DK152359B - 6-FORMYL-1,4-DIHYDROPYRIDINE DERIVATIVES USED AS INTERMEDIATES IN THE PREPARATION OF PHARMACEUTICAL ACTIVE 6-CYANO-1,4-DIHYDROPYRIDINE DERIVATIVES - Google Patents

Description

The present invention relates to novel 6-formyl-1,4-dihydropyridine derivatives for use as intermediates in the preparation of novel 6-cyano-1,4-dihydropyridine derivatives having vasodilatory and antihypertensive activity.

The 6-Formyl-1,4-dihydropyridine derivatives of the invention have the general formula I

wherein R represents phenyl substituted by nitro or halo-C1-6 alkyl, 2 R represents C1-6 alkoxycarbonyl, C1-6 alkoxy-C1-6 alkoxycarbonyl, phenyl-C1-6 alkoxy-C1-6 alkoxycarbonyl or NC ^ g alkyl-N-phenyl yl-C alkyl g-alkylamino-C alko-alkoxycarbonyl, 3 R represents g-alkoxycarbonyl, and 4 R represents C ^g-alkyl.

The novel 6-cyano-1,4-dihydropyridine derivatives prepared using the compounds of the invention have the general formula

12-4, wherein R, R, R and R 'have the meaning given above. They are referred to in DK-ans. No. 5047/81.

The meaning of the terms used in the definitions of the symbols in the general formulas given herein is apparent from the following: C 1-6 alkyl and C 1-6 alkyl moieties may be radicals having a straight or branched and saturated hydrocarbon chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl.

C ^gg alkoxy and C ^g alkoxy moieties may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and pentytoxy.

Halo-C1-6 alkyl may be monohalo-C1-6 alkyl such as chloromethyl, bromomethyl or chloropropyl; dihaloC 1-6 alkyl such as 1,2-dichloroethyl, 1,2-dibromoethyl or 2,2-dichloroethyl; and trihaloC1-6 alkyl such as trifluoromethyl or 1,2,2-trichloroethyl.

C 1-6 Alkoxyoarbonyl may be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or tert-butoxycarbonyl. Halogen C1-6 alkoxycarbonyl may be the halogen analogs of the above g-alkoxycarbonyl groups (e.g. 2-bromoethoxycarbonyl, 2-chloroethoxycarbonyl, 2 (or 3) -chloropropoxycarbonyl, 2 (or 3) -bromopropoxycarbonyl, 2.2- dichloroethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl). g-Alkoxy-C 1-6 alkoxycarbonyl may be 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl or 2 (or 3) -methoxy- (or ethoxy) propoxycarbonyl. Phenyl-C ^gg alkoxy-C ^ g-alkoxycarbonyl may be 2- (benzyloxyl) ethoxycarbonyl or 2 (or 3) - (benzyl-oxy) propoxycarbonyl NC ^ g alkyl-N-phenyl-Cg-alkylamino C 1-6 alk-oxycarbonyl may be 2- (N-methyl-N-benzylamino) ethoxycarbonyl.

Protected formyl may be acetals, cyclic acetals, thioacetals, cyclic thioacetals, cyclic monothioacetals or acylals. Examples of protected formyl are gem-di-C1-6 alkoxymethyl (e.g., dimethoxymethyl, diethoxymethyl or dipropoxymethyl); lower-C1-6 alkylenedioxy-C1-6 alkyl (e.g., 1,3-dioxolan-2-yl, 4-methyl-1,3-dioxolan-2-yl, 4,5-dimethyl-1,3 -dioxolan-2-yl or 1,3-dioxan-2-yl); gem-di-C 1-6 alkylthiomethyl (e.g., dimethylthiomethyl or diethylthiomethyl); gem-C 1-6 alkylenedithiomethyl (e.g. 1,3-dithiolan-2-yl, 4-methyl-1,3-dithiolan-2-yl, 4,5-dimethyl-1,3-dithiolan-2-yl) or 1,3-dithian-2-yl); and gem-di-Cj_g alkanoyloxymethyl (e.g., diacetoxymethyl or dipropionyloxymethyl); or 5- or 6-membered saturated 1-oxa-3-thioheterocyclyl-2-yl (e.g., 1,3-oxathiolan-2-yl, 4-methyl-1,3-oxathiolan-2-yl, 4,5-dimeth -yl-1,3-oxathiolan-2-yl or 1,3-oxothian-2-yl).

6-Formyl-1,4-dihydropyridine derivatives according to the invention can be prepared by the following method:

II

Wherein R, R, R and R are each as defined above and R 5 is protected formyl.

The hydrolysis can be carried out in a conventional manner, and removal of, for example, acetal-type and cyclic acetal-type protecting groups is preferably carried out by an acidic hydrolysis, ie. in the presence of an acid such as an inorganic acid (e.g. hydrochloric or sulfuric acid) or an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid); the removal of protecting groups of the thioacetal type, the type of cyclic thioacetals and the type of cyclic monothioacetals is preferably carried out by hydrolysis in the presence of heavy metal salt such as mercuric chloride or copper chloride; and the removal of the acylate-type protecting group is preferably carried out by the above acidic hydrolysis or a basic hydrolysis, i.e. in the presence of a base such as an inorganic base (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) or an organic base (e.g., sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, pyridine or picoline). These hydrolysis reactions can be carried out in a suitable conventional solvent such as water, acetone, methyl ethyl ketone, dioxane, ethanol, methanol, Ν, Ν-dimethylformamide, N-methyl-morpholine or dimethylsulfoxide, or an optional mixture thereof with water or a buffer solution thereof. The reaction temperature is not limited and the reaction is usually carried out under cooling, at room temperature or at some elevated temperature.

The starting compounds of the general formula II can be prepared by one of the methods which comprises:

1) a compound of general formula III

III

13 5

wherein R, R and R are each as defined above are reacted with an amino compound of general formula IV

IV

2, wherein R and R are each as defined above, or 2) a mixture of an aldehyde of the general formula 111 'R 1 - CHO 111' wherein R 1 is as defined above, an ester of a β-keto acid with the general formula 111 "R5 - COCH2 - R3 III" where R and R are each as defined above and an amino compound of the general formula IV is reacted.

The starting compound of general formula III used in reaction 1) may be novel and can be prepared by reacting the aldehyde of general formula 111 'with the β-ketoacid ester of general formula 111 "in a known manner.

In the above-mentioned reactions 1) and 2) the starting compounds III, IH "and IV can be used, where the symbols R and R are optionally interchanged, and in such cases the substantially the same compound can be obtained with the general formula II when R and R are the same groups.

With respect to reaction 1), the starting compound of general formula III may, due to the double bond in the molecule, comprise geometric isomers such as cis-trans isomers. Such cis-trans isomers can be equilibrated and therefore a single isomer or mixture of isomers of the general formula III can be used as starting compounds to prepare the same starting compound of the general formula 11.

Reactions 1) and 2) can be carried out at room temperature or under heating with or without a suitable solvent such as benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, methanol, propanol, butanol, water or other usual solvents. The reactions can usually be activated in the presence of an agent such as an acid (eg acetic acid), a base (eg pyridine or picoline) or in a conventional buffer solution. These agents can act as reaction activating agents and, when liquid, also as a solvent. Revenues can also be accelerated by heating. The reaction conditions may vary depending on the nature of the reactants used.

Certain of the starting compounds II, which may be indicated by general formula 11-1

11-1 wherein R ^, R *, R ^ and R ^ are each as defined above and R ^a is N-CC gl gl alkyl alkyl-N-Cphenyl-C ^ g alkyD-amino-C ^g -alkoxycarbonyl,

may be prepared by a compound of the general formula V

V

Wherein R, R, R and R are each as defined above and 2b R is halo-C 1-6 alkoxycarbonyl, reacted with N-C 1-6 alkyl-N- (phenyl-C 1-6 alkyl) amine.

