FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of fesoterodine of formula I and pharmaceutically acceptable salts thereof,

Formula I

via novel hydroxy carbonitrile intermediate of formula II.

Formula II

BACKGROUND OF THE INVENTION
Fesoterodine represented by formula I is a prodrug of 5-hydroxymethyl tolterodine and commercially available under the brand name of Toviaz® in the form of fumarate salt.

Formula I

It is a new, potent and competitive muscarinic antagonist and is useful in the potential treatment of urinary incontinence. Chemically it is known as [2-[(1R)-3-(di(propan-2-yl)amino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl]2-methyl propanoate.
Fesoterodine and its pharmaceutically acceptable salts were first disclosed in US patents 6,858,650 and 6,713,464. Synthetic approach for the production of fesoterodine as described in US patents ‘650 and ‘464 is represented below in scheme 1.

Scheme 1
As represented in scheme 1, fesoterodine is prepared by the reaction of (+)-6-bromo-4-phenylchroman-2-one with benzyl chloride in presence of sodium iodide and anhydrous potassium carbonate in a mixture of methanol and acetone to give (+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid methyl ester as a light yellow oil, which upon reduction and subsequent successive reactions with p-toluenesulphonyl chloride and N,N-diisopropylamine in acetonitrile produces (+)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine as a brown and viscous syrup. This is then converted to (R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol after number of chemical reactions. (R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol on deprotection using Raney-Nickel produces (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol which upon acylation using isobutyryl chloride in the presence of a base in an inert solvent gives fesoterodine.
In an alternate embodiment, US 6,713,464 disclose a process for the preparation of fesoterodine as represented in scheme 2.

Scheme 2
Fesoterodine is prepared through formation of a chiral amide, in which a phenyl magnesium compound is added and chiral derivative of diphenylpropanoic acid is obtained. This is converted to 3,3-diphenylpropylamino derivative intermediate by means of formation of a tertiary amide and subsequent reduction. The conversion of bromo-derivative into hydroxymethyl group is performed through a process of organometalation, carbonylation and subsequent reduction of the resulting carboxyl group. Finally, deprotection of phenol by hydrogenation of benzyl group and its subsequent acylation gives fesoterodine.
US patent 5,559,269, discloses preparation of 2-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxymethyl-phenol, which is a precursor of fesoterodine, via multistage synthesis as shown below in scheme 3.

Scheme 3
The processes disclosed in above US patents have one or the other disadvantage and in addition to that, owing to large number of process steps involved in the synthesis and result unsatisfactory low yields.
A different approach of synthesis of fesoterodine is described in US patent 6,809,214 in which a coupling of cinnamic acid and methyl 4-hydroxybenzoate is initially performed in acidic medium, forming a dihydrocoumarin as a racemic intermediate, which is then subjected to a stereoselective resolution to obtain a suitable enantiomer. The later is subsequently reduced to a lactol derivative, in which diisopropylamine is introduced via means of reductive amination. The synthetic process can be represented as shown below in scheme 4.

Scheme 4
Although, the above process is shorter, many synthesis steps are still required. In addition, the use of aluminum tert-butoxide as a reducing agent is a considerable problem on account of toxicity adds in the process.
A similar approach has been described in US patent 8,067,594 wherein dihydrocoumarin intermediate is prepared by following the process as presented below in scheme 5.

Scheme 5
The synthesis with respect to what is known in the prior art, is apparently advantageous in that it requires few steps and uses common reagents. However, the yield of (R)-feso deacyl derivative amounts to 12%. Such low yields are unsatisfactory in terms of industrial application, which is essentially due to the low yield of feso chromenyl derivative.
In PCT publication WO2011/154854, feso chromenyl derivative, an intermediate in the synthesis of fesoterodine is prepared by protecting methylene group of 4-hydroxymethylphenol with a silylated group and protected product is then reacted with cinnamaldehyde and morpholine to give (2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl)methanol i.e. feso chromenyl derivative with yields exceeding 60%. A schematic description of the synthesis is represented in the scheme 6 as shown below.

