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 OF PREPARING OLOPATADINE AND PHARMACEUTICAL ACCEPTABLE SALTS THEREOF."
Enaltec Labs Pvt Ltd, an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-I9, 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 OF PREPARING OLOPATADINE AND PHARMACEUTICAL ACCEPTABLE SALTS THEREOF
FIELD OF THE INVENTION:
The present invention relates to an improved process of preparing olopatadine and pharmaceutically
acceptable salts thereof comprising the steps of:
a. reacting 11 -oxo-6, 11 -dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyI)-triphenylphosphonium bromide hydrobromide compound of structural formula XVIII at a temperature in the range of 35°C to 65°C to get (Z)-ll-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I and

b. converting (Z)-l l-[3-(dimethylamino) propylidene]-6. 11-dihydrodibenz [b. e] oxepin-2-acetic acid compound of structural formula I into hydrochloric acid salt of (Z)-11-[3-(dimethylamino) propylidene]-6, 11 -dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I.
BACKGROUND OF THE INVENTION:
Chemically olopatadine hydrochloride is a hydrochloric acid salt of 1 l-[(Z)-3-(dimethylamino) propylidene]-6-l 1-dihydrodibenz [b, e] oxepin-2-acetic acid is known form U.S patent nos 4,871,865 and US 5,116,863, Olopatadine is represented by compound of structural formula 1.


The proprietor names of olopatadine hydrochloride are Patanol, Pataday and Patanase. Olopatadine hydrochloride ophthalmic solution is indicated for the treatment of ocular itching associated with allergic conjunctivitis.
U.S patent no 5,116,863 describe three different processes for preparing olopatadine compound of structural formula I. In two of the processes the side chain is introduced by "Grignard reaction" and in third process side chain is being introduced by employing "Wittig reaction".
The first process involves the conversion of ll-oxo-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid compound of structural formula II to its corresponding N-(l,)-dimethyl-2-hydroxyethyl)-ll-oxo-6, 1 l-dihydroxdibenz[b,e] oxepin-2-acetamide compound of structural formula III, which is being cyclised to obtain 2-(methyl(4,4-dimethyl-2-oxazoline-2yl))-l l-oxo-6,11-dihydrodibenz[b,e] oxepin compound of structural formula IV. The compound of structural formula IV on reaction with 3-dimethylaminopropyl chloride under Grignard conditions yield ll-(3-dimethylaminopropy])-l 1-hydroxy-2-(methyl(4,4-dimethyl-2-oxazoline-2yl))-6, 11-dihydrodibenz [b,e] oxepin compound of structural formula V, which is simultaneously dehydrated, deprotected and then esterified to get ethyl ll-(3-dimethylarninopropylidine)-6, I I-dihydrodibenz [b,e] oxepin-2-acetate compound of structural formula VI, The hydrolysis of the compound of structural formula VI yields olopatadine compound of structural formula I.


The second process involves the conversion of methyl 1 l-oxo-6, 11-dihydrodibenz [b,e] oxepin-2-acetate compound of structural formula VII to 1 l-hydroxy-2(2-hydroxyethyl)-6,l 1-dihydrodibenz [b,e] oxepin compound of structural formula VIII by the reduction with lithium aluminum hydride. The compound of structural formula VIII is being protected with trityl group to obtain 11-hydroxy-2-(2-triphenylmethyIoxy ethyl)-6, 11-dihydrodibenz [b, e] oxepin compound of structural formula IX. The compound of structural formula IX is being oxidized to ll-oxo-2-(2-triphenylmethyloxyethyl)-6, 11-dihydrodibenz [b, e] oxepin compound of structural formula X. The compound of structural formula X on reaction with 3-dimethylaminopropyl chloride under Grignard conditions yields 11 -(3-dimethylaminopropyl)-11 -hydroxy-2-(2-triphenyImethyloxy ethyl)-6, 11-dihydrodibenz [b,e] oxepin compound of structural formula XI, which is dehydrated to obtain 1 l-(3-dimethylaminopropyIidene)-2-(2-triphenylmethyloxyethyI)-6, 11-dihydrodibenz [b,e] oxepin compound of structural formula XII. The compound of structural formula XII is being deprotected to obtain 1 l-(3-dimethylamino propylidene)-2-(2-hydroxyethyl)-6, 11-dihydrodibenz [b, e] oxepin compound of structural formula XIII. The oxidation of compound of structural formula XIII by using Jones reagent yields olopatadine compound of structural formula I.


