DK152285B - METHOD OF ANALOGY FOR THE PREPARATION OF 1,4-DIHYDROPYRIDINE DERIVATIVES - Google Patents

Description

DK 152285 B

The present invention relates to an analogous process for the preparation of novel 1,4-dihydropyridine derivatives having the general formula If set forth in claim 1, which process is characterized by the characterizing part of claim 1. The present compounds have vasodilatory and antihypertensive activity. Pharmaceutical compositions containing the 1,4-dihydropyridine derivatives herein can be prepared which are used for the therapeutic treatment of cardiovascular diseases and hypertension in humans.

Thus, the compositions can be used as vasodilators and antihypertensive agents. It is possible by therapeutic methods to treat cardiovascular diseases such as coronary insufficiency, angina pectoris or myocardial infarction and hypertension.

DK-presenting publication no. 142,869 and DE-publication no. 2,248,150 describe lf4-dihydropyridine derivatives which are closely related to the compounds of formula I but do not have a CN group at the 6-position. However, as shown in the test results, the compounds of the application are superior to the known compounds.

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The 1,4-dihydropyridine derivatives prepared by the process of the invention have the general formula I

2 r1 H

R 2 represents phenyl substituted with nitro or halo-2-C 1-6 alkyl, R represents C 1-6 alkoxycarbonyl, C 1-6 alkoxy-C 1-6 alkoxycarbonyl, phenyl C L-β-alkoxy-C ^g-alkoxycarbonyl or NC - ^-g-alkyl-N- (phenyl-C --alkyl) -amino-C---alkoxycarbonyl, R R is C C ^-alkoxycarbonyl, and R R * is C 1-6 alkyl.

The meaning of the terms used in the definitions of the symbols in the general formula set forth herein is as follows: C 1-6 alkyl may be a straight or branched and saturated hydrocarbon chain having up to 6 carbon atoms such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl.

C 1-6 alkoxy may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and pentyloxy.

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

C 1-6 alkoxycarbonyl may be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or tert-butoxycarbonyl. C ^g--Alkoxy-C ^gg alkoxycarbonyl may be 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl or 2 (or 3) -methoxy (or ethoxy) propoxycarbonyl. Phenyl-C 1-6 alkoxy-C 1-6 alkoxycarbonyl may be 2- (benzyl-oxy) ethoxycarbonyl or 2 (or 3) - (benzyloxy) propoxycarbonyl.

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N “Cgg alkyl-N- (phenyl-C ^gg alkyl) -amino-C ^g-alkoxycarbonyl may be 2- (N-methyl-N-benzylamino) ethoxycarbonyl.

The process of the present invention is illustrated below.

i i 11

r4 ^ CH = N-OH

dehydrating agent ψ R1 «! JyR3 in T i

R * CN

Li

wherein R f R '.- R and R * each have the meaning given above. The compounds of general formula I

R4 CN

is prepared by treating a compound of general formula II with a dehydrating agent

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4 CH = N-OH

R H

Suitable examples of dehydrating agents may be organic or inorganic conventional agents such as an acid (e.g., sulfuric acid, phosphoric acid, polyphosphoric acid, formic acid, acetic acid, ethanesulfonic acid or p-toluenesulfonic acid), an acid anhydride (e.g. acetic anhydride, benzoic anhydride or ), an acid halide (eg <acetyl chloride, benzoyl chloride, trichloroacetyl chloride / mesyl chloride, tosyl chloride, ethyl chloroformate or phenyl chloroformate), an inorganic halogen compound (e.g. thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus oxychloride, phosphorus oxychloride e.g. NjN'-dicyclohexylcarbodiimide or N-cyclohexyl-N'-morpholinoethylcarbodiimide), Ν, Ν'-carbonyldiimidazole, pentamethylene ketene-N-cyclohexylimine, ethoxyacetylene, 2-ethyl-7-hydroxyisoxazolium phosphorus pentoxide, polyphosphoric acid ethyl ester, triethyl phosphate or phenyl phosphate). When an acid is used as an dehydrating agent, the reaction may conveniently be carried out in the presence of e.g. an alkali metal salt thereof (e.g., a sodium salt or potassium salt).

