An improved process for preparing Fesoterodine

Field of the invention

The present invention relates to an improved process for preparing Fesoterodine of formula (I).

Background of the invention

The chemical name of Fesoterodine is [2-[(1R)-3-(Di(propan-2-yl)amino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl]2-methylpropanoate. The product is marketed in the form of fumarate salt. The current pharmaceutical product containing this drug is being sold by Pfizer using the tradename Toviaz, in the form of extendend release oral tablets in 4mg and 8mg dosage form.

Fesoterodine is cholinergic antagonist and muscarinic antagonist. Fesoterodine is rapidly de-esterified to its active metabolite, (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxymethyl tolterodine, which is a muscarinic receptor antagonist. Fesoterodine is used as Urinary Incontinence Products. It is used to treat overactive bladder.

US patent 6,713,464 describes a process for the preparation of Fesoterodine which is shown in the Scheme- I, (a) & (b).

Scheme-I

The above processes for preparation of Fesoterodine use costly reagent which requires specific handling skill when used. Moreover, some of the reagents like Lithium aluminium hydride should be avoided while using at plant because it dangeraously reacts towards water and being more hygroscopic in nature compared to other reducing reagents like sodium borohydride. Further, the reduction with Lithium aluminium hydride takes 18 hours for reaction completion. The use of thionyl chloride in acid chloride formation process requires lengthy and tedious work up process to remove thionyl chloride. The reduction step with lithium aluminium hydride and chlorination with thionyl chloride causes a significant amount of waste on large scale, which is disadvantageous both from an economical as well as from an ecological point of view. These all drawbacks make the process costly and unsuitable at industrial level.

WO2009037569A2 discloses process for preparation of Fesoterodine wherein reduction of ester group is described using metal hydride such as sodium borohydride and sodium cyanoborohydride in presence of Lewis acid such aluminium chloride, calcium chloride, boron triflouride and zinc chloride as shown in Scheme-III

Scheme-III

The process involves reduction of ester to alcohol in the presence of sodium borohydride and aluminium chloride.

Fesoterodine obtained by the process described in the '464 patent is not satisfactory from purity point of view, the yields are very low, and have the following disadvantage and limitations:
i) Expensive and hazardous reagent like Lithium aluminium hydride is difficult to use at commercial scale since it reacts with water, including atmospheric moisture, and the pure material is pyrophoric.
ii) Amination reaction involves 97 hours for completion,
iii) Longer reaction times and lower yields in some steps.
iv) In prior art procedure intermediates are not isolated as solids in most of the steps and may lead to carryover of impurities to proceeding steps.

Based on the aforementioned drawbacks, prior art processes find to be unsuitable for preparation of Fesoterodine at lab scale and commercial scale operations.
Hence, a need still remains for an improved and commercially viable process of preparing pure Fesoterodine or a pharmaceutically acceptable salt thereof that will solve the aforesaid problems associated with process described in the prior art and will be suitable for large-scale preparation, in lesser reaction time, in terms of simplicity, purity and yield of the product.

All other processes in the prior art disclose reduction of ester to alcohol but none of the process describes a process for preparation of alcohol from acid whereas the present invention provides a reduction process form acid to alcohol using milder reducing reagent. The present invention provides a convenient, commercially viable and environment friendly process for the preparation of Fesoterodine. Moreover, the reagents used for present invention are non-hazardous and easy to handle at commercial scale and also involves less reaction time. The process avoids tedious and cumbersome procedures of isolation and uses process which is convenient to operate on a commercial scale. The present inventors have focused their research work towards developing economical, environment friendly and easy to operate process which is advantageous over prior art processes.

Object of the invention:
Accordingly, it is an object of the present invention to provide an improved process for the preparation of Fesoterodine.

Another object of the present invention is to provide a process which gives Fesoterodine with high purity.

Another object of the present invention is to provide a process which is operationally simple and cost effective.