The third process involves wittig reaction of 1 l-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-triphenylphosphoniurn bromide hydrobromide in cooling conditions yields (Z)-l I-[3-(dimethylarnino)propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid, which on reacting with methanol in the presence of sodium hydroxide gives a compound of structural formula XIV . The hydrolysis of compound of structural formula XIV with sodium hydroxide in mixed solvent of methanol and water yields olopatadine hydrochloride compound of structural formula I.


This process involves the formation of process related impurities, which are being purified by employing column chromatography technique and hence it is not suitable for commercial scale production of olopatadine hydrochloride.
U.S Patent no. 7,612,219 described the process of preparing olopatadine or a pharmaceutically acceptable salt thereof comprises reacting compound of structural formula XV in the presence of a palladium catalyst to obtain a compound of structural formula XVI and removing the acid protecting group R3 of said compound of formula XVI.

wherein one of R1and R2 is halogen and the other is CH=CH-CH2-CH2-N(CH3)2 and R3 is an acid protecting group.
The prior-art processes for preparing pure olopatadine hydrochloride employs column chromatography technique and therefore gives low yield and hence is not suitable for commercial scale production of olopatadine hydrochloride.
Accordingly there is a need in the art to develop an improved process of preparing olopatadine hydrochloride, which obviates the prior-art problems like low yield and use of column chromatography technique.

SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a process of preparing olopatadine
hydrochloride comprising the steps of:
a. reacting ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethyIaminopropyl)-triphenylphosphonium halide compound of structural formula XVII at a temperature in the range of 35°C to 65°C to get (Z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I and

wherein X is chloro, bromo or iodo group. b. converting (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I into hydrochloric acid salt of (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I.
Another aspect of the present invention is to provide a process of preparing olopatadine
hydrochloride comprising the steps of:
a. reacting ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide compound of structural formula XVIII at a temperature in the range of 35°C to 65°C to get (Z)-lI-[3-(dimethyIamino)propyIidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I and


b. converting (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I into hydrochloric acid salt of (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I.
DETAILED DESCRIPTION OF THE INVENTION:
1 l-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II may be prepared by methods know in the art such as those described in U.S. Patent nos 5.116,863, which is incorporated herein by reference only.
(3-dimethylaminopropyl)-triphenylphosphonium halide compound of structural formula XVII may be prepared by methods known in the art such as those described in E. Oshima et.al; European Patent application no. 235,796; Japanese Patent application no. 86/45,676, which are incorporated herein by reference only.
The examples of (3-dimethyIaminopropyl)-triphenylphosphonium halide compound of structural formula XVII may include acid addition salts of (3-dimethylaminopropyl)-triphenylphosphoniurn halide.
The examples of acid addition salts of (3-dimethylaminopropyi)-triphenylphosphoniurn halide may include of (3-dimethylaminopropyl)-triphenyIphosphonium bromide hydrobromide, or (3-dimethylaminopropyl)-tripheny]phosphonium chloride hydrochloride.

The reaction of ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-triphenylphosphohium halide compound of structural formula XVII may be carried out in an organic solvents.
The examples of organic solvent may include ether solvents such as tetrahydrofuran, 2-methyl-tetrahydrofuran, I, 4-dioxane, 1, 2-dimethyoxyethane: diethyl ether, dipropyl ether, diisopropyl ether, n-butyl ether, methyl tertiary butyl ether or mixture(s) thereof.
The reaction of II-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyI)-triphenylphosphosphoniurn halide compound of structural formula XVII may be carried out in the presence of base.
The examples of base may include n-butyl lithium.
The reaction of ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-triphenylphosphonium halide compound of structural formula XVII may be carried out at a temperature in the range of 35°C to 65°C.
The reaction of ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dirnethylaminopropyl)-triphenylphosphonium halide compound of structural formula XVII may be carried out at a temperature in the range of 35°C to 65°C for a period of 2 hours to 18 hours.
The (Z)-l l-[3-(dimethylarnino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be isolated by forming £m ester of (Z)-l l-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I.
The ester of (Z)-I l-[3-(dimethyIamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be prepared by reacting (Z)-1 l-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b; e] oxepin-2-acetic acid Compound of structural formula I with an alcohol solvents in the presence of thionyl chloride.

