JPH07196612A - 1,4-dihydropyridine derivative and production of 1,4-dihydropyridinecarboxylic acid derivative using the same - Google Patents

Abstract

PURPOSE:To obtain a new 1,4-dihydropyridine derivative which can readily be converted into 1,4-dihydropyridinecarboxylic acid derivative as an intermediate for cardio-vascular drugs. CONSTITUTION:1,4-Dihydropyridine derivative of formula I (R<1> is a 1-3C alkyl, 2-methoxyethyl; R<2> is 2,4-dimethoxybenzyl, alpha,alphadimethylbenzyl, 4,4'- dimethoxybenzhydryl), for example, (+ or -)-2,4-dimethoxybenzyl-methyl-1,4- dihydro-2,6-dimethyl-4-(3-nitro-phenyl)pyridine-3,5-dicarboxylate. The compound of formula I is prepared, for example, by reaction of an acetoacetate derivative of formula III with an aminocrotonate derivative of formula IV. The compound of formula I is deprotected to give a 1,4-dihydropyridinecarboxylic acid derivative of formula V which is useful as an intermediate for cardio-vascular drugs.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has the general formula

[Chemical 4] (In the formula, R ¹ is a lower alkyl group having 1 to 3 carbon atoms or 2
-Methoxyethyl group, R ² is 2,4-dimethoxybenzyl group, α, α-dimethylbenzyl group or 4,4 ′.
A dimethoxybenzhydryl group. ) 1,4-dihydropyridine derivative represented by the general formula (I) and the 1,4-dihydropyridine derivative represented by the general formula (I) are subjected to a deprotection reaction.

[Chemical 5] (In the formula, R ¹ is the same as above.) 1,4-
The present invention relates to a method for producing a dihydropyridinecarboxylic acid derivative.

It is known that the 1,4-dihydropyridinecarboxylic acid derivative represented by the general formula (II) is used as an intermediate for producing a circulatory system drug (for example, JP-A-51). -108075).

[0003]

2. Description of the Related Art 1, represented by the general formula (II)
As a method of producing a 4-dihydropyridinecarboxylic acid derivative, a method of selectively hydrolyzing one ester group of a 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative with a base is known. As an example of this method, (i) a method using a compound in which a protecting group is introduced into the nitrogen atom at the 1-position of the 1,4-dihydropyridine ring (TS
hibanuma et al. Chem. Phar
m. Bull. , 28, 2809 (1980)),
(B) A method using a compound in which the ester group to be deprotected is an alkyl group substituted with an electron-withdrawing group such as a cyano group (see JP-B-63-26749).

[0004]

The conventional method of hydrolysis under basic conditions requires a neutralization operation with an acid after the hydrolysis reaction of the ester group. Furthermore, in the method (a), the protecting group for the nitrogen atom at the 1-position must be deprotected,
In particular, there are many problems such as complicated operation in mass synthesis.

[0005]

[Means for Solving the Problems] The conventional general formula (II)
In the method for producing a 1,4-dihydropyridinecarboxylic acid derivative represented by the formula, as a result of intensive research aimed at finding a method for obtaining 1,4-dihydropyridinecarboxylic acid, the derivative represented by the general formula (I) Is capable of selectively and easily deprotecting the ester group R ² (the same as above) without decomposing the dihydropyridine ring under acidic conditions, and the 1,4-dihydropyridinecarboxylic acid represented by the general formula (I) is It was found that an acid derivative can be obtained, and the present invention was completed. By adopting the deprotection method of the present invention, it is possible to obtain a desired product with a high yield and a high purity only by collecting the precipitated crystals.

[0006] 1, represented by the general formula (I) of the present invention
In the 4-dihydropyridine derivative, R ¹ is a lower alkyl group having 1 to 3 carbon atoms or a 2-methoxyethyl group. Examples of the lower alkyl group having 1 to 3 carbon atoms include methyl group, ethyl group, n-propyl group and isopropyl group. R ² is 2,4-dimethoxybenzyl group, α, α-dimethylbenzyl group, or 4,
It is a 4'-dimethoxybenzhydryl group.

