NOVEL PROCESS FOR THE PREPARATION OF (3Sl-l-|2-(2.3~DHYDRO-5-BENOFURANYL)ETHYLL-α, α-D1PHENY L-3-PYRROLIDINEACETAMIDE

HYDROBROMIDE

TECHNICAL FIELD OF THE INVENTION

The present invention is directed to a novel, industrially viable and cost effective process for the manufacture of substantially pure form of (3S)-l-12-(2,3-Dihydro-5-benzofuranyl)ethyl1-a,a-diphenyl-3-pyrrolidineacetamide hydrobromide also known as Darifenacin hydrobromide.

This drug is a potent muscarinic receptor antagonists, a white to almost white crystalline powder which is soluble in water and used in the treatment of diseases associated with gut, trachea, bladder like bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia, chronic obstructive airways diseases and like.

US Patent No. 5096890 ( EP0388054, US5233053) discloses Darifenacin, its derivatives, salts and processes for preparing them. The process for the preparation of the key intermediate for darifenacin , is shown below as in Scheme 1.


which comprises of decarboxylation of (2S.4R)-4-hydroxypyrrolidine-2-carboxylic acid, followed by hydrochloride salt formation to give (R)-3-pyrrolidinol hydrochloride. This was further reacted with p-toluenesulphonyl chloride in presence of pyridine to furnish l-tosyl-3-(RHiydroxypyrrolidine a compound of formula IV. This compound of formula IV was reacted with methyl p-toluenesulphonate in presence of triphenylphosphine and dicthylazodicarboxylate to furnish l-tosyI-3-(S)-tosyloxypyrrolidine a compound of formula V which was condensed with diphenylacetonitrile in the presence of sodium hydride to afford 3-(R.S)-( l-cyano-l.l-diphenylmethyl)l-tosylpyrrolidinc a compound of formula VI which underwent deprotection in the presence of aqueous hydrobromic acid to afford 3-(R.S)-( l-eyano-l.l-diphenylmetlul)pyrrolidine a compound of formula VII. The 2,2-diphenyl-2-f(3S)-pyrrolidin-3-yl|acetamide tartarate a compound of formula VIII was obtained on controlled hydrolysis the compound of formula VII in presence of sulphuric acid, followed by L-(+) tartarate salt formation using L-(+) tartaric acid.

Thereafter, several routes are mentioned in the patent for the preparation of Darifenacin as described below.

Route A involves the reaction of the compound of Formula VIII with 5-(2-bromoethyl)-2,3-dihydroben/.ofuran. to give a compound of Formula IX in the presence of sodium or potassium carbonate to give a free base of Darifenacin, a compound of Formula X, which is in turn converted to


Route E involves the reduction of 3-(S)-(l-carbamoyl-l,l-diphenylmethyl)-l-[2-(2,3-dihydrobenzofuran-5-yl)-2-oxoethyl]pyrrolidone, a compound of Formula XIII with palladium carbon to give darifenacin of Formula X, as shown below.
Route E


• Contamination of the final product with triphenylphosphine oxide which was difficult to
remove.

• Requires column purification which was time consuming and cannot be performed at
manufacturing scale

