Field of the Invention
The present invention relates to crystalline 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine L-(+)-tartrate monohydrate (Darifenacin intermediate) and process for the preparation thereof. The present invention further relates to process for the preparation of darifenacin or its pharmaceutically acceptable salts from crystalline Darifenacin intermediate.
Background of the Invention
Darifenacin is used to treat urinary incontinence. Darifenacin works by blocking the Ms muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. It thereby decreases the urgency to urinate.
Darifenacin is administered as the hydrobromide salt, Darifenacin is chemically known as (S)-2-{ l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide having the chemical structure,

Darifenacin and its pharmaceutically acceptable acid addition salts are first known in US Pat. No. 5,096,890 where in (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid of formula-(I) undergoes decarboxylation in presence of 2-cyclohexen-l-one in cyclohexanol then salt formation with saturated ethanolic hydrochloric acid followed by crystallization from isopropyl alcohol gives 3-(R)-(-)-hydroxypyrrolidine hydrochloride of formula-(Ia).
Tosylation of formula (la) with p-toluenesulphonyl chloride in anhydrous pyridine followed by recrystallization from ethanol gives l-tosyl-3-(R)-(-)-hydroxypyrrolidine of formula (II), which on tosylation with methyl-p-toluenesulphonate in presence of

concentrated diethylazodicarboxylate (DEAD) and triphenyl phosphine in tetrahydro furan further crystallization from n-propano gives l-tosyl-3-(S)-(-)-tosyloxypyrrolidine of formula (III). Condensation of formula-Ill with diphenylacetonitrile is carried out in sodium hydride to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l-tosylpyrrolidine of formula (IV).

Formula (IV) is reacted with aqueous hydrobromic acid and phenol gives 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine of formula-V, which is subjected to hydrolysis followed by purification to give 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethy(pyrrolidine- L-(+)- tartrate of formula (VI),which on desaltification gives 3-(S)-(-)-(l-carbomoyl-I,l-diphenylmethyl)pyrroIidine of formula (Via).
The formula (Via) is reacted with 5-(2-bromoethyl)-2,3-dihydrobenzofuran in potassium carbonate followed by crystallization from dilsopropyl ether gives Darifenacin, which is further converted into its pharmaceutically acceptable salts by conventional methods.
According to US '890 3-(S)-(+)-(I-carbamoyl-l,l-diphenylmethyl)pyrrolidine. L-(+)-tartrate is isolated as a anhydrous form, which is further subjected to condensation reaction with 5-(2-bromoethyl)benzo[2,3-b]furan in the presence of potassium carbonate and acetonitrile.

According to the prior art process, 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethy(pyrrolidine. L-(+)-tartrate anhydrate is used as a starting material for condensation results in the formation of more dimer impurity, the removal of impurity in final product requires number of purifications to get desired quality, thus purifications in different solvent mixtures increases the raw material cost.
Based on the prior art processes, there is need to develop a commercially viable process for the preparation of Darifenacin and its pharmaceutically acceptable salts.
Object of the Invention
The main object of the present invention is crystalline 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine L-(+)-tartrate monohydrate (Darifenacin intermediate).
Another object of the present invention is process for the preparation of darifenacin intermediate.
Yet another object of the present invention is process for the preparation of darifenacin orjts pharmaceutically acceptable salts from darifenacin intermediate.
Summary of the Invention
The main aspect of the present invention is to provide crystalline 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyI) pyrrolidine L-(+)-tartrate monohydrate (Darifenacin intermediate).
Another aspect of the present invention is to provide process for the preparation of darifenacin intermediate.
Yet another aspect of the present invention is to provide process for the preparation of darifenacin or its pharmaceutically acceptable salts from darifenacin intermediate.

