JP3006904B2 - Method for producing 1,4-dihydropyridine derivative and intermediate thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a dihydropyridine derivative useful as a calcium antagonist and an intermediate thereof.

[0002]

2. Description of the Related Art 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative has calcium antagonism, blood pressure lowering action, coronary vasodilator action. It is widely used as antihypertensive and antianginal drug.

JP-A-59-137461 and JP-A-62-174
No. 071 discloses a dihydropyridine derivative in which a saturated cyclic amine compound is introduced into one of the ester side chains. These compounds have four dihydropyridine rings in the molecule.
Having two asymmetric carbon atoms derived from saturated cyclic amines at the position and ester side chains, there are two isomers in diastereomeric relationship. Their activity is only useful for one of the diastereomers since one of them shows stronger pharmacological activity.

Heretofore, product and equal amounts, Izu by the method of reusing the unnecessary one diastereoisomeric known to inevitably by-product, also selects only one of the diastereoisomers There is also no known method for producing the same.

[0005]

According to the present invention, a method for converting one unnecessary diastereomer to a useful compound and a useful intermediate thereof are provided.

[0006]

The present invention provides a compound represented by the general formula (I):

[0007]

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Wherein R ¹ represents hydrogen or lower alkyl; R ² represents hydrogen, lower alkyl, vinyl, phenyl,
Represents cyano, trifluoromethyl or trichloromethyl, m represents 0 or 1, n represents an integer of 1 to 3, and X represents halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy or toluenesulfonyloxy). 2,6-dimethyl-4- (3
-Nitrophenyl) -1,4-dihydropyridine-3,5-
Dicarboxylic acid diester derivatives and general formula (II)

[0009]

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Wherein R represents hydrogen, lower alkyl, N-benzyl-N-methylaminoethyl, N-benzylpiperidyl or N-benzylpyrrolidinyl. General formula (II
I)

[0011]

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(Wherein R has the same meaning as described above) and a process for producing a 1,4-dihydropyridine derivative represented by the general formula (I)

[0013]

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(Wherein R ¹ , R ² , m, n and X have the same meanings as described above).
-Nitrophenyl) -1,4-dihydropyridine-3,5-
Dicarboxylic acid diester derivative [hereinafter referred to as compound (I). The same applies to compounds of other formula numbers]. In the definition of each group of the compounds (I), (II) and (III), the lower alkyl is a straight-chain or branched C1-C4 group.
Of, for example, methyl, ethyl, propyl, isopropyl,
Butyl, sec-butyl, isobutyl, tert-butyl and the like are included, and halogen means each atom of chlorine, bromine and iodine.

The compound (I) used in the present invention is not particularly limited, but from the viewpoint of utilizing an unnecessary compound, diastereomers formed by the asymmetry of the carbon marked with * in the general formula (I). Isomers are preferred. Hereinafter, the production method of compound (I) will be described. Compound (I) has the general formula (IV)

[0016]

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Wherein n is as defined above, and a dihydropyridine represented by the general formula (V):

[0018]

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(Wherein R ¹ , R ² , X and m are as defined above). Here, the starting compound (IV) can be prepared by a known method (JP-A-59-137461; JP-A-62-174071).
Alternatively, it is manufactured according to this. Compound (IV)
Can be obtained by separating the diastereomer isomer obtained by the above production method by a fractional recrystallization method or the like. Usually, the residue obtained by separating one useful diastereomer isomer is suitably used from the viewpoint of recycling.

Compound (V) is added to compound (IV) in an amount of 0.
5 to 20 equivalents, preferably 0.8 to 2.0 equivalents are used.
As the solvent used in the reaction, for example, acetone, methyl ethyl ketone, ethyl acetate, ether, tetrahydrofuran, dioxane, acetonitrile, nitromethane,
Examples thereof include carbon tetrachloride, chloroform, methylene chloride, dichloroethane, toluene, benzene, hexane, and cyclohexane, which are used alone or in combination. The amount used is 1 to 200 times by weight, preferably 5 to 30 times, the compound (IV).