This reaction is carried out in the presence or absence of a base such as an inorganic base (e.g., sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate) or an organic base (e.g., N-methylpiperidine, triethylamine, pyridine, methylmorphorine or Ν, Ν-dimethylaniline). The reaction can be carried out in a suitable solvent such as chloroform, methylene chloride, benzene, acetone, ether, tetrahydrofuran, dimethylformamide, methanol, ethanol or propanoyl. The reaction temperature is not critical and the reaction is usually carried out at room temperature or at elevated temperature (e.g., under low heating or under heating).

In accordance with the present invention, the product obtained by the reaction is separated and isolated from the reaction mixture using methods commonly used for this purpose and routinely used purification methods, e.g., recrystallization of a suitable solvent or a mixture of such solvents can be used. .

The compounds thus obtained of the general formula I include stereoisomers due to the presence of at least one asymmetric carbon atom at the 4-position of the 1,4-dihydropyridine nucleus and may be present in each of the optical isomers or a racemic mixture. The racemic compound can be cleaved to each of the optical isomers by conventional means. racemic cleavage such as cleavage by fractional recrystallization of a salt of the racemic compound with an optically active acid (e.g. tartaric or camphorsulfonic acid).

As mentioned above, the compounds of the invention of formula I are useful as intermediates in the preparation of 6-cyano-1,4-dihydro-pyridine derivatives of the general formula VI

WE

Wherein R, R, R and R are each as defined above which have vasodilatory effects and are useful for the therapeutic treatment of hypertension and cardiovascular diseases such as coronary insufficiency, angina pectoris or myocardial infarction.

The above-mentioned 6-cyano-1,4-dihydropyridine derivatives of formula VI can be prepared according to the following reaction scheme.

12 3 4 wherein R, R, R and R are each as defined above.

WE YOU

WE

For a detailed description of the above reactions, reference is made to the application of the present application, namely Danish Patent Application No. 5047/81.

The pharmacological activity of the 6-cyano-1,4-dihydropyridine derivatives of the general formula VI is demonstrated by standard methods, i.e. by intravenous administration of the following 6-cyano-1,4-dihydropyridine derivatives to dogs anesthetized with pentobarbital, and determination of coronary blood flow. The test results are given below:

Increase in coronary blood flow (percent).

The values are given as a percentage compared to control (29.5 ± 5.5 ml / minute).

Compound \ Dose yg / kg 64 250 1000 A 169 118 dead B 185 215 144

Compound A is known by the generic name "Nifedipine" and is already marketed as a coronary vasodilator.

Other pharmacological data for the 6-cyano-1,4-dihydropyridine derivatives of formula VI are disclosed in Danish Patent Application No. 5047/81.

The invention is further elucidated by the following preparations, examples and productions wherein the preparation illustrates the preparation of protected starting materials and the productions illustrate the use of the compounds of the invention in the preparation of the pharmaceutically active end products of formula VI.

Preparation 1

A solution of 9.0672 g of 2-nitrobenzaldehyde, 13.0944 g of 4,4-diethoxyacetic acetic acid ethyl ester and 1 ml of piperidine in 45 ml of benzene is refluxed under azeotropic dehydration for 3 hours. To the resulting solution is added water and the solution is extracted with diethyl ether. The extract is washed three times with water and dried and then the solvent is removed under reduced pressure to give 2- (2-nitrobenzylidene) -4,4-diethoxyacetic acetic acid ethyl ester. A mixture of the above-prepared compound and 7.7496 g of 3-aminocrotonic acid ethyl ester is heated in an oil bath (95-100 ° C) for 8 hours. The resulting mixture is extracted with diethyl ether and the extract is washed with water and dried. The solvent is removed from the extract. The residue is purified by column chromatography on silica gel with an eluent (benzene ethyl acetate = 20: 1) to give 19.3 g of oily diethyl- (2-methyl-4- (2-nitrophenyl) -6-diethoxymethyl-1,4-dihydropyr -idin-3,5-dicarboxylate). The product is crystallized in n-hexane and the crystals are collected by filtration and then recrystallized from a mixture of n-hexane and diethyl ether to give the pure compound, mp 80-81.5 ° C. NMR Spectrum (δ, CDCl ^), ppm: 1.16 (3H, t, J = 7Hz), 1.18 (3H, t, J = 7Hz), 1.25 (6H, t, J = 7 Hz), 2.37 (3H, s), 3.4 - 4.4 (8H, m), 5.92 (1H, s), 6.20 (1H, s), 6.67 (1H, broad) s), and 7.0 - 7.8 (4H, m).

Preparation 2

A solution of 3.0224 g of 2-nitrobenzaldehyde, 4.3650 g of 4,4-diethoxyacetic acetic acid ethyl ester and 240 mg of piperidine in 12 ml of benzene is refluxed under azeotropic dehydration for 80 minutes. The reaction mixture is allowed to cool and ethyl acetate is added. The mixture is washed twice with water and dried. The solvent was removed to give 6.88 g of an orange-yellow oil. The oil is kept overnight in a refrigerator to obtain crystals. The crystals are collected by filtration to give 3.3690 g of pale yellow crystals recrystallized from diisopropyl ether to give 2.2479 g of 2- (2-nitrobenzylidene) -4,4-diethoxyacetic acetic acid ethyl ester in the form of a colorless granule, m.p. 67.5 ° C. The product is one of the two isomers of 2- (2-nitrobenzylidene) -4,4-diethoxyacetic acetic acid ethyl ester and gives signals at 5.23 ppm (methine proton) and 8.31 ppm (olefin in nproton) on NMR spectrum (δ, CDCl ^). The filtrate is condensed and the resulting brown oil contains the two isomers of 2- (2-nitrobenzylidene) -4,4-di-ethoxyacetic acetic acid ethyl ester in a ratio of approx. 1: 1 and gives signals at 4.93 and 5.23 ppm (methine proton) and 8.17 and 8.31 ppm (olefin proton) on NMR spectrum (6, CDCl3).

A mixture of 2.4497 g of the crystals obtained in the above manner and 1.3508 g of 3-aminocrotonic acid ethyl ester is heated at 75-82 ° C with stirring under slightly reduced pressure for 4 hours and further heated for 5 hours at 105-108 ° C. . The reaction mixture is cooled and crystallized. The resulting crystals are recrystallized from a mixture of diisopropyl ether and n-hexane to give 0.5128 g of crystalline diethyl ethyl (2-methyl-4- (2-nitrophenyl) -6-diethoxymethyl-1,4-dihydropyridine) -3,5-dicarboxylate) identical to the product obtained using the process described in Preparation 1.

Preparation 3

A solution of 2.27 g of 3-nitrobenzaide anhydride, 3.28 g of 4,4-diethoxyacetic acetic acid ethyl ester and 0.2 ml of piperidine in 15 ml of benzene is refluxed under azeotropic dehydration for 3 hours. The resulting solution is washed three times with water and dried over magnesium sulfate. The solvent is removed from the reaction solution to give 6.0 g of oily 2- (3-nitrobenzylidene) -4,4-diethoxyacetic acetic acid ethyl ester. A mixture of the above-prepared compound and 1.94 g of 3-aminocrotonic acid ethyl ester is heated at ca. 95-100 ° C for 7 hours and then at approx. 120 ° C for 1.5 hours with stirring. After cooling, the resulting oil is extracted with ethyl acetate and the extract is washed with water and dried. The solvent is removed from the resulting solution to give 7.8 g of oil. The product is purified by column chromatography on silica gel with an eluent (benzene: ethyl acetate = 20: 1) to give 4.65 g of diethyl- (2-methyl-4- (3-nitrophenyl) -6-diethoxymethyl-1,4-dihydropyridine). 3,5-dicarboxylate) in the form of a pure product. IR Spectrum (film), υ (cm 2): 3400, 1690, 1615, 1530, 1480, 1350, 1280, 1200, 1090, 920 and 765.

