FORM 2
THE PATENT ACT, 1970
(39 of l 970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A NOVEL PROCESS FOR THE PREPARTION OF BEPOTASTINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL PROCESS FOR THE PREPARTION OF BEPOTASTINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
FIELD OF THE INVENTION
The invention encompasses a process for the prepartion of bepotastine and its pharmaceutical^ acceptable salts thereof.
BACKGROUND OF THE INVENTION
Chemically, bepotastine is (+)-(S)-4-[4-[(4-chlorophenyl)-pyridin-2-ylmethoxy] piperidin-1-yl] butanoic acid having the structural formula I, and is known from U.S. Patent No. 6,780,877.

Bepotastine has been approved in USA as bepotastine besilate ophthalmic solution 1.5% and the proprietor name of bepotastine besilate is BEPREVE™. BEPREVE™ is a histamine H1 receptor antagonist and is indicated for the treatment of itching associated with allergic conjunctivitis.
U.S. Patent No. 6,780,877 discloses a process for the preparation of bepotastine compound of structural formula I by the N-alkylation of (S)-piperidine compound of structural formula II and hydrolysis of resulting compound as described in scheme no. I.


Wherein W represents a leaving group, including a halogen atom such as chlorine atom, bromine atom, iodine atom etc; or a reactive ester group such as methanesulfonyloxy group, p-toiuenesulfonyloxy group, etc., and R represents a lower alky! group such as methyl group, ethyl group etc.
PCT publication no. 2008/153289 discloses a process for the preparation of bepotastine compound of structural formula I by reacting (RS)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine with a 4-halobutanoic acid /-menthyl ester to produce (RS)-bepotastine l-menthyl ester compound of structural formula IV, which on reaction with N-benzyloxycarbonyl L-aspartic acid yields bepotastine /-menthyl ester .N-benzyloxycarbonyi L-aspartate compound of structural formula V. The bepotastine /-menthyl ester. N-benzyloxycarbonyl L-aspartate compound of structural formula V on treatment with base yields bepotastine /-menthyl ester compound of formula VI, which on hydrolysis yields bepotastine compound of structural formula J as described in scheme no. II.


Wherein X is a halogen atom
Indian Patent Application no. E-2/95/2011-MUM discloses a process for the preparation of bepotastine compound of structural formula 1 by treating the compound of structural formula XVI with resolving agent to get a compound of structural formula HI and then converting a compound of structural formula HI into bepotastine and its pharmaceutical!}' acceptable salts thereof.


The aforementioned prior-art processes yield deschloro bepotastine compound of structural formula VII as a major impurity, which is very difficult to remove by re-crystallization and column chromatography techniques due to similarities in its physical properties like solubility with bepotastine compound of structural formula I.

Accordingly there is a need in the art to develop an alternate process for the preparation of bepotastine and its pharmaceutically acceptable salts thereof, which overcomes the prior-art problems.
SUMMARY OF THE INVENTION
In one embodiment, the invention encompasses a process for preparing bepotastine and its pharmaceutically acceptable salts thereof comprising:
a. alkylating compound of structural formula VIII to get compound of structural formula IX,

b. hydrolyzing the resulting compound of structural formula IX into compound of structural formula X and,


c. converting compound of structural formula X into bepotastine compound of structural formula i and its pharmaceutically acceptable salts.

Wherein W represents a leaving group, including a halogen atom such as chlorine atom, bromine atom, iodine atom etc; or a reactive ester group such as methanesulfonyloxy group, p-toiuenesulfonyloxy group, etc., R represents substituted or unsubstituted C1-C6 alkyl group and aryl group and 2 represent a group which is capable of converting into a chlorine atom such as hydroxy or nitro group.
In another embodiment, the invention encompasses a process for preparing bepotastine and its pharmaceutically acceptable salts thereof comprising:
a. alkylating compound of structural formula XI to get compound of structural formula XII

b. resolving compound of structural formula XI1 through an intermediate compound of structural formula XIH to get compound of structural formula XIV,


c. hydrolyzing the resulting compound of structural formula XIV into compound of structural formula X and

d. converting compound of structural formula X into bepotastine compound of structural formula I and its pharmaceutical!;/ acceptable salts.

Wherein X is a halogen atom and Z represent a group which is capable of converting into a chlorine atom such as hydroxy or nitro group.
In another embodiment, the invention encompasses novel intermediates of structural formula VIII, IX, X, XI, XII, XIII and XIV.


Wherein Z and R are as defined above.
In another embodiment, the invention encompasses a substantially pure bepotastine and its pharmaceutically acceptable salts thereof obtained by using novel intermediates of structural formula VIII, IX, X, XI, XII, XIII and XIV.
The term "substantially pure" described herein refers to the HPLC purity of more than 99% weight / weight.
In another embodiment, the invention encompasses a bepotastine and its pharmaceutically acceptable salts thereof substantially free from deschloro bepotastine compound of structural formula VII.