Brief Description of the Drawing
Figure 1 is the X-ray powder diffraction pattern of Darifenacin intermediate.
Figure 2 is the DSC pattern of Darifenacin intermediate.
Figure 3 is the IR pattern of Darifenacin intermediate.
Figure 4 is the TGA pattern of Darifenacin intermediate
Figure 5 is the X-ray powder diffraction pattern of Darifenacin hydrobromide.
Detailed Description of the Invention
The present invention relates to crystalline 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine L-(+)-tartrate monohydrate (Darifenacin intermediate) and process for the preparation of Darifenacin intermediate, it is further reacted with 5-(2-bromoethyl) benzo[2,3-b]furan to get Darifenacin which is converted into its pharmaceutically acceptable salts by convention method with improved yield and quality.
According to our present invention crystalline 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine L-(+)-tartrate monohydrate which is characterized by PXRD peaks at 5.147 ±0.2, 10.3±0.2, 11.34 ±0.2, 15.46 ±0.2, 17.67 ±0.2, 18.79 ±0.2, 20.13 ±0.2, 20.68 ±0.2, 22.29 ±0.2, 25.13 ±0.2, 25.4 ±0.2, 36.05 ±0.2, 36.62 ±0.20.
According to our present invention, crystalline 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine L-(+)-tartrate monohydrate is characterized by its physical properties as well as by spectral data which includes X-ray powder diffraction pattern, differential scanning calorimeter (DSC), FTIR absorption spectrum (FTIR) and thermo gravimetric analysis (TGA).
Powder X-rav Diffraction (PXRD)
The said polymorph of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorph of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 0/ 9 configuration and X'Celerator detector. The Cu-

anode X-ray tube was operated at 40 KV and 30 mA. The experiments were conducted over the 2 9 range of 2.0°-5.0°, 0.030° step size and 50 seconds step time.
Differential Scanning Calorimetrv (DSO
The DSC experiments were carried out on Mettler Toledo 822 Star and TA QIOOO of TA instruments. The experiments were performed at a heating rate of 10.0 ° C/min over a temperature range of 30° C-300° C purging with nitrogen at a flow rate of 150 ml/min and 50ml/min.Standard aluminum crucibles covered by lids with three pin holes were used.
Thermo Gravimetric Analysis (TGA)
TGA was recorded using the instrument Mettler Toledo TGA/SDTA 85 I and TA Q
5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °
C/min over a temperature range of 30-300° C purging with nitrogen at a flow rate of
20ml/min and 25ml/min.
Fourier TransForm Infrared spectroscopy (FTIR)
Fourier transform infrared (FTIR) spectra were recorded with a Perkin-Elmer
spectrum one spectrophotometer. The samples were prepared as 13mm thickness
potassium bromide discs by triturating 1 to 2mg of sample with 300mg to 400mg of
KBR by applying pressure of about 1000 Ibs/sq inch. Then theses discs were scanned
in the spectral range of 4000 to 650 cm'' with a resolution of 4 cm''.
According to our present invention, process for the preparation of crystalline 3-(S)-
(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine L-(+)-tartrate monohydrate
comprises; reacting 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrroIidine
hydrobromide with base to form 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine. It is reacted with a hydrolyzing agent to form 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethy(pyrrolidine, which is further reacted with a tartaric acid solution to form crystalline 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine L-(+)-tartrate monohydrate.


According to our present invention , 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine hydrobromide is dissolved in dichloromethane and desaltification of hydrobromide salt is carried out in presence of aqueous base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or mixture thereof preferably sodium hydroxide solution to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine.
3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine is hydrolyzed to give 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl) pyrrolidine in presence of acid such as sulphuric acid , hydrochloric acid, hydrobromic acid, phosphoric acid preferably sulphuric acid, which is further treated with tartaric acid solution to give 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine L-(+)-tartrate monohydrate. Tartaric acid solution is prepared by dissolving tartaric acid in alcohol such as methanol, ethanol, n-propanol, isopropanol, pentanol, water or mixture thereof preferably npropanoi and water mixture at 30-50° C.
Another aspect of the present invention is process for the preparation of Darifenacin or its pharmaceutically acceptable salts which comprises:
a) reacting Darifenacin intermediate of formula (VI b) with 5-(2-bromoethyl)
benzo[2,3-b]furan in presence of a base to give Darifenacin;
b) treating Darifenacin with acid in solvent and
c) isolating Darifenacin pharmaceutically acceptable salts

According to our present invention, Darifenacin intermediate (VI b) is reacted with 5-(2-bromoethyl) benzo[2,3-b]furan in presence of a base to give Darifenacin. Base is selected from group comprising sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate preferably potassium hydroxide and solvent selected from group comprising acetonitrile, dimethylformamide, dimethyl sulfoxide, acetone, tetrahydrofuran preferably acetonitrile to give darifenacin and is treated with a acid to form Darifenacin acid addition salts. Acid is selected from hydrochloric acid, hydrobromic acid and preferred acid is hydrobromic acid.
According to our invention, Crystalline Darifenacin monohydrate is used for condensation reaction with 5-(2-bromoethyl) benzo[2,3-b]furan, whereas the formation of dimmer impurity and other impurities are less as compared to prior art. Avoided the number of purification steps at final stage to get the desire quality of Darifenacin.