The reaction is carried out at a temperature ranging from -20 ° C to the boiling point of the solvent used, preferably from room temperature to the boiling point of the solvent used.
It takes about 10 minutes to 1 week. Since the obtained compound (I) precipitates from the reaction system in many cases, it can be isolated by filtration or centrifugal sedimentation. Alternatively, isolation can also be performed by distilling off the reaction solution and washing the residue with an appropriate solvent.

Next, a method for producing the 1,4-dihydropyridine derivative (III) using the compound (I) will be described. Compound (III) can be obtained by reacting compound (I) with compound (II) in the presence of a base. Compound (II)
Is can be used also as a solvent from an equal amount relative to the compound (I) in large excess, preferably 1 to 20 equivalents. When an alcohol is used as the compound (II), the reaction can be carried out in the presence of water, and the amount of water used is based on the amount of the compound (II) used.

The base to be used includes lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydride, potassium hydride, calcium hydride, etc., preferably sodium hydroxide, potassium hydroxide. It is. The amount of the base used may be the compound (I)
1 to 20 equivalents, preferably 1 to 10 equivalents.

As the reaction solvent, those used in the production of the above-mentioned compound (I) are similarly used, and the reaction is carried out at a temperature ranging from -10 ° C to the boiling point of the solvent used, preferably from room temperature to the boiling point of the solvent. It takes 10 minutes to finish in 2 days. After the reaction,
The crude product is obtained by a combination of commonly used unit operations such as filtration, extraction, and washing, and the desired product is obtained by ordinary purification operations such as crystallization and chromatography.

In the above-mentioned method, a compound (IV) is used as a starting material, which is converted into a quaternary ammonium salt (I), and then subjected to a hydrolysis reaction or a transesterification reaction with water or various alcohols (II). As a result, a dihydropyridine derivative (III) can be obtained. here,
When one of the diastereoisomers is used as compound (IV), compound (III) is usually obtained again as a racemic form. In particular, when one unnecessary diastereomer isomer (IV) is used and a cyclic amine is used as the compound (II), the resulting compound (III) is a mixture of diastereomers, Diastereomeric isomers can be isolated by conventional methods. That is, by reusing the unnecessary compound (IV) as a starting material by the method of the present invention, a useful compound (III) can be obtained.

Next, embodiments of the present invention will be specifically described with reference to examples.

[0027]

【Example】

Embodiment 1 FIG. (±) - (4R ^{*)-2,6-dimethyl-4-} (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid (3S ^*) -3- (1-benzyl-3- Piperidyl) ester, 5-methyl ester 5.05 g (10.
0 mmol) was dissolved in 25 ml of chloroform and stirred at room temperature.
2.38 ml (20.0 mmol) of benzyl bromide are added, followed by 8
The mixture was stirred and refluxed for an hour. Thereafter, the reaction solution was cooled to room temperature,
The precipitated crystals were collected by filtration and dried under reduced pressure to give (3S ^* )-1,1-dibenzyl-3-[(4R ^* )-2,6-dimethyl-4-.
(3-nitrophenyl) -1,4-dihydropyridine-5
-Methoxycarbonyl-3-carbonyl] oxypiperidinium bromide (6.29 g, yield 93.0%) was obtained as yellow crystals. IR (KBr, cm ^-1 ); 1695, 1530, 1485, 1350, 1210 ¹ H-NMR (DMSO-d ₆ , δ); 1.4 to 3.6 (8H, m), 2.29 (3H,
s), 2.36 (3H, s), 2.52 (3H, s), 4.52 (2H, dd), 4.81 (2H,
s), 4.96 (1H, s), 5.44 (1H, brs), 7.5 to 8.3 (14H, m), 9.2
4 (1H, s) MS (m / z); 596 (M ⁺ -80)

