JPH0770066A - Optically active dihydropyridine compound and its synthesis - Google Patents

Abstract

PURPOSE:To obtain an optically active dihydropyidine compound useful e.g. as an intermediate for pharmaceuticals, etc., in high yield, purity and efficiency by carrying out transesterification reaction of a specific dihydropyridine compound with a specific alcohol in the presence of an enzyme. CONSTITUTION:A 1,4-dihydrophridine of formula III (* is optically active site) is produced by reacting a 1,4-dihydrophridine compound of formula I [X is group of formula II (R1 to R3 each is H, a halogen, nitro, nitrile or tifluoromethyl); R4 is a substituent easily transesterifiable with an enzyme or under alkaline condition; R5 is a lower alkyl or a substituted alkyl; R6 is H, a lower alkoxymethyl, etc.] in the presence of an alcohol of the formula R7OH (R7 is a <=12C alkyl), thereby performing the transesterification of one of the ester residues. The objective compound of formula IV is produced by further reacting the product with an alcohol of the formula R8OH (R8 is a <=4C alkyl) under alkaline condition to effect the transesterification of the other ester residue. The compound of formula IV is a new compound.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an enzymatic asymmetric synthesis method for optically active 1,4-dihydropyridine derivatives. More specifically, it relates to a method for synthesizing an optically active 1,4-dihydropyridine derivative by combining a transesterification reaction using an enzyme and a transesterification reaction with an alkali.

[0002]

2. Description of the Related Art Reports relating to the synthesis of optically active 1,4-dihydropyridine derivatives are roughly classified into the following three types. One is by utilizing a diastereoselective reaction, in which another compound having an asymmetric carbon atom is introduced into the molecule, and one enantiomer is preferentially obtained diastereoselectively in the synthesis of 1,4-dihydropyridine. , Tamazawa et al. [J. Med. Chem., Vol. 29, 2504]
Page (1986)], and a report by E. Wehinger et al. [JP-A-56-36]
455, JP 61-12663], Kataoka's report [JP 2-21247]
4], Report of Kakuiri et al. [JP-A-63-208573, JP-A-3-2027]
1] etc.

However, the method utilizing diastereomers requires another optically active compound and
The reaction conditions are complicated, neither one can be selectively induced, and the separation operation is complicated.

Another method is a method of obtaining an optically active monocarboxylic acid by utilizing a resolving agent or an enzyme and then conducting esterification to obtain an optically active 1,4-dihydropyridine drug. As a method for obtaining an optically active monocarboxylic acid,
Shinuma et al. [Chem. Pharm. Bull., 28, 2809 (198
0)], Kajino et al. [Chem. Pharm. Bull., 37, 2225 (19
89)], Ashimori et al. [Chem. Pharm. Bull., 39, p. 108 (19
91)] and examples of resolving agents using cinchonidine, cinchonine, etc. and Achinami et al. [Tetrahedron Lett., 32, 5805]
P. (1991), Sih et al. [Tetrahedron Lett., 32, 3465.
(1991)], there is an example of enzymatic asymmetric synthesis. For subsequent esterification of monocarboxylic acid, SoCl ₂ , PCl ₅
Generally, a method of passing through an acid chloride by the method such as However, the optical resolution method using a resolving agent has the drawbacks that the resolving agent is expensive, the number of times of crystallization is required, and the target optically active substance is at most 50%.

The remaining one method utilizes an enzyme-based transesterification reaction, which is described in Adachi et al. [JP-A-4-9999
4] is the only report.

According to this report, although the reaction step is short and the method is efficient, the final compound is limited to a substrate capable of reacting with an enzyme, resulting in lack of versatility.

[0007]

SUMMARY OF THE INVENTION There has been a demand for a versatile synthetic method as a means for efficiently synthesizing optically active 1,4-dihydropyridine.

The present inventor has investigated a novel prochiral 1,4-dihydropyridine compound suitable for an enzyme-catalyzed and base-catalyzed transesterification reaction, and was able to find an efficient asymmetric synthesis method here.

