JPS6012324B2 - Vasodilators and antihypertensive agents containing 1,4-dihydropyridine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a vasodilator and antihypertensive agent containing a novel 1,4-dihydropyridine derivative that has vasodilating and hypotensive effects and is useful as a pharmaceutical.

The 1,4-dihydropyridine derivative used in this invention has the general formula (wherein R is a phenyl group having a group selected from the group consisting of halogen, nitro, trifluoromethyl and alkenyloxy as a substituent, R2 and R
3 is the same or different alkoxycarbonyl group, alkoxyalkoxycarbonyl group, aralkoxyalkoxycarbonyl group or N-alkyl-N-aralkyl aminoalkoxycarbonyl group, R4 is a cyano group or hydroxy, unsubstituted lower alkanoyloxy, lower alkoxy an alkyl group substituted with mino, oxo, N-alkyl-N-aralkylamino lower alkanoyloxy or monohaloaryloxy lower alkanoyloxy; R5 means an alkyl group, respectively);

The terms used in the definitions of the general formula (1) and other general formulas and reaction agents described later in this specification are as follows.

Halogen and the halo moiety contained in other substituents refer to halogen atoms such as fluorine, chlorine, bromine, and bromine. The alkyl group and the alkyl moiety contained in other substituents are linear or branched monovalent saturated hydrocarbon groups, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl. , refers to a lower alkyl group such as bentyl, neobentyl, hexyl, heptyl, octyl, etc.

The alkoxy moiety contained in the alkoxy group or other substituents is preferably methoxy, ethoxy, propoxy,
It means a lower alkoxy group such as isopropoxy, putoxy, t-butoxy, bentoxy.

Alkenyl is a linear or branched monovalent unsaturated hydrocarbon group having one or more double bonds, preferably vinyl, allyl, 1-probenyl, 3-butenyl, 1.
It means lower alkenyl stems such as 3-ptadienyl and 2,4-bentadienyl.

Preferred examples of unsubstituted lower alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like.

Examples of N-alkyl-N-aralkyl aminoalkanoyl include 2(or 3)-(N-methyl-N-benzylamino)propionyl and the like.

Preferred examples of monohaloaryloxyalkanoyl include 2(or 3 or 4)-chlorophenoxyacetyl, 2(or 3)-[2(or 3 or 4)-chlorophenoxy]propionyl, and the like.

Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, and carbonyl.

Examples include poxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, and the like. As the alkoxyalkoxycarbonyl group, 2-methoxyethoxycarbonyl, 2
-ethoxyethoxycarbonyl, 2(or 3)-methoxy(or ethoxy)propoxycarbonyl, and the like.

Examples of the aralkoxyalkoxycarbonyl group include 2-(benzyloxy)ethoxycarbonyl and 2(or 3)-benzyloxypropoxycarbonyl.

Preferred examples of the N-alkyl-N-aralkyl aminoalkoxycarponyl group include 2-(N-methyl-N-pendylamino)ethoxycarponyl. The oxo-substituted alkyl group refers to an alkanoyl group, preferably a lower alkanoyl group or an alkanoyl alkyl group such as formyl, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, pivaloyl, etc., preferably formylmethyl, acetonyl, 2 - Means a lower alkyl group substituted with lower alkanoyl such as formylethyl, 3-formylpropyl, butyrylmethyl.

The oxo-substituted alkyl group that is considered to be an acetal is one in which the carbonyl group in the above alkanoyl group and alkanoyl alkyl group is protected as an acetal. Examples of alkanoyl groups and alkanoylalkyl groups having groups include dialkoxyalkyl groups, preferably dimethoxymethyl, 1,1-dimethoxyethyl, diethoxymethyl, diproboxymethyl, 202-diethoxyethyl. , 2-di-lower alkoxy-substituted lower alkyl groups such as 2-jethoxypropyl, m-alkylenedioxyalkyl groups, preferably 1
・3-dioxolan-2-yl, 2-methyl-1,3-dioxolan-2-yl, 4-methyl-1,3-dioxolan-2-yl, 4,5-dimethyl-1,3-dioxolan-2-yl, 1,3-dioxan-2 -il, 2
-M-lower alkylenedioxy such as methyl-1,3-dioxan-2-yl, 1,3-dioxolan-2-ylmethyl, 2-methyl-1,3-dioxolan-2-ylmethyl, 3-(1,3-dioxolan-2-yl)propyl, etc. Examples include chain or cyclic acetal types such as substituted lower alkyl groups. Compound (1) used in this invention is produced by the method shown below.

1. Elimination by hydrolysis of the protecting group in the carbonyl group: Among compound (1), the general formula (wherein R,, R2, R3 and R5 have the same meanings as before, and R4b is The compound represented by the general formula (where R, , R2, R3 and R5 have the same meanings as before, and R represents an oxo-substituted alkyl group protected as an acetal) It can be produced by hydrolyzing the compound shown in ).

Raw material compound (1-1) can be produced by the method described in the following Examples or a method similar thereto.

The acetal on the carbonyl group formed by substituting the alkyl group of R41 in compound (1-1) with oxo is eliminated by this hydrolysis, and compound (1)
12) is obtained.

This hydrolysis is usually carried out under acidic conditions, for example in the presence of an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid.

This hydrolysis reaction is usually carried out in a solvent, such as water, acetone, methyl ethyl ketone, dioxane,
Examples include methanol, ethanol, N·N-dimethylformamide, N-methylmorpholine, mixed solvents of these organic solvents and water, or ordinary buffer solutions.

The reaction temperature is not particularly limited, but it is usually carried out under cooling, room temperature, or humidification. 2 Imino group-forming condensation reaction: Of the compound (1), -Fumi formula (wherein R,, R2, R3 and R5 have the same meanings as before, R is an alkyl substituted with lower alkoxyimino) The compound represented by (representing a group) is the compound (1-2) produced by the above-mentioned method 1, which has the general formula R8-N ratio.
It can be produced by reacting with an amine compound represented by (0) (in the formula, R8 means a lower alkoxy group).

