferably potassium carbonate in a suitable solvent selected from nitrile solvents like acetonitrile and/or non-polar solvents like toluene and/or chloro solvents like methylene chloride and/or polar solvent like water with or without presence of phase transfer catalyst to provide the compound of formula- 13 a,

Formula- 13a e) optionally converting the compound of formula- 13a into compound of formula- 14 by reacting with suitable alkali and/or alkaline base like sodium hydroxide, potassium hydroxide in a suitable alcoholic solvents like methanol, ethanol and isopropyl alcohol preferably methanol followed by reacting the compound of formula- 14 with suitable chlorinating agent like thionyl chloride and an amine like ammonia to give darifenacin or with benzyl amine or substituted benzyl amine to give corresponding benzylated darifenacin and converting the same into darifenacin compound of formula-2 by debenzylation,

Formula- 14 f) reacting the compound of formula- 13a with alcoholic ammonia or with benzyl amine or substituted benzyl amine in presence or absence of a suitable solvent under vapor pressure or atmospheric pressure in an autoclave to provide darifenacin or corresponding benzylated darifenacin which on debenzylation provides the darifenacin compound of formula-2 and recrystallising the darifenacin in a suitable solvents selected from ester solvents like ethyl acetate, methyl acetate, propyl acetate, and/or alcohol solvents like methanol, ethanol, isopropyl alcohol and mixtures thereof,

Formula-2 g) reacting the darifenacin compound of formula-2 with a suitable acid selected from hydrochloric acid, hydrobromic acid in presence of ketone solvent like acetone, methyl ethyl ketone to obtain corresponding darifenacin acid addition salt, compound of formula- 1. h) purifying the darifenacin acid addition salt compound of formula- 1 in a suitable solvent selected from ketone solvents like acetone, methyl ethyl ketone, methyl isobutyl ketone; an alcohol solvents like methanol, ethanol, isopropyl alcohol or mixtures thereof.

26. A process according to step g) of claim 25, wherein the darifenacin is treated with hydrobromic acid to provide darifenacin hydrobromide compound of formula- Ia.

27. A process according to step g) of claim 25, wherein the darifenacin is treated with hydrochloric acid to provide darifenacin hydrochloride compound of formula- Ib.

28. The compound of general formula- 10 having following structural formulae.

Formula- 10 Wherein R is hydrogen or C₁- C₄ alkyl.

29. The darifenacin methyl ester compound of formula- 10a having the following structure.

30. The compound of general formula- 11 having the following structural formulae.

Formula- 11 Wherein R is hydrogen or Cj- C₄ alkyl.

31. The compound of formula- 1 Ia having the following structure.

Formula-l la

32. The compound of general formula- 12 having the following structural formulae.

Formula- 12 Wherein R is hydrogen or C₁- C₄ alkyl.

33. The compound of formula-12a having the following structure.

Formula- 12a

34. The use of compounds of formula- 10, formula- 11 and formula- 12 in the preparation of darifenacin and its pharmaceutically acceptable salts.

35. A process for the preparation of condensed compound having the following structure

Wherein Y = - CN₅ - CONH₂, - COOR and R is either H or C₁-C₄ alkyl. Which comprises of reacting the pyrrolidine compound of formula-5,

Formula-5 wherein L is a leaving group like p-toluene sulfonyloxy, chloro, bromo etc., with diphenyl compound of following structural formula,

Wherein Y = - CN, - CONH₂, - COOR and R is either H or C₁-C₄ alkyl in presence of a strong base selected from sodium hydride, sodium tertiary butoxide, potassium tertiary butoxide, sodium methoxide, sodium hydroxide and/or alkali metal carbonates like potassium carbonate in a suitable solvent selected from toluene, xylene, cyclohexane, hexanes, acetonitrile and dimethylsulfoxide.

36. Darifenacin hydrobromide prepared as per the above claims 13, 24 & 25, having a purity at least about 99.5 area-percent by high performance liquid chromatography.

37. Darifencin hydrobromide prepared according to claim 13, 24 & 25, is having each of the impurities, Nitrile Impurity (NI), Dimer Impurity- 1 (DI-I) and Dimer Impurity-2 (DI-2) are less than about 0.15 area-percent by HPLC.

38. Darifenacin hydrobromide prepared according to claim 13, 24 & 25, is having each of the impurities, Nitrile Impurity (NI), Dimer Impurity- 1 (DI-I) and Dimer Impurity-2 (DI-2) are less than about 0.10 area-percent by HPLC.

39. Darifenacin hydrobromide prepared according to claim 13, 24 & 25, is having each of the impurities, Nitrile Impurity (NI), Dimer Impurity- 1 (DI-I) and Dimer Impurity-2

(DI-2) are less than about 0.05 area-percent by HPLC.

40. Darifenacin hydrobromide having less than about 0.10 area percent of Nitrile

Impurity by HPLC.

41. Darifenacin hydrobromide having less than about 0.10 area percent of Dimer

Impurity- 1 by HPLC.

