A PROCESS FOR THE PREPERATION OF DARIFENACIN HYDROBROMIDE
TECHNICAL FIELD OF THE INVENTION
The present invention is directed to a novel, industrially viable and cost effective purification process for manufacturing substantially pure form of 3-(S)-(-)-(1 -carbamoyl-1,1 -diphenylmethyl)-1 -[2-(2,3-dihydrobenzofiiran-5-yl)ethyl]pyrrolidine hydrobromide also known as Darifenacin hydrobromide.
BACKGROUND OF THE INVENTION
3-(S)-(-)-( 1 -carbamoyl-1,1 -diphenylmethyl)-1 -[2-(2,3-dihydrobenzofijran-5-yl)ethyl] pyrrolidine hydrobromide commonly known as Darifenacin hydrobromide of Formula I is a potent muscarinic receptor antagonists and used in the treatment of diseases associated with gut, trachea, bladder like bowel syndrome, diverticular disease, urinary incontinence, esophageal achalasia, chronic obstmctive airways diseases. It is marketed under the trade name ENABLEX as extended release tablet.

US patent 5,096,890 discloses multiple routes for preparation of Darifenacin and its hydrobromide salt. The route for preparation of Darifenacin disclosed in this patent uses hazardous reagents like triphenylphosphine, diethylazodicarboxylate, pyridine, stannous chloride, tributyltin hydride. The final product gets contaminated by triphenylphosphine oxide which is difficult to remove. Therefore, it needs column chromatography purification, which is time consuming, cumbersome to use at commercial scale and reduces the yield. This patent is silent about the purification of Darifenacin hydrobromide.

US20070203221 discloses a process for preparation of Darifenacin hydrobromide, which comprises treating (3S)-hydroxypyrrolidine of Formula XIV in the presence of base and phase transfer catalyst to give l-tosyl-3-(S)-tosyloxypyrrolidine of formula V. The compound of formula V on condensation with diphenylacetonitrile in the presence of inorganic base affords 3-(R,S)-(l-cyano-l,l-diphenylmethyl)l-tosylpyrrolidine of formula VI. (S)-2,2-diphenyl-2-(3-pyrrolidinyl)acetonitrile hydrobromide salt of formula VII is synthesized by deprotection and followed by salt fonnation using aqueous hydrobromic acid and bromine acceptor (napthol, phenol). 3-(S)-( I-carbamoyl-1,1- diphenyl methyl)pyrrolidine tartarate of fomiula VIII is obtained by controlled hydrolysis of compound of fonnula VII in the presence of sulphuric acid and followed by L (+) tartarate salt formation using L-(+) tartaric acid. 3-(S)-( 1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartarate of formula VIII was coupled with 5-chloroacetyI-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 in below Scheme:

XVII. The compound of formula XVI and XVII were hydrolysed 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-{I-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylactamide toluene solvate of formula XVIII which was converted to hydrate form of formula XIX and further to its hydrobromide sah as (S)-2-{l-[2-(2,3-dihydro benzofuran-5-yl) ethyl]-3-pyrrolidinyl}-2,2-diphenylactamide hydrobromide of formula I.
Drawbacks:
• Use of toxic reagents like boron triflouride
• Costly (S)-2,2-diphenyl-2(3-pyrrolidinyl)acetonitrile
• Fonnation of solvate and hydrate increases the number of steps in the reaction.
PCT publication WO 2007/076157 describes the preparation of Darifenacin hydrobromide and its fiirther purification by treating crude Darifenacin hydrobromide with n-butanol and charcoal. The above prepared solution was then seeded to induce crystallization.
WO patent application WO 2009/007853 A2 discloses the preparation of Darifenacin hydrobromide and further cryslallizatiou using solvcnls like nicthanoi, ethanol, n-propanol, isopropyl alcohol, dichloromethane, acetonitrile or mixtures thereof Although in this patent application, water is also mentioned as one of the solvent for crystallization but as such there is no further details provided in this patent application.
WO2008/100651 describes a process for preparation and purification of Darifenacin hydrobromide. Darifenacin hydrobromide is dissolved in methanol at 45 to 50"C and carbon is added to it while stirring. After 10 minutes the reaction mixture is filtered over celite bed. The bed was washed with methanol and the filtrate was heated into another reactor to 60 to 65"C. Half of the methanol is distilled and cyclohexane is added to it and allowed to cool. Another lot of cyclohexane is added to the reacdon mass and filtered, washed with cyclohexane

