Related Applications

This application claims the benefit of Indian provisional patent application Nos.: 1393/CHE/2010 filed on 17 ^th May 2010; 2217/CHE/2010 filed on 4 ^th August 2010 and 3666/CHE/2010 filed on 6 ^th December 2010, the contents of which are incorporated herein in their entirety.

Field of the invention

The present invention relates to an improved process for the preparation of biologically active diphenylpropylamine derivatives. The present invention specifically relates to an improved process for the preparation of fesoterodine of formula (I) and its pharmaceutically acceptable salts.

(I)

The present invention further relates to an improved process for the preparation of (+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3- phenylpropylamine or (+)-5-hydroxymethyl tolterodine of formula (II) or its stereoisomers, which is an active metabolite and one of the important intermediate in the preparation of fesoterodine.

Background of the Invention

5 -hydroxy methyl tolterodine is an active metabolite of muscarinic receptor antagonist drugs selected from Tolterodine and Fesoterodine. Fesoterodine is a prodrug of 5-hydroxy methyl tolterodine and is chemically known as Isobutyric acid 2-((R)-3-diisopropylammonium- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester. Both Tolterodine and Fesoterodine are intended for the treatment of urinary urge incontinence and other symptoms of blader over activity. 5-hydroxy methyl tolterodine of formula (II) has been first disclosed in US

5,559,269. There are several patent publications disclosed the process for the preparation of 5-hydroxymethyl tolterodine of formula (II). For example, the process disclosed in US 5,559,269 is widely used and is schematically represented as below (scheme-A)

(g) (II) Scheme-A: Step-1: p-TsCl, pyridine, MDC; Step-2: Diisopropylamine, CH ₃ CN, reflux 4 days; Step-3: L(-)-tartaric acid, ethanol; Step-4: Mg, EtBr, I ₂ , dryice; Step- Si MeOH, H ₂ SO ₄ ; Step-6: LiAlH ₄ , diethylether; Step-7: RaNi, MeOH The above disclosed process involves the reaction of 3-(2-benzyloxy-5- bromophenyl)-3-phenylpropanol (a) with /^-toluene sulfonylchloride in the presence of pyridine in methylenechloride (MDC) at 0°C to provide 3-(2-benzyloxy-5- bromophenyl)-3-phenylpropyl-p-toluenesulfonate (b), which on reaction with diisopropylamine in acetonitrile under reflux conditions for 4 days to provide the N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenyl propylamine (c). This compound-c was resolved with L-(-)-tartaric acid in ethanol, followed by treatment of the obtained tartrate salt compound with sodium hydroxide in ethanol to provide (-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpr opylamine(d). Compound-(d) further reacted with Mg, ethylbromide, iodine and in presence of dryice in diethylether to provide (-)-N,N-diisopropyl-3-(2-benzyloxy-5- carboxyphenyl)-3-phenylpropylamine hydrochloride (e), which is further treated with methanol in presence of sulphuric acid to provide (-)-N,N-diisopropyl- 3-(2-(benzyloxy-5-carbomethoxyphenyl)-3-phenylpropylamine (f). Thus obtained compound-(f) on reduction with lithium aluminium hydride in diethyl ether to provide (+)-N,N-diisopropyl-3-(2-benzyloxy-5-hydroxymethylphenyl)-3- phenyl propyl amine(g), which is further reacted with Raney Ni under hydrogenation condition in methanol provides the compound of formula (II).

The above disclosed process have number of draw backs, such as it utilizes hazardous lithium aluminium hydride (LAH) for the reduction of (-)-Ν,Ν- diisopropyl-3-(2-(benzyloxy-5-carbomethoxyphenyl)-3-phenylpr opylamine

(compound-f). The use of LAH is difficult to handle in industrial scale and requires precaution measures. Further the preparation of N,N-diisopropyl-3-(2-benzyloxy-5- bromophenyl)-3-phenylpropylamine (compound-c) from 3-(2-benzyloxy-5- bromophenyl)-3 -phenyl propyl-p-toluenesulfonate (compound-b) takes about 4 days at reflux temperature to complete, which increases the time of production and over all cost of the product. Further the resolution of N,N-diisopropyl-3-(2-benzyloxy-5- bromophenyl)-3-phenylpropylamine (compound-c) with tartaric acid provides less pure compound. In addition the resolved compound unable to obtain as a solid, which make it not suitable for further purification. Hence this process is not suitable for commercial scale. US 6,858,650 discloses the preparation of fesoterodine by the reaction of

(+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3 -phenylpropylamine with isobutyryl chloride in the presence of triethylamine gives fesoterodine and further converted into its fumarate salt by treating it with fumaric acid in 2-butanone and cyclohexane. This patent discloses the melting point of both crude and re-crystallized fesoterodine fumarate but does not disclose the purity of the same.

We the present inventors working to find an improved process to prepare 5 -hydroxy methyl tolterodine of formula (II) to overcome the above said prior art problems, we surprisingly found that the use of vitride for the reduction of N,N- diisopropyl-3-(2-(benzyloxy-5-carbomethoxyphenyl)-3-phenylpr opylamine avoids the safety problems associated with the use of LAH. Further the usage of KI as a catalyst in the reaction of 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl-p- toluenesulfonate with diisopropylamine reduces the time taken for completion of the reaction to 1 -24 hours compared to 4 days as per the prior art.

