JPH08217749A - New production of nicardipine hydrochloride and new synthetic intermediate - Google Patents

Abstract

PURPOSE: To obtain the subject compound useful as an antihypertensive, an anticonvulsant, etc., in a high purity and in a good yield by reacting a specific methyl acetoacetate derivative with β-amino-crotonate ester and subsequently reacting the obtained compound with an acid catalyst. CONSTITUTION: (A) Highly pure methyl 2-(3'-nitrobenzylidene)acetoacetate ester not containing an acid as an impurity is reacted with (B) β-(N-benzyl-N- methylamino)ethyl K&B-amino-crotonate ester, and the obtained 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 3-methyl ester is reacted with an acid catalyst to obtain the objective compound.

Description

Detailed Description of the Invention

The present invention relates to 2,6-dimethyl-4, which is useful as an antihypertensive agent.
-(3'-Nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5-
The present invention relates to a novel method for producing β- (N-benzyl-N-methylamino) ethyl ester hydrochloride (hereinafter referred to as nicardipine hydrochloride) and a useful novel synthetic intermediate.

[0002]

2. Description of the Related Art Nicardipine hydrochloride has vasodilatory action, hypotensive action and antispasmodic action and is known to be useful as an antihypertensive agent, antispasmodic agent and vasodilator, particularly coronary and cerebral vasodilator ( (See Japanese Patent Publication No. 55-45075 and Japanese Patent Publication No. 56-6417). Conventionally, nicardipine hydrochloride has been manufactured by (1) 2- (3′-nitrobenzylidene)
Acetoacetic acid methyl ester (hereinafter abbreviated as BM)
And β-amino-crotonic acid β- (N-benzyl-N-
Methylamino) ethyl ester (hereinafter abbreviated as EM) is used as a starting compound, and these are reacted in a solvent under stirring and reflux to obtain nicardipine (cyclization reaction (Han
tzsch reaction)), (2) and then adding an excess amount of hydrochloric acid water after cooling to convert nicardipine to nicardipine hydrochloride (dehydration reaction) (Japanese Patent Publication No. 55-45075).
No. Example 3).

The above-mentioned conventional process has an advantage that nicardipine hydrochloride can be easily produced by carrying out a cyclization reaction and a dehydration reaction in series, but on the other hand, it is produced as a byproduct with the formation of nicardipine. The reaction with water decomposes BM and EM, which are raw material compounds, to give 2,6-dimethyl-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 and other by-products were produced, which also had the drawback of decreasing the yield of nicardipine hydrochloride. . Therefore,
In the conventional process, it is indispensable to separate the by-product and nicardipine, and this separation operation requires technical difficulty and great cost.

[0003]

Against this background, the present inventors have conducted earnest research on a production method capable of synthesizing nicardipine hydrochloride in a simple and high yield. as a result,
In the above-mentioned conventional method, when a high-purity BM containing no acid as an impurity is used as a starting compound, it is a novel intermediate compound which is stable to nicardipine without unexpectedly producing by-product of water. Hydroxy-2,6-dimethyl-4
-(M-Nitrophenyl) -1,2,3,4-tetrahydropyridine-3,5-dicarboxylic acid 5- [2- (N
-Benzyl-N-methylamino) ethyl] ester 3-
It was found that a methyl ester (a compound represented by the following formula (I)) was obtained, and that the intermediate compound (I) could be easily dehydrated by reacting with an acid catalyst and converted into nicardipine. In particular, by adding an equivalent or excess amount of hydrochloric acid to this intermediate compound, the dehydration reaction and the salt formation reaction are carried out in series, and as a result, crystals of nicardipine hydrochloride with high purity are obtained.
The present invention has been completed by finding that it can be obtained in high yield.

[0004]

Embedded image Hereinafter, the novel production method and novel intermediate compound (I) of the present invention
Will be described in detail. In the present production method, by using high-purity BM containing no acid, by-product of water can be suppressed and the intermediate (I) can be obtained in high yield without decomposing BM and EM. By adding hydrochloric acid to this, a dehydration reaction and salt formation are performed, and nicardipine hydrochloride is easily obtained. Therefore, it is not necessary to separate nicardipine, which is essential in the conventional process, from an analog compound derived from a decomposition product of BM and EM, which is generated by hydrolysis with water, and it is simpler and has high purity and high yield. Nicardipine can be obtained. Further, the novel synthetic intermediate compound (I) has a basic amine (formula (I)
During,

[0005]

Embedded image It is considered that there is no intramolecular dehydration, and that it exists stably. The production method of the present invention utilizes the stable property of this intermediate compound (I),
This makes it possible to manufacture nicardipine hydrochloride with high purity and high yield. Below, the process drawing of the manufacturing method of this invention is shown.