and dried to get pure Darifenacin hydrobromide.
WO2008/126106 A2 describes the purification of Darifenacin hydrobromide. In this process Darifenacin hydrobromide is dissolved in methanol, heated to reflux and treated with carbon. The soludon is filtered through hyflow and washed with hot methanol and the filtrate is distilled off under reduced pressure. Further, acetone was added and distilled off. Again refluxed in acetone, cooled, filtered the precipitated solid and washed with chilled acetone to obtain pure Darifenacin hydrobromide.
Almost all the prior art processes use multiple organic solvents and involve disfiUation of the solvent for the purification of Darifenacin hydrobromide, which is lengthy & cumbersome at industrial scale. We noticed that some of the impurities are not getting removed at commercial scale by following the process mentioned above.
Therefore, there is a continuing need for developing a new process for preparafion and purificafion of Darifenacin hydrobromide, which is very simple, cost effective, industrially viable and eco-friendly.
SUMMARY OF THE INVENTION
I'he present invention relates to a process for the purification of Darifenacin Hydrobromide of formula 1 comprising, treafing crude 3-(5}-( 1-carbamoyl-1,1-diphenylmethyl)-l-[2-(2,3-dihydrobenzofuran-5- yl)ethyl]pyrrolidine
Ph

0 H2NOC

Ph

,HBr
hydrobromide with purified water
This present invention also relates to a process for the preparation of Darifenacin Hydrobromide of formula 1, which comprises:

a) decarboxylation of (2S,4R)4-hydroxypyrrolidine-2-carboxylic acid in the presence of a suitable solvent to give (3R)-pyrrolidin-3-ol of Fonnula XX;
OH

XX b) condensation of (3R)-pyrrolidin-3-ol with 2,3-dihydro-5-(2-substituted-ethyl)benzofiiran to give a compound of (3R)-l-[2-(2,3-Dihydro-l-benzofiiran-5-yl)ethyl]pyrrolidin-3-ol of Formula XXV;


"OH

XXV
c) inversion of configuration of (3R)-l-[2-(2,3-Dihydro-l-benzofiiran-5-yl)ethyi]pyrrolidin-3-ol to furnish a compound of Formula XXVI;
r
XXVI d) reacting (3S)-l-[2-(2,3-Diliyclro-l-benzofuran-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 tosylate, mesylate more preferably tosylate in a suitable solvent to afford a compound (3S)-3-substituted-l-[2-(2,3-dihydro-l-benzofuran-5-yl)ethyl] pyrrolidine of Formula XXVII;

XXVII
e) reacting (3S)-3-substituted-l-[2-(2,3-dihydro-l-benzofiiran-5-
yl)ethyl]pyrrolidine of Formula XXVII with diphenylacetonitrile in the
presence of a strong base to give compound (3S)-(l-carbonitrile-l,l-
diphenylmethyl)-l-[2-(2,3-dihydro-l-benzofiiran-5-yl)ethyl]pyrrolidine of

Formula XXVIIl;

CN O'

XXVIIl f) controlled hydrolysis of (3S)-(l-carbonitrile-l,l-diphenylmethyl)-l-[2-(2,3-dihydro-l-benzofiiran-5-yl)ethyl]pyrrolidine of Formula XXVIIl, in the presence of a suitable base and a phase transfer catalyst to afford compound (3S)-(1-carbamoyl-l,l-diphenylmethyl)-l-[2-(2,3-dihydrobenzofuran-5-yl) ethyljpyrrolidine of Formula IX;

