JPH0160465B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to 1,4-dihydropyridine-3,5-
This invention relates to dicarboxylic acid diester derivatives and their production method. More specifically, the present invention provides a blood pressure lowering effect,
The present invention relates to a novel 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative having excellent pharmacological effects such as vasodilatory action and long duration of action, and a method for producing the same.

Prior Art Conventionally, as a compound having pharmacological effects such as hypotensive effect and vasodilatory effect, the formula 4-(O-nitrophenyl)-2, represented by
6-dimethyl-1,4-dihydropyridine-3,
5-dicarboxylic acid dimethyl ester (hereinafter abbreviated as nifedipine) is known. Nifedipine is a compound that has excellent pharmacological effects such as hypotensive action, but it has the disadvantage that its duration is short. Many niedipine derivatives have been studied with the aim of obtaining compounds that have long-lasting pharmacological effects such as hypotensive action. For example, Japanese Patent Publication No. 56-6417 describes 4-(m-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5- in which the 3- or 5-position of nifedipine is converted to an aminoalkyl ester. Dicarboxylic acid-3-methyl ester-5-β-(N-
Benzyl-N-methylamino)ethyl ester hydrochloride (hereinafter abbreviated as nicardipine) has been reported. Furthermore, JP-A-55-9083 reports a nifedipine derivative in which the 2'-nitrophenyl group at the 4-position of nifedipine is converted to a 2',3'-dichlorophenyl group.

Purpose of the Invention The present inventors have discovered that 1, in which the phenyl group at the 4-position of nifedipine is converted to a 2',5'-disubstituted phenyl group, etc.
A 4-dihydropyridine-3,5-dicarboxylic acid diester derivative was synthesized. The present invention was achieved by discovering that such nifedipine derivatives have strong pharmacological effects such as hypotensive effects, and that the duration of the pharmacological effects is extremely long.

Therefore, an object of the present invention is to provide a novel 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative that has excellent pharmacological effects such as hypotensive action and has a long duration.

A further object of the present invention is to provide a novel method for producing a 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative.

Structure and Effects of the Invention The compound provided by the present invention has the following formula [] [In the formula, X and Y each represent a hydrogen atom, a chlorine atom, or a nitro group. However, either X or Y represents a hydrogen atom. R ¹ and R ₂ are the same or different and represent a lower alkyl group or -CH ₂ CH ₂ OR ³ . R ₃ represents a lower alkyl group. ] 1,4-dihydropyridine-3,5 represented by
-Dicarboxylic acid diester derivative.

1,4-dihydropyridine-3,5- of the present invention
The dicarboxylic acid diester derivative has a
It is a new compound that has a 2', 3' or 2', 5'-disubstituted phenyl group and has not been specifically disclosed in the literature, and has long-lasting pharmacological effects such as hypotensive action. It has the following.

In the above formula [], R ¹ and R ² are the same or different, and represent a lower alkyl group or -CH ₂ CH ₂ OR ³ . R ³ represents a lower alkyl group. Lower alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
Examples include isobutyl and n-pentyl groups.

X and Y each represent a hydrogen atom, a chlorine atom or a nitro group. However, either X or Y represents a hydrogen atom.

1,4-dihydropyridine-3,5- of the present invention
Preferred examples of dicarboxylic acid diester derivatives are as follows.