WO 2009/037569 discloses a process for preparing fesoterodine in which di-aroyl-tartaricacid was used for the resolution of N,N-diisopropyl-3-(2-benzyloxy- 5-bromophenyl)-3-phenylpropyl amine. The chiral purity and yields of the resolved product was not satisfactory.

When the present inventors working on resolution process at different intermediate levels to get better yield, purity and isolation of the resolved product, we surprisingly found that resolution at N,N-diisopropyl-3-(2-benzyloxy-5- carboxyphenyl)-3-phenylpropylamine leads to a compound with high purity, yield and easy to isolate. US 2010/0168459 disclose the reaction of R(+)-2-(3-diisopropylamino-l- phenylpropyl) -4 -hydroxy 1 methylphenol with isobutyryl chloride in the presence of Huenig's base provides fesoterodine having maximum of 2.08% of diester impurity.

WO 2010/010464 discloses a process for the preparation fesoterodine furmarate, which involve the purification of intermediate compound (+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-ph enylpropylamine and converting it into fesoterodine then converted to its mandelate salt and then to free base before converting the same into fesoterodine furmarate. The disclosed process involves number of purifications and salt formations to get the desired purity of fesoterodine fumarate, which makes the process not suitable at commercial scale.

We the present inventor working on a process to prepare highly pure fesoterodine, surprisingly found that simple washings of the reaction mixture obtained after the reaction of (+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethyl phenyl)-3-phenylpropylamine with isobutyryl chloride with suitable non-polar solvents followed by isolation of the fesoterodine in pure states avoids additional purification and salt formation as required in the prior art. Accordingly the present invention provides improved process for the preparation of compound of formula (I) and its pharmaceutically acceptable salt with high purity.

Objectives of the invention

The main objective of the present invention is to provide an improved process for the preparation of highly pure fesoterodine of formula (I) and its pharmaceutically acceptable salts which is easy to implement in industry with good yield and high purity.

Another objective of the present invention is to provide a process for the resolution of compound of formula (VI) using optically active acid, which is easy to isolate with high purity and yield. Another objective of the present invention is to provide an improved process for the preparation of highly pure (+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxy methylphenyl)-3-phenylpropylamine of formula (II) and its intermediates like compound of formula (V) & (VIII). Summary of the invention

In first aspect of the present invention provides an improved process for the preparation of fesoterodine of formula (I) and its pharmaceutically acceptable salts, which comprising the steps of:

a) treating the compound of formula (IV) with diisopropyl amine in a solvent and in the presence of a catalyst to provide the compound of formula (V); wherein the improvement consist of use of catalyst;

b) converting the compound of formula (V) to formula (VI) or its salt; c) resolving the compound of formula (VI) or its salt with a suitable optically active acid in a solvent to provide corresponding optically active salt compound of formula (VII);

d) optionally neutralizing the optically active salt compound of formula (VII) to provide its free base;

e) reducing the compound of formula (VII) or its freebase using vitride in a solvent to provide compound of formula (VIII);

f) removing the protecting group from the compound of formula (VIII) under hydrogenation condition, in the presence of a catalyst in a suitable solvent to provide (+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-ph enyl propyl amine of formula-(II);

g) reacting the compound of formula (II) with isobutyryl chloride in a solvent and in the presence of a base to provide pure fesoterodine of formula (I), characterized in that reaction mixture obtained after completion of the reaction was washed with non-polar organic solvent; and

h) optionally converting fesoterodine into fesoterodine fumarate by conventional methods.

The following scheme illustrates the present invention:

In second aspect of the present invention provides an improved process for the preparation of compound of formula (VIII), which comprises reducing the compound of formula (VII) or its freebase using vitride in a suitable solvent.

In third aspect of the present invention provides an improved process for the preparation of compound of formula (V), which comprises steps of:

i) reacting the compound of formula (III) with alkyl or aryl sulfonyl halide in the presence of an organic base and a catalytic amount of dimethylaminopyridine (DMAP) in a solvent to provide the corresponding sulphonic acid compound of formula (IV); and

ii) reacting the compound of formula (IV) with diisopropylamine in solvent and in the presence of a catalyst to provide the N,N-diisopropyl-3-(2-benzyloxy-5- bromophenyl)-3-phenylpropylamine compound of formula (V).

In fourth aspect of the present invention provides a process for the resolution of compound formula (VI), which comprises of treating the compound of formula (VI) with a suitable optically active acid in a solvent to provide the corresponding optically active salt compound of formula (VII); and optionally racemizing the unrequired isomer.