[0009]

Means for Solving the Problems When the 1,4-dihydropyridine compound suitable as a substrate for the enzyme-catalyzed asymmetric synthesis of a transesterification reaction was earnestly studied, the general formula [I]

[0010]

[Chemical 9]

1,4-dihydropyridine compound represented by the formula [wherein X is a general formula [II]

[0012]

[Chemical 10]

(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), and R ₄
Represents a substituent which is easily transesterified under enzyme and alkaline conditions, 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. . ], R ₇ OH
(In the formula, R ₇ may be optionally substituted by a nitrogen atom with a linear, branched or cyclic alkyl group having up to 12 carbon atoms,
Further, the nitrogen atom represents a group which may be substituted with a methyl group or a benzyl group. ) By reacting an enzyme in the presence of an alcohol, the compound of the general formula [III]

[0014]

[Chemical 11]

[Wherein X is a general formula [II]

[0016]

[Chemical 12]

(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), and R ₄
Represents a substituent which is easily transesterified under enzyme and alkaline conditions, 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. , R ₇ is a linear, branched or cyclic alkyl group having up to 12 carbon atoms which may be optionally substituted with a nitrogen atom, and the nitrogen atom may be a group which may be substituted with a methyl group or a benzyl group. Show.
* Indicates an optically active point. ] The 1,4-dihydro pyridine compound represented by these could be obtained.

Further, in the presence of an alcohol represented by R ₈ OH (wherein R ₈ represents an alkyl group having up to 4 carbon atoms, which may be interrupted by oxygen or sulfur atom in the middle). , General formula [IV], which is highly valuable as a drug, because transesterification proceeds at the other ester site under alkaline conditions

[0019]

[Chemical 13]

[Wherein X is a general formula [II]

[0021]

[Chemical 14]

(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), and R ₄
Represents a substituent which is easily transesterified under enzyme and alkaline conditions, 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. , R ₇ is a linear, branched or cyclic alkyl group having up to 12 carbon atoms which may be optionally substituted with a nitrogen atom, and the nitrogen atom may be a group which may be substituted with a methyl group or a benzyl group. Shows,
R ₈ is an alkyl group having up to 4 carbon atoms and represents a group which may be interrupted by oxygen or sulfur atom in the middle thereof. * Indicates an optically active point. ] It was possible to synthesize an optically active 1,4-dihydropyridine compound represented by the following formula.

The above general formulas [I], [II], [III] and [IV] will be described more specifically.

R ₄ is a substituent which is easily transesterified under enzymatic and alkaline conditions, such as a carbamoylmethyl group,
It represents a methylaminocarbonylmethyl group, a dimethylaminocarbonylmethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group or the like.

R ₅ represents a lower alkyl group such as a methyl group or an ethyl group, or an alkyl group having a substituent. For example, the substituent is fluorine, chlorine, a hydroxyl group, a lower alkoxyl group or the like.

R ₆ represents a hydrogen atom, a lower alkoxymethyl group or a lower acyloxymethyl group.

R ₇ is a linear, branched or cyclic alkyl group having up to 12 carbon atoms, or a halogen or alkyl group,
12 carbon atoms including a benzene ring substituted with an alkoxyl group
Up to the above alkyl groups, which may be optionally substituted with a nitrogen atom, and the nitrogen atom is a group which may be substituted with a methyl group or a benzyl group.

R ₈ represents a linear or branched alkyl group having up to 4 carbon atoms, and may contain an oxygen atom or a sulfur atom in the middle of the chain.

The enzyme used in the present invention includes a prochiral 1,4-dihydropyridine compound represented by the above general formula [I] to an optically active 1,4 represented by the above general formula [IV].
Any enzyme may be used as long as it has an activity of producing a dihydropyridine compound, and specific examples thereof include proteases derived from the genus Aspergillus and the genus Bacillus. More specifically, proteases derived from Aspergillus melleus, Bacillus subtilis and the like can be mentioned. For example, these proteases include prozyme, protease P, seaprose S,
Commercially available under the trade names of acylase, proleather and the like (all manufactured by Amano Pharmaceutical Co., Ltd.), these can be used.

The enzyme used may be a crude product or a purified product. In addition, bacterial cells that produce these enzymes can also be used.

The reaction of the present invention is usually carried out at 0 to 40 ° C. for 1 to 120
It is preferable to carry out the reaction for a time and to stir the reaction system. Further, such a protease may be used as it is, but may be carried on an appropriate carrier to be used as an immobilized reactor.

