JPH0160466B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field The present invention relates to 1,4-dihydropyridine-3,5-
The present invention relates to a method for producing a dicarboxylic acid diester derivative or an acid addition salt thereof. More specifically, the present invention aims to provide novel 1,4 compounds that have excellent pharmacological effects such as hypotensive effect and vasodilatory effect and have a long duration of action.
-Dihydropyridine-3,5-dicarboxylic acid diester derivative or an acid addition salt thereof. 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 nifedipine derivatives have been studied with the aim of obtaining compounds that have pharmacological effects such as long-lasting blood pressure lowering effects. For example, Tokkosho
Publication No. 56-6417 describes the 3rd or 5th position of nifedipine.
4- position converted to aminoalkyl ester group
(m-nitrophenyl)-2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid-
3-methyl ester-5-β-(N-benzyl-
N-methylamino)ethyl ester hydrochloride (hereinafter abbreviated as nicardipine) has been reported. Also, in Japanese Patent Application Laid-open No. 55-9083, the fourth place of nifedipin is listed.
Nifedipine derivatives in which the 2'-nitrophenyl group is converted to a 2',3'-dihalogen-substituted phenyl group have been reported. However, although these compounds have excellent pharmacological effects, their sustained action is not fully satisfactory. Furthermore, in the literature Arzneim.Forsch. 29 , 226 (1979), the 2'-nitrophenyl group at the 4-position of nifedipine is 2'-nitro-5'-methoxyphenyl group, 2'-
Nifedipine derivatives converted to a disubstituted phenyl group such as nitro-5'-chlorphenyl group have been described, and these nifedipine derivatives are said to have the same or weakened coronary vasodilatory effect compared to nifedipine. It has been reported. 1 of these nifedipine, nicardipine, etc.
The Hantzsch synthesis method has been known for a long time as a method for producing 4-dihydropyridine-3,5-dicarboxylic acid derivatives. Also, a method of condensation ring closure using benzylideneacetoacetate and 3-aminocrotonic acid ester (References Knoevenagel et al., Chem.
Bar. vol. 31, p. 730 (1898)) is known. Similarly, JP-A-50-84576 discloses a method for producing a desired product by reacting 2-(3-nitrobenzylidene)acetoacetate and 3-aminocrotonic acid ester. Furthermore, a German patent (DOS2117571 (1972)) has been disclosed as a method for producing benzylidene acetoacetate. OBJECT OF THE INVENTION The present inventors have discovered that nifedipine derivatives 1,
As a result of detailed studies on the structure and activity of 4-dihydropyridine-3,5-dicarboxylic acid diester derivatives, we found that the phenyl group at the 4-position of nifedipine was
A 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative that has been converted into a 2',3'-disubstituted phenyl group and the methyl ester group at the 3- or 5-position has been converted into an aminoalkyl group has a strong ability to lower blood pressure. It has been found that the drug has pharmacological effects such as action, and that the duration of the pharmacological effects is extremely long. As a result of extensive research into industrially advantageous production methods for such 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivatives, we discovered that the corresponding benzylacetoacetate ester derivative was reacted with the corresponding 3-aminocrotonic acid. The present invention was achieved by discovering that the desired 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative can be produced industrially advantageously with low generation of by-products. Therefore, the object of the present invention is to produce a novel 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative or an acid addition salt thereof, which has excellent pharmacological effects such as hypotensive effect and has a long duration. It is about providing law. Structure and Effects of the Invention According to the present invention, the following formula [] [In the formula, R ¹ represents a methyl group. X represents a fluorine atom, and Y and Z represent a hydrogen atom, a chlorine atom or a nitro group. However, one of Y and Z is a hydrogen atom, and the other is a group other than a hydrogen atom. ] Benzylidene acetoacetate derivative represented by or the following formula [] [In the formula, R ¹ , X, Y, and Z are the same as defined above. R ⁴ represents a halogen atom. ] Benzyl acetoacetate derivative represented by and the following formula [] [In the formula, R ⁵ is

