JP2002275156A - Method for producing monoester derivative of 1,4- dihydropyridine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain asymmetrical diesters of 1,4-dihydropyridine-3,5-dicarboxylic acid having a hypotension activity and a vasodilator activity. SOLUTION: When diesters represented by the formula (wherein, Ar is an aryl group which may have a substituent; R<1> and R<2> are each independently a <=6C alkyl group) are hydrolyzed to provide the objective monoester derivative of the 1,4-dihydropyridine-3,5-dicarboxylic acid obtained by substituting one R<1> of the diester with H, the reaction is carried out in the presence of 0.8-2.0 mol metal hydroxide catalyst expressed in terms of OH group, and 10-50 mol water based on 1 mol diesters, and further in the presence of a polar organic solvent in an amount of 1-20 times as much as that of the diesters.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to various asymmetric compounds which have a hypotensive action and a vasodilator action and are useful as antihypertensives and vasodilators, especially as coronary and cerebral vasodilators.
The present invention relates to a method for producing a 1,4-dihydropyridine derivative useful as an intermediate for producing 1,4-dihydropyridine-3,5-dicarboxylic acid diesters.

[0002]

2. Description of the Related Art Various asymmetric 1,4-dihydropyridine-3,5-dicarboxylic acid diesters such as nicardipine, manidipine and benidipine are useful as antihypertensives and vasodilators, especially as coronary and cerebral vasodilators. Is known,
Further, such asymmetric 1,4-dihydropyridine-3,5-dicarboxylic acid diesters are 1,4-dihydropyridine-3,5-dicarboxylic acid diesters (hereinafter, referred to as (I)).
The diesters are also partially hydrolyzed to obtain (II) 1,4-dihydropyridine-3,5-dicarboxylic acid monoesters (hereinafter, also referred to as monoesters).

However, partial hydrolysis of the diesters is generally considered to be difficult, and the following method has been proposed as a method for producing the monoesters. For example, it is known that symmetric diesters are N-alkyl protected, then hydrolyzed under alkaline conditions, and then treated with acid to give the corresponding monoesters in a two-step process that removes the N-alkyl protecting group. (T.Shiban
uma et al, Chem. Pharm. Bull. 28 (9), 2809-2812 (1980)). However, this method requires multiple steps since N-alkyl protection and deprotection of the dihydropyridine ring is required, and is not an advantageous method in terms of economy and simplicity.

[0004] Separately from the above-mentioned method, the asymmetric diester in which an electron-withdrawing group such as a cyanoethyl group has been introduced into the ester group to be eliminated is hydrolyzed under alkaline conditions to form the corresponding monoester. It is known that it can be obtained (see JP-A-63-290874). However, this method requires a two-step reaction step when producing an asymmetric diester into which an electron-withdrawing group is introduced as a raw material compound, and is not an advantageous method in terms of economy and simplicity.

[0005] Furthermore, as a method which is considered to be more advantageous in terms of economy and simplicity than the above two methods,
A method is known in which the above diesters are partially hydrolyzed in a mixture of a polar organic solvent and water under alkaline conditions to obtain the corresponding monoesters (JP-A-62-178570).
And JP-A-63-41459). However, according to the examples of these publications, it is found that not only a large amount of a reaction solvent and an alkali are used in the hydrolysis step but also 1,4-dihydropyridine-3,5-dicarboxylic acids (hereinafter referred to as dicarboxylic acids) which are difficult to purify and remove. (Also referred to as acids).

[0006]

DISCLOSURE OF THE INVENTION The present invention aims to solve the above-mentioned problems, and reduces the amount of a polar solvent and the amount of an alkali catalyst used as much as possible, and reduces the amount of 1,2 produced as a by-product. An object of the present invention is to provide a production method capable of reducing 4-dihydropyridine-3,5-dicarboxylic acids as much as possible.

[0007]

That is, the present invention provides the following formula (I)

Embedded image (Wherein, Ar represents an aryl group which may have a substituent, and R ¹ and R ² independently represent an alkyl group having 6 or less carbon atoms) -3,5-dicarboxylic acid diesters in a mixed solvent of a polar organic solvent and water,
By hydrolysis in the presence of at least one metal hydroxide catalyst selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides, the following formula (II)

Embedded image (Wherein, Ar, R ¹ and R ² are the same as those of the formula (I)) in producing the 1,4-dihydropyridine monoester derivative represented by the above-mentioned 1,4-dihydropyridine-3,5- The amount of metal hydroxide catalyst used per mole of dicarboxylic diesters is 0.8 to 2.0 moles as OH groups, and the amount of water used is
10 to 50 mol, and the amount of the polar organic solvent used is
1 to 20 parts by weight based on 1 part by weight of 1,4-dihydropyridine-3,5-dicarboxylic diester
This is a method for producing a 1,4-dihydropyridine monoester derivative.