The present invention also encompasses the optically active salts of N,N-diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylprop ylamine, which is easy to isolate, obtained in good yield and purity. Further the present invention encompasses the use of optically active acid addition salts of N,N-diisopropyl- 3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine in the preparation of fesoterodine and its pharmaceutically acceptable salts. In fifth aspect of the present invention provides a process for the preparation of highly pure fesoterodine of formula (I) and its pharmaceutically acceptable salt, which comprises the steps of:

1) reacting the (+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3- phenylpropylamine of formula (II) with isobutyryl chloride in solvent and in the presence of a base;

2) quenching the reaction mixture with water;

3) washing the reaction mixture with non-polar organic solvent;

4) separating the organic and aqueous layers; 5) extracting the aqueous layers with solvent; and

6) distilling off the solvent under reduce pressure to get the highly pure fesoterodine. Drawings of the invention

Fig. 1 : illustrates the X-ray powder diffraction pattern of (-)-N,N-diisopropyl-3-(2- benzyloxy-5-carboxyphenyl)-3-phenylpropylamine (-)-di-p-toluoyl-L-tartaric acid of the present invention.

Fig. 2: illustrates the X-ray powder diffraction pattern of (-)-N,N-diisopropyl-3-(2- benzyloxy-5-carbomethoxyphenyl)-3-phenylpropylamine of the present invention. Fig. 3: illustrates the X-ray powder diffraction pattern of (+)-N,N-diisopropyl-3-(2- hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine of the present invention. Fig. 4: illustrates the X-ray powder diffraction pattern of fesoterodine fumarate prepared according to the process disclosed in example-6 of US 6,858,650.

The PXRD of said salt analyzed using following condition:

Detailed description of the invention

In an embodiment of the present invention, the solvent used in step (a) in the preparation of fesoterodine of formula (I) and solvent used in step (ii) in the preparation of compound of formula (V) is selected from nitrile such as acetonitrile, halogenated hydrocarbon such as dichloromethane, chloroform, aromatic hydrocarbon such as toluene, xylene or mixture thereof and more preferably acetonitrile.

In another embodiment of the present invention, the catalyst used in step (a) in the preparation of fesoterodine of formula (I) and catalyst used in step (ii) in the preparation of compound of formula (V) is selected from sodium iodide or potassium iodide and more preferably potassium iodide. The use of catalyst like sodium iodide or potassium iodide increase the rate of reaction and thereby decrease the reaction time taken for completion to less than 1 day (1-24 hrs) compared to the prior art process disclosed in US 5,559,269 that takes 4 days to complete, due to which the productivity increases.

In another embodiment of the present invention, the conversion of compound of formula (V) to formula (VI) can be done by the conventional methods known in the art. For example, by the process disclosed in US 5,559,269 using grignard reagent and dry ice (solid carbon dioxide) or by the process disclosed in US 2009/0306421 using grignard reagent and carbonate such as di(CrC ₆ alkyl) carbonates or a cyclic CrC ₆ alkylene carbonates. In an another embodiment of the present invention, the solvent used in step

(i) in the preparation of compound of formula (V) is selected from methylene chloride, chloroform, toluene, xylene or mixture thereof.

In another embodiment of the present invention, the optically active acid used for the resolution of formula (VI), wherein R represents H, and optically active acid used in step (c) in the preparation of fesoterodine is selected from but not limited to the group of (-) tartaric acid, (+) tartatric acid, R(+)-2-methyl succinic acid, N-CBZ-L-Glutamic acid, N-BOC-L-Glutamic acid, N-benzoyl-L-glutamic acid (-)-di-p-toluoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-dibenzoyl- L-tartaric acid, (+)-dibenzoyl-D-tartaric acid, and their hydrates thereof; preferably (-)-di-p-toluoyl-L-tartaric acid. The required isomer is selectively isolated either from the solid precipitated or by from the mother liquor by the conventional method known in the prior art. Preferably the use of (-)-dibenzoyl-L-tartaric acid resulted with crystallization of (-)-N,N-diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3- phenyl propylamine (-)-di-p-toluoyl-L-tartaric acid salt, which is isolated by filtration. After the salt has been isolated, it can be converted to the free base by treating it with base, or can be used as such for reduction. In another aspect, the present invention provides a method for racemization of unwanted isomer of compound of formula (VII) obtained after resolution of formula (VII), which comprises of reacting the unrequired isomer with a suitable base selected from sodium hydroxide, potassium hydroxide, piperidine, diisopropyl amine, diisopropylethyamine, DBU, sodium methoxide, sodium ethoxide, Potassium ethoxide, Potassium-tert-butoxide, Lithium hydroxide preferably potassium hydroxide in a solvent selected from dimethylformamide, dimethylsulfoxide, dimethylacetamide, methanol, ethanol, toluene, xylene, hexane, ethyl acetate, MTBE, chloroform and tetrahydrofuran or mixtures thereof, preferably dimethylsulfoxide at a temperature ranging from 0°C to reflux temperature of the solvent used to provide the racemic compound of formula (VI).

The racemic compound of formula (VI) can be further resolved with suitable optically active acid to get the required isomer of formula (VII) by the methods of the present invention. Thus obtained required isomer of formula (VII) can further utilized in the preparation of fesoterodine or its salts.