Embodiment 2 FIG. (±) - (4R ^{*)-2,6-dimethyl-4-} (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid (3S ^*) -3- (1-benzyl-3- 2.52 g of (piperidyl) ester, 5-methyl ester (5.0
Was dissolved in 12.5 ml of chloroform, and 0.48 ml (5.5 mmol) of allyl bromide was added thereto while stirring at room temperature.
The mixture was stirred and refluxed for an hour. Thereafter, the reaction solution was cooled to room temperature,
The precipitated crystals were collected by filtration and dried under reduced pressure to give (3S ^* )-1-allyl-1-benzyl-3-[(4R ^* )-2,6-dimethyl-4- (3-nitrophenyl) -1,4-. 2.98 g of dihydropyridine-5-methoxycarbonyl-3-carbonyl] oxypiperidinium bromide (yield 95.2%)
Was obtained as yellow crystals. IR (KBr, cm ^-1 ); 1705, 1530, 1490, 1350, 1210 ¹ H-NMR (DMSO-d ₆ , δ); 1.3 to 3.7 (8H, m), 2.32 (3H,
s), 2.34 (3H, s), 2.53 (3H, s), 4.05 (2H, m), 4.67 (2H,
s), 4.95 (1H, s), 5.16 (1H, brs), 5.6〜5.9 (2H, m), 6.1
~ 6.3 (1H, m), 7.1 ~ 8.1 (9H, m), 9.31 (1H, s) MS (m / z); 546 (M ⁺ -80)

Embodiment 3 FIG. (±) - (4R ^{*)-2,6-dimethyl-4-} (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid (3S ^*) -3- (1-benzyl-3- Piperidyl) ester, 5-methyl ester 5.05 g (10.
0 mmol) was dissolved in 25 ml of chloroform and stirred at room temperature.
4.32 mg (20.0 mmol) of p-nitrobenzyl bromide
Was added, and the mixture was stirred and refluxed for 12 hours. Thereafter, the reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration and dried under reduced pressure to give (3S ^* )-1-benzyl-1- (4-nitrobenzyl) -3-[(4R ^* )-2,6- Dimethyl-4- (3-
Nitrophenyl) -1,4-dihydropyridine-5-methoxycarbonyl-3-carbonyl] oxypiperidinium bromide (5.37 g, yield 74.1%) was obtained as yellow crystals. IR (KBr, cm ^-1 ); 1700, 1685, 1530, 1490, 1350, 121
0 ¹ H-NMR (DMSO-d ₆ , δ); 1.4 to 3.7 (8H, m), 2.30 (2H,
s), 2.32 (1H, s), 2.39 (1H, s), 2.40 (2H, s), 2.52 (1H,
s), 2.53 (2H, s), 4.2-4.7 (2H, m), 4.7-5.0 (2H, m), 4.9
3 (1H, s), 5.50 (1H, brs), 7.2 to 8.4 (13H, m), 9.30 (1H,
s) MS (m / z); 641 (M ⁺ -80)

Embodiment 4 FIG. (±) - (4R ^{*)-2,6-dimethyl-4-} (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid (3S ^*) -3- (1-benzyl-3- Piperidyl) ester, 5-methyl ester 5.05 g (10.
(0 mmol) was dissolved in 25 ml of acetone, 0.93 ml (12 mmol) of methyl iodide was added with stirring at room temperature, and the mixture was refluxed for 8 hours. Thereafter, the reaction solution was cooled to room temperature, and acetone was distilled off under reduced pressure to give (3S ^* )-1-benzyl-1-methyl-.
6.10 g of 3-[(4R ^* )-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-5-methoxycarbonyl-3-carbonyl] oxypiperidinium iodide (94 yield) .3%) as a yellow powder. ^{IR (KBr, cm -1);} 1695, 1530, 1490, 1350, 1215 1 H-NMR (DMSO-d 6, δ); 1.0 ~3.7 (8H, m), 2.30 (3H,
s), 2.35 (3H, s), 2.50 (3H, s), 2.98 (3H, s), 4.5-4.8 (2
H, m), 4.95 (1H, s), 5.16 (2 / 3H, brs), 5.30 (1 / 3H, brs),
7.4-8.1 (9H, m), 9.24 (1H, s) MS (m / z); 520 (M ⁺ -127)

