FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - An improved process for the preparation of 4-substituted 1, 4-
dihydropyridine
2. Applicant(s)
(a) NAME : ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION

The following specification describes the invention :
Field of the invention
The present invention provides improved process for the preparation of 4-substitude 1, 4-dihydropyrine, more particularly to the preparation of nisoldipine formula (I) with efficient parameters such as improvement in yield and purity

Background of the invention
Nisoldipine belongs to the class of 4-substitude 1, 4-dihydropyridine calcium channel antagonist which induces relaxation of vascular smooth muscles, preferentially in arteries and display a negative inotropic effect on isolated cardiac muscles. They exert these effect via binding to a high affinity binding site in L-type voltage dependant ca+2 channels
The preparation of Nisoldipine and related compounds typically involves multistep synthesis, the last step of which usually involves formation of dihydropyridine ring.
Nisoldipine (I) is first disclosed in US4154839 which disclose its process for preparation where in Nispldipine (I) is prepared by reacting 2-nitrobenzylidine acetocetic acid isobutyl ester and methyl-3-amino crotonate in ethanol. Morover, this process is silent about purity of final product.

US 5310917 disclose the synthesis of dihydropyridine by heating the mixture of benzylidine with amino crotonate ester in the presence of a strong acid. This may be detrimental to the environment impact. The efforts can be towards avoiding use of such strong acid as far as possible.
US4600778 describes a process for the preparation of dihydro pyridine compound by the reaction of a ketocarboxylic acid ester with an aldehyde and a catalytic amount of piperidine and aliphatic alcohol as a solvent.
US5977369 describes the synthesis of dihydropyridine by reacting benzylidine with amino crotonate in the absence of an acid in alcohol as a solvent.
Disadvantage with most of the prior art synthesis of 4-substituted 1, 4-dihydropyridine particularly nisoldipine from benzylidine intermediate processes of the prior art includes, extractive work up as well as less efficient for isolation of product due to time consumption, formation of symmetrical diesters by product which are very difficult to remove, and over all low yields
Accordingly, there is a continuously need for commercially viable synthetic route for the preparation of nisoldipine which is not only overcomes disadvantages associated with prior art but also gives improvement in terms of high yield and/or purity of final product.
Objet of the invention
It is an object of the present invention is to provide an improved process for the preparation of nisoldipine (formula I).


Formula (1)
with a substituted enamine formula (III)
A further object of the present invention is to provide improved process for the preparation of 4-substituted 1, 4-dihydropyridine comprising a step of reacting benzylidine intermediate of formula (II)


in the presence of buffer reagent and N-methyl-2-pyrrolidimone in suitable solvent.
Another object of the present invention is to provide pure Nisoldipine by purification process such as crystallization comprising dissolving crude Nisoldipine in acetonitrile, heating the solution and then cooling the solution to cause crystallization and collecting the pure Nisoldipine by filtration.

Summary of the invention
It is an object of the present invention is to provide an improved process for the preparation of Nisoldipine (formula I).

Formula (I)
with a substituted enamine formula (III)
A further object of the present invention is to provide an improved process for the preparation of 4-substituted 1, 4-dihydropyridine comprising a step of reacting benzylidine intermediate of formula (II)


in the presence of a buffer reagent and N-methyl-2-pyrrolidinone in a suitable non polar solvent.

Yet another object of the present invention is to provide pure Nisoldipine by purification process such as crystallization comprising dissolving crude Nisoldipine in acetonitrile, heating the solution and then cooling the solution to cause crystallization and collecting the pure Nisoldipine by filtration.
Detailed description of the invention
Accordingly process for present invention is represented schematically as follows

In another embodiment the process for the purification of Nisoldipine comprising dissolving the crude Nisoldipine in acetonitrile. Heating the solution and then cooling the solution to cause crystallization and collecting the pure Nisoldipine by filtration.
The term "buffer reagent" used herein above which maintains the PH level constant during the reaction. These includes but not limited to sodium acetate, disodium hydrogen phosphate, ammonium acetate.

The term "suitable non polar solvent" as used hereinabove include aromatic or aliphatic solvents such as toluene, xylene, hexane, heptane and like mixture there of.
The present invention further illustrated in detail by the below examples which are however not limit to the scope of the invention
Example-1 (Process for the preparation of Nisoldipine)
Step A
2-nitro benzaldehyde (100 g, 0.661 moles), isobutyl acetoacetate (99.3 g, 0.628 moles), formic acid (4.56 g, 0.099 moles) and piperidine (5.62g, 0.066 moles) in cyclohexane (200 ml) heated for 4-6 hours under reflux. After the reaction mixture cooled, the solvent was distilled off. Residue was mixed with toluene. Toluene layer was washed with 5% Sodium Bisulphite solution and then dilute HC1. Solvent was distilled off in vacuum and residue obtained was carried out for next step.
StepB
Residue obtained in step A, N-methyl-2-PyrroIidinone (48 ml), Methyl-3-amino crotonate (114 g,), anhydrous Di sodium hydrogen phosphate (61.2 gm, 0.43012) and toluene (432 ml) was stirred at 25-30 C. Raised the temperature slowly up to reflux temperature. Heat the reaction mixture at reflux for 5-7 hrs (water was removed by azeotropic distillation). After the reaction mixture cooled, the solvent was distilled off. Residue was mixed with toluene. Toluene layer washed with water. Further organic layer washed with dilute HC1 and then brine solution. Charge 2 gm Disodium hydrogen phosphate (2 gm) to the organic layer. Distilled out solvent completely under vacuum below 65 °C. Obtained residue was crystallized by Acetonitrile.

Claims
1. A process for manufacturing of isobutyl methyl 2,6-dimethyl-4-(2-nitrophenyl)-l,4-dihydropyridine-3,5-dicarboxylate comprising the step of reacting 2-nitrobenzylidine acetoaceticacid isobutyl ester with methyl 3-amino crotonate in the presence of buffer reagent and N-methyl-2-pyrrolidinone in suitable non polar solvent medium to give crude nisoldipine.
2. A process as claimed in claim 1 where in the non polar solvent is selected from the group consisting of aromatic or aliphatic solvents.
3. A process as claimed in claim 2 where in the solvent is selected from the group consisting toluene.
4. A process as claimed in claim 1 where in the buffer reagent is selected from the group consisting of anhydrous sodium acetate or anhydrous disodium hydrogen phosphate.
5. A process as claimed in claim 1 where in crude Nisoldipine is purified by crystallization.
6. A process as claimed in claim 5 where in the solvent used for crystallization is acetonitrile.