The reaction of the present invention is usually carried out in a water solvent. At this time, it is desirable to add salts having an appropriate buffering action to the reaction aqueous solution. Further, in the reactions of the general formulas [I] to [IV] utilizing the transesterification reaction, an organic solvent other than alcohol may be added to improve the solubility of the reaction substrate. Examples of the organic solvent include acetone and dimethyl sulfoxide. The added amount is usually 50% (V / V) or less.

In the transesterification reaction under alkaline conditions, alkali metal alkoxides in alcohol (for example, sodium methylate in methanol,
Sodium ethylate in ethanol, etc.) or in an aqueous solution of 0.5-2 normal alkali hydroxide, 0.5-10
Double the amount of alcohol may be added. At this time, an ester substituent can be arbitrarily introduced depending on the alcohol used.

The reaction products are chloroform, benzene,
It can be extracted and separated with ether. Furthermore, the reaction product can be easily purified by using, for example, silica gel column chromatography.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 Dimethylaminopyridine (10 mg) was dissolved in ethyl hydroxyacetate (10 g) and diketene (7.4 ml) was added at 70-80 ° C. to 1.
Appropriate for 5 hours, and further stirred at 70-80 ° C for 2 hours. The obtained ethoxycarbonylmethyl acetoacetate is m
-Nitrobenzaldehyde (7.3 g) was dissolved in isopropyl alcohol (150 ml), 28% aqueous ammonia (6 ml) was further added, and the mixture was heated under reflux for 3 hours. After allowing to cool, the solvent was concentrated, extracted with methylene chloride, washed with water, the methylene chloride layer was dried over magnesium sulfate, and the concentrated residue was subjected to silica gel chromatography (hexane: ethyl acetate =
4: 1) to give yellow crystals (14.7 g, 62%). The reaction formula of Reference Example 1 is as follows.

[0037]

[Chemical 15]

Reference Example 2 Bis (carbamoylmethyl ester) was efficiently obtained by leaving the crystal obtained by the method of Reference Example 1 in ethanol in the presence of ammonia gas at room temperature for 24 hours. The reaction formula of Reference Example 2 is as follows.

[0039]

[Chemical 16]

[0040]

【Example】

Example 1 Bis (carbamoylmethyl) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate (1.73 g) was added to 0.02 M phosphate buffer (pH).
7.8,400 ml), added seaprose S (8.65 g), further added (S) -N-benzyl-3-pyrrolidinol (4.6 g) dissolved in dimethyl sulfoxide (5 ml), and added at 48 at 25 ° C. Stir for hours.

The reaction solution was extracted with ethyl acetate, the ethyl acetate layer was washed with water, and concentrated to obtain a residue, which was subjected to silica gel column chromatography (dichloromethane / methanol = 29 /
The product was attached to 1) to obtain pale yellow crystals (1.32 mg, 62%).
[(S) -N-benzyl-3-pyrrolidinyl carbamoylmethyl 1,4-dihydro-2,6-dimethyl-4- (3
Specific rotatory power and various spectral data of the -nitrophenyl) -3-pyridinedicarboxylate] product are shown.

[Α] _D ²⁰ : + 5.8 ° (c = 0.8, Acetone) IR (KBr): 3450, 330, 1675cm ^{−1 1} H-NMR (CDCl ₃ ) ppm: 1.32-2.78 (6H, m, 3 × CH ₂ ), 2.31
(3H, s, CH ₃ ), 2.38 (3H, s, CH ₃ ), 3.61 (2H, s, CH ₂ N), 4.51 (2
H, ABq, J = 3.6Hz, OCH ₂ CO), 5.09 (1H, s,> CH-), 5.10-5.30 (1
H, m,> CH-), 5.60 (2H, s, NH ₂ ), 6.42 (1H, s, NH), 7.18-8.17
(9H, m, Aromatic) ¹³ C-NMR (CDCl ₃ ) ppm: 19.03, 19.31, 31.75, 39.71, 5
2.38, 59.94, 61.98,73.80, 100.85, 103.24, 121.48,
122.67, 126.99, 128.18, 128.70, 134.32, 138.47, 14
5.29, 147.96, 148.19, 149.72, 165.69, 166.77, 170.4
6 The reaction formula of Example 1 is as follows.