Summary of the invention:

In one aspect, the present invention provides an improved process for preparation of Fesoterodine (I)

comprising a step of reacting compound of formula (II) with chloroformate in the presence of base to give mix anhydride of formula (III) which is insitu further reacted with diisopropyl amine to give amide of formula (IV)

In second aspect, the present invention provides an improved process for preparation of Fesoterodine (I) comprising a step of reducing compound of formula (IV) with sodium borohydride and boron trifluoride to give compound of formula (V)

In third aspect, the present invention provides an improved process for preparation of Fesoterodine (I) comprising a step of reducing compound of formula (VI) with sodium borohydride in presence of acid to give compound of formula (VII)

In fourth aspect, the present invention provides an improved process for preparation of Fesoterodine (I) comprising a step of reducing compound of formula (II) with sodium borohydride in presence of acid to give compound of formula (X)

In fifth aspect, the present invention provides an improved process for preparation of Fesoterodine (I) comprising a step of reacting compound of formula (X) with halogenating reagent in the presence of triphenyl phosphine to give compound of formula (XI)

Hal is Cl, Br or I.

In sixth aspect, the present invention provides an improved process for preparation of Fesoterodine (I) comprising a step of reacting compound of formula (XI) with diisopropylamine to give compound of formula (V)

The present invention provides an improved process for preparation of Fesoterodine (I)

comprising,
(i) reacting compound of formula (II) with chloroformate in the presence of base give mix anhydride of formula (III) which is insitu further reacted with diisopropyl amine to give amide of formula (IV)

(ii) reducing compound of formula (IV) with sodium borohydride and boron trifluoride to give compound of formula (V)

(iii) reacting compound of formula (V) with a Grignard catalyst and Mg to form Grignard reagent and reacting it with carbon dioxide to give compound of formula (VI)

(iv) reducing compound of formula (VI) with sodium borohydride in presence of acid to give compound of formula (VII)

The present invention provides an improved process for preparation of Fesoterodine (I)

comprising
(a) reducing compound of formula (II) with sodium borohydride in presence of acid to give compound of formula (X)

(b) reacting compound of formula (X) with halogenating reagent in the presence of triphenyl phosphine to give compound of formula (XI)

Hal is Cl, Br or I.
(c) reacting compound of formula (XI) with diisopropylamine to give compound of formula (V)

Detailed description of the invention:

The embodiments of present invention is shown in the scheme IV.

Scheme-IV
‘Bn’ refers to benzyl group i.e –CH2Ph.

The process involves reacting compound of formula (II) with chloroformate in the in the presence of base and solvent to give mix anhydride of formula (III). The compound of formula (II) is either in racemic form or in its pure enantiomeric form. For preparation of Fesoterodine R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid is taken as preferred enantiomer.

Chloroformate used herein above includes ethyl chloroformate, methyl chloroformate and benzyl chloroformate or mixtures thereof.

Base used are organic base such as triethyl amine, diethylamine, diisopropyl amine, diisopropyl ethyl amine, dicyclohexylamine, pyridine, picoline, N-methyl piperazine, piperidine, methylamine, t-butylamine, morpholine, N-methyl morpholine, lutidines, collidines, 1,8 diazabicyclo [5,4,0] undec 7-ene (DBU), Tetramethyl guanidine (TMG), 1,4 diazabicyclo [2,2,2] octane (DABCO), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN)

Solvents used are selected from chlorinates solvents such as dichloromethane, chloroform, dichloroethane, 1,1,1 trichloroethane, carbontetrachloride, chlorobenzene, dichlorobenzene, trichlorobenzene or mixtures thereof. The more preferable solvent is dichloromethane.

The reaction is carried out at temperature from about 0° to 10°C. After completion of the reaction on thin layer chromatography (TLC), diisopropylamine is added to the reaction and then reaction mixture stirred for about 18 to 22 hours at 25 to 350C. DM Water is added to the reaction mixture and organic layer is separated, washed with saturated solution of sodium bicarbonate. The solvent is evaporated to give compound of formula (IV). In this process mixed anhydride of formula (III) is generated insitu which is without isolation is reacted with diisopropyl amine.

Amide of formula (IV) is reduced using sodium borohydride and boron trifluoride etherate to give compound of formula (V). R-(-)-N, N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide in THF is reacted with sodium borohydride and Boron trifluoride etherate at about 0°C to about 10°C. The reaction mixture is stirred at 25 to 35°C for about 16 to about 18 hours. The reaction is very sensitive to moisture. Therefore it is very necessary to maintain moisture free environment. 10 % hydrochloric acid is added to the reaction mixture and heated at temperature from about 65° to about 70°C for 2 hrs. The addition of hydrochloric acid is very critical and it requires slow addition due to frothing. The reaction mixture is diluted with water and extract with a solvent such as ethyl acetate. The organic layer is separated and washed with 10% sodium bicarbonate solution, DM Water and brine solution. The organic layer is distilled out to give R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine.