The term "substantially free" described herein refers to the non detectable amount of deschloro bepotastine compound of structural formula VII.
The limit of detection of deschloro bepotastine compound of structural formula VII is 0.1% weight / weight, which is determined by HPLC method.
The pharmaceutical!)' acceptable salt of bepotastine may include bepotastine benzene sulphonic acid salt, bepotastine p-toluene sulphonic acid salt, bepotastine o-toluene sulphonic acid salt, bepotastine calcium salt and bepotastine strontium salt.
In another embodiment, the invention encompasses a pharmaceutical composition of substantially pure bepotastine and its pharmaceutically acceptable salts thereof obtained by using novel intermediates of structural formula VIII, IX, X, XI, XII, XIII and XIV.
In another embodiment, the invention encompasses processes of preparing novel intermediates of structural formula VIII, IX, X, XI, XII, XIII and XIV.
DETAIL DESCRIPTION OF THE INVENTION
An alkylation of compound of structural formula VIII may be carried out in presence of inorganic base in ketone solvent under reflux condition for a period of 2 hours to 10 hours to get compound of structural formula IX.
The examples of ketone solvent may include but not limited to acetone, methyl isobutyl ketone, 2-butanone, 3-pentanone or mixture(s) thereof.
The examples of an inorganic base may include but not limited to sodium carbonate. potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium hydroxide or lithium carbonate.
The compound of structural formula IX may be isolated by filtration of insolubles followed by concentrating filtrate under reduced pressure at 40-45°C to get compound of structural formula IX.

The hydrolysis of compound of structural formula IX may be carried out with above mentioned inorganic base in an alcohol solvent at a temperature in the range of 20°C to 30°C for a period of 2 hours to 24 hours to get compound of structural formula X.
The examples of alcohol solvents may include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol or mixture(s) thereof.
The compound of structural formula X may be isolated by neutralizing the reaction mixture with aqueous hydrochloric acid to get precipitate, which may be removed by filtration and then extracting reaction mixture with halogenated aliphatic hydrocarbon solvent followed by concentrating it under reduced pressure at 40°C to 55°C to get compound of structural formula X.
The examples of halogenated aliphatic hydrocarbons solvents may include dichloromethane. dichloroethane, chloroform or carbon tetrachloride.
The conversion of compound of structural formula X into bepotastine compound of structural formula I may be carried out by the reaction of a compound of formula X with alkali metal chloride or alkali earth metal chloride in an organic solvent at temperature in the range of 25°C to 80°C for a period of 2 hours to 16 hours to get bepotastine compound of structural formula I.
The examples of alkali metal chloride or alkali earth metal chloride may include but not limited lo potassium chloride, sodium chloride or cesium chloride.
The conversion of compound of structural formula X into bepotastine compound of structural formula I may be carried out by reducing nitro group of a compound of formula X to obtain a compound of formula XV, which is converted into bepotastine compound of structural formula I by the diazotization reaction and reaction with sodium tetrachloroborate or HBCU.


The nitro group of compound of formula X may be reduced by the reaction of sodium dithionite in the presence of base in an organic solvent.
Example of base may include ammonia.
The compound of formula XV may be converted into bepotastine compound of structural formula I by diazotization reaction with sodium nitrite and hydrochloric acid followed by the reaction with sodium tetrachloroborate or HBCl4 in an organic solvent at a temperature in the range of 25°C to 80°C to get bepotastine compound of structural formula I.
The examples of organic solvent may include alcohol solvents, halogenated aliphatic hydrocarbons solvents, ether solvents or polar aprotic solvents.
The examples of alcohol solvents may include methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, pentanol or mixture(s) thereof.
The examples of ether solvents may include tetrahydrofuran, diethyl ether, diisopropy! ether, methyl tertiary butyl ether, methyl ethyl ether or mixture(s) thereof.
The examples of halogenated aliphatic hydrocarbon solvents may include dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixture(s) thereof.
The examples of polar aprotic solvents may be selected from the group comprising of dimethyl formamide, dimethyl sulfoxide, acetonitrile, dimethyl acetamide or mixture(s) thereof.

The bepotastine compound of structural formula 1 may be isolated by the steps of filtration, centrifugation, washing, drying and combination thereof.
The isolated bepotastine compound of structural formula I may be substantially free from deschloro bepotastine compound of structural formula VJJ and substantially pure having HPLC purity of more than 99% weight / weight.
The substantially pure bepotastine compound of structural formula I may be converted into bepotastine besilate by treating substantially pure bepotastine compound of structural formula 1 with benzene sulfonic acid in an alky I acetate solvent at 20°C to 30°C for a period of 2 hours to 12 hours to get bepotastine besilate salt.
The examples of alkyl acetate solvents may include but not limited to methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof

