FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION
AN IMPROVED PROCESS FOR THE PREPARATION OF EPINASTINE
HYDROCHLORIDE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.

3. PREAMBLE TO THE DESCRIPTION
The present invention provides an improved process for preparation of epinastine hydrochloride.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides an improved process for preparation of epinastine hydrochloride.
Epinastine hydrochloride is chemically known as 3-Amino-9, 13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine hydrochloride and is represented by following formula (I).

(I)
Epinastine hydrochloride, marketed under the name ELESTAT, is an antihistamine. ELESTAT is indicated for the prevention of itching associated with allergic conjunctivitis.
There are several patents and patent applications cited in the literature, which refer to process for the preparation of epinastine such as U.S. Patent No. 4,313,931, U.S. Patent No. 6,403,790, U.S. Patent No. 5,312,916, EP Patent No. 35749, GB Patent No. 2071095 and WO 2001/40229.
The prior art procedures for the preparation of epinastine have certain disadvantages, such as the use expensive solvents, low yields, isolation problems and duration of reaction time. Therefore, there is a continuing need for new methods for preparation of epinastine.
The present inventors have developed an improved process for preparation of epinastine hydrochloride by treating epinastine hydrobromide with base in presence of halogenated solvent. The process of present invention is industrially advantageous.


In one aspect of the present invention there is provided a process for the preparation of epinastine hydrochloride, wherein the process includes the steps of;
(a) treating epinastine hydrobromide of formula II with base in presence of
halogenated solvent;

(b) optionally, isolating free base of formula-ll; and
(c) converting freebase formula-ll into epinastine hydrochloride.
(d) Isolating epinastine hydrochloride from the reaction mass thereof.
The process of present invention involves stirring epinastine hydrobromide with a solution of a hydroxide base in presence of an organic solvent. The organic layer is separated, washed with water and evaporated under vacuum. The residue so obtained is strip out with little amount of methanol. The resulting solution is stirred for 0.5-2 hr with a precipitating solvent to precipitate a solid. The solid obtained was dissolved in methanol and is stirred with ethereal hydrochloride for 10-30 minutes. To this reaction mixture precipitating solvent is added and epinastine hydrochloride is isolated from the reaction mixture thereof.
The non-limiting examples of hydroxide salts include ammonium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, sodium hydroxide, strontium hydroxide, calcium hydroxide, lithium hydroxide, rubidium hydroxide, magnesium hydroxide, aluminium hydroxide and the like.
The non-limiting examples of organic solvent include toluene, methyl acetate, ethyl acetate, chloroform, carbon tetrachloride, dichloromethane, hexane, cyclohexane, 1,2-dichloroethane, diethyl ether, dimethyl formamide, heptane, methyl-tert-butyl ether, pentane, 2,2,4-trimethylpentane and the like.


The non-limiting examples of a precipitating solvent include dimethyl ether, diethyl ether, methyl-tert-butyl ether, diisopropyl ether and the like or a mixture thereof.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example Preparation of epinastine hydrochloride
Epinastine hydrobromide (83 gm) was added in dichloromethane (800 ml). Slowly sodium hydroxide solution (400 ml, 1 N) was added over period of 15 minutes. Reaction mass was stirred for 1 hour. Organic layer was separated, washed with water and concentrated. Solid obtained was strip out with little amount of methanol and precipitated with ether (500 ml) by stirring for 1 hour. The precipitate was then added to methanol (200 ml), added with ethereal hydrochloride (50 ml, 1:1) and stirred for 15 minutes. Reaction mass was precipitated with diethyl ether (500 ml) to yield epinastine hydrochloride. The epinastine hydrochloride obtained thereof was isolated from the reaction mass. Yield: 57.8gm.
HPLC purity: (99%).


We claim:
1. A process for the preparation of epinastine hydrochloride, wherein the process comprises steps of;
(a) treating epinastine hydrobromide of formula II with base in presence of
halogenated solvent;

(b) optionally, isolating free base of formula-ll; and
(c) converting freebase of freebase of formula-ll into epinastine hydrochloride.
(d) Isolating epinastine hydrochloride from the reaction mass thereof.

2. A process of claim 1, wherein a base is selected from group of ammonium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, sodium hydroxide, strontium hydroxide, calcium hydroxide, lithium hydroxide, rubidium hydroxide, magnesium hydroxide and aluminium hydroxide.
3. A process of claim 1, wherein halogenated solvent selected from the group of chloroform, carbon tetrachloride, dichloromethane, hexane, cyclohexane, 1,2-dichloroethane, dimethyl ether, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, dimethyl formamide, heptane, pentane and 2,2,4-trimethylpentane.
4. A process of claim 1, wherein the freebase of formula-ll is converted to epinastine hydrochloride by adding ethereal hydrochloride.

5. A process of claim 1, wherein the epinastine hydrochloride is isolated from the reaction mass thereof by adding precipitating solvent.
6. A process of claim 1, wherein the precipitating solvent is selected from group

of dimethyl ether, diethyl ether, methyl-tert-butyl ether, isopropyl ether and the like or a mixture thereof.




Abstract
The present invention provides an improved process for the preparation of epinastine hydrochloride.