JPH0951799A - Process for producing optically active 1,4-dihydropyridine derivative - Google Patents

Abstract

(57) [Summary] [Structure] General formula (I): (In the formula, R ¹ represents a hydrogen atom or a methyl group. R ² represents 2
A cyanoethyl group, a 2-acetoxyethyl group, a 2-hydroxyethyl group, an alkoxycarbonylmethyl group, and a carbamoylmethyl group), and an asymmetric dihydropyridine compound represented by the general formula (II): X (CH ₂ ) _n OH (here And n represents an integer of 1 to 10, X represents a halogen atom or a hydroxyl group),
By reacting in the presence of an enzyme, the compound of the general formula (III): A method for producing an optically active 1,4-dihydropyridine compound represented by (wherein R ¹ , X and n are as described above). An object of the present invention is to provide a method for industrially producing an optically active dihydropyridine derivative having high optical purity.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active 1,4-dihydropyridine derivative useful as a cardiovascular drug such as an antihypertensive agent and a vasodilator.

[0002]

The pharmacological activity of an optically active 1,4-dihydropyridine derivative is represented by the following formula:

Embedded image 4 [[(S) -2-hydroxy-3-phenoxypropyl] amino] butyl methyl 2,6-dimethyl [(S) -4- (m-nitrophenyl)]-1,4 represented by
-Dihydropyridine-3,5-dicarboxylate (Y
It has been reported that M-430) has both calcium antagonistic action and β-blocking action and is useful as an antihypertensive agent and a therapeutic agent for angina (JP-A-60-15667).
1).

The following formula useful as a synthetic intermediate for this compound

Embedded image A conventional synthetic method of methyl alkyl (4S) -1,4-dihydropyridine-3,5-dicarboxylate represented by is a method by optical resolution (Chem. Pharm. B
ull., 28 , 2809-12 (1980), J. Med. Chem., 29 , 2504-
11 (1986)), a method by asymmetric synthesis (Tetrahedron Let
t., 29 , 6437-6440 (1988), J. Med. Chem., 29 , 1696-
1702 (1986)), enzymatic method (Tetrahedron Lett.,
32 , 5805-5808 (1991), JP-A-6-107636, 6-41075).

[0004]

In the above-mentioned production method by optical resolution, an equal amount of optically active compound is required, and the resolution efficiency is very poor. The production method by asymmetric synthesis requires a long synthesis step and also requires an equal amount of an optically active compound in the asymmetric reaction step. Further, the conventional enzyme-based production method requires a large number of reaction steps because it has a special structure as a substrate. Further, several steps were required to induce the above-mentioned dicarboxylate.
Therefore, it is necessary to prepare methyl alkyl (4S) -1,4-dihydropyridine-3,5 necessary for producing an optically active 1,4-dihydropyridine derivative useful as the above drug.
-A more efficient method for producing dicarboxylates has been desired.

[0005]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have studied various enzymes capable of performing an asymmetric transesterification reaction between an asymmetric 1,4-dihydropyridine derivative and alcohols, and as a result, several The inventors have found that certain proteases have high activity for asymmetric transesterification reactions and completed the present invention.

The present invention has the general formula (I):

Embedded image (In the formula, R ¹ represents a hydrogen atom or a methyl group. R ² represents 2
A cyanoethyl group, a 2-acetoxyethyl group, a 2-hydroxyethyl group, an alkoxycarbonylmethyl group, and a carbamoylmethyl group), and an asymmetric dihydropyridine compound represented by the general formula (II): X (CH ₂ ) _n OH (wherein n represents an integer of 1 to 10, X represents a halogen atom or a hydroxyl group, and is reacted with an alcohol represented by the general formula (III):

[Chemical 6] (Wherein R ¹ , X, and n are as described above), and is a method for producing an optically active 1,4-dihydropyridine derivative.

[0007]

DETAILED DESCRIPTION OF THE INVENTION The present invention is described in detail below. In the general formula (I), the alkoxycarbonyl group means a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isobutoxycarbonyl group, a t-
Represents a butoxycarbonyl group and the like. Among the asymmetric dihydropyridine derivatives represented by the general formula (I) which are substrates of the present invention, those in which R ¹ is a methyl group can be synthesized by a conventionally reported conventional method (Japanese Patent Laid-Open No. 50-101365). .
Further, among the asymmetric dihydropyridine derivatives represented by the general formula (I), those in which R ¹ is a hydrogen atom can be obtained by hydrolyzing only one ester group of a corresponding symmetrical ester using an equivalent amount of a base.