The examples of alcohol solvents may include methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
The ester of (Z)-1 l-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may include methyl ll-(3-dimethylaminopropylidene)-6, 11-dihydrodibenz [b, e] oxepin-2-acetate compound of formula XIV.
The ester (Z)-l l-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be present in the form of hydrochloric acid salt.
The hydrochloric acid salt of ester (Z)-l l-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula 1 may be washed with an alkyl acetate and aliphatic hydrocarbons solvent.
The examples of alkyl acetate solvent may include methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate or isobutyl acetate.
The examples of aliphatic hydrocarbons solvent may include n-hexane, n-pentane, n-heptane or n-
octane.
The ester (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be hydrolyzed by inorganic base in an alcoholic solvent to (Z)-l 1-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula 1.
The examples of inorganic base may include sodium hydroxide or potassium hydroxide.
The ester (Z)-l l-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be hydrolyzed at a temperature in the range of 50°C to 64°C for a period of 2 hours to 6 hours.
The (Z)-l1-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be isolated by concentrating the reaction mixture under reduced pressure to get a residue compound, which may be dissolved in water and then after the adjustment of pH in the range of 6.8 to 7.2 by 3% dilute hydrochloric acid, the resulting solids may

be filtered, washed with water and dried at a temperature in the range of 50°C to 60°C for 3 hours to 6 hours under reduced pressure.
The isolated (Z)-1l-[3-(dimethylamino) propyiideneJ-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be further converted in the hydrochloric acid salt.
The hydrochloric acid salt of (Z)-l l-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be formed by reacting (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula 1 with an isopropanolic hydrochloride.
The hydrochloric acid salt of (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be further purified by crystallization of hydrochloric acid salt of (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I in the mixture of ketone and water.
The examples of ketone solvent may include acetone, methyl isobutyl ketone or 2-butanone.
The hydrochloric acid salt of (Z)-l l-[3-(dimethyIamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be isolated by the steps of filtration, centrifugation, washing , drying or the combination(s) thereof.
The hydrochloric acid salt of (Z)-l l-[3~(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be crystalline or amorphous in nature.
The hydrochloric acid salt of (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I may be dried at a temperature in the range of 50°C to 60°C under reduced pressure for a period of 4 hours to 18 hours.

EXAMPLE:
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 OLOPATADINE HYDROCHLORIDE
Step a: Preparation of olopatadine
A solution of (3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide (200gm) in tetrahydrofuran (650ml) was added n-butyl lithium (500ml, 1.6M in n-hexane) at 25°C and then resulting reaction mixture was stirred for 1 hour at 65-70°C and then a solution of ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid (35gm) in tetrahydrofuran (105ml) was slowly added in the reaction mixture at 60-65°C. The resulting reaction mixture was stirred for 30 minutes at 60-65°C and then it was gradually cooled to 250C and then it was again stirred for 4 hours at the same temperature. The reaction mixture was concentrated under reduced pressure at 50°C and then resulting residue was dissolved in methanol (1000ml) and then thionyl chloride (30ml) was added and then resulting reaction mixture was stirred 3 hours at 55-60°C. The resulting reaction mixture was concentrated under reduced pressure and then the resulting residue was dissolved in a mixture of ethyl acetate (500ml) and water (500ml) and then organic layer was separated and discarded. The aqueous layer was further washed with n-heptane (525ml). The pH of aqueous layer was adjusted to 8.5 by sodium carbonate (15gm) and then it was extracted with n-heptane (4x525ml). The n-heptane layer was concentrated under reduced pressure and then resulting residue was dissolved in methanol (400ml) and then the resulting solution was treated with aqueous sodium hydroxide solution [sodium hydroxide(4.5gm) dissolved in water (20ml)] at 55-60°C for 3 hours. The resulting reaction mixture was quenched with water (275ml) and then the pH of reaction mixture was adjusted to 6.8 with dilute hydrochloric acid (3% solution in water) and then the resulting reaction mixture was stirred for 1 hour. The resulting solids were filtered, washed with water (30ml) and dried at 50°C under reduced pressure to get (Z)-l l-[3-(dimethylamino)propylidene]-6, 1 l-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I (40gm).
Step b: Preparation of Olopatadine hydrochloride