Through this condensation reaction, the oxo group of the oxo-substituted alkyl group represented by R4b in the starting compounds (1-2) becomes an imino group represented by the formula =N-R8 (wherein R8 has the same meaning as before). A substituted compound (1-3) is obtained.

This condensation reaction is carried out in a suitable solvent such as water, dioxane, methanol, ethanol, dimethylformamide, or a mixed solvent of these organic solvents and water, and the reaction usually proceeds advantageously under acidic or basic conditions. In the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, boron trifluoride, poppy tetrachloride, titanium tetrachloride, or in a basic buffer. Preferably, the reaction is carried out with or by using an excess of amine compound (0).

The reaction temperature is not particularly limited, but it is usually carried out at room temperature under cooling, or under heating.The amine compound (0) used in this reaction is ○-methylhydroxyamine, 0
Examples include lower flukoxyamines such as -ethylhydroxyamine, 0-propylhydroxyamine, and 0-isopropylhydroxyamine.

This amine compound (b) can be used in the form of a salt with an acid such as an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as acetic acid. 3 Dehydration reaction: Among compound (1), the general formula (wherein R,, R2, R3 and R5 have the same meaning as before)
The compound represented by the general formula (wherein R,, R2, R3
and R5 have the same meanings as above) by reacting a dehydrating agent with the compound.

The raw material compounds (1-3) used in this dehydration reaction are produced by the methods described in the following Examples or by methods similar thereto.

Any organic or inorganic dehydrating agent commonly used in dehydration reactions can be used as a dehydrating agent in this reaction, preferred examples of which are sulfuric acid, phosphoric acid, topolyphosphoric acid, diic acid, acetic acid, ethanesulfonic acid, p- Acids such as toluenesulfonic acid; acid anhydrides such as acetic anhydride, benzoic anhydride, and phthalic anhydride; acid halides such as acetic chloride, benzoic acid chloride, trichloroacetic acid chloride, mesyl chloride, tosyl chloride, ethyl chlorocarbonate, phenyl chlorocarbonate, etc. , thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, stannic chloride, titanium tetrachloride, and other inorganic halogenated compounds; Carposimide compounds such as thylcarbodimide; N・N'-carponyldimidazole, bentamethyleneketene-N-
Cyclohexylimine; ethoxyacetylene: 2-ethyl-7-hydroxyisoxazolium salt; phosphorus pentoxide,
Examples include phosphoric acid compounds other than those listed above, such as ethyl polyphosphate and ethyl triphosphate, and phenyl phosphate.

In addition, when an acid is used as a dehydrating agent in this reaction, it can also be carried out in the presence of a salt of the acid with a metal such as sodium or potassium. This dehydration reaction involves the use of diethyl ether, dimethylformamide, pyridine, acetic acid, rhonic acid,
Benzene, carbon tetrachloride, chloroform, methylene chloride,
It is carried out in a solvent such as tetrahydrofuran or dioxane.

The reaction temperature is not particularly limited, but is usually room temperature or heating,
The reaction takes place under heat. 4 Reduction of oxo: Among compound (1), the compound represented by the general formula (wherein R,, R2, R3 and R5 have the same meanings as before and means an alkyl group substituted with R puma hydroxy) The compound can be produced by reducing a compound represented by the general formula (wherein R,, R2, R3, R4b and R5 have the same meanings as before).

As the reduction method, any method commonly used for reducing an oxo group to a hydroxy group can be applied, such as lithium borohydride, sodium borohydride, potassium borohydride, Examples include reduction using a reducing agent such as an alkali metal borohydride such as sodium cyanoborohydride, or catalytic reduction.

As the catalyst used for the catalytic reduction, in addition to palladium on carbon, palladium chloride, rhodium on carbon, etc., any catalyst normally used for the catalytic reduction can be used. This reaction is usually carried out in a solvent, and any solvent that does not adversely affect this reaction, such as water, methanol, ethanol, inpropyl alcohol, and dimethylformamide, can be used.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reduction method can be appropriately selected depending on the type of the raw material compounds (1-2). By this reduction, the oxo moiety in R'4b of the starting compound (1-2) is reduced, and a compound (1-5) in which it has been changed to hydroxy is obtained.

5 Acylation reaction of hydroxyl group: Among compound (1), the general formula (wherein R,, R2, R3 and R5 have the same meanings as before, R4f is unsubstituted lower alkanoyloxy, N-alkyl group A compound represented by the general formula (meaning an alkyl group substituted with N-aralkylamino lower alkanoyloxy or monohaloaryloxy lower alkanoyloxy) is a compound represented by the general formula (wherein R,, R2, R3, R4e and R5 are It can be produced by reacting a compound represented by (same meaning as above) with an acylating agent.

The raw material compound (1-5) used in this acylation reaction is produced by the method 4 described above.

The acylating agent used in this reaction has the general formula R910H
(m) (wherein R9 means unsubstituted lower alkanoyl, N-alkyl-N-aralkylamino lower alkanoyl or monohaloaryloxy lower alkanoyl) and reactive derivatives thereof.

Preferred examples of the acylating agent (m) include yield acid, acetic acid,
Propionic acid, butyric acid, isobutyric acid, cyanobic acid, isovaleric acid,
lower alkanoic acids such as pivalic acid, 2(or 3)-(N-
N-alkyl-N-aralkylamino lower alkanoic acids such as methyl-N-pendylamino)propionic acid, 2(or 3 or 4)-chlorophenoxyacetic acid, 2-[2(
or 3 or 4)-chlorophenoxy] lower alkanoic acids substituted with monohaloaryloxy such as propionic acid. The above-mentioned reactive derivatives of carboxylic acid (m) include acid halides, acid anhydrides, activated amides,
Examples include active esters such as azidomethyl ester, ethyl ester, cyanomethyl ester, and p-nitrophenyl ester. This reaction is usually carried out in pyridine, ether, dioxane, acetone, 1 chloroform, methylene chloride, tetrahydrofuran, dimethylformamide, benzene, water or other solvents that do not adversely affect the reaction, and preferably proceeds in the presence of a base. .

