FI83517C - Process for Preparation of Right-Twisting Optical Isomer of (+ -) - 2,6-Dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridin-3,5-dicarboxylic acid 3- (1-benzylpyrrolidin-3-yl) ester-5-methyl ester (YM-09730) of A-diastereomer - Google Patents

Description

183517 (±) -2,6-Dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-benzylpyrrolidin-3-yl) ester 5-methyl ester ( YM-09730) Process for the preparation of the dextrorotatory optical isomer of the A-diastereomer - For the preparation of the right-hand optical isomer of (±) -2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5 The present invention relates to a process for the preparation of pharmacologically valuable (+ -) - 2,6-dimethyl-4- (1-benzylpyrrolidin-3-yl) ester-5-methyl ester (YM-09730) (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-benzylpyrrolidin-3-yl) ester 5-methyl ester A-diastereoisomer (I) (I) H 3 COOC,> ^, 000 -1-f ΪΙ Ό a dextrorotatory optical isomer having a hydrochloride melting point of 223 to 230 ° C (decomposes) or a pharmaceutically acceptable acid addition salt thereof. This isomer is useful as a vasodilator.

2,6-Dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-benzylpyrrolidin-3-yl) ester 5-methyl ester (YM-09730) is reported to have vasodilatory activity and antihypertensive activity while having a long duration of action (U.S. Patent 4,220,649).

2,83517 ΥΜ-09730 has two asymmetric carbon atoms. Based on these asymmetric carbon atoms, the existence of isomers in terms of stereochemistry is believed. However, the presence of isomers has not been proven because these isomers are not described in said publication.

The inventors of the present invention have found that the dextrorotatory optical isomer of diastereomer A having a hydrochloride melting point of 223-230 ° C (decomposes) can be prepared by reacting m-nitrobenzaldehyde, 1-benzyl-3-acetoacetoxypyrrolidine and methyl 3-aminocrotonate, YM-09730 thus obtained, is chromatographed on silica gel using ethyl acetate-acetic acid as eluent to separate the A-diastereomer, and then the A-diastereomer is optically separated using L - (-) - maleic acid. The isomer thus obtained has much better and different pharmacological properties than the left. with an inverting optical isomer or a mixture of both isomers (European Patent Application No. 85302666.4).

Examining the process for the preparation of this novel and useful dextrorotatory optical isomer of the diastereomer of YM-09730, a process has been found which can improve the yield of the desired isomer and which constitutes the present invention.

The A-diastereomer (dl mixture) with a melting point of the hydrochloride of 200-206 ° C (decomposes) can be clearly separated from the B-diastereomer. a melting point of 180-185 ° C (decomposes).

It has already been mentioned above that the melting point of the hydrochloride of the dextrorotatory optical isomer of diastereomer A is 223 to 230 ° C (decomposes). The present invention provides a novel process 3 83517 for the preparation of the levorotatory optical isomer of YM-09730, its A-diastereomer hydrochloride, as determined by said melting point, or a pharmaceutically acceptable acid addition salt thereof.

The pharmaceutically acceptable acid addition salt referred to herein may be a salt of an organic acid such as L - (-) - maleate, etc. and a salt of a mineral acid such as hydrochloride, etc.

The dextrorotatory optical isomer (I) of the A-diastereomer of the present invention can be prepared by leaving the 5-methoxycarbonyl-2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid of formula (II) to the left. inverted, optical isomer or racemate n ° 2 JL (II>

H3COOC COOH

H 3 C H CH 3 or a reactive derivative thereof for reacting with a levorotatory odh lsen isomer or racemate of benzyl-3-hydroxypyrrolidine of formula (III)

HO

U

OF

ch2 ^ 3 4 83517 In this reaction, a carboxylic acid ester is formed, and generally applicable methods can be used. No stereochemical inversion occurs in this reaction. Examples of the reactive derivative of the compound (II) include an acid halide such as acid chloride, acid bromide, etc .; acid anhydride, mixed acid anhydride, active ester and the like. In the case where the compound (II) is used as a free carboxylic acid, the reaction is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, etc.