[Formula] (where A is ethylene group, 2,2-dimethyltrimethylene group, R ²
represents a methyl group, and R ³ represents an unsubstituted benzyl group. ) represents a group represented by ] The following formula [], which is characterized by reacting with a 3-aminocrotonic acid ester derivative represented by [In the formula, R ¹ , R ⁵ , X, Y, and Z are the same as defined above. ] 1,4-dihydropyridine-3,5 represented by
- A method for producing a dicarboxylic acid diester derivative or an acid addition salt thereof is provided. The 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative has a 2',3' or 2',5-disubstituted phenyl group at the 4-position and an aminoalkyl ester group at the 5-position. It is a novel compound that has not been specifically disclosed in the literature and has pharmacological effects such as long-lasting blood pressure lowering effects. In the benzylidene acetoacetate derivative represented by the above formula [], which is a raw material compound,
R ¹ represents a methyl group. In the above formula [], X represents a fluorine atom, and Y and Z represent a hydrogen atom, a chlorine atom, or a nitro group. One of Y and Z is a hydrogen atom, and in this case, the other is a group other than a hydrogen atom. The benzylidene acetoacetate derivative represented by the above formula [] represents two geometric isomers, either one of the E isomer and the Z isomer, or a mixture thereof. The benzylidene acetoacetate represented by the above formula [] can be prepared by a conventionally known method, e.g.
Knoevenagel et al., Chem. Ber. 31 , 730 (1898)
); Von. H. Meyer et al., Arzneim-Forsch. vol. 31
It can be synthesized according to a method such as that described on page 407 (1981). In the above formula [] which is a raw material compound, R ¹ ,
X, Y and Z are the same as defined above. _R4
represents a halogen atom, such as a chlorine atom. The benzyl acetoacetate derivative represented by the above formula [] is represented by the following formula [] [X, Y and Z are the same as defined above. ] Benzaldehydes represented by the following formula [] CH ₃ COCH ₂ CO ₂ R ¹ ... [] [In the formula, R ¹ is the same as the above definition. ] Acetoacetic acid esters represented by the following are heated in the presence of a hydrogen halide such as hydrogen chloride without solvent or using a non-aqueous organic solvent at a temperature range of -30° to 100°C for 2 to 10 minutes.
It can be produced by a time reaction. In the 3-aminocrotonic acid ester of the above formula [], which is one of the raw material compounds, R ⁵ is

[Formula] (where A is an ethylene group, a 2,2-dimethyltrimethylene group, R ² is a methyl group, R ³
represents an unsubstituted benzyl group. ) represents a group represented by The 3-aminocrotonic acid ester derivative represented by the above formula [] has the following formula [] CH ₃ COCH ₂ CO ₂ R ⁵ ... [] [wherein R ⁵ is the same as defined above]. ] It can be produced by a conventionally known method of reacting acetoacetic esters represented by the following with ammonia (NH ₃ ) [Reference: JNCollie: Ann.226 Vol. 294
(1884), S. Iwanami et al., Chem.Pharm.Bull.
27, 1426 (1979)]. In the 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative of the above formula [] which is the target compound, R ¹ , R ⁵ , X, Y and Z are the same as defined above. According to the present invention, a benzylideneacetoacetate derivative represented by the above formula [] or a benzylideneacetoacetate derivative represented by the above formula [] and a 3-aminocrotonic acid ester derivative represented by the above formula [] are reacted. At least the desired 1,4-dihydropyridine derivative represented by the above formula [] can be produced. If necessary, acid addition salts can also be produced by subjecting them to a salt-forming reaction. When reacting benzylidene acetoacetate derivatives or benzylacetoacetate derivatives with 3-aminocrotonic acid ester derivatives, they may be reacted without solvent or with a lower alcohol such as ethanol, propanol, isopropanol, n-butanol, t-butanol, etc. Class;
In an organic solvent such as a halogenated hydrocarbon such as chloroform, dichloroethane, or toluchloroethane; or an aromatic compound such as benzene or pyridine, at 30 to 180°C,
The heating reaction is preferably carried out at 50 to 150°C, usually for 1 to 24 hours. In this reaction, tertiary amines such as triethylamine, tripropylamine, N,N-dimethylaniline, N-methylmorpholine, etc.