(100) 2,6-dimethyl-4-(3-chloro-
2'-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-isopropyl ester-5-(2-methoxyethyl) ester (102) 2,6-dimethyl-4-(2'- Fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-isopropyl ester (104) 2,6-dimethyl-4-(3'-chloro-
2'-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester (106) 2,6-dimethyl-4-(3'-chloro-
2'-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid di(2-methoxyethyl) ester (108) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (110) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid Dimethyl ester (112) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(2-n- propoxyethyl) ester (114) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester ( 116) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-sec-butyl ester-5-isopropyl ester (118) 2 ,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-sec-butyl ester-5-n-propyl ester (120) 2, 6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester (122) 2,6-dimethyl-4-(2'-fluoro-3 '-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid di(methoxyethyl) ester (124) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4- Dihydropyridine-3,5-dicarboxylic acid di(ethoxyethyl) ester (126) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid di (n-propoxyethyl) ester (128) 2,6-dimethyl-4-(2'-fluoro-3'nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid di(butoxyethyl) ester (130) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methoxyethyl ester-5-ethoxyethyl ester (132) 2,6 -Dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethoxyethyl ester -5-n-propoxyethyl ester (134) 2,6- Dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-n-propoxyethyl ester-5-sec-butoxyethyl ester (136) 2,6 -dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-methoxyethyl ester (138) 2,6-dimethyl-4 -(2'-Fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-ethoxyethyl ester (140) 2,6-dimethyl-4-(2'-Fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-n-propyl ester-5-n-propoxyethyl ester (142) 2,6-dimethyl-4-(2'-Fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-sec-butyl ester-5-sec-butoxyethyl ester (144) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-sec-butoxyethyl ester (146) 2,6-dimethyl-4-(2'-fluoro -3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-n-propyl ester-5-n-pentyloxyethyl ester (148) 2,6-dimethyl-4-(2'- Fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid di(methoxyethyl) ester (150) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1 ,4-dihydropyridine-3,5-dicarboxylic acid di(ethoxyethyl) ester (152) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5- Di(n-propoxyethyl) dicarboxylic acid ester (154) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid di(butoxyethyl) Ester (156) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methoxyethyl ester-5-ethoxyethyl ester) ( 158) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethoxyethyl ester-5-n-propoxyethyl ester (160 ) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-n-propoxyethyl ester-5-sec-butoxyethyl ester ( 162) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester (164) 2,6 -Dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-sec-butyl ester-5-isopropyl ester (166) 2,6-dimethyl- 4-(2'-Fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-sec-butyl ester-5-n-propyl ester (168) 2,6-dimethyl-4 -(2'-Fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester (170) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-methoxyethyl ester (172) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4- Dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-ethoxyethyl ester (174) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid-3-n-propyl ester-5-n-propoxyethyl ester (176) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid-3-sec-butyl ester-5-sec-butoxyethyl ester (178) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid-3-methyl ester-5-sec-butoxyethyl ester (180) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5- Dicarboxylic acid-3-n-propyl ester-5-n-pentyloxyethyl ester (182) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5 -Dicarboxylic acid di(methoxyethyl) ester (184) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid di(ethoxyethyl) ester (186) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid di(n-propoxyethyl) ester (188) 2,6- Dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid di(butoxyethyl) ester (190) 2,6-dimethyl-4-(2'-fluoro 2,6-dimethyl-4-(2'-fluoro-3' -Chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethoxyethyl ester-5-n-propoxyethyl ester (194) 2,6-dimethyl-4-(2'-fluoro-3'- (196) 2,6-dimethyl-4-(2'-fluoro-3' -chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester (198) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1 ,4-dihydropyridine-3,5-dicarboxylic acid-3-sec-butyl ester-5-isopropyl ester (200) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4- Dihydropyridine-3,5-dicarboxylic acid-3-sec-butyl ester-5-n-propyl ester (202) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine -3,5-dicarboxylic acid diisopropyl ester (204) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester- 5-Methoxyethyl ester (206) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-ethoxyethyl Ester (208) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-n-propyl ester-5-n-propoxyethyl Ester (210) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-sec-butyl ester-5-sec-butoxyethyl Ester (212) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-sec-butoxyethyl ester ( 214) 2,6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-n-propyl ester-5-n-pentyloxyethyl ester 1,4-dihydropyridine-3,5- of the present invention
The dicarboxylic acid diester derivative has the following formula [] [In the formula, X and Y are the same as defined above. ] An aldehyde compound represented by the following formula [] CH ₃ COCH ₂ COO—R ² ... [] [In the formula, R ² is the same as defined above. ] Acetoacetate compound represented by and the following formula [] [In the formula, R ¹ is the same as defined above. ] It is produced by reacting with a 3-aminocrotonic acid ester compound represented by the following.

To obtain the aldehyde compound of the above formula [],
The following formula [] [In the formula, X and Y are the same as defined above, and R ⁴ represents methyl or hydroxymethyl. ] can be easily produced by oxidizing it in the presence of a known oxidizing agent. As an oxidizing agent, chromium,
Examples include oxidizing agents containing elements such as silver and selenium.

The acetoacetate compound of the above formula [] and the 3-aminocrotonic acid ester compound of the above formula [] can be easily produced by a known method [M. Iwanami et al., chem.pharm.Bull. vol. 27, 1426
(1979)].

When reacting the above-mentioned aldehyde compounds, acetoacetate compounds, and 3-aminocrotonic acid ester compounds, they may be reacted without a solvent or with lower alcohols such as ethanol, propanol, isopropanol, n-butanol, and t-butanol; chloroform; , halogenated hydrocarbons such as dichloroethane, toluchloroethane;
The reaction is carried out by heating in an organic solvent such as an aromatic compound such as benzene or pyridine at a temperature of 30 to 180°C, preferably 50 to 150°C, for usually 2 to 24 hours.

