KR0148125B1 - Processes for the preparation of 1,4-dihydropyridine - Google Patents

Abstract

The present invention relates to a novel 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative represented by general formula (I) and a method for producing the same.

R ¹ and R ² in formula (I) are the same or different hydrogen, halogen, or nitro; R ³ is 2-cyanoethyl or methylthiomethyl.

Description

1,4-dihydropyridine carboxylic acid derivative and preparation method thereof

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

R1 and R2 in the general formula (I) are the same or different hydrogen, halogen, or nitro; R 3 is 2-cyanoethyl or methylthiomethyl.

The 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative is an important intermediate of the synthesis of diesters useful as circulatory medicines and has the following preparation method.

1. Alkali hydrolysis of symmetric diesters

J. Heterocycl. chem., 12, 363 (1975)]

2. Method using symmetric esters protecting nitrogen

chem. Pharm. Bull., 27, 2809 (1980)]

3. Selective Alkaline Hydrolysis Method Using Cyanoethyl Esters

[JP-A 55-64570 (1980)]

4. Selective Hydrolysis Method Using Trimethylsilyl Iodide

[JP-A 61-161263 (1986)]

5. Acid hydrolysis method using acetic acid solution of bromic acid (HBr / HAc) in toluene solvent

[Japanese Patent Laid-Open No. 61-40,262 (1986)]

Their production method has many problems, such as extremely low yield, complicated or difficult reaction operation, and the use of toxic substances such as acetic acid solution of bromic acid (HBr / HAc). In order to synthesize complex and asymmetric esters of pyridine-3,5-dicarboxylic acid, the 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative is obtained with high selectivity and fine selectivity under mild conditions. There was a need for a method to prepare.

The present inventors have studied for the purpose of synthesizing with high selectivity and fine selectivity under mild conditions of 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivatives. The above object was achieved by using an alkali hydrolysis reaction.

The present invention provides a compound represented by formula (III) by reacting iodomethane with a compound represented by formula (II), wherein R3 is substituted with 2-cyanoethyl, which is hydrolyzed under alkaline conditions. To a 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative and a method for producing the same.

R <^1> and R <^2> in the said general formula (Ia), (II), (III) is the same as that of the general formula (I).

The compound represented by the general formula (II) can be easily prepared according to the generally known Hanzdihydropyridine Synthesis method (Hantsch Dihydropyridine Synthesis).

The compound represented by the general formula (III) is prepared by reacting the compound represented by the general formula (II) with iodine methane, where iodomethane is used as a reactant and a solvent. The reaction temperature can be carried out at room temperature or at the boiling point of iodomethane and the reaction time takes 6 to 24 hours. At this time, the compound represented by general formula (III) can be obtained almost quantitatively.

The compound of the present invention represented by the general formula (Ia) in which R ³ is substituted with 2-cyanoethyl may be substituted with water and lower alcohols such as methanol, ethanol, and isopropyl alcohol. A dilute aqueous solution of an alkali metal hydroxide may be added dropwise and hydrolyzed using a mixed solvent. At this time, the pH of the end point is 10-12, specifically, pH 11 ± 0.5 is suitable. The titration rate is carried out within 1 hour, specifically 30 minutes is most suitable at this time, the temperature is carried out at 0 ℃ ~ 20 ℃, but most can be carried out below 10 ℃, most reactions occur quantitatively, The desired product can be obtained in high yield. The production method of the present invention is a very sophisticated hydrolysis method compared to the conventional method. In other words, despite the presence of 2-cyanoethyl group which is well hydrolyzed, the compound represented by the above general formula (I) can be obtained in a high yield by selectively hydrolyzing at the ester of the methyl iodide salt side.

A compound in which R ³ is substituted with methylthiomethyl (formula (Ib)) is a compound of formula (IV) prepared according to a known method from a compound represented by formula (Ia) prepared by the above-described preparation method and It can be manufactured by hydrolysis according to a known method.

R ¹ and R ² in the general formula (Ib) or (IV) are the same as defined above.

The compound represented by formula (IV) is synthesized by reacting the compound represented by formula (Ia) with chloromethyl sulfide in acetonitrile using an acid acceptor such as triethylamine, sodium carbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate and the like. The compound of the general formula (IV) may be prepared in the form of the compound of the general formula (Ib) by hydrolysis in a dilute aqueous solution of hydroxide of metal alkali in water and ethanol mixed solvent. At this time, the reaction time is 6 to 24 hours, the reaction temperature is carried out at 0 ℃ ~ 40 ℃, but is carried out mostly at room temperature and can be obtained in high yield by diluting with dilute hydrochloric acid at low temperature below 5 ℃.