Compound of formula (V) is reacted with Mg metal in presence of a Grignard catalyst and in a solvent to form Grignard reagent which is further reacted with carbon dioxide to give compound of formula (VI).

Grignard catalyst is selected from dibromoethane, ethylbromide, methyl iodide, ethyl magnesium bromide, methyl magnesium bromide, iodine and the like or mixtures thereof.

The solvents used for this step are selected from THF, toluene, xylene, diethyl ether, methyl tert butyl ether and the like or mixtures thereof.

In this process, Mg metal in dry THF is heated to 55 to 65°C. Grignard catalyst such as iodine and dibromoethane is added and heated further. A solution of R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine (V) in dry THF is added slowly to the reaction mixture at a temperature of about 60° to about 70°C within 1 to 2 hours. The reaction mixture is stirred for 2 hours at the same temperature and then the reaction mixture is chilled to -60°C. Carbon dioxide solid is added to the reaction mixture within 1 to 2 hours and then heated at 25° to 35°C and stirred for 1 to 2 hours. Carbon dioxide gas can also be used by bubbling into the reaction mixture instead of using solid carbon dioxide. After completion of the reaction, the mixture is quenched with dropwise addition of aq. ammonium chloride. Conc. Hydrochloric acid is added to the reaction mixture till pH 1 is obtained. The product is filtered and dried at 55 to 60°C under vacuum to give hydrochloride salt of R-(-)-4-benzyloxy-3-(3- diisopropylamino-1-phenylpropyl)-benzoic acid (VI).

The hydrochloride salt of compound (VI) is made free base by treating it with base. Thus, R-(-)-4-benzyloxy-3-(3- diisopropylamino-1-phenylpropyl)-benzoic acid hydrochloride in dichloromethane and water is treated with base such as liq. Ammonia till pH 8 to 9 is obtained. The organic layer is separated and aq. layer is extracted with fresh dichloromethane. The combined organic layer is washed with brine solution. The organic layer is distilled to give R-(-)-4-benzyloxy-3-(3- diisopropylamino-1-phenylpropyl)-benzoic acid (VI). The obtained compound is reduced with sodium borohydride in the presence of an acid and solvent.

The solvents used for this step is selected from dioxane, tetrahydrofuran (THF), ethylene glycol dimethyl ether, methyl t-butyl ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide or mixtures thereof. Most preferable solvent is tetrahydrofuran (THF).

The acid used for this step is selected from the group comprising of methanesulfonic acid, sulfuric acid, trifluoroacetic acid and the like or mixtures thereof.

R-(-)-4-benzyloxy-3-(3- diisopropylamino-1-phenylpropyl)-benzoic acid (VI) is added to a suspension of sodium borohydride in THF at 25° to 35°C and stirred for about 1 hour. Conc. Sulfuric acid is added slowly to the reaction mixture at ambient temperature within 1 to 2 hours. The reaction mixture is heated at about 65°C to about 70°C till completion of the reaction. The completion of the reaction is checked on TLC. The solvent is distilled out from the reaction mixture at the same temperature and then reaction mass is cooled to 25 to 35°C. Aq. HCl solution is added to the reaction mass at 5 to 10°C. DM Water and dichloromethane is added to the reaction mixture. The organic layer is separated and washed with DM water, sodium bicarbonate solution and brine solution. The organic layer is distilled out to give R-(-)-[4-benzyloxy-3-(3- diisopropylamino-1-phenylpropyl)-phenyl]-methanol (VII).

The benzyl group of the compound of formula (VII) is deprotected by catalytic hydrogenation using Raney Nickel in alcoholic solvent such as methanol, ethanol, propanol, isopropanol. The reaction is carried out ambient temperature. After completion of reaction, the catalyst is filtered off and the solvent from filtrate is removed to give R-(-)-2-(3- diisopropyl amino-1-phenylpropyl)-4-hydroxymethylphenol (VIII).