The aldehyde compound, acetoacetate compound, and 3-aminocrotonic acid ester compound can be used in amounts of 0.8 to 1.5 and 0.8 to 1.5 equivalents, respectively, per equivalent of the aldehyde compound.

1,4-dihydropyridine-3,5- of the present invention
Dicarboxylic acid diester derivatives have pharmacological effects such as excellent blood pressure lowering effects and long-lasting effects, such as improving angina pectoris, cerebral blood flow, and circulation disorders.
It is effective as a therapeutic agent for cardiovascular diseases such as hypertension and ischemic heart disease. The present invention will be explained in more detail below with reference to Examples.

Reference Example 1 3.0 g of 2-fluoro-3-nitrotoluene was added to 20 ml of ice-cooled acetic anhydride, and 4 ml of concentrated sulfuric acid was added dropwise. 20ml of acetic anhydride while keeping the temperature below 10℃.
5 g of dissolved chromium trioxide was added in about 1 hour. After stirring for 2 hours, pour the reaction solution into 150ml of ice.
The generated precipitate was separated, and the resulting solid was washed with 2% aqueous sodium bicarbonate. Dioxane 10 to the resulting solid
ml, 4 ml of water, and 0.4 ml of concentrated sulfuric acid were added, and the mixture was heated under reflux for 30 minutes.

After removing the solvent and concentrating, it was extracted with CH ₂ Cl ₂ ,
The organic layer was separated, washed with water, and dried. When the solvent was removed, 3.0 g of the desired 2-fluoro-3-nitrobenzaldehyde was obtained.

Physical property values: - mp: 46-47℃ IR (KBr) νcm ^-1 max: 1690, 1610. NMR (CDCl ₃ ) δppm: 10.54 (s, 1H) 8.56
~8.14 (m, 2H) 7.69 ~ 7.34 (m, 1H) Other 2,3- and 2,5-disubstituted benzaldehyde compounds are also obtained in the same manner.

Reference Example 2 20 ml of acetic anhydride was placed in a 200 ml three-necked flask and cooled on ice. To this was added 3.0 g (19.4 mmol) of 2-fluoro-5-nitrotoluene, and 5 ml of concentrated sulfuric acid was added dropwise little by little. While keeping the temperature below 10°, add chromic anhydride 6.0g (57.0mmol) to acetic anhydride solution
ml) was added dropwise over about 1 hour. After stirring for an additional 2 hours (~5°), the reaction was poured into 150 ml of ice water and extracted with CH ₂ Cl ₂ . Wash the CH ₂ Cl ₂ phase with water,
After drying Na ₂ SO ₄ and distilling off the solvent, 4.23 g (15.6 mmol, 80
%) obtained.

Physical property values: - IRνcm ^-1 max (neat): 3090, 1754, 1528, 1488,
1348, 1190, 1092, 1056, 1046, 996 NMRδppm (CDCl ₃ ): 8.48-8.13 (m, 2H),
7.88 (s, 1H), 7.28 (dd, 1H, J=9
Hz), 2.13 (s, 6H) 4.02g of the above diacetylacetal derivative
(14.8 mmol) were added with 25 ml of dioxane, 10 ml of H ₂ O, and 1 ml of concentrated sulfuric acid, and the mixture was heated under reflux for 30 minutes. After evaporating the solvent under reduced pressure and concentrating, water was added, and the mixture was extracted with CH ₂ Cl ₂ . The CH ₂ Cl ₂ phase was washed with water, dried with Na ₂ SO ₄ , and the solvent was distilled off. The yellow-orange liquid obtained was purified by silica gel column chromatography, and 2-fluoro-5-nitrobenzaldehyde was obtained as pale yellow crystals at 1.96 g (11.6 mmol, 78%) was obtained.

Physical property values: - mp: 59-60゜ IRνcm ^-1 max (KBr): 1690, 1618, 1524, 1348,
1252 NMRδppm ( _CDCl3 ): 10.20 (s, 1H), 8.77
-8.32 (m, 2H), 7.42 (dd, 1H, J=9
Hz) Example 1 2-fluoro-3-nitrobenzaldehyde
340mg (2.01mmol), 2-propoxyethyl acetoacetate 450mg (2.40mmol) and 2-propoxyethyl 3-aminocrotonate 410mg (2.20mmol)
was added to 2 ml of isopropanol and heated under reflux overnight. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (CH ₂ Cl ₂ :AcOEt=
10:1), the desired product 4-(2-fluoro-3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-di(2-propoxyethyl) 500 mg (0.98 mmol, 49%) of the ester was obtained as pale yellow crystals.