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

When both starting materials, compound (II) and (III) are levorotatory optical isomers, the reaction product consists essentially only of the levorotatory optical isomer of diastereomer A. If necessary, the isomer can be isolated from the ordinary. . from the reaction mixture, such as by extraction, concentration, etc., or by flash chromatography. When at least one of the compounds (II) and (III) is a racemate, the resulting reaction mixture contains the desired dextrorotatory optical isomer of the A-diastereomer and the dextrorotatory or dextrorotatory isomers of the B-diastereomer. The desired isomer can be isolated from the reaction mixture by flash chromatography or fractional crystallization.

The dextrorotatory optical of diastereomer A of YM-09730. the resulting mixture of the isomer and the levorotatory optical B-isomer can be, for example, subjected to silica chromatography using silica gel as the support and ethyl acetate-acetic acid as the eluent to separate the dextrorotatory optical isomer of the diastereomer A of YM-09730. Alternatively, the mixture is reacted with L - (-) - maleic acid 5 83517 and the L - (-) - maleates thus obtained of the levorotatory optical isomer of the B-diastereomer are fractionally crystallized to give the L - (-) - maleate of the levorotatory optical isomer of the A-diastereomer. .

Separation by thin layer chromatography gives the dextrorotatory optical isomer of diastereomer A from the first eluate and the levorotatory optical isomer of diastereomer B in the later eluate. The silica gel used as a carrier is not limited in any way if it is commonly used in slurry chromatography. The mixing ratio of the mixture used as the eluent of ethyl acetate and acetic acid is also not particularly limited, but it is generally recommended that ethyl acetate be used as the main component and a small amount of acetic acid be mixed with it. The mixing ratio is preferably about 1 to 10 v / v acetic acid and 30 to 50 v / v ethyl acetate. As the amount of mixed acetic acid is reduced, the time required to elute the desired component increases.

The elution rate and temperature of the treatment can be selected appropriately.

On the other hand, the method using L - (-) - maleic acid can also be applied to the separation of the dextrorotatory optical isomer of diastereomer A by fractional crystallization, since the L - (-) maleate of the dextrorotatory optical isomer of diastereomer A is crystalline. Suitable solvents for fractional crystallization include methanol, ethanol, acetone, acetonitrile, etc.

. . The L - (-) - maleate thus obtained from the dextrorotatory optical isomer of diastereomer A can be used as such, but the acetate or the like of this isomer can optionally be treated with a base to form the free form, 6,83517 obtained by treatment with suitable acids.

The dextrorotatory optical isomer of diastereomer A of YM-09730 and its pharmaceutically acceptable acid addition salts, which are the target compounds of the present invention, are novel compounds not described in any publication. Their surface area ratio is about 40-fold greater than that of the levorotatory optical isomer (Form 1) and 2.5-fold greater than that of the corresponding mixture of both isomers (Form dl) when cardiac blood flow is increased by administration directly to the cardiac arteries. They also have a high affinity for the cardiac artery.

In the process of the present invention, the dextrorotatory optical isomer of diastereomer A of YM-09730, which is novel and useful, can be selectively prepared in good yield. The method is very useful from an industrial point of view.

The following experiment illustrates the pharmacological activities of the compounds obtained and known according to the invention.

The vasodilating effect of the heart was anesthetized11 a koi ri11a:

In dogs with thoracic opening and anesthetized 30 mg / kg i.v. pentobarbital sodium11a, was derived from the carotid artery into the circulatory branch of the left cardiac artery by means of a loop. Mice were connected to a servo-controlled pump (Model 1215D, Harvard Apparatus) to maintain a 120 mmHg perfusion pressure constant using a pump controller (SCS-22, Data Graph Co., Tokuya Tukada et al., Folia Pharmacol.

