FI63022B - FOERFARANDE FOER FRAMSTAELLNING AV VASODILATORISKA 1,4-DIHYDROPYRIDINDERIVAT - Google Patents

Description

63022

Process for the preparation of vasodilatory 1,4-dihydropyridine derivatives. - Förfarande för framställning av vasodilato-Riska 1,4-dihydropyridinderivat.

The present invention relates to a process for the preparation of vasodilatory dihydropyridines of the formula T X <*> N ^ R, which is separated from patent application 761912 (patent 61696).

B

where

R 1 is phenyl which may be substituted by the following substituent groups: halogen, nitro, halogen (lower) alkyl, lower alkoxy and lower alkenyloxy, or a 5- or 6-membered heterocyclic group containing one oxygen atom, a sulfur atom or a nitrogen atom, R2 and R3 represent lower alkoxycarbonyl, hydroxy (lower) alkoxycarbonyl, lower alkoxy- (lower) alkoxycarbonyl, phenyl (lower) alkoxy (lower) alkoxycarbonyl, phenoxy (lower) alkoxycarbonyl, N, N- (di) ( lower) alkylamino (lower) alkoxycarbonyl or N-lower alkyl-N-phenyl (lower) alkylamino (lower) alkoxycarbonyl, R4 is lower alkyl and R5 is cyano or U1-cyano (lower) alkyl, or

R 1, R 2, 3a r 4 are as defined above and R 3 and R 5 together form a group of formula

O

2 63022

Terms used in the specification and claims: "Lower" as used in connection with alkylene, alkyl and alkenyl means a group having 1-B carbon atoms.

Preferred examples of suitable substituents are halogen, nitro, hydroxy, halogen (lower) alkyl, lower alkoxy and lower alkenyloxy. Halogen or a halogen moiety is fluorine, chlorine, bromine or iodine.

The lower alkyl and lower alkyl moiety may be groups having a straight or branched and saturated hydrocarbon chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl, heptyl or octyl.

The lower alkoxy or lower alkoxy moiety may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and pentyloxy.

Halogen (lower) alkyl may be mono-halo (lower) alkyl, such as chloromethyl, bromomethyl or chloropentyl> di-halo (lower) alkyl, such as 1,2-dichloroethyl, 1,2-dibromoethyl or 2.2 -dikloorietyyli; and tri-halo (lower) alkyl such as trifluoromethyl or 1,2,2-trichloroethyl.

The lower alkenyl and lower alkenyl moiety may be groups having a straight or branched hydrocarbon chain containing one or more double bonds such as vinyl, allyl, butenyl, butanedienyl or Penta-2,4-dienyl.

In the definition of a group, a 5- or 6-membered heterocyclic group containing a nitrogen, sulfur and oxygen atom is, for example, thienyl, furyl, pyrrolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyridyl or pyrimidinyl.

63022

Lower alkoxycarbonyl may be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl> hydroxy (lower) alkoxycarbonyl may be 2-hydroxyethoxycarbonyl or 2 (or 3) -hydroxypropoxycarbonyl-lower alkoxy (lower) alkoxy (lower) ethoxycarbonyl, 2-ethoxyethoxycarbonyl or 2 (or 3) -methoxy (or ethoxy) propoxycarbonyl; phenyl (lower) alkoxy (lower) alkoxycarbonyl may be 2- (benzyloxy) ethoxycarbonyl or 2 (or 3) - (benzyloxy) propoxycarbonyl> phenoxy (lower) alkoxycarbonyl may be 2- (phenoxy) ethoxycarbonyl or 2 (or 3) - (phenoxy) propoxycarbonyl] N, N- (di) - (lower) alkylamino (lower) alkoxycarbonyl may be 1 (or 2) -N-methyl- (or N, N-dimethyl) aminoethoxycarbonyl, 1 (or 2) -iN-ethyl- (or N, N-diethyl) aminoetoxycarbonyl, or 1 (or 2) - (N-methyl-N-ethylaminoethoxycarbonyl) or N-lower alkyl-N-phenyl (lower) alkylamino (lower) alkoxycarbonyl may be 2- (N-methyl-N-benzylamino) -ethoxycarbonyl) and the like, and further the groups R 2 and R 3 may be the same or different.

Lower alkyl substituted with oxo may be lower alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyl, and lower alkanoyl (lower) alkyl such as formylmethyl, acetonyl, 2-formylethyl, 3-formylpropyl or butyrylmethyl.

The process according to the invention is characterized in that a) a dihydropyridine of formula R2YtR3 (ii) R4 h R5a 63022 wherein r1, R2f R3 and r4 are as defined above and R5a is? -Hydroxyimino- (lower) alkyl is treated, with a dehydrating agent, or b) a dihydropyridine of the formula R2 \ ^ ^ Ssy ^ R3 1 1 (iii>

R4 ^ N ^ R5h H

wherein R 1, R 2, R 3 and R 4 are as defined above and R 8b is -oxo (lower) alkyl, treated with hydroxylamine or a salt thereof and treating the compound of formula II thus obtained with a dehydrating agent.

The starting material of formula II can be prepared by reacting an agent of formula III with an amine of formula: HO-NH 2 (IV) In this method, the oxo group in the Rsb group of the starting compound (III) is replaced by an imino group = N-OH.

The starting compound (III) can be prepared by a hydrolysis method.

The reaction is carried out in the usual manner, for example in the presence of a catalyst such as an acid (for example hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, p-toluic acid, boron trifluoride, silicon tetrachloride or titanium tetrachloride) under suitable in a solvent such as water, dioxane, ethanol, methanol or dimethylformamide or a suitable mixture thereof with water.

5,63022

The reaction temperature is not limiting, and the reaction is usually carried out under cooling, at room temperature, or at a slightly elevated temperature. These amines can also be used as a salt with an acid such as an inorganic acid (e.g. hydrochloric acid or sulfuric acid) or an organic acid (e.g. acetic acid).