Scheme 6
The above scheme involves additional protection and deprotection steps. These additional steps further lengthen the process and obstruct main aim of reducing cost and developing industrially viable process for the preparation of fesoterodine.
In view of the above, there is a need to develop a process for the synthesis of fesoterodine that will overcome prior art disadvantages and provide an alternative and novel process for obtaining fesoterodine and 3,3-diphenylpropylamine analogs by reducing number of steps and using cost-effective reagents and novel intermediate.
OBJECTIVE OF THE INVENTION
It is a foremost objective of the present invention to provide a novel process for the preparation of fesoterodine and pharmaceutically acceptable salts thereof.

Another objective of the present invention is to provide a novel intermediate, 2-hydroxy-4-phenyl-chroman-6-carbonitrile, of formula II.

Still another objective of the present invention is to provide a process for synthesis of fesoterodine and pharmaceutically acceptable salts thereof via novel intermediate of formula II.

Yet another objective of the present invention is to provide a process for the synthesis of novel intermediate, 2-hydroxy-4-phenyl-chroman-6-carbonitrile, of formula II.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a novel, efficient and industrially advantageous process for the preparation of fesoterodine of formula I and pharmaceutically acceptable salts thereof

Formula I

via novel hydroxy-carbonitrile intermediate of formula II.

Formula II
According to one embodiment, the present invention provides a novel hydroxy-carbonitrile intermediate of formula II.

According to one another embodiment, the present invention provides a process for preparation of highly pure hydroxy-benzonitrile intermediate of formula III,

Formula III

from hydroxy-carbonitrile intermediate of formula II.

According to one another embodiment, the present invention provides isolation of hydroxy-benzonitrile compound of formula III in solid form.

According to one another embodiment, the present invention provides isolation of hydroxy-benzonitrile compound of formula III in solid form which is further converted to fesoterodine and pharmaceutically acceptable salts thereof.

According to one another embodiment, the present invention provides a process for the preparation of fesoterodine and pharmaceutically acceptable salts thereof, which comprises the steps of:
a) reacting 4-hydroxy-benzonitrile with trans cinnamaldehyde in the presence of a suitable base and a suitable solvent to form hydroxy-carbonitrile intermediate of formula II,

Formula II

b) reductively aminating hydroxy-carbonitrile intermediate of formula II by using a suitable reducing agent and a suitable amine such as diisopropylamine in the presence of a suitable solvent to form hydroxy-benzonitrile intermediate of formula III,

Formula III

c) hydrolyzing hydroxy-benzonitrile intermediate of formula III using a suitable hydrolyzing reagent to form hydroxy-benzoic acid intermediate of formula IV;

Formula IV

d) reducing hydroxy-benzoic acid intermediate of formula IV using a suitable reducing agent to form a hydroxymethyl-phenol intermediate of formula V;

Formula V

e) and converting hydroxymethyl-phenol intermediate of formula V into
fesoterodine and pharmaceutically acceptable salts thereof.
wherein intermediates of formulae III and IV include their specific isomer like (R), (S) or racemates, dissolved forms, solvent free form or hydrate, anhydrate or a solvate, non-solvate form, both in crystalline and amorphous form thereof.

According to one another specific embodiment, the present invention provides a process for the preparation of fesoterodine and pharmaceutically acceptable salts thereof, which comprises the steps of:
a) reacting 4-hydroxy-benzonitrile with trans cinnamaldehyde in the presence of a suitable base and a suitable solvent to form hydroxy-carbonitrile intermediate of formula II,

Formula II

b) reductively aminating hydroxy-carbonitrile intermediate of formula II by using diisopropylamine and a suitable reducing agent in the presence of a suitable solvent to form hydroxy-benzonitrile intermediate of formula III;

