KR900002342B1 - Process for preparing dextrorotatory optical isomer of diastereomer a of ym-09730 - Google Patents

Abstract

A dextrorotatory optical isomer of diastereomer A of (±-2, 6- dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate3-(1- benzylphrrolidine-3-yl)ester-5-methyl ester of formula (I) or its pharmaceutically accptable acid addn. salt is prepd. by reacting 5- methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4dihydropyridine-3- carboxylic acid with 1-benzyl-3-hydroxypyrrolidine in an org. solvent i.e. CH2Cl2 and DMFA, and pref. sepg. dextrorotatory optical isomer by column chromatography or fractional crystn.. The HCl salt of (I) shows 223-230 deg. C of mp.

Description

YM-09730 Novel Preparation Method of Priority Optical Isomers of Diastereomer A

The present invention relates to a novel method for preparing the preferred optical isomers of YM-09730 diastereomer A and pharmacologically acceptable acid addition salts thereof useful as vasodilators.

The chemical name of YM-09730 is 2,6-dimethyl--4-(m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- (1-benzylpyrrolidine-3). 1) ester-5-methyl ester, which is a dihydropyridine-3,5-dicarboxylic acid ester derivative represented by the following chemical structural formula.

YM-09730 is known to exhibit long-term vasodilating and blood pressure-lowering effects (see US Pat. No. 4,220,649).

YM-09730 has two asymmetric carbon atoms and isomers are present based on these asymmetric carbon atoms from a stereochemical point of view. However, since the patent publication lacks a description of isomers, the presence of isomers has not been confirmed.

Prior to this, the inventors first separated their diastereomer A from the diastereomer B of YM-09730, which exhibits a much better and unique pharmacological effect when compared to isomer B or a mixture of both isomers. Has found (see European Patent Application No. 85 302 666.4).

In addition, the present inventors found that the preferred optical isomers having a melting point of hydrochloride of diastereomer A between 223 ° and 230 ° C. (decomposition) are m-nitrobenzaldehyde containing 1-benzyl-3-acetoacetoxypyrrolidine and methyl 3-amino. The diastereomer A was isolated by subjecting YM-09730 obtained by reaction with crotonate to column chromatography using silica gel as the carrier and ethyl acetate-acetic acid as the eluent, to thereby separate this diastereomer A. Can be prepared by optical cleavage using L-(-)-malic acid, and the isomers thus obtained have a much better and unique pharmacological effect when compared with the left linear optical isomers or mixtures of these two isomers. Has found (see European Patent Application No. 85 302 666.4).

The present inventors studied a novel and useful method for preparing the preferred optical isomer of YM-09730 diastereomer A, and found a method for improving the yield of the desired isomer and completed the present invention.

In the present invention, the diastereomer A (dl-mixture) having the melting point of the hydrochloride at 200 ° to 206 ° C (decomposition) is clearly distinguished from the diastereomer B having the melting point of the hydrochloride at 180 ° to 185 ° C (decomposition).

The melting point of the hydrochloride of the preferential optical isomer of Diastereomer A is also 223 ° to 230 ° C. (decomposition) as mentioned above. The present invention is to provide a novel process for preparing the preferred optical isomers of YM-09730 diastereomer A or pharmacologically acceptable acid addition salts thereof as mentioned above. In the present specification, pharmacologically acceptable acid addition salts include organic acid salts such as L-(-)-maleate and the like and inorganic acid salts such as hydrochloride.

The preferred optical isomer (I) of diastereomer A of the present invention is represented by the following structural formula (II),

Left-handed optical isomer or racemate thereof of 5-methoxycarbonyl-2,6-dimethyl-4 (m-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid represented by: Reactive derivatives thereof are represented by the following structural formula (III),

It can be prepared by reacting with the left linear optical isomer of 1-benzyl-3 hydroxy-pyrrolidine or racemate thereof.

This reaction involves the production of carboxylic acid esters, and methods that may be used conventionally may be preferably used. There is no stereochemical reversal in this reaction. Examples of reactive derivatives of the above compound (II) include acid halides (eg, acid chlorides, acid bromides, etc.), acid anhydrides, complex acid anhydrides, active esters, and the like. When compound (II) is used in the form of free carboxylic acid, the reaction is carried out in the presence of a condensate such as dicyclohexylcarbodiimide or the like.