The 1,4-dihydropyridine derivative represented by the general formula (I) of the present invention is, for example, a compound represented by the general formula

[Chemical 6] (Wherein R ² is the same as above) and the general formula

[Chemical 7] It can be produced by reacting with an aminocrotonate derivative represented by the formula (R ¹ is the same as above).

The reaction can be carried out without solvent or in a solvent inert to the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether and tetrahydrofuran, and alcohols such as methanol and ethanol. The reaction can be performed at 0 ° C to 150 ° C.

The 1,4-dihydropyridine derivative represented by the general formula (I) is an optically active compound having an asymmetric center at the 4-position of the 1,4-dihydropyridine ring. Therefore, the optically active 1,4-dihydropyridine derivative represented by the general formula (I) is, for example, an acetoacetate derivative represented by the general formula (III) or a general formula

[Chemical 8] (Wherein R ¹ is the same as above and R ³ is an optically active amino group), and then reacted with ammonia or an acid addition salt thereof. be able to.

In order to carry out the reaction efficiently, it is preferable to use a base, and for example, butyl lithium, lithium diisopropylamide, sodium hydride, alkyl magnesium halide, phenyl magnesium halide and the like can be used. The amount of the base used is usually 0.5 to 5 relative to the crotonate derivative represented by the general formula (V).
1.5 equivalents can be used. The reaction is preferably carried out in an aprotic solvent, such as diethyl ether,
Solvents such as ethers such as tetrahydrofuran and aromatic hydrocarbons such as benzene and toluene can be used. The reaction proceeds at −120 to 110 ° C., but it is preferable to carry out at −100 to 20 ° C. for efficient reaction. The reaction is preferably carried out under anhydrous conditions and in an atmosphere of an inert gas such as nitrogen gas or argon gas in order to obtain the desired product with a high yield. Examples of ammonia or acid addition salts thereof include ammonia, ammonium acetate, ammonium chloride and the like. The amount used is preferably 1.0 to 20 equivalents relative to the acetate derivative represented by the general formula (III), and 1.2 to 5 equivalents for efficient reaction.

The reaction with ammonia or an acid addition salt thereof is preferably carried out in a solvent, for example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether and tetrahydrofuran, hexane, pentane and benzene. Hydrocarbons such as toluene and the like can be used. The reaction is 0-60 ° C
However, room temperature is preferable because the operation is simple.

The acetoacetate derivative represented by the general formula (III) used in the reaction includes diketene and the general formula R ² OH.
It can be produced by reacting with an alcohol derivative represented by (VI) (wherein R ² is the same as above). The aminocrotonate derivative represented by the general formula (IV) can be produced by reacting an acetate derivative with ammonia or an acid addition salt thereof. Furthermore, the aminocrotonate derivative represented by the above general formula (V) can be produced by reacting an acetate derivative with an optically active amine derivative (Japanese Patent Laid-Open No. Hei 5).
-78319).

The 1,4-dihydropyridine derivative represented by the general formula (I) obtained by the method of the present invention is, for example, (±) -2,4-dimethoxybenzyl methyl 1,4-dihydro-2,6. -Dimethyl-4- (3-
Nitrophenyl) -3,5-dicarboxylate,
(±) -α, α-Dimethylbenzyl methyl 1,4-
Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-dicarboxylate, (±) -4,4 ′
-Dimethoxybenzhydryl methyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-
3,5-dicarboxylate, (±) -2,4-dimethoxybenzyl methyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-dicarboxylate, (- ) -2,4-Dimethoxybenzyl
Methyl 1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl) -3,5-dicarboxylate, (+)-α, α-dimethylbenzyl methyl 1,
4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-dicarboxylate, (−)-α,
α-dimethylbenzyl methyl 1,4-dihydro-
2,6-dimethyl-4- (3-nitrophenyl) -3,
5-dicarboxylate, (+)-4,4'-dimethoxybenzhydryl methyl 1,4-dihydro-2,6
-Dimethyl-4- (3-nitrophenyl) -3,5-dicarboxylate, (-)-4,4'-dimethoxybenzhydryl methyl 1,4-dihydro-2,6-dimethyl-4- (3 -Nitrophenyl) -3,5-dicarboxylate, (±) -2,4-dimethoxybenzyl ethyl 1,4-dihydro-2,6-dimethyl-4- (3
-Nitrophenyl) -3,5-dicarboxylate,
(±) -2,4-dimethoxybenzyl propyl 1,
4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-dicarboxylate, (±) -2,
4-dimethoxybenzyl isopropyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)
-3,5-Dicarboxylate, (±) -2,4-dimethoxybenzyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-
3,5-dicarboxylate and the like can be mentioned.

