NL8402759A - Known 4-phenyl-di:hydro-pyridine-di:carboxylic acid ester(s) prodn. - by reaction of 2-benzylidene acetoacetate(s) with 3-amino-crotonate(s) - Google Patents

Abstract

Prodn. of dihydropyridine derivs. of formula (I) comprises reacting ylidene cpds. (II) or (III) with enamines (IV) or (V). (R = phenyl opt. substd. by 1 or 2 NO2 and/or Cl; R1 = 1-4C alkyl, opt. substd. by 1-4C alkxoy; R2 = 1-12C alkyl, opt. substd. by 1-4C alkoxy, CF3 or (benzyl)NMe and R1 and R2 must be different). The new feature is that (II) or (III) are prepd. by reacting RCHO with ketoester (VI) or (VII) in a solvent in presence of an amine acetate catalyst at -10 to 100 deg.C. Me.CO.CH2COOR1 (VI) Me.CO.CH2COOR2 (VII).

Description

N.0. 32722

Process for preparing asymmetric 1,4-dihydropyridinedi-carboxylic acid esters.

Applicant mentions as inventor! Dr. Werner Teller The present invention relates to a chemically special process for the preparation of known asymmetric 1,4-dihydro-pyridine dicarboxylic acid esters.

Several processes for the preparation thereof are already known.

For example, German Auslegeschrift 2,117,573 describes the one-step preparation of non-symmetrical dihydropyridines by reacting aldehydes with ketocarboxylic acids and enaminocarboxylic acid esters.

Drawbacks are seen in a two-stage process because the ylidene {J-ketocarboxylic acid esters which can be prepared from aldehydes and ketocarboxylic acid esters are very difficult to isolate and often only in low yields in pure form.

However, it appears that the one-step preparation of dihydropyridines leads to impurities which are difficult to remove by purification processes.

In view of the use of the non-symmetrical 1,4-dihydropyridines as a drug, there is still a need to provide these compounds with a high degree of purity. For example, in the preparation of 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbethoxy-1,4-dihydropyridine according to U.S. Pat. No. 3,448,847, seven by-products could be determined by thin layer chromatography .

The invention therefore relates to a process for the preparation of non-symmetrical 1,4-dihydropyridines of the formula 1, in which R represents a phenyl radical, which is optionally substituted one or two times with nitro and / or chlorine and R 1 represents a C ] - represents Chalkyl radical optionally substituted with a C 1 -C 6 alkoxy group and R 1 represents a C 1 -C 6 alkyl residue optionally with a C 1 -C 4 alkoxy group, a trifluoromethyl group or the residue [C 6 H 5 CH 2] [CH 3] is substituted, wherein the radicals R 1 and R 2 are not identical, by reacting a ylidene compound of formula 2 or 3 with an enamine compound of formula 4 or 5, characterized in that the 35 ylidene compounds of formula 2 or 3 by reacting a ketocarboxylic acid ester of the formula 6 or 7 with an aldehyde of the formula RCHO in a solvent in the presence of catalytic amounts of acetal 8402759 2 tate salts of amines at temperatures from -10 ° C to 100 ° C.

Preferred acetate salts of amines are: piperidine resp. alkylpiperidine acetate, morpholine or. alkyl morpho-linear acetate, piperazine or. alkylpiperazine acetate, pyrrolidine-5 resp. alkyl pyrrolidine acetate. In particular, piperidine acetate can be mentioned. The alkyl radicals of the catalysts preferably contain 1-4 C atoms.

As the solvent, aliphatic alcohols such as methanol, ethanol and / or isopropanol are preferably used. The conversion temperatures are preferably 20-60 ° C.

The catalyst is preferably added in amounts of 0.01 to 0.7 mol, in particular preferably 0.02-0.2 mol, in particular 0.04-0.2 mol, per mol of ylidene compounds.

Per mole of ketocarboxylic acid of the formula 4, preferably 1 to 15 moles, in particular 1 mole of aldehyde can be used.

Preferably in formula 1 R represents a 2- or 3-nitrophenyl radical, a 2- or 3-chlorophenyl radical or a 2,3-dichlorophenyl radical, methyl, ethyl, propyl, isopropyl, isobutyl or a propoxyethyl-20 radical, R2 methyl, ethyl, propyl, isopropyl, isobutyl, n-decyl, methoxyethyl, propoxyethyl, trifluoromethylmethyl or the residue [C6 H5 CH2] [CH3] N before. .

The reaction of the ylidene compound of the formula 2 or 3 with the enamine compound of the formula 4 or 5 takes place at temperatures from -10 to 130 ° C, preferably from 50 to 100 ° C.

Per mole of ylidene compound, preferably 1 to 1.5 moles, especially preferably 1 to 1.3, in particular 1 to 1.2 moles, of the enamine compound can be used.

According to a special embodiment, the crystalline ylidene compound remains in the reaction vessel and is reacted directly with the enamine compound.

It is remarkably surprising to note that according to the reaction according to the invention the ylidene-3-ketocarboxylic acid esters are formed in the purity and excellent yield in the presence of the said catalysts and can be isolated very well.

It is furthermore surprising that the 1,4-dihydropyridine compounds can be formed and isolated in such a high purity in the manner described. They do not contain any by-products without a further purification method.

8402759 £ s 3

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

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

The invention is illustrated by the following examples.

Example I

a) Ylidene carboxylic acid ester

80 g (0.5 mole) of acetic acetic acid-2-methoxyethyl ester, 75.5 g (0.5 mole) of 3-nitrobenzaldehyde, 1.8 g (0.5 g) are added to 325 ml of isopropanol 10 at room temperature with stirring. 0.03 mol) glacial acetic acid and 2.5 g (0.03 mol) piperidine.

