IE57630B1 - Process for the preparation of unsymmetrical 1,4-dihydro-pyridinedicarboxylic esters - Google Patents

Description

The present invention relates to a chemically original process for the preparation of known unsymmetri- 4 cal 1,4-dihydropyridinedicarboxylic esters.

Several processes for their preparation have 5 already been disclosed.

Thus, for example, DE-AS (German Published Specification) 2,117,573 describes the one-step preparation of unsymmetrical dihydropyridines by reaction of aldehydes with ketocarboxylic acids and enaminocarboxylic esters. A two-step process is regarded as having disadvantages, since the ylidene-^-ketocarboxylic esters, which can be prepared from aldehydes and ketocarboxyIic esters, are very difficult to isolate in the pure form and frequently only in low yields.

However, it emerges that one-step preparation of dihydropyridines gives rise to impurities which can be removed only with difficulty by purification processes.

Having regard to the use of unsymmetricaI 1,4-dihydropyridines as medicaments, there is a continuous need to make these compounds available in a high degree of purity. Thus, for example, on preparation of 4-(2'ni t rophenyI)-2,6-dimethy1-3,5-di carboethoxy-1,4-di hydropyridine by the method of U.S. Patent 3,485,847, seven by-products could be detected by thin-layer chromatography. i Processes for the preparation of unsymmetrical dihydropyridine esters have already been described in the earlier German Patent Applications DE-A-2 841 667, DE-A-2 210 672, DE-A-2 549 568 and DE-A-2 335 466. Processes for the preparation of dihydropyridines, which are known as Knoevenagel condensation reactions, have also been described in Organic Reaction, Vol. 15 (1967) pages 204-206, 265, 271 and 478. The use of basic catalysts in relation to the known COPE process has also been suggested.

Thus the invention relates to a process for the preparation of unsymmetrical 1z4-dihydropyridines of the formula I in which R represents a phenyl radical which is optionally substituted once or twice by nitro and/or chlorine and Rq represents a Cq-C^-alkyI radical which is optionally substituted by a Cq-C^-aIkoxy group, and 1*2 represents a Cq-Cq2**aLkyl radical which is optionally substituted by a Cq-C4*alkoxy group, a trifluoromethyl group or the radical CC4H5CH23 ECH3IN-, the radicals Rq and R2 not being identical, by reaction of an ylidene compound of the formula II or III .GOCHj R-CH=C^ ϋ ^COORq .,coch3 R-CH«C^ HI vN:oor2 with an enamine compound of the formula IV or V ch3-c=ch-coor1 iv nh2 ch3-och-coor2 V nh2 the ylidene compounds of the formulae II or III being prepared by reaction of a ketocarboxylic ester of the formula VI or VII CH3-C-CH2-COOR1 vi CH3-C-CH2-COOR2 VII with an aldehyde of the formula RCHO, in an organic solvent(lower aliphatic alcohol), in the presence of a catalytic amount of piperidine acetate, at a temperature from -10°C to 100°C.

The solvents which are preferably used are aliphatic alcohols, such as methanol, ethanol and/or isopropanol. The preferred reaction temperatures are 2060°C.

The catalyst is preferably added in amounts from 0.01 to 0.7 mole, particularly preferably from 0.02 to 0.2 mole, especially from 0.04 to 0.2 mole, per mole of the ketocarboxylic ester.

It is possible and preferred to use 1 to 2 mole, especially 1 mole, of aldehyde per mole of ketocarboxylic acid of the formula IV.

In the formula I, R preferably denotes a 2- or 3-nitrophenyl radical, a 2- or 3 chlorophenyl radical or a 2,3dichlorophenyl radical, R^ preferably denotes methyl, ethyl, propyl, isopropyl, isobutyl or a propoxyethyl radical, and R2 preferably denotes methyl, ethyl, propyl, isopropyl, isobutyl, n-decyl, methoxyethyl, propoxyethyI, trifluoromethyImethyI, or the radical CC6H5CH23 CCHjJN.