Further, 1, represented by the general formula (II)
The 4-dihydropyridinecarboxylic acid derivative can be produced by deprotecting one ester group of the 1,4-dihydropyridine derivative represented by the general formula (I) with an acid.

Examples of the acid used in this reaction include hydrochloric acid,
Mineral acids such as sulfuric acid, organic acids such as trifluoroacetic acid, hydrogen chloride and the like can be mentioned. Hydrogen chloride is preferably used by dissolving it in an organic solvent. The acid may be used in an amount of 1.0 to 5.0 equivalents with respect to the 1,4-dihydropyridine derivative represented by the general formula (I), but 1.0 to 1 is used for good yield. It is preferable to use 0.5 equivalent. The reaction is preferably carried out in an inert solvent, and examples of the solvent include aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as methylene chloride and chloroform, and esters such as methyl acetate and ethyl acetate. , Alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile and propionitrile, and the like can be used alone or in combination. The reaction is -30 to 80
Although the reaction proceeds at ℃, it is -30 to 10 for efficient reaction.
It is preferable to carry out at ℃.

Since the 1,4-dihydropyridinecarboxylic acid derivative represented by the general formula (II) obtained by this reaction is usually precipitated in the reaction solvent, the crystal of the general formula (II The 1,4-dihydropyridinecarboxylic acid derivative represented by) can be isolated.

[0017]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples.

Example 1 (±) -2,4-dimethoxybenzyl methyl 1,4
-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate

[Chemical 9]

2,4-dimethoxybenzyl 2- (3-
Nitrobenzylidene) acetoacetate 385 mg (1
mmol) and 3-aminocrotonate 115 mg
The mixture of (1.2 mmol) was heated at 110 ° C. for 30 minutes. The reaction mixture was dissolved in benzene, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title (±) -2,
4-dimethoxybenzylmethyl 1,4-dihydro-
2,6-Dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 460 mg (yield 9
5.4%).

NMR (δ, CDCl ₃ ): 2.35 (6H, s), 3.61 (3H,
s), 3.75 (3H, s), 3.82 (3H, s), 4.99 (1H, d, J = 12Hz), 5.06 (1
H, s), 5.10 (1H, d, J = 12Hz), 5.67 (1H, s), 6.40 (1H, dd, J = 8H
z, 2Hz), 6.42 (1H, d, J = 2Hz), 7.05 (1H, d, J = 8Hz), 7.28 (1H, d
d, J = 8Hz, 8Hz), 7.54 (1H, d, J = 8Hz), 7.96 (1H, d, J = 8Hz), 8.0
1 (1H, s)

Example 2 (±) -α, α-dimethylbenzyl methyl 1,4-
Dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate

[Chemical 10] The same reaction as in Example 1 was carried out using α, α-dimethylbenzyl 2- (3-nitrobenzylidene) acetoacetate and 3-aminocrotonate to obtain (±) -α, α-dimethylbenzyl methyl 1,4- Dihydro-2,6-
Dimethyl-4- (3-nitrophenyl) pyridine-3,
5-Dicarboxylate was obtained with a yield of 80%.