The reaction is advantageously carried out in an organic solvent such as methylene chloride or dimethylformamide under cooling or at room temperature.

When the starting materials (II) and (III) are both left-right optical isomers, the reaction product consists essentially of the preferential optical isomers of diastereoisomer A, which is usually carried out by conventional methods such as extraction method, concentration method or the like. If necessary, it can be isolated from the reaction mixture by column chromatography. If at least one of the compounds (II) and (III) is a racemate, the resulting reaction mixture contains the desired preferential optical isomer of diastereomer A and the lecitivity or preference of its left optical optical isomer and diastereomeric B Isomers and the like, and the desired isomers may be isolated from the reaction mixture by column chromatography or fractional crystallization.

For example, a mixture of the preferred optical isomers of diastereomer A of YM-09730 and the left-right optical isomers of YM-09730 diastereomer B is prepared using silica gel as carrier and ethyl acetate-acetic acid as eluent. Preferred optical isomers of YM-09730 diastereomer A are separated from the mixture by addition to column chromatography to be used. Alternatively, the mixture is subjected to L-(-)-malic acid to fractionate recrystallization of the L-(-)-malate of the preferred optical isomer of diastereomer A and the left-right optical isomer of diastereomer B. , L-(-)-maleate of the preferred optical isomer of diastereomer A is obtained.

In the case of separation by column chromatography, the preferred optical isomer of diastereomer A is obtained from the first eluent, and then the left-right optical isomer of diastereomer B can be obtained from the eluent. As long as silica gel is generally used in column chromatography, there is no particular limitation on using silica gel as a carrier in this method. There is no particular limitation regarding the mixing ratio of ethyl acetate and acetic acid, which is an eluent, but in general, it is suitable to use ethyl acetate as a main component and to mix a small amount of acetic acid thereto. The mixing ratio is advantageously used in the ratio of acetic acid 1-10v / v to ethyl acetate 30-50 v / v. When the mixing ratio of acetic acid is reduced, the time taken to elute the target compound becomes longer.

Elution rate and treatment temperature may be preferably selected.

On the other hand, the method using L-(-)-malic acid can also be applied to separate the preferential optical isomer of diastereomer A by fractional recrystallization, because the L of the preferential optical isomer of diastereomer A -(-)-Malate is crystalline. Examples of the solvent that can be used for fractional recrystallization include methanol, ethanol, acetone, acetonitrile and the like.

The L-(-)-maleate of the preferred optical isomer of diastereomer A thus obtained can be used as a drug per se, but the acetate or the like of the isomer is optionally treated with a base to obtain a free form. It can be treated with a suitable acid to lead to other suitable salts.

Priority optical isomers and pharmacologically acceptable acid addition salts of YM-09730 diastereoisomer A, the target compound of the present invention, are novel compounds not described in any publications, and have been shown to increase the rate of increase in coronary blood flow by In addition, it showed an increase rate of about 40 times or more than the left linear optical isomer (one body), 2.5 times more than the equivalent mixture of these two isomers (dl body), and also showed a high affinity for coronary arteries.

By the process of the present invention, the preferential optical isomers of novel and useful YM-09730 diastereomer A can be selectively produced in good yield, and are very valuable from an industrial point of view.

Hereinafter, the present invention will be described in more detail with reference to Examples. Compounds (II) and (III), which are starting materials used in the present invention, are known compounds, but in the present invention, these raw materials can be prepared by novel and useful methods as described in Reference Examples.

Reference Example 1

(1) A solution in which 6.04 g of m-nitrobenzaldehyde, 6.32 g of tert-butyl acetoacetate, 0.17 g of piperidine and 0.6 ml of acetic acid was dissolved in 20 ml of benzene was heated to reflux for 6 hours using an azeotropic dehydration apparatus. After cooling the reaction system, 10 ml of water was added thereto, and the benzene layer was partitioned. The benzene layer was washed successively using a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then the benzene layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then the resulting residue was subjected to silica gel column chromatography. The crystals obtained from the part eluted using n-hexane / ethyl acetate (volume ratio 5: 1) as the eluent were washed with n-hexane to give tert-butyl 2- (m-nitrobenzylidene) acetoacetate as a colorless crystal. 5.82 g of a geometric isomer mixture was obtained. Melting point: 33 ° -36 ° C.