IX
g) conversion of {3S)-(l-carbamoyl-l,l-diphenylmethyl)-l-[2-(2,3-
dihydrobenzofiiran-5-yl) ethyl]pyrrolidine of Formula IX to the Darifenacin hydrobromide salt of Formula I; and
h) optionally purifying the obtained Darifenacin hydrobromide by water.
The present invention further provides a process for the preparation of (3S)-3-substituted-l-[2-(2,3-dihydro-l-benzofuran-5-yl)ethyl] pyrrolidine of Formula XXVII, in a single step by the reaction of (3R)-l-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol of Formula XXV with a halogenating agent, like thionyl 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, chioroform, methylene chloride and a mixture thereof. The preferred solvent is methylene dichloride.
The above process is shown in below mentioned Scheme:

is performed using anhydrous 2-cyclohexen-l-one in a suitable solvent selected from the group consisting of cyclohexanol, cyclopentanol, cyclobutanol, preferably in cyclohexanol. The reaction mixture was heated to 140°C to 150°C for about 12 to 18 hours.
In another embodiment of the present invention, condensation in step (b) of (3R)-pyrrolidin-3-ol with 2,3-dihydro-5-(2-substituted-ethyl)benzofuran 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, 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, trimethyl benzyl ammonium chloride, preferably tetra-n-butyl ammonium bromide. The addition of 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 hours, preferably for about 6 to about 7 hours, depending on the time taken for the completion of the reaction.
In another embodiment of the present invention, inversion of configuration for (3R)-l-[2-(2,3-Dihydro-l-benzofiiran-5-yl)ethyl]pyrrolidin-3-ol of Formula XXV in step (c) 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-chlorobenzylazodiacrboxylate, 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-benzoftiran-5-yl)ethyl]pyrrolidin-3-ol of Formula XXV in suitable 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 or nitrile solvent selected from acetonitrile, propionitrile and mixture thereof, more preferably toluene, followed by the addition of triphenyl phosphine, diethylazodicarboxylate carboxylic acid selected from benzoic acid or acetic acid in a suitable solvent , 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-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol of Formula XXVI obtained in step (C) 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.
In another embodiment of the present invention, the condensation of (3S)-3-
substituted-l-[2-(2,3-dihydro-l-bcnzofuran-5-yl)ethyl] pyrrolidine of Formula
XXVII with diphenylacetonitrile in step (e) 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-
diraethylsulfoxide or a mixture thereof, preferably in toluene.
In another embodiment of the present invention, the controlled hydrolysis of (3 S)-( 1 -carbonitrile-1,1 -diphenylmethyl)-1 -[2-(2,3-dihydro-1 -benzofuran-5-yl)ethyl]pyrrolidine of Formula XXVIII in step (f) is carried out in presence of a phase transfer catalyst selected from the group consisting of tetra-n-butyl ammonium bromide, triethyl benzyl ammonium chloride, tributyl benzyl ammonium

chloride, trimethyl benzyl ammonium chloride and in the presence of a base selected from potassium or sodium hydroxide, in an alcoholic solvent such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert butanol. Preferably, the controlled hydrolysis of compound of formula XXVIII is carried out in presence of a phase transfer catalyst tetra-n-butyl ammonium bromide, base potassium hydroxide and solvent n- butanol.
The final conversion of Darifenacin to Darifenacin hydrobromide is done using 48% aqueous hydrobromic acid in a suitable ketonic solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, preferably in acetone.
Furthermore, the compound (3S)-3-substituted-l-[2-(2,3-dihydro-l-
benzofuran-5-yl)ethyl] pyrrolidine of 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-dimethylacetamide, N,N-dimethylsulfoxide, preferably, N,N-dimethylformamide along with a chlorinated solvent followed by the addition of the halogenating agent, preferably thionyl chloride. Preferably, the solution was stirred at a temperature of about 35°C to 50°C for a period of 2 to 5 hours.
Darifenacin hydrobromide of Formula I obtained by the present process has HPLC purity of more than 99.0%, single unknown impurity less than 0.15%, preferably 0.1% and other isomer less than 0.5 %, preferably 0.1% of (3R)l-[2-(2,3-Dihydro-5-benzofuranyl)ethyl]-a,a-diphenyl-3-pyrrolidineacetamide.
Darifenacin hydrobromide prepared according to the present invention and as described in Example 8 hereafter, has the characteristic XRPD peak values as shown in Table I below. The X-ray powder diffractogram is depicted in Figure I.
Table I
Peak (2?) d-spacing (A)
8.1493 10.8496