• Lower yield and quality of product

US20070203221 (US2007197630, US2007197631, WO2007076157, WO2007076158, WO2007076159) prepares Darifenacin hydrobromide by the process as shown below in Scheme II. The process of which comprises of treating (3S)-hydroxypyrrolidine of Formula XIV in the presence of base and phase transfer catalyst to give l-tosyl-3-(S)-tosyloxypyrrolidine, a compound of Formula V. Compound l-tosyl-3-(S)-tosyloxypyrrolidine of Formula V, on condensation with diphenylacetonitrile in the presence of inorganic base afforded 3-(R,S)-(l-cyano-l,l-diphenylmethyl)l-tosylpyrrolidine a compound of formula VI. The (S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile hydrobromide salt of formula VII have been synthesized by deprotection and followed by salt formation using aqueous hydrobromic acid and bromine acceptor (napthol, phenol). The 3-(S)-(l-carbamoyl-1,1- diphenyl methyl)pyrrolidine tartarate a compound of formula VIII were obtained by on controlled hydrolysis of compound of Formula VII in the presence of sulphuric acid and followed by L (+) tartarate salt formation using L-(+) tartaric acid. The 3-(S)-(l -carbamoyl-1,1- diphenylmethyl)pyrrolidine tartarate a compound of formula VIII was coupled with 5-chloroacetyl-2,3-dihydrobenzofuran in the presence of base in an inert solvent followed by treating the intermediate with 48% aqueous HBr in n-butanol to yield Darifenacin hydrobromide of Formula I as shown below in Scheme II.


Drawbacks :

• Use of a costly reagent 3-(S)-hydroxy pyrrolidine as the staring material.

US6930188 (EPI490357. US2003191176) discloses the preparation of Darifenacin hydrobiomide which comprises of reacting (S)-2.2-diphenyl 2-(3-pyrrolidinyl)acetonitrile of Formula VI1A with hydrobromic acid to form (S)-2,2-diphenyl-2-(3-pyrolidinyl)acetonitrile hydrobromide of formula VII which was coupled with 2(3-dihydrobenzofuran-5-aceticacid (formula A ) in the presence of N.N-carbonyldiimidazole to afford (S)-3-(cyanodiphenylmethyl)- l-[2-(2,3-dihydrobenzofuran-5-triflouride tetrahydrofuran complex to yield (S)-2-{ l-[2,.Vdihydrobenzoruran-5-yl)ethyl]-3-pyrolidinyli -2,2-diphenylacteonitrile of formula XVI which was further converted to its hydrobromide salt by reaction with aqueous hydrobromic acid ol' formula XVII. The compound of formula XVI and XVII were hydro[ysed with potassium hydroxide by heating with 2-methylbutanol and further refluxed with amberlite resin and the solvent 2-methylbutanol was replaced by toluene to furnish (S)-2-{l-[2-(.2.3-dihydroben/.ofuran-5-yl)ethyl]-3-pyrrolidinyl}-2.2-diphenylactamide toluene solvate of formula

Will which was converted lo hydrate form of formula XIX and further to its hydrobromide salt as (S)-2-j l-|2-(2.3-dihydro ben/ofuran-5-yl) ethyl]-.vpyrrolidinyl}-2.2-diphenylactamide hydrobromide o\' Ibrinula I as shown in Scheme III. Drawbacks:

• Use of toxic reagents as boron tritlouride

• Costly (S)-2,2-diphenyl-2(3-pyrrolidinyl)acetonitrile

• Formation of solvate and hydrate increases the number of steps in the reaction.
Therefore, there is a continuing need for developing a new process which is cost effective, industrially viable and eco friendly, for the manufacture of Darifenacin hydrobromide.

SUMMARY OF THE INVENTION

The aspect of the present invention is to provide a novel process for the preparation of
Darifenacin hydrobromide which comprises of:

(a) decarboxylation of l2S.4R)4-hydroxypyrrolidine-2-carboxylic acid in the presence of a suitable

(c) inversion of configuration of (3R)-I-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol to furnish a compound of Formula XXVI,


(g) conversion of (3S)-( I -carbamoyl-1.1 -diphenylmethyl)-1 -l2-(2,3-dihydrobenzofuran-5-yl)
ethyljpyrrolidine of Formula IX to the Darifenacin hydrobromidc salt of Formula 1

