FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF BEPOTASTINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thFloor, 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.

AN IMPROVED PROCESS FOR THE PREPARATION OF BEPOTASTINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of bepotastine and its pharmaceutically acceptable salts thereof. The process comprises treating the compound of structural formula II with resolving agent to get a compound of structural formula III and then converting a compound of structural formula III into bepotastine and its pharmaceutically acceptable salts thereof.

Formula I
Wherein R is C1-4 straight chain alkyl or substituted alkyl group or (S)-4-phenyloxazolidin-2-one group.
BACKGROUND OF THE INVENTION
Bepotastine is chemically (+)-(S)-4-[4-[(4-chlorophenyl)-pyridin-2-ylmethoxy] piperidin-1-yl] butanoic acid is disclosed in U.S. Patent No. 6,780,877 and is represented by compound of structural formula I.


Formula-I
The pharmaceutically acceptable salt of bepotastine is bepotastine besilate and it is marketed in USA under trade name Bepreve. Bepreve is a histamine H1 receptor antagonist indicated for the treatment of itching associated with signs and symptoms of allergic conjunctivitis.
U.S. Patent No. 6,780,877 discloses a process for the preparation of bepotastine as illustrated in process scheme no. 1, wherein racemic (RS)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine compound of structural formula IV is being resolved into levorotatory isomer, (S)-(-)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine compound of structural formula V and then converting it into bepotastine compound of structural formula I.

Scheme No. 1
U.S Patent publication no. 2010/0168433 describes a process for the preparation of bepotastine by resolving a compound of structural formula IX with resolving agent followed by the hydrolysis of resulting compound.


PCT Publication no. 2009/075504 describes crystalline form of bepotastine p-toluenesulfonate, method for preparing same and pharmaceutical composition containing same.
The prior art processes for preparing bepotastine is not commercially viable due to the high cost of a compound of structural formula IX and also the resolution of compound of formula IX with resolving agent practically resulted into low yield of bepotastine compound of structural formula I and therefore there is a need in the art to develop an improved process for the preparation of bepotastine and its pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a commercial viable process for the preparation of bepotastine and its pharmaceutically acceptable salts thereof.
A second aspect of the present invention is to provide a process of preparing bepotastine and its pharmaceutically acceptable salts thereof comprising the steps of: a. treating the compound of structural formula II with resolving agent to get a compound of structural formula III and

Formula II Formula III
b. converting a compound of structural formula III into bepotastine and its pharmaceutically acceptable salts thereof

Formula III Formula 1
Wherein R is C1-4 straight chain alkyl or substituted alkyl group or (S)-4-phenyloxazolidin-2-one group

A third aspect of the present invention is to provide a process of preparing a compound of structural formula III comprises reacting a compound of structural formula VI with a compound of structural formula VII to get a compound of structural formula III.

X = Cl, Br, O-Tosyl, O-Mesyl
Wherein R is C1-4 straight chain alkyl or substituted alkyl group or (S)-4-phenyloxazolidin-2-one group
A fourth aspect of the present invention is to provide a process for the purification of bepotastine compound of structural formula I comprising the steps:
a. reacting bepotastine compound of structural formula I with o-toluene sulfonic
acid to get a bepotastine o-toluene sulfonate salt and
b. converting bepotastine o-toluene sulfonate salt into substantially pure
bepotastine compound of structural formula I.
A fifth aspect of the present invention is to provide a solid state of bepotastine o-toluene sulfonate salt.
Another aspect of the present invention is to provide amorphous form of bepotastine p-toluene sulfonate salt.
Another aspect of the present' invention is to provide a process of preparing a compound of structural formula II comprising the steps of:


