CLIAMS:1. A process for the preparation of 2-methoxyethyl-2-[(3-nitrophenyl) methylene] acetoacetate or its salt thereof, compound of formula-II,

Formula-II
has purity more than 99 % when measured by HPLC, the process includes the steps of,
a) reacting m-nitro benzaldehyde with 2-methoxy ethylacetoacetate 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 2-methoxyethyl-2-[(3-nitrophenyl) methylene] acetoacetate or its 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 30 ?C to 45 ?C.

5. 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-methoxy ethylacetoacetate.

6. The process of claim 1, wherein 2-methoxyethyl-2-[(3-nitrophenyl) methylene] acetoacetate or its salt thereof has purity more than 99 %, when measured by HPLC.

7. The process according to claim 1, wherein compound of formula-II subsequently converted to Nimodipine or a pharmaceutically acceptable salt thereof.

,TagSPECI:Field of Invention

The present invention relates to a process for the preparation of Nimodipine intermediate, e.g. 2-methoxyethyl-2-[(3-nitrophenyl) methylene] acetoacetate (referred herein after “m-nitro arylidene”) or its salt thereof. In particular, of the present invention directs to process for the preparation of m-nitro arylidene, has purity more than 99 % when measured by HPLC. A further aspect of the present invention relates to conversion of m-nitro arylidene intermediate to Nimodipine or salt thereof.

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 marketed under the trade name 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. 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. 6,015,906; 4,795,814; 4,988,717; 4,892,730; 4,703,119 and 4,600,778.

Summary of the Invention

The present invention provides a process for the preparation of m-nitro arylidene or salt thereof, has HPLC purity more than 99 %. A further aspect of the present invention relates to conversion of m-nitro arylidene to Nimodipine or its salt thereof.

The present invention provides a process for the preparation of m-nitro arylidene or its salt thereof of formula-II,

Formula-II
has purity more than 99 % as measured by HPLC, the process includes the steps of;
a) reacting m-nitro benzaldehyde with 2-methoxy ethylacetoacetate 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 m-nitro arylidene from reaction mixture thereof.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The intermediates and starting materials of the present invention may be used as free bases or its salts.

The salt used is pharmaceutically acceptable salt and it refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoroacetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.

In an aspect, the present invention provides a process for the preparation of m-nitro arylidene or its salt thereof of formula-II,

Formula-II
has purity more than 99 % when measured by HPLC,
the process includes the steps of;
a) reacting m-nitro benzaldehyde with 2-methoxy ethylacetoacetate 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 m-nitro arylidene from reaction mixture thereof.

The step a) of the present invention involves reacting m-nitro benzaldehyde with 2-methoxy ethylacetoacetate in alcoholic solvent at temperature in between ranges of 25?C to 35?C, 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.

The step b) and step c) of the present invention involve 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 30 ?C to 45 ?C for a period of 3 hours to 5 hours, wherein the molar ratio of citric acid and morpholine are 0.02 mole and 0.06 mole of per mole of 2-methoxy ethylacetoacetate.

The step d) of the present invention involves the isolation of 2-methoxyethyl-2-[(3-nitrophenyl) methylene] acetoacetate or its salts thereof. The reaction mixture obtained in step c) is stirred at temperature between the ranges of 25 ?C to 35 ?C 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 40?C for a period of 7 to 9 hours to obtain 2-methoxyethyl-2-[(3-nitrophenyl)methylene]acetoacetate.

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 obtain 2-methoxyethyl-2-[(3-nitrophenyl) methylene] acetoacetate

Charged m-nitro benzaldehyde (0.662 mol, 100 gm) and 2-methoxy ethylacetoacetate (0.662 mol; 106 gm) in isopropyl alcohol (400 ml). The reaction mixture was stirred followed by addition of catalytic amount of citric acid. H2O (0.0132 mol, 2.8 gm) and catalytic amount of morpholine (0.039 mol, 3.4 gm) into the reaction mixture. The reaction mixture was further stirred at temperature between 35 ?C to 37 ?C for a period of 5 hours. After the completion of reaction, the reaction mixture was stirred at temperature between the range of 25 ?C to 27 ?C, until solid was precipitated followed by cooling the reaction mixture at temperature between the ranges of 5 ?C to 10 ?C and stirred for a period of 2 to 3 hours. The obtained solid 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 ?C to obtain the titled compound.

Yield: 79 % (154 gm)
HPLC purity: 99.59 %