The starting compound (II) can be prepared by the above-mentioned condensation method.

Suitable examples of the dehydrating agent are organic or inorganic dehydrating agents, for example an acid (for example sulfuric acid, phosphoric acid, polyphosphoric acid, formic acid, acetic acid, haloacetic acid or benzoic anhydride or p-toluenesulfonic acid), acid anhydride (for example for example, acetyl chloride, benzoyl chloride, trichloroacetyl chloride, mesyl chloride, tosyl chloride, ethyl chloroformate or phenyl chloroformate), an inorganic halogen compound (e.g. or N-cyclohexyl-N'-morpholinoethylcarbodiimide), N ', N'-carbonyldiimidazole, pentamethylene ketene-N-ketene-N-cyclohexylimide, ethoxyacetylene, 2-ethyl-7-hydroxyisoxazonium salt, any another phosphorus compound (for example, phosphorus pentoxide, polyphosphoric acid ethyl ester, triethyl phosphate or phenyl phosphate) or the like. When an acid is used as the dehydrating agent, the reaction is usually carried out in the presence of an alkali metal salt (for example, a sodium salt or a potassium salt) or the like.

6 63022

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, dioxane or the like. Usually, the reaction is carried out at room temperature or under heating, but the reaction temperature is not limited to the above.

In this method, the terminal -CH = N-OH function of the R5a groups of the starting compound (II) is converted into a cyanofunction in the obtained compound (I), whereby a compound of the formula

Rn O

(V>

B

wherein R 1, R 2 and R 4 have the same meaning as above, when the starting compound (II) in which R 5a is hydroxyiminomethyl is treated, for example, under highly acidic conditions.

This dehydration process can also be carried out following the above condensation process without isolating the compound (II).

The starting material of formula (II) can be prepared by the following method: 1. Ring formation of a 1,4-dihydropyridine ring.

Certain compounds (I) which may be represented by the following formula: 7 63022, "ϊΓϊ; ·

R4a ”^ N ^ 1 <5b H

where

R 1, R 2, R 3 and R 5b have the same meaning as above, and R 4a represents lower alkyl, the carbonyl group thus formed being protected by a suitable protecting group can be prepared by carrying out one of the following methods: (1) a compound of formula: RX - CH = C - CO - R 5b (VI) R 3a wherein R 1, R 3 and R 5b are as defined above is reacted with an amino compound of formula: R 4a - C = CH - R 2 (VH) NH 2 wherein R 2 and R 4a are as defined above, (2) reacting a mixture containing an aldehyde compound of the formula

R1 to CHO (VIII) wherein R1 is as defined above, f.

8 63022 β-ketonic acid ester of the formula: R5b - COCH2 - R3 (IX) wherein R3 and R5b are as defined above, and an amino compound (VII) or (3) an acetylene compound of the formula: R2 ~ C = C - R4a (X) wherein R 2 and R 4a have the same meaning as above, is reacted with ammonia or an ammonium salt and compound (VI).

The starting compound (VI) used in Reactions (1) and (2) may be novel, and is prepared by reacting the aldehyde (VIII) with β-keto acid ester (IX) in the usual manner. The ammonium salts used in the reaction (3) are inorganic ammonium salts such as ammonium chloride or ammonium sulfate or organic ammonium salts such as ammonium acetate.

From the above reactions (1), (2) and (3), starting compounds (VI), (IX), (vii) and (X) can be used in which the symbols R4a and R5b are sometimes interchanged, even when both symbols are not not the same groups. In such a case, substantially the same target compound (I-1) can be obtained, not only when R 4a and R 9b are the same groups, whether R 2 and R 3 are the same groups or not, but also when R 4a and R 5b are not the same. are not the same groups, and R2 and R3 are the same groups.

In reaction (1) and (3), the starting compound (VI) may contain geometric isomers such as cis-trans isomers due to the double bond in its molecule. Such cis-trans isomers have been able to be equilibrated, and thus 9,63022 of either isomer of compound (VI) or a mixture thereof can be used as a starting material to give the same desired compound (I-1).

Reactions (1), (2) and (3) can be carried out at ambient temperature or by heating or heating without solvent or with a suitable solvent such as benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, methanol, propanol, butanol, water or other conventional solvents. The reaction can usually be accelerated by using, for example, an acid (e.g. acetic acid), a base (e.g. pyridine or picoline) or by filtration in a conventional buffer solution. These substances can act as a reaction accelerator and can also be used as a solvent when they are liquid. The reaction can also be accelerated by heating. The reaction conditions may vary depending on the nature of the reactants used.

2. Hydrolysis to remove the protecting group of the protected carbonyl group.

A compound of the formula:

X

Rn — r-5 2 \\ I 3 (XI) Λ N Λ p H R R4b R5b where

R 1, R 2 and R 3 are as defined above, and R 4J- and R 5 {- are hydrogen, lower alkyl or lower alkyl substituted by an oxo group, provided that at least one of R 4b and R 55 is lower alkyl substituted by an oxo group can be prepared by hydrolysis compound (1-1) which can be produced by the above-mentioned ring-closing method. In this method, the protecting group or protecting groups located in the alkyl group representing the R4a and / or R5a group of the compound (1-1) are removed by hydrolysis.

The hydrolysis is carried out in the usual manner, for example acetal-type or cyclic acetal-type deprotection is best carried out by acid hydrolysis, for example in the presence of an acid such as an inorganic acid (e.g. hydrochloric acid or sulfuric acid) or an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid) or trifluoroacetic acid , removal of the thioacetal-type, cyclic thioacetal-type and cyclic monothioacetal-type protecting group is best carried out by hydrolysis in the presence of a heavy metal salt such as mercuric chloride or copper chloride; and the removal of the acylal type protecting group is best performed by the above-mentioned acid hydrolysis or basic hydrolysis, i. 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, N, N-dimethylformamide, N-methylmorpholine or dimethyl sulfoxide, and a suitable mixture with water or a buffer solution. The reaction temperature is not limiting, and the reaction is usually carried out under cooling, at room temperature, or at a somewhat elevated temperature.