The reaction is usually carried out in a conventional solvent such as diethyl ether, dimethylformamide, pyridine, acetic acid, formic acid, benzene, carbon tetrachloride, chloroform, methylene chloride, tetrahydrofuran and dioxane, and the reaction is usually carried out at room temperature or under heating, with the reaction temperature being limited to the reaction temperature.

The product obtained by the reaction is separated and isolated from the reaction mixture using methods usually used for this purpose and routinely used purification methods, e.g. recrystallization of a suitable solvent or a mixture of such solvents.

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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. Furthermore, some of the compounds of general formula I which have no less than two asymmetric carbon atoms in the molecule may be present in each of the diastereomers or mixtures thereof. The mixture of diastereomers can be cleaved to each of the racemic compounds using conventional cleavage methods such as chromatography or fractional recrystallization, and the racemic compound can be cleaved to each of the optical isomers by conventional means of racemic cleavage such as cleavage by fractional salt crystallization. of the racemic compound with an optically active acid (eg tartaric acid or camphor sulfonic acid).

Compounds of general formula I have vasodilatory activity and are useful for therapeutic treatment of hypertension and cardiovascular diseases such as coronary insufficiency, angina pectoris or myocardial infarction.

Compositions prepared contain as active ingredient 1,4-dihydropyridine derivatives of the general formula I in an amount of approx. 5 -ca. 500 mg, preferably approx. 25 - approx. 250 mg, per dosage unit.

To determine the amount of active ingredient in the unit dosage form, account must be taken of the activity of the ingredient and the size of the host animal. On a mg / kg body weight basis, the amount of active ingredient in the compositions will be from approx. 1 µg / kg body weight to approx.

10 mg / kg body weight and more, preferably approx. 0.5 - approx. 5 mg / kg body weight. For administration purposes, the active ingredients can usually e.g. be in the form of tablets, granules, powders, capsules, suppositories, suspensions and solutions. A pharmaceutical carrier or diluent comprises solid or liquid non-toxic pharmaceutically tolerable substances. Examples of solid or liquid carriers or diluents can be mentioned lactose, magnesium tearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive oil, sesame oil or cocoa butter. The carrier or diluent may contain

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contain a retardant material such as glyceryl monostearate or glyceryl distearate alone or together with a wax species.

A large number of pharmaceutical forms can be used. Thus, if a solid carrier is used, the composition may be tableted, placed in a hard gelatin capsule or in the form of a lozenge.

The compound of general formula II

13C 11

4 CH = N-OH

may be prepared by reacting a compound of general formula III with hydroxylamine 1k111

H4 ^ CHO

The reaction is carried out in the usual manner, e.g. in the presence of a catalyst such as an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, p-toluenesulfonic acid, boron trifluoride, silicon tetrachloride or titanium tetrachloride); under basic conditions obtained using the hydroxylamine; or in an acidic or basic conventional buffer solution, and usually in a suitable conventional solvent such as water, dioxane, ethanol, methanol or dimethylformamide or an optional mixture thereof with water.

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The reaction temperature is not limited and the reaction is usually carried out under cooling, at room temperature or at some elevated temperature. The hydroxylamine can be used in the form of a salt with an acid such as an inorganic acid (eg hydrochloric or sulfuric acid) or an organic acid (eg acetic acid).

The starting compound of the general formula III is novel and can e.g. is produced by the process shown below.

1 / AND ^ 4 2

R-CH = C-CO-CHx + R -C = CH-R

1-5 AND I

R-5 NH 2

Formation of the 1,4-dihydropyridine ring nucleus R1

TT

R h CH \ OCH3 hydrolysis v r2v ^ r3 I I 111

R4 CHO

Ή 12 3 4 where R ', R, R and R each have the meaning given above.

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Comparative Experiment I) Lowering Blood Pressure in Rats

Five Wister rats were used per day. group. Each animal was immobilized in a cage whose size was adapted to the body. Blood pressure was measured at the femoral artery using a pressure transducer and recorded as electrically integrated values of the mean arterial pressure, and the heartbeat was determined by a pulse wave detector. The operation for the catheterization was performed under light anesthesia with ether. Each of the test compounds (1 mg / kg) was administered orally 3 hours after completion of surgery. This test method will be well known to those skilled in the art.