The reaction of the ylidene compound of the formulae II or III with the enamine compound of the formulae IV or V is carried out at temperatures from -10 to 130°C, preferably from 50 to 100°C.

It 1s possible and preferred to employ 1 to 1.5 mole, particularly preferably 1 to 1.3, especially 1 to 1.2 mole, of the enamine compound per mole of ylidene compound.

According to a particular embodiment, the crystalline ylidene compound remains in the reaction vessel and * is directly reacted with the enamine compound. w It has to be denoted extremely surprising that, in the reaction according to the invention in the presence of the catalyst mentioned, the ylidene-3-ketocarboxylic esters are produced in high purity and excellent yield and can be very readily isolated.

Furthermore, it has to be denoted surprising that the 1,4-dihydropyridine compounds are produced in such high purity and can be isolated in the manner described.

Omitting a further purification process, they contain no by-products.

The process according to the invention has a number of advantages.

Thus, the yield is higher than according to the known processes, and the isolated product need not undergo any further purification steps.

The invention may be illustrated by means of the examples which follow: Example 1 a) Ylidenecarboxylic ester In the following sequence, 80 g (0.5 mole) of 2-methoxyethyI acetoacetate, 75.5 g (0.5 mole) of 3nitrobenzaldehyde, 1.8 g (0.03 mole) of glacial acetic acid and 2.5 g (0.03 mole) of piperidine are added, with stirring at room temperature, to 325 ml of isopropanol.

The mixture is warmed to 40°C and kept at this temperature for 30 minutes.

It is then cooled to 20°C and stirred for 16 hours. Thereafter it is cooled to 0°C and stirred at this temperature for 1 hour. The supiernatant solution is then removed by aspiration, and the crystals are washed with 166 ml of ice-cold Isopropanol.

The resulting 2-methoxyethyl 2-(3-nitrobenzyIidene)acetoacetate is immediately reacted in the same vessel, as described in b).

If the 2-methoxyethyl 2-(3'-nitrobenzylidene)acetoacetate is isolated and dried, then 132 g of pale brown crystals are obtained (90X of the theoretical yield) of melting point 68 - 72°C.

If other amounts of catalyst are employed in place of 0.03 mole of piperidine acetate, and the reaction times are varied, then the following yields are obtained: Amount 0.09 mole 0.25 mole Yield (X) 90.5 88.5 b) 270 ml of isopropanol and 64.4 g (0.45 mole) of isopropyl 3-aminocrotonate are added to the 2-methoxyethy12-(3’-nitrobenzyIidene)acetoacetate which has been prepared according to a) and is moist with isopropanol. The mixture is heated to reflux (83°C) and kept at this temperature for 24 hours.

After cooling to 0°C, the resulting crystals are isolated, washed with 86 ml of isopropanol and sucked dry. 173.2 g of 3-isopropyl, 5-(2-methoxy)-ethyl 1,4dihydro- 2,6-dimethyl-4-(3'-nitrophenyl)-3,5-pyridine dicarboxylate of melting point 122-127°C (92X of theory) are obtained.

Thin-layer chromatography on Merck silica gel ready-coated plates (mobile phase: chloroform : acetone : petroleum ether = 3 : 2 : 5) show no visible by-products.

Example 2 Analogous to example 1 ethyl 2-(3'-nitrobenzylidine)acetoacetate which has been prepared according to example 1 a) is heated to reflux in ethanolic solution with methyl 4 3-aminocrotonate for ten hours. The mixture is cooled to °C and kept at this temperature for 16 hours. After cooling to 5°C the resulting crystals of 3-methyl, 5ethyl 1,4-dihydro-2,6-dimethy1-4-(3'-nitrophenyl)-3,5pyridine dicarboxylate of melting point 159°C are obtained (Yield: 83 % of theory).

