JPS62174071A - Production of (4s)-2, 6-dimethyl-4-(m-nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylic acid (3s)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester - Google Patents

Abstract

PURPOSE:To obtain the titled substance useful as a medicine in high yield and optical purity without varying steric configuration of starting compound, by reacting a methyl esterification reagent to a compound or its salt corresponding to the titled substance provided that the 5-carboxylic acid is in free state. CONSTITUTION:The titled substance can be produced either by reacting a 3, 5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester derivative of formula (R' is ester residue easily eliminable by alkali hydrolysis treatment) directly with a methyl esterification reagent (e.g. diazomethane, methanol-hydrochloric acid, etc.) or by hydrolyzing the derivative under alkaline condition and reacting with a methyl esterification reagent.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing an optically active dihydropyridine compound or a salt thereof useful as a pharmaceutical.

(Prior art) 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5- having the following structure
It has been reported that dicarboxylic acid 3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester has vasodilating and hypotensive effects, and that these effects are long-lasting (Patent No. 1137506, Special Public Service 1987
-30111 publication).

This compound has two asymmetric carbon atoms, and it is presumed from a stereochemical standpoint that isomers based on these asymmetric carbon atoms exist. However, the existence of this isomer is not mentioned in the patent publication,
Unconfirmed.

(Solution Means) The present invention is characterized by reacting a methyl esterifying reagent with a rubonic acid (3S) -5-(1-benzyl-3-pyrrolidinyl) ester drug or a salt thereof.

Formula% Formula% Rubonic acid (3S) -3~(1-benzyl-3-bi and general formula (wherein R' is an ester that can be easily eliminated by alkaline hydrolysis treatment without affecting other groups) meaning a residue).

(4S) -2,6-dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-
(3) Directly react a methyl esterifying agent with a dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester derivative, or.

(4S) -2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3g) -3 -(1-benzyl-3-pyrrolidinyl) ester or a salt thereof is obtained, and this compound is reacted with a methyl esterification reagent.

(4S) -2,6-dimethyl-(m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester [ m] or a pharmacologically acceptable salt thereof. Examples of pharmacologically acceptable salts include organic acid salts such as L-(-1'J malate) and mineral acid salts such as hydrochloride.

Raw material compounds [I] and [
n] are novel compounds whose planar structures have not been described in any literature. Further, the starting compound and the target compound [m] are compounds in which both the asymmetric carbon atoms present in the dihydropyridine ring and the pyrrolidine ring have an S configuration.

In other words, the production method of the present invention uses a compound having a specific steric configuration as a raw material and directly methyl esterifies it without affecting the steric configuration, or methyl esterifies it after hydrolysis to achieve the corresponding purpose. A compound is obtained.

Hereinafter, nine manufacturing methods of the present invention will be explained.

Hydrolysis step: The hydrolysis step of the production method of the present invention is carried out by a reaction represented by the following reaction formula.

[I] [II] (in the formula R
(' is the same as above) Here, the "ester residue that can be easily eliminated by alkaline hydrolysis without affecting other groups" of R' is, for example, a cyanethyl group.

These include phenyl group, varamethoxyphenyl group, varanitrophenyl group, 2+4-sinitrophe=, n4+pentachlorophenyl group, and the like.

To carry out this reaction, the ester compound represented by the general formula [I] is reacted with a base.

As the base, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. can be used.

The amount of the base added is 9 equimole to an excess amount relative to compound [I]. Hydrolysis is usually carried out in an organic solvent at room temperature or under cooling. Acetone is the solvent.

Ketones such as methyl ethyl ketone, methanol.

Alcohols such as ethanol and ethers such as tetrahydrofuran, dioxane, and 1,2-dimethoxyethane are used.

The reaction time is about 10 minutes to 1 hour, depending on the reaction temperature, type of base, and amount added.

The reaction product can be used as a raw material compound for the first step as it is or after being isolated once.

Isolation and purification of the product from the reaction solution employs precipitation, extraction, recrystallization, etc. by adjusting the liquid properties.

