CS243591B1 - Method of 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxyl acid's diesters preparation - Google Patents

Description

(54) Preparation of 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters

2

The invention is in the field of synthetic drugs. It relates to a process for preparing 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters of the formula I

in which

R 1 and R 2 represent a straight or branched alkyl radical having a carbon number of 1 to 5, wherein the alkyl radical may be interrupted in the chain by an oxygen atom, wherein R 1 and R 2 may be the same or different and

X represents a nitro group at the 0-, m- or p-position.

These compounds have an antianginal and antihypertensive effect. The preparation is carried out by reacting acetic acid esters and nitrobenzaldehyde diacetate with 3-aminocrotonic acid esters.

243531

The present invention relates to a process for preparing 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters of general formula

in which

R 1 and R 2 are straight or branched alkyl radicals having a carbon number of 1 to 5, wherein the alkyl radical can be interrupted in the chain by an oxygen atom, wherein R 1 and R 2 can be the same or different and

X represents a nitro group at the 0-, m- or p-position.

These compounds are used as antianginal agents and antihypertensives.

To date, these compounds have been prepared by reacting nitrobenzaldehydes with acetic acid esters and ammonia in an inert solvent (F. Bossert, W. Vater .: US Pat. No. 3,644,627 (1972), Ger. Pat. No. 1,670,827 (1967)). (S. African, No. 6,801,482 (1982), British Pat. No. 1,173,104 (1968)).

Another method for preparing compounds of Formula I is by reacting nitrobenzaldehyde diacetate with acetic acid methyl ester and ammonia in the presence of organic bases, e.g., pyridine in an inert solvent.

Another known method for preparing compounds of formula I is by reacting nitrobenzaldehyde with aminocrotonic acid esters (Murakami M. et al., Japan Kakai Tokkyo Koho No. 8 002 652 (1980)).

Another method described for the preparation of compounds of formula I is the reaction of nitrobenzaldehyde with acetic acid ester and aminocrotonic acid ester (Murakami M. et al., Japan Kokai Tokkyo Koho No. 8,004,318 (1980)).

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of a compound of formula I from 1 to 1.5 molar parts of an acetic acid ester of formula II

CH 3 —CO — CH 2 —COOR 1 (II) in which R 1 has the same meaning as in formula I, from 1 mole of benzaldehyde diacetate of formula III

OCOCw OČOCtf ^ ₃ (III) wherein X has the same meaning as in formula I and from 1 to 1.5 molar parts of 3-amino-crotonate ester of the acid of formula IV

CH3-C = CH-COOR ₂ (IV) NH ₂ in which R2 has the same meaning as in formula I, in an inert organic solvent such as chloroform, dioxane, dimethylformamide, dimethylsulfoxide, acetic acid, aliphatic alcohols having a carbon number 1 to 3 or a mixture of said solvents at a temperature of 20 to 150 ° C. The reaction may be carried out in the presence of a base such as pyridine.

As the acetic acid esters of formula II, methyl, ethyl, isopropyl, methoxyethyl, ethoxyethyl, propoxyethyl and the like can be used. The substituted benzaldehyde acetates used may be o-nitro, m-nitro- and m-nitro-, respectively. p-nitro-benzaldehyde diacetate. As the 2-aminocrotonic acid esters of formula (IV), methyl, ethyl, isopropyl, propoxyethyl and others can be used.

The process according to the invention is carried out by heating an acetic acid ester of the formula II with a substituted aldehyde diacetate of the formula III and a 3-aminocrotonic acid ester of the formula IV in an environment of the aforementioned inert organic solvents to a temperature above 0.1 to 2. 5 MPa.

The reaction is preferably carried out at the reflux temperature of the solvent or solvent mixture used under normal pressure. Because of the low solubility of the reaction products of formula I in methanol, it is preferable to carry out the reaction at reflux temperature in this solvent.

The reaction time depends on the reaction temperature and the reactants used in the formulas II, III and IV. At the reflux temperature of the solvent or solvent mixture used, the reaction time is 4 to 10 hours. The isolation of the compounds of formula I is effected by filtering or centrifuging the crystallized product after cooling the reaction mixture. The crude products are purified by recrystallization from a suitable solvent.

An advantage of the process according to the invention over most of the processes described hitherto is the use of a substantially cheaper o- and resp. of p-nitrobenzaldehyde diacetate instead of o- and resp. p-nitrobenzaldehyde and a higher purity of the product compared to the procedure based on the reaction of methyl acetate, nitrobenzaldehyde diacetate and ammonia, respectively. in the presence of pyridine.

In the following, the subject matter of the invention is illustrated by way of example without being limited thereto.

Example 1

2,6-Dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester

7.54 g of 2-nitrobenzaldehyde diacetate, together with 4 ml of methyl acetic acid ester and 4.1 g of 3-aminocrotonic acid methyl ester, are heated in 10 ml of methanol for 7 hours at the boiling point. After cooling and filtering, the crude product is recrystallized from ethyl acetate. Clear yellow crystals (6.7 g) with a melting point of 172-174 ° C in a 65% yield are obtained.