NMR Spectrum: (6, CDCl 3 ppm: 1.23 (1.26 (12H, t, t, J = 7 Hz)), 2.4 (3H, s), 3.5 - 3.86 (4H, m ), 4.11 (4H, q, J = 7 Hz), 5.16 (1H, s), 6.82 (1H, broad), and 7.25 - 8.16 (4H, m).

Preparation 4

A mixture of 7.48 g of 2- (2-trifluoromethylbenzylidene) -4,4-diethoxyacetic acetic acid ethyl ester and 2.582 g of 3-aminocrotonic acid ethyl ester is heated at 130 ° C for 5 hours. The resulting mixture is dissolved in ethyl acetate and the solution is washed twice with water, dried over magnesium sulfate and concentrated under reduced pressure to give 9.8 g of a red oil. The oil is subjected to colon nechromatography on silica gel with an eluent (a mixture of 20 parts of benzene and 1 part of diethyl ether) to give an oily product. The product is converted into crystals which are recrystallized from a mixture of n-hexane and diethyl ether to give crystalline diethyl- (2-methyl-4- (2-trifluoromethylphenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5 -dicarboxylate) m.p. 82-83 ° C.

Preparation 5

A mixture of 3.02 g of 2-nitrobenzaldehyde, 3.48 g of acetic acid 2-ethoxyethyl ester and 272.5 mg of piperidine in 10 ml of benzene is refluxed under azeotropic dehydration for 1.5 hours. The mixture is washed three times with water and with an aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. To the resulting oil, namely 2- (2-nitrobenzylidene) acetacetic acid 2-ethoxyethyl ester, is added 4.77 g of 3-amino-4,4-diethoxycrotonic acid ethyl ester and the mixture is heated under stirring for 5 hours at 110 ° C. The reaction mixture is extracted with ethyl acetate and the extract is washed three times with water and dried over magnesium sulfate. After removal of the solvent, the resulting brown oil is purified by column chromatography with an eluent (a mixture of 10 parts of benzene and 1 part of ethyl acetate) to give 3.18 g of 2-ethoxyethyl- (2-methyl-4- (2- nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate in the form of an oil IR Spectrum (film), υ (cm -1): 3420, 1730, 1695, 1650, 1610, 1530, 1480, 1355, 1275, 1210, 1100, 860, 830, 785, 752 and 715. NMR Spectrum (δ, CDClCI), ppm: 1 -1.37 (12H, m), 2.37 (3H , s), 3.28 - 4.3 (12H, m), 5.93 (1H, s), 6.2 (1H, s), 6.78 (1H, m), and 7.23 - 7, 83 (4H, m).

Preparation 6 In substantially the same manner as described in Preparation 5, the following compounds are obtained:

From a mixture of 3.02 g of 2-nitrobenzaldehyde, 4.72 g of acetic acid-2-benzyloxyethyl ester, 272.5 mg of piperidine in 10.8 ml of benzene, 2- (2-nitrobenzylidene) acetacetic acid-2-benzyloxyethyl ester is obtained. which is further treated with 3-amino-4,4-diethoxycrotonic acid ethyl ester to give 4.80 g of 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-dieth-oxymethyl-1,4-dihydropyridine-3 carboxylic acid-2-benzyloxyethyl ester in the form of an oil. IR Spectrum (film), υ (cm 2): 3400, 1700, 1650, 1610, 1530, 1480, 1355, 1273, 1205, 1090, 1055, 750 and 700. NMR Spectrum (δ, CDCl3), ppm : 1.1 - 1.3 (9H, m), 2.32 (3H, s), 3.45 - 4.32 (10H, m), 4.46 (2H, s), 5.94 (1H) , s), 6.2 (1H, s), 6.82 (1H, s), and 7.16 - 7.74 (9H, m).

Preparation 7

A mixture of 4.54 g of 3-nitrobenzaldehyde, 5.23 g of acetacetic acid 2-ethoxyethyl ester and 85.2 mg of piperidine in 15 ml of benzene is refluxed under azeotropic dehydration for 3 hours. The resulting mixture is washed with water, an aqueous saturated sodium chloride solution and water in the order indicated, dried and concentrated to give 2- (3-nitrobenzylidene) acetacetic acid 2-ethoxyethyl ester in the form of an oil. To the oily product is added 6.5 g of 3-amino-4,4-diethoxycrotonic acid ethyl ester. The mixture is heated at 110 ° C for approx. 3 hours. The reaction mixture is dissolved in ethyl acetate, washed twice with water and dried. The solvent is removed from the mixture to give 15.58 g of oil. The oil is subjected to column chromatography on silica gel with an eluent (a mixture of 10 parts of benzene and 1 part of ethyl acetate) to give 8.09 g of an oily product. The oily product (0.93 g) is treated with a mixture of n-hexane and diethyl ether to obtain crystals which are further recrystallized from a mixture of n-hexane and diethyl ether to give 565.2 mg of 2-methyl-4 (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid-2-ethoxyethyl ester in the form of a yellow granule, mp 99-100 ° C.

Preparation 8

A mixture of 16 g of 2- (3-nitrobenzylidene) acetic acetic acid 2-chloroethyl ester and 10.85 g of 3-amino-4,4-diethoxycrotonic acid ethyl ester is heated at 100 ° C for 3 hours and allowed to stand overnight at room temperature. The crystals formed are collected by filtration to give 7.02 g of yellow crystals and then the filtrate is subjected to colon nechromatography on silica gel with an eluent (a mixture of 20 parts of benzene and 1 part of ethyl acetate) to give 7.4 g of oil. The oil is left to give 3.6 g of crystals and combined with the crystals prepared in the above manner (7.02 g). The crystals are recrystallized from a mixture of n-hexane and diethyl ether to give 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid 2-chloroethyl ester, m.p. -97 ° C.

Preparation 9

A mixture of 8.5 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid 2-chloroethyl ester, 2.70 g of N-methylbenzylamine and 2 6 g of triethylamine in 40 ml of ethanol are heated at reflux for 56 hours. After removal of the ethanol, the residue is dissolved in a mixture of ethyl acetate and water. The organic phase is separated and washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 11 g of an oil. The oil is subjected to column chromatography on silica gel with an eluent (a mixture of 10 parts of benzene and 1 part of diethyl ether) to give 7.35 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl -1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N-methylamino) ethyl ester in the form of an oil. IR Spectrum (film), υ (cm -1): 3400, 1700, 1690, 1610, 1523, 1475, 1350, 1275, 1197, 1092, 1055, 755 and 698.

NMR Spectrum (δ, CDCl 3 + D 2 O), ppm: 1.21 (9H, t, J = 7 Hz), 2.21 (3H, s), 2.36 (3H, s), 2.63 (2H , t, J = 6 Hz), 3.5 (2H, s), 3.65 (2H, q, J = 7 Hz), 3.66 (2H, q, J = 7 Hz), 4.1 ( 2H, q), 4.18 (2H, t, J = 6 Hz), 5.18 (1H, s), 6.2 (1H, s), 6.86 (1H, s) and 7.16 - 8.16 (4H, m).