The present invention further provides a process for the preparation of (3S)-3-substituted-l-[2-(2,3-dihydro-l-benzofiiran-5-yl)ethyl] pyrrolidine of Formula XXV11. in a single step by the reaction of (3R)-l-|2-(2.3-r)iliydro-l-benzofuran-5-yl)ethyl|pyrrolidin-3-ol of Formula XXV with a halogenating agent, like thonyl chloride, oxalyl chloride, phosphorous oxychloride preferably thionyl chloride in the presence of catalytic amount of N.N-dimethylformamide in presence of hydrocarbon solvent such as toluene, xylene, n- heptane, n-hexane. cyclohexane. methylcyclohexane and or chlorinated solvents such as dichloromethane. ethylene chloride, chloroform, methylene chloride and a mixture thereof. The preferred solvent is methylene dichloride.

c) inversion of configuration of (3R)-l-[2-(2,3-Dihydro-l-bcnzofuran-5-yl)ethyl]pyrrolidin-3-ol


g) conversion of (3S)-( I -carbamoyl-1.1 -diphenylmethyl)-1 -[2-(2,3-dihydrobenzofuran-5-yl) ethyljpyrrolidine of Formula IX to the Dariicnacin hydrobromide salt of Formula I

The present invention further provides a process for the preparation of N-(ethyl-2,3-dihydrobenzofuran)-3-substituted-pyrrolidine of Formula XXVII, in a single step by the reaction of N-(ethyl-2.3-dihydrobenzofuran)-3-hydroxypyrrolidine of Formula XXV with a halogenating agent, like thonyl chloride, oxalyl chloride, phosphorous oxychloride preferably thiony! chloride in the presence of catalytic amount of N.N-dimethylformamide in presence of hydrocarbon solvent such as toluene. xylene, n- heptane, n-hexane. cyclohexane, methyleyclohcxane and or chlorinated solvents such as diehloromethane. ethylene chloride, chloroform, methylene chloride and a mixture thereof. The preferred solvent is methylene dichloride. 1 he process can be described as in Scheme IV below :

The decarboxylation reaction in the present invention is performed using anhydrous 2-cyciohexen-l-one in a suitable reagent chosen from cyclohexanol, cyclopentanol. cyclobutanol more preferably eyelohexanol. The reaction mixture was heated to 14()°C to !5()°C for about 12 to 18 hours.

Condensation of (3R)-pyrroIidin-3-ol with 2,3-dihydro-5-(2-substituted-ethyl)bcnzofuran is conducted in a suitable nitrile solvent selected from acetonitrile, propionitrile wherein the substitution at the ethyl group may be chosen from chloro. bromo or iodo. more preferably, bromo, in a suitable base selected from the alkali metal carbonates such as potassium carbonate, sodium carbonate, cesium carbonate alkali metal bicarbonates such as potassium bicarbonate, sodium bicarbonate, preferably potassium carbonate with phase transfer catalyst selected from tetra-n-butyl ammonium bromide, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride, trimcthyl benzyl ammonium chloride more preferably letra-n-hutyl ammonium bromide. The addition o\~ 2.3-dihydro-5-(2-bromoethyl)benzofuran was done dropwise to the reaction mixture consisting of (3R)-pyrrolidin-3-ol. base and solvent selected from the group mentioned as above, in order to avoid exothermicity. The mixture was heated to reflux for about 5 to about 8 hovirs, more preferably 6 to about 7 hours, depending on the time taken for the completion of the reaction.

Inversion of configuration for (3R)-l-[2-(2.3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol of formula XXV is conducted by a in situ reaction consisting of Mitsunobu reaction followed by the hydrolysis of the ester to give the inverted alcohol. The Mitsunobu reaction was performed using a reagent selected from either diethylazodicarboxylate or diisopropylazodicarboxylate or Di-p-ehlorobenzylazodiaerboxyiate. more preferably diethylazodicarboxylate along with triphenyl phosphine. The hydrolysis of the crude product was performed using a suitable alkali metal hydroxide, selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, more preferably lithium hydroxide.
Preferably, the Mitsunobu reaction was performed by dissolving (3R)-l-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol of Formula XXV in suitable hydrocarbon solvent such as toluene, xylene, n-heptane, n-hexane, eyclohexane, methyleyclohexane and or chlorinated solvents such as dichloromethane. ethylene chloride, chloroform, methylene chloride and or nitrile solvent, selected from acetonitrile. propionitrile and mixture thereof, more preferably toluene, followed by the addition of triphenyl phosphine, diethylazodicarboxylate and benzoic acid, under cold conditions, preferably -5°C to 5°C. The solution was stirred at preferably. 25"C to 30°C for about 12-15 hours.

