IE80422B1 - Novel process for producing nicardipine hydrochloride and its novel intermediate compound - Google Patents

Abstract

The invention relates to a novel process for producing 2, 6-dimethyl -4- (3'-nitropheny1) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester 5-ß-(N-benzyl-N-methylamino) ethyl ester hydrochloride, (nicardipine hydrochloride) which is useful for a hypotensive agent, and also to a useful novel intermediate compound for producing it.

Description

NOVEL PROCESS FOR PRODUCING NICARDIPINE HYDROCHLORIDE AND ITS NOVEL INTERMEDIATE COMPOUND This invention relates to a novel process for producing 2,6-dimethyl-4-(3’nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-/3-(N5 benzyl-N-methylamino)ethyl ester hydrochloride (nicardipine hydrochloride) which is useful for a hypotensive agent, and also to a useful novel intermediate compound for producing it.

In more detail, this invention relates to a process for producing 2,6-dimethyl-4(3’-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-Z?10 (N-benzyl-N-methylamino)ethyl ester hydrochloride (nicardipine hydrochloride) which comprises reacting high purity methyl 2-(m-nitrobenzylidene)acetoacetate containing no acid as impurity, with 2-(N-benzyl-N-methylamino)ethyl 3-aminocrotonate ester to obtain 2-hydroxy-2,6-dimethyl-4-(m-nitrophenyl)-1,2,3,4tetrahydropyridine-3,5-dicarboxylic acid 5-[2-(N-benzyl-N-methylamino)ethyl]15 ester 3-methyl ester, and then reacting it with an acid catalyst.

It is known that nicardipine is useful for a hypotensive agent, a spasmolytic agent and a vascular dilator agent, particularly for a coronary dilator agent and a cerebral vascular dilator agent, since it possess vascular dilator activity, hypotensive activity and antispasmodic activity (cf. Japanese patent publication 20 Nos. Sho-55-45075 and Sho-56-6417).

In the prior-art manufacturing method, nicardipine hydrochloride is prepared via reaction steps comprsing (1) a step of reacting methyl 2-(m-nitrobenzylidene)acetoacetate (hereinafter referred to as “BM”) and 2-(N-benzyl-Nmethylamino)ethyl 3-aminocrotonate (hereinafter referred to as EM”) as starting materials while stirring in a solvent under reflux to obtain nicardipine (cyclization reaction(Hanzsch reaction)) and (2) a step of cooling and adding excess amount of aqueous hydrochloric acid to convert nicardipine to nicardipine hydrochloride (dehydration reaction), (cf. Japanese patent publication No. Sho-55-45075, Example 3) The above prior-art manufacturing process has advantage that nicardipine hydrochloride can be produced simply in view of serial reactions of cyclization and dehydration, but has also disadvantage that the starting materials, namely, BM and /or EM, tend to be decomposed by contact with water by-produced at the formation of nicardipine, and as a result, certain by-products such as 2,6dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester and 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid bis[2-(N-benzyl-N-methylamino)ethyl ester are formed, which results in lowering the yield of nicardipne hydrochloride.

Thus, in the prior-art process is absolutely necessary a separating procedre for the by-products and nicardipine, and the separation procedure accompanies technical difficulty leading to a very much increase of the manufacturing cost. Under the above circumstances, the inventors, have conducted extensive studies on the production processes for producing easily and in high yield.

