WO2005023768A1

WO2005023768A1 - An improved process for the preparation of pure nisoldipine

Info

Publication number: WO2005023768A1
Application number: PCT/IN2003/000309
Authority: WO
Inventors: Rajaram Sankarasubramaniam; Sankar Chinnakulandai
Original assignee: Sanmar Speciality Chemicals Limited
Priority date: 2003-09-11
Filing date: 2003-09-11
Publication date: 2005-03-17
Also published as: AU2003269486A1

Abstract

Nisoldipine is prepared by the process according to this invention by cyclocondensing 3-Aminocrotonoic acid isobutyl ester with 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester in the presence of a water immiscible organic solvent such as toluene and an aprotic organic solvent. The reaction product is recovered after refluxing with diisopropyl ether. Water miscible aprotic solvent may be selected from ethers and glycol ethers.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF PURE NISOLDIPINE

TECHNICAL FIELD OF THE INVENTION:

This invention relates to an improved process for the preparation of nisoldipine which avoids formation of by-products during the course of reactions. This results in the production of nisoldipine of high purity. 1,4- Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid methyl, 2-methylpropyl ester otherwise known as Nisoldipine is used as an antihypertensive and antianginal drug.

BACKGROUND ART;

US patent no.3932645, DE 21117573, DE 3222367, US 4154839, EP 7293, WO 9807698 and WO 0047560 disclose the use of 4-aryl-l₅4-dihydro- 2,6-dimethyl-3,5-pyridine dicarboxylic acid assymetric esters as active pharmaceutical compound for cardiovascular treatment. l,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid methyl, 2-methylpropyl ester having International Non-proprietary Name, Nisoldipine is a specific compound falling within the diesters disclosed in the above prior patent publications. Prior art discloses the preparation of nisoldipine by many routes. In a single step process 2-Nitrobenzaldehyde formula I of the reaction scheme I is reacted with methyl acetoacetate (II) and 3-amino crotonoic acid isobutyl ester (III). This reaction yields a lot of undesired by products and as such purification of nisoldipine involves repeated crystallization and chromatographic purification. It is also observed that normal crystallization techniques do not yield the required purity.

This reaction is shown in scheme I

IV

EP 124743, EP 319814 and EP 534520 disclose a two step synthesis process for reducing by product formation. The first step in this process involves condensation of 2-Nitrobenzaldehyde with an acetoacetic ester to produce 2-(2-nitrobenzylidene-3-oxo-butyric acid ester (V). 3-amino-crotonoic acid ester is reacted with the isolated butyric acid of formula (V) to give the corresponding dihydropyridine. Though this route reduces the impurities considerably, it does not avoid contamination fully to enable easy isolation of Nisoldipine of high purity.

It is also observed that relatively high purity is obtained in the preparation of symmetric dihydropyridines by this two step process. However, in the case of assymmetric dihydropyridines, considerable by-product formation is noticed. SCHEME-II (Prior-art)

Thus, it has become necessary to develop reaction scheme which avoids by-product generation. OBJECT OF THE INVENTION:

The object of this invention is to prepare Nisoldipine of very high purity in high yields. The process avoids by-product formation in Hantzsch synthesis of dihydropyridine. Intermediate compound IIIA shown in scheme III is prepared in high yield by the reaction of isobutylacetoacetate with ammonium acetate in isobutanol solvent medium at 60° - 100°C. Intermediate compound of formula VA shown in the following reaction scheme III is prepared by Knoevenagel condensation of 2-nitrobenzaldehyde with methyl acetoacetate in hexane as solvent medium and dibutylamine and acetic acid as catalyst.

Cyclocondensation of compound of the formula VA and IIIA is carried out in a solvent mixture consisting of a water immiscible solvent preferably toluene and an aprotic organic solvent preferably ether and most preferably ethylene glycol ethers. SUMMARY OF THE INVENTION:

This invention relates to an improved process for the preparation of pure Nisoldipine which comprises cyclocondensing 3-aminocrotonoic acid isobutyl ester of formula IIIA with 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester of formula VA in the presence of a water immiscible organic solvent and an aprotic organic solvent with subsequent recovery of nisoldipine from the reaction mixture in a known manner.

This reaction may be carried out at a temperature ranging from 60°C to 110°C. The ratio of toluene to water miscible aprotic solvent ranges from 30% of toluene to 70% water miscible aprotic solvent to 90% toluene to 10% of aprotic solvent. The present process results in highly pure nisoldipine under milder reaction conditions and easy work up procedure. After distillation of solvent from the reaction mixture, diisopropyl ether is added under reflux. The product is obtained by cooling and filtering the reflux mixture.

3-Aminocrotonoic acid isobutyl acetoacetate of the formula IIIA is prepared by reacting isobutyl acetoacetate with isobutanol and ammonium acetate.