EXAMPLES
Example-1: Preparation of l-tosvl-3-(R)-hvdroxvpvrrolidine
A mixture of cyclohexanol (200 ml), (2S,4R)-4-hydroxy-2-pyrroIidinecarboxylicacid (100 g) and 2-cyclohexen-l-one (10 ml) was heated to reflux. After completion of the reaction, reaction mass was cooled to R.T. Toluene (400 ml) and triethyl amine (92.4 g) were added to the reaction mass and cooled to 0-5° C. p-toluene sulphonyl chloride was added to the above reaction mass in lots and maintained at 0-5° C. Slowly heated the reaction mass to R.T. After completion of the reaction, distilled off solvent under vacuum and crystallization in isopropyl alcohol gave l-tosyl-3-(R)-hydroxypyrrolidine.
Example-2; Preparation of l-tosvl-3-(S)-(-)-tosvIoxvpvrrolidine
Methyl-p-toluenesulfonate (56 g) was added to the slurry of dichloromethane (250 ml), l-tosyl-3-(R)-hydroxypyrrolidine (50 g), and triphenylphosphine (77.5 g) under nitrogen gas at 0-5 ° C. Cooled the reaction mass to -20 to -25° C. Solution of diethylazodicarboxylate (69 g) and dichloromethane (400 ml) was added to the reaction mass at -20 to -25° C. Maintained for 1-2 hours then heated to 40-50° C. The reaction mass was washed with 10% sodium carbonate solution followed by washing with DM Water to quench excess diethylazodicarboxylate. Reaction mass was extracted with dichloromethane and distilled off solvent under vacuum, crystallized from n-propanol to give l-tosyl-3-(S)-(-)-tosyloxypyrrolidine.
Example-3; Preparation of 3-(S)-(+)-(l-cvano-l.l-diphenvlmethy)-l-tosylpyrrolidine
A mixture of diphenyl acetonitrile (77.0 g) and potassium hydroxide (40 g) was suspended in tetrahydrofuran (480 ml) at 25-35° C under nitrogen gas atmosphere. Cool the reaction mass to 10-20° C. Slowly add l-tosyl-3-(S)-(-)-tosyloxypyrrolidine (120 g) at 15-20° C and raise the temperature to reflux up to completion of the reaction. Cool the reaction mass to 25-35° C. DM water (1200 ml) and dichloromethane (600 ml) were added to reaction mass then two layers were separated and dichloromethane layer was subjected to distillation under vacuum to give residue.

Residue was crystallized from methanol (600 ml) to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-1 -tosylpyrrolidine.
Example-4; Preparation of 3-fS)-(+Hl-cvano-l,l-diphenvlmethvl) pyrrolidine HBr
A mixture containing 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l-tosylpyrrolidine (45 g), 48% aqueous hydrobromic acid (225 ml) and phenol (10.12 g) was heated under reflux for 2-4 hours then cooled to room temperature. The mixture was extracted with dichloromethane and distilled out dichloromethane under vacuum. Ethyl acetate was added to reaction mass at 40-45° C and maintained at that temperature. Distilled out solvent under vacuum. Reaction mass was cooled to 0-5° C gradually and filtered to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl) pyrrolidine HBr.
Example-5; Preparation of 3-(S)-(+)-(l-carbamovl-l.l-
diphenvlmethvnpvrrolidine L-(+)-tartrate monohvdrate
3-(S)-(+)-(l-cyano-l,l-diphenylmethyl) pyrrolidine HBr (25 g) was dissolved in dichloromethane (125 ml) and treated with sodium hydroxide solution and maintained the reaction mass pH at 10-12. After 60-80% distillation of the solvent, reaction mass was added to the sulphuric acid solution at 50-55° C. The solvent is distilled completely under vacuum. Reaction mass was heated to 90-100° C, after completion of the reaction, reaction mass was cooled to room temperature. The reaction mass pH was adjusted by adding above mass to solution of sodium hydroxide (80 g), water (500 mi) and toluene (138 ml). The combined toluene layers were treated with carbon and filtered. L-(+)-Tartaric acid solution (tartaric acid solution is prepared by dissolving in «-propanol and water at 30-50° C) was added to the reaction mass at 50-60° C. Cool and filter the reaction mass to give 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine L-(+)-tartrate monohydrate. m.p: 168-170° C.