The compound of formula (VIII) is condensed with isobutryl chloride in presence of solvent and base to give compound of formula (IX). Thus to a mixture of R-(-)-2-(3- diisopropyl amino-1-phenylpropyl)-4-hydroxymethylphenol (VIII), dichloromethane and isobutryl chloride is added triethylamine at 0°C to 5°C dropwise within 1 to 2 hours. Then the reaction mixture is stirred at 25° to 35°C for about 18 to 20 hours till completion of the reaction. The reaction mixture is washed with water and aq. NaHCO3. The solvent is distilled out from the organic layer to give R-(-)-2-(3- diisopropyl amino-1-phenylpropyl)-4-hydroxymethylphenol isobutyrate ester or Fesoterodine (I).

The other embodiments of present invention are shown in the scheme V.

Scheme-V

The process as shown in scheme V involves reduction of compound of formula (II) with sodium borohydride in the presence of acid to give compound of formula (X). The reduction process is similar to the process described in reduction of compound of formula (VI).

The solvents used for this step is selected from dioxane, tetrahydrofuran (THF), ethylene glycol dimethyl ether, methyl t-butyl ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide or mixtures thereof. Most preferable solvent is tetrahydrofuran (THF).

The acid used for this step is selected from the group comprising of methanesulfonic acid, sulfuric acid, trifluoroacetic acid and the like or mixtures thereof.

R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid (II) is added to a suspension of sodium borohydride in THF at 25° to 35°C and stirred for about 1 hour. Conc. Sulfuric acid is added slowly to the reaction mixture at ambient temperature within 1 to 2 hours. The reaction mixture is heated at about 65°C to about 70°C till completion of the reaction. The completion of the reaction is checked on TLC. The solvent is distilled out from the reaction mixture at the same temperature and then reaction mass is cooled to 25 to 35°C. Aq. HCl solution is added to the reaction mass at 5 to 10°C. Dichloromethane is added to the reaction mixture and extraced. The organic layer is separated and washed with DM water, and brine solution. Sodium sulfate and charcoal is added to the organic layer and stirred. The suspension is filtered through hyflo bed and the bed is washed with dichloromethane. The organic layer of filtrate is distilled out to give (3R)-3-[2-(benzyloxy)-5-bromophenyl]-3-phenylpropan-1-ol (X).

The compound of formula (X) is reacted with halogenating reagent in the presence of triphenyl phosphine to give compound of formula (XI).

Halogenating reagent can be chlorinating reagent, brominating reagent or iodinating reagent. Depending on the selection of chloro, bromo or iodo group, the halogenating reagent is chosen. The example of chlorinating reagents are N-chlorosuccinimide, phosphorous pentachloride, phosphorous trichloride and the like or mixtures thereof. The example of brominating reagents are N-chlorosuccinimide, dibromodimethyl hydantoin, phosphorous tribromide and the like or mixtures thereof. The example of iodinating reagents are potassium iodide, sodium iodide and the like or mixtures thereof.

Solvents used are selected from chlorinates solvents such as dichloromethane, chloroform, dichloroethane, 1,1,1 trichloroethane, carbontetrachloride, chlorobenzene, dichlorobenzene, trichlorobenzene or mixtures thereof. The more preferable solvent is dichloromethane.

(3R)-3-[2-(benzyloxy)-5-bromophenyl]-3-phenylpropan-1-ol (X) in dichloromethane is cooled at 5° to 15°C and triphenyl phosphine is added to it. N-bromosuccinimide (NBS) is added to the reaction mixture portion wise within half an hour. After completion of the reaction, the solvent is distilled out from the reaction mixture. Hexane and ethyl acetate (9-10:1) is added to the residue and stirred at ambient temperature for 1 hour. The solvent is decanted and the remaining solvent is removed from the slurry by distillation at 55° to 65°C to give 1-(benzyloxy)-4-bromo-2-[(1R)-3-bromo-1-phenylpropyl] benzene (XI).

The compound of formula (XI) is reacted with diisopropyl amine in solvent to give compound of formula (V).

Solvents used are selected from acetonitrile, toluene, xylene, THF, carbon tetrachloride, N, N-dimethyl formamide (DMF) and the like or mixtures thereof. The most preferred solvent is acetonitrile.