It can also be added in an amount of 0.1 to 2.0 equivalents per equivalent of the aminocrotonic acid ester derivative. The benzyl acetoacetate derivative of the above formula [] is dehydrohalogenated by the above tertiary amines or by a base based on the nitrogen atom in the molecule of the 3-aminocrotonic acid ester derivative of the above formula []. (HR ⁴ ), then the formula []
reacts with the 3-aminocrotonic acid ester derivative of The amount of the 3-aminocrotonic acid ester derivative to be used can be 0.8 to 1.5 equivalents per equivalent of the benzylideneacetoacetate ester derivative of the formula [] or the benzylacetoacetate ester derivative of the formula []. The desired 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative obtained by this reaction is separated and purified from the reaction mixture by commonly used separation means such as extraction and crystallization, or by column chromatography etc. be able to. Alternatively, the crude reaction product can be purified after forming an acid addition salt. Examples of acids used in forming such acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; acetic acid, propionic acid, citric acid, succinic acid, tartaric acid, maleic acid, etc. organic carboxylic acids; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; 1,4-dihydropyridine-3,5- of the present invention
Preferred examples of dicarboxylic acid diester derivatives are as follows. (104) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-benzyl -N-methylamino)ethyl] ester, (106) 2,6-dimethyl-4-(3'-chloro-
2'-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-benzyl-N-methylamino)ethyl] ester, (118) 2, 6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2,2-dimethyl-3-(N-
Benzyl-N-methylamino)propyl] ester, (154) 2,6-dimethyl-4-(5'-chloro-
2'-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-benzyl-N-methylamino)ethyl] ester, (156) 2, 6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-benzyl-N-methylamino ) ethyl] ester, (162) 2,6-dimethyl-4-(5'-chloro-
2'-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl] ester Hereinafter, the present invention will be explained in detail with reference to Examples. Reference example 1 Acetoacetic acid-3-(N-methylbenzylamino)-2,2-dimethylpropyl ester 5.07g
(17.4 mmol) was dissolved in 15 ml of EtOH and cooled with ice water. Ammonia gas was passed through this for a while, and after stirring at room temperature, it was left overnight. When ice water is added to the reaction solution, a white solid appears. This is washed separately with water and dried under reduced pressure to obtain the desired 3-aminocrotonic acid-3-(N-methylbenzylamino).
