JPH0426675A - Production of 1,4-dihydropyridine derivative - Google Patents

Abstract

PURPOSE:To shorten steps and obtain a compound useful as a coronary vascular agent in high yield by directly reacting the object diester with an alcoholate without protecting the nitrogen in the pyridine ring thereof. CONSTITUTION:Dimethyl 2,6-dimehyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5- dicarboxylate expressed by formula I is reacted with an alcoholate expressed by formula II (M is metal) in the presence of N-benzyl-N-methylamino-ethyl alcohol in dioxane at 20-80 deg.C for 4-24hr to carry out partial ester interchange. Thereby, the objective substance expressed by formula III is obtained. The aforementioned reaction is carried out by dissolving 1mol compound expressed by formula I in 3000-7000vol. dioxane and using 1-8mol alcoholate and 0.2-2mol N-benzyl-N-methylamino-ethyl alcohol. The protection and deprotection of the compound expressed by formula I are not required.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention provides 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5 represented by formula (I). -2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5 represented by formula [111) by reacting dicarboxylic acid dimethyl ester with the alcoholade of formula (II). -dicarboxylic acid 3-methyl ester 5-
The present invention relates to a method for producing β-(N-benzyl-N-methylamino)ethyl ester or a salt thereof.

[Prior art and problems to be solved by the invention] Above [
The 1,4-dihydropyridine derivative represented by the formula (2) or a salt thereof is a compound useful as a coronary vascular agent, and the following methods are conventionally known as methods for producing it.

(1) Method according to Japanese Patent Publication No. 55-4.5075 [
2-(3'-nitropenzylidene) acetoacetate represented by IV) and the acetoacetate represented by formula (V) are reacted with ammonia, or the compound of formula [IV] and the acetoacetate represented by formula (Vl) are reacted. By reacting β-aminocrotonic acid ester, the formula [■'] (in the formula, one of R1 and R2 is a methyl group and the other is an N-
Benzyl-N-methylaminoethyl group).

(2) Method according to Japanese Patent Publication No. 56-6417 The above formula [
By reacting the acetoacetate represented by the formula [m') (R
and R2 are as described above).

(3) Method according to Japanese Patent Publication No. 56-11702 1 represented by the above formula [■] (wherein X represents halogen),
A method for obtaining a compound of formula [my) by reacting a 4-dihydropyridine derivative with N-benzyl-N-methylamine.

In all of the above methods, since the target compound of formula [■] is an asymmetric diester, roundabout reactions are carried out to avoid side reactions, and the yields are also unsatisfactory.

(4) Method according to Japanese Patent Publication No. 59-30704 [1
'] (wherein R is a protecting group) A method for obtaining a compound of formula Cm3 by reacting a compound of formula [ff] with a protected form of the compound of formula [I].

Although the method of this publication is said to involve reacting the compound of formula [I'] with an amino alcohol, the specification states that the alcohol is an alkali metal alcoholade, that is, the compound of formula (I') is reacted with an amino alcohol.
It is described that it is preferable to use the compound I) in the reaction, and as described below, in the examples, the amino alcohol is changed to alcoholade, and the reaction is carried out in the absence of alcohol.

However, this method involves protecting the N atom of the 1,4-dihydropyridine ring of the compound of formula [■], reacting with the compound of formula (II), and finally removing the protecting group.
The process is complicated. In addition, the method for obtaining the same compound as the target substance of the present invention described in this publication is described in Example 4.
However, it uses benzene as a solvent,
1 m of N-benzyl-N-methylaminoethanol
Q (0,006 mol) with 60% oily sodium hydride 3
00■ (0,0075 mol) is added to convert the alcohol into alcoholade, thus converting alcoholade and 1-nitoxymethyl 2,6-dimethyl-4-(m
-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid dimethyl ester 800mg (0,
According to this method, the desired product can be obtained. However, if the compound of formula [11] is directly subjected to reaction without protection, instead of the method shown in this publication in which the compound of formula [I] is once protected and then subjected to the reaction, the experimental results described later As shown, the reaction does not proceed well when the solvent is benzene;
In addition, the reaction does not proceed well even in the absence of alcohol, that is, N-benzyl-N-methylaminoethanol,
The target product of formula (III) cannot be obtained.

(5) Method according to West German Patent Publication No. 2928022 This method uses a compound of formula CI) and N-benzyl N-methylaminoethanol as a catalyst, using an aluminum alkoxide, preferably aluminum isopropoxide, and a non-polar solvent as a solvent. The reaction is carried out using a hydrocarbon, preferably toluene.

However, in this method, the compound of formula (1) is difficult to dissolve in nonpolar solvents, and the reaction is carried out in a suspended state, which requires harsh conditions and also requires distillation of by-product methanol to azeotrobic. This method is industrially disadvantageous, and according to studies by the present inventors, the desired product of formula [■] cannot be obtained by this method.

