CLIAMS:We Claim:

1. A process for the preparation of a key impurity of Lercanidipine and nicardipine, the compound of formula II

Formula II
, which comprises:
i) reaction of hydroxypropanenitrile with ethylacetoacetate using Boric acid in presence of hydrocarbon to provide 2-cyanoethyl 3-oxobutanoate;

ii) reaction of 2-cyanoethyl 3-oxobutanoate of step i) with 3-nitrobenzaldehyde in presence of ammonia and an organic solvent to provide bis(2-cyanoethyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate of formula III; and

iii) hydrolysis of the compound of Formula III using sodium hydroxide to provide pure compound of formula II having purity greater than 94% by HPLC.

2. The process of claim 1, wherein said hydrocarbon of step (i) is selected from the group of n-hexane, cyclohexane, n-heptane and toluene.

3. The process of claim 1, wherein said organic solvent of step (ii) is selected from alcohol, nitrile, halogenated solvent, ether and ketone.

4. The process of claim 1, wherein said organic solvent of step (ii) is acetonitrile.

5. The process of claim 1, wherein said hydrolysis step (iii) is performed in presence of a solvent mixture, for example, water and dimethoxyethane.

6. The process of claim 1, wherein said the compound of formula II is having purity of greater than 94 % by HPLC.

7. The process of claim 1, wherein said the compound of formula II is used as an intermediate for the preparation of Lercanidipine and nicardipine.

8. The process of claim 1, wherein said the compound of formula II is used as an reference standard for the HPLC analysis of Lercanidipine and nicardipine and intermediates thereof.

Dated this 26th day of March, 2013 For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory
,TagSPECI:DESCRIPTION

The present invention provides a process for the preparation of key impurity of Lercanidipine and Nicardipine, the compound of formula II, which is pure:

Formula II

Lercanidipine of Formula IA is chemically known as 3-{1-[(3,3-diphenylpropyl)(methyl)amino]-2-methylpropan-2-yl} 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. Lercanidipine is marketed under the trade name Zanidip for the treatment of Hypertension, management of angina pectoris and Raynaud's syndrome.

Formula IA
Nicardipine Hydrochloride of formula IB is chemically known as (±)-2-(benzyl-methyl amino)ethyl methyl 1,4-dihydro-2,6 dimethyl- 4-(m-nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride. Nicardipine is marketed under the trade name CARDENE® SR for the treatment of hypertension.

Formula IB
CN 102850260 discloses a process for the preparation of key impurity of formula II by hydrolysis of di-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate, which is not providing good yield and purity when performed by the present inventors.

EP 0474129 B1 discloses a process for the preparation of the compound of Formula II from ethylene cyanohydrin by using hazardous chemicals and utilizes column chromatography technique to provide dicyanoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate, which is converted to the compound of Formula II using sodium hydroxide.

Therefore, there is a need to develop an improved process for the preparation of pure compound of formula II that is lower cost alternative, simple and industrially applicable, result in high yield and high purity of compound of Formula II as well as pharmaceutically acceptable salt thereof.

The compound of Formula II is useful as a reference marker (reference standard) for the analysis of Lercanidipine and nicardipine. Further, the pure compound of formula II is also useful as an intermediate for the preparation of Lercanidipine and nicardipine.

The present inventors found preferred reaction conditions for preparing the compound of Formula II from hydroxy propanenitrile that provided a faster rate of reaction to achieve higher yield and greater purity of compound of formula II.

In an aspect of the present invention provides a process for the preparation of a key impurity of Lercanidipine and nicardipine, compound of formula II

Formula II
, which comprises:
i) reaction of hydroxy propanenitrile with ethylacetoacetate using Boric acid in presence of hydrocarbon to provide 2-cyanoethyl 3-oxobutanoate;

ii) reaction of 2-cyanoethyl 3-oxobutanoate of step i) with 3-nitrobenzaldehyde in presence of ammonia and an organic solvent to provide bis(2-cyanoethyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate of formula III; and

iii) hydrolysis of the compound of Formula III using sodium hydroxide to provide pure compound of formula II having purity greater than 94% by HPLC.

The step i) involves reaction of hydroxy propanenitrile with ethylacetoacetate using Boric acid in presence of hydrocarbon to provide 2-cyanoethyl 3-oxobutanoate.

The hydrocarbon used for performing the reaction includes but are not limited to n-hexane, cyclohexane, n-heptane, toluene and the like. The reaction is conducted at a reflux temperature till the completion of the reaction. After completion of the reaction, the reaction mixture may be directly utilized for further reaction or it may be subjected for concentration followed by isolation of solid by using suitable techniques.

The step ii) involves reaction of 2-cyanoethyl 3-oxobutanoate of step i) with 3-nitrobenzaldehyde in presence of ammonia and an organic solvent to provide bis(2-cyanoethyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate of formula III.