Embodiment 5 FIG. (±) -2,6-dimethyl-4-
(3-nitrophenyl) -1,4-dihydropyridine-3,
5-dicarboxylic acid 3- (1-benzyl-3-bilolidinyl) ester, 5-methyl ester 2.45 g (5.00
mmol) was dissolved in 12.5 ml of chloroform, and the mixture was stirred at room temperature.
1.19 ml (10.0 mmol) of benzyl bromide are added and then 8 ml.
The mixture was stirred and refluxed for an hour. Thereafter, the reaction solution was cooled to room temperature,
The solvent was distilled off under reduced pressure, 20 ml of toluene was added to the residue, and the mixture was pulverized and washed in toluene. The obtained powder was collected by filtration and dried under reduced pressure to obtain (±) -1,1-dibenzyl-3- [2,6. -Dimethyl-4
-(3-nitrophenyl) -1,4-dihydropyridine-
3.19 g (yield: 96.4%) of 5-methoxycarbonyl-3-carbonyl] oxypyrrolidinium bromide was obtained as a brown powder. IR (KBr, cm ^-1 ); 1690, 1530, 1490, 1350, 1210 ¹ H-NMR (DMSO-d ₆ , δ); 1.8 to 4.0 (6H, m), 2.22 (3H,
s), 2.31 (3H, s), 2.53 (3H, s), 4.5-4.9 (5H, m), 5.12 (1
H, brs), 7.2 ~ 8.0 (14H, m), 9.22 (2 / 3H, s), 9.28 (1 / 3H,
s) MS (m / z); 582 (M ⁺ -80)

Embodiment 6 FIG. (±) -2,6-dimethyl-4- (3-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid 3-
2.45 g (5.00 mmol) of (1-benzyl-3-bilolidinyl) ester and 5-methylester were added to chloroform 1
Dissolved in 2.5 ml and stirred at room temperature with 0.87 ml of allyl bromide (1
(0.0 mmol) and then refluxed with stirring for 6 hours. Thereafter, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, 20 ml of toluene was added to the residue, and the mixture was pulverized and washed in toluene. The obtained powder was collected by filtration and dried under reduced pressure (±) -1- Allyl-1
- benzyl-3- [2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-5-methoxycarbonyl-3-carbonyl] oxy pyrrolidinylmethyl c Mubu b <br/> amide 2.80g (Yield 91.5%) as a yellow powder. IR (KBr, cm ⁻¹ ); 1695, 1530, 1490, 1350, 1210 ¹ H-NMR (DMSO-d ₆ , δ); 1.9 to 3.8 (6H, m), 2.30 (3H,
s), 2.32 (3H, s), 2.53 (3H, s), 3.9 ~ 4.1 (2H, m), 4.4 ~
4.7 (2H, m), 4.95 (1H, s), 5.26 (1H, brs), 5.5 ~ 5.8 (2H,
m), 6.0 to 6.3 (1H, m), 7.1 to 8.0 (9H, m), 9.23 (1 / 3H, s),
9.27 (2 / 3H, s) MS (m / z); 532 (M ⁺ -80)

Embodiment 7 FIG. Compound 6.7 obtained in Example 1
6 g (10.0 mmol) were suspended in 30 ml of tetrahydrofuran, and 30 ml of a 1N aqueous sodium hydroxide solution was stirred at room temperature.
(30.0 mmol) was added dropwise, followed by stirring at 40 ° C. for 5 hours. Thereafter, the reaction solution was concentrated under reduced pressure, and then ethyl acetate 2
0 ml was added and the mixture was separated, and the aqueous layer was adjusted to pH 2.5 with 4N hydrochloric acid. The precipitated solid was collected by filtration, dried under reduced pressure, and (±) -2,6.
1.69 g (yield 50.9%) of 3-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester was obtained. The physicochemical constant of the obtained compound is a known compound [Chem. Pharm.
l., 28 , 2809 (1980)].

