JP4544895B2 - Method for producing dihydropyridine derivatives - Google Patents

Description

The present invention is a compound which is an active ingredient having an excellent therapeutic effect as a vasodilator and antihypertensive agent, for example, 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5- The present invention relates to a novel process for producing a dihydropyridine derivative represented by hydrochloride (benidipine hydrochloride) of dicarboxylic acid-3- (1-benzyl-3-piperidyl) ester-5-methyl ester.

Many 4-aryl-1,4-dihydro-2,6-dialkyl-3,5-pyridinedicarboxylic acid asymmetric esters have reduced the yield and purity of the final product since these compounds began to be produced on an industrial scale. There are active efforts to improve.

As a production method of dihydropyridines,
Method A: Synthesis from dihydropyridine monocarboxylic acid chloride and alcohol Method B according to {Chem. Pharm. Bull, 28, 2809 (1980)} Method B: Benzaldehydes, 3-aminocrotonates, acyl acetates To synthesize in one step. So-called Hantzsch synthesis method C: a method of synthesizing in one step by reaction of benzaldehydes, acylacetates and ammonia (or ammonium salt) {J. Med. Chem. 17, 956, (1974)} Method D: Synthesis from benzylidene acyl acetate and 3-aminocrotonate {Chem. Pharm. Bull, 27, 1426 (1979)} Etc. are known.

However, these conventional methods have the following serious drawbacks.
In Method A, once 2,6-dialkyl-1,4-dihydropyridinedicarboxylic acid
After synthesizing a symmetric or asymmetric ester, one ester must be selectively hydrolyzed, acid chlorided and reesterified, resulting in a long number of steps and a low yield.
Method B and method C can be synthesized in one step, so that the operability is improved. However, a large amount of undesired by-products are produced, and it is extremely difficult to remove them. In particular, the target product can be obtained only in a low yield.

Although the method D is industrially common, when it is carried out in a water-immiscible solvent such as toluene, by-product formation is suppressed, but the reaction rate becomes extremely slow. Conversely, refluxing in a protic solvent until the cyclization reaction is complete produces unacceptably undesired by-products without the addition of a strong acid. Although it is indispensable to remove this by-product from the target product, this operation requires a complicated operation and a great amount of cost.
In the case of addition of a strong acid, side reactions are suppressed to some extent, but it becomes a factor for restricting the use of the reaction vessel and the steel device, and increases the operational risk. In addition, the treatment for removing the acid used requires labor and cost, and the environmental load cannot be ignored. Furthermore, in order to suppress a side reaction, the benzylidene acyl acetate used as a raw material must also have a high purity, and the labor and cost required for that purpose are also great.
As described above, the conventional method has many drawbacks in industrial production.
Chem. Pharm. Bull, 28, 2809 (1980) J. et al. Med. Chem, 17, 956, (1974) Chem. Pharm. Bull, 27, 1426 (1979)

An object of the present invention is to provide an industrial process capable of solving various problems particularly in the method D in the production of a dihydropyridine derivative and obtaining a highly pure dihydropyridine derivative in a high yield with a very simple operation.

[式中Ｒ１は、水素原子、ニトロ基、シアノ基、ハロゲン基、トリフルオロメチル基を表す。式中Ｒ２は、Ｃ１―Ｃ６の直鎖、分岐或いは環状の置換又は無置換アルキル基を表す。式中Ｒ３は、アルキル基を表す]で表されるベンジリデンアセト酢酸エステル類と
下記一般式（２）

[式中Ｒ４は、アルキル基を表す。式中Ｒ５は、Ｒ２と異なる直鎖、分岐或いは環状の炭素数１２までのアルキル基で任意にＮ原子で置換されていてもよく、更にＮ原子はＣ１―Ｃ６置換又は無置換アルキル基或いは芳香環が置換されたベンジル基で置換されていてもよい。]で表されるアミノクロトン酸エステル類との反応において、有機溶媒中で反応系内に乾燥剤および／または脱水剤を添加し、副生する水を除去しながら反応を行なうことを特徴とする
下記一般式（３）

[式中Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５は前記と同一である]で表されるジヒドロピリジン誘導体の高効率で工業化に適した製造法を提供するものである。 The method of the present invention comprises:
The following general formula (1)