It is heated to 40 ° C and left to stand at this temperature for 30 minutes.

The mixture is then cooled to 20 ° C and stirred for another 16 hours. The mixture is then cooled to 0 ° C and stirred at this temperature for 1 hour more. The above solution is then aspirated and the crystalline product is washed with 166 ml of ice-cold isopropanol.

The resulting 2- (3-nitrobenzylidene) -acetic acetic acid-2-methoxy-20 ethyl ester is immediately reacted in the same vessel as described under b).

The 2- (3-nitrobenzylidene) -acetacetic acid-2-methoxyethyl ester is isolated and dried, and 132 g of a light brown crystalline product (90% of theory) of melting point 68- are obtained. 72 ° C.

If other amounts of catalyst are used instead of 0.03 mole of piperidine acetate and the reaction times are varied, the following yields are obtained: 30 Amount of yield (%) 0.09 mole 90.5 0.25 mole 88.5 b) 270 ml of isopropanol and 64.4 g (0.45 mol) of 3-aminocrotonic acid isopropyl ester are prepared according to a) prepared from isopropanol-moist 2- (3-nitroben-35-zylidene) -acetacetic acid-2-methoxyethyl ethyl ester. It is heated to reflux (83 ° C) and allowed to stand at this temperature for 24 hours.

After cooling to 0 ° C, the resulting crystalline product 40 is isolated and washed with 86 ml isopropanol and sucked dry.

8402759.

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

Thin layer chromatography on finished silica gel plates of Merck 5 (running liquid: chloroform: acetone: petroleum ether = 3: 2: 5) shows no visible by-products.

Example II

Analogous Example I is obtained from the 3-nitrobenzylidene-acetacetic acid ethyl ester and the 3-aminocro-10 tonic acid methyl ester prepared in ethanolic solution after heating for 10 hours and then storing the 2,6-dimethyl for 16 hours at 20 ° C. 4- (3, -nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethyl ester, which is recrystallized from methanol (melting point 159 ° C; yield 83% of theory)

Example III

a) Ylidene carboxylic acid ester

58 g (0.5 mole) of acetacetic acid methyl ester, 82.5 g (1.5 mole) of 2,3-dichlorobenzaldehyde, 1.8 g (0.03 mole) are added to 325 ml of isopropanol at room temperature with stirring. glacial acetic acid and 2.5 g of piperidine (0.03 mol).

It is heated to 40 ° C and left to stand at this temperature for 30 minutes. The mixture is then cooled to 20 [deg.] C. and stirred for another 16 hours. The mixture is then cooled to 0 ° C and stirred at this temperature for 1 hour. The resulting 2- (2,3-dichlorobenzylidene) -acetacetic acid methyl ester is immediately reacted in the same vessel as described in b).

b) To the 2- (2,3-dichlorobenzylidene) -acetacetic acid methyl ester prepared according to a), 270 ml of isopropanol and 58.9 g (0.45 mol) of 3-aminocrotonic acid ethyl ester are added. It is heated to reflux (83 ° C) and allowed to stand at this temperature for 24 hours. After cooling to 30 ° C, the resulting crystalline product is isolated and washed with 86 ml of isopropanol and sucked dry. 138 g of 4- (2,3-dichlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ethyl ester with a melting point of 146 ° C are obtained (80% of theory).

8402759

Claims (7)

A process for the preparation of non-symmetrical 1,4-dihydropyridines of the formula 1, in which R represents a phenyl radical which is optionally substituted one or two times by 5 nitro and / or chlorine and a C 1 -C 4 alkyl radical optionally substituted with a C 1 -C 6 -alkoxy group and R 2 represents a C 1 -C 12 -alkyl radical, optionally with a C 1 -C 6 alkoxy group, a trifluoromethyl group or the radical 10 [ C 5 H 5 CH 2] [CH 3] N is substituted, wherein radicals R 1, R 2 are not identical, by reacting a ylidene compound of formula 2 or 3 with an enamine compound of formula 4 or 5, characterized in that the ylidene compounds are of the formula 2 or 3 by reaction of a ketocar-15 carboxylic acid ester of the formula 6 or 7 with an aldehyde of the formula RCHO in a solvent in the presence of catalytic amounts of acetate salts of amines at temperatures from -10 ° C to 100 ° C prepares. 2. Process according to claim 1, characterized in that the conversion is carried out at 20-60 ° C. Process according to claim 1 or 2, characterized in that 0.01 to 0.7 mol of catalysts are used per mol of ylidene compound. Process according to claim 3, characterized in that 0.02 to 0.2 mol of catalysts are used per mol of ylidene compound. 4 * 5. Process according to claim 4, characterized in that 0.04 to 0.2 mol of catalysts are used per mol of 25 ylidene compound. 6. Process according to claims 1 to 5, characterized in that 1 to 2 moles of aldehyde are used per mole of ketocarboxylic acid ester. 7. Process according to claim 6, characterized in that 1 mol of aldehyde is used per mol of ketocarboxylic acid ester. · Ι · ΗΊ · Η4 8402759% - ·> -Λ- cVh ° 3 i_ ± COCH3 ✓ coch3 R-CH-CT R-CH = C ^ * "Nvoor1 ^ N: ear2 ± _L CH3-C = CH-COOR1 ch3 -c = ch-coor2 nh2 nh2 _6_ ^ _7_ CH, -C-CH, -COOR- CH3-C-CH2-COOR2 O 0 8402759