Embodiment 8 FIG. (±) -2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid was prepared in the same manner as in Example 7 using the compound obtained in Example 2. 3-Methyl ester was obtained in a yield of 69.0%.

Embodiment 9 FIG. In 2.0 ml (34 mmol) of ethanol, potassium hydroxide 73 was added.
mg (1.1 mmol) was added with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. Then, 677 mg (1.0 mg) of the compound obtained in Example 1 was obtained.
0 mmol) and stirred at room temperature for 24 hours. Thereafter, 10 ml of toluene was added, the mixture was washed three times with 10 ml of water, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [n-hexane / ethyl acetate = 2/1 (v / v)]. (±)-2,6-di-methylcarbamoyl-4- (3-nitrophenyl
L ) 1,4-dihydropyridine-3,5-dicarboxylic acid
330 mg (yield 91.7%) of 3-ethyl ester and 5-methyl ester were obtained. The physicochemical constants of the obtained compound corresponded to those of a known compound (JP-A-63-208573).

Embodiment 10 FIG. (±) -2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid was prepared in the same manner as in Example 9 using the compound obtained in Example 2. 3-ethyl ester, 5
-Methyl ester was obtained in a yield of 85.2%.

Embodiment 11 FIG. Using the compound obtained in Example 4, the same operation as in Example 9 was performed, and (±) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid was used. 3-ethyl ester, 5
-Methyl ester was obtained in a yield of 90.7%.

Embodiment 12 FIG. Using the compound obtained in Example 5, the same operation as in Example 9 was carried out, and (±) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid was used. 3-ethyl ester, 5
-Methyl ester was obtained in a yield of 94.3%.

Embodiment 13 FIG. Using the compound obtained in Example 6, the same operation as in Example 9 was performed to obtain (±) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid. Acid 3-ethyl ester,
5-methyl ester was obtained in a yield of 91.9%.

Example 14.2 To a solution of 16.5 g (100 mmol) of 2- (N-benzyl-N-methylamino) ethanol in 20.0 ml of tetrahydrofuran was added 1.32 of potassium hydroxide.
g (20.0 mmol) was added with stirring at room temperature, and the mixture was further stirred at room temperature for 30 minutes. Then, 3.00 g of the compound of Example 1 (4.4
3 mmol) and stirred at room temperature for 24 hours. Thereafter, 50 ml of toluene was added, washed with 20 ml of water three times, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform / methanol = 20/1 (v / v)] to give (±)- 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid
1.31 g (yield 61.7%) of 3- (N-benzyl-N-methylamino) ethyl ester and 5-methyl ester were obtained. The physicochemical constants of the obtained compound corresponded to those of a known compound [Chem. Pharm. Bull., 28 , 2809 (1980)].

Embodiment 15 FIG. Using the compound of Example 2, the same operation as in Example 14 was carried out, and (±) -2,6-dimethyl-
4- (3-Nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (N-benzyl-N-methylamino) ethyl ester, 5-methyl ester was obtained in a yield of 26.3%. .

Embodiment 16 FIG. Using the compound of Example 4, the same operation as in Example 14 was performed, and (±) -2,6-dimethyl-
4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (N-benzyl-N-methylamino) ethyl ester, 5-methyl ester was obtained in a yield of 29.4%. .

Embodiment 17 FIG. The same operation as in Example 14 was performed using the compound of Example 5 to (±) -2,6-dimethyl-4.
-(3-nitrophenyl) -1,4-dihydropyridine-
3,5-dicarboxylic acid 3- (N-benzyl-N-methylamino) ethyl ester and 5-methyl ester in a yield of 4
Obtained at 7.6%.

