JPH06205686A - Production of optically active 1,4-dihydropyridine compound having selective steric configuration - Google Patents

Abstract

PURPOSE:To synthesize each optically active 1,4-dihydropyridinemonocarboxylic acid compound by selecting an enzymic reactional solvent. CONSTITUTION:Asymmetric synthetic reaction of a prochiral 1,4-dihydropyridine compound is carried out by using an enzyme in the presence of an organic solvent to produce an optically active 1,4-dihydropyridinemonocarboxylic acid compound. In the process, the organic solvent is selected to synthesize the compound having a specific steric configuration. Thereby, the compound satisfactory for both the optical purity and the yield can be synthesized. This compound is an important intermediate for medicines.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention utilizes a stereoselective hydrolysis reaction by selecting an organic solvent to be used in a method for producing an optically active 1,4-dihydropyridine monocarboxylic acid compound by an enzyme in the presence of an organic solvent. And a method for producing the optically active 1,4-dihydropyridine monocarboxylic acid compound.

[0002]

2. Description of the Related Art A method for resolving an optically active 1,4-dihydropyridine derivative has been reported [Chem. Pharmaceutical Bulletin (Chem. Pha.
rm. Bull. ), 37, 2225 (198)
9), [Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull.), 39,
108 (1991) and Journal Medicinal Chemistry (J. Med. Chem.), 29.
Vol. 2504 (1986)].

[0003]

However, the above-mentioned known method cannot be said to be an industrial method because it is not possible to selectively obtain either one of the optically active substances. That is, most of the drugs having a 1,4-dihydropyridine skeleton having an asymmetric carbon atom have been developed as racemates and are currently used as medicines.
It was hoped that the solution would be prompt. The present inventor has studied and completed an asymmetric synthesis method capable of efficiently synthesizing either one of the required optically active substances by asymmetric hydrolysis using an enzyme catalyst.

[0004]

Means for Solving the Problems When the enzyme is reacted in the presence of an organic solvent, by selecting the organic solvent to be used, the compound of the general formula [I]

[0005]

[Chemical 5]

[Wherein X is the following general formula [II]

[0007]

[Chemical 6]

(Wherein R ₁ , R ₂ and R ₃ may be the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, a nitrile group or a trifluoromethyl group) or an alkyl group. , R ₄ is an acyloxymethyl group, an acyloxymethyl group having a substituent, an alkoxycarbonyloxymethyl group, (2-oxo-1,3-dioxolen-4-yl) methyl group, (5-substituted-2-oxo-1 ，
3-dioxolen-4-yl) methyl group or an acyl group, R ₅ represents a lower alkyl group or an alkyl group having a substituent, and R ₆ represents a hydrogen atom, a lower alkoxymethyl group or a lower acyloxymethyl group] The prochiral 1,4-dihydropyridine compound represented by the following formula is stereoselectively hydrolyzed by an enzyme catalyst to give a compound represented by the general formula [III]

[0009]

[Chemical 7]

[Wherein X is the following general formula [II]

[0011]

[Chemical 8]

(Wherein R ₁ , R ₂ and R ₃ may be the same or different and represent a hydrogen atom, a halogen atom, a nitro group, a nitrile group or a trifluoromethyl group) or an alkyl group. , R ₄ is an acyloxymethyl group, an acyloxymethyl group having a substituent, an alkoxycarbonyloxymethyl group, (2-oxo-1,3-dioxolen-4-yl) methyl group, (5-substituted-2-oxo-1 ，
3-dioxolen-4-yl) methyl group or an acyl group, R ₅ represents a lower alkyl group or an alkyl group having a substituent, R ₆ represents a hydrogen atom, a lower alkoxymethyl group or a lower acyloxymethyl group, * Represents an optically active point], and a 1,4-dihydropyridine compound having a specific steric configuration was produced, and the asymmetric yield and the reaction yield were both satisfactory.

