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
PROCESS FOR THE PREPARATION OF EPINASTINE HYDROBROMIDE
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 a process for the preparation of epinastine
hydrobromide.
The following specification particularly describes the invention and the manner
in which it is to be performed.

4. DESCRIPTION
The present invention provides a process for the preparation of epinastine hydrobromide.
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.
Present inventors have developed an easy process for the preparation of epinastine hydrobromide. Inventors found that when fumarate salt of amino methyl dibenzo azepine compound of formula-Ill treated with base in presence of organic solvent as depicted in scheme-1, the epinastine hydrobromide is obtained with high yield in less time.
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In one aspect of the present invention there is provided a process for the preparation of epinastine hydrobromide. The process includes the steps of;
(a) treating the fumarate salt of dibenzo azepine compound of formula III with base in presence of organic solvent.

(b) optionally isolating free base of compound of formula-Ill;
(c) converting freebase base of compound of formula-Ill into epinastine hydrobromide; and
(d) Isolating epinastine hydrobromide from the reaction mass thereof.
The process of present invention involves stirring fumarate salt of dibenzo azepine compound of formula III with a base in presence of an organic solvent for 1-3 hours. The resulting solution is extracted with water and organic layer was separated and concentrated to obtain an oily liquid (free base of compound of formula III). The oily mass was further dissolved in an organic solvent and is treated with a solution of cyanogen bromide in an organic solvent. The solution mixture so obtained is stirred with a precipitating solvent to precipitate epinastine hydrobromide of formula (II).
The epinastine hydrobromide can be converted to epinastine hydrochloride by the methods known in the art for example as disclosed in U.S. 4313931.
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The non-limiting examples of base include organic and inorganic base. The non-limiting examples of organic base include methylamine, dimethyl amine, triethyl amine, pyridine, N, N-dimethylaniline, 2,6-dimethylpyridine, 4-methylpyridine, 4-dimethylaminopyridine, dicyclohexyl amine and the like.
The non-limiting examples of inorganic base include ammonia and inorganic salts. The non-limiting examples of inorganic salts include carbonate salts, bicarbonate salts, hydroxide salts and the like. The non-limiting examples of carbonate salts include lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, lanthanum carbonate and the like. The non-limiting examples of bicarbonate salts include sodium bicarbonate, potasium bicarbonate, calcium bicarbonate, ammonium bicarbonate and the like. 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 polar solvent and halogenated solvents. The non-limiting examples of polar solvents include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-methoxyethanol, tetrahydrofuran, dimethylsulfoxide, N, N-dimethylformamide, 1,4-dioxane, N, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone, ethylmethyl ketone, ethyl acetate, methyl acetate and the like or mixtures thereof. The non-limiting examples of halogenated solvents include dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane and the like or mixtures thereof.
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.
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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 hydrobromide
6-aminomethyl-6, 11-dihydro-5H-dibenz[b,e]azepine fumarate (100 gm) and dichloromethane (1.0 litre) was stirred at room temperature. Ammonia solution (600 ml) was added slowly over a period of 30 minutes. Reaction mass was stirred for 2 hour and then extracted with water (1.0 litre). Organic layer was evaporated to get dark yellowish oil. The oil so obtained was dissolved in ethanol (400 ml) and a solution of Cyanogen bromide (30 gm in 300 ml of tetrahydrofuran) was added over a period of 30 minutes. The reaction mixture was added with diethyl ether (600 ml) was added to the reaction mass after reaction completion. This solution was further stirred for 1 hour and filtered. The solid obtained was washed with two volumes of ether and the titled product was isolated from the reaction mass thereof. Yield: 83.4 gm HPLC purity: (98-99%)
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We claim:
1. A process for the preparation of epinastine hydrobromide. The process comprises the steps of;
(a) treating the fumarate salt of dibenzo azepine compound of formula-Ill with base in presence of organic solvent.

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

2. A process of claim 1, wherein compound of formula III, is converted into a free base in presence of a base and an organic solvent.
3. A process of claim 2, wherein a base is selected from methyl amine, dimethyl amine, triethyl amine, pyridine, N,N-dimethylaniline, 2,6-dimethylpyridine, 4-methylpyridine, 4-dimethylamino pyridine, dicyclohexyl amine, ammonia, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, lanthanum carbonate, sodium bicarbonate, potasium bicarbonate, calcium bicarbonate, ammonium bicarbonate, ammonium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, sodium hydroxide, strontium hydroxide, calcium hydroxide, lithium hydroxide, rubidium hydroxide, magnesium hydroxide and aluminium hydroxide.
4. A process of claim 2, wherein an organic solvent include polar solvent and halogenated solvent.
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5. A process of claim 4, wherein polar solvent includes methanol, ethanol, n-
propanol, isopropanol, n-butanol, isobutanol, 2-methoxyethanol, tetrahydrofuran,
dimethylsulfoxide, N,N-dimethylformamide, 1,4-dioxane, N,N-dimethylacetamide,
N-methylpyrrolidone, acetonitrile, acetone, ethylmethyl ketone, ethyl acetate,
methyl acetate or mixtures thereof.
6. A process of claim 4, wherein a halogenated solvent includes
dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane or
mixtures thereof.
7. A process of claim 1, wherein the freebase base of compound of formula-Ill is converted into epinastine hydrobromide by treating with cynogen bromide solution.
8. A process of claim 7, wherein the solution of cynogen bromide is prepared in tetrahydrofuran.



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Abstract
The present invention provides a process for preparation of epinastine hydrobromide.