Examples of such bases include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, N-methylpiveridine, triethylamine, pyridine, N-methylmorpholine, N. Examples include organic bases such as N-dimethylaniline. The reaction temperature is not particularly limited, usually under cooling, room temperature,
It is carried out under heating. In addition, as a condensing agent, if necessary, phosphorus oxychloride, thionyl chloride, N-N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarpodiimide, bentamethylene ketene, etc. N-cyclohexylimine, alkoxyacetylene, 2-ethyl-7-hydroxyisoxazolium salt, 2-ethyl-5-(hydroxide)
m-sulfophenyl)inxazolium, 6-chloro-1-tosyloxybenzotriazole, etc. can be used. In the above method, any target compound produced is isolated and collected by conventional methods.

Compound (1) used in this invention includes 1,4-
There are stereoisomers derived from the non-sacrificial carbon at the 4-position of the dihydropyridine ring, and some of compound (1) have one additional substituent at the 2-, 3-, 5-, and 6-positions of the 1,4-dihydropyridine ring. Some have more inhospitable carbon.

In these cases, compound (1) can exist as each optical isomer or racemate, as well as a diastereomer or a mixture thereof. Mixtures of diastereomers can be separated into their respective racemates by conventional methods such as chromatography or fractional recrystallization, if necessary. , respectively, into optically active salts such as tartaric acid and camphorsulfonic acid or bases such as ephedrine and strychnine, which are then separated into their respective optical isomers by fractional recrystallization. can do. Compound (1) used in this invention has vasodilatory and blood pressure lowering effects, and can treat hypertension, heart failure, angina pectoris,
It is effective against cardiovascular diseases such as myocardial infarction.

Among the compounds (1) used in this invention, compounds [B] to [N] represented by the following formulas are known compounds [A]
The results of pharmacological tests compared with

[11 Test compounds [Note] Known compound [A] has the generic name nifedipine (Ni
It is commercially available as a coronary vasodilator.

'21 Test results The amount of increase in coronary blood flow using dogs is as shown below.

The results are expressed as a percentage of the increase when no drug was administered [29.5±5.5/min], with the control being 100. (
i) Test results of compounds [A] to [E] at various doses.
] ~ [N] test results■ Test method The test compound was administered intravenously to a dog anesthetized with pentobarbital, and the coronary blood flow was measured according to the standard method, and the maximum value of the coronary blood flow at each dose ( (same/minute) was calculated.

Compound (1) of this invention is administered in the form of a composition containing an effective and non-toxic amount thereof.

This composition is used in a dosage form suitable for oral or parenteral administration together with inorganic or organic, solid or liquid pharmaceutical carriers commonly used in pharmaceutical formulations. Preferred dosage forms include tablets, jaw granules, powders, powders, capsules, sublingual tablets, suppositories, solutions, syrups, injections, and the like. Examples of solid or liquid pharmaceutical carriers include lactose, magnesium stearate, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, gum arabic, peanut oil, olive oil,
Examples include sesame oil and cacao butter. Each of the above-mentioned various formulations can be manufactured by a well-known method. When compound (1) is used as a medicine in this invention, the dosage is 0.1 to 500 mg per day for oral administration, preferably 1 to 50 mg per day for intravenous administration. City of oral administration.

Although the drug is administered in appropriate doses, it is preferable to select the dose appropriately, taking into consideration the mode of administration, patient's sex, age, weight, symptoms, etc. Here, the acute toxicity test results of compound (1) used in this invention are shown.

[1' Test animals JCL: SD rats (6 weeks old) '21 Administration method Each group consisted of 10 animals, and the compound to be saponified was suspended in a 0.5% methylcellulose solution and then administered orally.

■Test Compound 4) Test Results Next, a method for producing the 1,4-dihydropyridine derivative used in the present invention will be shown as an example.

Example 1'1} 2-chlorobenzaldehyde (14
．． A solution of 4,4-jethoxyacetoacetic acid ethyl ester (21.8240%) and piveridine (1%) dissolved in benzene (100%) was heated to reflux under azeotropic dehydration conditions for 4 hours.

The reaction solution was washed with water, dried, and concentrated to obtain oily 2-(2-chlorobenzylidene)-4,4-jethoxyacetoacetic acid ethyl ester. A mixture of this and 3-aminocrotonic acid ethyl ester (12.92 ml) is heated in an oil bath at about 10 to 0 ml. The reaction mixture was dissolved in ethyl acetate, washed with water, dried, and the solvent was removed to obtain a crude oil (52.4 mm). This was purified by silica gel column chromatography using an elution solvent (benzene: ethyl acetate = 20:1), and the obtained crystals were recrystallized from n-hexane.
Crystals of diethyl ester of methyl-4-(2-chlorophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate of mp75-770 (
20.2445 evening) is obtained. [2' 2-koo benzaldehyde (2.81 m), 4,4-dimethoxy-3-
7. Add a mixture of oxococyanate methyl ester (3.81 hours), piberidine (0.2 hours), and benzene (20 hours).
Immediately heat to reflux under vertical dehydration conditions.

