FI78472C - Process for the preparation of asymmetric 1,4-dihydropyridine carboxylic acid esters - Google Patents

Description

, 78472

Process for the preparation of asymmetric 1,4-dihydropyridine dicarboxylic acid ester

The present invention relates to a new process for the preparation of known asymmetric 1,4-dihydropyridinecarboxylic acid esters.

Several methods for preparing these compounds are now known.

For example, DE-A-2 117 573 describes an individual stepwise process for the preparation of asymmetric dihydropyridines by reacting an aldehyde with ketocarboxylic acids and enaminocarboxylic acid esters. However, the two-step process has disadvantages because the ylidene / β-ketocarboxylic acid esters prepared from aldehyde and ketocarboxylic acid esters are very difficult to isolate in pure form, while the yields are very low.

However, it has been found that the one-step preparation of dihydropyridines results in impurities that are only difficult to remove using purification methods.

Methods for the preparation of asymmetric dihydropyridines are also known from FI patents 70,887 and 60,704, DE applications 22 10 672 and 23 35 466 and U.S. patent 4 370 334.

Organic Reactions 1967, pp. 204-206, 265, 271 and 478 describe methods for the preparation of dihydropyridines based on Knoevenagel condensation. In addition, the use of basic catalysts has been proposed for 30 ns. In the context of the COPE method.

However, the use of the above methods in the preparation of asymmetric dihydropyridine esters results in only reasonable yields and the desired dihydropyridines are obtained in high impurity. In order for these compounds 35 to be used as drugs, additional purification steps must be performed. The above drawback can be avoided by using piperidine acetate as a catalyst according to the present invention. It is surprising that the use of said catalyst makes it possible to prepare asymmetric dihydropyridines in high yield and in very pure form.

When using asymmetric 1,4-dihydropyridines as drugs, it is important that these compounds can be prepared in very pure form. For example, in the preparation of 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbethoxy-1,4-dihydropyridine-10-dine according to U.S. Pat. No. 3,485,847, seven by-products have been identified using thin layer chromatography. .

The present invention relates to a process for the preparation of asymmetric 1,4-dihydropyridines of the formula

R

R 1 ° 2C V 2 Ssv-CO 2 R 2

Ti CH 2 N 2 CH 2 20 H wherein R is a phenyl group which may be mono- or di-substituted with nitro and / or chlorine, and R 1 is a C 1-4 alkyl group which may be substituted

A C 1-4 alkoxy group, and R 2 is a C 1-12 alkyl group which may be substituted by a C 1-4 alkoxy group, a trifluoromethyl group or a group wherein the groups R 1 and R 2 are not identical, by introducing a ylidene compound of the formula jcoch 3

R-CH = CT II

\ COORj ^ 35 or 3 78472 COCH-i /

R-CH = Cl 2

to react with an enamine compound of formula 5 CH -, - C = CH-COORt

3 I 1 IV

nh2 or 10 ch3-c = ch-coor2 nh2

The process is characterized in that the ylidene compound of formula II and III is prepared by reacting a keto carboxylic acid ester of formula

CH 2 -C-CH 2 COORj VI

O

or 20

ch3-c-ch2-coor2 VII

O

to react with an aldehyde of formula RCHO solvent-2j. (lower aliphatic alcohol) in the presence of a catalytic amount of piperidine acetate at a temperature of -10 to 100 ° C.

The solvent used is preferably methanol, ethanol and / or isopropanol. The reaction temperature is preferably 20 to 60 ° C.

The catalyst is preferably used in an amount of 0.01 to 0.7 mol, more preferably 0.02 to 0.2 mol, in particular 0.04 to 0.2 mol per mol of ketocarboxylic acid ester.

The amount of aldehyde is preferably 1 to 2 moles, especially 1 mole, per mole of ketocarboxylic acid ester.

In the formula I, the substituents preferably have the following meanings: R 78472 R is a 2- or 3-nitrophenyl group, a 2- or 3-chlorophenyl group or a 2,3-dichlorophenyl group, is a methyl, ethyl, propyl, isopropyl, isobutyl or propoxyethyl group, R 2 is methyl, ethyl, propyl, isopropyl, isobutyl, n-decyl, ethoxyethyl, propoxyethyl, trifluoromethyl, a group C 5 H 5 CH ZICH 3.7 N.

The reaction 10 between the ylidene compound of formula II or III and the enamine compound of formula IV or V is carried out at a temperature of -10 ° C to 130 ° C, preferably at a temperature of 50 to 100 ° C.

1 to 1.5 moles, particularly preferably 1 to 1.3 moles, especially 1 to 1.2 moles of the enamine compound can be preferably used per mole of the Ylidene compound.

In one embodiment, the crystalline ylidene compound remains in the reaction vessel and is reacted directly with the enamine compound.

It should be considered very surprising that according to the reaction according to the invention the ylidene-3-ketocarboxylic acid poesters are formed in the presence of said catalyst in very pure and excellent yield and are very well isolated.