According to the present invention, the product formed during the reaction is separated and isolated from the reaction mixture by the methods normally used for this purpose. It can be purified by methods routinely used, for example, by recrystallization from a suitable solvent or a mixture of such solvents.

The compounds (I) thus obtained in which at least R2 and R3 or R4 and R5 are not completely similar include stereoisomers because the 1,4-dihydropyridine nucleus has at least one asymmetric carbon atom in the fourth position and can exist as either optical isomer or racemic a mixture. Furthermore, some compounds (I) having not less than two asymmetric atoms in the molecule may exist as either diastereomer or a mixture thereof. The diastereomeric mixture can be separated into each racemic compound by conventional separation methods such as chromatography or fractional crystallization or the like, and the racemic compound can be separated into both optical isomers by conventional separation methods such as fractional crystallization of ) salt.

Compounds (I) have vasodilatory activity and are useful in the therapeutic treatment of hypertension and cardiovascular diseases such as heart failure, angina pectoris and myocardial infarction.

The compositions of this invention contain from about 5 mg to about 500 mg, preferably from about 25 to about 250 mg per unit dose, of the 1,4-dihydropyridine derivatives (I) as active ingredient.

Those skilled in the art will recognize that in determining the amounts of active ingredient in unit doses, account must be taken of the activity of the ingredient as well as the size of the animal using the dose. Calculated on a mg / kg basis, the amount of active ingredient in the compositions is from about 1 pg / kg to about 10 mg / kg and above, preferably from about 0.5 mg / kg to about 5 mg / kg. For administration of this pharmaceutical composition, the active ingredients are usually formed into tablets, granules, powders, capsules, suppositories, suspensions, solutions, and the like. The pharmaceutical carrier or diluent comprises solid or liquid, non-toxic pharmaceutically acceptable substances. Examples of solid or liquid carriers or diluents are lactose, magnesium stearate, Terra Alba, sucrose, wheat starch, talc, stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive oil or sesame oil or the like. Similarly, the carrier or diluent may contain a delaying agent, such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax.

Many different pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule, or made into a medicated button or lozenge.

The pharmacological activity of the 1,4-dihydropyridines of formula (I) is demonstrated by standard methods, i. by intravenous administration of the following test 1,4-dihydropyridines to dogs anesthetized with pentobarbital and recording blood flow in the heart. The experimental results are given below: nrN ° 2 Y "2 sCH3

H, Co00C. C00CH_CHoN

H oC00C —f COOCH-, 5 2 2 2 „3 1 |] 3 II II CH2C6H5

Hjt ^ CH3 NC l AcH3 * HCl / A / / B / 63022

Table. Increase in blood flow (%) in the heart

Figures represent a percentage increase over comparison [29.5 + 5.5 ml / min.J.

---------- ug / kg

Compound_ '-------_ 64_250_1000 A 169 118 dead _B_ 185_215_144

Compound A is known generically as "Nifedipine" and is already marketed as a cardiovascular dilator.

The following examples are provided to illustrate the syntheses of the compounds of the present invention.

Example 1 1) A solution of diethyl 2-methyl-4- (2-chlorophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (377.8 mg), hydroxylamine hydrochloride (83.4 mg) and sodium carbonate (63.9 mg) in ethanol (1 mL) was stirred at room temperature for 30 minutes. After concentrating the resulting solution, water was added to the residue. The mixture was extracted with ethyl acetate, after which the extract was washed with water and dried. The dried extract was concentrated to a yellowish oil (476 mg), the oil was crystallized from n-hexane to give diethyl 2-methyl-4- (2-chlorophenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. (318.8 mg), which was identified by conversion to the corresponding 6-cyano compound, m.p. 136-137 ° C.

2) - (1) A mixture of diethyl 2-methyl-4- (2-trifluoromethylphenyl) -143030 6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (R70 mg) was stirred at room temperature for 30 minutes, sodium carbonate (112.1 mg) and hydroxylamine hydrochloride (147 mg) in ethanol (5 ml). After removing the ethanol, water was added to the residue, and the solution was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to a pasty oil (0.992 g). The oil was purified by column chromatography on silica gel eluting with benzene (10) + ethyl acetate (1) 3 to give diethyl 2-methyl-4- (2-trifluoromethylphenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5- dicarboxylate as a yellow powder (0.52 g).

IR spectrum (Nujol) ν (cm -1): 3410, 1695, 1680, 1655, 1483, 1445, 1370, 1309, 1211, 1106, 1090, 1057, 1034, 1010, 985, 772 NMR spectrum (= CDC 3) ppm: 1.17 (3H, t, J = 7Hz), 1.20 (3H, t, J = 7Hz), 2.35 (3H, s), 3.8-4.4 (4H, m ), 5.64 (1H, broad s), 6.91 (1H, broad s), 7.2-7.7 (4H, m), 8.4 (1H, broad s), 8.8 (1H , s) 2) - (2) To a solution of diethyl 2-methyl-4- (2-trifluoromethylphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.23 g) and hydroxylamine hydrochloride (250.2 mg) in ethanol (5 ml), a solution of sodium carbonate (190.8 mg) in water (1.5 ml) was added. The mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to an oil. The oil was crystallized from n-hexane to give diethyl 2-methyl-4- (2-trifluoromethylphenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate as crude crystals (1.09 g).

3) To a mixture of 2- (N-methyl-N-benzylamino) ethyl 2-methyl 4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (1.015 g) and hydroxylamine hydrochloride (116.8 mg) in ethanol (3 ml), sodium carbonate (127.2 mg) as an aqueous solution (1 ml) was slowly added dropwise, and the resulting mixture was stirred at room temperature for 50 minutes. Ethanol was distilled off under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried and then concentrated under reduced pressure to give a yellow oil (1.01 g) of 2- (N-methyl-N-benzylamino) ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl- 6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate.