7 83517

Japan, 74, 49, 1978). An extracorporeal type electromagnetic flow electrode (MF-25, Nihon Koden) was also placed in the circuit to record cardiac blood flow. The test compound was administered in a dose of 1 μm directly to the cardiac artery and then the blood flow in the heart was monitored until the blood flow returned to the pre-treatment value. The area under the curve showing the percentage increase in blood flow in the heart after intracardiac injection was calculated and this value was used as an index of the total increase in blood flow in the heart. The results are shown in Table 1.

table 1

Cardiovascular dilating activity was anesthetized

Total increase in blood flow in the heart at 1 pg dose (%, min.) Exposure time Diastereoisomer A (Form D) hydrochloride 4559 ± 894 120 Diastereoisomer A (Form 1) hydrochloride 120 ± 21 5

A 1: 1 mixture of the hydrochlorides of diastereoisomers A (dl form) and B (dl form) 129 + 47 10 The total increase in cardiac blood flow caused by the dextrorotatory isomer of diastereoisomer A was about 35 times higher than the increase caused by the mixture of A and B isomers. equal doses. This indicates that the optical A-isomer1183535 has a higher affinity for the cardiac artery. In addition, the vasodilatory effect of the dextrorotatory isomer of the A-diastereoisomer was clearly longer in duration than when a mixture of the A and B diastereoisomers was used. Such a high affinity for the cardiac artery and a long duration indicate that the A-isomer hydrochloride is useful in the treatment of cardiac silicosis, such as angina pectoris.

The present invention is described in more detail below with reference to Examples. The crude compounds (II) and (III) used in the present invention are known compounds; however, in an embodiment of the present invention, these crude compounds can be prepared by the novel useful methods set forth in the Comparative Examples.

Comparative Example 1 (1) A solution of 6.04 g of m-nitrobenzaldehyde, 5.32 g of tert-butyl acetoacetate, 0.17 g of piperidine and 0.6 ml of acetic acid in 20 ml of benzene was heated under reflux for 6 hours using an azeotropic dehydrator. . After cooling, 10 ml of water was added and the benzene layer was fractionated. The benzene layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, followed by drying the benzene layer over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, after which the resulting residue was subjected to silica gel chromatography. Crystals obtained from n-hexane: ethyl acetate (5: 1 by volume). n-hexane11a was obtained. 5.82 g of a mixture of geometric isomers of tert-butyl 2- (m-nitrobenzylidene) acetoacetate were obtained as colorless crystals.

Melting point: 33-36 ° C

9,83517 (2) A mixture of 3.56 g of t-butyl 2- (m-nitrobenzylidene) acetoacetate obtained in (1) and 1.41 g of methyl 3-aminocrotonate in 7 ml of tert-butanol was heated under reflux for 20 hours. . The solvent was removed by distillation under reduced pressure. The oily residue thus obtained was treated with n-hexane to give 4.6 g of the desired 2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-tert-one. -butyl ester 5-methyl ester.

Melting point: 120-122 ° C

(3) 2.5 g of 2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-tert-butyl ester 5-methyl ester obtained in (2) 5 in 1 ml of toluene was added dropwise to 5 ml of a 25% solution of hydrogen bromide cooled in ice water in acetic acid. The mixture was stirred for 5 minutes under ice-cooling, after which the mixture was poured into 50 ml of ice water. The mixture was basified with 10% aqueous sodium hydroxide solution and 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 1.24 g of the desired 5-methoxycarbonyl-2,6-dimethyl-4- (m-nitrophenyl) 1,4-dihydropyridine-3-carboxylic acid (racemate).

Melting point: 203-204 ° C (decomposes).

Example 1 2

A solution of 55 g of m-nitrobenzaldehyde, 5.75 g of methyl 3-aminocrotonate and 7.90 g of tert-butyl acetoacetate in 25 ml of tert-butanol was heated at reflux for 22 hours. The solvent was removed by distillation under reduced pressure, after which the resulting residue was dissolved in 150 ml of toluene. The solution was washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and the solution was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give 19.62 g of an oily substance. This oily substance was dissolved in 20 ml of toluene, and the solution was added under ice-cooling and dropwise to 20 ml of 25% hydrogen bromide in acetic acid. The mixture was stirred for 5 minutes at the same temperature, after which the mixture was poured into 200 ml of ice-water. The mixture was made alkaline by adding 250 ml of 10% sodium hydroxide solution, followed by washing with 100 ml of toluene. The aqueous layer was acidified with concentrated hydrochloric acid and the precipitated crystals were collected by filtration to give 4.51 g of the desired 5-methoxycarbonyl-2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (racemate). ).