Preparation 10

A mixture of 15.19 g of methyl (2- (2-nitrobenzylidene) -4,4-dimethoxyacetoacetate) and 6.50 g of methyl (3-aminocrotonate) is heated to 60-63 ° C for 6 hours, 100-105 ° C for 4 hours and 45 minutes. The resulting crystalline mass is triturated with methanol and collected by filtration to give 12.04 g of dimethyl (2-methyl-4- (2-nitrophenyl) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate) crystals. 1.07 g of the crystals thus obtained are recrystallized from 5 ml of methanol to give 0.93 g of pure crystals, mp 132-133 ° C.

NMR Spectrum (δ, CDCl 3) ppm: 2.36 (3H, s), 3.40 (3H, s), 3.44 (3H, s), 3.56 (3H, s), 3.66 ( 3H, s), 5.76 (1H, s), 5.99 (1H, s), 6.85 (1H, broad s), and 7.1 - 7.8 (4H, m).

Preparation 11

A mixture of 6,8009 g of 2-nitrobenzaldehyde, 8.7204 g of methyl (4,4-dimethoxyacetoacetate), 0.5405 g of acetic acid and 0.4598 g of piperidine in 30 ml of benzene is heated to reflux for 2 hours under azeotrope. dehydration. The reaction mixture is diluted with 100 ml of benzene, washed twice with water and with dilute aqueous sodium bicarbonate solution and water in the order, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 15.23 g of oily methyl (2- (2-nitrobenzylidene) -4,4-di-methoxyacetoacetat).

A mixture of 15.23 g of the crude oil thus obtained and 6.6840 g of ethyl (3-aminocrotonate) are heated to ca. 65 ° C for 6 hours and then to 98-100 ° C for 5 hours. The resulting viscous brown oil is dissolved in ethyl acetate, the solution is washed three times with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 19.40 g of brown oil. The residual oil is crystallized by trituration with 10 ml of methanol to give 12.77 g of ethyl (2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl-6-dimethoxymethyl, 4-dihydropyridine-3-carboxylate ) in the form of a yellow crystalline powder. An additional 0.53 g of crystals is recovered from the mother liquor. By recrystallization from methanol, yellow granules are obtained, mp 122-124 ° C.

NMR Spectrum (δ, CDCl 3) ppm: 1.15 (3H, t, J = 7.5Hz), 2.38 (3H, s), 3.40 (3H, s), 3.45 (3H, s) ), 3.60 (3H, s), 4.04 (2H, q, J = 7.5Hz), 4.08 (2H, q, J = 7.5Hz), 5.83 (1H, s), 5.98 (1H, s), 6.77 (1H, broad s) and 7.1 - 7.85 (4H, m).

Preparation 12

To a solution of 6.80 g of 2-nitrobenzaldehyde, 8.72 g of methyl (4,4-dimethoxyacetoacetate) and 0.54 g of acetic acid in 30 ml of benzene are added 0.46 g of piperidine and the mixture is heated to reflux for 2 hours. during azeotropic dehydration. The reaction mixture is diluted after cooling with 100 ml of benzene, washed three times with water and with dilute aqueous sodium bicarbonate solution and water in the order, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 14.73 g of oily methyl (2- (2)). -n-trobenzyliden) -4,4-dimethoxyacetoacetat).

A mixture of 14.70 g of the oil obtained above and 7.09 g of isopropyl (3-aminocrotonate) is heated to 60-63 ° C for 2 hours and to 85-90 ° C for approx. 10 hours. The reaction mixture is treated with ethyl acetate to give yellow crystals, which are collected by filtration and washed with methanol. The filtrate is evaporated and the residue is treated with methanol to further crystals. The total crystal (11.10 g) is recrystallized from methanol to give pure crystals of isopropyl (2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl-6-dimethoxy-methyl-1,4-dihydropyridine-3 carboxylate) m.p. 143-145 ° C. NMR Spectrum (δ, CDCl 3) ppm: 0.99 (3H, d, J = 6Hz), 1.24 (3H, d, J = 6Hz), 2.39 (3H, s), 3.37 ( 3H, s), 3.45 (3H, s), 3.60 (3H, s), 4.96 (1H, hept., J = 6 Hz), 5.88 (1H, s), 5.96 (1H, s), 6.82 (1H, s) and 7.1 - 7.8 (4H, m).

Preparation 13

To a mixture of 7.56 g of 3-nitrobenzaldehyde, 9.69 g of methyl (4,4-dimethoxyacetoacetate) and 600 mg of acetic acid in 25 ml of benzene is added in five equal portions 851 mg of piperidine in 5 ml of benzene each 20. and the mixture is heated to reflux for 4 hours under azeotropic dehydration. After cooling, the reaction mixture is diluted with 50 ml of benzene, washed twice with dilute aqueous sodium bicarbonate solution, washed with water and saturated aqueous sodium chloride solution in the above order, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 17.82 g of methyl ( 3-nitrobenzylidene) -4,4-dimethylacetoacetate in the form of a crude reddish-brown oil, which is used for the following reaction without further purification. A mixture of 17.82 g of the above oil and 6.33 g of methyl (3-aminocrotonate) is heated to 60-65 ° C for 4 1/2 hours and to 100-105 ° C for 8 hours and 45 minutes. The reaction mixture is chromatographed on a column of 440 g of silica gel eluting with a mixture of benzene and ethyl acetate (10: 1, v / v) to give 10.46 g of crystalline dimethyl (2-methyl-4- (3-nitrophenyl)) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate). 720 mg of the crystals thus obtained are recrystallized from 10 ml of diisopropyl ether to give 560 mg of pure product, mp 99-100 ° C.

NMR Spectrum (δ, CDCl 3) ppm: 2.47 (3H, s), 3.52 (3H, s), 3.57 (3H, s), 3.77 (3H, s), 5.25 ( 1H, s), 6.1 (1H, s), 6.98 (1H, broad s), and 7.38 - 8.17 (4H, m).

Preparation 14

To a solution of 4.53 g of 3-nitrobenzaldehyde, 7.79 g of 2-benzyloxyethyl acetoacetate and 360 mg of acetic acid in 15 ml of benzene is added a solution of 306 mg of piperidine in 5 ml of benzene and the mixture is heated to reflux for 2.5 hours during azeotropic dehydration. The reaction mixture is allowed to cool and diluted with 50 ml of benzene, washed with water, diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and then evaporated to dryness under reduced pressure to give 12.58 g of 2-benzyloxyethyl (2- (3-nitrobenzylidene) ) Acetoacetate in the form of a brown oil A mixture of 12.58 g of the oil obtained above and 8.47 g of ethyl (3-amino-4,4-diethoxycrotonate) is heated to 100-102 ° C for 4 hours. After cooling, the reaction mixture is dissolved in ethyl acetate, washed twice with water and with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. (19.04 g) is chromatographed on a column of 570 g of silica gel and eluted with a mixture of benzene and ethyl acetate (13: 1, v / v) to give 9.64 g of 2-benzyloxyethyl (2-methyl -4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate) in the form of an oil.

NMR Spectrum (6, CDCl 3) ppm: 1.17 (6H, t, J = 7Hz), 1.23 (3H, t, J = 7Hz), 2.35 (3H, s), 3.43-4 , 4 (10H, m), 4.5 (2H, s), 5.18 (1H, s), 6.86 (1H, broad s), and 7.33 - 8.13 (9H, m).

Preparation 15

A mixture of 8.0 g of 4,4-dimethoxy-2- (3-nitrobenzylidene) acetoacetate and 4.07 g of isopropyl-3-aminocrotonate was heated at 70 ° C for 1 hour with stirring and stirring was continued at 100 ° C. C for 1 hour and at 120 ° C for an additional 2.5 hours. After dissolving the reaction mixture in ethyl acetate, the solution was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated to dryness under reduced pressure to give 11.03 g of a yellow orange oil of the isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl. -2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid.