EXAMPLES
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of bepotastine compound of structural formula I.
Step i: Preparation of (S)-ethyl 4-(4-((4-nitrophenyl) (pyridin-2-yl) methoxy)
piperidin-1-yl) butanoate.
A solution of (S)-2-({4-nitrophenyl) (piperidin-4-yloxy) methyl) pyridine (50gm) in
acetone (500ml) were added ethyl 4-bromobutanoate (31gm) and potassium carbonate
(20gm) and the resulting reaction mixture was refluxed for 8 hours. The insolubles
were filter and the filtrate was concentrated under reduced pressure at 40°C to get title
compound.
Yield: 68gm
Purity: 99.0% (By HPLC)
Step 2: Preparation of (S)-4-(4-((4-nitrophenyl) (pyridin-2-yl) methoxy) piperidin-i-yl) butanoic acid.
A solution of (S)-ethyl 4-(4-((4-nitrophenyl) (pyridin-2-yl) methoxy) piperidin-1-yl) butanoate (50gm) in ethanol (700ml) was added 5N aqueous sodium hydroxide solution (40ml) at 25°C and then the reaction mixture was stirred for 8 hours at same temperature. The resulting reaction mixture was neutralized by adding 5N aqueous hydrochloric acid (36ml). precipitated crystal were removed by filtration and then resulting reaction mixture extracted with dichloroethane (400ml). The organic layer was dried over anhydrous sodium sulfate (20gm) and then it was concentrated under reduced pressure at 400C to get title compound. Yield: 46.7gm Purity: 99.5% (By HPLC)

Step 3: Preparation of bepotastine compound of structural formula I.
A solution of (S)-4-(4-((4-nitrophenyl) (pyridin-2-yi) methoxy) piperidin-1-yl)
butanoic acid (40gm) in dimethylformamide (400ml) was added cesium chloride (9.6
gin) and then reaction mixture was stirred for 5 hours at 55-60°C. The resulting
reaction mixture then cooled to 25°C and the solid obtained was filtered, washed with
dimethylformamide (200ml) and dried to get title compound.
Yield: 35.4gm
Purity: 99.9% (By HPLC)

WE CLAIM:
1. A process for preparing bepotastine and its pharmaceutically acceptable salts thereof comprising:
a. alkylating compound of structural formula VIII to get compound of structural formula IX.

b. hydrolyzing the resulting compound of structural formula IX into compound of structural formula X and,
c. converting compound of structural formula X into bepotastine compound of structural formula I and its pharmaceutically acceptable salts.

Wherein W represents a leaving group, including a halogen atom such as chlorine atom, bromine atom, iodine atom etc; or a reactive ester group such as methanesulfonyloxy group, p-toluenesulfonyloxy group, etc., R represents substituted

or unsubstituted C1-C8 alkyl group and aryl group and Z represent a group which is capable of converting into a chlorine atom such as hydroxy or nitro group.
2. A process for preparing bepotastine and its pharmaceutically acceptable salts thereof comprising:
a. alkylating compound of structural formula XI to get compound of structural formula XII

b. resolving compound of structural formula XII through an intermediate compound of structural formula XIII to get compound of structural formula XIV,

c. hydrolyzing the resulting compound of structural formula XIV into compound of structural formula X and



d. converting compound of structural formula X into bepotastine compound of structural formula I and its pharmaceutically acceptable salts.
Wherein X is a halogen atom and Z represent a group which is capable of converting into a chlorine atom such as hydroxy or nitro group.
3. The process according to claim no. 1 wherein an alkylation of compound of
structural formula VIII is carried out in presence of inorganic base such as sodium
carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium
bicarbonate, potassium bicarbonate, lithium hydroxide or lithium carbonate in ketone
solvent such as acetone, methyl isobutyl ketone, 2-butanone or 3-pentanone under
reflux condition for a period of 2 hours to 10 hours.
4. The process according to claim no. 1 wherein hydrolysis of compound of structural formula IX is carried out with inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium hydroxide or lithium carbonate in an alcohol solvent such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol at a temperature in the range of 20°C to 30°C for a period of 2 hours to 24 hours.
5. The process according to claim no. 1 wherein conversion of compound of structural formula X into bepotastine compound of structural formula I is carried out by the reaction of a compound of formula X with alkali metal chloride or alkali earth metal chloride in an organic solvent at temperature in the range of 25°C to 80°C for a period of 2 hours to 16 hours.

6. The process according to claim no. 5 wherein alkali metal chloride or alkali earth metal chloride is selected from the group comprising of potassium chloride, sodium chloride, cesium chloride.
7. The process according to claim no. 5 wherein an organic solvent is selected from the group comprising of alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, pentanol or halogenated aliphatic hydrocarbons solvents such as dichloromethane, dichloroethane, carbon tetrachloride chloroform or ether solvents such as tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, methyl ethyl ether or polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, acetonitrile, dimethyl acetamide.
8. A novel intermediate compounds of structural formula VIII, IX, X, XI, XII, XIII
and XIV.

Wherein R represents substituted or unsubstituted C1-C6 alkyl group and aryl group and Z represent a group which is capable of converting into a chlorine atom such as hydroxy or nitro group.

9. Use of compound of structural formula VIII, IX, X, XI, XII, XIII or XIV in the preparation of bepotastine compound of structural formula I.