The present invention will be described in detail below. In the compounds represented by the above general formulas [I] and [III], X is an alkyl group [for example, a methyl group, a benzyl group, a cyclohexyl group, etc.] or a general formula [II] (in the formula,
R ₁ , R ₂ and R ₃ are a hydrogen atom, a halogen atom, a nitro group, a nitrile group, a trifluoromethyl group or the like, and these may be the same or different. And R ₄ represents an acyloxymethyl group [for example, pivaloyloxymethyl group,
Propylonyloxymethyl group, 1-acetoxyethyl group, etc.], alkoxycarbonyloxymethyl group [for example, 1- (ethoxycarbonyloxy) ethyl group], (2-
Oxo-1,3-dioxolen-4-yl) methyl group,
(5-Substituted-2-oxo-1,3-dioxolen-4-
Il) methyl group [for example, a substituent is a methyl group, ethyl group, etc.] and an acyl group [for example, pivaloyl group, etc.] R ₅ is a lower alkyl group such as a methyl group or an ethyl group or an alkyl group having a substituent [eg, a substituent is fluorine,
Chlorine, hydroxyl group, lower alkoxyl group and the like]. R ₆ represents a hydrogen atom, a lower alkoxymethyl group [eg methoxymethyl group, ethoxymethyl group etc.] and an acyloxymethyl group [eg pivaloyloxymethyl group etc.].

As the enzyme used in the present invention, the optically active 1,4-dihydropyridine monocarboxylic acid represented by the above general formula [III] is converted from the prochiral 1,4-dihydropyridine compound represented by the above general formula [I]. Any enzyme may be used as long as it has an activity to generate, and specific examples thereof include lipase derived from a microorganism belonging to the genus Pseudomonas. More specifically, lipases derived from Pseudomonas cepacia and the like can be mentioned. For example, lipase AH (manufactured by Amano Pharmaceutical Co., Ltd.) and the like can be used. The enzyme to be used may be a crude product or a purified product, and bacterial cells producing these enzymes can also be used.

The reaction of the present invention can be carried out usually within the range of 0 ° C. to the boiling point of the solvent, and it is preferable to carry out so that the enzyme is dispersed in the reaction system.

The reaction of the present invention is usually carried out in an organic solvent containing water, but the steric properties of the product are greatly affected by the type of organic solvent used. For example, when the reaction is carried out in the presence of an ether solvent such as diethyl ether, isopropyl ether, dimethoxyethane, tetrahydrofuran, 2,5-dimethyltetrahydrofuran, dioxane, an S-form product is obtained. In the presence of other solvents such as hexane, heptane, cyclohexane, cycloheptane, cyclooctane, etc.
The body product is given.

After completion of the reaction, the enzyme can be easily removed by a conventional method, for example, filtration using filter paper. The reaction product can be easily purified using diethyl ether, ethyl acetate, dichloromethane or the like when it contains a large amount of water. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

The synthesis of the general formula [I] as a substrate is as follows.
[Tetrahedron Letters (Tetrahedron
Letters, 32, 5805 (199).
1)] or [ibid, 32, 3465 (199)
1)] was followed.

[0019]

【Example】

Example 1 Bis (pivaloyloxymethyl) 1,4-dihydro-2,6 in isopropyl ether (20 ml) saturated with water.
-Dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate (500 mg) was dissolved, Lipase AH (500 mg) was added, and the mixture was stirred at room temperature for 48 hours. The insoluble material was filtered off, washed with dichloromethane, and the filtrate was concentrated under reduced pressure to give pale yellow crystals (344 mg, 87%). [(S) -1,4-dihydro-2,6-dimethyl-
4- (3-Nitrophenyl) -5-piparoyloxymethoxycarbosyl-3-pyridinecarboxylic acid]. The melting points, specific irradiances and various spectral data of the products are shown below.

Mp: 146-148 ℃ (ethyl ace
tate / n-Hexane) [α] _D : + 27.9 ° (c = 0.8, Acetone) IR (nujol): 3340, 1750, 1690cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 1.10 (9H, s, 3 × CH ₃ ), 2.38 (6H, s,
2 × CH ₃ ), 5.09 (1H, s,> CH-), 5.72 (1H, d, J = 5.3Hz, O
CH _A H _B O), 5.76 (1H, d, J = 5.3Hz, OCH _A H _B O), 6.04 (1H, s,
NH), 7.33-7.39, 7.66-7.69, 7.96-8.07 (4H, m, C ₆ H ₄ ).

¹³ C-NMR (CDCl ₃ ) δ: 19.89, 20.04, 26.74
(3 x C), 38.65, 39.19, 79.05, 102.63, 102.84, 121.5
5, 122.77, 128.73, 134.69,146.53, 146.77, 148.42,
148.94, 165.29, 172.21,177.18

(S) -Methylpivaloyloxymethyl-1,4-dihydro-2,6-dimethyl-4- (3) obtained by treating the product with a solution of diazomethane in diethyl ether.
The -nitrophenyl) -3,4-pyridinedicarbochelate was subjected to high performance liquid chromatography with Chiralcel AD (ethanol / hexane = 1/19), and the optical purity was determined to be> 99%.