NMR Spectrum (δ (CDCl 3) ppm: 1.13 (d, J = 7.0Hz), * 1.27 (d, J = 7.0Hz (6H), 2.40 (3H, s), 3 , 47 (s) +3.50 (s) (6H), 3.69 (3H, s), 5.0 (1H, heptet, J = 7.0Hz), 5.17 (1H, s), 6 , 04 (1H, s), 6.92 (1H, broad s), 7.2-8.2 (4H, m).

EXAMPLE 1

To a solution of 1,1563 g of diethyl (2-methyl-4- (2-nitrophenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate) in 10 ml of acetone is added 2.5 ml of 6N hydrochloric acid. and stir at room temperature for 30 minutes. After removal of the acetone, water is added to the residue and neutralized with an aqueous sodium hydrogen carbonate solution. The precipitated solid is collected by filtration, washed with water and then dried to give 0.9407 g of diethyl- (2-methyl-4- (2-nitro-phenyl) -6-formyl-1,4-dihydropyridine-3). 5 ~ dicarboxylate) in the form of a yellow powder. The product is recrystallized from a mixture of ethanol and n-hexane to give the pure product, mp 101-103 ° C.

EXAMPLE 2

To a solution of 462.5 mg of diethyl (2-methyl-4- (3-nitrophenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate) in 4r; ml of acetone is added 0.4 ml of 6N hydrochloric acid and stirred at room temperature for 1 hour. After the reaction, the solvent is removed from the resulting solution. Water is added to the residue and the residue is pulverized. The powder is collected by filtration, washed with water and dried to give 360 mg of diethyl (2-methyl-4- (3-nitrophenyl) -6-formyl-1,4-dihydro-pyridine-3,5-dicarboxylate) 130-133 ° C.

EXAMPLE 3

To a solution of 5.2 g of diethyl (2-methyl-4- (2-trifluoromethylphenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate in 5 ml of acetone is added 5 ml of 6N hydrochloric acid, and stirring at room temperature for about 1.5 hours. After removing the acetone, water is added to the residue and the resulting aqueous solution is extracted twice with ethyl acetate, the extract is washed with water and dried, and the solvent is removed to give 4.2 g of diethyl (2-methyl-4- (2-trifluoro-methylphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate) as a reddish oil. IR Spectrum (nujol), υ ( cm): 3350, 1700, 1640, 1605, 1480, 1370, 1308, 1200, 1100, 1035, 950 and 763.

NMR Spectrum (6, CDClCI + D₂O), ppm: 1.2 (6H, t, J = 7Hz), 2.4 (3H, s), 3.92 - 4.38 (4H, m), δ , 72 (1H, s), 7.06 (1H, s), and 7.24 -7.62 (4H, m).

EXAMPLE 4

From a mixture of 1.9 g of 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester in 19 ml of acetone and 1.9 ml of 6N hydrochloric acid are obtained using essentially the same method as described in Example 2, 1), crystalline 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4 dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester, mp 107-108 ° C (recrystallized from diisopropyl ether).

EXAMPLE 5

From a mixture of 2.5 g of 2-methyl-4- (2-nitrophenyl) -5-ethoxy-carbonyl-6-diethoxymethyl-1,4-dihydropyridin-3-carboxylic acid 2-benzene yloxyethyl ester in the form of an oil in 25 ml of acetone and 2 ml of 6N hydrochloric acid is obtained in substantially the same manner as described in Examples 2, 6), 2.05 g of 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl -6-formyl-1,4-di-hydropyridine-3-carboxylic acid-2-benzyloxyethyl ester in the form of a reddish oil. IR Spectrum (film), δ (cm -1): 3380, 1695, 1532, 1485, 1277, 1210, 1100, 1040, 860 and 750.

NMR Spectrum (δ, CDCl 3, ppm: 2.40 (3H, s), 4.48 (2H, s), 6.08 (1H, s), and 10.40 (1H, s)).

EXAMPLE 6

To a solution of 5.85 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxy-ethyl ester in 60 3 ml of 6N hydrochloric acid are added and the resulting mixture is stirred at room temperature for approx. 2 hours. The solvent is distilled off under reduced pressure and water is added to the residue. The mixture is extracted twice with ethyl acetate and the extract is washed with an aqueous sodium chloride solution and dried. The solvent is distilled off to give 5.7 g of a reddish oil which is converted into crystals. The crystals are pulverized with a mixture of n-hexane and diethyl ether and the resulting powder (4.81 g) collected by filtration. The powder (1.81 g) is recrystallized from a mixture of diethyl ether and ethyl acetate to give 1.2 g of 2-methyl-4- (3-nitro-phenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydroopy ridi n-3-carboxylic acid 2-ethoxyethyl ester in the form of an orange-yellow granule, mp 100-101 ° C.

EXAMPLE 7

To a solution of 7.25 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridin-3-carboxylic acids 2- (N-methyl) N-benzylamino) ethyl ester in 70 ml of acetone is added 7 ml of 6N hydrochloric acid and the resulting mixture is stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure. Water is added to the residue to give an oily product. The aqueous mixture is made alkaline by the addition of powdered sodium hydrogen carbonate and then extracted with ethyl acetate. The extract is washed with water and dried, and the solvent is distilled off under reduced pressure to give 5.8 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3 carboxylic acid 2- (N-methyl-N-benzylamino) ethyl ester in the form of a reddish oil. NMR Spectrum (6, CDCl 3 + D 2 O), ppm: 1.29 (3H, t, J = 7 Hz), 2.21 (3H, s), 2.45 (3H, s), 2.63 ( 2H, t, J = 6 Hz), 3.51 (2H, s), 3.95 - 4.42 (2H, t), 3.95 - 4.42 (2H, q), 5.28 (1H) , s), 7.08 (1H, s), 7.28 - 8.12 (4H, m) and 10.54 (1H, s).

IR Spectrum (film), υ (cm 2): 3350, 1735, 1700, 1690, 1635, 1600, 1525, 1480, 1350, 1279, 1215, 1100, 1030 and 735.

EXAMPLE 8

A solution of 10.68 g of dimethyl (2-methyl-4- (2-nitrophenyl) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate) in 110 ml of acetone is mixed with 10 ml of 6N hydrochloric acid, and the mixture is stirred at 25 ° C for 3 hours, then neutralized with aqueous sodium bicarbonate solution and the acetone is distilled off at reduced pressure. The resulting reddish-yellow oily precipitate solidifies and decomposes, it is filtered off, washed with water and air dried overnight to give 9.33 g of dimethyl (2-methyl-4- (2-nitrophenyl) -6-formyl-1,4 dihydropyridine-3,5-dicarboxylate) in the form of crude crystals.

NMR Spectrum (δ, CDCl 3) ppm: 2.41 (3H, s), 3.58 (3H, s), 3.71 (3H, s), 5.88 (1H, s), 7.10 ( 1H, broad s), 7.2 - 7.9 (4H, m) and 10.43 (1H, s).

EXAMPLE 9

To a solution of 10.5 g of isopropyl (2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl-6-dimethoxymethyl (4-dihydropyridine-3-carboxylate) in 105 ml of acetone is added 15.5 ml of 6N hydrochloric acid and the mixture is then stirred for 2 hours at 25 ° C. After evaporation of the acetone, the resulting solution is diluted with 50 ml of water, the solution is basified with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The ethyl acetate extract is washed twice with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The reddish-yellow oily residue (11.08 g) is triturated with a mixture of diethyl ether and n-hexane to give 8.94 g of isopropyl- (2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl-6- formyl 1,4-dihydropyridine-3-carboxylate) in the form of a yellowish crystalline powder.