A mixture of 1-(benzyloxy)-4-bromo-2-[(1R)-3-bromo-1-phenylpropyl] benzene (XI), acetonitrile, diisopropyl amine and potassium iodide is heated in autoclave at temperature from about 115°C to about 120°C. The reaction takes place generally from about 8 to 10 hours. The reaction mixture is cooled at room temperature. The solvent is distilled out from the reaction mixture at 55° to 65°C under reduced pressure. Diisopropyl ether is added to the reaction mass. Aq. NaOH solution is added to the reaction mixture till pH 10 to 11 is obtained. The organic layer is separated and DM Water is added. Conc. HCl is added to the reaction mixture till pH 2 is obtained. The organic layer is removed by decantation. To the aq. layer ethyl acetate is added and then aq. NaOH is added till pH 10 to 11 is obtained. The organic layer is separated, washed with brine solution and then distilled out under vacuum to give R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine (V)

The compound of formula (V) is converted to Fesoterodine according the process described for scheme IV or by the process given in the prior art e.g the process given in US 6,713,464.

The key starting material compound of formula (II) can be prepared according the methods given in the literature. For example (+)3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid or its R or S enantiomer can be prepared according the process given in US 6,713,464. Thus R enantiomer can be prepared by condensing 4-bromophenol with cinnamic acid in the presence of sulfuric acid at 125-130°C for 8 hours to give (±)-6-bromo-4-phenylchroman-2-one. This chroman is reacted with benzyl bromide in presence of anhydrous K2CO3, methanol, acetone and sodium idodide at reflux temperature to give ester which on refluxing with aq. KOH in ethanol gives (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid. The acid is resolved using 1S, 2R (+) ephedrine hemi hydrate in ethanol to form salt which on treatment with aq. HCl gives R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid. Similary by following process given in ‘464 the S enantiomer can also be obtained.

The scope of present invention covers the racemic as well as R or S enantiomer of compound of formula (II) as starting material for the process of present invention. Depending upon the selection of racemic, R or S enantiomer we get the intermediate and product respectively. If we take R enantiomer of compound of formula (II) as starting material then we get intermediate compound (III), (IV), (V), (VI), (VII), (X), (XI) is obtained in R-configuration. Similarly if we take racemic compound of formula (II) we get intermediate compound (III), (IV), (V), (VI), (VII), (X), (XI) in racemic forms. Thus, in carrying out the sequences of reactions, the stereochemistry does not change. At any particular intermediate stage, the compound can be resolved and we can get Fesoterodine which is having R configuration. For example, if we start with racemic compound of formula (II) and get compound of formula (V) as racemic which can be resolved and further reaction be carried out on R enantiomer of formula (V) to get Fesoterodine.

In an embodiment of the process of present invention all the compounds of formula (II), (III), (IV), (V), (VI), (VII), (X), (XI) is having R configuration.

The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.

Example-1
Preparation of R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenyl propionamide (IV)
R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid (50 g) in dichloromethane (250 ml) was cooled to 0-5°C. Triethylamine (15.8 g) was added to the reaction mixture and stirred for 15 min. Ethyl chloroformate (14.5 g) was added slowly to the reaction mixture and stirred for 30 mins. The reaction is monitored by TLC. After consumption of starting material, diisopropyl amine (23.67 g) is added to the reaction mixture slowly at 0-5°C. The reaction mixture was stirred for 18 hrs at 25-35°C. DM water (150 ml) was added to the reaction mixture at 25-35°C and stirred. The organic layer was separated and washed with saturated sodium bicarbonate (100 ml) solution. The solvent was distilled out from the organic layer to give the title product (57.0 g)
Yield: 94.8%
Purity: ~95%

Example-2
Preparation of R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine (V)
R-(-)-N, N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide) (28.0 g) in tetrahydrofuran (280 ml) was cooled at 0-5°C and sodium borohydride (10.38 g) was added to it. Boron trifluoride etherate (46.99 g) was added to the reaction mixture at 0-5°C within 3 to 4 hours. The reaction mixture was stirred at 25-35°C for 16 hours. 10% hydrochloric acid (14 ml) was added dropwise to the reaction mixture. The reaction mixture was heated at 65-70°C for 2 hours. The reaction mixture was diluted with water (280 ml) and extracted with ethyl acetate (140 ml x 2). The combined organic layer was washed with 10% sodium bicarbonate solution (280 ml), process water (280 ml) and brine solution (280 ml). The organic layer was distilled at 65-70°C to give the title product (22.0 g)
Yield: 80.8%
Purity: ~96%

