DESC:Field of the Invention
The present invention provides an improved process for the preparation of Bepotastine Besilate and its intermediate thereof.
Background of the Invention
Bepotastine (INN) is an antihistaminic drug used for the treatment of allergic diseases such as allergic rhinitis, allergic conjunctivitis and chemically known as (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid. Its benzene sulphonic acid salt is Bepotastine Besilate and marketed as BEPREVE in United States.

The US6,780,877discloses that (S)-bepotastine isomer has better pharmacological effects compared to (R)-bepotastine isomer and therefore presence of enantiomeric impurity in (S) bepotastine may possibly affect efficacy of drug formulation. Hence, enantiomeric pure Bepotastine is of outmost importance.
The US 6,780,877 patent discloses a process for preparation of Bepotastine (Scheme 1), wherein the process involves, resolution of racemic 4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine into S-enantiomer by employing optically active (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitro-5-chlorophenylthio)propionic acid and subsequent reaction of resolved (S)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine with ethyl 4-halobutanoate in the presence of inorganic base in monophasic inert solvent. The hydrolysis ofethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]-butanoateprovides (S)-bepotastine and its subsequent salt formation with benzene sulphonic acid yields compound of formula (I).

herein, W represents a leaving group such as a halogen atom or a reactive ester group such as methanesulfonyloxy, p-toluenesulfonyloxyetc and R represents a lower alkyl group such as methyl, ethyl etc. The method is economically disadvantageous since it involves tedious preparation of resolving agentand the purity of resolved S-enantiomer of Bepotastine is also less.
The publication US20100168433(herein after US’433) provides another process for preparation of Bepotastine, comprising reacting (RS)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine with 4-halobutanoic acid l-menthyl ester to obtain (RS)-bepotastine-l-menthyl esterin the presence of inorganic base in monophasic inert solvent. Resolution of (RS)-bepotastine-l-menthyl ester using N-benzyloxycarbonyl L-aspartate as resoluting agent provides (S)-bepotastine-l-menthyl ester subsequent hydrolysis yieldsBepotastine (Scheme-2).
The Korean publication KR20120060075 (herein after KR’075) discloses the preparation ofBepotastine by reacting (-) bornyl ester of 4-halo butanoic acid with (RS)-2-[(4-chloro phenyl)(4-piperidinyloxy)-methyl] pyridine(Scheme 3) in the presence of base in an inert solvent. The reaction provides preferentially S-enantiomer involving isomerization of R-enantiomer in presence of base. Subsequent hydrolysis of the intermediate provides Bepotastine.
The publications US’433 and KR’075 involves the use of intermediate,l-menthyland (-) - bornyl ester of 4-halobutanoic acid respectivelythat are not commercially available, thus needs to be synthesized.
Besides the availability of different methods for the preparation Bepotastine in state of the art, there isa need for an improved process for the preparation of Bepotastine, that is economically significant.
Summary of the Invention
An important aspect of the present invention is to provide an improved process for the preparation of benzene sulfonic acid salt of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula I,

comprising the steps of:
(i) reacting compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with alkyl 4-halo butanoate of formula V,
wherein X is halogen and R is C1-C5 alkyl group,

in biphasic solvent system in presence or absenceof phase transfer catalyst to obtain the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula III,

(ii) treating compound of formula III with polar solvent and water in presence suitable base to obtain the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula II,

(iii) contacting compound of formula II with benzene sulphonic acid in suitable solvent to obtain the benzene sulphonate salt of formula I;
(iv) optionally, the steps (i) and (ii) are performed without the isolation of intermediate compounds formed; and
(v) optionally purifying the compound of formula I with suitable solvent.
Another aspect of the present invention is to provide an improved process for the preparation of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula II,

comprising the steps of:
(i) reacting compound (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with alkyl 4-halo butanoate of formula V,
wherein X is halogen and R is C1-C5 alkyl group,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino] butanoate of formula III,

(ii) treating compound of formula III with polar solvent and water in presence of suitable base to obtain the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula II,

(iii) optionally, the steps (i) to (ii) are performed without the isolation of intermediate compound formed;and
(iv) optionally purifying the compound of formula II with suitable solvent.
Another aspect of the present invention is to provide an improved process for the preparation of alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoateof formula III,

comprising the steps of:
(i) reacting compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with alkyl 4-halo butanoate of formula V,
wherein X is halogen and R is C1-C5 alkyl group,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula III.
Another aspect of the present invention is to provide an improved process for the preparation of benzene sulfonic acid salt of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula I,

comprising the steps of:
(i) reacting compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with ethyl 4-bromobutanoate of formula Va,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound ethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula IIIa,