IR spectrum (membrane) ν (cm-1): 3350, 1690, 1460, 1375, 1348, 1205, 1098, 1044, 738, 710, 700 NMR spectrum (= CDCl 3) ppm: 1.22 (3H, t, J = 7Hz), 2.26 (3H, s), 2.36 (3H, S), 2.70 (2H, t, J = 6Hz), 3.58 (2H, s), 4.09 (2H, q, J = 7Hz), 4.18 (2H, t, J = 6Hz), 5.14 (1H, s), 7.1-8.1 (10H, m), 8.97 (1H , s) 4) By the methods of Examples 1— (1) to (3), the following compounds were obtained: 1

Diethyl 2-methyl-4- (2-nitrophenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate 16,63022 (2) Diethyl 2-methyl-4- (2-chloro-5 Nitrophenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate (3) Diethyl 2-methyl-4- (2-furyl) -6-hydroxyiminomethyl-1,4-dihydropyridine- 3,5-Dicarboxylate (4) 2-ethoxyethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate (5) 2 - (Ν, Ν-diethylamino) ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate (6) Diethyl 2-methyl- 4- (3-nitrophenyl) -6-hydroxyimino-methyl-1,4-dihydropyridine-3,5-dicarboxylate.

These compounds were prepared from the corresponding 6-formyl compounds in the same manner as the compounds of Examples 1- (1) to (3) and identified by conversion to the corresponding 6-cyano compounds.

Example 2 l) - (1) A mixture of diethyl 2-methyl-4- (2-chlorophenyl) -6-hydroxyiminomethyl 1,4-dihydropyridine-3,5-dicarboxylate (0.6135 g) and Ν, Ν'-dicyclohexylcarbodiimide (804.6 mg) in pyridine (3 ml) were heated at reflux for 6 hours. The resulting solution was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The insoluble product was filtered off and the filtrate was washed with water, dried over magnesium sulphate and evaporated under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered. The filtrate was concentrated in vacuo to a red oil (703.7 mg). The oil was purified by column chromatography on silica gel eluting with benzene (10) + ethyl acetate (1) and crystallized from n-hexane. The crystals were recrystallized from a mixture of n-hexane and diethyl ether to give yellow crystals (417.1 mg) of diethyl 2-methyl-4- (2-chlorophenyl) -6-cyano-1,4-dihydropyridine-3.5 dicarboxylate, m.p. 136-137 ° C.

17 63022 1) - (2) mixture containing diethyl 2-methyl-4- (2-chlorophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (377.8 mg), sodium formate (125 mg) and hydroxylamine hydrochloride (79.93 mg) in formic acid (1.5 ml) were refluxed for one hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was filtered, and the filtrate was washed alternately with water, aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed from the solution, after which ether was added to the residue. The solution was filtered and the filtrate was concentrated under reduced pressure to an oil (210 mg), the oil was crystallized from a mixture of n-hexane and diethyl ether to give crystals (154.1 mg) of diethyl 2-methyl-4- (2-chlorophenyl) -6-cyano-1,4-dihydropyridine. 3,5-dicarboxylate, which was identified by an authentic sample. The insoluble yellow powder (110 mg) recovered by filtration above was ethyl 1-oxo-6-methyl-8- (2-chlorophenyl) -5,8-dihydro-1H-pyrido [2,3-d] 1,2,2- oxazine-7-carboxylate.

IR spectrum (Nujol) ν (cm -1): 3340, 3250, 1730, 1693, 1686 (shoulder), 1670, 1504, 1374, 1235, 1169, 1094, 972, 834, 778, 755 NMR spectrum (DMSO- d6) ppm: 0.98 (3H, t, J = 7Hz), 2.37 (3H, s), 3.90 (2FI, q, J = 7Hz), 5.35 (1H, s), 7, 1-7.5 (4H, m), 10.02 (1H, s), 10.35 (1H, s) 1) - (3) A mixture of diethyl 2-methyl-4- (2-chlorophenyl phenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (377.8 mg), sodium formate (125 mg), hydroxylamine hydrochloride (79.93 mg) in formic acid (1.5 ml), was stirred at room temperature for 18 minutes and acetic anhydride (0.2 ml) was added to the solution. The mixture was stirred at room temperature for 20 minutes and heated at reflux for one hour. Water was added to the resulting solution, followed by extraction with ethyl acetate. The extract was washed alternately with aqueous sodium carbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to a brown oil (0.41 g). The oil was crystallized from a mixture of diethyl ether and n-hexane to give a powder (207 mg) which was diethyl 2-methyl-4- (2-chlorophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate, which was identified using an authentic sample.

1) - (4) A mixture of diethyl 2-methyl-4- (2-chlorophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (377.8 mg), sodium acetate (164 mg) and hydroxylamine hydrochloride (80 mg) in acetic acid (1.5 ml) were stirred at room temperature for 30 minutes. Acetic anhydride (0.2 ml) was added to the solution, after which the solution was stirred at room temperature for one hour and heated at reflux for 1 hour. Water was added to the reaction mixture, and the solution was extracted with diethyl ether. The extract was washed alternately with water, aqueous sodium bicarbonate solution and water, and dried over magnesium sulfate. The solution was concentrated in vacuo to a yellow oil (410 mg).

The oil was crystallized from n-hexane to give diethyl 2-methyl-4- (2-chlorophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate (342.4 mg) which was identified with an authentic sample.