The present invention also encompasses the optically active salts compound of formula (VII);

(VII)

wherein R represents H, or CrC ₄ alkyl carbon and wherein PG is a protecting group selected from group comprising benzyl, p-nitrobenzyl; preferably benzyl (Bn) and wherein Acid is an optically active acid which is selected from (-)tartatric acid, (+) tartatric acid, R(+)-2-methyl succinic acid, N-CBZ-L-Glutamic acid, N-BOC-L- Glutamic acid, N-benzoyl-L-glutamic acid (-)-di-p-toluoyl-L-tartaric acid, (+)-di-p- toluoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-dibenzoyl-D-tartaric acid, and hydrates thereof. In a further embodiment of the present invention, the solvent used in the resolution of formula (VI) and solvent used in step (c) in the preparation of fesoterodine is selected from methanol, ethanol, isopropanol, butanol, toluene, xylene or mixture thereof; preferably methanol. The optically active salt compound of formula (VII) can be neutralized by following the general methods known in the art to get the free base of compound of formula (VII).

In one more embodiment of the process, the compound of formula (VII), wherein R is H, is optionally converted to its ester derivative by a method known in prior art or by following the method provided in example before reduction (or) the compound of formula (VII) wherein R is hydrogen, is used as such for reduction. The use of (-)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxy phenyl)-3-phenylpropyl amine of formula (VII), where R is hydrogen, per se is preferable as it involves less step and leads to decrease in production time and cost.

In another aspect, the present invention provides a process for preparation of compound of formula (VIII) which comprises the steps of (i) esterifying the compound of formula (VI), wherein R is hydrogen, (ii) resolving the compound of formula (VI), where R is alkyl, and (iii) reducing the compound of formula (VI), where R is alkyl, using vitride. In still another embodiment of the present invention, the suitable solvent used for reduction of formula (VII) or its free base and solvent used in step (e) in the preparation of fesoterodine is selected from toluene, xylene, THF, 2-methyl tetrahydrofuran, diethyl ether, diisopropylether, methyl tert-butylether (MTBE) or mixture thereof, preferably toluene.

The use of vitride for reduction of formula (VII) or its free base avoids the drawbacks associated with use of LAH (lithium aluminum hydride) such as pyrophoric nature, a short shelf life, and limited solubility. Accordingly the present invention provides safer process for the preparation of compound of formula (II). Being a non pyrophoric under ambient conditions and will not react with oxygen under ambient conditions vitride is easier to handle and safer to use than LAH used in the prior art processes.

In a further embodiment of the present invention, the catalyst used in step (f) in the preparation of fesoterodine is selected from Pd/C, raney Nickel, raney cobalt and Pt, preferably Pd/C and the solvent utilized for hydrogenation is selected from methanol, ethanol, isopropanol, acetic acid, formic acid, water or mixture thereof, more preferably methanol. In another embodiment of the present invention, the base used in step (g) in the preparation of fesoterodine; base used in step (i) in the preparation of formula (V) and the base used in step (1) in the preparation of fesoterodine is selected from triethylamine, diisopropyl amine, diisopropylethylamine, tributylamine, 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), dimethylaminopyridine (DMAP) and pyridine, preferably triethylamine.

In a further embodiment of the present invention, the solvent used in step (g) in the preparation of fesoterodine and in step (1) in the preparation of fesoterodine is selected from of acetonitrile, propionitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetone, butanone, methyl isobutylketone, dichloromethane, chloroform, toluene or mixture thereof and the suitable non-polar organic solvent used for washing in step (g) in the preparation of fesoterodine and step (3) in the preparation of fesoterodine is selected from hexane, heptane, cyclohexane, cycloheptane, diisopropyl ether, diethyl ether and methyl tert-butylether or mixture thereof.

The conventional process of fesoterodine provides end product with more non-polar impurities especially diester impurity represented by the following structural formula

Diester impurity

which is difficult to remove and requires additional purification, thereby not suitable for commercial point of view. Even conducting the experiment at very low temperature the formation of diester impurity is resulted to an extent of 1-2%. The same has been avoided by the present invention by simple washings given with non-polar solvent to the reaction mixture obtained after completion of acylation help to remove impurities and provide highly pure fesoterodine.

Surprisingly the fesoterodine obtained from this present invention contain less than 1%, particularly less than 0.5% of diester impurity. No prior art teaches or motivates the invention provided in the present application, and constitute novelty of the present invention. Thus the present invention provides the robust process to eliminate the non-polar impurities particularly diester impurity which is otherwise requires additional purification. Accordingly the present invention provides a purification process for crude fesoterodine, which comprises treating crude fesoterodine with non-polar solvent. In accordance with the invention, the fesoterodine is isolated as an oil form from water layer by extracting the same into organic solvent selected from group consisting of dichloromethane, ethyl acetate, toluene, isopropylether, methyl tert- butylether, methylisobutylketone followed by removing the solvent. In another embodiment of the present invention, the fesoterodine freebase obtained as per present invention is converted in to its pharmaceutically acceptable salt by conventional method.