Physical property values: - mp: 86-88゜ IRνcm ^-1 max (KBr): 1696, 1660, 1528, 1476,
1356, 1214, 1112 NMRδppm (CDCl ₃ ): 7.8-7.4 (m, 2H),
7.1-6.8 (m, 1H), 6.34 (s, 1H), 5.20
(s, 1H), 4.0 (m, 4H), 3.27 (t,
4H, J=6Hz), 2.23(s, 6H), 1.7-
1.2 (m, 4H), 0.84 (t, 6H, J=6
Hz), 3.5 (m, 4H) Example 2 3-chloro-2-fluorobenzaldehyde
318 mg (2.00 mmol), acetoacetic acid-2-methoxyethyl ester 325 mg (2.03 mmol) and isopropyl 3-aminocrotonate 290 mg (2.03 mmol)
was added to 2 ml of isopropanol and heated under reflux for 10 hours. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain the desired product, 4-
(3′-chloro-2′-fluorophenyl)-2,6
-dimethyl-1,4-dihydropyridine-3,5
-Dicarboxylic acid-3-isopropyl ester-5
503 mg (1.18 mmol, 59%) of -(2-methoxyethyl) ester was obtained as pale yellow crystals.

Physical properties: - mp: 122-124゜ IRνcm ^-1 max (KBr): 1692, 1488, 1454, 1266,
1200, 1102, 1084 NMRδppm (CDCl ₃ ): 7.2-6.6 (m, 3H),
6.35 (s, 1H), 5.12 (s, 1H), 4.8 (m,
1H), 4.1 (m, 2H), 3.5 (m, 2H), 3.24
(s, 3H), 2.19 (s, 6H), 1.20 (d,
3H, J = 6Hz), 1.00 (d, 3H, J = 6
Hz) At the same time, 70 mg (0.17 mmol, 9% ), 4-(3'-chloro-2'-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid di(2-methoxyethyl) ester (B) is 50
mg (0.11 mmol, 6%) was obtained.

Physical properties of compound (A): - IRνcm ^-1 max (KBr): 1685, 1492, 1452, 1212,
1098 NMRδppm (CDCl ₃ ): 7.2-6.6 (m, 3H),
5.83 (s, 1H), 5.09 (s, 1H), 4.8 (m,
2H), 2.21 (s, 6H), 1.20 (d, 6H, J
= 6Hz), 1.00 (d, 6H, J = 6Hz) Physical properties of compound (B): mp: 156-157゜ IRνcm ^-1 max (KBr): 1692, 1496, 1448, 1278,
1202, 1088 NMRδppm (CDCl ₃ ): 7.2-6.6 (m, 3H),
5.92 (s, 1H), 5.13 (s, 1H), 4.1 (m,
4H), 3.5 (m, 4H), 3.24 (s, 6H),
2.22 (s, 6H) Example 3 2-fluoro-3-nitrobenzaldehyde (153 mg), acetoacetic acid isopropyl ester (158 mg), and methyl 3-aminocrotonate (126 mg)
was dissolved in isopropanol (1 ml) and heated under reflux overnight. The solvent was removed, the residue was subjected to chromatography, and the fractions eluted with a mixture of n-hexane and ethyl acetate were collected to give 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl). )
-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-isopropyl ester was collected.

Physical property values: - IRνcm ^-1 max (CHCl ₃ ): 3450, 1695, 1610,
1530, 1350 NMRδppm ( _CDCl3 ): 7.8-7.3 (m, 2H),
7.2-6.7 (m, 1H), 5.9 (brds, 1H),
5.17 (s, 1H) 4.8 (m, 1H), 3.45 (s,
3H), 2.21 (s, 6H) 1.20 (d, 3H),
1.00 (d, 3H) Example 4 2-fluoro-3-chlorobenzaldehyde (159 mg) and methyl 3-aminocrotonate (126 mg)
and methyl acetoacetate (127 mg) were heated under reflux in isopropanol (1 ml) for 8 hours. The solvent was removed, the residue was subjected to silica gel chromatography, and the desired 2,6-dimethyl-
4-(2'-fluoro-3'-chlorophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester was collected.