9.0512 9.7704
11.4756 7.7111
12.5036 7.0945
14.3636 6.1665
16.6873 5.3127
17.2663 5.1359
17.7544 4.9958
18.2089 4.8721
18.8083 4.7181
19.0948 4.6480
19.5218 4.5473
20.0858 4.4208
20.3183 4.3708
20.7737 4.2760
22.1031 4.0217
22.7182 3.9423
23.6245 3.7660
24.0948 3.6926
24.5418 3.6273
24.7172 3.6020
25.1462 3.5415
25.8664 3.4445
26.7677 3.3305
27.2960 3.2672
27.5731 3.2350
28.0626 3.1797
28.8252 3.0973
29.9635 2.9822
30.2894 2.9508
30.8051 2.9126
31.1332 2.8727
31.9302 2.8028
33.9816 2.6382
34.3070 2.6139
34.7107 2.5844

36.8883 2.4367
39.1257 2.3024
41.3971 2.1811
42.1005 2.1463
Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The term
The examples are provided to illustrate particular aspects of the disclosure and not to limit the scope of invention as defined by the claims.
Example 1: Preparation of (3R)-pyrroUdin-3-ol (Formula XX)
(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid was heated to a suspension of anhydrous cyclohexanol (500 ml) and cylohexen-1-one (5 ml) at 145"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)-pyrrolidin-3-ol. Dry Weight : 60 g Yield : 90.34 % Purity: 97 %
Example 2: Preparation of (3R)-l-[2-(2,3-Dihydro-l-benzofuran-5-
yl)ethyl]pyrrolidin-3-ol (Formula XXV)
(3R)-pyrrolidin-3-ol (28 g) and potassium carbonate (89 g) in anhydrous acetonitrile (200 ml) was stirred at room temperature for 10 minutes and the mixture was heated to reflux for 2 hours. The benzofliran derivative was added dropwise to the above mixture and refluxed for 6 hours. After the reaction completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was taken in methylene dichloride, washed with aqueous HCl followed by washing

with saturated potassium 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 % HPLC 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)-l-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol (16 g) in toluene (80 ml) was dissolved and to it was added triphenyl phosphine (20 g), diethylazodicarboxylate (15 ml) and benzoic acid (9.3 g) at 0"C. The reaction mixture was stirred for 12 hrs at room temperature. 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 g) and water (27 ml) in methanol (81 ml) at room temperature for 5 hours. The completion of reaction was observed by TLC. The reaction mixture was concentrated and extracted with methylene dichloride. The organic layer was dried and concentrated to fiimish solid of above desired compound. Dry Weight: 11 g Yield : 67.9 % HPLC purity : 89 %
Example 4: Preparation of (3S)-3-tosyloxy-l-|2-(2,3-dihydro-l-benzofuran-5-yi)ethyl] pyrrolidine (Formula XXVII)
The compound (3S)-l-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol (10 g) was dissolved in methylene dichloride (65 ml) and p-tolunesulphonyl chloride (9.8 g) and triethylamine (8.66 g) were added to it at -10"C. 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. Dry Weight: 15.7 g