42. Darifenacin hydrobromide having less than about 0.10 area percent of Dimer Impurity-2 by HPLC.

43. Darifenacin hydrobromide having less than about 0.05 area percent of Nitrile Impurity by HPLC.

44. Darifenacin hydrobromide having less than about 0.05 area percent of Dimer Impurity-1 by HPLC.

45. Darifenacin hydrobromide having less than about 0.05 area percent of Dimer Imρurity-2 by HPLC.

46. An improved process for the preparation of dihydrobenzofuran compound of formula-9, which comprises of the following steps; a) Reducing 2-chloro-l-(2,3-dihydrobenzofuran-5-yl)ethanone compound of formula- 18 using a mixture of trifluoroacetic acid and triethyl silane with or without solvent to provide the 5-(2-chloroethyl)-2,3 -dihydrobenzofuran compound of formula- 19 , b) treating the 5-(2-chloroethyl)-2,3-dihydrobenzofuran compound of formula-19 with sodium halide in a suitable solvent to provide corresponding 5-(2-haloethyl)- 2,3-dihydrobenzofuran compound of formula-9.

47. An improved process for the preparation of dihydrobenzofuran compound of formula-9, which comprises of the following steps; a) Reducing 2-chloro-l-(2,3-dihydrobenzofuran-5-yl)ethanone compound of formula-9 using sodium borohydride in presence of sulphuric acid or trifluroacetic acid in a suitable solvent selected from tetrahydrofuran or methylenechloride to provide the 5-(2-chloroethyl)-2,3-dihydrobenzofuran compound of formula-19, b) treating the 5-(2-chloroethyl)-2,3-dihydrobenzofuran compound of formula-19 with sodium bromide or sodium iodide in a suitable solvent such as acetone to provide corresponding 5-(2-bromoethyl)-2,3-dihydrobenzofuran compound of formula-9a or 5-(2-iodoethyl)-2,3-dihydrobenzofuran compound of formula-9b.

48. Amorphous darifenacin hydrobromide compound of formula- Ia.

49. Amorphous darifenacin hydrobromide compound according to claim 48 is characterized by the PXRD and IR substantially as illustrated in figure- 1 and figure-2 respectively.

50. A process for the preparation of novel amorphous darifenacin hydrobromide compound of formula- Ia which comprises of the following steps; a) Dissolving darifenacin hydrobromide in a suitable organic solvent, b) heating the reaction mixture to reflux temperature of the solvent to get a clear solution, c) spray drying the above obtained solution gives amorphous darifenacin hydrobromide compound of formula- Ia, or d) distilling off the solvent from the solution obtained in step b), to dryness, e) isolating the amorphous darifenacin hydrobromide by adding a non-polar hydrocarbon solvent followed by filtration.

51. A process according to claim 50 wherein in step a) the organic solvent is selected from the group of C_1-5 alcohols like methanol, ethanol, propanol, butanol and/or ether solvents like tetrahydrofuran and/or mixtures thereof.

52. An organic solvent according to claim 50 is methanol.

53. An organic solvent according to claim 50 is tetrahydrofuran.

54. A process according to claim 50 wherein in step e), the non polar hydrocarbon solvent is a solvent selected from the group of C_5-7 aliphatic hydrocarbon preferably n-heptane.

55. Crystalline form-M of darifenacin hydrochloride characterized by its strong powder X-ray peaks at about 8.1, 9.0, 11.5, 18.2, 20.3, 22.1, 24.6 ± 0.2 degrees two theta as illustrated in figure-6.

56. A process for preparation of novel crystalline polymorph form-M of darifenacin hydrochloride, which comprises of a) Dissolving the darifenacin compound of formula-2, in acetone, b) adding hydrochloric acid to the above mixture at 0-10⁰C, c) increasing the temperature of the mixture to 25-30⁰C and stirring it for 12 hours and cooling it to 0-10°C, d) filtering and drying the solid obtained to provide pure crystalline form-M of darifenacin hydrochloride.

57. Darifenacin hydrobromide has a mean particle size of approximately 50 microns or less and D(v. 0.9) is 80 microns or less.

58. A method of packing for darifenacin hydrobromide comprising: a) placing darifenacin hydrobromide in a white low density polythene bag and sealed, b) disposing the primary packing into a secondary packing of black polythene bag with or without silica gel bags and sealed, c) disposing the secondary packing into a triple aluminated bag with or without silica gel bags and sealed, d) enclosing the sealed aluminated bag in to a closed HDPE container.

59. A process for the purification of darifenacin hydrobromide compound of formula- Ia which comprises of the following steps, a) Dissolving darifenacin hydrobromide in polar protic solvent, b) heating the solution to reflux, c) treating the solution with activated carbon, d) distilling off the solvent under reduced pressure, e) adding suitable ketone and/or alcohol solvent to the residue and refluxing for a while, f) cooling the reaction mixture to low temperature preferably at 0-5⁰C, g) stirring the reaction mixture at low temperature preferably to 0-5⁰C, h) separating the solid by filtration, i) drying the solid gives pure crystalline darifenacin hydrobromide compound of formula- Ia.

60. A process of claim 59 wherein in step a) the polar protic organic solvent is a solvent selected from the group of Ci_-5 alcohol consisting of methanol, ethanol, propanol, butanol or their mixture thereof.

61. A process according to claim 59, wherein in step a) the alcohol is methanol.

62. A process according to claim 59, wherein in step e) the ketone solvent is a solvent selected from the group C_3-6 ketones consisting of acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, 2-butanone and/or alcohol solvents like isopropyl alcohol and/or mixtures thereof.