It is further surprising that the 1,4-dihydropyridine compounds are formed as described so that they can be isolated. They do not contain any by-products, although no other purification method has been used.

The method according to the invention has numerous advantages.

Thus, the yield is higher than when using known methods 30 and no further purification steps need be performed on the isolated product.

The invention is illustrated by the following examples.

Example 1 a) Ylidenecarboxylic acid esters 35 At room temperature, 80 g (0.5 mol) of 5 78472 acetic acid 2-methoxyethyl ester, 75.5 g (0.5 mol) of 3-nitrobenzaldehyde, 1.8 g, are added in the following order to 325 ml of isopropanol with stirring. g (0.03 moles) of glacial acetic acid and 2.5 g (0.03 moles) of piperidine.

Heat to 40 ° C and allow to stand for 30 minutes 5 at this temperature.

It is then cooled to 20 [deg.] C. and stirred for a further 16 hours. It is then cooled to 0 [deg.] C. and further stirred at this temperature for 1 hour. The supernatant solution is then filtered off with suction, the crystals are washed with 10 166 ml of ice-cold isopropanol.

The 2- (3-nitrobenzylidene) -acetic acetic acid-2-methoxyethyl ester formed is reacted immediately in the same vessel as described in Example b).

If 2- (3-nitrobenzylidene) -acetic acid 2-methoxy-15-ethyl ester is isolated and dried, 132 g of light brown crystals (90% of theory) with a melting point of 68-72 ° C are obtained.

If different amounts of catalyst are used instead of 0.03 mol of piperidine acetate and the reaction times are varied, the following yields are obtained: Amount Yield (%) 0.09 mol 90.5 0.25 mol 88.5 b) Isopropanol-25 la prepared according to a) 270 ml of isopropanol and 64.4 g (0.45 mol) of 3-aminocrotonic acid isopropyl ester are added to the moistened 2- (3-nitrobenzylidene) acetic acid 2-methoxyethyl ester. Heat to reflux (83 ° C) and allow to stand for 24 hours at this temperature.

After cooling to 0 [deg.] C., the crystals formed are isolated and washed with 86 ml of isopropanol and filtered off with suction.

173.2 g of 4- (3-nitrophenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid isopropyl- (2-methoxyethyl) ester are obtained, m.p. is 122-127 ° C. (92% of theory).

6 78472

Thin layer chromatography on Merck silica gel pre-plates (eluent: chloroform: acetone; petroleum ether = 3: 2: 5) showed no visible by-products.

5 Example 2

Similarly, as in Example 1, 3-nitrobenzylideneacetic acid ethyl ester prepared according to Example 1a) and 3-aminocrotonic acid methyl ester are obtained after heating for 10 hours in an ethanolic solution and finally allowing to stand for 16 hours at 20 ° C, 2,6-dimethyl -4- (3'-Nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethyl ester, recrystallized from methanol (m.p .: 159 ° C; yield = 83%) theoretical amount).

Example 3 a) Ylidenecarboxylic acid esters

58 g (0.5 mol) of acetic acid methyl ester, 82.5 g (1.5 mol) of 2,3-di-20-chlorobenzaldehyde, 1.8 g (0.03 mol) are added in the following order to 325 ml of isopropanol with stirring at room temperature. glacial acetic acid and 2.5 g (0.03 mol) of piperidine.

Heat to 40 ° C and allow to stand for 30 minutes at this temperature.

It is then cooled to 20 [deg.] C. and stirred for a further 16 hours. It is then cooled to 0 ° C and stirred at this temperature for 1 hour.

The 2- (2,3-dichlorobenzylidene) acetic acid methyl ester formed is reacted immediately directly in the same vessel as described in Example b).

B) To 2- (2,3-dichlorobenzylidene) acetic acid methyl ester prepared according to a) are added 270 ml of isopropanol and 58.9 g (0.45 mol) of 3-aminocrotonic acid ethyl ester. Heat to reflux (83 ° C) and allow to stand for 24 hours at this temperature.

After cooling to 0 [deg.] C., the crystals formed are isolated and washed with 86 ml of isopropanol and filtered off with suction.

7 78472

138 g of 3- (2,3-dichlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3/5-dicarboxylic acid methyl ethyl ester are obtained, m.p. is 146 ° C (80% of theory).

Claims (4)

A process for the preparation of asymmetric 1,4-dihydropyridines of the formula 5 R r1 ° 2cvA. C02R2 I Ϊ Wherein R is a phenyl group which may be mono- or disubstituted with nitro and / or chlorine, and R 2 is a C 1-4 alkyl group which may be substituted by a C 1-4 alkoxy group and R 2 is a C 1-4 alkyl group which may be substituted by a C 1-4 alkoxy group, trifluoromethyl group or a group 20, wherein R 1 and R 2 are not identical, by reacting an ylidene compound of the formula; ^ coch3 R-CH = C II 25> Ss' COOR1 or COCH3 R "CH = C III coor2 with an enamine compound of formula CH3- (j: = CH-COOR1 IV Or NH 2 or