In the diester represented by the formula (I), which is a starting compound in the present invention, Ar is an aryl group which may have a substituent, and examples thereof include aryl groups such as phenyl, naphthyl and heteroaryl. The substituent is one or two selected from the group consisting of a halogen atom, a nitro group, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkylamino group, a trifluoromethyl group and a trifluoromethoxy group. The above substituents are preferred. Ar as a pharmaceutical intermediate is 2-nitrophenyl group, 3-nitrophenyl group, 2-chlorophenyl group, 2,3-dichlorophenyl group, from the viewpoint of its usefulness or applicability.
Preferable examples include a 2-trifluoromethylphenyl group and a 3-trifluoromethylphenyl group, and a 3-nitrophenyl group is more preferable. R ¹ and R ² are
Independently represents an alkyl group having 6 or less carbon atoms, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-
Examples thereof include a pentyl group, an n-hexyl group and the like, preferably a straight-chain alkyl group having 3 or less carbon atoms such as a methyl group, an ethyl group and an n-propyl group, and a methyl group is particularly preferable.

The diester represented by the formula (I) can be obtained by a known method, and the production method is not limited. For example, Hantzsch 1,4- by reacting 3-nitrobenzaldehyde, methyl acetoacetate and ammonia in an inert organic solvent at the reflux temperature of the reaction mixture.
Dihydropyridine derivative synthesis method (J. Heterocycle. Chem, 2
1,1849-1856 (1984)).

[0010] The hydrolysis reaction of the present invention is carried out in a mixture of a polar organic solvent and water under alkaline conditions,
Preferably, it is carried out in a mixture of water and an aprotic polar solvent that does not undergo hydrolysis under alkaline conditions. Here, an aprotic polar solvent that is not hydrolyzed under alkaline conditions is, under the reaction conditions,
Any substance that does not substantially undergo hydrolysis may be used, and examples thereof include dimethyl sulfoxide (DMSO), sulfolane, hexamethylphosphoramide, acetonitrile, and methanol. DMSO and sulfolane are preferred. The amount of the polar organic solvent used may be an amount sufficient to dissolve at least part, preferably most of the diesters, which are the raw material compounds, in the reaction system. And the reaction rate decreases. Therefore, the amount of the polar organic solvent used varies depending on the type of the polar organic solvent and the raw material diester, but is 1 to 20 times, preferably 2 to 10 times the weight of the raw material diester. From another viewpoint, it is preferable that the amount of the starting diester is 0.5 to 2 which is sufficient to dissolve the starting diester in the reaction system.
The range is twice as large. If the amount of polar organic solvent used is small,
Not only is the dissolution of the diesters of the raw materials or the monoesters of the product insufficient, but also the by-products of the dicarboxylic acids cannot be suppressed. If the amount is too large, the reaction does not proceed.

The amount of water used is 10 to 50 moles, preferably 15 to 50 moles, per mole of the diester as the starting compound.
30 moles. If the amount of water used is small, the reaction does not proceed, and if it is too large, the by-production of dicarboxylic acids cannot be suppressed, and the yield is significantly reduced. Excess water increases the production of dicarboxylic acids, as water promotes hydrolysis.

[0012] The hydrolysis reaction is carried out using at least one metal hydroxide selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides as an alkali catalyst. Examples of the metal hydroxide catalyst include strongly basic alkali metal hydroxides and alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and barium hydroxide. Strongly basic alkali metal hydroxides such as sodium oxide and potassium hydroxide are preferred. The amount of the metal hydroxide catalyst to be used is 0.8 to 2.0 moles, preferably 1.0 to 1.2 moles, as OH groups, relative to 1 mole of the diester as a raw material compound. In addition, 1 mol as an OH group corresponds to 1 mol in the case of an alkali metal hydroxide, and 0.5 mol in the case of an alkaline earth metal hydroxide. The alkali catalyst acts as a hydrolysis catalyst, but is consumed as a result of reacting with a carboxyl group generated as a result of hydrolysis to form a salt. Therefore, if the amount used is small, the reaction does not proceed sufficiently. On the other hand, if the amount is too large, the hydrolysis proceeds too much, so that the by-products of the dicarboxylic acids cannot be suppressed, and the by-products increase significantly.