The inverted hydroxide (3S)-l-[2-(2. 3-Dihydro-1-bicn/oluran-S-y I)ethyl]pyrrolidin-3-ol of Formula XXVI obtained was converted to a good leaving group, preferably acetate, tosylate or mesylate using reagents like acetyl chloride, p-toluenesulfonyl chloride or methane sulfonyl chloride, in the presence of a suitable base selected from triethylamine, diisopropyl ethyl amine, pyridine, N.N-dimethylaminopyridine, more preferably triethylamine in a suitable chlorinated solvents such as dichloromethane. ethylene chloride, chloroform, methylene chloride, preferably methylene dichloride.

The condensation of (3S)-3-substituted-l-12-(2.3-dihydro-l-ben7.ofuran-5-yl)ethylJ pyrrolidine of formula XXVII with diphenylacetonitrile is conducted in the in the presence of a strong base selected from sodium or potassium hydride, lithium hydride potassium tert-butoxide, sodium tert-butoxide more preferably sodium hydride in a suitable hydrocarbon solvent such as toluene, xylene, n- heptane, n-hexane, cyclohexane, methylcyclohexane, tetrahydrofuran, N.N-Dimethylformamide, N,N-Dimethylsulfoxide or a mixture thereof, more preferably toluene.

followed by controlled hydrolysis in presence of phase transfer catalyst selected from tetra-n-butyl ammonium bromide, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride, trimethyl benzyl ammonium chloride more preferably tetra-n-butyl ammonium bromide, in the presence of a base selected from potassium or sodium hydroxide, more preferably potassium hydroxide, in a suitable alcoholic solvent such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert butanol, more preferably n- butanol .

The final conversion of Darifenacin to Darifenacin hydrobromide was done using 48 % aqueous hydrobromic acid in a suitable ketonic solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, more preferably, acetone.

furthermore, the compound (3S)-3-substituted-l-12-(2,3-dihydro-l-benzofuran-5-yl)ethyl] pyrrolidine oC Formula XXVII. could also be prepared from (3R)-l-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl)pyrrolidin-3-ol of Formula XXV, by an SN2 reaction , where the preferred substituent is the chloro group. The preferred mode of reaction being the addition of a catalytic amount of aprotic solvent selected from N.N-Dimethylformamide, N,N-Dimethylavetamidc, N,N-DimethyIsulfoxide,

preferably. N.N-Dimethylformamide along with a chlorinated solvent followed by the addition of the halogenating agent, preferably tliionyl chloride. Preferably, the solution was stirred at a temperature of about 35C to 50°C for a period of 2 to 5 hours

Darilenacin hydrobromide of Formula I as obtained by this process has HPLC purity of more than 99.5 % and having other isomer less than 0.5 % of (3R)l-[2-(2.3-Dihydro-5-benzofuranyl)ethyl]-a,tt-diphenyl-3-pyrrolidineacetamide.

Parifenacin hydrobromide. prepared as in the present invention and as described in Example 6 hereafter, has the characteristic XRPD peak values as shown in Table 1 below. The X-ray powder diffractogram is depicted in Figure I.
fable 1

Peak (28) d-spacing (A)
8.14 10.86
9.04 9.78
11.46 7.72
12.49 7.09
14.35 6.17
16.99 5.22
17.25 5.14
17.72 5.01
18.2 4.88
18.79 4.72
19.7 4.65 19.49 4.56 20.09 4.42 20.31 4.37 20.74 4.28 21.96 4.05
22.7 4.03 23.61 3.77 24.08 3.69