NMR Spectrum (6, CDCl 3) ppm: 0.97 (3H, d, J = 6Hz), 1.21 (3H, d, J = 6Hz), 2.43 (3H, s), 3.70 (3H) , s), 4.97 (1H, hept., J = 6Hz), 6.00 (1H, s), 6.95 (1H, broad s), 7.2 - 7.9 (4H, m) and 10.38 (1H, s).

EXAMPLE 10

To a solution of 7.5 g of dimethyl (2-methyl-4- (3-nitrophenyl) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate) in 75 ml of acetone is added 7.5 ml of 6N hydrochloric acid and the mixture is then stirred at room temperature for 6 hours. The precipitate which precipitates during the reaction is filtered off to give 2.26 g of dimethyl (2-methyl-4- (3-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate) in the form of yellow crystals, the filtrate is adjusted to pH 7.5 - 8 with aqueous sodium bicarbonate solution and the acetone is distilled off under reduced pressure to give an additional 3.84 g of the same product in the form of orange crystals (total yield 6.1 g ). A small portion of the first yield is recrystallized from methanol to give pure crystals, mp 157-157.5 ° C.

NMR Spectrum (δ, CDCl 3) ppm: 2.48 (3H, s), 3.7 (3H, s), 3.81 (3H, s), 5.3 ΠΗ, s), 7.13 - 8 , 17 (5H, m) and 10.5 (1H, s).

EXAMPLE 11

To a solution of 6.0 g of 2-benzyloxyethyl (2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridin-3-carboxylate) in 60 ml of acetone are added 6 ml of 6N hydrochloric acid and the mixture is stirred at room temperature for 2 hours. The reaction mixture is adjusted to pH 7.5 - 8 with aqueous sodium bicarbonate solution and the acetone is distilled off under reduced pressure. The resulting solution is diluted with 150 ml of water to separate oily precipitates, which is extracted twice with ethyl acetate (100 ml and 50 ml, respectively). The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 5.02 g of 2-benzyloxyethyl (2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-form-yl). 1,4-dihydropyridine-3-carboxylate) in the form of an oil.

NMR Spectrum (δ, CDCl 3) ppm: 1.25 (3H, t, J = 7Hz), 2.41 (3H, s), 4.5 (4H, s), 3.5-4.4 (6H) , m), 5.29 (1H, s), 7.3 - 8.15 (10H, m) and 10.45 (1H, s).

EXAMPLE 12 In substantially the same manner as in Example 11, the isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridin-3 was prepared. carboxylic acid.

NMR Spectrum (δ (CDCl 3) ppm: 1.22 (3H, t, J = 7.5Hz), 2.40 (3H, s), 4.0 - 4.6 (6H, m), 5.71 (1H, s), 6.7 - 7.7 (10H, m), 10.26 (1H, s).

Production 1

A mixture of 870 mg of diethyl (2-methyl-4- (2-trifluoromethylphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate), 112.1 mg of sodium carbonate and 147 mg of hydroxylamine hydrochloride in 5 ml of ethanol is stirred at room temperature for 30 minutes. After removing the ethanol, water is added to the residue and the solution is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to give 0.992 g of doughy oil. The oil is purified by colon nechromatography on silica gel with an eluent (benzene: ethyl acetate = 10: 1) to give 0.52 g of diethyl- (2-methyl-4- (2-trifluoromethylphenyl) -6-hydroxyiminomethyl-1 (4-dihydropyridine-3,5-dicarboxylate) in the form of a yellow powder.

IR Spectrum (nujol), ν (cm: 3410, 1695, 1680, 1655, 1483, 1445, 1370, 1309, 1221, 1106, 1090, 1057, 1034, 1010, 985 and 772. NMR Spectrum (5, CDCl δ), ppm: 1.17 (3H, t, J = 7 Hz), 1.20 (3H, t, J = 7 Hz), 2.35 (3H, s), 3.8 - 4.4 ( 4H, m), 5.64 (1H, wide s), 6.91 (1H, wide s), 7.2 - 7.7 (4H, m), 8.4 (1H, wide s), and 8, 8 (1H, s).

The compound is converted to the corresponding 6-cyano compound as set forth in Production 5 or 6.

Production 2

To a solution of 1.23 g of diethyl (2-methyl-4- (2-trifluoromethylphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid) and 250.2 mg of hydroxylamine hydrochloride in 5 ml of ethanol is added a solution of 190.8 mg of sodium carbonate in 1.5 ml of water. The mixture is stirred at room temperature for 30 minutes and concentrated under reduced pressure. To the residue is added water and the mixture is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. The oil is crystallized with n-hexane to give 1.09 g of diethyl (2-methyl-4- (2-trifluoromethylphenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate) as crude crystals.

The compound is converted to the corresponding 6-cyano compound as specified in Production 5 or 6.

Production in

To a mixture of 1,015 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid 2- (N-methyl-N-benzylamino) ) ethyl ester and 116.8 mg of hydroxylamine hydrochloride in 3 ml of ethanol are slowly added dropwise to a solution of 127.2 mg of sodium carbonate in 1 ml of water and the resulting mixture is stirred at room temperature for 50 minutes. The ethanol is distilled off under reduced pressure until the residue is added to water and the mixture is extracted with ethyl acetate. The extract is washed with an aqueous sodium chloride solution, dried and then concentrated under reduced pressure to give 1.01 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3 carboxylic acid 2- (N-methyl-N-benzylamino) ethyl ester in the form of a yellow oil. IR Spectrum (film), V (cm 3): 3350, 1690, 1460, 1375, 1348, 1205, 1098, 1044, 738, 720 and 700.

NMR Spectrum (δ, CDCl 3), ppm: 1.22 (3H, t, J = 7 Hz), 2.26 (3H, s), 2.36 (3H, s), 2.70 (2H, t, J = 6 Hz), 3.58 (2H, s), 4.09 (2H, q, J = 7 Hz), 4.18 (2H, t, J = 6 Hz), 5.14 (1H , s), 7.1 -8.1 (10H, m) and 8.97 (1H, s).

The compound is converted to the corresponding 6-cyano compound as set forth in Production 8.

Production 4

A mixture of 2.03 g of diethyl (2-methyl-4- (2-nitrophenyl) - 6-formyl-1,4-dihydropyridine-3,5-dicarboxylate), 417 mg of hydroxylamine hydrochloride and 861, 4 mg of sodium acetate in 15 ml of acetic acid is stirred at room temperature for 30 minutes. To the reaction mixture is added 1 ml of acetic anhydride and the mixture is stirred at room temperature for 90 minutes and refluxed for an additional 1 hour. The acetic acid is distilled off under reduced pressure until the resulting residue is added to water and the aqueous mixture is adjusted to a pH of 7 - 8 with sodium bicarbonate and extracted with diethyl ether. The extract is washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to give an oil. The oil is subjected to column chromatography on silica gel with an eluent (a mixture of 4 parts of benzene and 1 part of ethyl acetate). The resulting oily product (1.7 g) is crystallized by treatment with a mixture of diethyl ether and n-hexane (1.5 g). The crystals are recrystallized from a mixture of diethyl ether and n-hexane to give 1.23 g of diethyl (2-methyl-4- (2-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate) in the form of pure crystals, mp 126 -127.5 ° C.

Production 5

A solution of 0.49 g of powdered diethyl (2-methyl--4- (2-trifluoromethylphenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate) and 1.5 ml of thionyl chloride in 1 5 ml of dry diethyl ether is stirred at room temperature for 30 minutes. After evaporation of the resulting solution to dryness, water is added to the residue and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 0.39 g of a brown oil. The oil is purified by column chromatography on silica gel with an eluent (benzene: ethyl acetate = 5: 1) and crystallized by treatment with n-hexane to give 50 rag yellow powder. The powder is recrystallized from a mixture of diethyl ether and n-hexane to give crystalline diethyl- (2-methyl-4- (2-trifluoromethylphenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate) 140 - 143 ° C.

