PROCESS FOR PREPARATION OF 2-(DIMETHYLAMINOMETHYL)-4-
THIAZOLEMETHANOL
INTRODUCTION TO THE INVENTION
The present invention relates to a process for the preparation of 2-(dimethylaminomethyl)-4-thiazolemethanol compound of Formula II an intermediate used in the preparation of nizatidine compound of Formula I.

Nizatidine is a histamine H2 -receptor antagonist described chemically as N- [2-[[[2- [(dimethylamino) methyl] -4-thiazolyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1, 1-ethenediamine and is available commercially in pharmaceutical products sold under brand name AXID™.

U.S. Patent No. 4,375,547 discloses nizatidine, its related compounds and processes for their preparation. It discloses a process for the preparation of 2-(dimethylaminomethyl)-4-thiazolemethanol comprises reacting ethyl 2-(dimethylaminomethyl)-4-thiazolecarboxylate lithium triethylborohydride in THF.
EP Paten No. 515,121 discloses a process for the preparation of 2-(dimethylaminomethyl)-4-thiazolemethanol comprises reacting dimethylamino thioacetamide hydrochloride with dichloroacetone and the product was subsequently

reacted with potassium hydroxide. The resulting solution was reduced to dark brown oil by vacuum distillation to afford a yellow oil of (dimethylaminomethyl)-4-thiazolemethanol.
Since 2-(dimethylaminomethyl)-4-thiazolemethanol compound of Formula II is a key intermediate in the synthesis of Nizatidine, it would be a significant contribution to the art to provide a simple and industrially feasible process for its preparation.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of 2-(dimethylaminomethyl)-4-thiazolemethanol compound of Formula II.
In one aspect the present invention relates to a process for the preparation of 2-(dimethyl-aminomethyl)-4-thiazolemethanol compound of Formula II, which process comprises of:
a) reacting dimethylamino thioacetamide hydrochloride compound of Formula III with 1,3-dichloroacetone compound of Formula IV in presence of halogenated solvent and alkali metal carbonate to form the compound of Formula V; and
b) reacting the compound of Formula V with alkali metal hydroxide.
The process of the present invention is cost effective, eco-friendly and easily scaleable to industrial levels.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of 2-(dimethylaminomethyl)-4-thiazolemethanol compound of Formula II.
In one aspect the present invention relates to a process for the preparation of 2-(dimethyl-aminomethyl)-4-thiazolemethanol compound of Formula II, which process comprises of:
a) reacting dimethylamino thioacetamide hydrochloride compound of Formula III with 1,3-dichloroacetone compound of Formula IV


in presence of halogenated solvent and alkali metal carbonate to form the compound of Formula V; and
b) reacting the compound of Formula V with alkali metal hydroxide to give 2-(dimethylaminomethyl)-4-thiazolemethanol compound of Formula II.
Step a) involves reaction of dimethylamino thioacetamide hydrochloride compound of Formula III with 1,3-dichloroacetone compound of Formula IV in presence of halogenated solvent and alkali metal carbonate to form the compound of Formula V.
Suitable solvents that can be used include but are not limited to halogenated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like.
The alkali metal carbonates include but are not limited to sodium carbonate, potassium carbonate and the like.
After completion of the reaction, by-products are removed by suitable techniques such as filtration, centrifugation and the like. The organic layer separated can be directly used in the next reaction, or it can be concentrated to form a residue.
Suitably the organic layer containing compound of Formula V is reacted with a alkali metal hydroxide to give 2-(dimethylaminomethyl)-4-thiazolemethanol compound of Formula II.
The alkali metal hydroxides include but are not limited to potassium hydroxide, sodium hydroxide and the like.

Suitably alkali metal hydroxide is used in the form of a solution in a suitable solvent include but are not limited to water, methanol, ethanol and the like. After completion of the reaction the organic layer can be cooled to a temperature of below 25 °C and can be distilled under vacuum to concentrate the solution.
The process is cost effective, reduced time cycle, eco-friendly and easily scaleable to industrial levels and an invention made toward this goal is described below.
The following example is illustrative of specific aspects of the present invention but is not intended to limit the scope of the invention in any manner.
EXAMPLES EXAMPLE 1 PREPARATION OF2- (DIMETHYLAMINOMETHYL)-4-THIAZOLEMETHANOL
232 g of dimthylamino thioacetamide hydrochloride compound of Formula III, 225 g of 1,3-dichloroacetone compound of Formula IV and 275 g of sodium carbonate were charged into a round bottom flask containing 1276 ml of chloroform under stirring. The reaction mixture was then heated to a temperature of about 43 °C and stirred for about 50 minutes. The reaction mixture was further heated to about 54 °C and stirred for about 3 hours 25 minutes at 54-56 °C. The reaction mixture was filtered and the solid was washed with 464 ml of the chloroform. The chloroform filtrate was washed with 300 ml of water. 185.5 ml aqueous sodium hydroxide solution was added to the organic layer at below 20 °C and then the temperature of reaction mixture was slowly raised to 28 °C. The reaction mixture was stirred for about 1 hour 20 minutes and then organic and aqueous layers were separated. Aqueous layer was extracted with chloroform (4 X 464 ml). The chloroform layers were combined and subjected to distillation under vacuum at below 50 °C to afford 300 gm of crude.
The crude material obtained above was distilled under high vacuum at about 110 to180 °C to afford 205 g of the title compound as a dark brown color liquid.
Purity: 99.6 area % as analyzed by Gas chromatography

We claim:
1. A process for preparation of 2-(dimethyl-aminomethyl)-4-thiazolemethanol
compound of Formula II:

which process comprises:
a) reacting an acid addition salt of dimethylamino thioacetamide of Formula III:

with 1,3-dichloroacetone compound of Formula IV:

in the presence of halogenated solvent and alkali metal carbonate to form the compound of Formula V:

b) converting the compound of Formula V to 2-(dimethylaminomethyl)-4-
thiazolemethanol compound of Formula II.
2. The process of claim 1, wherein said acid addition salt is a hydrochloride salt of
the formula

3. The process of claim 1, wherein said converting step includes reacting the
compound of Formula (II) with an alkali metal hydroxide.

4. The process of claim 3, wherein said alkali metal hydroxide is potassium
hydroxide.
5. The process of claim 3, wherein said alkali metal hydroxide is used in the form of solution in a solvent.
6. The process of claim 5, wherein said solvent is selected from the group consisting of water, methanol, and ethanol.
7. The process of claim 1, wherein said halogenated solvent is selected from the
group consisting of dichloromethane, dichloroethane, chloroform, and carbon
tetrachloride
8. The process of claim 1, wherein said halogenated solvent is chloroform.
9. The process of claim 1, wherein said alkali metal carbonate is selected from the group consisting of sodium carbonate and potassium carbonate.
10. The process of claim 1, further comprising converting the compound of Formula (II) into nizatidine.