KR910005232B1 - Process for rpoducing 1-4 dihydro pyridine carboxylic acids - Google Patents

Abstract

A process for preparing 1,4-dihydropyridine carboxylic acid derivs. of formula (I) comprises (a) reacting a cpd. of formula (II) with iodomethane, (b) alkali hydrolyzing the resulting cpd. in a mixt. soln. of H2O and a lower alcohol, and (c) diluting it with a weak acid. In the formulas, R1 and R2 each= H, halogen, trifluoromethyl or nitro; R3= H or C1-4 alkyl. (I) are intermediates in the prodn. of diester derivs. useful as a circulatory drug.

Description

Method for preparing 1,4-dihydropyridine carboxylic acid

The present invention relates to a method for producing a compound represented by general formula (I), that is, 1,4-dihydropyridine monoester monocarboxylic acid or 1,4-dihydropyridine-3,5-dicarboxylic acid derivative.

R ¹ and R ² in Formula (I) represent the same or different hydrogen, halogen, trifluoromethyl, or nitro group; R ³ represents hydrogen or a C _{1 to} C ₄ straight or branched lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl group do.

Monoesters of 1,4-dihydropyridine-3,5-dicarboxylic acid or 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives are important intermediates for the preparation of diesters useful as circulatory drugs. Manufacturing methods such as are known.

1) Method of producing symmetric diesters by alkali hydrolysis [J. Hetrkocycl. Chem., 12, 363 (1975)]

2) Manufacturing method using symmetric diesters protecting the first nitrogen atom [Chem. Pharm. Bull., 27, 2809 (1980)]

3) Preparation Method by Selective Alkaline Hydrolysis Method Using Cyanoethyl Esters [Japan Kokai 55-64570 (1980)]

4) Preparation by selective hydrolysis using trimethylsilyl iodide [(Japan Kokai 61-161263 (1986)]

5) Manufacturing method using acid hydrolysis using HBr / AcOH in toluene solvent [Japan Kokai Tokkyokoho 61-40,262 (1986)]

Among these production methods, the production method of 1) has a very low yield. The production method of 2) has a complicated reaction operation, and the production method of 3) has a yield of 31-81%, but most of the yield is less than 60%. The production process of 4) is difficult to carry out the reaction conditions such as performing under anhydrous conditions and 5) the use of toxic substances such as HBr / AcOH. Therefore, there is a need for a method capable of producing monoester derivatives of 1,4-dihydropyridine-3,5-dicarboxylic acid in high yield under relaxed conditions.

The present inventors have studied for the purpose of synthesizing monoesters of 1,4-dihydropyridine-3,5-dicarboxylic acids or high yields under moderate conditions of 1,4-dihydropyridine-3,5-dicarboxylic acids. As a result, the above object was achieved by using an alkali hydrolysis reaction of specific 1,4-dihydropyridine.

The present invention is a compound represented by the general formula (I) characterized by reacting the compound represented by the general formula (II) and iodomethane to make a compound represented by the general formula (III) and hydrolyzing it under alkaline conditions That is, the present invention relates to a monoester of 1,4-dihydropyridine-3,5-dicarboxylic acid or a method for producing 1,4-dihydropyridine-3,5-dicarboxylic acid derivative.

R ¹ and R ² in the general formula (II) have the same definitions as in general formula (I); Linear or branched lower alkyl groups of R 1 C _{1 to} C ₄ , for example methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, 3-butyl groups or 2- A methylthioethyl group is shown.

R ¹ and R ² in the general formula (III) have the same definitions as in general formula (I); R ³ represents a C _{1 to} C ₄ straight or branched lower alkyl group such as methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl group or -CH ₂ CH ₂ S ⁺ (CH ₃ ) ₂ I ^- is indicated.

The compound represented by general formula (II) was manufactured by a well-known method. [EP 0,001,767 A1 (1979)]

The compound represented by the general formula (III) is prepared by reacting the compound represented by the general formula (II) with iodomethine, where iodomethane is used as a reactant and a solvent. The reaction temperature is carried out at room temperature or at the boiling point of iodomethane and the reaction time takes 6 to 24 hours. The compound represented by the general formula (III) can be obtained almost quantitatively. In particular, it was found that the compound represented by the general formula (II) is selectively hydrolyzed.

In the present invention, the compound represented by the general formula (I) is prepared by alkali hydrolysis of the compound represented by the general formula (III). At this time, the reaction solvent is hydrolyzed using a dilute aqueous solution of an alkali metal hydroxide using a mixed solvent of water and a lower alcohol such as methanol, ethanol and isopropyl alcohol.