2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (VA) is prepared by reacting 2-nitrobenzoldehyde with methyl acetoacetate. DESCRIPTION OF PREFERRED EMBODIMENTS:

The improved process of this invention will be described with reference to the following example.

Preparation of 3-Aminocrotonoic acid isobutyl ester (Formula IIIA)

500g (3.161mole) of isobutyl acetoacetate is added to stirred isobutanol (3 L). To this 487g (6.32mole) of ammonium acetate was added and heated to 90-100°C. The reaction mixture is maintained at a temperature of 90-100°C for 6-10 hours. The solvent was distilled under vacuum leaving a thick mass of the product. The product is distilled using high vacuum giving 400g of 3- Aminocrotonoic acid isobutyl ester as a colorless liquid, which on cooling solidified to a crystalline solid. (G.C.Purity>99). NMR and IR confirmed product. NMR (CDC1₃):0.99 (6H, d), 1.93 (1H, m), 1.935(3H,s), 3.82 (2H, d), 4.58 (1H, s), 7.93 (2H, bs); IR (KBr): 3439,3336,1659, 1621, 1560.

2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (VA)

lOOg of 2-Nitrobenzaldehyde (0.6623 mole) is suspended in 1 litre of hexane. Under stirring 76g of methyl acetoacetate (0.6623 mole) is added and heated to 50-55°C. To this reaction mass was added lOg of dibutyl amine lOg of and acetic acid. The reaction mixture is refluxed and water was collected using Dean-Stark apparatus. After 7 hours the hexane was distilled off completely and the residue was crystallized from isopropanol. The product on isolation and drying gave 120g of pure product which is having a purity of >99%. NMR and IR confirmed product. NMR (CDC1₃):2.49 (3H, s), 3.61 (3H, s), 7.45 (IH, m), 7.63 (2H, m), 8.08 (IH, m), 8.24 (IH, m);IR (KBr): 1736, 1724, 1522, 1244.

Nisoldipine:

50g (0.2 mole) of 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester and 31.5g (0.2 mole) of 3-aminoisobutylcrotonate were mixed in a 300 ml solvent mixture of toluene and dimethoxymethane (1 :1) in a one litre round bottom flask under nitrogen atmosphere. The reaction flask is connected to a Dean- Stark apparatus and heating was given to raise reaction mass to a temperature of 80-105°C. Water was removed from time to time. The reaction was carried out from 15-25 hours. After the completion of the reaction the solvent was distilled off completely. To the residue after distillation was added diisopropyl ether (400ml) and refluxed for one hour. The reaction mixture is cooled to 10- 20°C and the product is filtered to give a solid, which is washed with 50 ml of isopropyl ether to give 48g of Nisoldipine after drying. HPLC purity:99.69%; m.p.l51-152°C. Nisoldipine is identified by 1H NMR (CDC1₃):0.685(3H, d), 0.75(3H, d), 1.86 (IH, m), 2.26 (3H, s), 2.33 (3H, s), 3.55 (3H, s), 3.78 (2H, m), 5.74 (IH, s), 5.82 (IH, s), 7.22 (IH, m), 7.42 (IH, m), 7.51 (IH, m), 7.66 (IH, m); IR(KBr):3333,2967,1706,1656,1531,1240.

Claims

CLAIMS:

1. An improved process for the preparation of pure Nisoldipine which comprises cyclocondensing 3-aminocrotonoic acid isobutyl ester with 2- (2-nitro benzylidene)-3-oxo-butyric acid methyl ester in the presence of a water immiscible organic solvent and an aprotic organic solvent with subsequent recovery of nisoldipine from the reaction mixture in a known manner.

2. The process as claimed in claim 1, wherein the solvent mixture for carrying out said cyclocondensation is toluene and ether, preferably ethylene glycol ether.

3. The process as claimed in claims 1 and 2 wherein said solvent ratio ranges from 30% of toluene to 70% of water miscible aprotic solvent to 90% toluene to 10% water miscible solvent.

4. The process as claimed in claims 1 to 3, wherein said cyclocondensation is carried out at 70°C to 105°C.

5. The process as claimed in claims 1 to 4, wherein the water miscible organic solvent is dimethoxy ethane, diethoxy ethane, diethylene glycol dimethyl ether and diethylene glycol diethyl ether.

6. The process as claimed in claims 1 to 5 wherein the cyclocondensation product refluxed with diisopropyl ether to remove a unreacted starting materials before crystallization of nisoldipine.

7. The process as claimed in claims 1 to 6 wherein said 3-aminocrotonoic acid isobutyl ester of the formula IIIA is prepared by reacting isobutyl acetoacetate with isobutanol and ammonium acetate.

8. The process as claimed in claims 1 to 6 wherein said 2-(2- nitrobenzylidene)-3-oxo-butyric acid methyl ester of formula (VA) is prepared by reacting 2-Nitrobenzaldehyde with methyl acetoacetate in the presence of dibutylamine and acetic acid catalyst.