X = CI, Br, O-Tosyl, O-Mesyl
Wherein R is C1-4 straight chain alkyl or substituted alkyl group or (S)-4-phenyloxazolidin-2-one group.
Another aspect of the present invention is to provide a process for the purification of bepotastine compound of structural formula I comprising the steps:
a. reacting bepotastine compound of structural formula I with p-toluene sulfonic
acid to get a bepotastine p-toluene sulfonate salt and
b. converting bepotastine p-toluene sulfonate salt into substantially pure
bepotastine compound of structural formula I.
DETAIL DESCRIPTION OF THE INVENTION:
The reaction of a compound of formula VIII with a compound of formula VII may be carried out in an aprotic polar solvent in the presence of base at a temperature in the range of -15°C to 10°C for a period of 1 hour to 12 hours to get a compound of structural formula II.
The examples of aprotic polar solvent may be selected from the group comprising of dimethyl formamide, dimethyl sulfoxide, acetonitrile, dimethyl acetamide or mixture(s) thereof.
The examples of base may include diethyl amine, triethyl amine, sodium methoxide, strontium hydroxide, sodium ethoxide, N, N-diisopropyl ethyl amine, benzyl amine, tertiary butyl amine or lithium hydroxide.
The compound of structural formula II may be isolated by quenching the resulting reaction mixture with water followed by extracting the reaction mixture with an alkyl

acetate solvent, washing the organic layer with a saturated solution of sodium chloride followed by concentrating an organic layer under reduced pressure to get compound of structural formula II.
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.
The reaction of a compound of structural formula II with resolving agent may be carried out in an organic solvent at a temperature in the range of 0°C to 60°C for a period of 2 hours to 24 hours to get the salt of compound of structural formula II (with resolving agent).
The examples of resolving agent may be selected from the group comprising of N-
acetyl-L-phenylalanine, N-acetyl-L-leucine, N-benzyloxycarbonyl-L-phenylalanine,
N-benzyloxycarbonyl-L-valine, N-benzyloxycarbonyl-L-threonine, N-
benzyloxycarbonyl-L-serine, N-benzyloxycarbonyl-L-aspartic acid or (2R, 3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitro-5-chlorophenylthio) propionic acid.
The examples of an organic solvent may include but not limited to acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, diethyl ether, dichloromethane, chloroform or mixture(s) thereof.
The salt of compound of structural formula II (with resolving agent) may be isolated by cooling the reaction mixture at a temperature in the range of 0°C to 20°C to get solid followed by filtration, centrifugation, washing, drying and combination thereof
The compound of structural formula III may be obtained by treating a salt of compound of structural formula II (with resolving agent) with above mentioned inorganic base in mixture of above mentioned organic solvent and water at 25°C to 30°C for a period of 30 minutes to 4 hours to get a compound of structural formula III.

The compound of structural formula III may be isolated by separating organic layer followed by concentrating under reduced pressure at a temperature in the range of 40°C to 50°C to get a compound of structural formula III.
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 conversion of a compound of structural formula III into a bepotastine compound of structural formula I may be carried out by treating a compound of structural formula III with inorganic base in 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 a bepotastine compound of structural formula I.
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 bepotastine compound of structural formula I 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 a bepotastine compound of structural formula I.
The examples of halogenated aliphatic hydrocarbons solvents may include dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
The purification of bepotastine compound of structural formula I may be carried out by treating bepotastine compound of structural formula I with o-toluene sulfonic acid in nitrile solvent at a temperature in the range of 0°C to 20°C for a period of 2 hours to 48 hours to get bepotastine o-toluene sulfonate salt.

The examples of nitrile solvents may include acetonitrile, propionitrile, butyronitrile or isobutyronitrile.
The bepotastine o-toluene sulfonate salt may be isolated by the steps of filtration, centrifugation, washing, drying and combination thereof.
The bepotastine o-toluene sulfonate salt may be crystalline or amorphous in nature.
The conversion of bepotastine o-toluene sulfonate salt into substantially pure bepotastine compound of structural formula I may be carried out by treating bepotastine o-toluene sulfonate salt with inorganic base in an above mentioned alcohol solvent at 25°C to 30°C.
The purification of bepotastine compound of structural formula I may be carried out by treating bepotastine compound of structural formula I with p-toluene sulfonic acid in nitrile solvent at a temperature in the range of 0°C to 20°C for a period of 2 hours to 48 hours to get bepotastine p-toluene sulfonate salt.
The bepotastine p-toluene sulfonate salt may be isolated by the steps of filtration, centrifugation, washing, drying and combination thereof.
The bepotastine p-toluene sulfonate salt may be amorphous in nature.
The conversion of bepotastine p-toluene sulfonate salt into substantially pure bepotastine compound of structural formula I may be carried out by treating bepotastine p-toluene sulfonate salt with inorganic base in an above mentioned alcohol solvent at 25°C to 30°C.
The substantially pure bepotastine compound of structural formula I may be converted into bepotastine besilate by treating substantially pure bepotastine compound of structural formula I with benzene sulfonic acid in above mentioned alkyl acetate solvent at 20°C to 30°C for a period of 2 hours to 12 hours to get bepotastine besilate salt.