Further the fesoterodine fumarate obtained as per the present invention can be further micronized, milled or sieved to get the desired particle size required for pharmaceutical composition to achieve the desired dissolution profile. Fesoterodine fumarate prepared by the present invention is a free flow solid and suitable for pharmaceutical composition. The present invention is illustrated with the following example, which should not be construed to limit the scope of the invention.

Example-1: Preparation of 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl-p- toluenesulfonate of formula (IV), wherein LG is tosyl and PG is benzyl:

Method A: To dichloromethane (MDC) (500 ml), (±)-3-(2-benzyloxy-5- bromophenyl)-3-phenylpropane-l-ol (lOOg), dimethylaminopyridine (DMAP) (1.2 g), triethylamine (52.7 g) were added and stirred in RB flask. To the reaction mixture of -tolylsulphonylchloride (57.6 g) was added and stirred till the completion of the reaction at room temperature. The pH of the reaction mixture adjusted to 0.5 by using 2.5% of aqueous HCl and stirred. The layers were separated and the organic layer was washed with water and dried over Na ₂ SO ₄ , followed by distillation of dichloromethane and dichloromethane striped off with acetonitrile. The product obtained was taken to next stage as such.

Method B: The mixture of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropan-l- ol (200 g), dichloromethane, dimethylaminopyridine (DMAP) (2.46 g) and triethylamine (76.5 g) was stirred at room temperature for 15 minutes. -tolylsulphonyl chloride (125 g) was added lotwise over 2 hours at room temperature. Heated the reaction mixture to reflux and stirred for 2-3 hours at 40-45°C. The pH of the reaction mixture was adjusted to 0.5 using aqueous HCl and the organic and aqueous layers were separated. Organic layer washed with water, sodium carbonate solution followed brine solution. Then organic layer was distilled up to 3 volumes and dichloromethane striped off with acetonitrile. Example-2: Preparation of N,N-Diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropylamine of formula (V) wherein PG is benzyl:

Method A: To (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl-p-toluene sulfonate (30 g) in acetonitrile, diisopropylamine (150 ml; lOeq) and potassium iodide (18 g) were added and refluxed for 21-24 hrs. After completion of reaction the solution was evaporated, to the resulting syrup was added isopropyl ether and water and stirred. The isopropyl ether layer was separated and the product was extracted into aqueous layer from isopropyl ether at acidic pH, followed by re-extracting the product into isopropyl ether at basic pH. Isopropyl ether distilled completely to yield the title compound in pale yellow oil.

Method B: (±)-Toluene-4-sulphonicacid-3-(2-benzyloxy-5-bromophenyl)-3 -phenyl propylester (110 g), acetonitrile, 10 equivalents of diisopropylamine and potassium iodide (1.66 equivalents) were added in RB flask. The reaction mixture was stirred and refluxed for 15 hrs. The reaction was monitored by HPLC, after the completion of the reaction the resulting reaction mixture was cooled to room temperature. Acetonitrile was distilled off completely, striped off with isopropyl ether, and to 13 V of isopropyl ether, water was charged and stirred. The isopropyl ether layer was separated and pH of aqueous layer adjusted to 0.5-0.9 and washed with isopropyl ether. Layers separated and pH of aqueous layers adjusted to 9-11 using 40% NaOH. The product was extracted with isopropyl ether at room temperature and dried over Na ₂ SO ₄ followed by distillation of isopropyl ether yield the product obtained as pale yellow oil. (Yield: 68 g.)

Advantage: Reaction time reduced to less than 1 day (1-24 hrs) while using KI, whereas prior art process takes about 4 days. Example-3: Preparation of N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)- 3-phenyl propylamine hydrochloride of formula (VI) wherein R is H and PG is benzyl:

To tetrahydrofuran (THF), 5.3 equivalents of Mg turnings, pinch of iodine and 2.5 ml of ethyl bromide were added and heated to 60-65°C. To this N,N-Diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl amine (50 g) in tetrahydrofuran and ethyl bromide (3.3 equivalent) were added. The reaction mixture was stirred at reflux. After completion of the reaction cooled to -25 to -30°C and dry ice (solid carbon dioxide) (~ 65 g) and stirred for an hour at -60 to -55°C. The temperature of reaction mixture was raised to -10 to 0°C, quenched with 20% NH ₄ C1 and stirred at room temperature. Reaction mass was distilled upto 50% under vacuum at 35-45°C. The pH of the reaction mixture was adjusted to 6.5-6.9 by using con HCl and filtered to remove the unreacted magnesium under vacuum. The reaction mixture was washed with isopropyl ether, followed by drop wise addition of con HCl at room temperature and cooled for 0-5°C. The reaction mixture was stirred for 1 hour at 0-5°C, filtered and washed with water then dried at 45-50°C. The obtained compound was treated with 10% acetone in ethylacetate and stirred at room temperature. The solid was filtered under vacuum, washed with ethylacetate and then dried under vacuum at 50°C for 10 hrs. (Yield: 97 grams)

Example-4: Preparation of N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)- 3-phenylpropyl amine of formula (VI) wherein R is hydrogen and PG is benzyl:

Method A: To the mixture of water (150 ml) and dichloromethane (MDC) (150mL), N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylprop ylamine hydrochloride (30 g) was added and pH adjusted to 8-9 using aqueous ammonia. The layers were separated; aqueous layer was again extracted with dichloromethane (150 ml). The combined dichloromethane washed with water and evaporated under vacuum at 40°C. The white solid was obtained.