(2) A mixture of 3.56 g of t-butyl 2- (m-nitrobenzylidene) acetoacetate and 1.41 g of methyl 3-aminocrotonate obtained in (1) above was dissolved in 7 ml of tert-butanol for 20 hours. Heated to reflux. The solvent was removed by distillation under reduced pressure. The oily residue thus obtained was treated with n-hexane to give the desired 2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-. 4.6 g of 3-tert-butyl ester-5-methyl ester was obtained. Melting Point: 120 °-122 ℃

(3) To 5 ml of 25% ice water cooling solution of hydrogen bromide dissolved in acetic acid, and to 5 ml of toluene, 2,6-dimethyl- 4-(m-nitrophenyl) -1,4-dihydropyridine obtained in (2) above. A solution of 2.5 g of 3,5-dicarboxylic acid-3 tert-butyl ester-5 methyl ester dissolved in 5 ml of toluene was added dropwise. The mixture was stirred for 5 minutes under ice cooling and then poured into 5 ml of ice. The mixture was made alkaline with 10% aqueous sodium hydroxide solution and then extracted with toluene. The aqueous layer was acidified with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with ether to give the desired 5-methoxycarbonyl-2,6-dimethyl-4 (m-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (racemate). 1.24 g was obtained. Melting point: 203 ° -204 ° C (decomposition).

Reference Example 2

A solution of 7.55 g of m-nitrobenzaldehyde, 5.75 g of methyl 3-aminocrotonate and 7.90 g of tert-butylacetoacetate in 25 ml of tert-butanol was heated to reflux for 22 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 150 ml of toluene. The solution was washed successively using 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 19.62 g of an oily product. This oily product was dissolved in 20 ml of toluene and this solution was added dropwise to 20 ml of 25% hydrogen bromide solution dissolved in acetic acid under ice cooling. The mixture was stirred at the same temperature for 5 minutes and then poured into 200 ml of ice water. 250 ml of 10% aqueous sodium hydroxide solution was added to the mixture to make it alkaline and washed with 100 ml of toluene. The aqueous layer is made acidic with concentrated hydrochloric acid, and the desired crystals are filtered to filter out the desired 5-methoxycarbonyl-2,6-dimethyldimethyl-4 (m-nitrophenyl) -1,4-dihydropyridine-3. 4.51 g of carboxylic acids (racemates) were obtained.

Each optical isomer of the racemate is Chem. T. Shibanuma et al. Pharm. Bull., Vol. 28, p. 2809 (1980).

Reference Example 3

(1) 17.7 g of dl-1 benzyl-3-hydroxypyrrolidine and 15.2 g of D-(-)-mandelic acid were heated and dissolved in 66 ml of acetone. The solution was left at 4 ° C. overnight, and 8.5 g of the precipitated crystals were recrystallized in 26 ml of acetone to obtain 5.1 g of D-(-)-mandelate of S-(-)-benzyl-3-hydroxypyrrolidine. Specific light [α] 20 _D = + 45.5 ° (c = 1, methanol). Even if recrystallization was performed further, there was no change in specific light intensity. Melting point: 101 ° -102 ° C.

A nuclear magnetic resonance spectrum of N-CH ₂ -Ph was observed at 4.03 ppm (single line, 2H), but no (R)-(-) type AB quartet (J = 12.5 Hz) was observed at 4.01 ppm. .

(2) 22 g of D-(-)-mandelate of S-(-)-1-benzyl-3-hydroxypyrrolidine was dissolved in 50 ml of chloroform. The chloroform layer was washed with an aqueous solution of 14.4 g of anhydrous sodium carbonate dissolved in 90 ml of water, and the mixture was dried over anhydrous magnesium sulfate. Chloroform was distilled off, and the residue was distilled under reduced pressure to obtain 11.5 g of S-(-)-benzyl-3-hydroxypyrrolidine. Boiling point 109 ° C./0.65 mmHg. [a] 20 _D =-3.77 ° (c = 5, methanol).