Test compounds:

Compounds prepared by the process of the present invention

Diethyl [2-methyl-4- (2-trifluoromethylphenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate] described in Example 2 (hereinafter referred to as Compound I), diethyl [2-methyl -4- (3-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate] described in Example 8 (hereinafter referred to as Compound II), dimethyl [2-methyl-4- (2- nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate1 described in Example 11 (hereinafter referred to as Compound III), isopropyl [2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl] 6-cyano-1,4-dihydropyridine-3-carboxylate] described in Example 12 (hereinafter referred to as compound IV), isopropyl [6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) 1,4-dihydropyridine-3-carboxylate] described in Example 15 (hereinafter referred to as Compound V),

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Reference compound 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate-5-methyl ester-3-p- (N-methyl-N-benzyl) aminoethyl ester described in Example 2 of Danish Patent Specification No. 142869 (hereinafter referred to as Nicardipine (generic name registered with WHO)).

Test results: The following table shows the average values of the maximum drop in blood pressure (mm Hg).

Test compounds Maximum drop in blood pressure (mm Hg) I 30 II 15 III 23 IV 42 V 45

Nicardipine 8 II) Increase in coronary blood flow in dogs

The test compounds are administered intravenously to pentobarbital anesthetized dogs.

Test compounds:

Compounds prepared by the process of the present invention

Compound I Compound II Compound III Compound IV

DK 152285 B

diethyl [2-methyl-4- (2-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate] described in Example 1 (hereinafter referred to as compound VI), 2- (N -benzyl-N-methylamino) ethyl [2-methyl-4- (3-nitrophenyl) -5-ethoxy-carbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate] described in Example 5 (hereinafter referred to as Compound VII), 2-Benzyloxyethyl [2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate] described in Example 9 (hereinafter referred to as Compound VIII) ), 2-ethoxyethyl [2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate] described in Example 10 (hereinafter referred to as compound IX), dimethyl [2-methyl-4- (3-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate] described in Example 13 (hereinafter referred to as compound X).

Reference compounds dimethyl [2,6-dimethyl-4- (2-nitrophenyl) -1,4-dihydropyridine-3,5-di-1-carboxylate] (hereinafter referred to as Nifedipine), diethyl [2-methoxycarbonyl-4- ( 2-Chlorophenyl) -6-methyl-3,5-dicarboxylate ^ 2 (hereinafter referred to as compound Z) * 1 Nifedipine, a representative compound within the dihydropyridine region, is a generic name registered with WHO.

* 2 The connection is described in German publication no.

2,248,150, which corresponds to Danish publication no.

137,722th

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Test Results: The following table shows the percentage increase in coronary blood flow at a dose of 64 µg / kg.

Test compounds Increase in coronary blood flow (%) I 87 II 110 III 97 IV 78 VI 92 VII 85 VIII 76 IX 92 X 82

Nifedipine 69 Z 46

The process according to the invention is illustrated in more detail by the following examples.

Example 1.

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, whereby

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an oil is obtained. 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.

Example 2.

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 mg of 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), m.p. - 143 ° C.

The starting diethyl- (2-methyl-4- (2-trifluoromethylphenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate) is prepared as follows:

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 stirred. gene is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and

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concentrated under reduced pressure to give 0.992 g of doughy oil. The oil is purified by column chromatography 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 "1): 3410, 1695, 1680, 1655, 1483, 1445, 1370, 1309, 1221, 1106, 1090, 1057, 1034, 1010, 985 and 772. NMR Spectrum ( 6, CDCl 3), 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).

Example 3

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, N'-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.

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Example 4

A mixture of 205.7 mg of diethyl (2-methyl-4- (2-trifluoro-methylphenyl) -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).

Example 5

A mixture of 0.91 g of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-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), ν (cm -1): 3320, 3250 (shoulder), 2240, 1708, 1685, 1525, 1500, 1345, 1293, 1210, 1100, 1030, 780, 735 and 700.

NMR Spectrum (6, 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 (COOCH 2 CH 2 N)), 5.26 (1H, s) and 7.1 - 8.2 (10H, ττΛ

DK 152285 B

Λ

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 460.8 mg of yellow pure crystals of the respective hydrochloride compound, melting point 228 - 229 ° C.