NMR (δ, CDCl ₃ ): 1.63 (3H, s), 1.75 (3H,
s), 2.30 (3H, s), 2.36 (3H, s), 3.66 (3H, s), 5.16 (1H, s), 5.6
2 (1H, s), 6.97-7.06 (2H, m), 7.12-7.25 (3H, m), 7.41 (1H, d
d, J = 8Hz, 8Hz), 7.67 (1H, d, J = 8Hz), 8.06 (1H, d, J = 8Hz), 8.1
6 (1H, s)

Example 3 (±) -4,4'-dimethoxybenzhydryl methyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate

[Chemical 11] The same reaction as in Example 1 was carried out using 4,4′-dimethoxybenzhydryl 2- (3-nitrobenzylidene) acetoacetate and 3-aminocrotonate to obtain (±)-
4,4'-Dimethoxybenzhydryl methyl 1,4
Yield 7-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate
It was obtained at 7.1%.

NMR (δ, CDCl ₃ ): 2.33 (3H, s), 2.39 (3H,
s), 3.65 (3H, s), 3.75 (3H, s), 3.80 (3H, s), 5.16 (1H, s), 5.7
3 (1H, s), 6.68 (2H, d, J = 9Hz), 6.75 (1H, s), 6.86 (2H, d, J = 9H
z), 6.87 (2H, d, J = 9Hz), 7.21 (2H, d, J = 9Hz), 7.28 (1H, dd, J =
8Hz, 8Hz), 7.56 (1H, d, J = 8Hz), 7.98 (1H, d, J = 8Hz), 8.05 (1
H, s)

Example 4 (R)-(+)-2,4-dimethoxybenzyl methyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate

[Chemical 12]

Under a N ₂ gas atmosphere, (−)-methyl
(R)-[N- [1- (t-butoxycarbonyl) -2
-Methylpropyl] aminocrotonate 2.985 g
To a solution of (11 mmol) in 15 ml of anhydrous tetrahydrofuran, 1.2 equivalents of a tetrahydrofuran solution of phenylmagnesium bromide [magnesium 340 mg (14
mg atom), 1,2-dibromoethane 188 mg
(1 mmol), 2.073 g of bromobenzene (13.
2 mol), adjusted from 13 ml of anhydrous tetrahydrofuran] was added dropwise at −15 ° C., and the mixture was further stirred for 1 hour. Then, this solution was cooled to −80 ° C., and a solution of 2,4-dimethoxybenzyl 2- (3-nitrobenzylidene) acetoacetate (3.854 g, 10 mmol) in anhydrous tetrahydrofuran (19 ml) was added dropwise, and the mixture was further stirred for 3 hours after completion of the addition. did. 20% citric acid in the reaction solution
(34 mmol) was added dropwise, the temperature was returned to room temperature, the organic layer was separated, the aqueous layer was extracted with tetrahydrofuran, the organic layer was combined with the organic layer, and washed with saturated saline. 10% -Citric acid ml (22 mmol) was added to the organic layer, the mixture was stirred at room temperature for 3 hours, saturated saline was added to separate the organic layer, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Dissolve the residue in 50 ml of methanol,
3.85 g (50 mmol) of ammonium acetate was added,
After stirring overnight at room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title (R)-(+)-2,4-dimethoxybenzyl methyl 1,4-dihydro-2,6-dimethyl-4- (with an optical purity of 94.8% ee. 3.65 g (yield 75.6%) of 3-nitrophenyl) pyridine-3,5-dicarboxylate was obtained. 18 ml more
Recrystallized from methanol to give 100% ee of the title (R)
-(+)-2,4-dimethoxybenzyl methyl 1,
4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 2.8
9 g (recrystallization recovery rate 79%) was obtained.