The solution of (Z)-ll-[3-(dimethylamino) propylidene]-6. 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I (40gm) in isopropanol (200ml) was added isopropanolic hydrochloride (44ml, 20% wt/wt solution) at 30°C and then resulting reaction mixture was stirred for 1 hours at 30°C and then it was concentrated under reduced pressure at 40°C and then resulting residue was dissolved in a mixture of acetone (80ml) and water (40ml) and then resulting solution was first stirred at 55°C for 30 minutes and then at 20°C for 2 hours and finally at 0-5°C for 2 hours and then resulting solids were filtered, washed with acetone (20ml) and then dried at 50°C under reduced pressure.
Yield: 40gm
Purity: 99.89% (By HPLC)

WE CLAIM:
1. A process of preparing olopatadine hydrochloride comprising the steps of:
a. reacting l]-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-tripheny!phosphonium halide compound of structural formula XVII at a temperature in the range of 35°C to 65°C to get (Z)-l I-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I and

wherein X is chloro, bromo or iodo group.
b. converting (Z)-l l-[3-(dimethyIamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I into hydrochloric acid salt of (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I. 2. A process of preparing olopatadine hydrochloride comprising the steps of:
a. reacting 1 l-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide compound of structural formula XVIII at a temperature in the range of 35°C to 65°C to get (Z)-l1-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I and


b. converting (Z)-l 1-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I into hydrochloric acid salt of (Z)-ll-[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I.
3. The process according to claim 1, wherein the reaction of ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-triphenylphosphonium halide compound of structural formula XVII is carried out at a temperature in the range of 35°C to 65°C.
4. The process according to claim 2, wherein the reaction of ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide compound of structural formula XVIII is carried out at a temperature in the range of 35°C to 65°C.
5. The process according to claim I, wherein the reaction of ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-triphenylphosphonium halide compound of structural formula XVII is carried out in the presence of n-butyl lithium base.
6. The process according to claim 2, wherein the reaction of ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide compound of structural formula XVIII is carried out in the presence ofn-buty\ lithium base.
7. The process according to claim 1, wherein the reaction of ll-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-rriphenylphosphonium halide compound of structural formula XV11 is carried out in ether solvents such as tetrahydrofuran, 2-methyl-tetrahydrofuran, 1, 4-dioxane, I, 2-dimethyoxyethane, diethyl ether, dipropyl ether, diisopropyl ether, n-butyl ether, methyl tertiary butyl ether or mixture(s) thereof.
8. The process according to claim 2, wherein the reaction of 1 l-oxo-6, 11-dihydrodibenz [b. e] oxepin-2-acetic acid compound of structural formula II with (3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide compound of structural formula XVIII is carried out

in ether solvents such as tetrahydrofuran, 2-methyl-tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethyoxyethane, diethyl ether, dipropyl ether, diisopropyl ether, n-butyl ether, methyl tertiary butyl ether or mixture(s) thereof.
9. The process according to claims 1 and 2 wherein (Z)-l l-[3-(dimethylamino) propylidene]-6, 11-
dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I is reacted with an
isopropanolic hydrochloric acid to get hydrochloric acid salt of (Z)-ll-[3-(dimethylamino)
propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid compound of structural formula I.
10. The process for the preparation of olopatadine hydrochloride as herein described in
specification and example.