CLIAMS:1. A process for the preparation of Nimodipine, compound of formula-I,

Formula-I
has purity more than 99 % when measured by HPLC, the process comprising,
a) reacting 2-methoxyethyl 2-(3-nitrobenzylidene)-3-oxobutanoate with isopropyl 3-aminobut-2-enoate in a alcoholic solvent,
b) adding aqueous citric acid and morpholine to the solution obtained in step a),
c) stirring the reaction mixture obtained in step b) at suitable temperature,
d) isolating Nimodipine or its pharmaceutical acceptable salt thereof from reaction mixture thereof.

2. The process of claim 1, wherein the alcoholic solvent is selected from the group comprising one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, 2-pentanol, ethylene glycol, diethylene glycol, propylene glycol, 2-ethyl hexanol, benzyl alcohol and mixture thereof.

3. The process of claim 2, wherein the alcoholic solvent is isopropanol.

4. The process of claim 1, wherein the suitable temperature is in between the range of 60oC to 90oC.

5. The process of claim 1, wherein the molar ratio of isopropyl 3-aminobut-2-enoate is 1.02 mole for per mole of 2-methoxyethyl 2-(3-nitrobenzylidene)-3-oxobutanoate.

6. The process of claim 1, wherein the molar ratio of citric acid and morpholine are 0.02 mole and 0.06 mole of per mole of 2-methoxyethyl 2-(3-nitrobenzylidene)-3-oxobutanoate.

7. The process of claim 1, wherein Nimodipine or its pharmaceutical acceptable salt thereof has purity more than 99 %, when measured by HPLC.
,TagSPECI:Field of Invention

The present invention relates to a process for the preparation of Nimodipine or its pharmaceutical acceptable salt thereof. In particular, of the present invention directs to process for the preparation of Nimodipine, has purity more than 99 % when measured by HPLC.

Background of the invention

Nimodipine is chemically described as isopropyl-(2-methoxyethyl)-1 ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate. Nimodipine is a member of the dihydropyridine class of drugs belonging to the calcium channel antagonist family of pharmaceutical agents and has the structure of formula I.

Formula I

Nimodipine is manufactured and marketed by Bayer AG as Nimotop. Nimodipine has been indicated for use in neurological conditions such as aneurysms, subarachnoid hemorrhage, neuropathic pain, arthritis, etc. Nimodipine was first described in U.S. Patent No. US 3,799,934 with its process for the preparation. The process for the preparation for Nimodipine is described in several patents, e.g. US patent Nos.; US 6,015,906; US 4,795,814; US 4,988,717; US 4,892,730; US 4,703,119 and US 4,600,778.

Summary of the Invention

The present invention provides a process for the preparation of Nimodipineor its pharmaceutical acceptable salt thereof, compound of formula-I,

Formula-I
has purity more than 99 % as measured by HPLC, the process includes the steps of;
a) reacting 2-methoxyethyl 2-(3-nitrobenzylidene)-3-oxobutanoate with isopropyl 3-aminobut-2-enoate in a alcoholic solvent,
b) adding citric acid and morpholine to the solution obtained in step a),
c) stirring the reaction mixture obtained in step b) at suitable temperature,
d) isolating Nimodipine or its pharmaceutical acceptable salt thereof from reaction mixture thereof

Description of the Invention

In an aspect, the present invention provides a process for the preparation of Nimodipine, compound of formula-I,

Formula-I
has purity more than 99 % as measured by HPLC, the process includes the steps of
a) reacting 2-methoxyethyl 2-(3-nitrobenzylidene)-3-oxobutanoate with isopropyl 3-aminobut-2-enoate in a alcoholic solvent,
b) adding citric acid and morpholine to the solution obtained in step a),
c) stirring the reaction mixture obtained in step b) at suitable temperature,
d) isolating Nimodipine from reaction mixture thereof.

The step a) of the present invention involves reacting 2-methoxyethyl 2-(3-nitrobenzylidene)-3-oxobutanoate with isopropyl 3-aminobut-2-enoate in alcoholic solvent at temperature in between range of 25?C to 35?C, wherein the molar ratio of isopropyl 3-aminobut-2-enoate is 1.02 mole for per mole of 2-methoxyethyl 2-(3-nitrobenzylidene)-3-oxobutanoate.

The alcoholic solvent is selected from the group comprising one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, 2-pentanol, ethylene glycol, diethylene glycol, propylene glycol, 2-ethyl hexanol, benzyl alcohol and mixture thereof.

The step b) and step c) of the present invention involves addition of catalytic amount of aqueous citric acid and morpholine to the solution obtained in step a). The reaction mixture is then stirred at temperature between the range of 75 oC to 80 oC for a period of 6 hours to 7 hours, wherein the molar ratio of citric acid and morpholine are0.02 mole and 0.06 mole of per mole of 2-methoxyethyl 2-(3-nitrobenzylidene)-3-oxobutanoate.

The step d) of the present invention involves the isolation of Nimodipineor its pharmaceutical acceptable salt thereof. The reaction mixture obtained in step c) is stirred at temperature between the ranges of 25 oC to 35 oC till the solid precipitates. The reaction mixture is allowed to cool at temperature between the ranges of 5 oC to 10 oC and further stirred for a period of 2 hours to 3 hours. The isolation step further involves filtration and washing of obtained solid with the alcoholic solvent and further dried under vacuum at temperature 40oC for a period of 7 to 9 hours to obtain Nimodipine free base.

The process of the present invention is depicted in the following scheme:

Scheme-1
The present invention is further illustrated by the following example, which does not limit the scope of the invention. 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 application.

Examples

Example-1: Preparation of Nimodipine

Charged 2-methoxyethyl 2-(3-nitrobenzylidene)-3-oxobutanoate (0.0341 mol, 10 gm) and isopropyl 3-aminocrotonate (0.0349 mol; 5.0 gm) in isopropyl alcohol (30 ml). The reaction mixture was stirred followed by addition of catalytic amount of citric acid. H2O and catalytic amount of morpholine into the reaction mixture. The reaction mixture was further stirred at temperature between the ranges of 75oC to 80 oC for a period of 6 hours to 7 hours. After the completion of reaction, the reaction mixture was stirred at temperature between the range of 25oC to 27 oC until solid was precipitated followed by cooling the reaction mixture at temperature between the ranges of 5oC to10 oC and stirred for a period of 2-3 hours. The solid obtained was filtered, washed with chilled isopropyl alcohol to obtain the wet cake. The wet cake was dried under vacuum for a period of 7 to 9 hours at temperature 40 oC to obtain the titled compound.

Yield:77 % (11 gm)
HPLC purity: 99.47 %