(ii) treating compound of formula IIIa with polar solvent and water in presence of suitable base to obtain the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula II,

(iii) contacting compound of formula II with benzene sulphonic acid in suitable solvent to obtain the benzene sulphonate salt of formula I; and
(iv) optionally, the steps (i) and (ii) are performed without the isolation of intermediate compound formed.
Another aspect of the present invention is to provide an improved process for the preparation of anhydrous Bepotastine salt of formula I,

comprising the steps of:
(i) reacting compound (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with ethyl 4-bromo butanoate of formula Va,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound ethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula IIIa,

(ii) separating the organic layer of biphasic solvent system from step (i) containing the compound of formula IIIa;
(iii) treating the organic layer of step (ii) with polar solvent and water in presence of suitable base and adjusting the pH of the reaction mixture with suitable acids;
(iv) separating the aqueous layer of step (iii) and isolating the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula II as residue,

(v) treating the residue of step (iv) with alcohol to remove solid impurities by filtration;
(vi) treating the filtrate of step (v) with a solution of benzene sulphonic acid in alcohol;
(vii) removing the alcohol solvent from the solution of step (vi) to provide a residue and treating the residue with water and then isolating the compound of formula I;
(viii) dissolving the product of step (vii) in ketone solvent optionally with the aid of co-solvent;
(ix) filtering the solution of step (viii) and subjecting the solution under condition which facilitate crystallization of compound of formula I; and
(x) isolating compound of formula I
Detailed Description of the Invention
The first embodiments of the present invention is to provide an improved process for the preparation of benzene sulfonic acid salt of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula I,

comprising the steps of:
(i) reacting compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with alkyl 4-halo butanoate of formula V,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula III,

(ii) treating compound of formula III with polar solvent and water in presence of suitable base to obtain the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula II,

(iii) contacting compound of formula II with benzene sulphonic acid in suitable solvent to obtain the benzene sulphonate salt of formula I;
(iv) optionally, the steps (i) and (ii) are performed without the isolation of intermediate compound formed; and
(v) optionally purifying the compound of formula I with suitable solvent.
The compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV may be obtained from the racemicmixture by resolution with suitable optical resoluting agent. The optical resoluting agent which may be employed includes but not limited to N-acyl-amino acids, D-lactic acid, D-tartaric acid, D-malic acid, 1S-10-camphor sulfonic acid, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, D-mandelic acid, di-p-anisoyl-D-tartaric acid, D-tartaric acid monoparachloroanilide, dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-1,1'-binaphthalene-2,2'-dihydrogen phosphate, Di-p-toluyl-D-tartaric acid and mixtures thereof. Preferably N-acyl-amino acids which further comprises of N-acetyl-L-phenylalanine, N-acetyl-L-leucine, N-benzyloxycarbonyl-L-phenylalanine, N-benzyloxycarbonyl-L-valine, N-benzyloxycarbonyl-L-threonine and N-benzyloxycarbonyl-L-serine, and more preferably N-acetyl-L-phenylalanine. The resolution of (RS)-2-[(4-chloro phenyl) (4-piperidinyloxy)-methyl] pyridine may be achieved by techniques and methods known to a person skilled in the art using aforementioned optical resoluting agent.
Accordingly, the step (i) of the present invention involves reaction of compound of formula IV with alkyl 4-halo butanoate of formula V in presence of phase transfer catalyst in a biphasic solvent system, of which one of the phase is aqueous phase. The non-aqueous phase solvent comprises of chlorinated solvents, ethers, esters, aromatic hydrocarbons or mixtures thereof. Examples of such solvents include but not limited to dichlormethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, diisopropyl ether, dimethyl ether, ethyl acetate, butyl acetate, methyl acetate, benzene, toluene, cyclohexane, and xylene. Preferably aromatic hydrocarbons and more preferably toluene.
The compound alkyl 4-halo butanoate of formula V, wherein X represents a leaving group such as a halogen atom or a reactive ester group such as methanesulfonyloxy, p-toluenesulfonyloxy etc. Preferably halogen and more preferably chloro or bromo and R represents a lower alkyl group such as methyl, ethyl, propyl etc.
The phase transfer catalyst in step (i) is selected from group comprising of crown ether or quaternary ammonium salt. Quaternary ammonium salts may be aryl and alkyl-ammonium halide, examples of which include tetrabutyl-ammonium chloride, tetrabutyl-ammonium bromide, tetrabutyl-ammonium fluoride, tetrabutyl-ammonium iodide, cetyltrimethyl-ammonium chloride and benzyltrialkyl-ammonium chloride or mixtures thereof. Preferably quaternary ammonium salts and more preferably tetrabutyl-ammonium bromide (TBAB).
The reaction is preferably carried out at temperature of about 0 °C to 150 °C, more preferably at 50°C to 100 °C.
Accordingly, the step (ii) of the present invention is performed by hydrolyzing the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula III, wherein (R represent lower alkyl group likes methyl, ethyl or propyl) by treating product of step (i) with polar solvent and water in presence of suitable base. The suitable base selected from group comprising of alkali or alkaline earth metal hydroxide, which includes but not limited to sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, and the like, preferably sodium hydroxide. The polar solvent selected from group comprising alkanols, which includes but not limited to methanol, ethanol, propanol, isopropanolpreferably ethanol.
Accordingly, step (iii) of the present invention is performed by reacting compound of formula II with benzene sulphonic acid salt in suitable solvent. The suitable solvent selected from group comprising methanol, ethanol, propanol, isopropanol and water,preferably isopropanol in presence or absence of water.
Accordingly the invention disclosed herein, provides a process wherein the step (i) and (ii) are performed without the isolation of the intermediate formed.
Accordingly, the purity of benzenesulfonic acid salt of formula (I) (i.e. Bepotastine Besilate) may be enhanced by conventional methodssuch as recrystallization. For recrystallization of the benzenesulfonic acid salt of formula I, a person skilled in the art may select an appropriate solvent to carry out recrystallization. For example, in accordance with one embodiment of the present invention, a mixed solvent of acetone and water may be used for recrystallization of the benzenesulfonic acid salt, thereby obtaining BepotastineBesilate with optical purity of more than about 99.9 %.
Thesecond embodiment of the present invention is to provide an improved process for the preparation of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula I,