At this time, the pH is performed at an alkalinity of 9 to 12, and specifically, pH 10 to 11 is appropriate.

The reaction time is performed within 1 hour, specifically, the reaction is completely terminated within 30 minutes. The temperature of the hydrolysis reaction is carried out at 0 ℃ to 40 ℃ but most of the reaction at room temperature and most of the reaction occurs quantitatively, and the acid was obtained by diluting with dilute acid to obtain the target product in high yield.

The preparation method of the present invention can be carried out more conveniently than the conventional method, and monoester or 1,4-dihydropyridine-3,5- of 1,4-dihydropyridine3,5-dicarboxylic acid, which is a target product in high yield. The dicarboxylic acid derivative can be obtained purely.

Example 1

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl 5- (2'-methylnioethyl) ester iodomethane salt

Iododomethane 2.03 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5- (2'-methylthioethyl) ester Mix with 4 ml and reflux for 10 hours. After cooling to room temperature, 10 ml of ethyl ether was added, stirred for 10 minutes, and the resulting crystals were separated by filtration. Drying the crystals under reduced pressure yields 2.56 g of yellow crystals.

Yield: 93.4%

Melting Point: 149 ~ 152 ℃

Example 2

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3,5-bis (2'0methylthioethyl) ester

3.52 g of 2- (methylthioethyl) acetoacetate, 3.5 g of 2- (methylthioethyl) 3-aminocrotonate and 3.04 g of 3-nitro benzaldehyde are mixed in 40 ml of isopropyl alcohol and refluxed for 6 hours. After cooling to room temperature, the resulting crystals are separated by filtration. The crystals are recrystallized from methanol to give 6.2 g of yellow crystals.

Yield: 66.05%

Melting Point: 120 ~ 124 ℃

Example 3

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3,5-bis (2'merylthioethyl) ester diiodomethane salt

Iodomethane 1.4 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-polyhydropyridine-3,5-dicarboxylic acid 3,5-bis (2'-methylthioethyl) ester It is suspended in 5.6 ml and refluxed for 24 hours. After the reaction was cooled to room temperature, 10 ml of ethyl ether was added thereto, stirred for 10 minutes, and the resulting crystals were separated by filtration. The crystals were dried under reduced pressure to yield 2.4 g of yellow crystals.

Yield: 98%

Melting Point: 141 ~ 144 ℃

Example 4

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl 5- (2'-methylthioethyl) ester iodomethane salt

2,6-midetyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl 5- (2'-methylthioethyl) ester 1.73G Suspension in 5 ml of ethane and reflux for 6 hours. The reaction is cooled to room temperature, 10 ml of ethyl ether is added and stirred for 10 minutes. The resulting crystals were filtered off and dried under reduced pressure to yield 2.23 g of yellow crystals.

Yield: 91.4%

Melting Point: 65 ~ 68 ℃

Example 5

2,6-dimethyl-4- (2'-nitrophenyl) -1,4-polyhydropyridine-3,5-dicarboxylic acid 3-methyl 5- (2'-methylthioethyl) ester iodomethane salt

2.3 g of 2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5- (2'-methylthioethyl) ester Mix with 6 ml and reflux for 6 hours. The reaction is cooled to room temperature, 10 ml of ethyl ether is added and stirred for 10 minutes. The resulting crystals were separated by filtration and dried under reduced pressure to yield 2.6 g of yellow crystals.

Yield: 83.9%

Melting Point: 120 ~ 124 ℃

Example 6

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-polyhydropyridine-3,5-dicarboxylic acid 3-monomethyl ester

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5- (2'-methylthioethyl) ester iodomethane salt 0.55 g Was suspended in a mixture of 15 ml of ethyl alcohol and 15 ml of water. 1N-NaOH solution was added dropwise to the reaction to adjust the pH to 10-11 and stirred for 30 minutes to dissolve clearly. Crystals produced by the reaction solution d-HC1 are separated by filtration. The crystals were dried over P ₂ O ₅ under reduced pressure to yield 0.29 g of yellow crystals.

Yield: 87.9%

Melting Point: 202 ~ 203 ℃

Example 7

2.6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid

0.75 g of 2.6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3,5-bis- (2-methylthioethyl) ester diiodomethane salt It is added to a mixture of 10 ml of ethyl alcohol and 10 ml of water and dissolved. 1N-NaOH solution was added dropwise thereto to adjust pH to 10-11, followed by stirring for 30 minutes. D-HC1 was added to the reaction solution, and the resulting crystals were separated by filtration. 0.30 g of yellow crystals were obtained by drying over P ₂ O ₅ under reduced pressure.

