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IMPROVED PROCESS FOR THE PREPARATION OF RANOLAZINE

IP.com Disclosure Number: IPCOM000178842D
Publication Date: 2009-Jan-27

Publishing Venue

The IP.com Prior Art Database

Abstract

An improved process for the preparation of pure ranolazine and its pharmaceutically acceptable salts

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Improved process for the preparation of Ranolazine

    Provided here is an improved process for the preparation of pure ranolazine and its pharmaceutically acceptable salts. It also provides isolation, characterization and synthesis of impurities in ranolazine. Ranolazine is chemically known as N-(2,6- dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy) propyl]-1-piperazine acetamide, compound represented by the following structural formula-1.

                         Formula-1 and its pharmaceutically acceptable salts.

     Provided below is an improved process for the preparation of pure ranolazine and its pharmaceutically acceptable salts containing each of the impurity-B and impurity- C and impurity-D less than 0.15 % area by HPLC, which comprises of the following steps:
a) reacting 2-methoxy phenol compound of formula-2

                     Formula-2 with epichlorohydrin compound of formula-3

                     Formula-3
in presence of a suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide preferably sodium hydroxide in a suitable polar solvent like water, dimethyl sulfoxide preferably water gives epoxypropane compound of formula-4,

Formula-4

2942/CHE/2007- dated- 7/12/2007 Page 1 of 11

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Improved process for the preparation of Ranolazine

b) reacting the epoxypropane compound of formula-4 with piperazine in a suitable alcoholic solvent like methanol, ethanol and isopropyl alcohol preferably methanol, followed by washing with a suitable solvent to remove the impurity B, gives the condensed compound of formula-5 free of impurity-B,

Formula-5
c) reacting the dimethyl aniline compound of formula-6

                       Formula-6
with chloro acetyl chloride in a suitable chloro solvent like methylene chloride in presence of a suitable base like sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarnonate, potassium bicarnonate to provide chloro compound of formula-7,

Formula-7
d) reacting the condensed compound of formula-5

                       Formula-5 with chloro compound of formula-7

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Improved process for the preparation of Ranolazine

                     Formula-7
in presence of a suitable organic amine base like diisopropyl ethylamine, diisopropylamine, triethyl amine; or an inorganic base like sodium carbonate, potassium carbonate and the like in a suitable alcoholic solvent like methanol gives pure ranolazine compound of formula-1,

Formula-1
e) optionally purifying ranolazine using suitable solvent selected from alcoholic solvent like methanol, ethanol, isopropyl alcohol; ester solvent like ethyl acetate; or ketone solvent like actone and mixtures thereof and optionally converting into its pharmaceutically acceptable salts by treating the ranolazine with suitable acid in a suitable solvent or by methods...