Method B: To the mixture of water (150 ml) and Ethylacetate (150 mL), N,N- diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylam ine hydrochloride (30g) was added and pH adjusted to 8-9 using aqueous ammonia. The layers were separated, aqueous layer was again extracted with ethyl acetate (150 ml). The combined ethyl acetate washed with water, saturated sodium chloride solution and evaporated under vacuum at 40°C. The white solid was obtained. The product obtained was taken to next stage as such. (Yield: 23 g)

Example-5: Preparation of (-)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxy phenyl)-3-phenylpropyl amine (-)-di-p-toluoyl-L-tartaric acid of formula (VII) wherein R is hydrogen and PG is benzyl:

To methanol (100 ml), (±)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxy phenyl)-3-phenylpropyl amine (20g) and (-)-di-p-toluoyl-L-tartaric acid (DPTTA) (18. lg) were added at 50-55°C. The reaction mixture was heated to 65°C. The reaction mixture was cooled to room temperature and stirred about 5 to 6 hours at room temperature, then cooled to 0-5°C for lhr. The solid obtained was filtered and washed with chilled methanol to yield (-)-4-Benzyloxy-3-(3-diisopropylamino-l- phenylpropyl)-benzoic acid (-)-di-p-toluoyl-L-tartaric acid. DSC thermogram having an endotherm peak at about 220°C.

Yield: 16 g.

1H NMR (400 MHz, DMSO-2 drops of Aq.Ammonia) δ 0.9 (12H, m), 3.04-3.07 (3H, m), 5.1 (2H,s), 5.5 (lH,s), 6.9 (2H,d), 7.1-7.4 (12H,m), 7.9 (3H,m) Example-6: Preparation of (-)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxy phenyl)-3-phenylpropyl amine:

To the mixture of water and dichloromethane (80 ml), (-)-N,N-Diisopropyl- 3-(2-benzyloxy-5-carboxy phenyl)-3-phenylpropyl amine (-)-di-p-toluoyl-L-tartaric acid of formula (VII) (wherein R is hydrogen and PG is benzyl) (16g) was added and pH adjusted to 8-9 using aqueous ammonia. The layers were separated and the aqueous layer was again extracted with dichloromethane, Combined dichloromethane layer was evaporated under vacuum at 40°C. (Yield: 1 lg). Racemization of (+)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3- phenyl propyl amine:

Mother liquor obtained from example-5 and 6 was evaporated and to the obtained residue of (+)-N,N-diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3- phenyl propylamine (2 g), dimethylsulfoxide (20 ml) and potassium hydroxide (2.5 g) was added and heated to 110-120°C then stirred for 5.5hours. After completion of the reaction, water (80 ml) was added to the reaction mixture at room temperature. Extracted the reaction mixture with toluene and dried the toluene layer with sodium sulphate. Toluene layer was distilled off and the obtained residue was dissolved in methanol at room temperature. The reaction mass subjected to carbon treatment and then filtered through hyflow. The filtrate was distilled off completely to get the (±)-N,N-diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-pheny lpropyl amine. (Yield: >1 g)

Example-7: Preparation of (-)-N,N-diisopropyl-3-(2-benzyloxy-5-carbomethoxy phenyl)-3-phenylpropylamine (free base of (VII) wherein R is methyl):

Method A: To methanol, (-)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3- phenyl propyl amine (3 g) and con H ₂ SO ₄ were added in RB flask at room temperature and heated at reflux temperature. After completion of the reaction methanol was distilled off completely. To residue dichloromethane added and washed with water, the layers were separated. The organic layer was again washed with 3% sodium carbonate and water. The resulting organic layer was dried over Na ₂ SO ₄ and distilled off to get the title compound. (Yield: 1.7 g).

Method B: Sulphuric acid was added to a solution of (-)-4-benzyloxy-3-(3- diisopropylamino-1 -phenyl -propyl)-benzoic acid in methanol at 0-5°C and then heated to reflux for 6-7 hours. After reaction completion, solution evaporated completely under vacuum. The obtained residue dissolved in ethylacetate and washed with DM water. Organic layer separated, washed with 3% sodium carbonate solution and brine solution. Reaction mixture was distilled upto the residual volume of 2V with 2V of isopropanol chasing. The reaction allowed to attain room temperature and then stirred for an hours. Isopropanol was added and heated to reflux temperature for 1 hr and slowly allowed to room temperature. Then stirred for 0-5°c for hour. The obtained solid is filtered, washed with chilled isopropanol and dried at 45-50°C for 8 hours. DSC thermogram having an endotherm peak at about 93 °C

Method C: Sulphuric acid was added to a solution of (-)-4-benzyloxy-3-(3- diisopropylamino-1 -phenyl -propyl)-benzoic acid (-)-di-p-toluoyl-L-tartaric acid salt in methanol at 0-5°C and then heated to reflux and stirred till the completion of the reaction. After reaction completion, solution evaporated upto 2V under vacuum. The obtained residue dissolved in ethylacetate and washed with DM water. Organic layer separated, washed with 3% sodium carbonate solution and brine solution. Reaction mixture was distilled and striped of with isopropanol. The reaction was cooled to room temperature and then stirred for an hours. Isopropanol was added and heated to reflux temperature for 1 hr and slowly allowed to room temperature. Then stirred for 0-5°C for hour. The obtained solid is filtered, washed with chilled isopropanol and dried at 45-50°C for 8 hours.