Yield: 93.8%

Melting Point: 172 ~ 179 ℃

Example 8

2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-monomethyl ester

2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5- (2'-methylthioethyl) ester iodomethane salt 1.1 g Was suspended in a mixture of 4 ml of ethyl alcohol and 4 ml of water. 1N-NaOH solution is added dropwise and adjusted to pH 10-11. After 30 minutes of stirring, the solution is clear and dissolved in d-HC1 solution. The resulting crystals are filtered. The crystals are dried over P ₂ O ₆ under reduced pressure to yield 0.6 g of a yellow crystal.

Yield: 91%

Melting Point: 169 ~ 170 ℃

Example 9

2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-monoisopropyl ester

2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl 5- (2-merylthioethyl) ester iodomethane salt 0.97 g Is suspended in a mixture of 5 ml of ethanol and 5 ml of water. 1N-NaOH solution is added dropwise and adjusted to pH 10-11. After stirring for 30 minutes, the resulting crystals were filtered off with d-HC1. The crystals were solid on P ₂ O ₅ under reduced pressure to yield 0.82 g of yellow crystals.

Yield: 97.6%

Melting Point: 180 ~ 183 ℃

Example 10

2,6-dimethyl-4- (2 ', 3'-dichlorophenyl) -1,4-polyhydropyridine-3,5-dicarboxylic acid 3-methyl 5- (2-methylthioethyl) ester

3.5 g of 2,3-dichlorobenzaldehyde, 2,4 g of methyl 3-amino crotonate and 3.52 g of 2-methylthioethyl aceto acetate are mixed in 40 ml of isopropyl alcohol and refluxed for 24 hours. The solvent is distilled off and the remaining residue is separated using silica gel column chromatography. Concentrate the eluate to afford 7.64 g of a yellow oil.

Yield: 88.8%

Example 11

2,6-dimethyl-4- (2 ', 3'-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5- (2-methylthioethyl) ester iodomethane salt

2.15 g of 2,6-dimethyl-4- (2 ', 3'-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5- (2-methylthioethyl) ester After mixing with 4 ml of ethane, it is refluxed for 20 hours. After cooling to room temperature, 10 ml of ethyl ether was added to the reaction solution and stirred for 1 hour. The resulting crystals were filtered off and dried under reduced pressure to yield 2.45 g of yellow crystals.

Yield: 92.1%

Melting Point: 69 ~ 73 ℃

Example 12

2,6-dimethyl-4- (2'3'-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester

2,6-dimethyl-4- (2 ', 3'-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5- (methylthioethyl) ester iodomethane salt 1.14 g Is dissolved in a mixture of 4 ml of ethyl alcohol. 1N-NaOH solution was added thereto, adjusted to pH 10-11, and stirred for 1 hour. The crystals formed by adding d-HC1 solution to the reaction solution were separated by filtration and dried over P ₂ O ₅ under reduced pressure to obtain 0.68 g of pale yellow crystals.

Yield: 96%

Melting Point: 204 ~ 208 ℃

Claims (6)

The compound represented by formula (II) is reacted with iodoomethane to prepare a compound represented by formula (III) as an intermediate, which is subjected to alkali hydrolysis under a mixed solvent of water and lower alcohol, A method for producing a compound represented by the general formula (I), which is characterized by the above-mentioned.

R ¹ and R ² in formula (I) represent the same or different hydrogen, halogen, trifluoromethyl or nitro group; R ³ is hydrogen or a C ₁ -C ₄ straight or branched lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl Display the flag.

R <^1> , R <^2> in general formula (II) is the same as that of general formula (I); R ³ is C ₁ -C | _A linear or branched lower alkyl group of ₄ , for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl group or 2-methylthioethyl group Is displayed.

R ¹ and R ² in formula (III) have the same definitions as in formula (I); R ³ represents a C to C straight or branched lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl or -CH ₂ CH ₂ S ⁺ (CH ₃ ) | It represents a ^- ₂ I. The method for producing 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-monomethyl ester according to claim 1. The method for producing 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid according to claim 1. The method for producing 2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-monomethyl ester according to claim 1. The method for producing 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-monoisopropyl ester according to claim 1. The method for producing 2,6-dimethyl-4- (2 ', 3'-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-monomer ester according to claim 1.