The present invention has been made in view of the above circumstances, and provides a method for efficiently and industrially advantageously obtaining the target compound of formula (nT) by directly reacting a compound of formula (13) with a compound of formula (U) without protection. The purpose is to provide

[Means and effects for solving the problem] The present inventors,
As a result of intensive studies to achieve the above objective, we found the formula (I
) is partially transesterified by reacting the alcoholade of dioxane Nakata [11) in the presence of N-benzyl-N methylaminoethyl alcohol,
It was discovered that the target product of formula (III) can be obtained industrially advantageously, and the present invention was completed.

(In the formula, M represents a metal atom such as sodium, potassium, calcium, etc.) To synthesize the target diester CI) which is the starting material of the present invention, a lower alcohol, preferably methanol, ethanol, isopropanol 200, etc. is used as a solvent. Yo~3
Using 0.00 volume, 2.5 moles of methyl acetoacetate, 1 mole of m-nitrobenzaldehyde and about 1.3 moles of ammonium hydrogen hydrogen acid were mixed at 60°C to 75°C, preferably 70°C to 74°C, with stirring. 10 hours, preferably 6~
After reacting for 8 hours, the reaction mixture is allowed to cool, whereby the desired diester CI) is obtained as precipitated crystals. The target diester (1) obtained as described above can be used as it is in the next transesterification reaction, but if necessary, it can also be purified by recrystallization from acetone and used in the next reaction.

To partially transesterify the target diester (11) obtained as above, add 3000 to 70 vol of dioxane.
Dissolve 131 mol of the target diester in 0.00 volume, add 1 to 8 mol, preferably 1.5 to 3 mol of alcoholade [■], and 0.2 to 2 mol, preferably 0.8 to 1.2 mol.
Add mol of N-benzyl-N-methylaminoethyl alcohol and stir at 20-80°C, preferably 3o-40°C.
The reaction is carried out under stirring for ~24 hours, preferably 8 to 12 hours, and the reaction solution is then treated with conventional chemical operations such as extraction and column chromatography to isolate the desired product.
If necessary, this is converted into a suitable inorganic or organic salt by a conventional method.

In addition, as the alcoholade used at this time, sodium alcoholade, potassium alcoholade, and calcium alcoholade are suitable.

Next, examples of the present invention will be shown, but the present invention is not limited by the following examples unless it departs from the gist thereof.

〔Example〕

15.5g of ammonium hydrogen carbonate in 40mQ of methanol
(0,196 mol) and acetoacetic acid methyl ester4.
3.2 g (0,372 mol) and 22.5 g (0,149 mol) of m-nitrobenzaldehyde were added, and the mixture was reacted with stirring at 72 to 74° C. for 8 hours. The reaction mixture was left at room temperature overnight, and the precipitated crystals were collected and washed with methanol.
Dry under reduced pressure to obtain 2,6-dimethyl-4-(3'-nitrophenyl)-1,4 dihydropyridine-3,5-dicarboxylic acid dimethyl ester crystals 44. I got og. Recrystallize from acetone if necessary. Melting point: 214°C.

Next, 3.46 g (0.01 mol) of the above compound was dissolved in 35 g of dioxane, and sodium N-benzyl-N
3.75 g (0.02 mol) of -methylaminoethoxide and 16.5 g (0.1 mol) of N-benzyl-N-methylaminoethyl alcohol were added and reacted at room temperature for 8 hours. The reaction solution was poured into water and extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the oily residue was subjected to silica gel column chromatography. Elute with a chloroform-methanol mixture (volume ratio 100:1), collect the eluate containing the target product, and evaporate the solvent to obtain 2,6-dimethyl-4-(
3'-ditrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid 3-methyl ester 5-β-(N
-benzyl-N-methylamino)ethyl ester 2.1
5g was obtained.

Further, if necessary, after introducing hydrogen chloride in chloroform, the solvent is distilled off and recrystallization from acetone is performed to obtain the hydrochloride. Melting point 168-170°C (hydrochloride).

Infrared absorption spectrum 1-Characteristic absorption (■-1): 336
0.3240, 3150, 3060°2940.279
0,2580.1G90°1640, 1620 Nuclear magnetic resonance absorption spectrum (base) (deuterochloroform)
(δ+PP”)' 34 (6H,S,C2,5-CH5).

62 (2H, t, -CH, N<).

50 (2H,s, -Cdan2-C6H9)63 (3H
, s, COOCH3).

17 (2H, t, -COOCH2-) 17 (LH,
s, C4-H).

14 (LH, s, >N-H) (base): M/e=479 Next, in order to clearly demonstrate the effects of the present invention, the following experiment was conducted.

[Experiment 1] N-benzyl-N-methylaminoethanol ld (0
,006 mol) in benzene 4d and diluted to 60% at room temperature.
300 μ (0,0075 mol) of oily sodium hydride was added and stirred for 30 minutes. Add 69% of 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester to this solution.
3 (0,002 mol) was added and stirred at room temperature for 2 hours.