2) A mixture of diethyl 2-methyl-4- (2-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.03 g), hydroxylamine hydrochloride (417 mg), sodium acetate (861 , 4 mg) in acetic acid (15 ml) was stirred at room temperature for 30 minutes. Acetic anhydride (1 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 90 minutes to 63022 minutes and refluxed for a further 1 hour. Acetic acid was distilled off under reduced pressure, and water was added to the resulting residue. The aqueous mixture was adjusted to pH 7-8 with sodium carbonate and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. The oil was subjected to column chromatography on silica gel and eluent (a mixture of 4 volumes of benzene and 1 volume of ethyl acetate). The resulting oily substance (1.7 g) was crystallized by treatment with a mixture of diethyl ether and n-hexane. These crystals were recrystallized from a mixture of diethyl ether and n-hexane to give pure crystals (1.23 g) of diethyl 2-methyl-4- (2-nitrophenyl) -6-cyano-1,4-dihydropyridin-3, 5-dicarbonate a, m.p. 126-127.5 ° C.

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

3) - (2) A mixture of crystalline diethyl 2-methyl-4- (2-trifluoromethylphenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.09 g) and N, N'-dicyclohexylcarbodiimide (1.319 g) in pyridine (5 ml) was heated at reflux for 6.5 hours. After removal of the pyridine, dilute hydrochloric acid was added to the residue, and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate, and the insoluble matter was separated by filtration. The filtrate was washed with water, dried over magnesium sulfate and concentrated in vacuo to a brown oil (1.09 g). the oil was purified by column chromatography on silica gel eluting with benzene (10) + ethyl acetate (1) 1 to give an oil (720 mg), the oil was crystallized by treatment with n-hexane and the precipitate was collected by filtration and washed with n-hexane to give a yellow powder (610 mg). The powder was 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 was identified by an authentic sample, m.p. 140-143 ° C.

3- (3) A mixture of diethyl 2-methyl-4- (2-trifluoromethylphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (205.7 mg), sodium acetate (82 mg ) and hydroxylamine hydrochloride (40 mg) in acetic acid (1.5 ml) were stirred at room temperature for 30 minutes. Acetic anhydride (0.1 ml) was added to the solution, followed by stirring at room temperature for 1.5 hours and then heating under reflux for 1 hour. Water was added to the resulting solution, and the solution was extracted with diethyl ether. The extract was washed successively with water, aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure to an oil (201 mg). The oil was purified by column chromatography on silica gel [eluent; benzene (5) + ethyl acetate (1) 3 to give a pure oil (172.4 mg), the oil was crystallized by treatment with n-hexane to give a powdery diethyl 2-methyl-4- (2-trifluoromethylphenyl) -6-cyano-1 , 4-dihydropyridine-3,5-dicarboxylate (118 mg).

4) A mixture of diethyl 2-methyl-4- (2-chloro-5-nitro-21,63022 phenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.70 g), hydroxylamine hydrochloride (695 mg), sodium acetate (1,436 g) in acetic acid (36 ml) was stirred at room temperature for 2.5 hours, after which acetic anhydride (2 ml) was added. The resulting mixture was stirred for 30 minutes and refluxed for 1.5 hours. After removing the acetic acid, water and acetate were added to the reaction mixture, and the resulting mixture was washed twice with dilute aqueous sodium carbonate solution and then with aqueous sodium chloride solution, and dried over magnesium sulfate. After removal of the solvent, the residue was washed with diethyl ether to give a powder (2.5 g). The powder was subjected to column chromatography on silica gel (eluting with a mixture of 10 parts by volume of benzene and 1 part by volume of ethyl acetate). The fraction of eluate which gave only one spot in thin layer chromatography was concentrated to crude crystals (450 mg) and the fraction of eluate with several spots in thin layer chromatography was also concentrated to crude crystals (1.0 g). The crude crystals thus obtained were combined and recrystallized from a mixture of benzene and ethyl acetate to give pure crystals (657 mg) of diethyl 2-methyl-4- (2-chloro-5-nitrophenyl) -6-cyano-1,4- dihydropyridine-3,5-dicarboxylate, m.p. 204.5-205.5 ° C.

5) A mixture of diethyl 2-methyl-4- (2-furyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.6 g), hydroxylamine hydrochloride (383.6 mg) and sodium acetate (787.6 mg) in acetic acid (14 ml) was stirred for 30 minutes at room temperature. Acetic anhydride (1 ml) was added to the mixture and stirred for 1.5 hours at room temperature and further for 1 hour at reflux. Acetic acid was removed from the reaction mixture, then water was added to the residue, and the mixture was extracted from ethyl acetate. The extract was washed with saturated sodium bicarbonate solution and water and dried, after which the solvent was distilled off under reduced pressure. The resulting brown oil (1.8 g) was purified by column chromatography on silica gel eluting with a mixture of 15 parts by volume of chloroform and 1 part by volume of ethyl acetate. Crystals (total 875 mg) were obtained from the concentrate (920 mg) of the fraction of the eluate which gave one spot in thin layer chromatography and the concentrate (450 mg) of the fraction which gave several spots. The crystals were recrystallized from a mixture of diethyl ether and n-hexane to give pure crystals (818 mg) of diethyl 2-methyl-4- (2-furyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate. mp. 139-141 ° C.

6) - (1) A mixture containing 2- (N-benzyl-N-methylamino) ethyl-2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4 dihydropyridine-3-carboxylate (0.91 g) and N, N'-dicyclohexylcarbodiimide (0.987 g) in pyridine (5 ml) were heated at reflux for 3 hours. The pyridine was removed under reduced pressure, after which water was added to the residue. The mixture was extracted with ethyl acetate. The insoluble product was filtered off and the filtrate was washed with water, dried over magnesium sulphate and concentrated in vacuo to a red oil (1.6 g). the oil was purified by column chromatography on silica gel. Cellulose: benzene (2) + ethyl acetate (1) 1 to give a reddish oil (0.68 g) of 2- (N-benzyl-N-methylamino) ethyl 2-methyl- 4- (3-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate.