Both optical isomers of this racemate can be obtained by the following method: T. Shibanuma et al., Chem. Pharma. Bull. 28, 2809 (1980).

Comparative Example 3 (1) 17.7 g of dl-1-benzyl-3-hydroxypyrrolidine and 15.2 g of D - (-) - mandelic acid were dissolved by heating in 66 ml of acetone. The solution was allowed to stand overnight at 40 ° C. 8.5 g of precipitated crystals were recrystallized from 26 ml of acetone to give 5.1 g of (S) - (-) - 1-benzyl-3-hydroxypyrrolidine (D) - (-) - mandalate. Specific rotation [α] D + 45.5 ° (C = 1, methanol). Recrystallized once more, but no change in intrinsic inversion was observed.

Melting point: 101-102 ° C

The NMR spectrum showed a signal of N-CH.2-Ph at 4.03 ppm (singlet, 2H), but an AB-type quartet (J = 12.4Hz) of the (R) - (-) form at 4.01 ppm was not detected.

li 8351 7 (2) 22 g of (S) - (-) - 1-benzyl-3-hydroxypyrrolidine (D) - (-) - mandalate were dissolved in 50 ml of chloroform. The chloroform layer was washed with a solution of 14.4 g of anhydrous sodium carbonate in 90 ml of water, and dried over anhydrous magnesium sulfate. The chloroform was removed by distillation, after which the residue was distilled under reduced pressure to give 11.5 g of S - (-) - 1-benzyl-3-hydroxypyrrolidine. The boiling point is 109 ° C / 0.65 mmHg. [α] D -3.77 ° (C =%, methanol). Comparative Example 4 75 g of (S) - (-) - maleic acid and 75 ml of benzylamine were reacted for 3 hours at 170 ° C to give 52.7 g of (S) - (-) - 1-benzyl-3-hydroxysuccinimide ( melting point 20 99 - 101 ° C, specific rotation [α] β -51.5 ° (C = 1, methanol)).

9.73 g of lithium aluminum hydride were suspended in 340 ml of absolute tetrahydrofuran, and a solution of 20.5 g of imide in 200 ml of absolute tetrahydrofuran was added dropwise to the suspension under ice-cooling. After refluxing for 3 hours, the mixture was cooled and 100 g of sodium sulfate decahydrate was added. The mixture was stirred overnight under ice-cooling. The insoluble matter was 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 / 0.8 mmHg and a specific inversion of [α] D -3. at 0 °.

The (S) - (-) form thus obtained contained 10% of the R - (+) form calculated from the NMR spectrum of the 3-position hydrogen using a transfer reagent (EuTFMC (III)). The (S) - (-) form was converted to the D - (-) mandalate as described in Comparative Example 3, which was recrystallized from three times the volume of ethanol and then from six times the volume of ethanol and toluene (1: 5). The mandalate thus obtained ([α] D -45.2 °) was treated as above to give 8.6 g of (S) - (~) -1-benzyl-3-hydroxypyrrolidine (boiling point 115-120 ° C / l, 2-1.5 mmHg, [α] D 20 -3.77 ° (c = 5, methanol)).

Comparative Example 5 3.4 g of 2 - (+) - pinene was added to 50 ml of 9-borabicyclo-3.3.3-nonane (0.5M tetrahydrofuran solution), and the mixture was stirred for 5 hours at 60 ° C. 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, after which 1.3 ml of acetone aldehyde was added to the mixture 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 to the mixture. The mixture was stirred. The precipitate formed was removed by distillation. The ether solution was extracted with 1N hydrochloric acid. The hydrochloric acid layer was basified with sodium carbonate and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated to give 1.1 g of crude product. The crude product was distilled under reduced pressure to give 0.6 g of pure product. Boiling point 106 ° C / 0.9 mmHg. The (S) - (-) - 1-benzyl-3-hydroxypyrrolidine thus obtained had a 30% excess of the enantiomeric form (e.e.), calculated from the NMR spectrum of the 3-position hydrogen after the addition of the transfer reagent (Eu-TFMC (III)).