In the same way, using the appropriate starting materials, the following compounds are obtained:

(a) 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, m.p. 206-208 ° C;

(b) 2,6-dimethyl-4- (4'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, m.p. 196-197 ° C; cj 2,6-dimethyl-4 diethyl ester - (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid, m.p. 122-124 ° C,

d] 2,6-dimethyl-4- (3 (-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, m.p. 160-161 ° C;

e) Diethyl 2,6-dimethyl-4- (4'-nitrophenyl) -l, 4-dihydropyridine-3,5-dicarboxylate of melting point 132-134 C. ^3, f diisopropyl 2,6-dimethyl-4- (2'-nitrenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid, m.p. 140-142 ° C;

g) 3,6-dimethyl-4- (S-nitrophenyl) -N-dihydropyridine-S-dicarboxylic acid diisopropyl ester, m.p. 123 degrees C; hj 2,6-dimethyl-4- (4'-nitrophenyl) diisopropyl ester -1,4-dihydropyridine-3,5-dicarboxylic acid, m.p. 151-152 ° C;

(i) 2,6-dimethyl-4- (4‘-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid bis-methoxyethyl ester, m.p. 108-112 ° C;

j] 2,6-dimethyl-4- (2'-morphophenyl] -1,4-dihydropyridine-3,5-dicarboxylic acid bis-ethoxyethyl ester, m.p. 93-96 ° C;

k) bis-Cyano 2,6-dimethyl-4- ^(3: of nitro-phenyl) -l, 4-dihydropyridine-3,5-dicarboxylic acid mp 101-104 ° C lj propoxyetylester acid bis-2 6-Dimethyl-4- (3'-nitro-phenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid, m.p. 83-86 ° C;

m) 2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-isobutyl ester-5-methyl ester, m.p. 141-142 ° C;

(n) 2,6-dimethyl-4- (3‘-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid isopropyl-2-methoxyethyl ester, m.p. 125-126 ° C;

o) 2,6-Dimethyl-4- (3'-nitro-phenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester, m.p. 157-158 ° C.

Example 2

2,6-Dimethyl-4- (2‘-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester

7.54 g of 2-nitrobenzaldehyde diacetate, together with 4 ml of methyl acetoacetic acid ester and 4.1 g of 3-aminocrotonic acid methyl ester, are heated in a mixture with 10 ml of methanol and 0.2 ml of pyridine at reflux for 5 hours. After cooling and filtering, the crude product is recrystallized from a mixture of glacial acetic acid and ethyl acetate. Clear yellow crystals (8.8 g, i.e. 66%) with a melting point of 171-173 ° C are obtained. By the same method, using the appropriate starting materials, the compounds of Examples 1a to 0 are obtained.

Example 3

2,8-Dimethyl-4- (2-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester g of 2-nitrobenzaldehyde diacetate together with 1.6 ml of methyl acetoacetate and 1.5 g of 3-aminocrotonone of methyl methyl is heated at boiling point in 4 ml of dioxane for 3 hours. After cooling and filtering, the crude product is recrystallized from glacial acetic acid. Obtained crystals having a temperature of 171-173 ° C in a 36% yield are obtained. In the same way the compounds of Examples 1a to 0 are obtained.

Example 4

2,6-Dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester

7.54 g of 2-nitrobenzaldehyde diacetate, together with 4 ml of methyl acetoacetic acid ester and 3.55 g of methyl 3-aminocrotonate, are heated at boiling point in 8 ml of 2-propanol for 4 hours. The reaction mixture is worked up in analogy to Example 1. Obtained crystals having a melting point of 172-174 ° C in 64% yield.

Example 5

2,6-Dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester

7.54 g of 2-nitrobenzaldehyde diacetate, together with 4 g of 3-aminocrotonic acid methyl ester and 4 ml of methyl acetic acid ester, are heated in 6 ml of chloroform at reflux for 3 hours. The reaction mixture was worked up analogously to Example 1. Light yellow crystals having a melting point of 171-174 ° C were obtained in 48% yield.

Example 6

2,6-Dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester

7.54 g of 2-nitrobenzaldehyde diacetate, together with 4.2 g of 3-aminocrotonic acid methyl ester and 4 ml of methyl acetic acid ester, are heated at boiling point in 8 ml of N, N-dimethylformamide for 2 hours. After cooling and standing for 2 days, crystals precipitate which are worked up analogously to the example

1. Obtained crystals having a melting point of 172-174 ° C in a 45% yield.

Claims (5)

SUBJECT 1. Process for the preparation of 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters of the general formula I I (I) in which R 1 and R 2 represent a straight or branched alkyl radical having a carbon number of 1 to 5, wherein the alkyl radical may be interrupted in the chain by an oxygen atom, wherein R 1 and R 2 may be the same or different and X is a nitro group in the o-, m- or β-position, characterized in that 1 to 1.5 molar parts of the acetic acid ester of formula II CH3-CO-CH2-COOR1 (II) wherein R1 is as defined above and 1 mole of substituted benzaldehyde diacetate of formula III OF THE INVENTION in which X is as defined above, is reacted with 1 to 1.5 moles of a 3-aminocrotonic acid ester of formula IV CH3 — C = CH — COOR (IV) NH 2 in which R 2 is as defined in formula I in an inert organic solvent such as chloroform, dioxane, dimethylformamide, dimethylsulfoxide, acetic acid, aliphatic alcohols having a carbon number of 1 to 3, or mixtures of these solvents at 20 to 150 Deň: 32 ° C. 2. The method of claim 1, wherein the inert organic solvent is methanol. 3. The process according to claim 1, wherein the reaction is carried out at the reflux temperature of the solvent used. 4. The process of claim 1 wherein the reaction is carried out in the presence of an organic base, preferably pyridine. 5. The process according to claim 1, wherein the reaction is carried out at a pressure of from 1 to 2.5 MPa.