In the hydrolysis reaction of the present invention, the reaction solution contains a solvent composed of a polar organic solvent and water, an alkali catalyst, diesters as raw materials, and monoesters as a product. Although it is preferable to form it, it may be partially dissolved to cause phase separation. The ratio of the polar organic solvent to water is 10: 1 to 10: 8 by volume.
Range is good. The weight ratio of the raw material to the solvent at the time of charging is preferably in the range of 1:10 to 1: 2.

[0014] The reaction temperature is preferably about 20 to 180 ° C, and more preferably 50 to 120 ° C. When the reaction temperature is low, the reaction rate is remarkably reduced. When the reaction temperature is too high, side reactions cannot be suppressed, and by-products increase. The reaction time is such that the reaction rate of the starting diesters is 50% or more, preferably 60 to 80%.
Is controlled so that If the reaction rate of the raw material diesters is too high, the amount of by-products such as dicarboxylic acids increases, which not only increases the load on purification, but also greatly reduces the yield after purification and improves the purity sufficiently. There are problems such as not doing. The reaction time varies depending on the reaction conditions such as the amount of the alkali catalyst and water used, but is preferably about 0.5 to 24 hours.

The reaction mixture obtained by the above method contains a solvent, a catalyst, and the like, as well as unreacted starting diesters and monoesters of the target compound, as well as dicarboxylic acids by-produced and other by-products. Dicarboxylic acids and monoesters exhibit greater water solubility than diesters, but dicarboxylic acids exhibit the greatest water solubility. When a dicarboxylic acid or a monoester reacts with an alkali catalyst to form a salt, it shows greater water solubility. Accordingly, a known method can be employed for isolating the monoester as the target compound from the reaction mixture, but it is preferable that the method has at least one step of separation utilizing the difference in solubility. For example, the reaction mixture obtained by the above method is sufficiently diluted with water to precipitate diesters, which are unreacted starting compounds, and then separated by filtration to separate diesters. Thereafter, the obtained mother liquor is acidified with a mineral acid such as hydrochloric acid to precipitate a free monoester, which is separated by filtration to obtain a monoester as a target compound. At this time, if a large amount of dicarboxylic acid is present, a part of the dicarboxylic acid is precipitated together with the monoester, and separation and purification are difficult.

The method of the present invention solves the problem that when the reaction rate of the starting diester is increased, a large amount of dicarboxylic acid is produced, which makes purification difficult and reduces the yield of monoester. By setting the use amount of the polar solvent and the use amount of the water-alkali catalyst in the specific ranges, even if the reaction rate of the raw material diester is increased, it is possible to significantly reduce by-products.

[0017]

The present invention will be described by the following examples.
It is not limited by this.

Example 1 10.6 g (0.03 mol) of 2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (abbreviated as diester) was added to 40 ml (44 g) of DMSO. ), An aqueous solution of 1.2 g (0.03 mol) of sodium hydroxide dissolved in 10 ml (0.56 mol) of water was added thereto with stirring at room temperature, and then 90 ° C.
And the mixture was stirred for 5 hours. After cooling the reaction mixture, high-performance liquid chromatography (HPLC) was used to determine the starting diester and the desired product, 3-methoxycarbonyl-2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-5.
-Carboxylic acid (abbreviated as monoester) and 2,6- by-product
Dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine
When quantification of -3,5-dicarboxylic acid (abbreviated as dicarboxylic acid) was performed, diester was 26.5 mol%, monoester was 50.4 mol%, and dicarboxylic acid was 0.29 mol%. In this quantitative analysis, the solvent and the alkali catalyst are not analyzed. The reason that it does not become 100 mol% in the above analysis is presumed to be due to the formation of other by-products. Further, it is presumed that the monoester and the dicarboxylic acid are in the form of a sodium salt.

Then, at room temperature, 30 ml of water was added and stirred for 30 minutes, after which yellow crystals were deposited. The unreacted starting compound diester was separated by filtering the precipitate. On the other hand, the obtained filtrate is acidified with concentrated hydrochloric acid (about pH
2). The precipitated crystals were collected by filtration to separate 5.0 g (crude yield; 49.7 mol%) of the monoester of the target product. The obtained product was analyzed by HPLC, and the dicarboxylic acid as a by-product and the monoester of the target product were quantified. As a result, the content of the dicarboxylic acid in the monoester was 0.5 mol%,
The diester content was less than 0.1 mol%. This monoester can be made to have a purity as a pharmaceutical intermediate by means such as recrystallization.