Production 6

A mixture of 1.09 g of crystalline diethyl (2-methyl-4- (2-trifluoromethylphenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate) and 1,319 g of N 2 '- dicyclohexylcarbodiimide in 5 ml of pyridine is heated and refluxed for 6.5 hours. After removing the pyridine, dilute hydrochloric acid is added to the residue and the mixture is stirred for 10 minutes. The mixture is extracted with ethyl acetate and the undissolved product is filtered off. The filtrate is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 1.09 g of a brown oil. The oil is purified by column chromatography on silica gel with an eluent (benzene: ethyl acetate = 10: 1) to give 720 mg of oil. The oil is crystallized by treatment with n-hexane and the precipitate is collected by filtration and washed with n-hexane to give 610 mg of yellow powder. The powder is recrystallized from a mixture of ether and n-hexane to give pure diethyl- (2-methyl-4- (2-trifluoromethylphenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate) which is identified with an authentic sample, mp 140 - 143 ° C.

Production 7

A blandinc; of 205.7 mg of diethyl (2-methyl-4- (2-trifluoromethylphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate), 82 mg of sodium acetate and 40 mg of hydroxylamine hydrochloride in 1 , 5 ml of acetic acid is stirred at room temperature for 30 minutes. After the addition of 0.1 ml of acetic anhydride, the solution is stirred at room temperature for 1.5 hours and then refluxed for 1 hour. To the resulting solution is added water and the solution is extracted with diethyl ether. The extract is washed with water, an aqueous sodium bicarbonate solution and water in the order indicated, dried over magnesium sulfate and concentrated under reduced pressure to give 201 mg of oil. The oil is purified by column chromatography on silica gel with an eluent (benzene ethyl acetate = 5: 1) to give 172.4 mg of pure oil. The oil is crystallized by treatment with n-hexane to give 118 mg of powdered diethyl- (2-methyl-4- (2-trifluoromethylphenyl) -6-cyano-1,4-dihydro-pyridine-3,5-dicarboxylate).

Production 8

A mixture of 0.91 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxy-carbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N-methylamino) ) ethyl ester and 0.987 g of N, N'-dicyclohexylcarbodiimide in 5 ml of pyridine are heated under reflux for 3 hours. After removing the pyridine under reduced pressure, water is added to the residue. The mixture is extracted with ethyl acetate. The undissolved product is filtered off and the filtrate is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 1.6 g of red oil. The oil is purified by column chromatography on silica gel with an eluent (benzene: ethyl acetate = 2: 1) to give 0.68 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4 -dihydropyridine-3-carboxylic acid 2- (N-benzyl-N-methylamino) - ethyl ester in the form of a reddish oil. IR Spectrum (nujol), v (cm -1): 33.20, 3250 (shoulder), 2240, 1708, 1685, 1525, 1500, 1345, 1293, 1210, 1100, 1030, 780, 735 and 700.

NMR Spectrum (δ, CDCl 3), ppm: 1.25 (3H, t, J = 7 Hz), 2.15 (3H, s), 2.39 (3H, s), 2.62 (2H, t, J = 7 Hz), 3.48 (2H, s), 3.9 - 4.3 (4H, q (CH 2 CH 3), t (COOCS 2 CH 2 N)), 5.26 (1H, s) and 7.1 - 8.2 (10H, m).

The product prepared in the above manner is dissolved in diethyl ether. After adding ethanolic hydrochloric acid to the solution, the solution is evaporated to dryness. The residue is pulverized with n-hexane and the precipitated powder is collected by filtration. The powder is recrystallized from aqueous ethanol to give 4 £ 0.8 mg of yellow pure crystals of the respective hydrochloride compound, mp 228 - 229 ° C.

Production 9

A mixture of 253.8-ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxy-carbonyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N- methylamino) ethyl ester, 82 mg sodium acetate and 40 mg hydroxylamine hydrochloride in 1 ml of acetic acid are stirred at room temperature for 30 minutes. After addition of 0.1 ml of acetic anhydride, the solution is stirred at room temperature for 1 hour and then refluxed for 1 hour. . To the reaction mixture is added water and the solution is neutralized with sodium bicarbonate and then extracted with ethyl acetate. The extract is washed with an aqueous sodium bicarbonate solution and water in the order indicated, dried over magnesium sulfate and then concentrated under reduced pressure to give 250 mg (quantitative) 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-cyano 1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N-methylamino) ethyl ester in the form of an oil identified by an authentic sample.

Production 10

A b landing of 3.00 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester, 0.5547 g of hydroxylamine hydrochloride and 1.1282 g of sodium acetate in 10 ml of acetic acid are stirred for 30 minutes at room temperature.

To the mixture is added 1.4 ml of acetic anhydride and the resulting mixture is stirred for 1 hour at room temperature and refluxed for 1 hour. The acetic acid is distilled off under reduced pressure and water is added to the residue. The resulting mixture is neutralized with an aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The extract is washed with water and an aqueous saturated sodium chloride solution and dried. The solvent is distilled off and the viscous oily product (3.19 g) is subjected to column chromatography on silica gel with an eluent (a mixture of 5 parts of benzene and 1 part of ethyl acetate) and obtained from the fraction containing the product, 1.74 g of a yellow oil. The oil is converted to 1.56 g of crystals. The crystals are recrystallized from benzene to give 1.5 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylic acid-2-ethoxyethyl ester / 3-benzene in the form of a yellow powder, m.p. 89 - 91 ° C. The yellow powder obtained is further recrystallized from a mixture of diethyl ether and n-hexane to give crystalline 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylic acid. 2-ethoxyethyl ester, m.p. 115 - 116 ° C.

Production 11

A mixture of 1.9418 g of diethyl (2-methyl-4- (3-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate), 399.6 mg of hydroxyamine hydrochloride and 820 mg of sodium acetate in 7.5 ml of acetic acid are stirred at room temperature for 30 minutes. After adding 1 ml of acetic anhydride, the resulting mixture is stirred for 1 hour at room temperature and refluxed for an additional 1 hour. The acetic acid is distilled off and water is added to the residue. The resulting aqueous mixture is neutralized with an aqueous saturated sodium hydrogen carbonate solution. A precipitated oily product is extracted twice with ethyl acetate. The extract is washed with an aqueous sodium chloride solution and dried. The solvent is distilled off under reduced pressure to give 2,0103 g of an orange-yellow oil. The oil is converted into crystals and the crystals are recrystallized from a mixture of diethyl ether, ethyl acetate and n-hexane to give 0.9119 g of a yellow powder. The powder is dissolved in a mixture of 5 parts of benzene and 1 part of ethyl acetate and filtered on silica gel to give 1.02 g of crystals. The crystals are recrystallized from a mixture of benzene and diethyl ether to give 0.8497 g of diethyl- (2- ™ ethyl 1-4- (3-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylic acid in the form of a yellow granule, mp 174 - 177 ° G <,

Production 12

From a mixture of 2.0 g of 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxyethyl ester in the form of a red oil, 336.9 mg hydroxylamine hydrochloride and 662.9 mg sodium acetate in 15 ml of acetic acid and 1.5 ml of acetic anhydride are obtained by analogy as described in Example 4, 2), 767 mg of crystals. The crystals are recrystallized from a mixture of benzene and diethyl ether to give 450 mg of 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxyethyl ester in the form of pale yellow crystals, m.p. 139-140 ° C (further recrystallized from a mixture of diethyl ether and n-hexane).