comprising the steps of:
(i) reacting compound (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with alkyl 4-halo butanoate of formula V,
wherein X is halogen and R is C1-C5 alkyl group,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula III,

(ii) treating compound of formula III with polar solvent and water in the presence of suitable base to obtain the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula II,

and
(iii) optionally, the steps (i) to (ii) are performed without the isolation of intermediate compound formed.
The compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV may be obtained from the racemic mixture by resolution with suitable optical resoluting agent. The optical resoluting agent which may be employed includes but not limited to N-acyl-amino acids, D-lactic acid, D-tartaric acid, D-malic acid, 1S-10-camphor sulfonic acid, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, D-mandelic acid, di-p-anisoyl-D-tartaric acid, D-tartaric acid monoparachloroanilide, dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-1,1'-binaphthalene-2,2'-dihydrogen phosphate, Di-p-toluyl-D-tartaric acid and mixtures thereof. Preferably N-acyl-amino acids which further comprises of N-acetyl-L-phenylalanine, N-acetyl-L-leucine, N-benzyloxycarbonyl-L-phenylalanine, N-benzyloxycarbonyl-L-valine, N-benzyloxycarbonyl-L-threonine and N-benzyloxycarbonyl-L-serine, and more preferably N-acetyl-L-phenylalanine. The resolution of (RS)-2-[(4-chloro phenyl) (4-piperidinyloxy)-methyl] pyridine may be achieved by techniques and methods known to a person skilled in the art using aforementioned optical resoluting agent.
Accordingly, the step (i) of the present invention involves reaction of compound of formula IV with alkyl 4-halo butanoate of formula V in presence of phase transfer catalyst in a biphasic solvent system, of which one of the phase is aqueous phase. The non-aqueous phase solvent comprises of chlorinated solvents, ethers, esters, aromatic hydrocarbons or mixtures thereof. Examples of such solvents include but not limited to dichlormethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, diisopropyl ether, dimethyl ether, ethyl acetate, butyl acetate, methyl acetate, benzene, toluene, cyclohexane, and xylene. Preferably aromatic hydrocarbons and more preferably toluene.
The compound alkyl 4-halo butanoate of formula V, wherein X represents a leaving group such as a halogen atom or a reactive ester group such as methanesulfonyloxy, p-toluenesulfonyloxy etc. Preferably halogen and more preferably chloro or bromo and R represents a lower alkyl group such as methyl, ethyl, propyl etc.
The phase transfer catalyst in step (i) is selected from group comprising of crown ether or quaternary ammonium salt. Quaternary ammonium salts may be aryl and alkyl-ammonium halide, examples of which include tetrabutyl-ammonium chloride, tetrabutyl-ammonium bromide, tetrabutyl-ammonium fluoride, tetrabutyl-ammonium iodide, cetyltrimethyl-ammonium chloride and benzyltrialkyl-ammonium chloride or mixtures thereof. Preferably quaternary ammonium salts and more preferably tetrabutyl-ammonium bromide (TBAB).
The reaction is preferably carried out at temperature of about 0 °C to 150 °C, more preferably at 50°C to 100 °C.
Accordingly, the step (ii) of the present invention is performed by hydrolyzing the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula III, wherein (R represent lower alkyl group likes methyl, ethyl or propyl) by treating product of step (i) with polar solvent and water in presence of suitable base. The suitable base selected from group comprising of alkali or alkaline earth metal hydroxide, which includes but not limited to sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, and the like, preferably sodium hydroxide. The polar solvent selected from group comprising alkanols, which includes but not limited to methanol, ethanol, propanol, isopropanol preferably ethanol.
Accordingly the invention disclosed herein, provides a process wherein the step (i) and (ii) are performed without the isolation of the intermediate formed.
The third embodiments of the present invention is to provide an improved process for the preparation of alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino] butanoateor salts thereof of formula III,

