FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rule13)
1. TITLE OF THE INVENTION:IMPROVED PROCESS FOR RANOLAZINE 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 DESCRIPTIONThe present invention relates to improved process for [(2,6-dimethylphenyl)-aminocarbonylmethyl]chloride, as a ranolazine 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 relates to improved process for [(2,6-dimethylphenyl)-aminocarbonylmethyl]chloride, as a ranolazine intermediate.
Ranolazine of Formula I, is chemically 1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-,(±) and it is indicated for the treatment of chronic angina.

U.S. Patent No. 4,567,264 discloses racemic (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl].The '264 patent further discloses the process for ranolazine intermediate, [(2,6-dimethylphenyl)-aminocarbonyl methyl]chloride using of 2,6-dimethylaniline and chloroacetylchloride in 1:1 molar ratio using DCM in Triethylamine (TEA).
European application EP483932 A1 discloses the use of 1-(2-methoxyphenoxy)-3-aminopropan-2-ol as an intermediate for ranolazine preparation.
PCT application WO2006008753 disclosed polymorphic Form A of Ranolazine, and process for the same.
While working on the process for Ranolazine intermediates, It was found by the present inventors that synthesis of [(2,6-dimethylphenyl)-aminocarbonyl methyl]chloride using of 2,6-dimethylaniline and chloroacetylchloride in 1:1 molar
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ratio leads to an incomplete reaction, which contributes to the poor yield. Also the product is contamination by unreacted 2,6-dimethylaniline.
In one aspect of the present invention there is provided a process for ranolazine intermediate, [(2,6-dimethylphenyl)-aminocarbonylmethyl]chloride compound of formula II. The process includes step of, reacting 2,6-dimethylaniline compound of formula III,

with a chloroacetylchloride compound of formula IV,

Formula IV
wherein the compound of formula IV is at a molar excess over the compound of formula III.
The new procedure surprisingly results in a higher yield of [(2,6-dimethylphenyl)-aminocarbonylmethyl]chloride than reported in the prior art. In addition, the reaction is complete and it is rapid.
Preferably, the compound of formula IV is at a molar excess over the compound of formula III. The compound of formula IV and the compound of formula III are
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preferably at a molar ratio from about 1.2:1 to about 100:1. More preferably, the compound of formula IV and the compound of formula III are at a molar ratio from about 1.2:1 to about 10:1. Most preferably, the compound of formula IV and the compound of formula III are at a molar ratio from about 1.2:1 to about 3:1.
In another aspect there is provided a process for [(2,6-dimethylphenyl)-aminocarbonylmethyl]chloride, as an intermediate in synthesis of Ranolazine and salt thereof.
The [(2,6-dimethylphenyl)-aminocarbonylmethyl]chloride is converted to ranolazine and its salt thereof by any process known to the skilled artisan. For eg. The [(2,6-dimethylphenyl)-aminocarbonylmethyl]chloride is coupled with piperazine to get [(2,6-dimethylphenyl)-aminocarbonylmethyl]piperazine, which is coupled with epoxy propane intermediate under reflux to get ranolazine.
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.
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Example 1: Preparation of [(2,6-dimethylphenyl)-aminocarbonylmethynchloride.
To a stirred mixture of 2,6-dimethylaniline (100 g) in DCM was added triethylamine (97 g). The reaction mixture was cooled to about 15 °C, and then chloroacetylchloride (113 g) was added in lots. The content was stirred for 2 hours at about 15 °C. The reaction mixture was quenched with 10% HCI, and stirred for 10 minutes The organic layer was separated and concentrated under vacuum to obtain the crude product.
Example 2: Preparation of [(2,6-dimethylphenyl)-aminocarbonylmethyl]chloride.
To a stirred mixture of 2,6-dimethylaniline (100 g) in DCM was added triethylamine (97 g). The reaction mixture was cooled to about 15 °C, and then chloroacetylchloride (283 g) was added in lots. The content was stirred for 2 hours at about 15 °C. The reaction mixture was quenched with 10% HCI, and stirred for 10 minutes The organic layer was separated and concentrated under vacuum to obtain the crude product.
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WE CLAIM:
1. A process for ranolazine intermediate, [(2,6-dimethylphenyl)-amino carbonylmethyl]chloride compound of formula II. The process comprising, a) reacting 2,6-dimethylaniline compound of formula III,

wherein the compound of formula IV is at a molar excess over the compound of formula III.
2. The process of claim 1, wherein the compound of formula IV and the compound of formula III are at a molar ratio from about 1.2:1 to about 100:1.



Abstract
The present invention relates to improved process for [(2,6-dimethylphenyl)-aminocarbonylmethyl]chloride, as a ranolazine intermediate.