[Wherein R 1 represents a hydrogen atom, a nitro group, a cyano group, a halogen group, or a trifluoromethyl group. In the formula, R2 represents a C1-C6 linear, branched or cyclic substituted or unsubstituted alkyl group. In the formula, R3 represents an alkyl group] and benzylideneacetoacetic acid esters represented by the following general formula (2)

[Wherein R 4 represents an alkyl group. In the formula, R5 may be optionally substituted with a linear, branched or cyclic alkyl group having up to 12 carbon atoms different from R2, and the N atom may be a C1-C6 substituted or unsubstituted alkyl group or an aromatic group. The ring may be substituted with a substituted benzyl group. In the reaction with the aminocrotonic acid ester represented by the formula, the reaction is carried out while adding a desiccant and / or a dehydrating agent to the reaction system in an organic solvent and removing by-product water. The following general formula (3)

[Wherein R1, R2, R3, R4, and R5 are the same as described above], and provides a highly efficient production method suitable for industrialization.

According to the present invention, it is possible to produce a high-purity dihydropyridine derivative having very simple and highly flexible reaction conditions with almost no by-product, and its industrial utility value is extremely high.

The production method of the present invention will be described in detail.
The general formula (1) used in the present invention can be easily obtained by a condensation reaction between a substituted benzaldehyde compound and an acetoacetate ester. For example, m-nitrobenzaldehyde and methyl acetoacetate can be easily produced by stirring in an organic solvent in the presence of a catalytic amount of a base, and can be obtained in high yield.

The general formula (2) used in the present invention can be easily obtained by synthesizing an acetoacetate ester with an alcohol corresponding to diketene and further reacting with ammonia. For example, it can be obtained in a high yield by reacting N-benzyl-3-hydroxypiperidine and diketene in a solvent and taking out, then reacting with ammonia in the solvent and concentrating.

The step of reacting these compounds (1) and (2) to obtain the final product of the general formula (3) includes lower aliphatic alcohols such as methanol, ethanol and propanol, methyl cellosolve, ethyl cellosorb, ethyl acetate, methyl acetate, Of solvents such as butyl acetate, dioxane, DMF, DMSO (dimethyl sulfoxide), CCl4, CHCl3, CH2Cl2, THF, hexane, ligroin, methyl ethyl ketone, methyl isobutyl ketone, acetone, toluene, benzene, xylene, acetonitrile, preferably alcohol solvents Among these, ethanol is particularly preferably used as a reaction solvent from the viewpoint of suppression of solvent-derived byproducts.
A desiccant and / or a dehydrating agent is used to remove water produced as a by-product from the reaction, and anhydrous magnesium sulfate, anhydrous sodium sulfate, zeolite, etc. are mainly used, and molecular sieves are particularly preferable from the viewpoint of suppression of by-products. Is added to carry out the reaction.
The reaction is carried out at room temperature to warming (preferably 50 ° C.-reflux) with stirring for 1 hour to 24 hours (preferably 5-10 hours).

The dihydropyridine derivative represented by the general formula (3) thus obtained is isolated by subjecting the reaction solution to general filtration, extraction and / or concentration and distillation. If desired, it can be purified by known methods such as column chromatography, distillation, recrystallization and the like.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1
Hydrochloride of 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- (1-benzyl-3- piperidinyl ) ester-5-methyl ester (hydrochloric acid synthesis of benidipine) 2- (3-nitro-benzylidene) acetoacetic acid methyl ester 25g and (0.1 mol) 3-aminocrotonate-3-(N-benzyl) piperidinyl ester 33 g (0.11 mol) and molecular sieves 15g and ethanol The solution of was reacted at 50 ° C. for 10 hours. Next, 150 ml of chloroform and 52 g of 35% hydrochloric acid are added to the residue obtained by distilling off the solvent after removing the molecular sieve, and the mixture is reacted at room temperature for 30 minutes to produce the desired hydrochloride. Next, the solvent is distilled off and the residue obtained is dissolved in ethanol / acetone = 65 ml / 130 ml, and slowly cooled to 5 ° C. or lower with stirring. After about 20 hours, the precipitated crystals were collected by filtration, washed with acetone, and then dried under reduced pressure at room temperature in a desiccator. A yellow crystal having a melting point of 198 ° C., ie, 19 g of benidipine hydrochloride was obtained. Yield 70%. Was analyzed by HPLC, area percentage of the main ingredients are target compound 99.9%, di 3- (N- benzyl) piperidinyl ester was 0.1%.