IR spectrum (Nujol) ν (cm-1): 3320, 3250 (shoulder), 2240, 1708, 1685, 1525, 1500, 1345, 1293, 1210, 1100, 1030, 780, 735, 700 NMR spectrum (: CDCl 3) ppm: 1.25 (3H, t, J = 7Hz), 2.15 (3H, s), 2.39 (3H, s), 2.62 (2H, t, J = 7Hz), 3 , 48 (2H, s), 3.9-4.3 (4H, q (CH 2 CH 3), t (COOCH 2 CH 2 N), 5.26 (1H, s), 7.1 - 8.2 (10H, m) 23 63022

The product obtained above was dissolved in diethyl ether. Ethanolic hydrochloric acid was added to the solution and the solution was evaporated to dryness. The residue was triturated with n-hexane and the precipitated powder was collected by filtration. The powder was recrystallized from aqueous ethanol to yellow pure crystals (460.8 mg) which were the hydrochloride of the desired compound, m.p. 228-229 ° C.

6) - (2) Mixture containing 2- (N-benzyl-N-methylamino) -ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3 carboxylate (253.8 mg), sodium acetate (82 mg) and hydroxylamine hydrochloride (40 mg) acetic acid (1 ml) were stirred at room temperature for 30 minutes. Acetic anhydride (0.1 ml) was added to the solution, followed by stirring at room temperature for 1 hour and then heating under reflux for 1 hour. Water was added to the reaction mixture, and the solution was neutralized with sodium bicarbonate and then extracted with ethyl acetate. The extract was washed alternately with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure to give an oil (250 mg) (quantitative) of 2- (N-benzyl-N-methylamino) -ethyl-2-methyl-4- (3-nitrophenyl). -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate and identified by an authentic sample.

7) Starting from a mixture of oily 2- (N, N-diethylamino) ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3 carboxylate (1.66 g), hydroxylamine hydrochloride (0.302 g) and sodium acetate (0.593 g) in acetic acid (12 ml) and acetic anhydride (1.8 ml), crystals (700 mg) were obtained in the same manner as in Example 4-2. ), which were recrystallized from ethanol. There were thus obtained pure crystals (420 mg) of 2- (N, N-diethylamino) ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3 carboxylate, m.p. 150-152 ° C.

24 63022 8) A mixture of 2-ethoxyethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (3.00 g), hydroxylamine hydrochloride (0.5547 g), sodium acetate (1.1382 g) in acetic acid (10 ml) was stirred for 30 minutes at room temperature. To this mixture was added acetic anhydride (1.4 ml), and the resulting mixture was stirred for one hour at room temperature, followed by refluxing for one hour. Acetic acid was distilled off under reduced pressure, and water was added to the residue. The resulting mixture was neutralized with aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, and dried. The solvent was distilled off, and the viscous oily substance thus obtained (3.19 g) was subjected to column chromatography on silica gel (eluting with a mixture of 5 parts by volume of benzene and 1 part by volume of ethyl acetate). The fraction containing the desired product gave a yellow oil (1.74 g) which crystallized (1.56 g). These crystals were recrystallized from benzene to a yellow powder (1.5 g) which was 2-ethoxyethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate. . 1/3 benzene, m.p. 89-91 ° C. The yellow powder thus obtained was recrystallized from a mixture of diethyl ether and n-hexane to give crystalline 2-ethoxyethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate, m.p. 115-116 ° C.

9) A mixture of diethyl 2-methyl-4- (3-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.9418 g), hydroxylamine hydrochloride (399.6 mg), sodium acetate (820 mg) in acetic acid (7.5 ml) was stirred at room temperature for 30 minutes. The mixture obtained after adding acetic anhydride (1 ml) was stirred at room temperature for 1 hour and further refluxed for 1 hour. Acetic acid was distilled off and water was added to the residue. The resulting aqueous mixture was neutralized with an aqueous solution saturated with sodium bicarbonate. The precipitated oily substance was extracted twice with ethyl acetate.

25 63022

The extract was washed with aqueous sodium chloride solution and dried. The solvent was distilled off under reduced pressure to give an orange-yellow oil (2.0103 g). This oil crystallized and the crystals were recrystallized from a mixture of diethyl ether, ethyl acetate and n-hexane to a yellow powder (0.9119 g). This powder was dissolved in a mixture of 5 volumes of benzene and 1 volume of ethyl acetate and filtered through silica gel to give crystals (1.02 g). These crystals were recrystallized from a mixture of benzene and diethyl ether to give diethyl 2-methyl-4- (3-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate as yellow granules (0.8479 g), mp. 174-177 ° C.

10) Starting from a mixture of reddish 2-benzyloxyethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate oil (2.0 g) , hydroxylamine hydrochloride (336.9 mg), sodium acetate (662.9 mg) in acetic acid (15 ml) and acetic anhydride (1.5 ml) were obtained by the method of Example 2-2) to give crystals (767 mg). These crystals were recrystallized from a mixture of benzene and diethyl ether to give pale yellow crystals (450 mg) of 2-benzyloxyethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate. -tia, sp. 139-140 ° C (recrystallized from a mixture of diethyl ether and n-hexane).

11) Starting from a mixture of 2-phenoxyethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (1.03 g), hydroxylamine hydrochloride ( 178.6 mg) and sodium acetate (352 mg) in acetic acid (8 ml) and acetic anhydride (1 ml) were obtained by the method of Example 2-2) to give oily 2-phenoxyethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl -6-cyano-1,4-dihydropyridine-3-carboxylate (420 mg).

26 6 3 0 2 2 IR spectrum (KBr) ν (cm-1): 3330, 2250, 1710, 1600, 1530, 1500, 1300, 1216, 1110, 757 NMR spectrum (, CDCl 3) ppm: 1, 2 (3H, t, J = 7Hz), 2.36 (3H, s), 4-4.4 (6H, m), 6.05 (1H, s), 6.73 (1H, m), 6 , 83-7.66 (9H, m) 12) Starting from a mixture of 2-ethoxyethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3 carboxylate (900 mg), hydroxylamine hydrochloride (167 mg) and sodium acetate (341 mg) in acetic acid (7 ml) and acetic anhydride (1 ml) were obtained by the method of Example 2-2) to give crystalline 2-ethoxyethyl 2-methyl-4 - (2-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate (420 mg), m.p. 129-130.5 ° C (recrystallized from a mixture of diethyl ether and n-hexane).