Physical property values: - IRνcm ^-1 max (CHCl ₃ ): 3450, 1695, 1615,
1460, 1300 NMRδppm (CDCl ₃ ): 7.2-6.6 (m, 3H),
5.75 (brds, 1H), 5.03 (s, 1H), 3.52
(s, 6H), 2.20 (s, 6H) Example 5 2-fluoro-5-nitrobenzaldehyde (169 mg) and methyl 3-aminocrotonate (126 mg)
and methyl acetoacetate (127 mg) were heated under reflux in isopropanol (1 ml) for 8 hours. After removing the solvent, the residue was subjected to silica gel chromatography, and the desired 2,6-dimethyl-4- was extracted from the fraction eluted from a mixture of n-hexane and ethyl acetate.
(2′-fluoro-5′-nitrophenyl)-1,4
-Dihydropyridine-3,5-dicarboxylic acid dimethyl ester (165 mg) was collected.

Physical property values: - IRνcm ^-1 max (CHCl ₃ ): 3450, 1695, 1610,
1470, 1350 NMRδppm ( _CDCl3 ): 8.1-7.5 (m, 2H),
7.1-6.6 (m, 1H), 5.90 (brds, 1H),
5.15 (s, 1H), 3.48 (s, 6H), 2.20
(s, 6H) Example 6 2-fluoro-3-nitrobenzaldehyde (153 mg) and methyl 3-aminocrotonate (120 mg)
and acetoacetic acid-(2-n-propoxyethyl) ester (188 mg) were mixed in isopropanol (1 ml) and heated under reflux for 12 hours. The solvent was removed and the residue was subjected to silica gel chromatography and n-
The target 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3 was extracted from the fraction eluted from a mixture of hexane and ethyl acetate. -Methyl ester-5-(2-n-propoxyethyl) ester (195 mg) was collected.

Physical property values: - IRνcm ^-1 max (CHCl ₃ ): 3450, 1680, 1610,
1450, 1345 NMRδppm ( _CDCl3 ): 7.8-7.2 (m, 2H),
7.1~6.7 (m, 1H), 6.2 (brds, 1H),
5.10 (s, 1H), 3.98 (t, 2H), 3.45
(s, 3H), 3.20 (t, 2H), 2.10 (s,
6H), 1.45 (m, 2H), 0.92 (t, 3H) Example 7 2-fluoro-5-nitrobenzaldehyde
17.2g and 11.9g of methyl acetoacetate in toluene
The mixture was dissolved in 50 ml and hydrogen chloride gas was passed through it for about 10 minutes under ice cooling. After standing overnight, it was washed with water and the solvent was distilled off. tert-butyl 3-aminocrotonate in the residue
17.0 g, 2-propanol 100 ml and trimethylamine 17 ml were added, and the mixture was heated under reflux for 2 hours. After the reaction, add 100ml of dichloromethane, wash with water,
After drying with Na ₂ SO ₄ , the solvent was distilled off, and the 4-
(2-fluoro-5-nitrophenyl)-2,6
-dimethyl-1,4-dihydropyridine-3,5
-dicarboxylic acid-3-methyl ester-5-tert
-22.8g of butyl ester was obtained.

Physical property values IRνcm ^-1 max (KBr): 1670, 1526, 1486, 1340,
1224, 1108 NMR (CDCl ₃ ) δppm: 8.3-7.9 (m, 2H),
7.06 (dd, 1H, J=9Hz), 5.83 (brs,
1H), 5.25 (s, 1H), 3.62 (s, 3H),
2.32 (s, 6H), 1.38 (s, 9H)

Claims (1)

[Claims] 1. The following formula [] [In the formula, X and Y each represent a hydrogen atom, a chlorine atom, or a nitro group. However, either X or Y represents a hydrogen atom. R ¹ and R ² are the same or different and represent a lower alkyl group or -CH ₂ CH ₂ OR ³ . Here, R ³ represents a lower alkyl group. ] 1,4-dihydropyridine-3,5 represented by
-Dicarboxylic acid diester derivative. 2 The following formula [] [In the formula, X and Y each represent a hydrogen atom, a chlorine atom, or a nitro group. However, either X or Y represents a hydrogen atom. ] An aldehyde compound represented by the following formula [] CH ₃ COCH ₂ COO―R ² … [] [In the formula, R ² is a lower alkyl group or -
Represents CH ₂ CH ₂ OR ³ . R ³ represents a lower alkyl group. ] Acetoacetate compound represented by and the following formula [] [In the formula, R ¹ is a lower alkyl group or -
Represents CH ₂ CH ₂ OR ³ . R ³ represents a lower alkyl group. ] The following formula is characterized by reacting with a 3-aminocrotonic acid ester compound represented by [] [In the formula, X, Y, R ¹ and R ² are the same as defined above. ] 1,4-dihydropyridine-3,5 represented by
-Production method of dicarboxylic acid diester derivative.