Add a small amount of benzene to the reaction solution, wash with water, and then dry with magnesium sulfate. A mixture of the obtained red oily substance of methyl ester of 2-(2-chlorobenzylidene)-4,4-dimethoxy-3-oxocyanate (7.04 evening) and 3-aminocrotonic acid methyl ester (2.33 evening) was heated to 1320 ml.
So 3. After heating for a period of time, the reaction solution was allowed to cool and then dissolved in ethyl acetate. The resulting solution was washed with water and then with an aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a sticky brown oil (8.28 pm).
This oily substance was mixed with an elution solvent (benzene: ethyl acetate = 20
When subjected to silica gel column chromatography using 1), an oily substance (5.26 min.) is obtained. This oil was dissolved in a mixture of ethyl acetate and diethyl ether, and the solvent was distilled off under reduced pressure to give a colorless powder (1.0625 mm). When this powder was recrystallized from a solution of n-hexane and ethyl acetate, pale yellow granular crystals of mp145-14600 were obtained.
1-dimethoxyethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester is obtained. '3'
2-nitrobenzaldehyde (9.0672 evening), 4
・4-Jethoxyacetoacetic acid ethyl ester (13.0
944) and piveridine (1) to benzene (4)
A solution dissolved in 5-glycerol is heated under reflux under conditions of dehydration for 3 hours.

Add water to the reaction solution and extract with ethyl acetate. 3 extracts
After washing with water twice and drying, the solvent is distilled off under reduced pressure. Obtained 2
A mixture of the crude oil of ethyl -(2nitobenzylidene)-4,4-diethoxyacetoacetate and ethyl 3-aminocrotonic acid ester (7.7496) is heated in an oil bath at 90-100°C for 8 hours.

The reaction mixture was extracted with diethyl ether, the extract was washed with water, dried, and the solvent was distilled off. Remove the residue from the solvent (benzene:
Purification by silica gel column chromatography using ethyl acetate (20:1) yields an oily 2-methyl-4-(2-nitrophenyl)-6-diethoxymethyl-
1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (19.3 evening) is obtained. This oily substance is
- Crystallization from hexane and recrystallization from a mixture of n-hexane and ethyl acetate gives yellow granular crystals with a mp of 80-81.500. ■ In the same manner as in Example 1-[1], 3-nitrobenzaldehyde (2.27 hours), 4,4-diethoxyacetoacetic acid ethyl ester (3.28 hours), piveridine (0.2 hours) and benzene ( Oily 2-(3 nit.penzylidene)-4 prepared using 15')
．． An oil (7.8 min.) is obtained from 4-jethoxyacetoacetic acid ethyl ester (6.0 min.) and 3-aminocrotonic acid ethyl ester (1.94 min.). When this dendritic material was purified by silica gel chromatography using an elution solvent (benzene: ethyl acetate = 20:1), 2-
Methyl-41(3-nitrophenyl)-16-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (4.65 yen) is obtained. Infrared absorption spectrum (film) 3400, 1690, 1615, 1530, 1480,
1350, 1280, 120ri 1090, 920, 76
5-arc-1 nuclear magnetic resonance absorption spectrum (6, CDC13)
1.231.26 (12th, t, t, J=7Hz), 2
．． 4 (Su, s), 3.5-3.86 (4th, m), 4.
11 ('day, q, J = 7 days 2), 5.16 (IH, s)
, 6.82 (IH, broad), 7-25-8-16
(Rainbow Day, m) ■ A mixture of 2-(2-trifluoromethylbenzylidene)-4,4-diethoxyacetoacetic acid ethyl ester (7.48 pm) and 3-aminocrotonic acid ethyl ester (2.582 pm) was heated at 130 qo for 5 hours. do.

A solution of the reaction mixture in ethyl acetate is washed twice with water, dried, and concentrated under reduced pressure. The resulting red oily residue (9.8) was eluted with a solvent (benzene:diethyl ether, 20:1).
Subject to silica gel column chromatography using
The obtained oil was crystallized and recrystallized from a solution of n-hexane and diethyl ether to give mp82-83.
Crystals of 2-methyl-4-(2-trifluoromethylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of qo are obtained. {6) A mixture consisting of 2-chloro-5-nitrobenzaldehyde (3.73 mm), 414-jethoxyacetoacetic acid ethyl ester (4.365 mm), piveridine (9 of 272.5) and benzene (10) 1.
Heat to reflux under azeotropic dehydration conditions.

Add ethyl acetate to the reaction solution, wash with water three times, then wash with aqueous sodium chloride solution and dry. The solvent was removed under reduced pressure, and the obtained 2-(2-chloro-5nitrobenzylidene)-4
・Add 3-aminocrotonic acid ethyl ester (3.48 evenings) to the reddish brown oily substance of 4-diethoxyacetoacetic acid ethyl ester (7.87 evenings) and make it on Yuyu 105-107q.
0 and 4. Insect time heat loss. The reaction solution was extracted with ethyl acetate, the extract was washed three times with an aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was removed and Isosumi (10.
872) as an elution solvent (chloroform:ethyl acetate i20
: Subjected to silica gel chromatography using 1),
The obtained fractions were followed by thin layer chromatography, and crystals (
6.02 evening). This crystal is called jetyl ether.
Recrystallization from a mixed solution of -hexane gives crystals of 2-methyl-4-(2-chloro-5-nitrophenyl)-16-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester with mpl17-11 of ○. {7} 2-nitrobenzaldehyde (3.02), 2-ethoxychetyl ester of acetoacetic acid (3.4)
8 nights), piberidine (272.5 females) and benzene (
The mixture of 10') was heated under boiling dehydration conditions. Heat to reflux for an hour.

The reaction solution was washed three times with water, then with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting oily 2-(2-nitrobenzylidene)acetoacetic acid
Add 3-amino-4,4-diethoxycrotonic acid ethyl ester (4.77 pm) to ethoxyethyl ester,
Heat at 110 ○ for 5 hours. The reaction solution was extracted with ethyl acetate, the extract was washed three times with water, and then dried over magnesium sulfate. The solvent was removed and the brown oily residue was purified by silica gel column chromatography using an eluent (benzene:ethyl acetate = 10:1) to obtain oily 2-methyl-4-(2nitrophenyl)-5-ethoxy. 2-ethoxychetyl ester of carbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid (3
．． 18 evening). Infrared absorption spectrum (film)
3420, 1730, 1695, 1650, 1610,
1530, 1480, 1355, 1275121○11
00, 860, 830, 78fu 752/715 skin-1
Nuclear magnetic resonance absorption spectrum (6, CDC13) 1-1.
37 (12th, m), 2.37 (ga, s), 3.28-
4,3 (1 is, m), 5・93 (IH, s), 6.2 (
IH, s), 6.78 (IH, m), 7.23-7.8
3 (Misaki, m) {8} Example 1 - Same as '7',
2-nitrobenzaldehyde (3.02 evenings), 2-benzyloxyethyl ester of acetoacetic acid (4.72 evenings)
, piveridine (9 of 272.5) and benzene (10
．． 3 to 2-benzyloxyethyl ester of 2-(2-nitrobenzylidene)acetoacetic acid prepared from [) of 8.
-Amino-4,4-diethoxycrotonic acid ethyl ester was reacted with oily 2-methyl-4-(2-nitrophenyl)-5-ethoxycarponyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid. 2
-benzyloxyethyl ester (4.80 pm) was obtained.