Yield : 95 %
Example 5: Preparation of (3S)-(l-carbonitrile-l,l-diphenylmethyI)-l-[2-(2,3-dihydro-l-benzofuraii-5-yl)ethyl|pyrrolidine (Formula XXVIIl)
Diphenylacetonitrile (62.5 gm) was added to the stirred suspension of sodium hydride (27 gm) in anhydrous toluene (325 ml) and reflux for 2 hours. The reaction mixture was cooled to room temperature and to it was added compound (3S)-3-tosyloxy-l-[2-(2,3-dihydro-l-benzofuran-5-yl)ethyl] pyrrolidine (125 gm) dissolved in toluene in portions and heated under reflux for 9 hrs. After completion of reaction, toluene was added to the reaction mixture and washed with 5% aqueous NaOH solution and brine, dried on sodium sulphate and concentrated under reduced pressure to furnish a semi solid residue of the desired product. Dry Weight: 112 g Yield : 69 %
Example 6: Preparation of (3S)-(l-carbamoyI-l,l-diphenylmethyl)-l-[2-(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 g) and tetra-n-butyl ammonium bromide (0.9 g) at room temperature. Then the reaction mass was heated to reflux for 48 hours. 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 layer 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)-(l-carbamoyl-l,l-diphenylmethyl)-l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine 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-l,l-diphenylmethyl)-l-[2-(2,3-
dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide .
Dry Weight: 1.7g
Yield: 65 %
HPLC purity-.99.11 %
Other isomer : 0.23 %
EXAMPLE 8: Purification of 3-(5)-(l-carbamoyl-l,l-diphenylmethyl)-l-[2-(2,3-dihydrobenzofuraii-5-yl)ethyl]pyrrolidine hydrobromide
The crude 3-(^-(l-carbamoyl-l,l-diphenylmethyl)-l-[2-(2,3-
dihydrobenzoiuran-5-yl)ethyl] pyrrolidine hydrobromide (11.1 g) was retluxed in purified water (200 mL) to get clear solution. Charcoal (0.55 g) was added to it, filtered and washed with hot water (20 mL). The filtrate was again heated to reflux temperature and cooled slowly to 60-65"C and maintained at this temperature for 1 hour. It was fiirther cooled to 30-35°C and then to 0-5°C, maintained at 0-5°C for 1 hour, filtered and washed with purified water (20 mL) to afford pure Darifenacin Hydrobromide. Dry Weight: 8.9 g Yield : 80.0% Purity : 99,87%

We Claim:
1. A process for the purification of Darifenacin hydrobromide of formula I

comprising treating crude 3-(5)-(l-carbamoyl-1,1-diphenylmethyl)-!-[2-(2,3-dihydrobenzofuran-5- yl)ethyl]pyrrolidine hydrobromide with water
2. A process for the preparation of Darifenacin hydrobromide having HPLC
purity more than 99.0%, single unknown impurity less than 0.15% ,
preferably 0.1% and other isomer i.e. R-isomer of Darifenacin less than
0.5%, preferably 0.15% which comprises:
a) decarboxylation of (2S,4R)4-hydroxypyrrolidine-2-
carboxylic acid in the presence of a solvent to give (3R)-pyrrolidin-3-oloffomiulaXX;

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


d) reacting (3S)-l-[2-(2,3-Dihydro-l-benzofuran-5-
yl)ethyl]pyrrolidin-3-ol of formula XXVI with a leaving group
selected from methanesulfonyl chloride, p-toluenesulphonyl chloride,
in a solvent to afford (3S)-3-substituted-l-[2-(2,3-dihydro-l-
benzofuran-5-yl)ethyl] pyrrolidine of fonnula XXVII;

Where L is a leaving group selected from tosylate or mesylate
e) reacting (3S)-3-substituted-l-[2-(2,3-dihydro-l-
benzofuran-5-yl)ethyl]pyrrolidine of formula XXVII with
diphenylacetonitrile in the presence of a strong base to give (3S)-(I-
carbonitrile-1,1 -diphenylmethyl)-1 -[2-(2,3-dihydro-1 -benzofiiran-S-
yl)ethyl]pyrrolidine of formula XXVIII;