Reference Example 4

75 g of S-(-)-malic acid was reacted with 75 ml of benzyl amine at 170 ° C. for 3 hours, whereby S-(-)-1 benzyl-3-hydroxysuccinimide [melting point: 99 ° -101 ° C., non-fluorescence) 52.7 g of [a] 20 _D =-51.1 ° (c = 1, methanol). 9.73 g of lithium aluminum hydride was suspended in 340 ml of anhydrous tetrahydrofuran, and a solution of 20.5 g of the imide dissolved in 200 ml of anhydrous tetrahydrofuran was added dropwise to the suspension under ice cooling. The mixture was cooled by reflux heating for 3 hours, and then 100 g of sodium sulfate decahydrate was added thereto. The mixture was stirred overnight under ice cooling. Insoluble components were removed by filtration, and the solvent was removed by distillation under reduced pressure. The residue was distilled under reduced pressure to give 13.8 g of S-(-)-1-benzyl-3-hydroxypyrrolidine having a boiling point of 109 ° -115 ° C / 0.8mmHg and a specific light intensity [α] 20 _D of -0.3 °. Got. The S − (−) sieve thus obtained contained an R − (+) sieve when viewed from the nuclear magnetic resonance spectrum of the third position hydrogen when using a shift reagent [Eu-TFMC (III)]. This S − (−) body was converted to D − (−) − mandelate according to the method described in Reference Example 3, and then it was converted from 3 times of ethanol, followed by 6 times of ethanol-toluene (1: 5). Recrystallized. The mandelate thus obtained ([α] 20 _D = -45.2 °) was treated as described above, yielding S-(-)-1 benzyl-3-hydroxypyrrolidine [boiling point: 115 ° -120 ° C]. /1.2-1.5 mmHg, [?] 20 _D =-3.77 ° (c = 5, methanol)] 8.6 g was obtained.

Reference Example 5

To 50 ml of 9-borabicyclo [3.3.1] nonane (0.5M tetrahydrofuran solution) was added 3.4 g of 2-(+)-pinene and the mixture was stirred at 60 ° C. for 5 hours. The mixture was cooled to room temperature and 1.75 g of 1-benzyl-3-pyrrolidinone was added thereto. The mixture was stirred at room temperature for 4 days, then 1.3 ml of acetaldehyde were added at 0 ° C. The solvent was removed by distillation under reduced pressure, and 20 ml of ether was added to the residue. The mixture was cooled to 0 ° C., and 1.5 ml of 2-aminoethanol was added thereto. This mixture was stirred. The resulting precipitate was removed by distillation. The ethereal solution was extracted with 1N hydrochloric acid. The hydrochloric acid layer was made alkaline with sodium carbonate and extracted with dichloromethane. This extract was dried over anhydrous magnesium sulfate and concentrated to give 1.1 g of crude product. This crude product was distilled off under reduced pressure to obtain 0.6 g of pure product. Boiling point 106 ° C./0.9 mmHg. Thus obtained S-(-)-1-benzyl-3-hydroxypyrrolidine was added from the nuclear magnetic resonance spectrum of the hydrogen in the third position after the addition of a shift reagent [Eu-TFMC (III)] 30 % Enantio excess (ee).

Example 1

5C₁₈4.6mmψ×300mm, 컬럼 온도 : 30℃, 이동상 : 테트라 - n - 펜틸암모늄 브로마이드를 함유하는 0.05몰 인산이수소칼륨 (pH 3) - 아세토니트릴 (80 : 20 v/v), 유속 : 0.9ml/분, UV검출기 (λ254nm)]내에서의 체류 기간이 28분간인 YM - 09730 부분 입체 이성질체 A의 우선성 광학 이성질체(Ⅰ)을 얻었다. 이와 같이 하여 얻은 이성질체를 클로로포름 중에서 탄산수소나트륨의 포화 수용액, 묽은 염산의 순으로 처리하여, YM - 09730 부분 입체 이성질체 A의 우선성 광학 이성질체 염산염 161mg을 얻었다. 융점 : 228°- 230℃(분해) ; 비선광도 : [α]20_D= + 116.3°(c = 0.5, 메탄올).332 mg of 5-methoxycarbonyl-2,6-dimethyl-4 (m-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid are dissolved in 3 ml of dichloromethane and 250 mg of phosphorus contaminated under ice-cooling It was added with stirring. The mixture was stirred for another 1 hour at the same temperature. The reaction mixture was cooled to −30 ° C., and 177 mg of (S) -1-benzyl-3-hydroxypyrrolidine was added thereto. The reaction mixture was stirred at −30 ° C. for 2 hours and washed sequentially with water and saturated aqueous sodium hydrogen carbonate solution. The solvent was distilled off to obtain an oily substance. This oily substance was added to silica gel column chromatography using ethyl acetate-acetic acid (5: 1 v / v) as the eluent, and a high-performance liquid chromatography apparatus [column: Nucleosil_