Infrared absorption spectrum 3400, 1700, 1650, 1610, 1530,
1480, 13551273120fu10901055
750, 700 skin nuclear magnetic resonance absorption spectrum (6, C
DC13) 1.1-1.3 (field, m), 2.32 (thin,
s), 3.45-4.32 (1 plate, m), 4.46 (ga, s), 5.94 (IH, s), 6.2 (IH, s),
6.82 (IH, s), 7.16-7.74 (group, m)
'91 Example 1 In the same aircraft, 3-nitrobenzaldehyde (4.54 hours), 2-ethoxyethyl ester of acetoacetic acid (5.23 hours), and piverizine (85.2 hours) were prepared.
2) and benzene (15 [)]
The crystals obtained by reacting 2-ethoxychetyl ester of -(3nitrobenzylidene)acetoacetic acid with 3-amino-4,4-jethoxycrotonate ethyl ester (6.5 yen) were combined with n-hexane. Recrystallization from diethyl ether solution yields 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid as yellow granular crystals with a mp of 99-100°C. 2-ethoxyethyl ester (
565.2 imitation).

00 2-chlorobenzaldehyde (351.4-9)
, 4,4-jethoxyacetoacetic acid ethyl ester (54
5.6-3), 3-aminocrotonic acid ethyl ester (
A mixture of 322.9 of 9) and n-propanol (2 of [)] is refluxed for 1 m hour.

The reaction solution was concentrated, the resulting residue was dissolved in ether, and 2
Wash twice with water. After drying the extract, the solvent was distilled off, and the resulting clear color oil (1.1765) was purified by silica gel column chromatography using an eluent (benzene: ethyl acetate = 20:1). Oily substances (374.6
9) is obtained. Dissolve this in n-hexane and leave in a cool place. The precipitated crystals were filtered and washed with n-hexane to give crystals of 2-methyl-4-(2-chlorophenyl)-16-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of mp75-770 ( 9) of 374.6 is obtained. OU The following compound is obtained in the same manner.

{1) Infrared 2-(N-penzyl-N-methylamino)ethyl ester of 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3 monoluponic acid Absorption spectrum (film) 3400, 1700, 1690, 1610, 1528,
1475, 135012761197, 1092, 10
5fu 755 698 Fox 11 nuclear magnetic resonance absorption spectrum (6, CDC130D20) 1.21 (group, t, J=7
HZ), 2.21 (ga, s), 2.36 (ban, s), 2
．． 63 (ga, t, J; 6HZ), 3.5 (ga, s), 3
．． 65 (ga, q, J = 7HZ), 3.66 (ga, q, J
=7HZ), 4,1 (ga, q), 4,18 (ga, t, J
=6HZ), 5.18 (IH, s), 6.2 (IH, s
), 6.86 (IH, s), 7.16-8.16 (4 days, m) ■ 2-Methyl-4-(2-nitrophenyl)-
6-ethylenedioxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (mpl5
2-153.5℃) Example 2{1) 2-methyl-4-(2-chlorophenyl)-6-diethoxymethyl-1.
Add hydrochloric acid (0.2-0.3') to a solution of 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (452 evening) in acetone (5') and stir at room temperature for 1 hour. .

The solvent was removed, the residue was extracted twice with ethyl acetate, and the extract was washed with water and dried. Stripping off the solvent gives an oily residue which crystallizes. When this crystal is recrystallized from a tear fluid of n-hexane and diethyl ether, it produces 2-methyl-4-(2-chlorophenyl) as yellowish granular crystals with an mp of 87-88°C.
-6-formyl-1,4-dihydroviridine-3,5-
Dicarboxylic acid diethyl ester is obtained. '21 2-Methyl-4-(2-chlorophenyl)-6-(1,1-dimethoxyethyl)-1,4-dihydropyridine-315
- Carp in a solution of dicarboxylic acid dimethyl ester (409.9 2) in acetone (15 [)] - Hydrochloric acid (0.5 ')
Add to the mixture and stir at room temperature for 17 minutes.

The reaction solution was neutralized with saturated aqueous sodium bicarbonate solution, and the solvent was evaporated under reduced pressure. If you add water to the afterlight and leave it for a while, crystals will precipitate. This crystal (9 of 350.2) was taken in a furnace, and after drying, n
-When recrystallized from a mixture of hexane and ethyl acetate, mp1
61-16?0 yellow granular crystals of 2-methyl-4-(2-
(chlorophenyl)-6-acetyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester. [31 2-Methyl-4-(2nitrophenyl)-6-diethoxymethyl-1'4-dihydropyridine-3
・To a solution of 5-dicarboxylic acid diethyl ester (1.1563 mm) in acetone (10 mm), add carp-hydrochloric acid (2.5 mm) and stir at room temperature for 30 minutes.