Example-3
Preparation of R-(-)-4-benzyloxy-3-(3- diisopropylamino-1-phenylpropyl)-benzoic acid hydrochloride (VI)
A suspension of magnesium (18.57 g) and dry tetrahydrofuran (456 ml) was heated at 55-65°C. Iodine (1.0 g) and dibromoethane (10.0 g) was added slowly to it and stirred for 10 min. A solution of R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine (228 g), dibromoethane (12.8 g) and tetrahydrofuran (456 ml) was added to the reaction mixture at 60-70°C within 1-2 hours. The reaction mixture was stirred at 65-75°C for 2 hours. The reaction mixture was chilled to -60°C. Slowly solid carbon dioxide (500 g) was added to the reaction mixture at -60°C within 1-2 hours. The reaction mixture was heated to 25-35°C and stirred for 1-2 hours. Check the completion of reaction by TLC. Aqueous ammonium chloride solution (200 ml, 10%) was added dropwise to the reaction mixture. Conc. hydrochloric acid was added to the reaction mixture till pH 1 was obtained. The product was filtered and dried at 55-60°C for 10 hours under vacuum to give the title product (147 g).
Yield: 64.2%

Example-4
Preparation of R-(-)-[4-benzyloxy-3-(3- diisopropylamino-1-phenylpropyl)-phenyl]-methanol (VII)
To a stirred mixture of R-(-)-4-benzyloxy-3-(3- diisopropylamino-1-phenylpropyl)-benzoic acid hydrochloride (30.0 g), dichloromethane (150 ml) and water (30.0 ml) was slowly added liq. ammonia (10 ml) till pH 8 to 9. The organic layer was separated and the aq. layer was extracted with dichloromethane (60 ml). The combined organic layer was washed with brine solution (60 ml). The organic layer was distilled at 35-45°C and high vacuum was applied for 0.5 hour to remove trace amount of solvent to get free base. To a suspension of tetrahydrofuran (75 ml) and sodium borohydride (3.31 g) was added above free base {26.0 g) in tetrahydrofuran (75 ml) at 25-35°C and stirred for 1 hour. Con. Sulphuric acid (5.71 g) was added to the reaction mixture at 25-35°C within 1-2 hours. The reaction mixture was heated at 65-70°C till completion of the reaction on TLC. The solvent was distilled out from the reaction mixture and the residue was cooled to 25-35°C. Aq. HCl solution (18 ml Con. Hydrochloric acid in 60 ml water) was slowly added to the reaction mixture at 5-10°C. DM Water (180 ml) and dichloromethane (140 ml) was added to the reaction mixture at 25-35°C and extracted. The organic layer was separated and washed with DM Water (60 ml), 10% sodium bicarbonate solution (60 ml) and brine solution (60 ml). The solvent was distilled out from the organic layer at 35-45°C to give the title compound (26.0 g).
Yield: 91.0%

Example-5
Preparation of R-(-)-2-(3- diisopropyl amino-1-phenylpropyl)-4-hydroxymethylphenol (VIII)
A mixture of R-(-)-[4-benzyloxy-3-(3- diisopropylamino-1-phenylpropyl)-phenyl]-methanol (91.0 g), methanol (1000 ml) and raney nickel (45.0 g) was hydrogenated using hydrogen gas at 25-35°C. After completion of reaction on TLC, the catalyst was filtered off and solvent was distilled out at 65-75°C from the reaction mixture to give the title product (69.5 g).
Yield: 96.0%

Example-6
Preparation of R-(-)-2-(3- diisopropyl amino-1-phenylpropyl)-4-hydroxymethylphenol isobutyrate ester or Fesoterodine (IX)
To a cooled mixture of R-(-)-2-(3- diisopropyl amino-1-phenylpropyl)-4-hydroxymethylphenol (171.0 g), dichloromethane (6000 ml) and Isobutrylchloride (53.0 g) at 0-5°C was slowly added a solution of triethylamine (50.2 g) in dichloromethane (1000 ml) within 1-2 hours. The reaction mixture was stirred for 18 hours at 25-35°C till completion of reaction on TLC. The reaction mixture was washed with water (1250 ml x 2) and aq. 5% NaHCO3 (1250 ml x 2). The organic layer was distilled at 35-45°C and then high vacuum was applied for 2 hours to give the title compound Fesoterodine (155.0 g)
Yield: 75.0%