13) Starting from a mixture of diethyl 2-methyl-4- (2-nitrophenyl) -6-formylmethyl-1,4-dihydropyridine-3,5-dicarboxylate, hydroxylamine hydrochloride and sodium acetate in acetic acid and acetic anhydride, essentially Example 2 was obtained. -2) oily diethyl 2-methyl-4- (2-nitrophenyl) -6-cyanomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

IR spectrum (liquid) δ (cm -1): 2210 NMR spectrum (δ CDCl 3) ppm: 1.17 (6H, t, J = tHz), 2.32 (3H, s), 3.9 - 4.3 (4H, m), 4.78 (2H, s), 5.89 (1H, s), 7.14 (1H, broad s), 7.2 to 7.85 (4H, m), 27,63022

Example 3

At room temperature, a mixture of diethyl 2-methyl-4- (2-allyloxyphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (4.53 g), hydroxylamine hydrochloride ( 866.9 mg), sodium acetate (1.2093 g) in acetic acid. Acetic anhydride (3.5 ml) was added to the mixture, and the resulting mixture was stirred for 3 hours at 93-98 ° C. The acetic acid was distilled off under reduced pressure, and the residue was neutralized with saturated aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The extract was washed twice with water and dried. Removal of the solvent gave a brown oil (6.42 g) which was crystallized immediately. The crystals were triturated with diisopropyl ether to give a yellow powder (3.21 g) which was recrystallized from 90% methanol.

There was thus obtained diethyl 2-methyl-4- (2-allyloxyphenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate as orange-yellow crystals,

Sp. 143-145 ° C.

Example 4 1) A mixture of dimethyl 2-methyl-4- (2-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.6 g), hydroxylamine hydrochloride (764 mg) and sodium acetate (1.06 g) in acetic acid (20 ml) was stirred for 45 minutes at room temperature to form dimethyl 2-methyl-4- (2-nitrophenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. Acetic anhydride (3.37 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes and then heated at 100 ° C for 3 hours with stirring. After removal of acetic acid, the residue was adjusted to pH 7.5 with aqueous sodium bicarbonate solution and extracted with 28,63022 ethyl acetate. The extract was washed twice with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resulting oil (3.80 g) was chromatographed on a silica gel column (110 g) and eluted with a mixture of benzene and ethyl acetate (9: 1 v / v) to give crystals (2.05 g) which were recrystallized from ethyl acetate (12 ml) and from a mixture of n-hexane (6 ml) to yellow dimethyl 2-methyl-4- (2-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate granules (1.19 g), m.p. 170.5-171.5 ° C.

NMR δ PPm (CDCl 3) 2.37 (3H, s), 3.6 (3H, s), 3.7 (3H, s), 5.9 (1H, s), 7.34 - 7.83 ( 4H, m) 2) A mixture of isopropyl 2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (3.88 g), hydroxylamine hydrochloride (0.7644 g) and sodium acetate (1.0664 g) in acetic acid (20 ml) were stirred at room temperature for 1 hour isopropyl 2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl-6- to form hydroxyiminomethyl 1,4-dihydropyridine-3-carboxylate. Acetic anhydride (3.37 g) was added to the reaction mixture, and the mixture was heated at 95 to 100 ° C. After removal of acetic acid, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed alternately with water, aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residual oil (3.69 g) was chromatographed on a silica gel column (100 g) and eluted with a mixture of benzene and ethyl acetate (5: 1, v / v) to give oily isopropyl 2-methyl-4- (2-nitrophenyl) -5-methoxy carbonyl 6-cyano-1,4-dihydropyridine-3-carboxylate (2.0 g) which was left in the refrigerator for several days to crystallize. Recrystallization from methanol gave pure crystals, m.p. 175.5-176.5 ° C.

63022 29 NMR δ ppm (CDCl 3) 0.91 (3H, d, J = 7Hz), 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), 7.23-7.85 (4H, m) 3) containing dimethyl 2-methyl-4- (3-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.0 g), hydroxylamine hydrochloride (424.3 mg) and sodium acetate (591, 8 mg) in acetic acid (12 ml) was stirred at room temperature for 80 minutes to form dimethyl 2-methyl-4- (3-nitrophenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. Acetic anhydride (1.87 g) was added to the reaction mixture, and the mixture was heated at 110 ° C for 3.5 hours with stirring. The reaction mixture was evaporated to a crystalline mass which was neutralized by treatment with dilute aqueous sodium bicarbonate solution, and the crystalline mass was pulverized, collected by filtration and washed well with water to give crystals (1.92 g). Recrystallization from a mixture of methanol and ethyl acetate gave dimethyl 2-methyl-4- (3-nitrophenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylate as pure crystals (1.04 g), m.p. 206-207 ° C. Additional compound was obtained from the above recrystallization mother liquor (0.6 g).

NMR δ ppm (CDCl 3) 2.4 (3H, s), 3.65 (3H, s), 3.78 (3H, s), 5.12 (1H, s), 6.76 (1H, broad s ), 7.36-8.1 (4H, m) 4) A mixture of 2-benzyloxyethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3 carboxylate (2.44 g), hydroxylamine hydrochloride (377 mg) and sodium acetate (526 mg) in acetic acid (15 ml) were stirred for 1 hour at room temperature. 2-Benzyloxyethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl- To form 6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate. Acetic anhydride (1.66 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour and then heated at 100 ° C for 3 hours with stirring. After removal of acetic acid, the pH of the residue was adjusted to 7.5 with aqueous sodium bicarbonate solution, and the residue was extracted twice with ethyl acetate. The extracts were washed twice with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residual brown oil (2.6 g) was chromatographed on a silica gel column (78 g) and eluted with a mixture of benzene and ethyl acetate (12: 1, v / v) to give an oil (1.45 g), the oil was crystallized by trituration with a small amount. a mixture of diisopropyl ether and diethyl ether and recrystallized from a mixture of diisopropyl ether (9 ml) and ethanol (1 ml) to give 2-benzyloxyethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-cyano-1 , 4-dihydropyridine-3-carboxylate as pure crystals (840 mg), m.p. 114-115 ° C. Additional compound (560 mg) was obtained from the filtrate by concentrating the filtrate and allowing the residue to stand in the refrigerator.