comprising the steps of:
(i) reacting compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with alkyl 4-halo butanoate of formula V,
wherein X is halogen and R is C1-C5 alkyl group,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula III.
The compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV may be obtained from the racemic mixture by resolution with suitable optical resoluting agent. The optical resoluting agent which may be employed includes but not limited to N-acyl-amino acids, D-lactic acid, D-tartaric acid, D-malic acid, 1S-10-camphor sulfonic acid, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, D-mandelic acid, di-p-anisoyl-D-tartaric acid, D-tartaric acid monoparachloroanilide, dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-1,1'-binaphthalene-2,2'-dihydrogen phosphate, Di-p-toluyl-D-tartaric acid and mixtures thereof. Preferably N-acyl-amino acids which further comprises of N-acetyl-L-phenylalanine, N-acetyl-L-leucine, N-benzyloxycarbonyl-L-phenylalanine, N-benzyloxycarbonyl-L-valine, N-benzyloxycarbonyl-L-threonine and N-benzyloxycarbonyl-L-serine, and more preferably N-acetyl-L-phenylalanine. The resolution of (RS)-2-[(4-chloro phenyl) (4-piperidinyloxy)-methyl] pyridine may be achieved by techniques and methods known to a person skilled in the art using aforementioned optical resoluting agent.
Accordingly, the step (i) of the present invention involves reaction of compound of formula IV with alkyl 4-halo butanoate of formula V in presence of phase transfer catalyst in a biphasic solvent system, of which one of the phase is aqueous phase. The non-aqueous phase solvent comprises of chlorinated solvents, ethers, esters, aromatic hydrocarbons or mixtures thereof. Examples of such solvents include but not limited to dichlormethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, diisopropyl ether, dimethyl ether, ethyl acetate, butyl acetate, methyl acetate, benzene, toluene, cyclohexane, and xylene. Preferably aromatic hydrocarbons and more preferably toluene.
The compound alkyl 4-halo butanoate of formula V, wherein X represents a leaving group such as a halogen atom or a reactive ester group such as methanesulfonyloxy, p-toluenesulfonyloxy etc. Preferably halogen and more preferably chloro or bromo and R represents a lower alkyl group such as methyl, ethyl, propyl etc.
The phase transfer catalyst in step (i) is selected from group comprising of crown ether or quaternary ammonium salt. Quaternary ammonium salts may be aryl and alkyl-ammonium halide, examples of which include tetrabutyl-ammonium chloride, tetrabutyl-ammonium bromide, tetrabutyl-ammonium fluoride, tetrabutyl-ammonium iodide, cetyltrimethyl-ammonium chloride and benzyltrialkyl-ammonium chloride or mixtures thereof. Preferably quaternary ammonium salts and more preferably tetrabutyl-ammonium bromide (TBAB).
The reaction is preferably carried out at temperature of about 0 °C to 150 °C, more preferably at 50°C to 100 °C.
The four embodimentsof the present invention is to provide an improved process for the preparation of benzene sulfonic acid salt of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy] piperidino]butanoic acid of formula I,

comprising the steps of:
(i) reacting compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with ethyl 4-bromobutanoate of formula Va,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound ethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula IIIa,

(ii) treating compound of formula IIIa with polar solvent and water in presence of suitable base to obtain the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula II,