Formula III

c) optionally purifying hydroxy-benzonitrile intermediate of formula III from a suitable solvent;
d) optically resolving hydroxy-benzonitrile intermediate of formula III to optically active compound of formula IIIa;

Formula IIIa

e) hydrolyzing optically active hydroxy-benzonitrile compound of formula IIIa using a suitable reagent to form a hydroxy-benzoic acid intermediate of formula IVa;

Formula IVa

f) reducing hydroxy-benzoic acid intermediate of formula IVa using a suitable reducing agent to form hydroxymethyl-phenol intermediate of formula V; and

Formula V

g) converting hydroxymethyl-phenol intermediate of formula V into fesoterodine and pharmaceutically acceptable salts thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1 is an exemplary XRPD pattern of hydroxy-carbonitrile intermediate of Formula II.

Figures 2 is an exemplary XRPD pattern of hydroxy-benzonitrile intermediate of Formula III.
DETAILED DESCRIPTION OF THE INVENTION
As used herein “hydroxy-benzonitrile compound of formula III” or “hydroxy-benzoic acid compound of formula IV” as well as “all the intermediates” used herein includes in each case one of its pure stereoisomer, enantiomer, diastereomer, or racemates, or mixture of stereoisomer, mixture of enantiomer, mixture of diastereomer in any ratio, salts, solvates, and hydrates thereof”.
The present invention provides a novel, efficient and industrially advantageous process for preparation of fesoterodine of formula I and pharmaceutically acceptable salts thereof.
According to one embodiment, the present invention provides a process for the preparation of fesoterodine and pharmaceutically acceptable salts thereof via novel hydroxy-carbonitrile intermediate of formula II. The process involves reaction of 4-hydroxy-benzonitrile with trans cinnamaldehyde in presence of a suitable base and a suitable solvent to give a cyclic intermediate, hydroxy-carbonitrile intermediate of formula II, which is then converted into 3-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzonitrile of formula III, via reductive amination using a suitable reducing agent.Hydroxy-benzonitrile compound of formula III is optically resolved using a suitable chiral acid which, upon subsequent hydrolysis gives 3-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzoic acid of formula IVa. Reduction of acid intermediate of formula IVa using a suitable reducing agent gives 2-(3-diisopropylamino-1-phenyl propyl)-4-hydroxymethyl-phenol of formula V, which is a key intermediate, and can be converted to fesoterodine and pharmaceutically acceptable salts thereof.
Generally, hydroxy-carbonitrile intermediate of formula II is prepared by reacting the 4-hydroxy-benzonitrile with trans cinnamaldehyde in presence of a suitable base in a suitable solvent. The suitable base includes secondary amines such as N-methylpiperazine, piperazine, N-benzylpiperazine, morpholine, diethylamine, diisopropylamine, dibutylamine, dibenzylamine, piperidine, 1,1,3,3-tetramethylguanidine. In a preferred embodiment, N-methylpiperazine and morpholine are used.
The solvent used in the reaction can be selected from the group comprising hydrocarbons such as benzene, toluene, xylene; aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, diisopropyl ether, methyl-tert-butyl ether, diethyl ether, dibutyl ether, diphenyl ether, bis(2-methoxyethyl)ether; protic or aprotic solvents such as N,N- dimethylformamide, N,N-dimethyl acetamide, 1-methyl-2-pyrrolidinone, diethylamine, propylamine, butylamine, sulfolane, dimethyl sulfoxide; C1-C10 alcohols such as methanol, ethanol, n-propanol, isopropanol, benzyl alcohol, amyl alcohol and mixtures thereof.
The reaction can be carried out at a temperature -20 to 150 ºC for few minutes to several hours, preferably till the completion of the reaction. Preferably reaction can be performed at reflux temperature of solvent employed. The completion of reaction can be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), High pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), and the like. After completion of the reaction, hydroxy-carbonitrile intermediate of formula II can be isolated by conventional methods by quenching the reaction mixture with water and extracting desired compound in organic layer or precipitation and filtration. Optionally, organic layer can be charcoalized and/or washed with water/dilute acid/dilute basic solution. Hydroxy-carbonitrile intermediate of formula II can be recovered from the resulting organic layer after removal of solvent and forms inventive part of the invention.