NMR δ ppm (CDCl 3) 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), 7.2-8.1 (9H, m).

31 630 2 2

Example 5

To a solution of 6-formyl-5-methoxycarbonyl-2-methyl-4- (2-thienyl) -1,4-dihydropyridine-3-carboxylic acid isopropyl ester (5.0 g) and acetic acid (30 mL) hydroxylamine hydrochloride (1.19 g) and sodium acetate (1.76 g) were added, and the mixture was stirred at room temperature for 1 hour.

Acetic anhydride (5.11 g) was then added to the mixture, and the mixture was stirred at room temperature for half an hour and at 95-100 ° C for another four and a half hours. Acetic acid and excess acetic anhydride were removed in vacuo, then water was added to the residue and neutralized with saturated aqueous sodium bicarbonate solution. The aqueous suspension was extracted twice with ethyl acetate, and the combined extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a brown oil (5.95 g) which was washed with a mixture of n-hexane and diethyl ether. The residue (3.75 g) was chromatographed on silica gel using a mixture of benzene and ethyl acetate (5: 1 by volume) as eluent to give crude crystals which were recrystallized from isopropyl ether to give 6-cyano-5-methoxycarbonyl-2-methyl-4- (2-thienyl). ) Yellow prisms of -1,4-dihydropyridine-3-carboxylic acid isopropyl ester (2.50 g), m.p. was 129-130 ° C.

The following compounds were further prepared according to Example 5: 6-Cyano-5-methoxycarbonyl-2-methyl-4- (4-pyridyl) -1,4-dihydropyridine-3-carboxylic acid isopropyl ester, m.p. 192-195 ° C (dec.).

6-Cyano-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydro-pyridine-3-carboxylic acid isopropyl ester, m.p. 130-131 ° C.

32 63022 6-Cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid isopropyl ester, m.p. 148-150 ° C.

6-Cyano-4- (2-trifluoromethyl-phenyl) -5-methoxycarbonyl-2-methyl-1H-4-dihydro-pyridine-3-carboxylic acid isopropyl ester, m.p. 172-173 ° C.

6-Cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-phenoxyethyl ester, m.p. 118-119 ° C.

6-Cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester, m.p. 104-105 ° C.

6-Cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxyethyl ester, m.p. 146-167.5 ° C.

6-Cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid hydrochloride 2- (N-benzyl-N-methylamino) ethyl ester, m.p. 203-204 ° C (dec.).

Claims (6)

33 63022 A process for the preparation of vasodilatory dihydropyridines of the formula R 2 XX m H ° wherein R 1 is phenyl which may be substituted by the following substituent groups: halogen, nitro, halogen (lower) alkyl, lower alkoxy and lower alkenyloxy, or 5- or a β-membered heterocyclic group containing one oxygen atom, a sulfur atom or a nitrogen atom, R 2 and R 3 denote lower alkoxycarbonyl, hydroxy (lower) alkoxycarbonyl, lower alkoxy- (lower) alkoxycarbonyl, phenyl (lower) alkoxy (lower) - alkoxycarbonyl, phenoxy (lower) alkoxycarbonyl, N, N- (di) (lower) alkylamino (lower) alkoxycarbonyl or N-lower alkyl-N-phenyl (lower) alkylamino (lower) alkoxycarbonyl, R4 is lower alkyl and R5 is cyano or u> -cyano (lower) alkyl, or R 1, R 2 and R 4 are as defined above and R 3 and R 5 together form a group of formula 0 • ^ 0 N 34 63022 characterized in that a) a dihydropyridine of formula is W R. ^ ^ Rc 4 N 5a H wherein R 1, R 2, R 3 and R 4 are as defined above and R 5a is N, N-hydroxyimino (lower) alkyl, with a dehydrating agent, or b) a dihydropyridine of formula R 3 J 1 {(III) rAn 4. R 5b wherein R 1, R 2, R 3 and R 4 are as defined above and R 5b is OJ-oxo (lower) alkyl, is treated with hydroxylamine or a salt thereof and treating the compound of formula II thus obtained with a dehydrating agent. Process according to Claim 1, characterized in that, in the compound of the formula I and II, R 1 is 3-nitrophenyl, R 2 and R 3 are lower alkoxycarbonyl, R 50 is hydroxyiminomethyl and R 5 is cyano. 35 6 3 0 2 2 1. A method for the preparation of a vasodilatory dihydropyridine, the formula of which R2'V '/ ^ sr / R3 I i (I, which is phenyl, which may be substituted by a substituent group having the following substituent groups: halogen, nitro, halogen ( alkoxy) -alkyl, alkoxy-alkoxy and alkenoyl-alkoxy, or heterocyclic groups having 5 or 6 carbon atoms in which they are hydrogen, hydrogen or quaternary, R? and R3 are alkoxycarbonyl, hydroxy (alkoxy), alkoxy (lagre) -alkoxycarbonyl, phenyl (lagre) alkoxy (lagre) alkoxycarbonyl, phenoxy- (lagre) alkoxycarbonyl, N, N- (di) (lagre) alkylamino (lagre) alkoxycarbonyl or N-lagre alkyl-N-phenyl (lagre) ) alkylamino (alkoxy) -carbonyl, R4 is alkyl or R5 is cyano or & cyano (alkyl), or R1, R2 and R4 are as defined above and R3 and R5 are group-containing O Ao In this case, a) the dihydropyridine arm of formula R1 R2tV3 (ii) ^ R5a H