Melting point: 113.9-114.8 ° C. Optical rotation: [α] _D ²⁵ = 24.8 ° (c = 1.023, methanol) IRν (cm ⁻¹ , KBr): 3368, 1704, 16
96, 1530, 1348 NMR (δ, CDCl ₃ ): 2.35 (6H, s), 3.61 (3H, s), 3.75 (3H,
s), 3.82 (3H, s), 4.99 (1H, d, J = 12Hz), 5.06 (1H, s), 5.10 (1
H, d, J = 12Hz), 5.67 (1H, s), 6.40 (1H, dd, J = 8Hz, 2Hz), 6.42
(1H, d, J = 2Hz), 7.05 (1H, d, J = 8Hz), 7.28 (1H, dd, J = 8Hz, 8H
z), 7.54 (1H, d, J = 8Hz), 7.96 (1H, d, J = 8Hz), 8.01 (1H, s)

Example 5 (±) -1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) pyridine-3-carboxylic acid

[Chemical 13]

(±) -2,4-dimethoxybenzyl methyl 1,4-dihydro-2,6-synthesized in Example 1
Dimethyl-4- (3-nitrophenyl) pyridine-3,
A solution of 482 mg (1 mmol) of 5-dicarboxylate in 10 ml of acetonitrile was cooled to -15 ° C. 1N
1.2 ml of hydrogen chloride-ethyl acetate solution was added dropwise to 30
Stir for minutes. The precipitated crystals were collected by filtration, washed with a small amount of cold acetonitrile and dried under reduced pressure to give the title (±) -1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4.
-(3-Nitrophenyl) pyridine-3-carboxylic acid 2
82 mg (yield 85%) was obtained.

Melting point: 177 ° C. (decomposition) Mass analysis: Theoretical value as molecular formula C ₁₆ H ₁₆ N ₂ O ₆ ; 332.2008 actual value; 332.0095 IR ν (cm ^-1 , KBr);
34,1352 NMR (δ, acetone-d ₆ ); 2.37 (6H, s), 3.61 (3H, s), 5.
18 (1H, s), 7.52 (1H, t, J = 8Hz), 7.74 (1H, d, J = 8Hz), 8.01 (1
H, s), 8.15 (1H, s), 10.4 (1H, s)

Example 6 (±) -1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) pyridine-3-carboxylic acid

[Chemical 14]

(±) -α, α-Dimethylbenzylmethyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5 synthesized in Example 2
A solution of 225 mg (1 mmol) of dicarboxylate in 10 ml of acetonitrile was cooled to -15 ° C. 1N
1.2 ml of hydrogen chloride-ethyl acetate solution was added dropwise, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with a small amount of cold acetonitrile and dried under reduced pressure to give the title (±) -1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-.
(3-Nitrophenyl) pyridine-3-carboxylic acid 13
7 mg (yield 83%) was obtained. This compound is obtained in Example 5
The same melting point, mass spectrometry, IR and NM as the compound synthesized in
The R analysis result was obtained.

Example 7 (±) -1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) pyridine-3-carboxylic acid

[Chemical 15]

(±) -4,4'-Dimethoxybenzhydryl methyl 1,4-dihydro-2,6-dimethyl-
A solution of 558 mg (1 mmol) of 4- (3-nitrophenyl) pyridine-3,5-dicarboxylate in 10 ml of acetonitrile was cooled to -15 ° C. 1.2 ml of 1N hydrogen chloride-ethyl acetate solution was added dropwise, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with a small amount of cold acetonitrile and dried under reduced pressure to give the title (±) -1,4-dihydro-
2,6-dimethyl-5-methoxycarbonyl-4- (3
-Nitrophenyl) pyridine-3-carboxylic acid 289 m
g (yield 87%) was obtained. This compound gave the same melting point, mass spectrometry, IR and NMR analysis results as the compound synthesized in Example 5.