Hydroxy-carbonitrile intermediate of formula II as described by the present invention can be in solid or dissolved state and can be characterized by suitable techniques known in the art. Preferably, hydroxy-carbonitrile intermediate of formula II of the present invention can be characterized by any of various spectroscopic techniques like 1H and 13C Nuclear magnetic resonance (NMR), Mass spectrometry (MS), Infrared spectroscopy (IR) and X-ray diffraction chromatogram (XRD, Differential scanning calorimetry (DSC).
Specifically, hydroxy-carbonitrile intermediate of formula II of the present invention can be characterized by LCMS and XRD.
LCMS: m/z = 250.28 (M-1)+
XRD: powdered X-ray diffraction pattern of crude compound shows that material is amorphous.
Hydroxy-carbonitrile intermediate of formula II is then converted to hydroxy-benzonitrile compound of formula III by employing reductive amination reaction.
Generally, hydroxy-carbonitrile intermediate of formula II is reacted with diisopropyl amine and a suitable reducing agent in an organic solvent and forms hydroxy-benzonitrile compound of formula III, via imine intermediate. Imine intermediate is generated in situ and is not isolated. The suitable reducing agent can be selected from the class of compounds such as alkali or alkaline metal borohydrides such as potassium borohydride, sodium borohydride, lithium borohydride, sodium acetoxy borohydride and the like. Alternatively, the reduction leading to hydroxy-benzonitrile compound of formula III can also be performed via catalysis hydrogenation in the presence of catalysts like palladium/carbon, palladium/alumina, platinum/carbon, platinum oxide, rhodium/carbon, ruthenium catalysts in a suitable solvent.
In an alternate embodiment, the amination reaction can be performed with diisopropyl amine in the presence of titanium isopropoxide followed by reduction with sodium borohydride to achieve highly chemoselective reduction.
The solvent used for the reaction includes but not limited to hydrocarbons such as benzene, toluene, xylene; aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, dibutyl ether, diphenyl ether bis(2-methoxyethyl)ether; protic or aprotic solvents such as N,N- dimethylformamide, N,N-dimethyl acetamide, 1-methyl-2-pyrrolidinone, diethylamine, propylamine, butylamine, dimethyl sulfoxide; C1-C10 alcohols such as methanol, ethanol, n-propanol, isopropanol, benzyl alcohol, amyl alcohol and mixtures thereof.
The reaction can be carried out at ambient temperature to reflux temperature of solvent employed for 1 to 24 hours or till the completion of reaction. The completion of reaction can be monitored by any one of the chromatographic techniques such as thin layer chromatography (TLC), High pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), and the like. The intermediate of formula III can be isolated from the reaction mixture using suitable techniques known in the art.
Specifically hydroxy-benzonitrile compound of formula III can be isolated from reaction mixture by generation of biphasic system in reaction mixture. After the layer separation, organic layer is washed with water and concentrated to give solid compound.
In one another embodiment, the isolated solid material can optionally be purified using suitable purification to enhance purity of product. Any suitable purification procedure like crystallization, slurry wash, solvent anti-solvent system or combination of these procedures, may be employed to get purified material. Solvent for purification can be chosen amongst hydrocarbons such as benzene, toluene, n-hexane, n-heptane; aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate; halogenated solvents such as dichloromethane, dichloroethane, chloroform, chlorobenzene; ethers such as methyl tert-butyl ether, dioxane, diisopropylether, dimethyl ether, diethyl ether, methyl propyl ether or mixtures thereof with other solvents.
Optionally hydroxy-benzonitrile compound of formula III can be converted to compound of formula I without further purification.
In one another embodiment, hydroxy-benzonitrile compound of formula III can be resolved through the formation of diastereomeric salt of formula IIIb with an

