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:
AN EFFICIENT PROCESS FOR THE PREPARATION AND PURIFICATION
OF NIZATIDINE
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 efficient process for the preparation and purification of nizatidine
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 efficient process for the preparation and purification of nizatidine.
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.
OgNCH-C /—N
NHCHsCH$DHf 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. 4,904,792 also provides a process for preparation of nizatidine by the reaction dimethylaminothioacetamide hydrochloride with ethyl bromopyruvate to obtain 2-(dimethylaminomethyl)-4-thiazolecarboxylate. Reduction of this 4- thiazolecarboxylate derivative with lithium triethylborohydride gives 2- (dimethylaminomethyl)-4-thiazolemethanol, which is then converted into 4- (2-aminoethyl) thiomethyl-2-dimethylaminomethylthiazol by reacting with 2-aminoethanethiol hydrochloride (cysteamine hydrochloride). This 2-dimethylaminomethylthiazol derivative is then converted into Nizatidine by reacting with N-methyl-1-methylthio-2-nitroethyleneamine in the presence of an acid.
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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.
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 other processes of preparation of nizatidine are also disclosed in U.S. Patent Nos. 4,777,260; 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. The present inventors surprisingly found that the process of preparation of nizatidine without isolating intermediate compound, (2-dimethylaminomethyl-4-thiazolyl methyl thio) ethyl amine (thioether intermediate). The thioether intermediate is prepared from 2-(Dimethylaminomethyl)-4-thiazole (thiazole intermediate) in aqueous medium at pH around 7, which gives pure nizatidine.
The present inventors also developed a purification technique for nizatidine by using alcohol solvent or organic solvent mixture to yield pure nizatidine having purity greater than 99 % or more.
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In one of the aspect of the present invention there is provided a process for the preparation of nizatidine, wherein the said process comprises of,
a) reacting 2-(Dimethylaminomethyl)-4-thiazole methanol with cysteamine hydrochloride,
b) treating reaction mass of step a) with N-methyl-1-methylthio-2-nitroethylene amine,
c) isolating and purifying the nizatidine from the reaction mass thereof.
In another aspect of the present invention there is provided a purification process of nizatidine, wherein said process is comprises of,
a) crystallizing nizatidine in alcohol solvent
b) isolating nizatidine from the reaction mass thereof.
In yet another aspect of the present invention there is provided a purification process of nizatidine, wherein said process is comprises of,
a) crystallizing nizatidine in alcohol solvent and isolating nizatidine,
b) recrystallizing nizatidine of step a) in organic solvent mixture,
c) isolating nizatidine from the reaction mass thereof.
The process involve reacting 2-(Dimethylaminomethyl)-4-thiazole methanol, which can be prepared by the method known in the art with cysteamine hydrochloride in aqueous solution of mineral acid. The mineral acid includes hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid and the like. The product obtained is neutralized by using aqueous solution of alkali metal hydroxide and extracted in halogenated solvent to yield [2-(dimethyl aminomethyl)-4-thiazolyl-methylthio) thio] ethylamine compound, which is in-situ condensed with N-methyl-1-methylthio-2-nitroethylene amine in polar protic solvent to yield nizatidine. The halogenated solvent includes chloroform, dichloromethane, ethylene chloride and the like. The polar protic solvent includes water, ethanol, acetic acid and the like.
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The nizatidine is crystallized in alcoholic solvent by dissolving and isolating crystallized material from the reaction mixture at lower temperature. The examples of alcoholic solvent include straight and branched chain C1-C4 alcohols, such as methanol, ethanol, n-propanol and isopropanol and the like. Optionally, crystallized nizatidine is recrystallised by dissolving in the mixture of solvent, such as water and acetone, and isolating by cooling from reaction mixture. The nizatidine solution in the solvent or in the mixture of solvent can be prepared by heating up to temperature 80°-90°C and product is isolated at temperature below 40°C from the reaction mixture. The examples of alcoholic 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 Nizatidine
The thiazole (115gm) was refluxed with cysteamine hydrochloride solution (76.66gm in 264ml concentrated hydrochloric acid) at 110°C for 15 hrs. After completion of reaction water (410ml) was added, and pH was adjusted with aqueous potassium hydroxide (44% W/V) solution to 9.2. At 9.2 pH reaction mixture was concentrated under reduced pressure to get syrupy mass which was dissolved in chloroform salt were removed by filtration. The chloroform filtrate was concentrated and water (184ml) was added to concentrated mass. The pH of reaction mass was adjusted to about 11 with aqueous potassium hydroxide solution (30 %). To above reaction mass N-methyl-1-methylthio-2-nitro ethylene amine aqueous solution (89 gm, 450 ml respectively) was added in 30 minutes and reaction mixture was further stirred at room temperature for 15 hours. After
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completion of reaction nizatidine is extracted in dichloromethane, the organic layer was washed with water and then concentrated to yield nizatidine. Yield: 156 gm
Crystallization of nizatidine
Nizatidine (156 gm) was dissolved in N-propanol (450ml) by heating to 80°-85°C and then stirred under cooling at 15°-20°C for 2 hrs. Filtered the precipitated material and wet solid (72 gm). Purity: 98.5% by HPLC
Recrystallization of nizatidine
The wet nizatidine (70 gm) was dissolved in Acetone (255 ml) and water (25 ml)
by heated to 60°C. Stirred the clear solution at 0-5°C for 1 hr for the complete
precipitation of material. The precipitated material was filtered washed and dried
to yield titled compound.
Yield: 48 gm.
Purity: 99.5% by HPLC
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WE CLAIM:
1. A process for the preparation of nizatidine of formula I, wherein the said
process comprises of,
a) reacting 2-(Dimethylaminomethyl)-4-thiazole methanol with cysteamine hydrochloride,
b) treating reaction mass of step a) with N-methyl-1-methylthio-2-nitroethylene amine,
c) isolating and purifying the nizatidine from the reaction mass thereof.

2. A process of claim 1 wherein reaction of 2-(Dimethylaminomethyl)-4-thiazole methanol and cysteamine hydrochloride is carried out in in aqueous solution of mineral acid.
3. A process of claim 2, wherein the mineral acid is hydrochloric acid.
4. A process of claim 1, wherein reaction with N-methyl-1-methylthio-2-nitroethylene amine is carried out in polar aprotic solvent.
5. A process of claim 4, wherein polar aprotic solvent is water, acetic acid, ethanol and the like.
6. A purification process of nizatidine, wherein said process is comprises of,

a) crystallizing nizatidine in alcohol solvent
b) isolating nizatidine from the reaction mass thereof.
7. A purification process of nizatidine, wherein said process is
comprises of,
a) crystallizing nizatidine in alcohol solvent and isolating nizatidine,
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b) recrystallizing nizatidine of step a) in organic solvent mixture,
c) isolating nizatidine from the reaction mass thereof.

8. A process of claim 6 and 7, wherein the alcoholic solvent includes straight and branched chain C1-C4 alcohols, such as methanol, ethanol, n-propanol and isopropanol and the like.
9. A process of claim 7, the organic solvent mixture is water and acetone.
10. Nizatidine having purity 99.5% or more by HPLC.

Dated this 1 st day of l,December 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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