(iii) contacting compound of formula II with benzene sulphonic acid in suitable solvent to obtain the benzene sulphonate salt of formula I; and
(iv) optionally, the steps (i) and (ii) are performed without the isolation of intermediate compound formed.
The compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV maybe obtained from the racemic mixture by resolution with suitable optical resoluting agent. The optical resoluting agent which may be employed includes but not limited to N-acyl-amino acids, D-lactic acid, D-tartaric acid, D-malic acid, 1S-10-camphor sulfonic acid, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, D-mandelic acid, di-p-anisoyl-D-tartaric acid, D-tartaric acid monoparachloroanilide, dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-1,1'-binaphthalene-2,2'-dihydrogen phosphate, Di-p-toluyl-D-tartaric acid and mixtures thereof. Preferably N-acyl-amino acids which further comprises of N-acetyl-L-phenylalanine, N-acetyl-L-leucine, N-benzyloxycarbonyl-L-phenylalanine, N-benzyloxycarbonyl-L-valine, N-benzyloxycarbonyl-L-threonine and N-benzyloxycarbonyl-L-serine, and more preferably N-acetyl-L-phenylalanine. The resolution of (RS)-2-[(4-chloro phenyl) (4-piperidinyloxy)-methyl] pyridine may be achieved by techniques and methods known to a person skilled in the art using aforementioned optical resoluting agent.
Accordingly, the step (i) of the present invention involves reaction of compound of formula IV with alkyl 4-halo butanoate of formula V in presence of phase transfer catalyst in a biphasic solvent system, of which one of the phase is aqueous phase. The non-aqueous phase solvent comprises of chlorinated solvents, ethers, esters, aromatic hydrocarbons or mixtures thereof. Examples of such solvents include but not limited to dichlormethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, diisopropyl ether, dimethyl ether, ethyl acetate, butyl acetate, methyl acetate, benzene, toluene, cyclohexane, and xylene. Preferably aromatic hydrocarbons and more preferably toluene.
The compound alkyl 4-halo butanoate of formula V, wherein X represents a leaving group such as a halogen atom or a reactive ester group such as methanesulfonyloxy, p-toluenesulfonyloxy etc. Preferably halogen and more preferably chloro or bromo and R represents a lower alkyl group such as methyl, ethyl, propyl etc.
The phase transfer catalyst in step (i) is selected from group comprising of crown ether or quaternary ammonium salt. Quaternary ammonium salts may be aryl and alkyl-ammonium halide, examples of which include tetrabutyl-ammonium chloride, tetrabutyl-ammonium bromide, tetrabutyl-ammonium fluoride, tetrabutyl-ammonium iodide, cetyltrimethyl-ammonium chloride and benzyltrialkyl-ammonium chloride or mixtures thereof. Preferably quaternary ammonium salts and more preferably tetrabutyl-ammonium bromide (TBAB).
The reaction is preferably carried out at temperature of about 0 °C to 150 °C, more preferably at 50°C to 100 °C.
Accordingly, the step (ii) of the present invention is performed by hydrolyzing the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula III, wherein (R represent lower alkyl group likes methyl, ethyl or propyl) by treating product of step (i) with polar solvent and water in presence of suitable base. The suitable base selected from group comprising of alkali or alkaline earth metal hydroxide, which includes but not limited to sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, and the like, preferably sodium hydroxide. The polar solvent selected from group comprising alkanols, which includes but not limited to methanol, ethanol, propanol, isopropanol preferably ethanol.
Accordingly, step (iii) of the present invention is performed by reacting compound of formula II with benzene sulphonic acid salt in suitable solvent. The suitable solvent selected from group comprising methanol, ethanol, propanol isopropanol and water, preferably isopropanol in presence or absence of water.
Accordingly the invention disclosed herein, provides a process wherein the step (i) and (ii) are performed without the isolation of the intermediate formed.
Accordingly, the purity of benzenesulfonic acid salt of formula (I) (i.e. BepotastineBesilate) maybe enhanced by conventional methods such as recrystallization. For recrystallization of the benzenesulfonic acid salt of formula I, a person skilled in the art mayselect an appropriate solvent to carry out recrystallization. For example, in accordance with one embodiment of the present invention, a mixed solvent of acetone and water maybe used for recrystallization of the benzenesulfonic acid salt, thereby obtaining Bepotastine Besilate with optical purity of more than about 99.9 %.
The fifth embodimentsof the present invention is to provide an improved process for the preparation of benzene sulfonic acid salt of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula I,

comprising the steps of,

(i) reacting compound (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with ethyl 4-bromo butanoate of formula Va,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound ethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula IIIa,

(ii) separating the organic layer of biphasic solvent system from step (i) containing the compound of formula (IIIa);
(iii) treating the organic layer of step (ii) with polar solvent and water in presence of suitable base and adjusting pH of the reaction mixture with suitable acids;
(iv) separating the aqueous layer of step (iii) and isolating the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula II as residue,