Formula IIIb

optically active organic acid. An optically active organic acid can be selected from (-)-camphoric acid, (+)- and (-)-camphorsulphonic acid, (+)-and(-)- tartaric acid, (+)-and(-)-di-p-toluyl tartaric acid, (+)-and(-)-dibenzoyltartaric acid, (-)-malic acid, (+)-and(-)mandelic acid and (+)-lactic acid. The specific isomer of the resolving agent [whether (R) or (S)] used for resolution depends on the isomer which needs to be prepared. The solvent employed for resolution is not critical, thus suitable solvent can be selected on the basis whether diastereomeric salt precipitates out differently. Preferably solvent includes but not limited to protic solvents such as water; alcohols; aliphatic ethers; halogenated solvents; aliphatic or aromatic hydrocarbon solvents; alkyl nitriles; aliphatic esters; ketones; and the like or mixture thereof. Usually, the reaction is carried out at a temperature of 0 to 80 oC for 1 hour to few hours, preferably at a temperature of 25 oC to boiling point of the solvent for 0- 24 hours, more preferably till the completion of salt formation. The reaction mass is thereafter cooled to ambient temperature for a time sufficient to ensure the complete precipitation of the desired salt. The diastereomeric salt can be isolated from the reaction mixture by employing suitable separation techniques such as filtration or centrifugation. The diastereomeric salt of compound of formula III b can be cleaved to afford the compound of formula IIIa. The intermediate of formula III thus prepared by the present invention is found to be highly pure having purity more than 92.3 % by HPLC, preferably more than 95 %, more preferably 98%.
In one another aspect of present invention, the compound of formula III can be converted to compound of formula IVa.
In one preferred embodiment, the compound of formula IIIa can be hydrolyzed in acidic or basic conditions in presence or absence of solvent. The suitable acid employed for hydrolysis is selected from inorganic acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid etc. Alternatively the hydrolysis can also be performed under basic conditions using lithium hydroxide, sodium hydroxide, potassium hydroxide etc. The hydrolysis is performed in presence of solvents selected from the class of compounds such as C1-C8 alcohols such as methanol, ethanol; ethylene glycol etc, After completion of the hydrolysis the neutralization can be performed by employing acid or base depending upon the mode of hydrolysis of reaction mass as described above. Desired compound can be isolated from reaction mass by conventional methods for example by extraction into suitable solvent or precipitation and filtration. Solvent employed for extraction can be selected from water immiscible solvents such as halogenated solvents like dichloromethane, 1,2-dichloroethane, chloroform,ethyl acetate, toluene, methylisobutyl ketone, methylethyl ketone, cyclohexane etc.
In second embodiment, diastereomeric salt of hydroxy-benzonitrile compound of formula IIIb is directly hydrolyzed using suitable reagent to form a hydroxy-benzoic acid compound of formula IVa;
In third embodiment, racemic hydroxy-benzonitrile compound of formula III is hydrolyzed using a suitable reagent to form a racemic hydroxy-benzoic acid compound of formula IV; followed by resolution of racemic hydroxy-benzoic acid compound of formula IV through formation of diastereomeric salt of formula IVb by using optically active organic acid, and