I) controlled hydrolysis of (3S)-(I-carbonitrile-I,I-
diphenylmethyl)-1 -[2-(2,3-dihydro-1 -benzofuran-5-yl)ethyl]pyrroIidine of formula XXVIII, in the presence of a suitable base and a phase transfer catalyst to afford (3S)-(l-carbamoyl-l,l-diphenylmethyl)-1 -[2-(2,3-dihydrobenzofuran-5-yl) ethyl]pyrrolidine of formula IX;


g) conversion of (3 S)-(l-carbamoyl-1,1-
diphenylmethyl)-l-[2-(2,3-dihydrobenzofuran-5-yl) ethyl]pyrrolidine of formula IX to the Darifenacin hydrobromide salt of formula I; and
h) optionally purifying the obtained Darifenacin
hydrobromide by water.
3. A process according to claim 2, wherein the decarboxylation in step (a) is carried out in using 2-cyclohexane-l-one and the solvent for it is selected from the group consisting of cyclohexanol, cyclopentanol, cyclobutanol, preferably in cyclohexanol.
4. A process according to claim 2, wherein the condensation in step (b) is done in the presence of 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 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 preferably, bromo with a 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.
5. A process according to claim 2, wherein the inversion of configuration as in Step (c) is done by a Mitsunobu reaction followed by a hydrolysis of the ester using alkali metal hydroxide selected from the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably lithium hydroxide in a solvent selected from methanol, ethanol, iso-propanol, preferably, methanol, to give the inverted alcohol of Formula XXVI.
6. A process according to claim 5, wherein the Mitsunobu reaction is done using triphenylphosphine, diethylazodicarboxylate and benzoic acid in a suitable hydrocarbon solvent such as toluene, xylene, n- heptane, n-hexane, cyclohexane, methylcyclohexane, dichloromethane, ethylene chloride, chloroform, methylene chloride, acetonitrile, propionitrile and mixture thereof, preferably toluene, under cold condifions, preferably -5°C to 5°C,

followed by stirring the solution at preferably 25°C to 30°C for about 12 to 15 hours.
7. A process according to claim 2, wherein the base used for condensation in
Step (e) is selected from the group consisting of sodium hydride, potassium
hydride, lithium hydride potassium tert-butoxide, sodium tert-butoxide,
preferably sodium hydride in a suitable hydrocarbon solvent selected from
the group consisting of toluene, xylene, n- heptane, n-hexane, cyclohexane,
methylcyclohexane, tetrahydrofuran, N,N-Dimethylformamide, N,N-
Dimethylsulfoxide or a mixture thereof, preferably toluene.
8. A process according to claim 2, 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, preferably tetra-
n-butyl ammonium bromide, in the presence of a base selected from
potassium hydroxide or sodium hydroxide, preferably potassium hydroxide,
in a alcoholic selected from ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, tert butanol, preferably n- butanol.
9. The compound (3R)-l-[2-(2,3-Dihydro-l-benzofiiran-5-yl)ethyl]pyrrolidin-
3-ol of Formula XXV.

11. The compound N-(ethyl-2,3- dihydrobenzofuran)-3-chloropyrrolidine.
12. A process for the preparation of (3S)-3-substituted-l-[2-(2,3-dihydro-l-
benzofuran-5-yl)ethyl] pyrrolidine of formula XXVII.


with an inversion of configuration using halogenating agent selected from thionyl chloride, oxalyl chloride, phosphorous oxychloride, preferably thionyl chloride in the presence of catalytic amount of N,N-dimethylfomiamide in presence of a hydrocarbon solvent selected from the group consisting of toluene, xylene, n- heptane, n-hexane, cyclohexane, methylcyclohexane, dichlororaethane, ethylene chloride, chloroform, methylene chloride and a mixture thereof, preferably methylenedichloride. 13. A process for preparation of (3S)-l-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol of formula XXVI comprising:
a) reacting (3R)-l-[2-(2,3-Dihydro-l-benzofliran-5-yl)ethyl]pyrrolidin-
3-ol of Formula XXV with triphenylphosphine,
diethylazodicarboxylate and carboxylic acid selected from benzoic
acid or acetic 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; and
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.