(v) treating the residue of step (iv) with alcohol to remove solid impurities by filtration;
(vi) treating the filtrate of step (v) with a solution of benzene sulphonic acid in alcohol;
(vii) removing the alcohol solvent from the solution of step (vi) to provide a residue and treating the residue with water and then isolating the compound of formula I;
(viii) dissolving the product of step (vii) in ketone solvent optionally with aid of co-solvent;
(ix) filtering the solution of step (viii) and subjecting the solution under condition which facilitate crystallization of compound of formula I; and
(x) isolating compound of formula I.
The compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV may be obtained from the racemic mixture by resolution with suitable optical resoluting agent. The optical resoluting agent which maybe employed includes but not limited to N-acyl-amino acids, D-lactic acid, D-tartaric acid, D-malic acid, 1S-10-camphor sulfonic acid, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, D-mandelic acid, di-p-anisoyl-D-tartaric acid, D-tartaric acid monoparachloroanilide, dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-1,1'-binaphthalene-2,2'-dihydrogen phosphate, Di-p-toluyl-D-tartaric acid and mixtures thereof. Preferably N-acyl-amino acids which further comprises of N-acetyl-L-phenylalanine, N-acetyl-L-leucine, N-benzyloxycarbonyl-L-phenylalanine, N-benzyloxycarbonyl-L-valine, N-benzyloxycarbonyl-L-threonine and N-benzyloxycarbonyl-L-serine, and more preferably N-acetyl-L-phenylalanine. The resolution of (RS)-2-[(4-chloro phenyl) (4-piperidinyloxy)-methyl] pyridine maybe achieved by techniques and methods known to a person skilled in the art using aforementioned optical resoluting agent.
Accordingly, the step (i) of the present invention involves reaction of compound of formula IV with alkyl 4-halo butanoate of formula V in presence of phase transfer catalyst in a biphasic solvent system, of which one of the phase is aqueous phase. The non-aqueous phase solvent comprises of chlorinated solvents, ethers, esters, aromatic hydrocarbons or mixtures thereof. Examples of such solvents include but not limited to dichlormethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, diisopropyl ether, dimethyl ether, ethyl acetate, butyl acetate, methyl acetate, benzene, toluene, cyclohexane, and xylene. Preferably aromatic hydrocarbons and more preferably toluene.
The compound alkyl 4-halo butanoate of formula V, wherein X represents a leaving group such as a halogen atom or a reactive ester group such as methanesulfonyloxy, p-toluenesulfonyloxy etc. Preferably halogen and more preferably chloro or bromo and R represents a lower alkyl group such as methyl, ethyl, propyl etc.
The phase transfer catalyst in step (i) is selected from group comprising of crown ether or quaternary ammonium salt. Quaternary ammonium salts maybe aryl and alkyl-ammonium halide, examples of which include tetrabutyl-ammonium chloride, tetrabutyl-ammonium bromide, tetrabutyl-ammonium fluoride, tetrabutyl-ammonium iodide, cetyltrimethyl-ammonium chloride and benzyltrialkyl-ammonium chloride or mixtures thereof. Preferably quaternary ammonium salts and more preferably tetrabutyl-ammonium bromide (TBAB).
The reaction is preferably carried out at temperature of about 0 °C to 150 °C, more preferably at 50°C to 100 °C.
Accordingly, the step (ii) of the present invention is performed by hydrolyzing the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoate of formula III, wherein (R represent lower alkyl group likes methyl, ethyl or propyl) by treating product of step (i) with polar solvent and water in presence of suitable base. The suitable base selected from group comprising of alkali or alkaline earth metal hydroxide, which includes but not limited to sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, and the like, preferably sodium hydroxide. The polar solvent selected from group comprising alkanols, which includes but not limited to methanol, ethanol, propanol, isopropanol preferably ethanol.
Accordingly, in step (iii) the pH of the reaction mass may be adjusted by suitable acids. The suitable acids selected from group comprising of mineral acids, organic acids etc. Preferably mineral acids comprising of hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid etc. More preferably hydrochloric acid.
Accordingly, in step (iv) the separation of aqueous layer may performed by techniques known to a person skilled in the art such as distillation, evaporation etc. Preferably distillation.
Accordingly, step (v) of the present invention is performed by reacting compound of formula II with benzene sulphonic acid salt in alcohol. The alcoholic solvent selected from group comprising methanol, ethanol, propanol, isopropanol and water, more preferably isopropanol in presence or absence of water.
Accordingly, the purity of benzenesulfonic acid salt of formula (I) (i.e. BepotastineBesilate) maybe enhanced by conventional methods such as recrystallization. For recrystallization of the benzenesulfonic acid salt of formula I, a person skilled in the art mayselect an appropriate solvent to carry out recrystallization. In accordance, one embodiment of the present invention, a mixed solvent of acetone and water maybe used for recrystallization of the benzenesulfonic acid salt, thereby obtaining BepotastineBesilate with optical purity of more than about 99.9 %.
Accordingly the invention disclosed herein, provides a process wherein the step (i) and (ii) are performed without the isolation of the intermediate formed.
The sixth embodiments of the present invention is to provide an improved process for the preparation of benzene sulfonic acid salt of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula I, as illustrated the scheme-4,