The solvent is removed, water is added to the liquid, and then neutralized with aqueous sodium bicarbonate solution. The precipitated solids are collected in an oven, washed with water and dried to give a yellow powder (0.07 mm). When this is recrystallized from n-hexane and ethanol solution, mplo
2-Methyl-4-(2nitrophenyl)-6-formyl-1,4-dihydrobiridine-3,5 at 103°C
- Obtain crystals of dicarboxylic acid diethyl ester. [41
Add carp-hydrochloric acid (0) to a solution of 2-methyl-4-(3-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (462.5-9) in acetone (4-[)]. Add .4 secretion),
Let stand for 1 hour at room temperature. The solvent is removed and water is added to the residue to form a powder. When the powder is heated in a furnace, washed with water and dried, it becomes MP13.
2-Methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5 at 0-133°C
-dicarboxylic acid diethyl ester (360 mo) is obtained. [512-Methyl-4-(2-trifluoromethylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (5.
Add carp hydrochloric acid (5 parts) to a solution of acetone (5 parts) of 1 part at room temperature. Worshiping insect time.

The solvent was removed under reduced pressure, and the residue was extracted twice with ethyl acetate.
After washing the extract with water and drying, the solvent was distilled off to give a red oily 2-methyl-41 (2-trifluoromethylphenyl)-16-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (4.2 evening). Infrared absorption spectrum (Nujol) 3350, 1700, 16
40, 1605, 1480, 1370, 130 & 120
110QI03F950763 arc-1 nuclear magnetic resonance absorption spectrum (6, CDC130D20) 1,2 (dark blue, t
, J=7HZ), 2.4 (3 days, s), 3-92-4-
38 (Yamahi, m), 5-72 (IH, S), 7.06 (
IH, s), 7.24-7.62 (4th, m) [6]
2-methyl-4-1 (2-chloro-5-nitrophenyl)
-6-diethoxymethyl-1,4-dihydropyridine-
Carp-hydrochloric acid (5') in a solution of 3,5-dicarboxylic acid diethyl ester (5,45') acetone (54,5')
After stirring at room temperature for 1.5 hours, the solvent was removed under reduced pressure.

If you add water to Qianlong and leave it for 15 minutes, crystals will precipitate. The crystals were taken out of the oven, washed with water, dried, and then recrystallized from a tear solution of hexane and ethyl acetate.
Methyl-4-(2-chloro-5-nitrophenyl)-6
- Obtain crystals of formyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (9 of 347). [71 In the same manner as in Example 2-11, 2-ethoxy of 2-methyl-4-(2nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid Ethyl ester (1.
2-methyl-4-(2
Crystals of 2-ethoxychetyl ester of (nitrophenyl)-5-ethoxycarponyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid (recrystallized from diisopropyl ether) are obtained.

[81 Example 2-[2-methyl-4]
-(2-nitrophenyl)-5-ethoxycarponyl-
6-diethoxymethyl-1,4-dihydropyridine-3
-2-benzyloxyethyl ester of carboxylic acid (2
．． 5), acetone (25') and carp-hydrochloric acid (2') to give a red oil of 2-methyl-4-(2nitrophenyl)-5-ethoxycarbonyl-6-formyl-1.
2-benzyloxyethyl ester of 4-dihydropyridine-3-carboxylic acid (2.05 hours) is obtained.

Infrared absorption spectrum (film) 3380, 1695, 1532, 1485, 1277,
1210, 110 Ri 1040860750 Skin-1 Nuclear Magnetic Resonance Absorption Spectrum (6, CDC13) 2-40 (Chihito, S>, 4-48 2 days, S>, 6-〇8 (IH, s)
, 10.40 (IH, s) [91 2-methyl-4-(
3-nitrophenyl)-5-ethoxycarbonyl-6-
Add carp-hydrochloric acid (3M) to a solution of 2-ethoxymethyl ester (5.85%) of diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid in acetone (60%),
Boil at room temperature for about 2 hours.

The solvent was distilled off under reduced pressure, water was added to the liquid, and the mixture was extracted twice with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and the solvent was removed to give a red oily substance (5.7 hours). This oil crystallizes. This was treated with a dew solution of n-hexane and diethyl ether to powder, and the obtained powder (
4.81 evening) was taken to the oven. When this powder (1.81 evening) was recrystallized from a mixture of diethyl ether and ethyl acetate, m
2-Methyl-4- in light yellow granular crystals at 101°C
(3-nitrophenyl)-5-ethoxycarbonyl-6
-formyl-2-ethoxyethyl ester of 1,4-dihydropyridine-3-carboxylic acid (1.2 hours) is obtained.
00 2-Methyl-4-(3-nitrophenyl)-5-
Ethoxycarponyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid 2-(N-methyl-N-pendylamino)ethyl ester (7.25 evening)
Add carp-hydrochloric acid (7') to a solution of acetone (70') and leave at room temperature for 3 hours. The solvent is removed under reduced pressure and water is added to the residue to separate an oily substance. The liquid is made alkaline by adding sodium bicarbonate powder and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off to give a red oily 2-(N-methyl-N
-benzylamino)ethyl ester (5.8) is obtained.
Infrared absorption spectrum (film) 3350, 1735
, 1700, 1690, 1635, 1600, 1525
, 1480, 1350, 1279, 1215, 1100
, 103u 735-1 nuclear magnetic resonance absorption spectrum (
6, CDC130D20) 1.29 (9th, t, J =
7 days 2), 2.21 (3 days, s), 2.45 (9H, s
), 2.63 (2 days, t, J=6HZ), 3.51 (spots, s), 3.95-4, 42 (ga, t), 3.95-4
．． 42 (2 days, q), 5.28 (IH, s), 7.08
(IH, s), 7.28-8.12 (4th, m), 10
．． 54 (IH, s) Example 3 '1'2-Methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (9 of 377.8), hydroxylamine hydrochloride (83. A solution of 4 part 9) and sodium carbonate (63.6 part 9) in ethyl alcohol (1 part') is stirred at room temperature for 30 minutes.