Embodiment 18 FIG. The same operation as in Example 14 was carried out using the compound of Example 6 to (±) -2,6-dimethyl-4
-(3-nitrophenyl) -1,4-dihydropyridine-
3,5-dicarboxylic acid 3- (N-benzyl-N-methylamino) ethyl ester and 5-methyl ester in a yield of 4
Obtained at 1.3%.

Example 1 2- (N-benzyl-N-methylamino) ethanol In a solution of 16.5 g (100 mmol) of ethanol in 20.0 ml of tetrahydrofuran, 0.80 g (20.0 mmol) of 60% sodium hydride was stirred at room temperature. The mixture was added under reduced pressure and stirred at room temperature for 30 minutes. Then, 3.00 g of the compound of Example 1 (4.4
3 mmol) and stirred at room temperature for 24 hours. Thereafter, 50 ml of toluene was added, washed with 20 ml of water three times, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform / methanol = 20/1 (v / v)] to give (±)- 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid
1.12 g (yield 52.8%) of 3- (N-benzyl-N-methylamino) ethyl ester and 5-methyl ester were obtained.

Embodiment 20 FIG. Using the compound of Example 2, the same operation as in Example 19 was carried out, and (±) -2,6-dimethyl-
4- (3-Nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (N-benzyl-N-methylamino) ethyl ester, 5-methyl ester was obtained in a yield of 17.9%. .

Embodiment 21 FIG. 2- (N-benzyl-N-methylamino) ethanol 1
To a solution of 6.5 g (100 mmol) in 20.0 ml of tetrahydrofuran was added 0.82 g (20.0 mmol) of sodium hydroxide with stirring at room temperature, and the mixture was further stirred at room temperature for 30 minutes. Then, 3.00 g (4.43 mmol) of the compound of Example 1 was added, and the mixture was added at room temperature for 2 hours.
Stir for 4 hours. Thereafter, 50 ml of toluene was added, and 20
ml of water 3 times washing, the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography [chloroform / methanol = 20/1 (v / v ) ], (±)-2,6-di menu
Chi-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (N- Benzyl -N
-Methylamino) ethyl ester, 5-methyl ester
1.31 g (yield 61.7%) were obtained.

Embodiment 22 FIG. The same operation as in Example 21 was performed using the compound of Example 2 to (±) -2,6-dimethyl-4.
-(3-nitrophenyl) -1,4-dihydropyridine-
3,5-dicarboxylic acid 3- (N-benzyl-N-methylamino) ethyl ester, 5-methyl ester in a yield of 1
Obtained at 6.1%.

[0050]

Industrial Applicability According to the present invention, there is provided a method for producing a useful dihydropyridine derivative by recycling one unnecessary diastereomer, and an intermediate thereof.

──────────────────────────────────────────────────の Continued on the front page (58) Fields surveyed (Int. Cl. ⁷ , DB name) C07D 401/12 C07D 211/90 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the general formula (I) (Wherein, R ¹ represents hydrogen or lower alkyl, R ² represents hydrogen, lower alkyl, vinyl, phenyl, cyano, trifluoromethyl or trichloromethyl;
Or 1, n represents an integer of 1 to 3, and X represents 2,6-dimethyl-4- (3-nitrophenyl) represented by halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy or toluenesulfonyloxy. ) -1,4-Dihydropyridine-3,5-dicarboxylic acid diester derivative and a compound of the general formula (II) Wherein R is hydrogen, lower alkyl, N-benzyl-N-
Methylaminoethyl, N-benzylpiperidyl or N-
(Representing benzylpyrrolidinyl)), characterized by reacting with a compound represented by the general formula (III): (Wherein R has the same meaning as described above). 2. The process according to claim 1, wherein the compound represented by the general formula (I) is a diastereomeric isomer resulting from the asymmetry of the carbon marked with * in the general formula (I). 3. A compound of the general formula (I) (Wherein, R ¹ , R ² , m, n and X are as defined above). Dicarboxylic acid diester derivatives.