The reaction of a compound of formula VI with a compound of formula VII may be carried out in above mentioned aprotic polar solvent in the presence of above mentioned base at a temperature in the range of -15°C to 10°C for a period of 1 hour to 12 hours to get a compound of structural formula III.
The compound of structural formula III may be isolated by quenching the resulting reaction mixture with water followed by extracting the reaction mixture with above mentioned alkyl acetate solvent, washing the organic layer with a saturated solution of sodium chloride followed by concentrating an organic layer under reduced pressure to get compound of structural formula III.
The term "substantially pure bepotastine" refers bepotastine having purity more than 99% as detected by HPLC method.
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 1: Preparation of (S) ethyl 4-(4-((4-chlorophenyl) (pyridin-2-yl) methoxy)
piperidin-1-yl) butanoate N-benzyloxycarbonyl-L-aspartate
A solution of (RS) ethyl 4-(4-((4-chlorophenyl) (pyridin-2-yl) methoxy) piperidin-1-
yl) butanoate (50gm) in ethyl acetate (500ml) was added N-benzyloxycarbonyl-L-
aspartic acid (32gm) at 25°C. The resulting reaction mixture was stirred at 25°C for
12 hours and then the reaction mixture was cooled to 0°C to 5°C to get solid. The
solid obtained was filtered, washed with ethyl acetate (150ml) and dried to get title
compound.
Yield: 40gm.
Purity: 99.0%

Step 2: Preparation of (S)-ethyl 4-(4-((4-chlorophenyl) (pyridin-2-yl) methoxy)
piperidin-1-yl) butanoate.
A solution (S) ethyl 4-(4-((4-chlorophenyl) (pyridin-2-yl) methoxy) piperidin-1-yl)
butanoate N-benzyloxycarbonyl-L-aspartate (50gm) in mixture of ethyl acetate
(500ml) and water (300ml) was added aqueous sodium bicarbonate solution [ 100 ml,
15% wt/wt (15gm sodium bicarbonate dissolved in 100ml water)] at 25°C. The
resulting reaction mixture was stirred for 30 minutes at 25°C and then organic layer
was separated and concentrated under reduced pressure at 40°C to get title compound.
Yield: 30gm
Purity: 99.1% (By HPLC)
Step 3: Preparation of bepotastine compound of structural formula I.
A solution of (S)-ethyl 4-(4-((4-chlorophenyl) (pyridin-2-yl) methoxy) piperidin-1-yl)
butanoate (25gm) in ethanol (350ml) was added 5N aqueous sodium hydroxide
solution (20ml) 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 (18ml), precipitated crystal were removed by filtration and then
resulting reaction mixture extracted with dichloroethane (200ml). The organic layer
was dried over anhydrous sodium sulfate (20gm) and then it was concentrated under
reduced pressure at 40°C to get title compound.
Yield: 23.3gm
Purity: 99.1% (By HPLC)
Example 2: Preparation of substantially pure bepotastine
Step 1: Preparation of bepotastine o-toluene sulfonate salt.
A solution of bepotastine compound of structural formula I (20gm) in acetonitrile
(200ml) was added o-toluene sulfonic acid (8.8gm) at 0°C to 5°C and then resulting
reaction mixture was stirred for 24 hours at 0°C to 5°C. The resulting solids were
filtered and recrystallized with acetonitrile (100ml) to get title compound.
Yield: 28gm
Purity: 99.98% (By HPLC)