As its result, the inventors have unexpectedly found that, when using as starting materials, high purity BM not containing an acid as impurity in the case of the above prior art method, a novel stable intermediate compound, namely, 2-hydroxy-2,6-dimethyl-4-(m-nitropheny)-1,2,3,4-tetrahydropyridine-3,5dicarboxylic acid 5-[2-(N-benzyl-N-methylamino)ethyl]ester 3-methyl ester (the formula (I) compound shown below) is obtained without the formation of water as by-product, and this intermediate compound (I) can be easily subjected to dehydration reaction in contact with an acid catalyst to give nicardipine. Particularly, the present invention was accomplished on the basis of the finding that, when adding equivalent amount or excess amount of hydrochloric acid to the above intermediate compound, crystals of nicardipine hydrochloride can be obtained in high purity and high yield, as a result of simultaneous reactions of dehydration and salt-forming: HaCOOC H· H0fl3C The novel production process and the novel intermediate compound (I) of the present invention are explained in more detail. in case of the present production process, the by-formation of water is inhibited as a result of using high purity BM containing no acid, and the intermediate compound can be obtained in high yield without decomposition of BM and EM. By adding hydrochloric acid therto, both reactions of dehydration and saltformation are accomplished, which results in the easy obtainment of nicardipine hydrochloride. Thus, the present method need no separating procedure for nicardipine and some impurity compounds derived from decomposition product of BM and/or EM formed by hydrolysis with water, and hence, nicardipine hydrochloride can be obtained in more simply, easily, in high purity and in high yield.

The above novel intermediate compound (I) is considered to be stable, since the ester part of the compound (I) contains amine structure portion of basic character (namely, the portion shown by and so, intramolecular dehydration does not arise. Thus, by taking advantage of the stability characteristic of the intermediate compound (I) in the present invention, it has become possible to produce nicardipine hydrochloride in high purity and in high yield.

I.

The reaction steps of the present invention are given below.

NO, CH H-^COOHaCOOC ... i + Λ HaC^ Q H,N CHa (BM) (EM) CH, CHa NO, ^00 v=/ 'CHa (I) H07^iAcHa HaC H ch,-/A COO-'X/N^ ^=/ 'CH3 HC£ (nicardipine hydrochloride) The step of obtaining the intermediate compound (I) by reaction of BM and EM as the starting compounds is conducted usually in a solvent such as acetone, 5 isopropyl alcohol, toluene, etc., at room temperature or under heating (preferably,at about 40-100°C), under stirring for 1 to 2 days (preferably, for 5-24 hours).

The intermediate compound (I) can be easily converted to nicardipine by contact with acid catalyst. Particularly, in the present production process, both 1 θ dehydration reaction and salt-forming reaction can be conducted together, by addition of equivalent- or excess-amount hydrochloric acid, and crystals of nicardipine hydrochloride can be separated and obtained in high purity and in high yield. This crystallization step is conducted under cooling (preferably, at about 0°C), while stirring in a solvent such as acetone.

The production process of the present invention is useful for a industrially excellent production method, since nicardipine hydrochloride(a highly useful medicine) can be produced in high purity and high yield, even without using a chloroalkyl type solvent.

The intermediate compound (I) of the present invention is also useful as an excellent intermediate for producing nicardipine hydrochloride in high purity and high yield.

(Examples) The production process of nicardipine hydrochloride by the present invention is specificcaly explained by illustrating the following Example.

Example 1 (1) To 10 g of methyl 2-(m-nitrobenzylidene)acetoacetate (BM) and 9.96 g of 2(N-benzyl-N-methylamino)ethyl 3-aminocrotonate -(EM) was added 10 ml of acetone followed by stirring at 55°C for 24 hours to complete the reaction. Acetone was distilled off under reduced pressure to give 20 g of 2-hydroxy-2,6dimethyl-4-(m-nitrophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylic acid 5-[2(N-benzyl-N-methylamino)ethyl]ester 3-methyl ester as viscous material.