This step is shown by the following reaction formula.

This methyl esterification can be carried out by reacting the carboxylic acid represented by the formula [■], its salt, or a reactive derivative of the carboxylic acid with a methyl esterification reagent. Suitable salts of carboxylic acids include alkali metal salts, such as sodium and potassium salts. Also,
Reactive derivatives of carboxylic acids include acid halides (eg, acid chlorides, acid bromides, etc.).

Examples include acid anhydrides and acid amides. As the methyl esterification reagent, diazomethane, methyl halide (eg, methyl iodide, methyl bromide, etc.), methanol-hydrochloric acid, etc. are used. Methyl esterification is usually carried out in a solvent. Examples of the solvent include ether, dichloromethane, chloroporm, etc., but when methanol is used as the methyl esterification reagent, it can also serve as the solvent. The solvent is appropriately selected depending on the type of methyl esterification reagent. For example, when methanol is used as a solvent, good results can be obtained by adding hydrogen chloride, a mineral acid such as sulfuric acid, or a Lewis acid such as boron trifluoride.

In addition, as a manufacturing method different from the above manufacturing method, compound [I]
The target compound [ml] can also be obtained by directly reacting with a methyl esterifying agent to transesterify. This method is useful when the ester residue of R' in the starting compound [I] is a substituted or unsubstituted phenyl ester.

(Effects of the Invention) Although the nine detailed descriptions of the present invention have been made above, two methods can be used without affecting the steric configuration of the compound.

Optically pure target compounds can be obtained in high yields.

Furthermore, the thus obtained target compound in which both the asymmetric carbon atoms of the dihydropyridine ring and the pyrrolidine ring have an S configuration has a unique pharmacological effect that is far superior to that of the corresponding racemic compound.

The compound of the present invention (diastereomer A (6 forms)) and its pharmacologically acceptable acid addition salt are other stereoisomers (diastereomer A (6 forms)) that correspond to the rate of increase in coronary flow rate upon direct intracoronary administration at °C. It exhibits an area ratio about 40 times that of diastereomer A (4 forms) and about 25 times that of the isomer compound (dZ form), and has a high affinity for coronary arteries.

The chemical names of each isomer in the same specification are as follows.

Diastereomer A (6 bodies): (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl -3-pyrrolidinyl) ester 5-methyl ester diastereomer A (4R) -2,6-dimethyl-4-(m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid (3R)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester diastereomer B (61 bodies): (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1, 4-dihydropyridine-3,5-dicarboxylic acid (3R)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester and (4R)-2,6
-dimethyl-4-(m-nitrophenyl)-1,4,-
Dihydropyridine-3,5-dicarboxylic acid (3S)-
3-(1--<Fuji-3-pyrrolidinyl)ester
Mixture with 5-methyl ester.

(Example) Next, the manufacturing method of the present invention will be further explained with reference to Examples.

In addition, since the raw material compound of this example is a new product, its manufacturing method will be shown as a reference example.

Reference example 1 ■ (S)-(-3-1-benzyl-3-hydroxypyrrolidine 5.23 g ([α seat = -3.77°, C = 5
．． methanol) and diketene 2.4Sg at 70-80°
(S)-3-acetoacetoxy-1-benzylpyrrolidine obtained by reacting at C for 3 hours is dissolved in 20 ml of benzene. Add 4. m-nitrobenzaldehyde to this solution.
46 g, 0.1 ml piperidine and 0.3 ml glacial acetic acid
1 and heated under reflux for 3 hours. Thereafter, the 9 reaction solutions were sequentially washed with 10+nZ each of a saturated aqueous sodium bicarbonate solution and a saturated saline solution. The oily substance obtained by concentrating the benzene layer under reduced pressure was subjected to column chromatography using 22 kg of silica gel, and toluene-ethyl acetate (3:1
v/v) to form an oily (S)-1-benzyl-
8.3 Sg of 3-[2-(m-nitrobenzylidene)acetoacetoxylopyrrolidine was obtained.