Example 1 332 mg of 5-methoxycarbonyl-2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid were dissolved in 3 ml of dichloromethane, and 250 mg of phosphorus pentachloride was added to the solution under stirring and cooling on ice. The mixture was stirred for a further 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. After stirring for 2 hours at -30 ° C, the reaction mixture was washed with water and then with saturated aqueous sodium hydrogencarbonate solution. The solvent was removed by distillation to give an oily substance. This oily substance was flash chromatographed on silica gel eluting with ethyl acetate-acetic acid (5: 1 v / v) to give the dextrorotatory optical isomer (I) of diastereomer A of YM-09730 with a retention time of 28 minutes in a high speed liquid chromatography system. [Column: Nucleosil <R> 5 Ci e 4.6 mm $ x 300 mm, column temperature: 30 ° C, mobile phase: 0.05 moles of dihydrogen potassium phosphate (pH 3) -acetonitrile (80: 2 = v / v), with tetra-n-pentylammonium bromide, flow rate: 0.9 ml / min, UV detector (> .254 nm)]. The isomer thus obtained was treated with a saturated aqueous solution of sodium hydrogencarbonate in chloroform and then with dilute hydrochloric acid to give 161 mg of the hydrochloride of the dextrorotatory optical isomer of the diastereomer of YM-09730. Melting point: 228-230 ° C (decomposes).

20

Specific rotation: [α] 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 were dissolved in 3 ml of dichloromethane and added to the solution under stirring and ice-cooling. 250 mg of phosphorus pentachloride. Mixture: 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 to the mixture. After stirring for 2 hours at -30 ° C, the reaction mixture was diluted with 5 ml of dichloromethane and washed successively with water and twice with saturated aqueous sodium hydrogen carbonate solution in 5 ml portions. The solvent was removed by distillation under reduced pressure to give an oily substance. This oily substance was column chromatographed on silica gel (15 g) eluting with a mixture of toluene and acetic acid (4: 1 v / v). The fraction containing the desired isomer was concentrated under reduced pressure, and the resulting residue was dissolved in 5 ml of chloroform. To chloroform1 was added 1 ml of a 0.8 N solution of hydrogen chloride in ethanol, after which the solution was again concentrated under reduced pressure. The residue was dissolved in 2 ml of methanol and the solution was allowed to stand overnight under ice-cooling. The precipitated crystals were collected by filtration and dried to give 550 mg of the hydrochloride of the dextrorotatory optical isomer of the A-diastereomer A of YM-09730.

Melting point: 226-228 ° C (decomposes) 20

Specific inversion: [α] β + 116.4 ° (C = 1, methanol) NMR (CDsDD, TM® internal standard, δppm): 1.80 - 2.70 (2H, broad m, C4'-H2) 2, 32, 2.34 (6H, s, C2, e-CH3) 3.0 - 4.0 (4H, m, O2 · 5 · -Η2) 3.64 (3H, s, -COOCH3) 4.42 ( 2H, s, -CH 2 (J) 5.08 (1H, s, C 4 -H) 5.30 (1H, m, C 3 · -H) 7.30 - 8.20 (9H, m, benzene ring-H)

Example 3 840 mg of (-) - 5-methoxycarbonyl-2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid were suspended in 6 ml of a mixture of dichloromethane and N, N-dimethylformamide ( 4: 1 v / v) and 0.2 ml of thionyl chloride was added to the solution under cooling. The mixture was stirred for 1 hour at the same temperature.

is 8351 7

To the reaction mixture was added dropwise 450 mg of (S) -1-benzyl-3-hydroxypyrrolidine in 3 ml of dichloromethane under ice-cooling. The resulting mixture was stirred for an additional 15 hours under ice-cooling, and then the reaction mixture was diluted with 10 ml of dichloromethane. The resulting solution was washed successively with 10 ml of water and 10 ml of saturated aqueous sodium hydrogencarbonate solution, and the solution was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give an oily substance. This oily substance was flash chromatographed on silica gel (40 g) eluting with a mixture of toluene and acetic acid (4: 1 v / v, then 1: 1 v / v). The fraction containing the desired isomer was concentrated under reduced pressure to give 990 mg of a concentrated oily substance. This oily substance was dissolved in 10 ml of chloroform. 2.6 ml of a 0.8 N solution of hydrogen chloride in ethanol was added, after which the solution was concentrated again under reduced pressure. The resulting residue was dissolved in 5 ml of methanol, and the solution was allowed to stand overnight under ice-cooling. The precipitated crystals were collected by filtration and dried to give 850 mg of the hydrochloride of the dextrorotatory optical isomer of diastereomer A of YM-09730.