Formula IVb

thereafter converting novel diastereomeric salt of hydroxy-benzoic acid of formula IVb into optically active hydroxy-benzoic acid compound of formula IVa. Preparation and isolation of novel diastereomeric salt of hydroxy-benzoic acid of formula IVb forms an inventive part of invention. Hydroxy-benzoic acid compound of formula IVa has high enantiomeric purity, which can be calculated by chiral HPLC and can be expressed in terms of enantiomeric ratio. Hydroxy-benzoic acid of formula IVa, obtained above, can be converted to hydroxymethyl-phenol intermediate of formula V by treating with a suitable reducing agent known in the art. Suitable reducing agent can be selected from alkali or alkaline metal hydrides or borohydrides such as lithium aluminiun hydride, potassium borohydride, sodium borohydride, lithium borohydride and the like. The reduction is performed in presence of solvent suitable for reduction reactions as known in literature. Desired compound can be isolated from reaction mass by conventional methods for example by extraction into suitable solvent or precipitation and filtration.
Further, hydroxymethyl-phenol intermediate of formula V can be selectively converted into compound of formula I using the methods known in the art or the methods with variation as can be employed and suitable as per present invention. In a preferred embodiment, hydroxymethyl-phenol compound of formula V produces the compound of formula I by reaction with an acylating agent in the presence of suitable base and solvent. The acylating agent that may be used are acid chloride preferably isobutryl chloride. The suitable base selected from the aliphatic amines class of compounds such as trialkylamines with straight chain or branched alkyl residue containing 1 to 20 carbon atoms. Particularly aliphatic amine such as triethylamine and diisopropylethyl amines are preferred. The suitable solvent selected for this reaction are aprotic solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 2-methyl tetrahydrofuran; alkyl ether such as diethyl ether, diisopropyl ether, methyltertiarybutyl ether, ethyl acetate, acetone, dimethylformamide, acetonitrile, propionitrile, toluene, dimethylsulfoxide, C1-C4 alcohols and their mixtures thereof. Preferably dichloromethane is used. The compound of formula I can be converted to pharmaceutically acceptable salts. Preferably fumarate salt is prepared using fumaric acid by methods known in art for salt formation. Intermediates described here, in the present invention may be isolated by using conventional methods and optionally be purified to enhance the purity. Any suitable purification procedure such as, for example, crystallization, derivatisation, slurry wash, salt preparation, various chromatographic techniques, solvent anti-solvent system or combination of these procedures, may be employed to get the purified material. However, other equivalent procedures such as acid-base treatment or acid-acid treatment could, also be used, to purify the intermediates as well as final product. The solvents used for the purification of intermediates or final compound may be selected amongst water, C1-6 alcohols, aliphatic C3-6 ketones, C5-10 aliphatic or C5-12 aromatic hydrocarbons, C3-12 aliphatic esters, C3-6 ethers, nitrile, halogenated solvents such as chloroform, dichloromethane, aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidinone, sulfolane and the like or mixtures thereof in suitable proportion.
As used herein the term “conventional methods for the isolation of intermediates as well as final product” may be varied depending upon the nature of the reactions, nature of product of the reaction, medium of the reaction and the like. The suitable conventional methods can be selected amongst but not limited to distillation of the solvent, addition of water to the reaction mixture followed by extraction with water immiscible solvents, removal of the insoluble particles from the reaction mixture, if present, by filtration or centrifugation or by decantation, addition of water immiscible organic solvent, addition of a solvent to the reaction mixture which precipitate the product, neutralizing the reaction mixture with a suitable acid or base whichever is applicable.
The order and manner of combining the reactants at any stage of the process are not critical and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further, any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order. The time required for the completion of the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. Wherever required, progress of the reaction may be monitored by suitable chromatographic techniques such as High performance liquid chromatography (HPLC), gas chromatography (GC), ultra pressure liquid chromatography (UPLC) or thin layer chromatography (TLC).