[0043]

[Chemical 17]

Example 2 The diester (267 mg) obtained in Example 1 was dissolved in methanol (10 ml), sodium (200 mg) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours.

The reaction solution was added to ice-cold water, and methylene chloride (10
ml). The methylene chloride layer was washed with water, dried and concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = 29/1) to give pale yellow crystals (201 mg, 82%). [(S) -N-benzyl-
3-pyrrolidinyl 1,4-dihydro-2,6-dimethyl-4
-(3-Nitrophenyl) -3-pyridinedicarboxylate] product specific rotation and various spectral data.

[0046] ^{_{[α] D 20: + 64.3}} ° (c = 0.9, Methanol) IR (KBr): 3380, 1690cm -1 1 H-NMR (CDCl 3) ppm: 1.30-2.92 (6H, m, 3 × CH ₂ ), 2.33
(3H, s, CH ₃ ), 2.35 (3H, s, CH ₃ ), 3.64 (5H, s, CH ₂ + CH ₃ O), 5.
06 (1H, s,> CH-), 5.02-5.28 (1H, m,> CH-), 5.93 (1H, s, N
H), 7.12-8.17 (9H, m, Aromatic) ¹³ C-NMR (CDCl ₃ ) ppm: 19.65, 31.93, 39.99, 51.19, 5
2.61, 60.00, 60.22,73.92, 103.35, 121.42, 123.07,
127.10, 128.35,128.81, 134.55, 138.92, 145.00, 14
8.41, 149.89, 166.88, 167.62

[0047]

[Chemical 18]

Example 3 Bis (carbamoylmethyl ester) (432 mg) was added to 0.02
Suspended in M phosphate buffer (pH 7.8, 100 ml), added seaprose S (2.2 g), and further added N-benzyl-N-methylaminoethanol (1.2 g) dissolved in dimethyl sulfoxide (1 ml). The mixture was stirred at 25 ° C for 48 hours.

The reaction solution was extracted with ethyl acetate, the ethyl acetate layer was washed with water, and concentrated to obtain a residue, which was subjected to silica gel column chromatography (dichloromethane / methanol = 29 /
The product was attached to 1) to give yellow crystals (302 mg, 58%).
[(S) -N-benzyl-N-methyl-aminoethyl
Carbamoylmethyl 1,4-dihydro-2,6-dimethyl-
4- (3-nitrophenyl) -3-pyridinedicarboxylate] product specific rotation and various spectral data.

[0050] ^{_{[α] D 20: -13.5 °}} (c = 1.0, Acetone) IR (KBr): 3420, 3400, 1690cm -1 1 H-NMR (CDCl 3) ppm:

[0051]

[Chemical 19]

Example 4 (S) -N-benzyl-N-methyl-aminoethyl, carbamoylmethyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) obtained in Example 3 -3-
Pyridine dicarboxylate (261 mg) was added to methanol (1
0 ml), add sodium (200 mg) under ice cooling,
Stir at room temperature for 3 hours.

The reaction solution was added to ice-cold water, and methylene chloride (10
ml). The methylene chloride layer was washed with water, dried and concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = 29/1) to give pale yellow crystals (120 mg, 50%).

The obtained diester was identified as the S-form of nicardipine based on various spectral data described in the literature.

[0055]

[Chemical 20]

[0056]

INDUSTRIAL APPLICABILITY As described above, the optically active 1,4-dihydropyridine represented by the above formula [III] is transesterified with an enzyme catalyst from the prochiral 1,4-dihydropyridine compound represented by the above formula [I] of the present invention. Excellent results were obtained for industrially carrying out the compound in both the asymmetric yield and the reaction yield. Furthermore, the transesterification reaction was carried out by carrying out the reaction in the presence of alcohol. From the optically active substance represented by the above formula [IV] can be produced. According to the present invention, a novel method has been found in which many 1,4-dihydropyridine drugs which have been conventionally developed as racemates and used as medicines are provided as optically active forms and used as medicines.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Seiji Sasaki Seiji Sasaki, Nishiharu Kasugai-gun, Aichi 51 Kunotsubo Saijo Yashiki 51, Amano Pharmaceutical Co., Ltd. Central Research Laboratory (72) Inventor Kazuo Achinami 15-5 Kamizaya, Shizuoka, Shizuoka Prefecture