Production 13

From a mixture of 900 mg of 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid-2-ethoxyethyl ester, 167 mg of hydroxylamine hydrochloride and 341 mg of sodium acetate in 7 ml of acetic acid and 1 ml of acetic anhydride are obtained using essentially the same method as described in Production 4,420 mg of crystalline 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-cyano 1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester, mp 129-130.5 ° C (recrystallized from a mixture of diethyl ether and n-hexane).

Production 14

A mixture of 3.6 g of dimethyl (2-methyl-4- (2-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate), 7 64 mg of hydroxylamine hydrochloride and 1.06 g sodium acetate in 20 ml of acetic acid is stirred at room temperature for 45 minutes to give dimethyl- (2-methyl-4- (2-nitrophenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate). To the reaction mixture is added 3.37 g of acetic anhydride and the mixture is stirred at room temperature for 15 minutes and then heated to 100 ° C for 3 hours with stirring. After removing the acetic acid, the residue is adjusted to pH 7.5 with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract is washed twice with water and with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resulting oil (3.80 g) is chromatographed on a column of 110 g of silica gel and eluted with a mixture of benzene and ethyl acetate (9: 1, v / v) to give 2.05 g of crystals which are recrystallized from a mixture of 12 ml ethyl acetate and 6 ml of n-hexane to give 1.19 g of dimethyl (2-methyl-4- (2-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate) in the form of yellow granules mp 170.5 - 171.5 ° C.

NMR Spectrum (<5, CDCl3 / ppm: 2.37 (3H, s), 3.6 (3H, s) 3.7 (3H, s), 5.9 (1H, s), and 7.34 - 7.83 (4H, m).

Production 15

A mixture of 3.88 g of isopropyl (2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate), 0.7644 g of hydroxylamine hydrochloride and 1, 0664 g of sodium acetate in 20 ml of acetic acid is stirred at room temperature for 1 hour to form isopropyl- (2-methyl-4- (2-nitrophenyl) -5-methoxycarbony-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate ). To the reaction mixture is added 3.37 g of acetic anhydride and the mixture is heated to 95-100 ° C for 6 hours. After removing the acetic acid, water is added to the residue and the mixture is extracted with ethyl acetate. The extract is washed with water, aqueous sodium bicarbonate solution and water in the above order, dried over roagnesium sulfate and evaporated to dryness under reduced pressure. The residual oil (3.69 g) is chromatographed on a column of 100 g of silica gel and eluted with a mixture of benzene and ethyl acetate (5: 1, v / v) to give 2.0 g of isopropyl (2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate) in the form of an oil which is left in a freezer for several days for crystallization. Methanol is recrystallized to give pure crystals, mp 175.5 - 176.5 ° C.

NMR Spectrum (<S, CDCl 3) ppm: 0.91 (3H, d, J = 6Hz), 1.17 (3H, d, J = 6Hz), 2.33 (3H, s), 3.65 ( 3H, s), 4.9 (1H, hept., J = 6Hz), 5.95 (1H, s), 6.8 (1H, wide s), and 7.23 - 7.85 (4H, m) .

Production 16

A mixture of 2.0 g of dimethyl (2-methyl-4- (3-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate, 424.3 mg of hydroxylamine hydrochloride and 591.8 Sodium acetate mg in 12 ml of acetic acid is stirred at room temperature for 80 minutes to give dimethyl (2-methyl-4- (3-nitrophenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate). 1.87 g of acetic anhydride is added and the mixture is heated to 110 ° C for 3.5 hours with stirring. The reaction mixture is evaporated to form a crystalline mass which is neutralized by treatment with dilute aqueous sodium bicarbonate solution and the crystalline mass is pulverized. and washed thoroughly with water to give 1.92 g of crystals. On crystallization of a mixture of methanol and ethyl acetate 1.04 g of dimethyl (2-methyl-4- (3-nitrophenyl) -6-cyano-1,4) are obtained. -dihydropyridine-3,5-dicarboxylate) in the form of pure crystals, mp 206 - 207 ° C. An additional amount of 0.6 g is obtained from the above mother liquor. a recrystallization. NMR Spectrum (6, CDCl3) ppm: 2.4 (3H, s), 3.65 (3H, s), 3.78 (3H, s), 5.12 (1H, s), 6.76 (1H, broad s) and 7.36 - 8.1 (4H, m).

Production 17

A mixture of 2.44 g of 2-benzyloxyethyl (2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate), 377 mg of hydroxylamine hydrochloride and 526 mg of sodium acetate in 15 ml of acetic acid is stirred at room temperature for 1 hour to form 2-benzyloxyethyl (2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6--hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate). To the reaction mixture is added 1.66 g of acetic anhydride and the mixture is stirred at room temperature for 1 hour and then heated to 100 ° C for 3 hours with stirring. After removing the acetic acid, the residue is adjusted to pH 7.5 with aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The extracts are washed twice with water, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residual brown oil (2.6 g) is chromatographed on a column of 78 g of silica gel and eluted with a mixture of benzene and ethyl acetate (12: 1, v / v) to give 1.45 g of an oil. The oil is crystallized by trituration with a small amount of a mixture of di-isopropyl ether and diethyl ether and recrystallized from a mixture of 9 ml of diisopropyl ether and 1 ml of ethanol to give 840 mg of 2-benzyloxyethyl (2-methyl-4- (3-nitrophenyl)) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate) in the form of pure crystals, mp 114 - 115 ° C. An additional amount of 560 mg is obtained from the filtrate by evaporating this and leaving the residue in a freezer.

NMR Spectrum (δ, CDCl3) ppm: 1.27 (3H, t, J = 7Hz), 2.37 (3H, s), 3.65 (2H, t), 4.13 - 4.35 (4H , m), 4.5 (2H, s), 5.21 (1H, s), and 7.2 - 8.1 (9H, m).

Production 18

To a solution of 4.5 g of 6-formyl-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid isopropyl ester in 35 ml of acetic acid is added 0.97 g of hydro -xylamine hydrochloride and 1.43 g of sodium acetate, and the mixture is stirred at room temperature for 2.5 hours. After adding 4.14 g of acetic anhydride to this reaction mixture, the mixture is stirred at room temperature for 1.5 hours and at 95-100 ° C for an additional 4 hours. The acetic acid and excess acetic anhydride are evaporated in vacuo, then water is added to the residue and neutralized with a saturated aqueous sodium bicarbonate solution. This aqueous suspension is extracted twice with ethyl acetate and the combined extracts washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give 4.88 g of a reddish brown oil which is chromatographed over 150 g of silica gel with a mixture of benzene and ethyl acetate (10: 1 by volume) as eluent to give 2.99 g of crude crystals. These are recrystallized from ethanol to give 1.89 g of 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid isopropyl ester in the form of yellow prisms, m.p. 148 - 150 ° C.

Claims (1)

6-Formyl-1,4-dihydropyridine derivatives for use as intermediates in the preparation of 6-cyano-1,4-dihydropyridine derivatives of the general formula wherein R represents phenyl substituted by nitro or halo-C 1-6 alkyl, 2 R represents C 1-6 alkoxycarbonyl, C 1-6 alkoxy-C 1-6 alkoxycarbonyl, phenyl C 1-6 alkoxy-C 1-8 -alkoxycarbonyl or NC ^g-alkyl-N-phenyl-C ^gg-alkylamino-C ^ _--alkoxycarbonyl, 3R represents Cgg-alkoxycarbonyl, and 4R represent C alkyl g-alkyl, characterized in that they have the general formula I 12 3 4 wherein R, R, R and R each have the meaning given above.