Example 8 (S)-(+)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) pyridine-3-carboxylic acid

[Chemical 16]

(R)-(+)-2 synthesized in Example 4
4-dimethoxybenzyl methyl 1,4-dihydro-
2,6-Dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 482 mg (1 mmo
A solution of 1) in 5 ml of acetonitrile was cooled to -15 ° C. 1.2 ml of 1N hydrogen chloride-ethyl acetate solution was added dropwise, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with a small amount of cold acetonitrile and dried under reduced pressure, and the title (S)-
200 mg (yield 60%) of (+)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) pyridine-3-carboxylic acid were obtained.

[0037] mp: 171-172 ° C. (decomposition) Mass analysis: Calculated as molecular formula _{C 16 H 16 N 2 O 6} ; 332.10081 Found: 332.10107 rotation: [α] _D ²⁵ = + 19.3 ° [C = 0.992
4, acetone] NMR (δ, acetone-d ₆ ); 2.37 (6H, s), 3.61 (3H, s), 5.
18 (1H, s), 7.52 (1H, t, J = 8Hz), 7.74 (1H, d, J = 8Hz), 8.01 (1
H, s), 8.15 (1H, s), 10.4 (1H, s)

Comparative Examples 1 to 5 As the 1,4-dihydropyridine compounds represented by the general formula (VII) shown in Table 1, the corresponding acetoacetate derivative and 3-aminocrotonate were used. It was produced by the method of Japanese Patent Publication No. 51-08075. Each of the obtained compounds was subjected to the same deprotection reaction as in Example 5. For the unreacted compound, the reaction temperature was raised from -15 ° C to room temperature to continue the reaction. The results of Comparative Examples 1 to 5 are shown in Table 1.

The compounds of Comparative Examples 1, 2 and 5 in which the reaction did not proceed under the reaction conditions of Example 5 were further reacted with trifluoroacetic acid at room temperature using thioanisole as a solvent. Under this reaction condition, the compounds of Comparative Examples 1, 2, and 5 were accompanied by decomposition reactions other than the deprotection reaction of the target ester group, and the target carboxylic acid was not obtained.

[0040]

[Table 1]

[0041]

The 1,4-dihydropyridinecarboxylic acid derivative represented by the general formula (II) is a synthetic intermediate of the 1,4-dihydropyridine derivative useful as a therapeutic agent for cardiovascular diseases. The compound represented by the general formula (II) can be easily produced with a high yield by treating the 1,4-dihydropyridine derivative represented by the general formula (I) under acidic conditions.

Claims (10)

[Claims] 1. A general formula: 1,4-dihydropyridine derivative represented by the formula (in the formula, R
¹ is a lower alkyl group having 1 to 3 carbon atoms or a 2-methoxyethyl group, and R ² is a 2,4-dimethoxybenzyl group, an α, α-dimethylbenzyl group or a 4,4′-dimethoxybenzhydryl group. Is). 2. The 1,4-dihydropyridine derivative according to claim 1, wherein R ² is a 2,4-dimethoxybenzyl group. 3. The 1,4-dihydropyridine derivative according to claim 1, wherein R ² is an α, α-dimethylbenzyl group. 4. The 1,4-dihydropyridine derivative according to claim 1, wherein R ² is a 4,4′-dimethoxybenzhydryl group. 5. The 1,4-dihydropyridine derivative according to claim 2, 3 or 4, wherein R ¹ is a methyl group. 6. A general formula: A 1,4-dihydropyridine derivative represented by the general formula: A method for producing a 1,4-dihydropyridinecarboxylic acid derivative represented by the formula (wherein R ¹ is a lower alkyl group having 1 to 3 carbon atoms or a 2-methoxyethyl group, and R ² is 2,4-
A dimethoxybenzyl group, an α, α-dimethylbenzyl group or a 4,4′-dimethoxybenzhydryl group). 7. The production method according to claim 6, wherein the deprotection reaction is carried out using an acid. 8. The production method according to claim 7, wherein R ² is a 2,4-dimethoxybenzyl group. 9. The method according to claim 7, wherein R ² is an α, α-dimethylbenzyl group. 10. The production method according to claim 7, wherein R ² is a 4,4′-dimethoxybenzhydryl group.