Comparative Example 1
Hydrochloride of 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- (1-benzyl-3- piperidinyl ) ester-5-methyl ester (hydrochloric acid synthesis of benidipine) 2- (3-nitro-benzylidene) -3-methyl acetoacetate 25 g (0.1 mol) and 3-aminocrotonate (N- benzyl) piperidinyl ester 33 g (0.11 mol) and a solution of 50 in ethanol The reaction was carried out at 0 ° C. for 10 hours. Next, 150 ml of chloroform and 52 g of 35% hydrochloric acid are added to the residue obtained by distilling off the solvent, and the mixture is reacted at room temperature for 30 minutes to produce the desired hydrochloride. Next, the solvent is distilled off and the residue obtained is dissolved in ethanol / acetone = 65 ml / 130 ml, and slowly cooled to 5 ° C. or lower with stirring. After about 20 hours, the precipitated crystals were collected by filtration, washed with acetone, and then dried under reduced pressure at room temperature in a desiccator.
19 g of yellow crystals having a melting point of 198 ° C. were obtained. Yield 70%. Was analyzed by HPLC, area percentage of the main ingredients are target compound 99.3%, di 3- (N- benzyl) piperidinyl ester was 0.7%.

Comparative Example 2
Hydrochloride of 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- (1-benzyl-3- piperidinyl ) ester-5-methyl ester (hydrochloric acid solution of the synthesis 2- (3-nitro-benzylidene) acetoacetic acid methyl ester 25g and (0.1 mol) 3-aminocrotonate-3-(N-benzyl) piperidinyl ester 33 g (0.11 mol) and n- butanol benidipine) Was heated to reflux for 5 hours. Next, 150 ml of chloroform and 52 g of 35% hydrochloric acid were added to the residue obtained by distilling off the solvent, and the mixture was reacted at room temperature for 30 minutes to produce the desired hydrochloride. Next, the solvent was distilled off, and the residue obtained was dissolved in ethanol / acetone = 65 ml / 130 ml, and slowly cooled to 5 ° C. or lower with stirring. After about 20 hours, the precipitated crystals were collected by filtration, washed with acetone, and then dried under reduced pressure at room temperature in a desiccator. 19 g of yellow crystals having a melting point of 198 ° C. were obtained. Yield 70%. Was analyzed by HPLC, area percentage of the main ingredients are target compound 99.0%, di 3- (N- benzyl) piperidinyl ester 0.7%, butyl 3- (N- benzyl) piperidinyl ester 0.3% Met.

Claims (6)

The following general formula (1)

[Wherein R 1 represents a hydrogen atom, a nitro group, a cyano group, a halogen group, or a trifluoromethyl group. In the formula, R2 represents a C1-C6 linear, branched or cyclic substituted or unsubstituted alkyl group. In the formula, R3 represents an alkyl group] and benzylideneacetoacetic acid esters represented by the following general formula (2)

[Wherein R 4 represents an alkyl group. In the formula, R5 represents an N-benzyl-3-piperidinyl group . In the reaction with aminocrotonic acid esters represented by the following formula, the reaction is performed while adding a desiccant and / or a dehydrating agent to the reaction system in ethanol and removing by-product water. General formula (3)

[Wherein R1, R2, R3, R4, and R5 are the same as defined above]. 2. The process for producing a dihydropyridine derivative according to claim 1, wherein the addition to the reaction system is a desiccant. The method for producing a dihydropyridine derivative according to claim 2 , wherein the desiccant added to the reaction system is zeolite. The method for producing a dihydropyridine derivative according to claim 3 , wherein the desiccant added to the reaction system is a molecular sieve. The method for producing a dihydropyridine derivative according to any one of claims 1 to 4, wherein R1 is a nitro group, and R2, R3, and R4 are methyl groups . The method for producing a dihydropyridine derivative according to any one of claims 1 to 5, wherein the reaction is carried out at room temperature to under heating.