EXAMPLES

Example I: Preparation of (3R)-pyrrolitlin-3-ol (Formula XX)

To a suspension of anhydrous eyclohexanol (500 ml) and cylohexen-l-one (5 ml) was added (2S.4R)-4-hydro\ypyrrolidinc-2-carbo.\ylic acid and the reaction mixture was heated at I45°C for 15 hours. The reaction mixture was cooled to room temperature and then followed by the addition of hexane and water. The water layer was distilled to afford a wine red colored residue of (3R)-pyrrolitlin-3-ol. Dry Weight : 60 g

Yield: 90.34% Purity : 97 %

Example 2 : Preparation of (3R)-I-/2-(2,3-Di/iydro-l-benzofuran-5-yl)etltyl/pyrrolidin-3-ol (Formula XXV)

(3R)-pyrrolidin~3-ol (28 gm) and potassium carbonate (89 gm) in anhydrous acetonitrile (200 ml) was stirred at room temparature for 10 minutes and the mixture was heated to reflux for 2 hrs. The benzofuran derivative was added dropwise to the above mixture and refluxed for 6 hrs. After the reaction completion, the reaction mixture was filtered and concentrated under reduced pressure .The residue was taken in methylene dichloride, washed with Aq.HCI followed by washing with saturated pot.carbonate solution. The MDC layer was dried over Sodium sulphate and concentrated to furnish white solid of the desired compound. Dry Weight : 53.3 g Yield: 78.2%

11 PLC purity : 98 %

Example 3: Preparation of (3S)-l-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol (Formula XXVI)

The compound (3R)-I-f2-(2,3-Dihydro-l-benzofuran-5-yl)ethylJpyrrolidin-3-ol (16 gm) in toluene (80ml) was dissolved and to it was added triphenyl phosphine (20 gm). diethylazodicarhoxylate (15 ml) and benzoic acid (9.3 gm) at 0°C.The reaction mixture was stirred for 12hrs at room temparature. Once the reaction was completed the reaction
mixture was partitioned between toluene and 10% aqueous sodium bicarbonate solution.

The organic layer was dried and concentrated to afford residue. The residue was treated with lithium hydroxide (10 gm) and water (27 ml) in methanol (81 ml) at room temparature for 5 hrs. The completion of reaction was abserved by TLC. The reaction mixture was concentrated and extracted with methylen dichloride. The organic layer
was dried and concentrated to furnish solid of above desired compound.
I)r\ Weight : 11 g Yield : 67.9 % HPLC purity : 89 %

Example 4 : Preparation of (3S)-3-tasyloxy-1-/2-(2,3-dihydro-1-henzofuran-5~yl)ethyl/ pyrrolidine (Formula XXVII)

The compound (3S)-l-/2-(2J-Dihydro-l-benzofuran-5-yl)ethyl/pyrrolidin-3-oJ (10 gm) was dissolved in methylene dichloride (65 ml) and to it was added p-tolune sulphonyl chloride (9.8 gms) and triethylamine (8.66 gm) at -KFC.The mixture was stirred for 6 hrs from 0"C to room temperature. Once the reaction was completed the reaction mixture was partitioned between dichloromethane and water. The organic layer was dried and concentrated under reduced pressure to yield sticky mass of the desired product. Dr\ Weight : 15.7 g Yield : 95 %

Example 5 : Preparation of (3S)-(l-carbonitrUe-I,l-diphenylmethyl)-I-f2-(2,3-dihydro-J-henzofuran-5-yl)ethyl]pyrrolidine (Formula XXVIII)

Diphenylacetonitrile (62.5 gm) was added to the stirred suspension of sodium hydride (27 gm) in anhydrous toluene (325 ml) and reflux for 2hrs.The reaction mixture was cooled to room temperature and to it was added compound (3S)-3~tosyloxy~I-/2-(2,3-dihydro-l-benzofuran-S-yl)ethylJ pyrrolidine (125 gm) dissolved in toluene in portions and heated under reflux for 9 hrs. After reaction completion, toluene was added to the reaction mixture and washed with 5% aqueous NaOH solution and hrine. dried on sodium sulphate and concentrated under reduced pressure to furnish a semi solid residue of the desired product. Dr\ Weight : 112g Yield ; 69 %