5C ₁₈ 4.6 mmψ × 300 mm, column temperature: 30 ° C., mobile phase: 0.05 mol potassium dihydrogen phosphate (pH 3) -acetonitrile (80: 20 v / v) containing tetra-n-pentylammonium bromide, flow rate: 0.9 The preferred optical isomer (I) of YM-09730 diastereoisomer A having a retention period of 28 minutes in ml / min and a UV detector (λ254 nm) was obtained. The thus obtained isomer was treated in chloroform with a saturated aqueous solution of sodium bicarbonate and dilute hydrochloric acid in order to obtain 161 mg of the preferred optical isomer hydrochloride of YM-09730 Diastereomer A. Melting point: 228 ° -230 ° C. (decomposition); Specific light intensity: [α] 20 _D = + 116.3 ° (c = 0.5, methanol).

Example 2

332 mg of (-)-5-methoxycarbonyl-2,6-dimethyl-4 (m-nitrophenyl-1,4-dihydropyridine-3-carboxylic acid) are dissolved in 3 ml of dichloromethane and added to this solution. 250 mg of phosphorus pentachloride was added under ice cooling with stirring The mixture was stirred for an additional hour at the same temperature The reaction mixture was cooled to -30 [deg.] C. and (S) -1 -benzyl-3 hydroxypyrrolidine 177 mg were added The reaction mixture was stirred for 2 h at −30 ° C., then diluted with 5 ml of dichloromethane and washed twice successively with 5 ml of water and saturated aqueous sodium hydrogen carbonate solution. The oily substance was subjected to silica chromatography (15 g) column chromatography using toluene-acetic acid (4: 1 v / v) as eluent.The fractions containing the desired isomers were concentrated under reduced pressure. The resulting residue It was dissolved in 5 ml of loform, and 1 ml of a solution of 0.8 N hydrogen chloride dissolved in ethanol was added to the chloroform solution, and the solution was concentrated under reduced pressure, and the residue was dissolved in 2 ml of methanol, and the solution was left overnight under ice-cooling. The precipitated crystals were collected by filtration and dried to obtain 350 mg of the preferential optical isomer hydrochloride of YM-09730 diastereomer A. Melting point: 226 ° -228 ° C. (decomposition), specific ray: [α] 20 _D = + 116.4 ° (c = 1, methanol) NMR (in CD ₃ OD, internal standard TMS, δ ppm): 1.80-2.70 (2H, broad m, C ₄ , -H ₂ ); 2.32, 2.34 (6H, s, C ₂ , 6-CH ₃ ); 3.0-4.0 (4H, m, C ₂ ' ₅ ', -H ₂ ); 3.64 (3H, s, -COOCH ₃ ); 4.42 (2H, s, -CH ₂ ψ; 5.08 (1H, s, C ₄ -H); 5.30 (1H, m, C ₃ ', -H); 7.30-8.20 (9H, m, benzene ring-H).

