A PROCESS FOR THE PREPARATION OF HIGHLY PURE RANOLAZINE BASE

FIELD OF THE INVENTION;

The present invention relates to an improved and novel process for the preparation of highly pure (>99.8) N-(2,6-Dimethyl phenyl)-4-[2-hydroxy-3-(2-methoxy phenoxy) propyl]- 1-piperazine acetamide (Ranolazine) of formula-I and its pharmaceutically acceptable salts process for preparation thereof.

Formula-I

Back ground of the invention

Ranolazine (Formula-I) is a novel anti-anginal agent which has been reported to protect against biochemical electrophysiological and thermodynamic consequences of transient myocardial ischmia in the pentobarbitone-anesthetized dog, without inducing overt hemodynamic effects.

Formula-I

US patent 4567264 describes the preparation of Ranolazine base from basic stages by condensing ofN-(2,6-dimethylphenyl)-l-piperazineacetamide (II) with l-(2- methoxyphenoxy)2,3-epoxypropane (III). The base thus obtained was of 75-80% pure and was purified by column chromatography and isolated as oil. The hydrochloride salt was prepared in methanol using hydrochloric acid and the salt was isolated by addition of ether.

(ID (III) Formula-I

EP 0483932 describes the preparation of Ranolazine base by condensation of α-[N,N-bis(2-chloroethyl)-amino]-2,6-dimethylacetanilide Hydrochloride(IV) with l-[3- (2-methoxy phenoxy)-2-hydroxy]-propylamine(V). The base thus obtained was of 75- 80% pure and was purified by column chromatography and isolated as oil.The hydrochloride was crystallized by addition of diethyl ether as co solvent.

Formula - 1

Ranolazine base is the precursor of the salt forms of Ranolazine. As such, there is a need for Ranolazine base of high purity which may be conveniently used as a precursor in the preparation of highly pure Ranolazine dihydrochloride.

It is observed that pharmaceutically acceptable salts of Ranolazine when prepared from Ranolazine of lower purity do not. meet with the pharmaceutically acceptable quality.

There is therefore an unfulfilled need to provide industrially feasible process for the preparation of pharmaceutically acceptable salts of Ranolazine from less pure Ranolazine without column chromatography purification as described in the prior art.

To overcome the problem the inventors have tried to prepare highly pure Ranolazine base through acid addition salts of Ranolazine of lower purity. When the base is liberated from the acid addition salts, Ranolazine base of higher purity results.

It is surprisingly found by the inventors that when the less pure Ranolazine is reacted with fumaric acid it selectively forms the corresponding acid addition salt, leaving behind the other related substances and impurities which are otherwise difficult to remove by the conventional methods. The fumaric acid salt of Ranolazine is further converted to highly pure Ranolazine base which in turn is converted into other pharmaceutically acceptable salts with higher purity. Summary of the invention

The main object of the present invention is to provide an improved process for the preparation of highly pure (>99.8%) Ranolazine base and/or its pharmaceutically acceptable salts

Another object of the invention is to provide a process for preparation of highly pure (>99.8%) Ranolazine and/or its pharmaceutically acceptable salts using fumaric acid salt of Ranolazine.

Accordingly in the present invention highly pure Ranolazine and its pharmaceutically acceptable salts are prepared by i. preparing Ranolazine base by the condensation of N-(2,6-dimethylρhenyl)-l- piperazineacetamide (II) with l-(2-methoxyphenoxy)2,3-epoxypropane (III) to afford Ranolazine base as syrup of purity 75-80%

ii. Treatment of impure Ranolazine with hydrochloric acid and again liberation of Ranolazine of purity of 97.0% iii. Treating Ranolazine with fumaric acid yielding fumaric acid addition salt of Ranolazine(Ranolazine fumarate) iv) neutralizing Ranolazine fumarate and isolating Ranolazine of purity 99.85% and v) converting highly pure Ranolazine to other acceptable acid addition salts

Detailed description of the invention

Thus in accordance with the present invention preparation of Ranolazine and its pharmaceutically acceptable salts comprise the following steps

i. condensation of N-(2,6-dimethylphenyl)-l-piperazineacetamide (II) with l-(2-methoxyphenoxy)2,3-epoxyproane (III) to yield crude Ranolazine base as syrup of purity 75-80% ii. Treatment of impure Ranolazine with hydrochloric acid again liberation of Ranolazine of purity 97.0%

iii. Treating crude Ranolazϊne with fumaric acid yielding fumaric acid addition salt of

Ranolazine(Ranolazine fumarate) iv. Converting Ranolazine fumaric acid addition salt to highly pure(>99.8)Ranolazine