Method D: Sulphuric acid was added to a solution of (-)-4-benzyloxy-3-(3- diisopropylamino-1 -phenyl -propyl)-benzoic acid (-)-di-p-toluoyl-L-tartaric acid salt in methanol at 0-5°C and then heated to reflux for 6-7 hours. After reaction completion, solution evaporated upto 2V under vacuum. To the obtained residue IV of toluene and 5V water added, stirred for lOmins and toluene layer was separated out. To aqueous layer 5 V of toluene added . And pH was adjusted to 9-10 using Sodium carbonate. Aqueous layer was again extracted with 5V of toluene. Organic layer separated, washed with water and brine solution. Toluene layer was distilled out under vacuum and taken for next stage.

Example-8: Preparation of (+)-N,N-Diisopropyl-3-(2-benzyloxy-5-hydroxy methyl phenyl)-3-phenylpropyl amine of formula (VIII) wherein PG is benzyl: Method A: To toluene, (-)-N,N-diisopropyl-3-(2-benzyloxy-5-carbomethoxy phenyl)-3-phenylpropylamine (2 g) was added followed by addition of vitride (3 equivalents) and stirred. After completion of the reaction, the reaction mass was diluted with toluene, cooled the reaction mixture to 10-15°C. To reaction mass, 5% sodium hydroxide (5V) was added and layers were separated. The separated organic layer was washed with 3V of brine. Finally the toluene was completely distilled off and the product obtained as pale yellow oil. (Yield 1.8 g)

Method B: To (-)-N,N-Diisopropyl-3-(2-benzyloxy-5-carbomethoxyphenyl)-3- phenyl propylamine (2 g) in toluene vitride (in toluene) was added drop wise under nitrogen and stirred for 3 hrs. After completion of reaction, aqueous sodium hydroxide solution was added into the reaction mass. The layers were separated and toluene layer washed with water, followed by removal of toluene to give the title compound as a colorless to pale yellow oil.

Method C: Dichloromethane (300 ml), water (150 ml) was added to (-)-4- Benzyloxy-3-(3-diisopropylamino-l-phenylpropyl)benzoic acid (-)-di-p-toluoyl-L- tartaric acid salt (15 grams) and pH of the reaction mixture was adjusted to 10-11 with aqueous sodium hydroxide. Methanol (100 ml) was added to the reaction mixture, heated to 30-35°C and stirred for 30 min. Organic layers were separated and dried over sodium sulphate. Organic layer was distilled off and the solvent changed to toluene. Toluene (80 ml) was added to the residue and stirred for 10 min at room temperature. Vitride (28 ml) in toluene (20 ml) was added drop wise at 30-50°C and stirred at 25-35°C. After completion of the reaction, aqueous sodium hydroxide was added at 0-5°C and stirred for 20 mins. Organic layer was separated and then washed with brine. Distilled off the organic layer up to the residual volume and chased with methanol. (Yield: 10-10.5 g).

Method D: Vitride (13.9 ml) was added to a solution of (-)-4-Benzyloxy-3-(3- diisopropylamino-l-phenylpropyl)benzoic acid (5 g) in toluene (50 ml) at 30-50°C and stirred at 50-55°C. After completion of the reaction, aqueous sodium hydroxide was added drop wise at 0-5 °C and stirred for 20 mins. Organic layers were separated and washed with brine. Distilled off the organic layer up to the residual volume and chased with methanol. (Yield: 4.8-5 g).

Method E: Vitride (38 ml) in toluene (40 ml) was added to a solution of (-)-4- Benzyloxy-3-(3-diisopropylamino-l-phenylpropyl)benzoic acid (-)-di-p-toluoyl-L- tartaric acid salt (10 g) in toluene (130 ml) at 50-55°C and stirred for 2 hours. After completion of the reaction, aqueous sodium hydroxide (50 ml) was added at 0-5°C and stirred for 20 mins. Organic layers were separated and washed with brine. Distilled off the organic layer up to the residual volume and chased with methanol. (Yield: 6.7-7 g). Example-9: Preparation of (+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxy methyl phenyl)-3-phenylpropylamine of formula (II):

Method A: (+)-N,N-Diisopropyl-3-(2-benzyloxy-5-hydroxymethylphenyl)-3- phenylpropyl amine (19.7 g) was dissolved in 220 ml of methanol at room temperature. To this solution Raney nickel (5 g) was added, the reaction mixture was hydrogenated under 2-3 Kg pressure at room temperature till completion of the reaction (if reaction not completed, excess quantity Raney nickel was added and hydrogenated). The mixture was then filtered and washed with methanol, which is evaporated completely under vacuum at 60 °C. The resulting oily residue was dissolved in dichloromethane washed with water. The organic layer was dried over Na ₂ SO ₄ and evaporated completely. The product was obtained as oily mass (Yield: 14.1 g).