wherein X represents a leaving group such as a halogen atomor a reactive ester group such as methanesulfonyloxy, p-toluenesulfonyloxy etc. Preferably halogen and more preferably chloro or bromo and R represents a lower alkyl group such as methyl, ethyl, propyl etc.
The inventors of the present invention surprisingly found that when reaction of (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl] pyridine of formula IV with ethyl 4-bromobutanoate carried out in biphasic system and in presence of phase transfer catalyst such as quaternary ammonium salts in catalytic amount, improves the efficiency of the reaction by felicitating the coupling of (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl] pyridine with ethyl 4-bromobutanoate. This reduces the residual amount of (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl] pyridine impurity about 10 fold in the reaction product, compared to the reaction performed in the absence of phase transfer catalyst. The reduction in quantity of (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl] pyridine impurity at beginning of reaction sequence, significantly reduces theimpurity in the final Bepotastine Besilate API.
The inventors also observed that dialkylation of (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl] pyridine with ethyl 4-bromobutanoate significantly reduced when reaction is performed in biphasic system in presence of phase transfer catalyst, in turn increases the conversion efficiency of the reaction.
S.NO
TBAB quantity (mR) REACTION MONITORING
Reaction Time % Impurity (compound IV) in product III (HPLC)
1. 0.0 15hrs 1.55
2. 0.1 15hrs 1.01
3. 0.2 13hrs 0.17

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.
Example 1: Preparation of N-Acetyl-L-phenylalanine salt of (S)-2-[(4-chlorophenyl) (4-piperidinyloxy) methyl] pyridine.
A mixture of(RS)-2-[(4-chloro phenyl)(4-piperidinyloxy)-methyl] pyridine (200 g)and N-Acetyl-L-phenylalanine (82g) in ethylacetate (6000 ml) was heated at 70-75 °C for nearly 2hours. The contents were cooled to 45-50 °C and seeded with N-Acetyl-L-phenylalanine salt of (S)-2-[(4-chlorophenyl) (4-piperidinyloxy) methyl] pyridinesolid (1 g). The contents were stirred at 45-50 °C for nearly 5hours and cooled to 30-35 °C. The solid obtained was filtered and washed with ethylacetate (800 ml) to get title compound as an off white to pale brown wet solid (380 g). The wet solid was recrystallized from ethyl acetate to yield titled compound. Yield:120 gm.
Example 2: Preparation of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acidmonobenzenesulfonate:
Step (a):-To a solution of product of example-1 (300 g) in water (600 ml), sodium hydroxide solution (47.1 g in 300 ml of water) was added at ambient temperature and stirred at the same temperature. The reaction mass was extracted with toluene(900 ml) and the toluene layer was washed with water to get a yellow hazy to clear toluene solution containing (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl]pyridine. This toluene solution was taken to next stage as such.
Step (b):-The toluene layer (from step a) containing the (S)-2-[(4-chlorophenyl)(4-piperidinyloxy)-methyl] pyridinewas treated with water. To this biphasic reaction mass potassium carbonate (162.4 g), tetrabutylammonium bromide (37.9 g) and ethyl-4-bromo butyrate (126.2 g) was added. The contents were heated to about 80 °C and stirred till the completion of reaction. The reaction mass was cooled and the layers were separated. The aqueous layer was extracted with toluene and the combined organic layers were washed with water and then charcoalised with activated carbon to get a yellow clear solution of toluene containing ethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino] butanoate. This toluene layer was taken to next stage as such.
Step (c):-The toluene layer (from step b) containing product was treated with rectified spirit (300 ml), sodium hydroxide (42.3 g) and water (75 ml). The reaction mass was stirred till the completion of reaction. The pH of the reaction mass was adjusted to 6.0±0.5 with dilHCl. The aqueous layer was separated and washed with toluene. The aqueous layer was distilled under vacuum. The residue was co-distilled with isopropanol to remove residual water. The residue was stirred with isopropanol and filtered to remove the inorganic solids. The filtrate containing the product was charcoalised and recovered as pale yellow clear solution of isopropanol containing the (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acidwas taken to next stage as such.
Step (d):-The isopropanol solution (from step c) containing the product was treated with a solution of benzene sulphonic acid monohydrate (93.2 g) in isopropanol to get a white solid, which was filtered and washed with isopropanol. The wet solid was dissolved in mixture of water and isopropanoland then distilledoff to remove about 1.5-2.0X of water-isopropanol mixture. The content was cooled, seeded Bepotastine Besilate solid and allowed to stir for crystallization. The reaction mass was further cooled and stirred. The solidwas filtered, washed with water and dried to give title compound as an off white to white solid. Yield:210 gm.
Example 3: Purification of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acidmonobenzenesulfonate:
A slurry of product of example-2 in acetone and water were heated to get a clear solution. The clear solution was filtered through a 0.2 micron filter paper. The filtrate was allowed to cool gradually and stirred to crytallize. The solid was filtered, washed with acetoneand dried to get title compound as a white solid. Yield:150 gm.
,CLAIMS:
1. A process for the preparation of benzene sulfonic acid salt of (S)-4-[4-[(4-chlorophenyl) (2-pyridyl)-methoxy]piperidino]butanoic acid of formula I,