Step 2: Preparation of substantially pure bepotastine
A solution of bepotastine o-toluene sulfonate (25gm) in ethanol (250ml) was added aqueous sodium hydroxide solution (10% weight/volume) at 25°C. The resulting reaction mixture was stirred for 1 hour followed by extracted with dichloroethane (200ml). The organic layer dried over anhydrous sodium sulfate (20gm) and then it was concentrated under reduced pressure at 40°C to get title compound. Yield: 13.8gm Purity: 99.9%

WE CLAIM:
1. A process of preparing bepotastine and its pharmaceutically acceptable salts thereof comprising the steps of:
a. treating the compound of structural formula II with resolving agent to get a compound of structural formula III and

Formula II Formula III
b. converting a compound of structural formula III into bepotastine and its pharmaceutically acceptable salts thereof

Formula III Formula I
Wherein R is C1-4 straight chain alkyl or substituted alkyl group or (S)-4-phenyloxazolidin-2-one group.
2. A process of preparing a compound of structural formula III comprises reacting a compound of structural formula VI with a compound of structural formula VII to get a compound of structural formula III.

Formula VI Formula VII Formula III
X = CI, Br, O-Tosyl, O-Mesyl
Wherein R is C1-4 straight chain alkyl or substituted alkyl group or (S)-4-phenyloxazolidin-2-one group

3. A process for the purification of bepotastine compound of structural formula I
comprising the steps:
a. reacting bepotastine compound of structural formula I with o-toluene sulfonic
acid to get a bepotastine o-toluene sulfonate salt and
b. converting bepotastine o-toluene sulfonate salt into substantially pure
bepotastine compound of structural formula I.
4. A solid state of bepotastine o-toluene sulfonate salt.
5. A amorphous form of bepotastine p-toluene sulfonate salt.
6. A process of preparing a compound of structural formula II comprising the steps of:

Formula VIII Formula VII Formula II
X = CI, Br, O-Tosyl, O-Mesyl
Wherein R is C1-4 straight chain alkyl or substituted alkyl group or (S)-4-phenyloxazolidin-2-one group.
7. A process for the purification of bepotastine compound of structural formula I
comprising the steps:
a. reacting bepotastine compound of structural formula I with p-toluene sulfonic
acid to get a bepotastine p-toluene sulfonate salt and
b. converting bepotastine p-toluene sulfonate salt into substantially pure
bepotastine compound of structural formula I.
8. The process according to claim no. 1 wherein resolving agent is selected from the
group comprising of N-acetyl-L-phenylalanine, N-acetyl-L-leucine, N-
benzyloxycarbonyl-L-phenylalanine, N-benzyloxycarbonyl-L-valine, N-
benzyloxycarbonyl-L-threonine, N-benzyloxycarbonyl-L-serine, N-

benzyloxycarbonyl -L-aspartic acid or (2R, 3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitro-5-chlorophenylthio) propionic acid.
9. The process according to claim no. 1 wherein compound of structural formula III is
obtained by treating a salt of compound of structural formula II (with resolving agent)
with inorganic base such as sodium carbonate, potassium carbonate, sodium
hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium
hydroxide or lithium carbonate, in a mixture of organic solvent such as acetonitrile,
methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl
acetate, diethyl ether, dichloromethane or chloroform and water at 25°C to 30°C for a
period of 30 minutes to 4 hours to get a compound of structural formula III.
10. The process according to claim no. 2, wherein reaction of compound of structural
formula VI with a compound of structural formula VII is carried out in an aprotic
polar solvent such as dimethyl formamide, dimethyl sulfoxide, acetonitrile, dimethyl
acetamide or mixture(s) thereof in the presence of base such as diethyl amine, triethyl
amine, sodium methoxide, strontium hydroxide, sodium ethoxide, N, N-diisopropyl
ethyl amine, benzyl amine, tertiary butyl amine or lithium hydroxide at a temperature
in the range of-15°C to 10°C for a period of 1 hour to 12 hours to get a compound of
structural formula III.