-2,2-dimethylpropyl ester 4.70g
(16.2 mmol, 93%) obtained. Physical property values mp: 68-70゜ IR (KBr) νcm ^-1 max: 1648, 1624, 1552, 1292,
1164, 1002 NMR (CDCl ₃ ) δppm: 7.12 (s, 5H), 4.40
(s, 1H), 3.80 (s, 2H), 3.45 (s,
2H), 2.26 (s, 2H), 2.10 (s, 3H), 1.76
(s, 3H), 0.86 (s, 6H) Example 1 2-fluoro-3-nitrobenzaldehyde
208 mg (1.23 mmol) and methyl acetoacetate 143
mg (1.23 mmol) was added to 1 ml of ethanol, further 0.1 ml of piperidine was added, and the mixture was stirred overnight under ice cooling. After adding dichloromethane, washing with water, drying, and distilling off the solvent, methyl 2-(2-fluoro-3-nitrobenzylidene)acetoacetate (NMR (CDCl ₃ ) δppm: 8.0-6.8 (m, 4H), 3.8
(s, 3H), 2.3(s, 3H)) was obtained. to this,
3-Aminocrotonic acid-3-(N-benzyl-N
350 mg (1.21 mmol) of -methylamino)-2,2-dimethylpropyl ester and 1 ml of isopropanol were added, and the mixture was heated under reflux overnight. The residue obtained by distilling off the solvent is subjected to silica gel column chromatography (hexane:ethyl acetate = 2:1) to obtain the desired 2,6-dimethyl-4-
(2'-fluoro-3-nitrophenyl)-1,4
-dihydropyridine-3,5-dicarboxylic acid-3
-Methyl ester-5-[3-(N-benzyl-
N-methylamino)-2,2-dimethylpropyl]ester was obtained as the main product. Physical properties NMR (CDCl ₃ ) δppm: 7.9 to 7.5 (m, 2H), 7.3
~7.1 (m, 6H), 6.19 (brs, 1H), 5.39 (s,
1H), 3.95 (s, 2H), 3.62 (s, 3H), 3.47
(s, 2H), 2.35 (s, 8H), 2.08 (s,
3H), 0.90 (s, 6H) Hydrochloride IR (KBr) νcm ^-1 max: 3450, 1692, 1532,
1492, 1352 Reference example 2 2-chloro-3-nitrobenzaldehyde 984
mg (5.3 mmol) and methyl acetoacetate 620 mg
(5.3 mmol) was dissolved in 10 ml of toluene and cooled on ice.
Hydrogen chloride gas was passed through. After the mixture was gradually warmed to room temperature and left overnight, 10 ml of benzene was added, and the organic phase was washed with water and dried over Na ₂ SO ₄ . When the solvent was distilled off, methyl 2-(α-chloro-2'-chloro-3'-nitrobenzyl)acetoacetate (NMR (CDCl ₃ )
δppm: 7.7-7.1 (m, 3H), 5.9 (d, 1H, J=10
Hz), 4.4 (d, 1H, J=10Hz), 3.5 (s, 3H),
2.4(s, 3H)) was obtained. To this, 1.50% of 3-aminocrotonic acid-3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl ester
(5.2 mmol), 5 ml of isopropanol and 530 mg of triethylamine were added, and the mixture was heated under reflux overnight.
After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to obtain the desired 4-(2'-chloro-3'-
Nitrophenyl)-2,6-dimethyl-1,4-
Dihydropyridine-3,5-dicarboxylic acid-3-
Methyl ester-5-[3-(N-benzyl-N
-Methylamino)-2,2-dimethylpropyl]
Ester was obtained as the main product. Physical properties NMR (CDCl ₃ ) δppm: 7.6-7.0 (m, 8H),
5.65 (brs.1H), 5.50 (s, 1H), 3.95 (s,
2H), 3.66 (s, 3H), 3.46 (s, 2H), 2.30
(s, 8H), 2.08 (s, 3H), 0.89 (s, 6H) Hydrochloride mp: 192-201° IR (KBr) νcm ^-1 max: 3400, 1686, 1532, 1490,
1428 Example 2 In the same manner as in Example 1, 4-(2-fluoro-5
-nitrophenyl)-2,6-dimethyl-1,4
-dihydropyridine-3,5-dicarboxylic acid-3
-Methyl ester-5-[3-(N-benzyl-
N-methylamino)-2,2-dimethylpropyl]ester was obtained. IR (CHCl ₃ ) νcm ^-1 max: 3450, 2950, 1686,
1616, 1466, 1346, 1308, 1118, 1100. NMR (CDCl ₃ ) δppm: 8.23-7.76 (m, 2H),