Example 6 : Preparation of (3S)-(J-carbamoyl-IJ-diplu'nylmethyl)-I-f2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine (Formula IX)

The residue (10.7 gm) was dissolved in 2-butanol (160.5 ml) and added potassium hydroxide (37 gm) and tetra-n-butyl ammonium bromide (0.9 gm) at room temperature.

Then the reaction mass was heated to reflux for 48 hrs. The completion of the reaction was monitored by TLC. The reaction mixture was cooled and extracted with ethyl acetate and washed with water and brine solution. The organic laser was dried and concentrated under reduced pressure to yield a liquid residue of the compound of Formula IX.

Dry Weight : 8.4 g Yield: 80%

Example 7 : Preparation of (3S)-(I-carbamoyl-I,!-diplienyhMthyl)-I-[2~(2J-dihydrobenzofuran-5' y/)etftyl/pyrrofidifie hydrobromide (Formula I)
The residue (2.2 gm) was dissolved in acetone (9 ml) and added aqueous hydrobromide(0.87 gm). The reaction mixture was cooled to 0"C. and the product was collected by filtration, washed with acetone and dried at 50°C under reduced pressure to afford (3S)-(l-carbamoyl-lJ-dipheiiylmethyl)-l-[2-(2J-dihydrohenzofiMm-5-yl)ethyllpyrrolidine hydrobromide . Dry Weight : 1.7 g Yield : b5 % 1 (PLC purity : 99.84 % Other isomer: 0.23%

We claim :

1. The process for the preparation of Darifenacin hydrobromide, wherein the HPLC purity of Darifenacin hydrobromide is more than 99.5 % and other isomer i.e. R-isomer of Darifenacin HBr being less than 0.5 % which comprises o\';

XXVI e) reacting (3S)-l-[2-(2,3-Dihydro-l-ben/.ofuran-5-yl)ethyl|pyrrolidin-3-ol of Formula XXVI with methane sulfonyl chloride, p-toluenesulphonyl chloride, to form a suitable leaving group selected from group comprising of tos\late. mesylate more preferably tosylate in a suitable solvent to afford a compound (3S)-3-subslituted-l-(2-(2.3-dihydro-l-benzofuran-5-yl)ethyl] pyrrolidine of Formula XXV11,


i) conversion of (3S)-(l-earbamoyl-l.l-cliphcnylmcihyl)-l-[2-(2.3-cliliyclrobcnzofuran-5-yl) ethyljpyrrolidine of Formula IX to the Darilenacin hydrohromide salt of Formula I

2. The process for the preparation of (3R)-pyrrolidinol. free base as in Claim 1, wherein the
decarboxylation as in Step (a) was done using 2-cyelohexane-l-one in suitable solvent like cyclohexanol.

3. The process as in Claim 1, wherein the condensation in Step (b) was done in the presence of suitable base selected from the alkali metal carbonates such as potassium carbonate, sodium carbonate, caseium carbonate alkali metal bicarbonates such as potassium bicarbonate, sodium bicarbonate . preferably potassium carbonate as a base in a suitable nitrile solvent selected from acetonitrile, propionitrile wherein the substitution at the ethyl group may be chosen from chloro.

bromo or iodo, more preferahly, bromo with phase transfer catalyst selected from tetra-n-butyl ammonium bromide, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride, trimethyl benzyl ammonium chloride more preferably tetra-n-butyl ammonium bromide,

4. The process as in Claim 1, wherein the inversion of configuration as in Step (c) was done by a Mitsunobu reaction followed by a hydrolysis of the ester using alkali metal hydroxide, to give the inverted alcohol of Formula XXVI.