Method B: (+)-N,N-Diisopropyl-3-(2-benzyloxy-5-hydroxymethylphenyl)-3- phenylpropyl amine (33 g) was dissolved in methanol at room temperature. To this solution palladium carbon (1.6 g) was added over it and hydrogenated under 3-4kg pressure at room temperature till completion of reaction. After completion, catalyst filtered and washed with methanol. Carbon was added to the filtrate and stirred for an hour at room temperature. The reaction mixture was filtered through hyflow. Filtrate was concentrated upto 3 V under vacuum at 45°C. The reaction mixture was heated to 40-45°C and DM water was added to it then stirred for 1 hour. Allow the reaction mixture to room temperature and seed. After solid formation, water was added and stirred for 1 hour. The material was filtered and washed with DM water. DSC thermogram having an endotherm peak at about 104°C. (Yield: 0.9-0.95 g) Purification of (+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3- phenylpropylamine of formula (II):

Method A: Ethylacetate was added to (+)-N,N-diisopropyl-3-(2-hydroxy-5- hydroxy methylphenyl)-3-pl enylpropylamine at room temperature. Carbon was added and heated to 50°C for an hour. Carbon was filtered and filtrate was distilled upto 2 .5 V at 50°C. Hexane was added and stirred for 1 hour. The solid was filtered under vacuum at room temperature and washed with hexane. Dried the solid under vacuum at 50°C for 8 hours Method B: (+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-ph enyl propylamine was treated with chilled toluene and stirred for 1 hour at 0-5°C. The solid was filtered and washed with 1 V of chilled toluene. Suck dried under vacuum for 0.5 hours. Example-10: Preparation of fesoterodine:

Method A: A solution of isobutyryl chloride (0.62g) were added to a solution of (+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-ph enylpropylamine of formula (II) (2g) in acetonitrile at -10°C. Tri ethyl amine in acetonitrile were added drop wise to the reaction mixture at -10°C. After completion, the reaction mixture was quenched with chilled water at same temperature and gradually cooled to room temperature. The obtained solution is washed with hexane and separated. The product is extracted into dichloromethane from separated aqueous mixture layer. Finally dichloromethane layer was washed with 5% sodium bicarbonate solution and water. Organic layer dried with sodium sulphate, concentrated under vacuum at 40°C and isolated as viscous oil.

Yield: 83.3%

Purity by HPLC: Fesoterodine freebase: 99.37%; Diester: 0.21% Method B: A solution of isobutyryl chloride (0.656 g) were added to a solution of (+)-N,N-diisopropyl-3-(2-benzyloxy-5-hydroxymethylphenyl)-3- phenylpropyl amine of formula (II (2 g) in acetonitrile at -10°C. Triethylamine in acetonitrile were added drop wise to the reaction mixture at -10°C. After completion, reaction mixture quenched with chilled water at same temperature and gradually cooled to room temperature. The obtained solution is washed with hexane and separated. The product is extracted by dichloromethane from separated aqueous mixture layer. Finally dichloromethane layer washed with 5% sodium bicarbonate solution and water. Organic layer dried with sodium sulphate, concentrated under vacuum at 40°C and isolated as viscous oil.

Yield: 75%

As evidenced from the table the hexane water wash helps to remove the diester impurity.

Method C: To dichloromethane, (+)-N,N-diisopropyl-3-(2-benzyloxy-5-hydroxy methylphenyl)-3-phenylpropylamine of formula (II (65 g) and triethylamine (20 g) were added followed addition of isobutyryl chloride (23.4 g) in 250 ml dichloromethane at 0-5 °C, and stirred till completion of reaction. The resulting reaction mixture washed with 250 ml water and 250 ml 5%NaHCO ₃ solution at RT. The separated dichloromethane layer dried under vacuum at 40°C. The product was obtained as colorless viscous oil. (Yield 77.1 g.) This oil was converted into its fumarate salt by taking the oil in 90 ml of 2-butanone followed by addition fumaric acid (11.8 g). The reaction mixture stirred the solid obtained was filtered, washed with cyclohexane/2-butanone, dried to yield Fesoterodine Fumarate.

Example-11: Preparation of fesoterodine fumarate salt:

To fesoterodine freebase (6 g) in 2- butanone, fumaric acid (1.6 g) was added and heated to get clear solution. The reaction mixture gradually cooled to room temperature and then to - 5 to 0°C. To this cyclohexane were added, and seeded with Fesoterodine fumarate and stirred for an hour. The reaction mixture was diluted with cyclohexane and stirred for 2 hours at - 5 to 0°C. The obtained solid was slurried in 10% acetone/ethyl acetate mixture, filtered and dried. DSC thermogram having an endotherm peak at about 108°C.

Yield: 60%

Purity: Fesoterodine Fumarate: 99.47%; Diester: 0.08%