Example-7
Preperation of (3R)-3-[2-(benzyloxy)-5-bromophenyl]-3-phenylpropan-1-ol (X)
A solution of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid {45.0 g) in tetrahydrofuran (180 ml) was added to a mixture of tetrahydrofuran (90 ml) and sodium borohydride (18.56 g) at 25-35°C and stirred for 1 hour. Con. sulphuric acid (10.72 g) was added slowly to the reaction mixture at 25-35°C within 1 hour. The reaction mixture was heated at 65-70°C till completion of reaction on TLC. The solvent was distilled out from the reaction mixture at 65-75°C. Cool the reaction mass at 25-35°C. DM Water was added to the reaction mixture. Aq. hydrochloric acid solution (125 ml Con. hydrochloric acid in 600 ml water) was added to the reaction mixture at 5-10°C. Dichloromethane (250 ml) was added to the reaction mixture and extracted. Organic layer was separated and the aq. layer was extracted with fresh dichloromethane (250 ml). The combined organic layer was washed with DM Water (250 ml) and brine solution (250 ml). Sodium sulphate and charcoal was added to the organic layer and stirred. The mixture was filtered through hyflow bed and the bed was washed with dichloromethane (50 ml). The solvent was distilled out from the organic layer at 35-45°C to give the title compound (38.0 g).
Yield: 87.5%

Example-8
Preperation of 1-(benzyloxy)-4-bromo-2-[(1R)-3-bromo-1-phenylpropyl] benzene (XI)
A mixture of (3R)-3-[2-(benzyloxy)-5-bromophenyl]-3-phenylpropan-1-ol (39 g), dichloromethane (390 ml) was cooled 8-120C. Triphenyl phosphine (30.89 g) was added to the reaction mixture. N-bromo succinimide was added portionwise to the reaction mass at 8-120C within 0.5 hour. The solvent was distilled out from the reaction mixture at 35-450C. Hexane (450 ml) and ethyl acetate (50 ml) was added to the residue and stirred at 25-350C for 1 hrs. The organic layer was decanted. The remaining solvent was distilled out from the slurry at 55-650C to give the title compound (38.0 g)
Yield: 84.2%

Example-9
Preparation of R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropyl amine (V)
A mixture of 1-(benzyloxy)-4-bromo-2-[(1R)-3-bromo-1-phenylpropyl] benzene (36.0 g), diisopropyl amine (39.49 gm), acetonitrile (290 ml) and KI (3.6 gm) was heated to 115-1200C in autoclave for 12 hours. After completion of reaction on TLC, the reaction mixture was cooled at 25-350C. The solvent was distilled out from the reaction mixture at 55-650C under vacuum. Diisopropyl ether (250 ml) and water (250 ml) was added to the residue and stirred at 25-35°C. Aq. sodium hydroxide was added to the reaction mixture till pH 10 is obtained. The organic layer was separated. To this organic layer DM Water was added and then Conc. hydrochloric acid was added till pH 2 is obtained. The organic layer was decanted and ethyl acetate (250) was added to the aq. layer and stirred. Aq. sodium hydroxide was added to the reaction mixture till pH 10 is obtained. The organic layer was separated and washed with brine solution. The organic layer was distilled out at 45-550C under vacuum to give the title product (31.0 g).
Yield: 84.2%

We claim,
1. A process for preparation of Fesoterodine (I)

comprising a step of reacting compound of formula (II) with chloroformate in the presence of base to give mix anhydride of formula (III) which is insitu further reacted with diisopropyl amine to give amide of formula (IV)

2. The process as claimed in claim 1, wherein chloroformate is selected from ethyl chloroformate, methyl chloroformate and benzyl chloroformate or mixtures thereof.

3. The process as claimed in claim 1, wherein base is selected from triethyl amine, diethylamine, diisopropyl amine, diisopropyl ethyl amine, dicyclohexylamine, pyridine, picoline, N-methyl piperazine, piperidine, methylamine, t-butylamine, morpholine, N-methyl morpholine, lutidines, collidines, 1,8 diazabicyclo [5,4,0] undec 7-ene (DBU), Tetramethyl guanidine (TMG), 1,4 diazabicyclo [2,2,2] octane (DABCO), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN) or mixtures thereof.