Mass spectrum (m/z) FAB-MS:498 (MH+) a 'HNMR : (o, ppm), DMSO Position major minor 3 2, 61 Cd. J = 12. 2Hz) 2. 88 (d, J=6. 7Hz) 4 4. 22 (d, J=12. 2Hz) 4, 09 (overlapped) 7 1. 39 (s) 1. 31(s) 8 2. 22 (s) 2. 29(s) 11 3. 43 (s) 3. 51(s) 13 7. 51(m) 7. 52 (m) 14 7. 42 (m) 7. 44 (n>) IS 7. 96 (m) 7. 95 (m) 17 7. 89 (m) 7. 89 (m) 20 3. 62 (m), 3. 69 (m) 3. 79 (m) 21 2. 00 (t, J=6. 7Hz) 2. 09 (m) 23 1. 96 (s) 1. 93(s) 24 3. 43 (d, J=13. 4Hz) 3. 30 (d. J=13. 4Hz) 3. 45 (d, J=13, 4Hz) 3. 35 (d. J=13. 4Hz) 26, 30 7. 20 (m) 7. 17 (m) 27, 29 7. 31(m) 7. 29 (m) 28 7. 23 (m) 7. 23 (m) 1-NH 7. 41(s) 7.39(s) 2-OH 5. 60 (s) 5. 65 (s) '3C NMR (δ,ppm), DMSO Position • major minor 2 76. 7 78. 8 3 58. 2 56. 7 4 40. 4 42. 1 5 94. 7 91. 2 6 151. 6 153.6 7 27. 0 24. 7 8 19. 4 20. 0 9 170. 6 171. 5 11 51. 2 51. 4 12 149. 0 148. 8 13 134. 4 134. 2 14 129. 1 129.0 15 120. 7 120. 5 16 147. 3 147. 3 17 122. 0 121.8 18 166. 4 166.6 20 59. 7 59. 9 21 54. 6 54. 9 23 41. 9 41. 9 24 61. 5 61. 4 25 138. 7 138.8 26. 30 128. 4 128. 4 27. 29 128. 0 128. 0 28 126. 7 126. 7 (2) To 20 g of 2-hydroxy-2,6-dimethyl-4-(m-nitrophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylic acid 5-[2-(N-benzyl-N-methylamino)ethyl]ester 3methyl ester obtained at above (1) was added 80 ml of acetone for solving.The thus obtained solution was mixed with 3.7 ml of cone, hydrochloric acid, and 5 authentic crystals of nicardipine hydrochloride were added for promoting the formation of crystals of the aimed compound at 0°C followed by stirring for 18 hours at 0°C.

Precipitared crystals were collected by filtration, and dried under reduced pressure to give 17.4 g of nicardipine hydrochloride . o The physico-chemcal character of the thus obtained nicardipine hydrochloride is shown below.

Melting point: 169°C(/3 -type crystals)

Claims (5)

Claims

1. 2-hydroxy-2,6-dimethyl-4-(m-nitrophenyl)-1 ,2,3,4-tetrahydropyridine-3,5dicarboxylic acid 5-[2-(N-benzyl-N-methylamino)ethyl]ester 3-methyl ester.

2. A process for producing 2,6-dimethyl-4-(3’-nitrophenyl)-1,4-dihydropyridine5 3,5-dicarboxylic acid 3-methyl ester 5-yS-(N-benzyl-N-methylamino)ethyl ester hydrochloride (nicardipine hydrochloride) which comprises reacting high purity methyl 2-(m-nitrobenzylidene)acetoacetate containing no acid as impurity, with 2-(N-benzyl-N-methylamino)ethyl 3-aminocrotonate to produce 2-hydroxy-2,6dimethyl-4-(m-nitrophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylic acid 5-[2i 0 (N-benzyl-N-methylamino)ethyl] ester 3-methyl ester, and then reacting it with an acid catalyst.

3. A process according to Claim 2 wherein the acid catalyst is hydrochloric acid.

4. A process according to Claim 2 for producing 15 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5dicarboxylic acid 3-methyl ester

5. -β-(N-benzyl-N-methylamino)ethyl ester hydrochloride, substantially as hereinbefore described and exemplified. 20 5. 2,6-Dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridi ne-3,5- dicarboxylic acid 3-methyl ester 5-S-(N-benzyl-N-methylamino)ethyl ester hydrochloride, whenever produced by a process claimed in a preceding claim.