5. The process as claimed in Claim 3. wherein the Mitsunobu reaction was done using triphenylphosphine. diethylazodicarboxylate and benzoic acid in a suitable hydrocarbon solvent such as toluene, xylene, n- heptane, n-hexane. cyclohexane. mcthylcyclohexane and or chlorinated solvents such as dichloromethane. ethylene chloride, chloroform, methylene chloride and or nitrite solvent selected from acetonitrile, propionitrile and mixture thereof, more preferably toluene, under cold conditions, preferably -5°C to 5°C, followed by stirring the solution at preferably 25°C to 30°C for about 12 to 15 hours.

6. The process as in Claim 1, wherein the the alkali metal hydroxide chosen for the hydrolysis of the ester in sodium, potassium or lithium hydroxide, more preferably lithium hydroxide in a suitable solvent selected from methanol, ethanol. iso-propanol. more preferably, methanol.

7. The process as in Claim 1. wherein the base used for condensation as in Step (e) strong base selected from sodium or potassium hydride, lithium hydride potassium tert-butoxide, sodium tert-butoxide more preferably sodium hydride in a suitable hydrocarbon solvent such as toluene, xylene, n- heptane, n-hexane. cyclohexane. methylcyclohexane. tetrahydrofuran, N,N-Dimethylformamide. N.N-Dimethylsulfoxide or a mixture thereof, more prefrably toluene.

8. The process as in Claim I. wherein the controlled hydrolysis as in Step (f) was done in presence of phase transfer catalyst selected from tetra-n-butyl ammonium bromide, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride, trimethyl benzyl ammonium chloride more preferably tetra-n-butyl ammonium bromide, in the presence of a base selected from potassium or sodium hydroxide, more preferably potassium hydroxide, in a suitable alcoholic solvent such as ethanol, n-propanol, isopropanol, n-butanol. isobutanol, tert butanol, more prefrably n- butanol .

9. The process for preparing the compound (3R)-l-l2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol of formula XXV.


with an inversion of configuration using halogenating agent, like thonyl chloride, oxalyl chloride, phosphorous oxychloride preferably thionyl chloride in the presence of catalytic amount of N.N-diinethylformamide in presence of hydrocarbon solvent such as toluene, xylene. n- heptane, n-hexane, cyelohexane. rnethylcyelohexane and or chlorinated solvents such as dichloromethane. ethylene chloride, chloroform, methylene chloride and a mixture thereof. The preferred solvent is methylenedichloride.


13. The process for preparing (3S)-l-|2-(2.3-Dihydro-l-benzofuran-5-yl)cthyl]pyrrolidin-3-ol oF Formula XXVI comprising of

a) reacting (3R)-l-f2-(2,3-Dihydro-l-henzo(unin-5-\l)eth\l]pyrroliclin-3-ol of Formula XXV with triphenylphosphine. diethyla/odicarboxvlate and benzoic acid in a suitable solvent, more preferably, toluene under cold conditions, preferably -5°C to 5°C\ followed by stirring the solution at preferably 25°C to 30°C for about 12 to 15 hours,

b) hydrolysis of the ester in the presence of a suitable base, preferably lithium hydroxide in a suitable solvent selected from methanol, ethanol. iso-propanol. more preferably, methanol.

14. Darifenacin hydrobromide prepared in accordance to the Claims I to 13 above having 20 values at approximately 8.14, 9.04, 11.46. 12.49, 14.35. 16.99, 17.25, 17.72, 18.2, 18.79. 19.07. 19.49, 20.09, 20.31, 20.74, 21.96, 22.08, 23.61. 24.08, 24.52, 24.71, 25.14, 25.86, 26.73, 27.25, 27.55, 28.03. 28.69, 28.78. 29.87. 30.28. 30.75. 31.1. 31.88, 33.93. 34.26, 34.88. 36.86, 39.11, 41.45.42.03.