Incidentally, this product was a mixture of two E.

Mass spectrum m/z: 394 (M”) Nuclear magnetic resonance spectrum (CDCl3. TMS internal standard.

Ppm) 1.6-3.0 (6H, broad m, CH2 at the 2nd and 4.5th positions of the pyrrolidine ring) 2.3S, 2.40 (3H, s 2, COCH
3: E, mixture of two bodies) 3.4 to 3.8 (2H, m, CH2O:, E, mixture of two bodies) 5.4 (I H+ m, CH at position 3 of pyrrolidine ring) 7.0 to 8.4 (IOH, m, H and - of be/zene ring=)■ (S)-1-benzyl-3-
[3.94 g of 2-(m-nitrobenzylidene)acetoacetoxylopyrrolidine and 3-aminocrotonic acid (2-
1.54 g of cyanethyl) ester was dissolved in 4.0 ml of isopropanol and heated under reflux for 20 hours. From now on, the 9 reaction solutions were concentrated under reduced pressure to obtain crude (4R8)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-
(1-hensyl-3-pyrrolidinyl) ester 5-(
2-cyanethyl) ester (hereinafter referred to as diester) was obtained in the form of caramel (5.3 g: mixture of diastereomers A and B).

When the free base of the crude diester obtained here was analyzed for the production ratio of diastereomers by high performance liquid chromatography under the conditions described below, it was found that diastereomer A (retention time 20.7 minutes): diastereomer B ( Retention time 2
30 minutes) ratio was 1:1.

Column: Nucleosi J' 5c, 814.6 mm9
! 5 x 300 mm mobile phase: 0.05 m containing tetra-n-pentylammonium bromite (3mmoZ)
ol potassium dihydrogen phosphate (pH 3)-acetonitrile (80:20 v/v).

Flow rate: 0.9 ml per minute.

Ultraviolet detection wavelength: 254 nm Diastereomers A and B are diester N
- Differences are observed in the nuclear magnetic resonance spectrum signals of methylene in the benzyl group. Diastereomer A, determined in deuterochloroform, is 3.62
ppm, and B is.

Singlet signals corresponding to two hydrogen atoms each are shown at 3.55 ppm.

■ The free base of the crude diester obtained was immersed in silica gel (
1.5 kg) was subjected to column chromatography, eluted with ethyl acetate-glacial acetic acid (6:1 v/v), and only diastereomer A of the diester, which showed a retention time of 20.7 minutes in high performance liquid chromatography, was isolated. The fractions were collected and concentrated under reduced pressure to obtain the acetate salt of diester sheath rethiomer A as an oil (1.7 g). This oil was dissolved in 20 ml of chloroform, washed with 10 ml of saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the free base of diastereomer A of the diester in the form of a caramel (1.1 g ).

Mass spectrum m/Z: 531 (M+1) nuclear magnetic resonance spectrum (CDC13, TMS internal standard, ppm
) 1.4 to 3.0 (8H, m, -CH2O and CI(2) at the 2°4.5 position of the pyrrolidine ring 2.36.2.4 (6H,s, CH3 at the 2,5 position of the dihydropyridine ring 3 ,62(2I(,s,N CR2)4.28
(2FI, t, -CH2CN)5.10
(IH, 8, 4th position of dihydropyridine ring) 5.0
(LH, m, 3rd position of pyrrolidine ring) 5.8
6 (LH+ m, NH) 7.1-8.2 (9H, m, benzene ring, !i) Signal of N-CH2 of diastereomer B of diester (3,55 ppm > is not detected.

Example 1 ■ Free base of diastereomer A of diester 0.9
Dissolve g in 6 ml of 1,2-dimethoxyethane.

While stirring under water cooling, 5.1 ml of IN=sodium hydroxide aqueous solution was added dropwise, and the mixture was stirred at 0 to 5°C for 30 minutes.