4. A process for preparation of Fesoterodine (I)

comprising a step of reducing compound of formula (IV) with sodium borohydride and boron trifluoride to give compound of formula (V)


5. A process for preparation of Fesoterodine (I)

comprising a step of reducing compound of formula (VI) with sodium borohydride in presence of acid to give compound of formula (VII)

6. The process as claimed in claim 5, wherein acid is selected from methanesulfonic acid, sulfuric acid, trifluoroacetic acid or mixtures thereof.

7. A process for preparation of Fesoterodine (I)

comprising
(i) reacting compound of formula (II) with chloroformate in the presence of base to give mix anhydride of formula (III) which is insitu further reacted with diisopropyl amine to give amide of formula (IV)

(ii) reducing compound of formula (IV) with sodium borohydride and boron trifluoride to give compound of formula (V)

(iii) reacting compound of formula (V) with a Grignard catalyst and Mg to form Grignard reagent and reacting it with carbon dioxide to give compound of formula (VI)

(iv) reducing compound of formula (VI) with sodium borohydride in presence of acid to give compound of formula (VII)

8. The process as claimed in claim 7, wherein chloroformate is selected from ethyl chloroformate, methyl chloroformate and benzyl chloroformate or mixtures thereof and base is selected from triethyl amine, diethylamine, diisopropyl amine, diisopropyl ethyl amine, dicyclohexylamine, pyridine, picoline, N-methyl piperazine, piperidine, methylamine, t-butylamine, morpholine, N-methyl morpholine, lutidines, collidines, 1,8 diazabicyclo [5,4,0] undec 7-ene (DBU), Tetramethyl guanidine (TMG), 1,4 diazabicyclo [2,2,2] octane (DABCO), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN) or mixtures thereof.

9. The process as claimed in claim 7, wherein Grignard catalyst is selected from dibromoethane, ethylbromide, methyl iodide, ethyl magnesium bromide, methyl magnesium bromide, iodine or mixtures thereof.

10. The process as claimed in claim 7, wherein acid is selected from methanesulfonic acid, sulfuric acid, trifluoroacetic acid or mixtures thereof.

11. A process for preparation of Fesoterodine (I)

comprising a step of reducing compound of formula (II) with sodium borohydride in presence of acid to give compound of formula (X)

12. The process as claimed in claim 11, wherein acid is selected from methanesulfonic acid, sulfuric acid, trifluoroacetic acid or mixtures thereof.

13. A process for preparation of Fesoterodine (I)

comprising a step of reacting compound of formula (X) with halogenating reagent in the presence of triphenyl phosphine to give compound of formula (XI)

Hal is Cl, Br or I.

14. The process as claimed in claim 13, wherein halogenating reagent is selected from chlorinating reagents such as N-chlorosuccinimide, phosphorous pentachloride, phosphorous trichloride or mixtures thereof, brominating reagents such as N-chlorosuccinimide, dibromodimethyl hydantoin, phosphorous tribromide or mixtures thereof and iodinating reagents such as potassium iodide, sodium iodide or mixtures thereof.

15. A process for preparation of Fesoterodine (I)

comprising a step of reacting compound of formula (XI) with diisopropylamine to give compound of formula (V)

16. A process for preparation of Fesoterodine (I)

comprising ,
(a) reducing compound of formula (II) with sodium borohydride in presence of acid to give compound of formula (X)

(b) reacting compound of formula (X) with halogenating reagent in the presence of triphenyl phosphine to give compound of formula (XI)

Hal is Cl, Br or I.
(c) reacting compound of formula (XI) with diisopropylamine to give compound of formula (V)

17. The process as claimed in claim 16, wherein acid is selected from methanesulfonic acid, sulfuric acid, trifluoroacetic acid or mixtures thereof.

18. The process as claimed in claim 16, wherein halogenating reagent is selected from chlorinating reagents such as N-chlorosuccinimide, phosphorous pentachloride, phosphorous trichloride or mixtures thereof, brominating reagents such as N-chlorosuccinimide, dibromodimethyl hydantoin, phosphorous tribromide or mixtures thereof and iodinating reagents such as potassium iodide, sodium iodide or mixtures thereof.

19. The process according to any preceding claim characterized in that the compound of formula (II), (III), (IV), (V), (VI), (VII), (X), (XI) is having R configuration.