After the reaction was completed, the solvent was distilled off and subjected to column chromatography using chloroform:acetone as an eluent. Dihydropyridine-3,5-
Dicarboxylic acid dimethyl ester 3.04g (recovery rate 8
7.9%) were recovered. The others were impurities, and the target product of the present invention could not be obtained.

[Experiment 2] The treatment was carried out in the same manner as in Experiment 1 except that the reaction time was extended from 2 hours to 6 hours, but the raw material compound 2,6-dimethyl-4-
(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester 2.91 g
(recovery rate 84.1%) was recovered (others are impurities)
However, the object of the present invention could not be obtained.

[Experiment 3] 1.65 g of N-benzyl-N-methylaminoethanol
(0.1 mol) was dissolved in dioxa') 35 mii, and after adding 0.46 g (0.02 mol) of metallic sodium, the mixture was heated to reflux with stirring. After the reaction, return to room temperature,
2,6-dimethyl-4-(3'nitrophenyl)-1,
3.46 g (0.01 mol) of 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester was added, and 2
After stirring for 4 hours, 1.15 mQ (0.02 mol) of acetic acid was added to stop the reaction.

In addition, in the experiment described in Section 2, the same operation was performed except that benzene and toluene were used as the solvent instead of dioxane.

Furthermore, in the above experiment, using each of the above solvents, Experimental Example 1
In the same manner as above, all N-benzyl-N-methylaminoethanol was replaced with alcoholade, and the same operation was carried out in the absence of N-benzyl-N-methylaminoethanol.

Table 1 shows the results obtained in the above experiment (yield or recovery rate of the target substance and raw material compound of the present invention by high performance liquid chromatography).

Table 1 *N-benzyl-N-methylaminoethanol The analysis conditions are as follows.

Standard solution in analytical hole: Methanol solution of propyl paraoxybenzoate (3→5
000) Add methanol/water mixture (1:1) to 1mQ to make 10ml Detector: Ultraviolet absorption photometer (measurement wavelength 254nm) Column: 5mm in stainless steel tube with inner diameter of 6mm and length of about 15an
Fill with μs octadecylsilylated silica gel.

Column temperature: 30°C Mobile phase: Methanol/pH 3,01-sodium pentasulfonate solution (Note 1) mixture (6:4) Flow rate: Adjust so that the retention time of nicardipine hydrochloride is approximately 8 minutes (approximately 1 , 0 mQ/m1n).

(Note 1) Add glacial acetic acid to O, OIM 1-pentasulfonic acid sulfur to lithium solution to adjust the pH to 3.0.

[Experiment 4] 2,6-dimethyl-4-(3'
-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid dimethyl ester 3.4.6g (0
, 01 mol), 1.50 g (0.009 mol) of N-hydroxyethyl-N-methylbenzylamine and 20 d of anhydrous toluene were added. Next, 0.15 g of aluminum isopropoxide was added, and the mixture was heated under reflux for 12 hours while stirring. At that time, an azeotropic mixture of methanol and toluene was separated using a rectification column. After the reaction, the mixture was allowed to cool and the precipitate was collected by filtration. When the filtered material was recrystallized from acetone, raw material compounds 2,6
-Simethyl-4-(3'-nitrophenyl)-1,4-
3.12 g (recovery rate 90.2%) of dihydropyridine-3,5 dicarboxylic acid dimethyl ester was recovered. The others were inert substances such as raw materials, and the target substance of the present invention could not be obtained.

[Experiment 5] The same procedure as in Experiment 4 was carried out except that 0.41 g of sodium N-benzyl-N-methylaminoethoxide was added instead of 0.15 g of aluminum isopropoxide, but the raw material compound 2,6-dimethyl-4- (3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester 2.51 g (recovery rate 72.5
%) (others are impurities such as raw materials),
The target substance of the present invention was not obtained.

From the above results, using dioxane as the solvent and N-
2,6-Simethyl-4-(3
'-nitrophenyl)-1,4-dihydropyridine-3
, 5-dicarboxylic acid dimethyl ester proceeded well and the desired product was advantageously obtained.

〔Effect of the invention〕

According to the present invention, the target diester of formula (I) is directly reacted with the compound of formula [■] without protecting the nitrogen atom of its pyridine ring to obtain the target compound of formula (m) in a good yield. and thus protection of the compound of formula (1),
There is no need for deprotection, the process is shortened, and it is industrially advantageous.

Claims (1)

[Claims] 1. 2,6-dimethyl-4-(3'-nitrophenyl)-1 represented by the formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] , 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester in dioxane [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ... [II] (In the formula, M represents a metal atom) 2,6-dimethyl-4-(2,6-dimethyl-4-(
3'-nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid 3-methyl ester 5-β-(N
A method for producing -benzyl-N-methylamino)ethyl ester or a salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[III]