The reaction solution diluted with 30 ml of water was added to 15 ml of chloroform.
After washing twice with
g). The precipitate was recrystallized from 3.4 ml of methanol/l/ to give (4S)-2,6-dimethyl-4=(m-nitrophenyl)-1,4-dihydropyridine-3,5
-dicarboxylic acid (3S)-3-(1-benzyl-3-
0.6 g of hydrochloride monohydrate of (pyrrolidinyl) ester was obtained.

Melting point 174-176°C (decomposition) Elemental analysis value (C26H27N306・HCI-H2
O) C
α] Amase 1465° (C = 1. methanol) nuclear magnetic resonance spectrum (CD30D, TMS internal standard, T
) pm ) 1.9-2.6 (2H, m, CH2 at position 4 of pyrrolidine ring) 2.33. 2.35 (6H,s
, dihydropyridine ring 2, CH3) 3,:3-3.9 (4H,m, pyrrolidine ring 2,
CH at position 5, )4.40 (2H,s, N-
CH2) 5.08 (IH, s, 4th position of dihydropyridine ring) 5.1-5.4 (I H, m,
3-8.2 (9H, m
(4S)-2,6-dimethyl-4- (m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-
230 mg of hydrochloride monohydrate of (1-benzyl-3-pyrrolidinyl) ester is dissolved in 30 ml of methanol, stirred at room temperature, then 10 mZ of an ether solution of diazomethane is added and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 10 mZ of chloroform, followed by a saturated aqueous solution of sodium bicarbonate and water.

After treatment with IN-hydrochloric acid and drying the chloroform layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. After heating and dissolving the residue in methanol 0.5 mZ.

- Cool on ice at night, collect the precipitated crystals, and collect 180 mg (4
S)-2,6-dimethyl-4-(m-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid
(3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester hydrochloride was obtained. The hydrochloride obtained here exhibits the following physical and chemical properties.

Melting point 228-230°G (decomposition) Elemental analysis value (as C27H3ON306C1) c(
@H(@N(@cl(@ Theoretical value 61,42 5,73 7,96 6.71
Experimental value 61.25 5,67 7,95 6.92
Specific optical rotation [α] Amasesen 116.2° (C' = 1. Methanol) nuclear magnetic resonance spectrum (CD30D, TMS
Internal standard, ppm ) is ~2.7 (2H1m, CH2 at position 4 of pyrrolidine ring) 2.32.2.34 (6H
, s, CH3 at positions 2 and 6 of the dihydropyridine ring) 3.0 to 4.0 (4H, m, CH3 at positions 2 and 6 of the dihydropyridine ring)
CH2) 3.64 (3H,s, COO
CH3)4.42' (21(,s,N CR
2) 5.08 (IH, s, position 4 of dihydropyridine ring) 5.1-5.5 (I H, m, position 3 of pyrrolidine ring) 7.3-8.2 (9H, m,
Of the benzene ring! i) (4S) −2 obtained here,
6-dimethyl-4-(m-nitrophenyl)-1,4-
Dihydropyridine-3,5-dicarboxylic acid (3S)-
3-(1-benzyl-3-pyrrolidinyl) ester 5
-Methyl ester hydrochloride was measured by high performance liquid chromatography under the same conditions as Reference Example 1■, only a peak indicating diastereomer A was observed with a retention time of 28 minutes, and a peak indicating diastereomer B was observed with a retention time of 29 minutes. No peak was observed.

Claims (2)

[Claims] (1) (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S), which is characterized by reacting a methyl esterification reagent with a salt thereof or a salt thereof with a methyl esterification reagent. )-3-(1-benzyl-3-pyrrolidinyl)
A method for producing ester 5-methyl ester or a pharmacologically acceptable salt thereof. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R' means an ester residue that can be easily eliminated without affecting other groups by alkaline hydrolysis treatment.) (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl), shown
(4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4- by (a) directly reacting the ester derivative with a methyl esterifying agent or (b) hydrolyzing it under alkaline conditions. Dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl)
(4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-, which is characterized by reacting a methyl esterifying agent after obtaining the ester or its salt. Dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl)
A method for producing ester 5-methyl ester or a pharmacologically acceptable salt thereof.