In another aspect of invention, the compound obtained by following the above process can suitably be formulated to provide a pharmaceutical composition and which is further provided by the present invention a pharmaceutical composition comprising fesoterodine or pharmaceutically acceptable salt thereof.
The main advantage of the present invention is to provide an industrially advantageous and efficient process for preparation of fesoterodine and pharmaceutically acceptable salts thereof via less number of steps, which saves time and minimizes the human error by employing very few steps for obtaining the final compound. Further, the present invention provides a novel intermediate which is converted to fesoterodine and pharmaceutically acceptable salts thereof by using industrially friendly reagents and conditions. The process of the present invention is efficient, reproducible as well as industrially viable.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
EXAMPLES:
Example 1: Preparation of 2-Hydroxy-4-phenyl-chroman-6-carbonitrile
4-Cyanophenol (10g) and N-methyl piperazine (21g) was taken in toluene (100ml) and heated to reflux. To this, trans cinnamaldehyde (38.9g) was added slowly with azeotropic removal of water and reaction mass was refluxed for about 6-8 hours and then cooled to 60°C. Water (100ml) was added and stirred for another 30 minutes and layers were separated. Ethyl acetate was added to the organic layer for dilution and the combined organic layer was washed several times with 1N hydrochloric acid followed by aqueous sodium bicarbonate and aqueous sodium metabisulphite and finally with water. Organic layer was concentrated under vacuum to obtain a solid title compound.
Example 2: Preparation of 3-(3-Diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzonitrile
A solution of 2-hydroxy-4-phenyl-chroman-6-carbonitrile (25g) and diisopropylamine (25.36g) in toluene (150 ml) was refluxed for about 3-4 hours and thereafter cooled to room temperature. A clear solution of sodium hydroxide (0.10g) in methanol (100 ml) was prepared in a separate vessel and cooled to 0-5°C. In the cooled solution, sodium borohydride (4g) was added slowly. Reaction mass prepared above in toluene, was added to sodium borohydride solution slowly at 0-5°C and stirred for 1-2 hour. After completion of reaction, aqueous sodium bicarbonate solution was added and the layers were separated. Organic layer was washed with water and concentrated to give title compound as a brown solid. Yield 25 g.
Example 3: Purification of 3-(3-Diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzonitrile
3-(3-Diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzonitrile obtained in above example was dissolved in toluene (250ml) and ethyl acetate (250ml) and cooled to 5-10°C. Hydrochloric acid was added to the solution, stirred and layers were separated. The aqueous layer was washed with toluene (250ml). Ethyl acetate (250ml) was charged to the aqueous layer and pH was adjusted to 8-9 by adding aqueous sodium hydroxide solution, layers were separated and organic layer was washed with brine (100ml) and concentrated to get light brown solid having purity of 92.3% by HPLC.
Example 4: Preparation of (R)-3-(3-Diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzoic acid tartrate
3-(3-Diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzonitrile (5.0g) was dissolved in isopropyl alcohol (30ml). L-tartaric acid (2.5g) was added and the reaction mass was heated to 50°C for 30 minutes. The reaction mass was slowly cooled to 25-30°C and stirred for 3 hours. The resulted crystals were filtered, washed with ethanol and dried to obtain title compound. Yield 3.0 g.
Example 5: Preparation of 3-(3-Diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzoic acid
3-(3-Diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzonitrile (2.0g) was refluxed in dilute aqueous sulfuric acid (10%, 20ml) for 24 hours. The reaction mass was neutralized with aqueous sodium hydroxide solution and the product was extracted with dichloromethane. Organic layer was washed with water and concentrated under reduced pressure to get the product as solid. Yield 1.0 g.
Example 6: Preparation of 2-(3-Diisopropylamino-1-phenyl-propyl)-4-hydroxymethyl-phenol
3-(3-Diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzoic acid (2.0g) was taken in tetrahydrofuran (20 ml), lithium aluminium hydride was added slowly at 0-5°C and the reaction mass was stirred for 2 hours. After completion of the reaction, the reaction mass was quenched slowly with water and then extracted with ethyl acetate (30ml). Organic layer was washed with aq. sodium bicarbonate solution and then with brine. Organic layer was concentrated under vacuum to get the title product as yellow solid.
Ind-Swift Laboratories Limited No. of Sheets 1
Application no. 2635/DEL/2012 Sheet No. 1 of 1