Examples 2 to 4 and Comparative Examples 1 to 3 In the same manner as in Example 1, sodium hydroxide, water and D
The experiment was performed with the amount of MSO used as shown in Table 1. Also, the reaction mixture was cooled and analyzed by HPLC,
Table 1 shows the crude yield of the obtained monoester of the target compound and the content of dicarboxylic acid in the monoester. In addition,% in Table 1 is mol%.

[0021]

【table 1】

Comparative Example 4 1.04 g (0.003 mol) of the starting diester was dissolved in 100 ml of DMSO, and 20 ml of 0.2N sodium hydroxide was added thereto with stirring at room temperature. The reaction mixture was stirred at 80 ° C. for 6 hours. After cooling the reaction mixture, the diester as a raw material, the monoester as a target product, and the dicarboxylic acid as a by-product were determined by HPLC. The acid was 0.21 mol%. The same work-up as in Example 1 was carried out, but no monoester of the desired product could be isolated.

Comparative Example 5 17.3 g (0.05 mol) of the raw material diester was suspended in 280 ml of methanol, and sodium hydroxide 1 dissolved in 52 ml of water was added thereto.
After adding 5.9 g (0.4 mol) of the aqueous solution at room temperature with stirring, the reaction mixture was stirred at reflux temperature for 5 hours. After cooling the reaction mixture, the diester as the raw material, the monoester of the desired product, and the dicarboxylic acid as a by-product were quantified by HPLC.The diester was 25.6 mol%, and the monoester was 54.
The content was 9 mol%, and the content of dicarboxylic acid was 3.8 mol%. The same post-treatment as in Example 1 was carried out, and 9.3 g (yield; 55 mol%) of a monoester of a target product was isolated. HP
LC analysis was performed to determine the amount of dicarboxylic acid as a by-product and the monoester of the target product. As a result, the content of dicarboxylic acid in the monoester was 7.8 mol%. If the content of dicarboxylic acid is as high as 7.8 mol%, it is practically impossible to purify it until it can be used as a pharmaceutical intermediate.

[0024]

According to the method of the present invention, it is possible to greatly reduce the amount of the reaction solvent and alkali used, which is excellent in economy and simplicity, and is difficult to purify and remove. , 4-dihydropyridine-3,5-dicarboxylic acid by-products can be reduced as much as possible,
3-Alkoxycarbonyl-1,4-dihydropyridine-5-carboxylic acids can be produced, and various asymmetric 1,4-dihydropyridines having blood pressure lowering action and vasodilatory action
It is extremely useful for obtaining high purity 3,5-dicarboxylic acid diesters.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Takahiro Kai 46-80, Nakahara-san, Ohata, Tobata-ku, Kitakyushu-shi, Fukuoka Inside Nippon Steel Chemical Research Institute (72) Inventor Istaka Ishikawa Tobata, Kitakyushu-shi, Fukuoka 46-80 Nakahara-Sannohama, Nara-ku F-term in Nippon Steel Chemical Research Laboratory (reference) 4C054 AA07 BB03 CC01 DD03 DD08 EE32 EE33 FF05

Claims (1)

[Claims] (1) The following formula (I): (Wherein, Ar represents an aryl group which may have a substituent, and R ¹ and R ² independently represent an alkyl group having 6 or less carbon atoms) -3,5-dicarboxylic acid diesters in a mixed solvent of a polar organic solvent and water,
Hydrolysis in the presence of at least one metal hydroxide catalyst selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides gives the following formula (II): (Wherein, Ar, R ¹ and R ² are the same as those of the formula (I)) in producing the 1,4-dihydropyridine monoester derivative represented by the above-mentioned 1,4-dihydropyridine-3,5- The amount of metal hydroxide catalyst used per mole of dicarboxylic diesters is 0.8 to 2.0 moles as OH groups, and the amount of water used is
10 to 50 mol, and the amount of the polar organic solvent used is
1 to 20 parts by weight based on 1 part by weight of 1,4-dihydropyridine-3,5-dicarboxylic diester
A method for producing a 1,4-dihydropyridine monoester derivative.