Claims (2)

[Claims] 1. A compound represented by the general formula [I]: 1,4-dihydropyridine compound represented by the formula [wherein X is a general formula [II] (In the formula, R ₁ , R ₂ and R ₃ may be the same or different and each is a hydrogen atom, a halogen atom, a nitro group, a nitrile group,
Represents a trifluoromethyl group. ), R ₄ represents a substituent that easily undergoes transesterification under enzymatic and alkaline conditions, R ₅ represents a lower alkyl group, an alkyl group having a substituent, R ₆ represents a hydrogen atom, a lower alkoxymethyl group, Represents a lower acyloxymethyl group. ], R ₇ OH (wherein
R ₇ is a linear, branched or cyclic alkyl group having up to 12 carbon atoms which may be optionally substituted with a nitrogen atom, and the nitrogen atom is a group which may be substituted with a methyl group or a benzyl group. . ), An enzyme is allowed to act in the presence of an alcohol, and one ester residue is transesterified to give a compound of the general formula [III] [Wherein X is a general formula [II] (In the formula, R ₁ , R ₂ and R ₃ may be the same or different and each is a hydrogen atom, a halogen atom, a nitro group, a nitrile group,
Represents a trifluoromethyl group. ), R ₄ represents a substituent that easily undergoes transesterification under enzymatic and alkaline conditions, R ₅ represents a lower alkyl group, an alkyl group having a substituent, R ₆ represents a hydrogen atom, a lower alkoxymethyl group, Represents a lower acyloxymethyl group, R ₇ may be optionally substituted with a nitrogen atom with a linear, branched or cyclic alkyl group having up to 12 carbon atoms, and the nitrogen atom may be substituted with a methyl group or a benzyl group. Represents an optional group. * Indicates an optically active point. ] 1,4-dihydropyridine represented by the formula: R ₈ OH (wherein R ₈ is an alkyl group having up to 4 carbon atoms, which may be interrupted by an oxygen or sulfur atom in the middle) under alkaline conditions. Of the general formula [IV] obtained by reacting the alcohol represented by [In the formula, X is a general formula [II] (In the formula, R ₁ , R ₂ and R ₃ may be the same or different and each is a hydrogen atom, a halogen atom, a nitro group, a nitrile group,
Represents a trifluoromethyl group. ), R ₄ represents a substituent that easily undergoes transesterification under enzymatic and alkaline conditions, R ₅ represents a lower alkyl group, an alkyl group having a substituent, R ₆ represents a hydrogen atom, a lower alkoxymethyl group, Represents a lower acyloxymethyl group, R ₇ may be optionally substituted with a nitrogen atom with a linear, branched or cyclic alkyl group having up to 12 carbon atoms, and the nitrogen atom may be substituted with a methyl group or a benzyl group. R ₈ represents an optionally substituted group, and R ₈ represents an alkyl group having up to 4 carbon atoms, which may be interrupted by an oxygen or sulfur atom on the way. * Indicates an optically active point. ] The synthetic | combination method of the optically active 1, 4- dihydro pyridine compound represented by these. 2. A compound represented by the general formula [III]: [Wherein X is a general formula [II] (In the formula, R ₁ , R ₂ and R ₃ may be the same or different and each is a hydrogen atom, a halogen atom, a nitro group, a nitrile group,
Represents a trifluoromethyl group. ), R ₄ represents a substituent that easily undergoes transesterification under enzymatic and alkaline conditions, R ₅ represents a lower alkyl group, an alkyl group having a substituent, R ₆ represents a hydrogen atom, a lower alkoxymethyl group, Represents a lower acyloxymethyl group, R ₇ may be optionally substituted with a nitrogen atom with a linear, branched or cyclic alkyl group having up to 12 carbon atoms, and the nitrogen atom may be substituted with a methyl group or a benzyl group. Represents an optional group. * Indicates an optically active point. ] The 1,4-dihydro pyridine compound represented by these.