Examples 2 to 7 Various substrates having different R ₄ substituents of the general formula [I] were subjected to an enzymatic reaction in the same manner as in Example 1 to obtain an optically active monocarboxylic acid. The results of each Example including the results of Example 1 are shown in Table 1.

In the table, the substituent R ₄ of the general formula [I] is P
OM is a pivaloyloxymethyl group, MBOM is an α-methylbutyroyloxymethyl group, IVOM is an isovaleryloxymethyl group, IBOM is an isobutyroyloxymethyl group, BOM is a butyroyloxymethyl group, and PROM is propionyloxy. A methyl group and ACOM represent an acetyloxymethyl group.

[0025]

[Table 1]

Experimental Examples 8 to 12 For the various substrates used in Example 1 and Examples 4 to 7, instead of the water-saturated isopropyl ether of Example 1,
An enzymatic reaction was performed using water-saturated cyclohexane to obtain an optically active monocarboxylic acid. The results are shown in Table 2.

In the table, the substituent R ₄ of the general formula [I] is P
OM is a pivaloyloxymethyl group, IBOM is an isobutyroyloxymethyl group, BOM is a butyroyloxymethyl group, PROM is a propionyloxymethyl group, ACO
M represents an acetyloxymethyl group.

[0028]

[Table 2]

Examples 13 to 18 The same reaction was carried out in various solvents using a substrate in which the R ₄ substituent of the general formula [I] was POM, and the results shown in Table 3 were obtained.

[0030]

[Table 3]

[0031]

As described above, the above general formula [I] of the present invention is used.
In the case of asymmetrically hydrolyzing a prochiral 1,4-dihydropyridine compound represented by by using an enzyme in the presence of an organic solvent, by selecting the type of the organic solvent to be used, the above-mentioned general formula having each configuration is obtained. [III]
It becomes possible to separately prepare the optically active 1,4-dihydropyridine compound represented by, and extremely excellent results were obtained in terms of both asymmetric yield and reaction yield for industrial implementation. According to the present invention, a novel method for developing and providing medical treatment for many 1,4-dihydropyridine drugs, which have been conventionally developed as a racemate and used for medicine as a medicine, as an optically active substance, was found.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Seiji Sasaki 27, Kunotsubo Hanno, Nishiharu-cho, Nishikasugai-gun, Aichi Pref., Central Research Laboratory, Amano Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. A compound represented by the general formula [I]: [Wherein X is the following general formula [II] (In the formula, R ₁ , R ₂ and R ₃ may be the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, a nitrile group or a trifluoromethyl group.) Or an alkyl group, R ₄ Is an acyloxymethyl group, an acyloxymethyl group having a substituent, an alkoxycarbonyloxymethyl group, (2-oxo-1,3-dioxolen-4-yl) methyl group, (5-substituted-2-oxo-1,3- Dioxolen-4-yl) methyl group or an acyl group, R
₅ represents a lower alkyl group or an alkyl group having a substituent, and R ₆ represents a hydrogen atom, a lower alkoxymethyl group or a lower acyloxymethyl group] in the presence of an organic solvent in the 1,4-dihydropyridine compound. When an enzyme is allowed to act, a compound of the general formula [III] [Wherein X is the following general formula [II] (In the formula, R ₁ , R ₂ and R ₃ may be the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, a nitrile group or a trifluoromethyl group.) Or an alkyl group, R ₄ Is an acyloxymethyl group, an acyloxymethyl group having a substituent, an alkoxycarbonyloxymethyl group, (2-oxo-1,3-dioxolen-4-yl) methyl group, (5-substituted-2-oxo-1,3- Dioxolen-4-yl) methyl group or an acyl group, R
₅ represents a lower alkyl group or an alkyl group having a substituent, R ₆ represents a hydrogen atom, a lower alkoxymethyl group or a lower acyloxymethyl group, and * represents an optically active point.]
In the method for synthesizing an optically active 1,4-dihydropyridine compound represented by, a method for selectively synthesizing an optically active 1,4-dihydropyridine compound having a specific configuration by selecting an organic solvent.