7.16 (s, 5H), 6.94 (dd, 1H, J=9Hz),
6.60 (brs, 1H), 5.28 (s, 1H), 3.84 (s,
2H), 3.56 (s, 3H), 3.39 (s, 2H), 2.30
(s, 3H), 2.26 (s, 5H), 2.05 (s,
3H), 0.86(s, 6H). Hydrochloride mp: 209-212゜ IR (KBr) νcm ^-1 max: 3450, 2970, 1684, 1522,
1344, 1210, 1114, 1090, 1014 Example 3 2,6-dimethyl-4-
(2′-fluoro-3′-chlorophenyl)-1,4
-dihydropyridine-3,5-dicarboxylic acid-3
-Methyl ester-5-[2,2-dimethyl-3
-(N-benzyl-N-methylamino)propyl]ester was obtained. Physical properties NMR (CDCl ₃ ) δppm: 7.2 to 6.8 (m, 8H),
5.90 (brs, 1H), 5.20 (s, 1H), 3.85 (s,
2H), 3.60 (s, 3H), 3.42 (s, 2H), 2.28
(s, 5H), 2.26 (s, 3H), 2.02 (s,
3H), 0.88 (s, 6H) IRνcm ^-1 max (CHCl ₃ ): 3450, 1690, 1650, 1620,
1455 Hydrochloride IRνcm ^-1 max (KBr): 3450, 1690, 1495, 1450,
1380. Example 4 2,6-dimethyl-4-
(3′-chloro-2′-fluorophenyl)-1,4
-dihydropyridine-3,5-dicarboxylic acid-3
-Methyl ester-5-[2-(N-benzyl-
N-methylamino)ethyl]ester was obtained. Physical properties IR (CHCl ₃ ) νcm ^-1 max: 1688, 1616, 1452 NMR (CDCl ₃ ) δppm: 7.27-6.85 (m, 8H),
5.99 (brs, 1H), 5.24 (s, 1H), 4.13 (t,
2H, J=6Hz), 3.58 (s, 3H), 3.47 (s,
2H), 2.60 (t, 2H, J=6Hz), 2.26 (s,
6H), 2.15 (s, 3H) MS m/e: 486 (M ⁺ ), 455, 338 Hydrochloride mp: 170-175゜ IR (KBr) νcm ^-1 max: 3425, 2600, 1688, 1490 Reference example 3 2,6-dimethyl-4-
(2',3'-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-benzyl-N-methylamino)ethyl] ester was obtained. Ta. Physical property values IR (CHCl ₃ ) νcm ^-1 max: 1690, 1614 NMR (CDCl ₃ ) δppm: 7.38 to 6.98 (m, 8H),
6.01 (brs, 1H), 5.45 (s, 1H), 4.15 (t,
2H, J=6Hz), 3.56 (s, 3H), 3.45 (s,
2H), 2.58 (t, 2H, J=6Hz), 2.23 (s,
6H), 2.13 (s, 3H) Example 5 Measurement of blood pressure lowering effect Male Wistar rats weighing approximately 250 g were anesthetized with α-chloralose with urethane ip, and carotid artery pressure was measured. The antihypertensive activity of the compound (test substance) was measured over time when the compound (test substance) was administered intravenously. The antihypertensive activity was calculated using the following formula and was expressed as follows. Antihypertensive activity = mean blood pressure value before compound administration - mean blood pressure value after compound administration / mean blood pressure value before compound administration × 100 (
%) Activity display Antihypertensive activity: Less than 5%: ± 5 to less than 10%: + 10 to 15%: ++ The results are as shown in Table 1.

【table】

[Table] Example 6 Blood pressure lowering effect of oral administration Male Wistar rats (weighing approximately 250 g) that had been fasted for 16 hours or more were fixed in a Bollman cage after a catheter was inserted into the femoral artery under ether anesthesia.
After one hour or more had elapsed after the animals became narcotized, the test compound was forcibly administered using an oral probe. The test compound was prepared by dissolving it in water. The femoral artery pressure was measured over time, and the values calculated using the following formula: change in mean blood pressure (mmHg) = mean blood pressure after administration (mmHg) - mean blood pressure before administration (mmHg) are shown in Table 2.