[0006]

Embedded image In the above process diagram, the step of reacting the raw material compounds BM and EM to obtain the intermediate compound (I) is usually carried out in a solvent such as acetone, isopropyl alcohol or toluene at room temperature or under heating (preferably 40 to 100 ° C), 1
It is carried out under stirring for 1 to 2 days (preferably about 5 to 24 hours). The intermediate compound (I) can then be easily converted to nicardipine by contact with an acid catalyst. In particular, in the present production method, the dehydration reaction and the salt-forming reaction are carried out in series by adding an equivalent or excess amount of hydrochloric acid, and it is possible to isolate crystals of nicardipine hydrochloride with high purity and high yield. This step is performed under cooling (preferably about 0 ° C.) in a solvent such as acetone with stirring.

[0007]

INDUSTRIAL APPLICABILITY The production method of the present invention is useful as an industrial production method capable of producing nicardipine hydrochloride, which is highly useful as a drug, in a high yield. Further, the novel intermediate compound (I) of the present invention is useful as an excellent synthetic intermediate for synthesizing nicardipine hydrochloride with high purity and high yield.

[0008]

[Examples] Hereinafter, examples of producing nicardipine hydrochloride by the production method of the present invention will be specifically described.

Example 1 (1) To 10 g of methyl 2- (m-nitrobenzylidene) acetoacetate and 9.96 g of 2- (N-benzyl-N-methylamino) -ethyl 3-aminocrotonate, 10 ml of acetone was added, and 55 The reaction was terminated by stirring at 24 ° C. for 24 hours. Acetone was distilled off under reduced pressure, and candy-like 2-hydroxy-2,6-dimethyl-4- (m-nitrophenyl) -1,2,3,4-tetrahydropyridine-3,5-dicarboxylic acid 5 -[2- (N-benzyl-
20 g of N-methylamino) ethyl] ester 3-methyl ester was obtained. Mass spectrum (m / z) FAB-MS: 498 (MH ⁺ ).

[0010]

[Chemical 4]

[0011]

Embedded image

(2) 2-hydroxy-2 obtained in (1),
6-dimethyl-4- (m-nitrophenyl) -1,2,
3,4-Tetrahydropyridine-3,5-dicarboxylic acid 5- [2- (N-benzyl-N-methylamino) ethyl] ester 3-methyl ester 20 g and acetone 8
Add 0 ml to dissolve and add 3.7 ml of concentrated hydrochloric acid at 0 ° C or lower.
, And inoculate the crystal of nicardipine hydrochloride at 0 ℃,
Stir at ℃ for 18 hours. The separated crystals were filtered and dried under reduced pressure to obtain 17.4 g of nicardipine hydrochloride. The physical properties of nicardipine hydrochloride obtained in this step are listed below. Melting point 169 ° (β-type crystal) H-NMR (δ, ppm), DMSO solvent 2.28 (3H), 2.33 (3H), 2.59 (3
H) 3.25 to 3.40 (2H), 3.56 (3H), 4.
10 to 4.35 (2H), 4.40 (2H), 5.00
(1H), 7.40 to 7.65 (7H), 7.90 to
8.00 (2H), 9.30 (1H), 10.8 (1
H)

Claims (2)

[Claims] 1. High-purity 2-containing no acid as an impurity
(3'-Nitrobenzylidene) acetic acid methyl ester and β-amino-crotonic acid β- (N-benzyl-
Reacting with N-methylamino) ethyl ester to give 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 3-methyl ester was prepared and then reacted with an acid catalyst to give 2,6-dimethyl-
4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5
A process for producing nicardipine hydrochloride, which comprises -β- (N-benzyl-N-ethylamino) ethyl ester hydrochloride (nicardipine hydrochloride). 2. 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 3-
Methyl ester