comprising the steps of:
(i) reacting compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with alkyl 4-halo butanoate of formula (V),
wherein X is halogen and R is C1-C5 alkyl group,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino] butanoate of formula III,

(ii) treating compound of formula III with polar solvent and water in presence of suitable base to obtain the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy] piperidino]butanoic acid of formula II,

(iii) contacting compound of formula II with benzene sulphonic acid in suitable solvent to obtain the benzene sulphonate salt of formula I;
(iv) optionally, the steps (i) and (ii) are performed without the isolation of intermediate compound formed; and
(v) optionally purifying the compound of formula I with suitable solvent.
2. The process according to claim 1, wherein said phase transfer catalyst is selected from a group comprising crown ether and quaternary ammonium salt.
3. The process according to claim 2, wherein said quaternary ammonium salt selected from a group comprising aryl and alkyl-ammonium halide.
4. The process according to claim 3, wherein said alkyl-ammonium halide is tetra butyl-ammonium bromide (TBAB).
5. The process according to claim 1, wherein said suitable base selected from a group comprising alkali or alkaline earth metal hydroxide.
6. The process according to claim 5, wherein said the alkali earth metal is sodium hydroxide.
7. The process according to claim 1, wherein said polar solvent is selected from a group comprising water and alkanol.
8. The process according to claim 1, wherein said suitable solvent is selected from a group comprising methanol, ethanol, propanol and isopropanol and water.
9. A process for the preparation of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidino]butanoic acid of formula I,

comprising the steps of:
(i) reacting compound (S) 2-[(4-Chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with alkyl 4-halo butanoate of formula (V),
wherein X is halogen and R is C1-C5 alkyl group,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino] butanoate of formula III,

(ii) treating compound of formula III with polar solvent and water in presence of suitable base to obtain the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy] piperidino]butanoic acid of formula II,

and
(iii) optionally, the steps (i) to (ii) are performed without the isolation of intermediate compound formed.
10. The process according to claim 9, wherein said phase transfer catalyst is selected from a group comprising crown ether and quaternary ammonium salt.
11. The process according to claim 10, wherein said quaternary ammonium salt selected from a group comprising aryl and alkyl-ammonium halide.
12. The process according to claim 11, wherein said alkyl-ammonium halide is tetra butyl-ammonium bromide (TBAB).
13. The process according to claim 1, wherein said suitable base selected from a group comprising alkali or alkaline earth metal hydroxide.
14. A process for the preparation of alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino] butanoate of formula III,

comprising the steps of:
(i) reacting compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with alkyl 4-halo butanoate of formula (V),
wherein X is halogen and R is C1-C5 alkyl group,

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound alkyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy] piperidino] butanoate of formula III.
15. The process according to claim 16, wherein said phase transfer catalyst is selected from a group comprising crown ether and quaternary ammonium salt.
16. The process according to claim 17, wherein said quaternary ammonium salt selected from a group comprising aryl and alkyl-ammonium halide.
17. The process according to claim 18, wherein said alkyl-ammonium halide is tetra butyl-ammonium bromide (TBAB).
18. A process for the preparation of benzene sulfonic acid salt of (S)-4-[4-[(4-chlorophenyl) (2-pyridyl)-methoxy]piperidino]butanoic acid of formula I,

comprising the steps of:
(i) reacting compound (S) 2-[(4-chloro-phenyl) (4-piperidinyloxy)methyl]pyridine of formula IV,

with ethyl 4-bromobutanoate of formula (Va),

in biphasic solvent system in presence or absence of phase transfer catalyst to obtain the compound ethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino] butanoate of formula IIIa,

(ii) treating compound of formula IIIa with polar solvent and water in presence of suitable base to obtain the compound (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)-methoxy] piperidino]butanoic acid of formula II,

(iii) contacting compound of formula II with benzene sulphonic acid in suitable solvent to obtain the benzene sulphonate salt of formula I; and
(iv) optionally, the steps (i) and (ii) are performed without the isolation of intermediate compound formed.