Melting point: 226-228 ° C (decomposes).

20

Specific rotation: [α] + 116.4 ° (C = 1, methanol)

D

The NMR spectra corresponded to those of the product prepared in Example 2.

Example 4 1) 990 mg of a concentrated oily substance obtained by following the procedure of Example 3 was dissolved in 10 ml of ethanol, and the solution was concentrated again under reduced pressure. The resulting residue was dissolved in 5 ml of ethanol, and the solution was allowed to stand overnight under ice-cooling. The precipitated crystals were collected by filtration 8351 7 and dried to give 730 mg of the free base of the dextrorotatory optical isomer of diastereomer A of YM-09730.

Melting point: 137-139 ° C

20

Specific rotation: [α] D + 64.8 ° (C = 1, methanol) NMR (CDCl 3, TMS internal standard, 6ppm) 1.4 - 3.0 (6H, m, C 2 ', 4 ·, 5 * -H 2) 2 , 34, 2.36 (6H, s, C2,6-CH3) 3.65 (5H, s, -COOCH3 and -CH2 / 6) 5.10 (1H, s, C4-H) 5.12 (1H , m, C 3 * -H) 5.78 (1H, broad s, NH) 7.16-8.24 (9H, m, benzene ring-H) 2) 700 mg of the free base obtained above was dissolved in 10 ml of chloroform and To 1.8 ml of a 0.8 N solution of hydrogen chloride in ethanol, and the solution was concentrated under reduced pressure. The resulting residue was dissolved in 3.5 ml of methanol, and the solution was allowed to stand overnight under ice-cooling. The precipitated crystals were collected by filtration and dried to give 630 mg of the hydrochloride of the dextrorotatory optical isomer of diastereomer A of YM-09730.

Melting point: 228-230 ° C (decomposes) 20

Specific inversion: [α] D + 116.7 ° (C = 1, methanol) The NMR spectrum corresponded to that of the product prepared in Example 2).

Claims (1)

A process for the preparation of pharmacologically valuable (+ -) - 2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-benzylpyrrolidine) 3-yl) ester-5-methyl ester A-diastereoisomer (I) T (i) H3COOC - R II IJ a dextrorotatory optical isomer having a melting point of the hydrochloride of 223 to 230 ° C (decomposes) or a pharmaceutically acceptable acid addition salt thereof , characterized in that the compound of formula (II) NO 2 (II) HjCOOCv / X / COOH H 3 C Jv N i ^ CH 3 H is reacted with a compound of formula (III) HO Ό 18 8351 7 which starting materials (II, III) are to the left inverted optical isomers or racemates, and when both compounds (II) and (III) are levorotatory agents, the levorotatory optical isomer (I) is isolated from the resulting reaction mixture, or when at least one of these compounds (II) and (III) is ground, isolated right-turning optical i some (I) from the obtained reaction mixture by flash chromatography or fractional crystallization. I9 8351 7 For the preparation of pharmacologically active hydrogenated optical isomer (I) of (±) -2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3 - (1-Benzylpyrrolidin-3-yl) Ester-5-methyl ester Δ-diastereoisomer m2 (I) H3COOC - XX Η3 ^ Ν CH3 I / -VH stem hydrochloride melting point 224-230 ° C (sulfuric acid) or of the pharmaceutical composition of the compound of formula (I) N02 (II) H3COOCv ^ As ^ COOH 1 Ϊ h3c / Vn ^ ch3 H ring to react with the formula (III) HO I -hQ 20 8351 7 is a solid-state-derived isomer or a racemic, and, in particular, a compound of formula (II, III) is a mixture of the isomers or racemates (II, III) and the solid-state optical isomer (I) of the reaction mixture (II) ) and (III) and the racemic isolates of the higher optical isomers (I) from different reaction reactions by chromatographic or genomic fractional crystallization.