The enzyme used in this reaction includes an asymmetric 1,4-dihydropyridine derivative represented by the above general formula (I) and an optically active 1,4-diamine represented by the above general formula (III).
Any enzyme may be used as long as it has an activity of producing a dihydropyridine derivative.
llus) and Aspergillus genus. These are Alcalase, SP539, Subtilisin A (above Novo Co.), Protease-type VIII, XXIII, X.
It is commercially available as XIV, XXXI (above Sigma), protease K, pronase (above Boehringer), prozyme, protease K (above Amano Pharmaceuticals). Of these, it is preferable to use alcalase which has sufficient activity and is extremely inexpensive. These enzymes can be used in both crude and purified products. It is also possible to use bacterial cells that produce the enzyme. The amount of enzyme used is 0.01 to 10 times by weight, preferably 0.1 to 5 times by weight that of the substrate.

The reaction is usually 0 to 50 ° C., preferably 1
The reaction is performed at a temperature range of 0 to 40 ° C. for 1 to 72 hours. The reaction system may be stirred or may be shaken with a usual shaker. Even if these proteases are used as they are,
It may be used by supporting it on an appropriate simple substance. This reaction is carried out in an aqueous solution, but it is desirable to add salts having a buffering effect to the system in order to adjust the pH to the optimum pH for the enzymatic reaction. The amount of water used with respect to the substrate is 2-500 times by weight, preferably 10-200 times by weight, more preferably 20-150 times.
It is twice the weight. As salts having a buffering action, a combination of potassium dihydrogen phosphate-disodium hydrogen phosphate (phosphate buffer), a combination of tris (hydroxymethyl) aminomethane-dilute hydrochloric acid (Tris buffer)
And the like. The amount of each salt added was 0.
It is 1 g to 100 g, preferably 1 g to 10 g. In addition, an organic solvent other than alcohol or a surfactant can be added to enhance the solubility of the reaction substrate and improve the reactivity. As the organic solvent, dimethylformamide (DMF), dimethylsulfoxide (DMSO),
Acetone etc. can be mentioned, and the addition amount is 0.1 to 50.
%, Preferably 1 to 20%, more preferably 2 to 10%
It is. As the surfactant, nonionic surfactants are preferable, and specific examples thereof include polyoxyethylene castor oil ethers, and the addition amount is 0.00
It is 1 to 10%, preferably 0.01 to 0.1%.

This reaction can also be carried out in a two-phase system by adding an organic solvent having low water solubility to the reaction aqueous solution. The organic solvent used here is tetrahydrofuran (THF)
And the like, and hydrocarbons such as toluene and cyclohexane. The amount used is 0.1 to 0.1%
It is 10 times, preferably 0.2 to 5 times. The amount of alcohol represented by the general formula (II) added as a reagent for transesterification reaction is 1 to 500 equivalents, preferably 10 to 40 equivalents relative to the substrate. As for the addition method, they may be added all at once at the start of the reaction, or may be added sequentially within the reaction time.

The post-processing is as follows. After the enzymatic reaction,
An alkaline compound such as sodium hydroxide is added to the system to hydrolyze the unreacted substrate into the corresponding monocarboxylic acid. From the mixed aqueous solution of the target substance and monocarboxylic acid, the target substance is extracted with toluene, chloroform, methylene chloride or the like. Furthermore, the reaction product may be recrystallized by a conventional method,
It can be produced by liquid chromatography.

Hereinafter, the present invention will be described more specifically with reference to Examples and Reference Examples, but the scope of the present invention is not limited to the following Examples.

[0013]

【Example】

Reference Example 1 2-Cyanoethyl methyl 1,4-dihydro-2,
6-dimethyl-4- (3-nitrophenyl) -3,5-
Synthesis method of pyridinedicarboxylate (compound of general formula (I), R ¹ = methyl group, R ² = 2-cyanoethyl group) m-benzaldehyde (12 g, 79.4 mmol),
Methyl aminocrotonate (9.66g, 84mmo
l), 2-cyanoethyl acetylacetonate (13
g, 84 mmol) was dissolved in 12 ml of isopropanol and heated to reflux at 80 ° C. for 4 hours. After cooling, the reaction solution was concentrated and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to give 2
-Cyanoethyl methyl 1,4-dihydro-2,6-
25 g (64.9) of pale yellow crystals of dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate.
mmol, yield 87%). mp 135.0-135.5 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.34 (s, 6H),
2.64 (t, 2H, J = 6.3 Hz), 3.62
(S, 3H), 4.26 (t, 2H, J = 6.3H
z), 5.10 (s, 1H), 6.16 (s, 1H),
7.32-8.24 (m, 4H)