The suitable organic solvent is selected from alcohol, nitrile, halogenated solvent, ether and ketone. The alcohol solvent includes but are not limited to methanol, ethanol, isopropyl alcohol, and the like; the nitrile includes but are not limited to acetonitrile, propionitrile, and the like; the chlorinated solvent such as dichloromethane, chlorobenzene and the like; ethers such as diethyl ether, diisopropyl ether, ethyl tert-butyl ether, 1,4-dioxane, THF, and the like; the ketone solvent such as acetone, ethylmethylketone and the like.

The reaction is conducted at reflux for a period of 10 to 15 hours to complete the reaction without effecting reaction to form the impurities.

After completion of the reaction, the reaction mixture may be concentrated and it subjected to precipitation of solid from the reaction mixture by usuing suitable organic solvent such as ethyl acetate, isopropyl acetate, 2-methoxyethyl acetate, dichloromethane and the like.

The step iii) involves hydrolysis of the compound of Formula III using sodium hydroxide to provide pure compound of formula II having purity greater than 94% by HPLC.

The hydrolysis step may be performed in presence of water, dimethoxyethane, diethyl ether, diisopropyl ether, ethyl tert-butyl ether, 1,4-dioxane, THF, and the like. The reaction is conducted at a temperature of about 25 to about 40°C and maintained for a period of about 2 to 5 hours or more.

After completion of the reaction, the reaction mixture may be neutralized by using acid and then extracted into chlorinated solvent, for example, dichloromethane followed by subjected for precipitation of solid using suitable techniques like recrystallization, anti-solvnet and then like. The acid, for example, hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, phosphoric acid and the like.

The purity the compound of Formula II obtained from the process of the present invention is greater than 94% determined by the HPLC method.

The yield of the compound of Formula II is greater than or equal to 80%.

The present invention provides a process for the preparation of impurity related to Lercanidipine and nicardipine comprising
i) providing a compound of Formula II by hydrolysis of bis(2-cyanoethyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate in presence of dimethoxyethane and water using sodium hydroxide.
ii) conversion of the compound of Formula II to Lercanidipine and Nicardipine.

Lercanidipine and Nicardipine may be prepared from the compound of formula II as per the process disclosed in the prior art.

Further, the pure compound of formula II obtained from the present invention is useful as reference standard for the HPLC analysis to identify the content of impurity in the final compound.

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: A process for the preparation of the compound of Formula II:

Formula II

Step-1: Preparation of 2-cyanoethyl 3-oxobutanoate

Ethylacetoacetate (20g; 0.1538 mol), hydroxy propanenitrile (18g; 0.253 mol) and boric acid (0.52g; 0.0085 mol) were subjected to reflux in toluene (250 ml) in a 500 ml three-necked RB flask using a Dean-Stark apparatus for 20 hours. The reaction mixture was concentrated after the completion of the reaction (TLC) and the residue obtained (20 g) was taken further with out purification.

1H NMR (400 MHz, DMSO–d6): d 2.17 (3H, s), 2.86 (2H, t, J = 6Hz), 3.63 (2H, s), 4.22 (2H, t, J = 6 Hz).

Step-2: Preparation of bis(2-cyanoethyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

A mixture containing 2-cyanoethyl 3-oxobutanoate (20g; 0.129 mol), 3-nitrobenzaldehyde (9.7 g; 0.064 mol) and ammonia solution (10 ml) in acetonitrile (100 ml) were subjected to reflux in a 250 ml 3-necked RB flask for 15 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was taken in ethyl acetate, stirred and the solid formed was filtered, washed with water and dried. The amount obtained was 9 g.

1H NMR (400 MHz, DMSO–d6): d 2.30 (6H, s), 2.77- 2.85 (4H, m), 4.05- 4.20 (4H, m), 4.97 (1H,s), 7.47-7.52 (1H, m), 7.62- 7.67 (1H, m), 7.95-8.0 (2H, m), 9.18 (1H, s).

Step-3: Preparation of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid

bis(2-cyanoethyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3 g; 0.007 mol) obtained in the step-2 was taken in dimethoxyethane (15ml) and water (30 ml) and transferred to a 250 ml 3-necked RB flask. Sodium hydroxide (0.85g; 0.02mol) was added and the reaction mixture was stirred at RT for 5 hours. After completion of the reaction, water (30 ml) was added to the reaction mixture after the completion of the reaction, neutralized and extracted with dichloromethane (200 ml). The amount of product obtained was 1.8 g. (Yield: 80%)

1H NMR (400 MHz, DMSO–d6): d 2.25 (6H, s), 4.96 (1H, s), 7.47-7.62 (2H, m), 7.90- 8.05 (2H, m), 8.82 (1H, s, -NH-), 11.74 (2H, bs, -COOH).

13 C NMR (100 MHz, DMSO–d6): 169.2, 150.9, 148.2, 146.6, 134.7, 130.1, 122.2, 121.5, 101.9, 39.8, 18.9.

IR (KBr, cm-1): 3454, 3371, 2976, 1681, 1604, 1529, 1477, 1432, 1380, 1351, 1321, 1224, 1136, 1017, 905, 791.

Purity by HPLC: 94.4 %.