Example 3

In 6 ml of a mixture of dichloromethane and N, N-dimethylformamide (4: 1 v / v), (-)-5-methoxycarbonyl-2,6-dimethyldimethyl-4 (m-nitrophenyl) -1, 840 mg of 4-dihydropyridine-3-carboxylic acid were suspended and 0.2 ml of thionylchloride was added to the suspension under ice cooling. This mixed solution was stirred at the same temperature for 1 hour. To the reaction mixture was added dropwise a solution of 450 mg of (S) -1-benzyl-3-hydroxypyrrolidine in 3 ml of dichloromethane dropwise under ice-cooling, and the resulting mixture was further stirred under ice-cooling for 15 hours. Dilute with 10 ml of dichloromethane. The solution thus obtained was washed successively with 10 ml of water and 10 ml of saturated aqueous sodium hydrogen carbonate solution, and the solution was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain an oily substance. This oily material was submitted to silica gel (40 g) column chromatography using toluene-acetic acid (4: 1 v / v, then 1: 1 v / v) as eluent. The fractions containing the desired isomers were concentrated under reduced pressure, to give 990 mg of concentrated oily material, which was then dissolved in 10 ml of chloroform. 2.6 ml of ethanol solution of 0.8N hydrogen chloride was added to this solution, and this solution was concentrated under reduced pressure again. The obtained residue was dissolved in 5 ml of methanol, and then the solution was left overnight under ice cooling. The precipitated crystals were collected by filtration and dried to obtain 850 mg of the preferred optical isomer hydrochloride of YM-09730 Diastereomer A. Melting point: 226 ° -228 ° C. (decomposition), specific lightness: [α] 20 _D = + 116.4 ° (c = 1, ethanol). The NMR spectrum was consistent with that of the product prepared in Example 2 above.

Example 4

(1) The concentrated oily substance (990 mg) obtained by the method of Example 3 was dissolved in 10 ml of ethanol, and the solution was concentrated under reduced pressure again. The resulting residue was dissolved in 5 ml of ethanol and the solution was left overnight under ice cooling. The precipitated crystals were collected by filtration and dried to obtain 730 mg of the free base of the preferred optical isomer of YM-09730 Diastereomer A. Melting Point: 137 ° -139 ° C. Specific light intensity: [a] 20 _D = + 64.8 ° (c = 1, methanol). NMR (in CDCl ₃ , internal standard TMS, δ ppm): 1.4-3.0 (6H, m, C ₂ ', ₄ ', ₅ '-H ₂ ); 2.34, 2.36 (6H, s, C ₂ , ₆ -CH ₃ ); 3.65 (5H, s, -COOCH ₃ and -CH ₂ ψ); 5.10 (1H, m, C ₃ ', -H); 5.12 (1H, s, C ₄ -H); 5.78 (1H, broad s, NH); 7.16-8.24 (9H, m, benzene ring-H).

(2) The solution obtained by dissolving the free base (700 mg) obtained above in 1.8 ml of ethanol solution of 10 ml of chloroform and 0.8 N hydrogen chloride was concentrated under reduced pressure. The obtained residue was dissolved in 3.5 ml of methanol, and the solution was left overnight under ice cooling. Precipitated crystals were collected by filtration and dried to obtain 630 mg of the preferred optical isomer hydrochloride of YM-09730 Diastereomer A. Melting point: 228 °-230 ° C. (decomposition). Specific light intensity: [α] 20 _D = + 116.7 ° (c = 1, methanol). NMR spectrum was consistent with that of the product prepared in Example 2.

Claims (3)

After reacting the compound represented by the following structural formula (II) with the compound represented by the structural formula (III), and when the compound (II) and (III) are both lefty substances, the reaction mixture of the following structural formula (I) If the preferential optical isomer is isolated, or if at least one of the compounds (II) and (III) is a racemate, the preferred optical isomer of the following structural formula (I) is subjected to column chromatography or fractional crystallization from the resulting reaction mixture. (±) -2, 6-dimethyl-4- (m-nitrophenyl) -1, 4 of the following structural formula (I), characterized by isolating by Preferred optical isomers or pharmacologically acceptable of diastereomer A of dihydropyridine-3,5-dicarboxylic acid-3 (1-benzinepyrrolidin-3-yl) ester-5 methyl ester Method for producing acid addition salt thereof.

(±) -2, 6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3, represented by the following structural formula (I) having a melting point of 223 ° to 230 ° C (decomposition); Preferred optical isomer of partial isomer A of 5-dicarboxylic acid-3- (l-benzylpyrrolidin-3-yl) ester-5-methyl ester or a pharmacologically acceptable acid addition salt thereof.

Hydrochloride of the preferential optical isomer of diastereomer A according to claim 1.