Reference Example 2 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5-cyanoethyloxycarbonyl-3
-Synthesis method of pyridinecarboxylic acid (general formula (I), R ¹ = hydrogen atom, R ² = 2-cyanoethyl group compound) m-benzaldehyde (12 g, 79.4 mmol),
2-Cyanoethyl acetylacetonate (26 g, 1
68 mmol) was dissolved in 12 ml of isopropanol and heated to reflux at 80 ° C. for 4 hours. After allowing to cool, the reaction solution was concentrated and the resulting residue was added with 100 ml of acetone and 1N KOH.
82 ml was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with diluted hydrochloric acid, the reaction product was extracted with ethyl acetate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to give 1,4-dihydro-2,6-dimethyl-4- (3-.
Nitrophenyl) -5-cyanoethyloxycarbonyl-3-pyridinecarboxylic acid pale yellow crystal 20.6 g (5
5.6 mmol, yield 70%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.36 (s, 6H),
2.74 (t, 2H, J = 6.3 Hz), 3.64
(S, 1H), 4.26 (t, 2H, J = 6.3H
z), 5.12 (s, 1H), 7.34-8.2 (m,
4H)

(Example 1) 2-Cyanoethyl methyl
1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate
1.0 g (2.6 mmol), Protease XXIII 5 g,
4-chlorobutanol (12.5 ml) and 50 ml of dimethyl sulfoxide were mixed with 0.2 M phosphate buffer (pH =
7.8, 100 ml) and stirred at 30 ° C. for 44 hours. 1N NaOH solution (5 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. After the reaction mixture was extracted with toluene, the organic phase was washed with a saturated aqueous sodium carbonate solution and then with water, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate =
7: 3) and (S) -4-chlorobutyl methyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate 0.49 g (1 .17 mmol, yield 45%) was obtained as pale yellow crystals. The optical yield is determined by the column for separation of optical isomers (U
It was 99% ee or more as determined by comparison with a standard separately synthesized by a known method (Yamanouchi Pharmaceutical Co., Ltd. Tokuhei 3-388) by high performance liquid chromatography using LTRON ES-OVM). Specific rotation [α] _D = + 18.0 ^° (C = 0.32, acetone, 25 ° C.) mp 126-127 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.65-1.8 (m,
4H), 2.35 (s, 3H), 2.40 (s, 3)
H), 3.50 (t, 2H, J = 9.1 Hz), 3.6
6 (s, 3H), 3.97-4.15 (m, 2H),
5.12 (s, 1H), 5.75 (s, 1H), 7.4
0 (t, 1H, J = 14Hz), 7.64 (d, 1H,
J = 14 Hz), 8.05 (d, 1H, J = 14H
z), 8.15 (m, 1H) The reaction formula of Example 1 is shown below.

[0016]

[Chemical 7]

(Examples 2 to 6) The same reaction as in Example 1 was performed except that only the enzyme was changed. The results are shown in Table 1.

[0018]

[Table 1]

(Embodiments 7 to 10) In Embodiment 1, 4-
The same reaction was performed except that only chlorobutanol was replaced. The reaction formula is shown below, and the results are shown in Table 2.

[0020]

Embedded image

[0021]

[Table 2] a) Enzyme uses alcalase

(Embodiments 11 to 15) In Embodiment 1, 2
-Cyanoethyl methyl 1,4-dihydro-2,6-
The same reaction was performed by changing only dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate. The reaction formula is shown below, and the results are shown in Table 3.

[0023]

Embedded image

[0024]

[Table 3] a) After converting R ¹ into a methyl group, the optical purity was measured.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroaki Tan 6-1-2 Waki, Waki-cho, Kuga-gun, Yamaguchi Prefecture, Mitsui Petrochemical Industries, Ltd. 6-1-2, Mitsui Petrochemical Industry Co., Ltd.

Claims (1)

[Claims] 1. A compound of the general formula (I): (In the formula, R ¹ represents a hydrogen atom or a methyl group. R ² represents 2
A cyanoethyl group, a 2-acetoxyethyl group, a 2-hydroxyethyl group, an alkoxycarbonylmethyl group, and a carbamoylmethyl group), and an asymmetric dihydropyridine compound represented by the general formula (II): X (CH ₂ ) _n OH (wherein n represents an integer of 1 to 10, X represents a halogen atom or a hydroxyl group, and is reacted with an alcohol represented by the general formula (III): A method for producing an optically active 1,4-dihydropyridine derivative represented by (wherein R ₁ , X, and n are as described above).