The reaction solution is concentrated, water is added to the isosumi, and the mixture is extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to give a yellow oily substance (47
6 evening). This oily substance was treated with n-hexane to produce 2-methyl-4-(2-chlorophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3.
Crystals of 5-dicarboxylic acid diethyl ester (318.8
9) and the corresponding 6-cyano form (mp136-13
7°C) and confirmed. '2) 2-methyl-41 (
2-chlorophenyl)-6-formyl-1-4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (
525.3 in 9), 0-methylhydroxylamine hydrochloride (139.34 in 9) and 99% ethanol (2 in!) in sodium carbonate (88.5 in 9) in water (
The solution of 1) was added dropwise to the fly at room temperature over a period of 20 minutes.
Pray for another 10 minutes.

The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract is washed twice with water, then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The oil obtained crystallizes. Powder obtained by washing this crystal with n-hexane (504.6 female)
n-hexane (10 parts) and diethyl ether (1 part)
When recrystallized from a mixed solution of mpllo-11 or 0, yellow granular crystals of 2-methyl-4-(2-chlorophenyl)-16-methoxyiminomethyl-144-dihydropyridine-3,5-dicarboxylic acid diethyl ester (301.5 of 9
). '3} 2-Methyl-4-(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (8
70 of 9), hydroxylamine hydrochloride (147 female) and sodium carbonate (112.1 of 9) in ethanol (
Incubate the solution in step 5') at room temperature for 30 minutes.

The reaction solution was concentrated, water was added to the residue, and the mixture was 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 a viscous oil (0.992 mm). The obtained oily substance was purified by silica gel column chromatography using an eluent (benzene: ethyl acetate = 10:1) to obtain 2-methyl-4-(2-trifluoromethylphenyl) as a yellow powder. 1-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (0
．． 52 evening). Infrared absorption spectrum (Nujol) 3410, 1695 "1680, 1655, 1483
, 1445, 1370, 1309, 1221, 1106
, 1090, 1057, 1034101Q 98fu 7
72ka-1 nuclear magnetic resonance absorption spectrum (6, CDC13
) 1.17 (fine, t, J=7HZ), 1.20 (spotted, t
, J=7HZ), 2.35 (Pongee, s), 3.8-4.4
(4th day, m), 564 (IH, broad s), 6.
91 (IH, broad s), 7.2-7.7 (Misaki,
m), 8.4 (IH, broad s), 8.8 (IH
, s) (4) 2-methyl-4-(2-trifluoromethylphenyl)-6-formyl-114-dihydropyridine-315-dicarboxylic acid diethyl ester (1.23
evening), add sodium carbonate (190.2 mm) to a solution of hydroxylamine hydrochloride (250.2 mm) in ethanol (5).
Add a solution of &9) water (1.5') and incubate for 30 minutes at room temperature.

The reaction solution was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. When this oily substance is treated with n-hexane and crystallized, it produces 2-methyl-4-(2-trifluoromethylphenyl).
Crystals of 1-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (
1.09 evening). (5) 2-methyl-4-(3nitrophenyl)-5-ethoxycarbonyl-6-formyl-114-dihydropyridine-3-carboxylic acid 2
-(N-methyl-N-benzylamino)ethyl ester (1.015 m), hydroxylamine hydrochloride (116 m)
．． A solution of sodium carbonate (127.2, 9) and water (1, 1) was gradually added dropwise to a mixture of 8, 9) and ethanol (3), and the mixture was incubated at room temperature for 50 minutes.

The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution, dried, and concentrated under reduced pressure to yield a yellow oily 2-methyl-4-(3
(nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3
2-(N-methyl-N-pendylamino)ethyl ester of -carboxylic acid (1.01 min.) is obtained. Infrared absorption spectrum (film) 3350, 1690, 1460,
1375, 1 I8, 1205, 10 pair 1044 73
〆 72 700 Ka-1 Nuclear Magnetic Resonance Absorption Spectrum (
6, CDC13) 1.22 (spot, t, J:7HZ), 2
, 26 (field, s), 2.36 (thin, s), 2.70 (ga, t, J=6HZ), 3. Spot (bait, s), 4.09 (bait, q, J=7HZ), 4.18 (ga, t, J=6HZ)
, 5.14 (IH, s), 7.1-8.1 (1 Cape, m)
, 8.97 (IH, S) [61 Said Example 3-{11
The following compound is obtained in the same manner as in ~3-■.

(1} 2-methyl-4-(2-nitrophenyl)-6
-Hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethylester (2' 2-methyl-4-(2-chloro-5-nitrophenyl)-6
-Hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carvone The 2-ethoxycetyl ester compounds of the acid were confirmed by converting them into the corresponding 6-cyano compounds.

Example 4 (1'1 [11 2-methyl-41 (2-k.

(lofenyl)-6-hydroxyiminomethyl-1,4-
A mixture of dihydropyridine-3,5-dicarboxylic acid diethyl ester (0.6135 mm), N.N'-dicyclohexylcarbodiimide (804.6 mm) and pyridine (3 mm) is heated to reflux for 6 hours. The reaction solution was made acidic with dilute hydrochloric acid and extracted with ethyl acetate. The precipitated insoluble substances are removed from the furnace, and the furnace solution is washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure, and diethyl ether was added to the residue and heated. A red oily substance obtained by concentrating the furnace liquid under reduced pressure (70
3.7-9) with elution solvent (benzene: ethyl acetate = 10
:1) and purified by silica gel column chromatography and crystallized by treatment with n-hexane. When the obtained crystals are recrystallized from a mixture of n-hexane and diethyl ether, mp136-2-methyl-
Yellow crystals (417.1-3) of 4-(2-chlorophenyl)-6-cyano 1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are obtained.

[1}-■ 2-methyl-4-(2-chlorophenyl)
1-6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (377.8 females), sodium chloride (125 females), hydroxylamine hydrochloride (
A mixture of 79.93 of 9) and odoric acid (1.5 of) is heated to reflux for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and insoluble matter was removed in an oven.