Figure 1

Figure 2

,CLAIMS:We Claim

1. A process for the preparation of fesoterodine of formula I and pharmaceutically acceptable salts thereof

Formula I
comprises;
a). reacting 4-hydroxy-benzonitrile with trans cinnamaldehyde in the
presence of a suitable base and a suitable solvent to form hydroxy-
carbonitrile intermediate of formula II;

Formula II

b). reductively aminating hydroxy-carbonitrile intermediate of formula II with diisopropylamine using a suitable reducing agent in the presence of a suitable solvent to form hydroxy-benzonitrile intermediate of formula III;

Formula III
c). optionally purifying hydroxy-benzonitrile intermediate of formula III from a suitable solvent;
d). optically resolving hydroxy-benzonitrile compound of formula III to optically active compound of formula IIIa;

Formula IIIa

e). hydrolyzing hydroxy-benzonitrile intermediate of formula IIIa using a suitable hydrolyzing reagent to form hydroxy-benzoic acid intermediate of formula IVa;

Formula IVa

f). reducing hydroxy-benzoic acid intermediate of formula IVa using a suitable reducing agent to form a hydroxymethyl-phenol intermediate of formula V; and

Formula V

g). converting hydroxymethyl-phenol intermediate of formula V into fesoterodine and pharmaceutically acceptable salts thereof.
2. The process as claimed in claim 1 wherein in step a) base is selected from N-methylpiperazine, piperazine, N-benzylpiperazine, morpholine, diethylamine, diisopropylamine, dibutylamine, dibenzylamine, piperidine, 1,1,3,3-tetramethylguanidine preferably N-methylpiperazine and morpholine; solvent is selected from hydrocarbons aliphatic esters; ethers; protic or aprotic solvents; C1-C10 alcohols and mixtures thereof.
3. The process as claimed in claim 1 wherein in step b) reducing agent is selected from alkali or alkaline metal hydrides or borohydrides or hydrogenating catalyst; solvent is selected from hydrocarbons; aliphatic esters; ethers; protic or aprotic solvents; C1-C10 alcohols and mixtures thereof.
4. The process as claimed in claim 1, wherein in step c) solvent for purification is selected from hydrocarbons; aliphatic esters; halogenated solvents; ethers and mixtures thereof.
5. The process as claimed in claim 1, wherein in step d) resolving agent is selected from (-)-camphoric acid, (+)- and (-)-camphorsulphonic acid, (+)-and(-)- tartaric acid, (+)-and(-)-di-p-toluyl tartaric acid, (+)-and(-)-dibenzoyltartaric acid, (-)-malic acid, (+)-and(-) mandelic acid and (+)-lactic acid.
6. The process as claimed in claim 1 wherein in step e) hydrolysis is carried out in acidic or basic conditions and hydrolyzing agent is selected from inorganic acid or alkali hydroxides.
7. The process as claimed in claim 1 wherein in step f) reducing agent is selected from alkali or alkaline metal hydrides or borohydrides or hydrogenating catalyst; solvent is selected from hydrocarbons; aliphatic esters; ethers; protic or aprotic solvents; C1-C10 alcohols and mixtures thereof.
8. A hydroxy-carbonitrile compound of formula II.

Formula II

9. A process for the preparation of fesoterodine of formula I and pharmaceutically acceptable salts thereof using compound of formula II as claimed in claim 8.
10. A process for the preparation of hydroxy-benzonitrile compound of
formula III, comprises;
a). reacting 4-hydroxy-benzonitrile with trans cinnamaldehyde in the
presence of a suitable base and a suitable solvent to form hydroxy-
carbonitrile intermediate of formula II;
b). reductively aminating hydroxy-carbonitrile intermediate of formula II
with diisopropylamine using a suitable reducing agent in the presence
of a suitable solvent to form hydroxy-benzonitrile intermediate of
formula III;
c). isolating the hydroxy-benzonitrile intermediate of formula III in solid
form;
d). converting the hydroxy-benzonitrile intermediate of formula III into
fesoterodine of formula I and pharmaceutically acceptable salts
thereof.