Example 3 a) Ylidenecarboxylic ester In the following sequence, 58 g (0.5 mole) of methyl acetoacetate, 82.5 g (0.5 mole) of 2,3-dichlorobenzaldehyde, 1.8 g (0.03 mole) of glacial acetic acid and 2.5 g (0.03 mole) of piperidine are added, with stirring at room temperature, to 325 ml of isopropanol.

The mixture is warmed to 40°C and kept at this temperature for 30 minutes.

It is then cooled to 20°C and stirred for 16 hours. Thereafter it is cooled to 0°C and stirred at this temperature for 1 hour.

The resulting methyl 2-(2,3-dichlorobenzylidene )acetoacetate is immediately reacted in the same vessel, as decribed in b). b) 270 ml of isopropanol and 58.1 g (0.45 mole) of ethyl 3-aminocrotonate are added to the methyl 2-(2,3-dichlorobenzylidene )acetacetate which haa been prepared according to a) and o ' is moist with isopropanol. The mixture is heated to reflux (83 C) and kept at this temperature for 24 hours. 4 After cooling to 0°C, the resulting crystals are isolated, washed with 86 ml of isopropanol and sucked dry. 138 g of 3-methyl, 5-ethyl l,4-dihydro-2,6-dimethyl-4(2,3-dichlorophenyl)-3,5-pyridine dicarboxylate of melting point 146°C (80 S> of theory) are obtained.

Claims (9)

CLAIMS :

1. A prooess for the preparation of an unsyimetrical 1,4dihydropyridine of the formula I ’Ό’ 1 CH 3 H CH 3 in uhich R represents a phenyl radical which is optionally mono- or disubstituted by nitro and/or chlorine, Rq represents a Cq-C^-alkyl radical which is optionally substituted by a Cq-C^-aIkoxy group, and R? represents a Cq-Cqg-alkyI radical which is optionally substituted by a Cq-C^-alkoxy group, a trifluoromethyl group or the radical CC4H5CH23 CCHjJN, the radicals Rq and R? not being identical, which comprises reacting an ylidene compound of the formula II or III COCH, / 3 R-CH=C * 11 COOR 1 X R-CH«C COCH 3 ccor 2 III with an enamine compound of the formula IV or V CH,-C=CH-COOR 1 J 1 · IV nh 2 CH^-C=CH-COOR_ 1 Α ψ NH 2 I the ylidene compound of the formula II or III being prepared by reaction of a ketocarboxylic ester of the formula VI or VII CH,-C-CH 0 -COOR, J „ Z I i VI CH 3 -C-CH 2 -COOR 2 vii with an aldehyde of the formula RCHO, in anorganic solvent (lower aliphatic alcohol,, in the presence of a catalytic amount of piperidine acetate, at a temperature from -10°C to 100°C.

2. A process according to Claim 1, wherein the reaction for preparing the ylidene compound is carried out at 20-60°C.

3. A process according to Claim 1, wherein 0.01 to 0.7 mole of piperidine acetate is employed per mole of the ketocarboxylic ester.

4. A process according to Claim 1, wherein 0.02 to 0.2 mole of piperidine acetate is employed per mole of the ketocarboxylic ester.

5. A process according to Claim 1, wherein 0.04 to 0.2 mole of piperidine acetate is employed per mole of the ketocarboxylic ester.

6. A proaess according to Claim 1, wherein 1 to 2 mole of aldehyde is employed per mole of ketocarboxylic ester.

7. A process according to Claim 1 z wherein 1 mole of aldehyde is employed per mole of Jcetocarboxylic ester. ί

8. A process for the preparation of an unsymmetrical 1,4-dihydropyridine of the formula I given and defined in Claim 1, substantially as hereinbefore described with particular reference to the accompanying Examples.

9. An unsymmetrical 1,4-dihydropyridine of the formula I given and defined in Claim 1, whenever prepared by a process claimed in a preceding claim.