The starting material 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-hydroxy-iminomethyl-1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N-methylamino) ethyl ester is prepared on the following way:

To a mixture of 1.015 g of 2-methyl-4- (3-nitrophenyl) -etho-xycarbonyl-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. , to the residue is added 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 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).

Example 6

A mixture of 253.8 mg of 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N- methylamino) ethyl ester, 82 mg of sodium acetate and 40 mg of hydroxy lamin hydrochloride in 1 ml of acetic acid are stirred at room temperature for 30 minutes. After the addition of 0.1 ml of acetic anhydride,

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under reflux 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.

Example 7

A mixture 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.

Example 8.

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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 hydroxylamine hydrochloride and 820 mg of sodium acetate in 7.5 ml of acetic acid is 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-methyl-4- (3-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylic acid

ISLAND

boxylate) in the form of a yellow granule, m.p. 174 DEG-177 DEG C. Example 9.

From a mixture of 2.0 g of 2-methyl-4- (2-nitrophenyl) -5-ethoxycar-b-phenyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxyethyl ester in the form of a red oil , 336.9 mg of hydroxylamine hydrochloride and 662.9 mg of sodium acetate in 15 ml of acetic acid and 1.5 ml of acetic anhydride are obtained by analogy as described in Example 1, 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, mp 139-140 ° C (further recrystallized from a mixture of diethyl ether and n-hexane).

Example 10.

DK 152285B

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 Example 1/420 mg of crystalline 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-cyano -1 / 4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester, m.p. 129-130.5 ° C (recrystallized from a mixture of diethyl ether and n-hexane).

Example 11 ·

A mixture of 3.6 g of dimethyl (2-methyl-4- (2-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate), 764 mg of hydroxylamine hydrochloride and 1.06 g of sodium acetate in 20 ml of acetic acid is stirred at room temperature for 45 minutes to form 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 (δ, 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).

Example 12.

19 DK 152285 B

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-methoxycarbonyl-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 that order, dried over magnesium 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 (<5, 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, broad s), and 7.23 - 7.85 (4H, m ).

Example 13

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 mg of sodium acetate 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). 87 g of acetic anhydride and the mixture is heated to 110 ° C for 3.5 hours with stirring. The reaction mixture is evaporated to give a crystalline

DK 152285 B

mass is neutralized by treatment with dilute aqueous sodium bicarbonate solution and the crystalline mass is pulverized, filtered and washed thoroughly with water to give 1.92 g of crystals. By crystallization of a mixture of methanol and ethyl acetate, 1.04 g of dimethyl (2-methyl-4- (3-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate) is obtained as pure crystals mp 206 - 207 ° C. An additional amount of 0.6 g is obtained from the above mother liquor from the recrystallization.

NMR Spectrum (6, CDCl 3) 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).

Example 14.

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 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

ISLAND

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.

Claims (2)

NMR Spectrum (δ, CDCl3) ppm: 1.27 (3H, t, J = 7Hz), 2.37 (3H, s), 3.65 (2H, t), 4.13-4. 35 (4H, τη), 4.5 (2H, s), 5.21 (1H, s), and 7.2 - 8.1 (9H, m). Example 15. 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 hydroxylamine 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 are 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. 1 in R4 wherein R 1 is phenyl substituted with nitro or 2 halo-C 1-6 alkyl, R represents C 1-6 alkoxycarbonyl, C 1-6 alkoxy - C 1-8 alkoxycarbonyl, phenyl C 1-6 alkoxy -C- g-alkoxycarbonyl or NC g g-alkyl-N- (phenyl-C ^ g-alkyl) -amino-C ^ g-alkoxycarbonyl, R3 is C1g-alkoxycarbonyl, and R er is Cj g-alkyl, characterized wherein a compound of the general formula II # - r4 ™ CH = N-OH wherein R 2, R 2, R 3 and R 1 each have the meaning given above, are treated with a dehydrating agent · 1. Analogous Process for Preparation of 1,4-Dihydropyridine Derivatives of General Formula I DK 152285B R1 Process according to claim 1, characterized in that compounds are prepared, wherein R is 3-nitrophenyl, R and R are each C, 1-6 -alkoxycarbonyl, and R is methyl.