Example 1

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

3-nitrobenzaldehyde (5.63 g, 0.037 mole), 2-methylthioethyl acetoacetate (7.05 g, 0.04 mole) and 0.5 ml of piperidine are mixed in 150 ml of anhydrous benzene and refluxed for 3 hours. The reaction solution was concentrated under reduced pressure, 2'-cyanoethyl 3-aminocrotonate (5.7 g, 0.037 mole) and 150 ml of isopropyl alcohol were added thereto, mixed and refluxed for 12 hours. The red oily substance produced by concentration under reduced pressure is purified using silica gel chromatography (eluent ethyl acetate: n-hexane = 1: 1 (v / v)).

Yield: 7 g (42.5%)

Melting Point: 148 ~ 150 ℃

Example 2

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2'-cyanoethyl) ester 5- (2'methylthio Ethyl ester methyl iodide salt

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2'-cyanoethyl) ester 5- (2'methylthio Ethyl) ester (11.14 g, 0.025 mole) is suspended in 50 ml of methyl iodide and stirred for 16 hours. The solvent is removed by concentration under reduced pressure, and ether (150 ml) is added to the residue, followed by stirring. The resulting yellow crystals are separated by filtration and dried.

Yield: 13.64 g (92%)

Melting Point: 140 ~ 142 ℃

Example 3

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

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2'-cyanoethyl) ester 5- (2'methylthio ) Ethyl ester methyl iodide salt (11.75 g, 0.02 mole) is suspended in a mixture of 100 ml of ethanol and 100 ml of water. The pH is adjusted to 11 ~ 12 by slowly adding 2-sodium hydroxide solution to give a clear yellow solution. After stirring for 1 hour, when d-hydrochloric acid is added to pH 1-2, yellow precipitates are formed. Filtration and yellow crystals are obtained under vacuum drying in a phosphorus pentoxide.

Yield: 7.43 g (92%)

Melting Point: 178 ~ 181 ℃

Example 4

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

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2'-cyanoethyl) ester (6.68 g, 0.018 mole) Is suspended in acetonitrile (100 ml) and cooled to 0 ° C. on an ice water bath. Triethylamine (5ml, 2eq) was added thereto and stirred for 30 minutes to dissolve clearly. Chloromethylmethylsulfide (2.3 ml, 1.5 eq.) Was added thereto, and the mixture was stirred at room temperature for 72 hours. The reaction mixture is concentrated under reduced pressure to remove the solvent, ethyl acetate (100 ml) is added, and the mixture is washed with water and brine. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to recrystallize the resulting yellow solid with ethanol.

Yield: 7.2 g (88.1%)

Melting Point: 147 ~ 149 ℃

Example 5

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

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methylthiomethylester 5- (2'-cyanoethyl) ester ( 4.31 g, 0.01 mole) is suspended in 50 ml of water and 50 ml of ethanol, and then 2N-sodium hydroxide (6 ml) is added and stirred at room temperature for 4 hours to give a clear yellow solution. 3N hydrochloric acid was added thereto to pH 1-2, and the yellow precipitate produced by filtration was dried by filtration.

Yield: 3.14 g (83%)

Melting Point: 184 ~ 186 ℃

Claims (3)

1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative represented by the following general formula (I).

Wherein R ¹ and R ² are the same or different hydrogen, halogen, or nitro and R ³ is 2-cyanoethyl or methylthiomethyl. 1,4-dihydro represented by general formula (Ia) characterized by reacting a compound of general formula (II) with iodine methane to produce a compound of general formula (III), and then hydrolyzing it under alkaline conditions. Process for the preparation of pyridine-3,5-dicarboxylic acid monoester derivatives.

Wherein R ¹ and R ² are the same or different hydrogen, halogen, or nitro. 1,4-dihydropyridine-3,5-dicar represented by formula (Ib) characterized by preparing a compound of formula (IV) from a compound of formula (Ia) and then hydrolyzing it Method for producing acid monoester derivative.

Wherein R ¹ and R ² are the same or different hydrogen, halogen, or nitro.