In a specific embodiment, the present invention provides a process for the preparation of Ranolazine and its pharmaceutically acceptable salts, which involve

i. Charging of N-(2,6-dimethylphenyl)-l-piperazineacetamide (II) and l-(2- methoxyphenoxy)2,3-epoxyproane (III) to a solvent mixture of toluene and methanol ii. Heating to reflux temperature and maintenance at the same temperature for 5-6 hours iii. Removal of the solvents completely under vacuum iv. Cooling reaction mass to the room temperature and dissolving the residue in ethyl acetate v. Extracting organic layer thoroughly with diluted hydrochloric acid vi. Adjusting the aqueous layer P ^H to 9.0 to 10.0 vii. extraction with Ethyl acetate and carbon treatment. viii. Concentration of the organic layer . ix. Isolation of the separated Ranolazine base of purity 97.0% by filtration

Further reacting the resultant base of of Ranolazine with fumaric acid by

i. Dissolving Ranolazine base in acetone by heating to reflux temperature

ii. Adding fumaric acid directly or as a suspension in acetone, maintaining the reaction mixture at 40-50 ⁰ C iii. Cooling reaction mass to room temperature and maintaining at the same temperature for 2-3 hours iv. Filtering , washing with acetone and drying the product at 60-70 ⁰ C affords the pure Ranolazine as an acid addition salt of fumaric acid.

The prepared Ranolazine fumaric acid addition salt is novel, identified and characterized by chemical analysis, IR ₅ NMR & Mass spectral. Ranolazine acid addition salt is further converted to Ranolazine by i. Neutralizing Ranolazine fumaric acid with a base such as organic amines, alkali hydroxides, alkali carbonates, alkali bicarbonates and ammonia, in a mixture of water and water immiscible solvent ii. Extracting with organic solvent and Separating the layers, iii. Washing the organic layer with water, and giving carbon treatment iv. Concentrating the organic layer under vacuum affords Ranolazine of purity 99.8% by HPLC

The required N-(2,6-dimethylphenyl)-l-piperazineacetamide (II) and l-(2- methoxyphenoxy)2,3-epoxyproane (IιI)can be prepared by the prior art processes

The details of the inventions are given in the Examples which are provided for illustration only and therefore the Examples should not be construed to limit the scope of the invention.

EXAMPLES

Example-l : Process for the preparation highly pure Raήolazine of the formula -I Step-1 : Condensation of N-(2,6-dimethylphenyl)-l-piperazineacetamide (II) and l-(2-methoxyphenoxy)2,3-epoxyproane (III) ; Into the reactor a mixture of 5OL of methanol and IOOL of toluene is charged. 5.6Kgs of l-(2-methoxyphenoxy)2,3-epoxyproane (III) and 7.0kgs of N-(2,6-dimethylphenyl)-l- piperazineacetamide (II) are charged and heated reflux temperature. Reaction mass is maintained at reflux temperature for 5-6 hours. After reaction completion solvents are distilled off completely under vacuum and the residue is brought to room temperature. Residue is dissolved in 5L of Ethyl acetate and extracted with 4L of diluted hydrochloric acid. Aqueous layer is basified with Ammonia solution to a pH of 9-10 and extracted with 2x1 OL Ethyl acetate... Carbon treatment is given to the Ethyl acetate layer. Organic layer is dried over sodium sulfate and distilled off under vacuum to a residual volume of 2.5L . The product of the formula-I is centrifuged and washed with 2-3L Ethyl Acetate. It is dried in oven at 60-70°C Dry weight : 9.1 kgs Purity by HPLC : 97.3%

Step - II : Preparation of Ranolazine fumarate : Ranolazine (9kgs, purity 97.3%) is suspended in acetone (45L) at and heated reflux temperature. Fumaric Acid suspension (2.4kgs in 1OL acetone) is added to the above solution over 30 min at 40-50 ⁰ C. Reaction mass temperature is raised to reflux and maintained for about l-2hrs. Slowly cooled the reaction mass to room temperature and maintained for about 2-3 hr at the same temperature. The precipitated material is filtered and washed with 5L of acetone. Dried the product at 60-70 ⁰ C under vacuum till constant weight. Dry weight : 10.0 kg Step - III : Preparation of highly pure Ranolazine from Ranolazine fumarate:

Ranolazine fumarate (lO.Okgs) is suspended in DM water(150L)and stirred for 1 hour. Aqueous 5% sodium hydroxide solution(30L) is added over a period of 30 min to a pH of 9-12 and extracted with Ethyl acetate(2x50L). Organic layer is washed with DM water and carbon treatment is given. Ethyl acetate distilled off under vacuum to a residual volume of 4OL and stirred for 1-2 hours. The precipitated product is filtered and washed with ethyl acetate. The product is dried at temperature of 60-70 ⁰ C till constant weight.

Dry weight of Ranolazine : 5 kgs Purity: 99.85% (by HPLC)

Advantages of the invention

1) The Ranolazine base is produced in more than 99.8% purity.

2) The process can be used for commercial preparation of Ranolazine salts of pharmaceutical grade.