Example-6; Preparation of Darifenacin hydrobromide
5-(2-Bromoethyl)benzo[2,3-b]furan (17.2 g) was added to the mixture of 3-(S)-(+)-(l-carbamoyl-I, l-diphenylmethyl)pyrrolidine.L-(+)-tartrate (25 g), potassium hydroxide (11.4 g) in acetonitrile solvent at 25-35° C. Reaction mass was heated to 40-45° C and maintained up to completion of the reaction . Reaction mass was cooled to R.T and extracted the reaction mass with dichloromethane, distilled off solvent under vacuum to give residue. Acetone was added to the residue and cooled to 10-15° C. Hydrobromic acid was added to the above solution and heated to 20-25° C and maintained for 10-12 hours. Filtered the reaction mass to give Darifenacin hydrobromide.
Example-?: Preparation of Darifenacin hydrobromide
5-(2-Bromoethyl)benzo[2,3-b]furan (17.2 g) was added to the mixture of 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine.L-(+)-tartrate monohydrate (25 g), potassium hydroxide (11.4 g) in tetrahydrofuran solvent. Reaction mass was heated under reflux and maintained up to completion of the reaction. Reaction mass was cooled to R.T and extracted the reaction mass with dichloromethane, distilled off solvent under vacuum to give residue. Acetone was added to the residue and cooled to 10-15° C. Hydrobromic acid was added to the above solution and heated to 20-25° C and maintained for 10-12 hours. Filtered the reaction mass to give Darifenacin hydrobromide.
Example-8; Purification of Darifenacin Hydrobromide.
Darifenacin hydrobromide (50 g) was dissolved in methanol 300 ml treated with carbon and filtered. The clear filtrate was distilled off methanol, ethanol was added 400 ml, then reaction mass was heated to reflux. The resulting reaction mass was cooled to 25-30° C, separated solid was filtered to give Darifenacin hydrobromide.

We Claim:
1. Crystalline 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine L-(+)-
tartrate monohydrate of the formula (V1 b).

2. A crystalline formula (VI b) according to claim 1, wherein crystalline formula (VI b) is having the PXRD pattern as shown in the figure 1.
3. A crystalline formula (VI b) according to claim I, where in crystalline formula (VI b) is having 20 values 5.147 ±0.2, 10.3 ±0.2, 15.46 ±0.2, 17.67 ±0.2, 22.29 ±0.2, 25.13 ±0.2.
4. A crystalline formula (VI b) according to claim 1, where in crystalline formula (VI b) is having DSC peaks at 99.63° C and 182.94° C; shown in figure-3.
5. A crystalline formula (VI b) according to claim 1, where in crystalline formula (VI b) is having the TGA pattern as shown in figure-4.
6. An improved process for the preparation of Crystalline 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine L-(+)-tartrate monohydrate which comprising the steps of:

a) reacting 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine hydrobromide of formula (V) with base to form 3-(S)-(+)-(l-cyano-1,1-diphenylmethyl) pyrrolidine,
b) treating 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine in-situ with a acid to give 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine,
c) reacting 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl)pyrrolidine in-situ with a tartaric acid solution to give 3-(S)-(+)-(l-carbamoyl-1,1-diphenyl -methy1) pyrrolidine tartrate monohydrate.

7. According to claim 6a, wherein base is selected from sodium hydroxide,
potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium
carbonate, potassium bicarbonate or mixture thereof.
8. A process according to claim 6b, wherein acid is selected from sulphuric acid,
hydrochloric acid, hydrobromic acid, phosphoric acid or mixture thereof.
9. A process according to claim 6c, wherein tartaric acid solution is prepared by
dissolving tartaric acid in a solvent.
10. A process according to claim 9, wherein solvent is selected from alcohol such as
methanol, ethanol, n-propanol, isopropanol, water or mixture thereof.
11. A process for the preparation of Darifenacin hydrobromide which comprising

the steps of:
a) condensing of 3-{S)-(+)-(l-carbamoyl-l,l-diphenylmethyl) pyrrolidine
.L-(+)-tartrate monohydrate of formula (VI) with 5-(2-
bromoethyl)benzo[2,3-b]furan in presence of base and solvent;

b) treating with hydrobromic acid to give Darifenacin hydrobromide.
12. A process according to claim 11a, wherein base is selected from the group
comprising of sodium hydroxide, potassium hydroxide, magnesium oxide,
calcium oxide or mixture thereof
13. A process according to claim 11a, wherein solvent is selected from hexane,
benzene, toluene, diethyl ether, chloroform, ethyl acetate, 1,4-dioxane,
tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide,
dimethyl sulfoxide, or mixture thereof
I