[Table] Example 7 In the same manner as in Reference Example 2, hydrogen chloride gas was passed through a toluene solution (5 ml) containing 583 mg of 2-fluoro-3-nitrobenzaldehyde and 380 mg of methyl acetoacetate, and 2-(α-chloro-2-fluoro ―
Methyl 3-nitrobenzyl)acetoacetate was obtained.
To this, 879 mg of 3-aminocrotonic acid-2-(N-benzyl-N-methylamino)ethyl ester,
5 ml of 2-propanol and triethylamine
0.5 ml was added and heated under reflux for 3 hours. After evaporation of the solvent, the residue was purified by silica gel column chromatography to obtain 4-(2-fluoro-3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-methyl ester-5-[2 ―
(N-benzyl-N-methylamino)ethyl] ester was obtained. Physical properties NMR (CDCl ₃ ) δppm: 7.94-7.55 (m, 2H),
7.27 (s, 5H), 7.06 (m, 1H), 5.83 (brs,
1H), 5.31 (s, 1H), 4.13 (t, 2H, J=
6Hz), 3.59 (s, 3H), 3.48 (s, 2H),
2.60 (t, 2H, J=6Hz), 2.30 (s, 6H),
2.15 (s, 3H). Example 8 In the same manner as in Reference Example 2, 3.26 g of 2-fluoro-3-nitrobenzaldehyde and methyl acetoacetate were added.
Hydrogen chloride gas was added to 2.40 g of toluene solution (20 ml) to obtain methyl 2-(α-chloro-2-fluoro-3-nitrobenzyl)acetoacetate. To this, 3.10 g of 3-aminocrotonic acid-3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl ester, 10 ml of 2-propanol, and 1.5 ml of triethylamine were added, and the mixture was heated and refluxed for 3 hours. The desired product of Example 1 was obtained as the main product. Example 9 3-chloro-2-fluorobenzaldehyde (15.85 g) and methyl acetoacetate (11.6 g) are dissolved in toluene (120 ml), and hydrogen chloride is passed through the solution at 0-5°C for 15 minutes. Seal the reaction mixture container tightly and
After standing at ~5℃ overnight, benzene (80ml) was added.
After removing the water in the lower layer, washing with water (20 ml), dehydrating and drying (mirabilite), and distilling off the solvent under reduced pressure, 2-
Methyl acetoacetate (α-chloro-3-chloro-2-fluorobenzyl) was obtained, and this
Add propanol (40 ml) to dissolve, then 3
-Aminocrotonic acid 3-(N-benzyl-N-methylamino)-2,2-dimethyl-propyl ester (30.2 g) was added, followed by triethylamine (10.1 g), and the mixture was heated under reflux for 3 hours. After the reaction,
The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (200 ml), washed with water, dehydrated and dried (mirabilite). The solvent was distilled off, and the residue was purified by crystallization from ethyl acetate and n-hexane to obtain 37.0 g of the same target product as in Example 3.

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ represents a methyl group. X represents a fluorine atom, and Y and Z represent a hydrogen atom, a chlorine atom or a nitro group. However, one of Y and Z is a hydrogen atom, and the other is a group other than a hydrogen atom. ] benzylideneacetoacetate derivative represented by or the following formula [] [In the formula, R ¹ , X, Y, and Z are the same as defined above. R ⁴ represents a halogen atom. ] Benzyl acetoacetate derivative represented by and the following formula [] [In the formula, R ⁵ is [Formula] (where A is an ethylene group, a 2,2-dimethyltrimethylene group, R ²
represents a methyl group, and R ³ represents an unsubstituted benzyl group. ) represents a group represented by ] The following formula [ ], which is characterized by reacting with a 3-aminocrotonic acid ester derivative represented by [] and then subjecting it to a salt-forming reaction as necessary. [In the formula, R ¹ , R ⁵ , X, Y, and Z are the same as defined above. ] 1,4-dihydropyridine-3,5 represented by
-Production method of dicarboxylic acid diester derivative or its acid addition salt.