FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A PROCESS FOR THE PREPARATION OF NIZATIDINE INTERMEDIATE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides an improved process for the preparation of nizatidine intermediate.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides an improved process for the preparation of nizatidine intermediate.
Nizatidine of formula I is chemically known as N-[2-[[[2-[(dimethylamino) methyl]-4-thia-zolyl] methyl] thio] ethyl]-N'-methyl-2-nitro-1,1-ethenediamine, which is a histamine H2 receptor antagonist and useful in the treatment of peptic ulcers.
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Formula I
U.S. Patent No. 4,375,547 provides a process for preparation of nizatidine by the reaction of 4-[[(2-aminoethyl) thio]-methyl]-N,N-dimethyl-2-thiazolemethanamine with 1,1-dimethylthio-2-nitroethene to provide the corresponding 2-nitro-1-methylthio-1-etheneamine derivative, which is subsequently converted to nizatidine upon reaction with monomethylamine.
U.S. Patent No. 5,541,335 discloses a process for preparation of nizatidine by the reaction of N-[2-[[[2-(hydroxymethyl)-4-thiazolyl] methyl] thio] ethyl]-N'-methyl-2-nitro-1, 1-ethenediamine with excess dimethylamine and an (N,N-dimethylamino) phophonium halide such as (N,N-dimethylamino) triphenylphosphonium bromide.
U.S. Patent No. 5,574,054 discloses quaternary ammonium salts and nizatidine salts of nizatidine and the like, for use in treating gastrointestinal disorders.

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U.S. Patent No. 6,069,256 discloses a process for preparation of nizatidine by the reaction of 2-(nitromethylene) thiazolidine with 4-(substituted methyl) thiazole-2-yl)-N,N-dimethylmethaneamine in the presence of methylamine and in the presence of an inert diluent.
The various processes for the preparation of nizatidine are also disclosed in U.S. Patent Nos. 4,777,260; 4,904,792; 4,968,808; 5,334,725; 5,457,206; 5,750,714; 5,981,757 and PCT application WO 2004069817.
Present invention provides a simple and convenient process for the preparation of nizatidine. This involves preparation of intermediate of formula-Ill, known as 2-(dimethylaminomethyl)-4-thiazolemethanol (thiazole intermediate) by reducing the compound of formula II, known as ethyl-2-dimethylaminomethyl-4-thiazole carboxylate (thiazole ester) using non-hazardous, eco-friendly commercially available reducing agent like sodium borohydride. The thiazole intermediate is then converted to nizatidine.
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In one of the aspect of the present invention there is provided an improved process for the preparation of nizatidine of formula I, wherein the said process comprises of,
a) reducing the thiazole ester of formula II to thiazole intermediate of formula III,
b) converting thiazole intermediate of formula III to nizatidine.
The thiazole ester intermediate of formula II is prepared by treating ethyl bromo pyruvate with dimethyl amino acetamide hydrochloride by the method known in
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the art. The thiazole ester reduced to thiazole intermediate of formula-Ill with alkali metal borohydride such as sodium borohydride in organic solvent at temperature below 70°C. After the completion of reaction, the thiazole intermediate compound is extracted in organic solvent and concentrated.
Thiazole intermediate of formula-Ill is then converted to nizatidine by the methods known by the artisan.
Organic solvents include single solvent or the mixture of tetrahydrofuran-methanol, diglyme-methanol and dimethoxyethane-methanol, alcohol, ethyl acetate and the like.
The examples of alcohol solvent include straight and branched chain C1-C4 alcohols, such as methanol, ethanol, n-propanol and isopropanol and the like.
While the present invention has been described in terms of its specific embodiments, 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 thiazole intermediate of formula III
Thiazole ester (172.0gm) was treated with sodium borohydride (151gm) in tetra hydrofuran (1.0 litre) at 55°-60°C. Methanol was added to above mass at 55°-60°C and then cooled to 25-30°C. Water (1.0 litre) was added to reaction mass and tetra hydro furan and methanol was distilled out under reduced pressure. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extract was concentrated to yield titled compound. Yield: 115.5gm Moisture: 2.08%.
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WE CLAIM:
1. A improved process for the preparation of nizatidine of formula I, wherein the
said process comprises of,
a) reducing the thiazole ester of formula II to thiazole intermediate of formula III,
b) converting thiazole intermediate of formula III to nizatidine.
2. A process of claim 1 wherein the reduction is carried out by using reducing
agent such as sodium borohydride and the like.
3. A process of claim 1 wherein, the reduction is carried out in mixture of organic
solvents selected from the group consisting of tetrahydrofuran -methanol, diglyme-methanol and dimethoxyethane -methanol.
4. A process of claim 1 wherein reduction temperature is 40-60°C.
Dated this 1 st day of December, 2006 For Wockhardt Limited
(Mandadr Kodgule) Authorized Signatory
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