The filtrate was washed successively with water, sodium bicarbonate, water and then a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was removed. Diethyl ether is added to the residual liquid, the insoluble powder is removed by a furnace, and the furnace liquid is concentrated under reduced pressure. When the obtained oily substance (9 of 210) is treated with a mixture of n-hexane and diethyl ether, 2-methyl-4-(2-chlorophenyl)-6-cyano-1,4-dihydropyridine-3,5 is obtained.
- Obtain crystals of dicarboxylic acid diethyl ester (9 of 154.1).

This substance was identified using a specimen. {11-(31 2-
Methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (377.8-2), sodium dinate (1
After heating a mixture of 25-9), hydroxylamine hydrochloride (79.93-9) and sulfuric acid (1.5 [)] at room temperature for 5 minutes, acetic anhydride (0.2) was added and the mixture was heated at room temperature. Stir for 20 minutes, then heat under reflux for 1 hour.

Add water to the reaction solution and extract with ethyl acetate. The extract is washed successively with aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. When the obtained brown oily substance (0.41 μm) is treated with a mixture of diethyl ether and n-hexane, a yellow powder of 2-methyl-4-(2-chlorophenyl)-16-cyano-1,4-dihydropyridine-305-dicarboxylic acid diethyl ester is obtained. (207 females) were obtained.

This substance was identified using a specimen. {1)-{4) 2-
Methyl-4-(2-chlorophenyl)-6-formyl-
104-dihydropyridine-305-dicarboxylic acid diethyl ester (377.8 double 9), sodium acetate (1
A mixture of 64-9), hydroxylamine hydrochloride (80-9) and acetic acid (1.5') was stirred at room temperature for 30 minutes, then acetic anhydride (0.2) was added and the mixture was stirred at room temperature for 1 hour. The mixture is then heated under reflux for an additional hour.

Water was added to the reaction solution, extracted with ethyl acetate, and the extract was diluted with water and
After washing successively with aqueous sodium bicarbonate and then water, dry over magnesium sulfate and concentrate under reduced pressure. When the obtained yellow oily substance (9 of 410) was treated with n-hexane, 2-methyl-4-(2-chlorophenyl)-6-cyano1
Crystals of diethylester 04-dihydropyridine-315-dicarboxylate (342.4-9) are obtained. This substance was identified using a specimen. ■ 2-Methyl-4-(2nitrophenyl)-6-formyl-IQ4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (2.0
3 evenings), sodium acetate (9 of 861.4), hydroxylamine hydrochloride (417 females) and acetic acid (15 of [)]
After the mixture was stirred at room temperature for 30 minutes, acetic anhydride (1') was added, and the mixture was heated at room temperature for 90 minutes and then heated under reflux for an additional hour.

After removing the acetic acid under reduced pressure, water was added to the reaction mixture, the pH was adjusted to 7 with sodium bicarbonate, and the mixture was extracted with diethyl ether. The extract is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is subjected to silica gel column chromatography using an elution solvent (benzene:ethyl acetate=4:1). When the obtained oily substance (1.7 night) was treated with a mixture of diethyl ether and n-hexane and the crystals obtained (1.5 night) were recrystallized from a mixture of diethyl ether and n-hexane, mp126-127.5 was obtained.
Crystals (1.23 poly) of 2-methyl-4-(2-nitrophenyl)-6-cyano-1,4-dihydropyridine-315-dicarboxylic acid diethyl ester are obtained at a temperature of 1.23 °C. [3
}1[11 2-Methyl-4-(2-trifluoromethylphenyl)-6-hydroxyiminomethyl-114-dihydropyridine-3,5-dicarboxylic acid diethyl ester (0.49 m) and thionyl chloride (1. 5
Incubate a solution of dry diethyl ether (1.5') for 30 min at room temperature.

The reaction solution is concentrated, water is added to the residue, and then extracted with ethyl acetate. After washing the extract with water, dry it with magnesium sulfate,
Concentrate under reduced pressure. The obtained oil (0.39 mm) was purified by silica gel column chromatography using an eluent (benzene: ethyl acetate = 5:1), and then treated with n-hexane to give a yellow powder. (2 of 50) is obtained. When this is recrystallized from a mixture of diethyl ether and n-hexane, mp140-143 is 2-methyl-4 of C.
Crystals of -(2-trifluoromethylphenyl)-6-cyano-104-dihydropyridine-3,5-dicarboxylic acid diethyl ester are obtained. [3'-1'21 2-Methyl-4-(2-trifluoromethylphenyl)-6-formyl-114-dihydropyridine-315-dicarboxylic acid diethyl ester (1.09 poly), N・N'-dicyclohexylcarbodiimide ( A mixture of 1.319 minutes) and pyridine (5 hours) is heated to reflux for 6.5 hours.

After distilling off the pyridine, dilute hydrochloric acid was added to the mixture, stirred for 10 minutes, and then extracted with ethyl acetate. Insoluble materials are removed from the furnace, and the furnace solution is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained brown oil (1.09 pm) is purified by silica gel column chromatography using an eluent (benzene: ethyl acetate = 10:1) and crystallized by treatment with n-hexane. After collecting the precipitate in a furnace and washing it with n-hexane, the obtained yellow powder (9 of 610) was recrystallized from a solution of diethyl ether and n-hexane, resulting in mp14.
Crystals of 2-methyl-4-(2-trifluoromethylphenyl)-6-cyano-114-dihydropyridine-3,5-dicarboxylic acid diethyl ester of 0-14300 are obtained. (3'-[3} 2-methyl-4-1(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (205.7 o), sodium acetate (82 females), hydroxylamine hydrochloride (9 of 40) and acetic acid (1.5
After the mixture of [) was stirred at room temperature for 30 minutes, acetic anhydride (0.1M) was added, and the mixture was stirred at room temperature for 1. After heating for an hour, the mixture was heated under reflux for an additional hour.

Water was added to the reaction solution, extracted with ethyl acetate, and the extract was diluted with water and
After washing successively with aqueous sodium bicarbonate and then water, drying over magnesium sulfate and concentrating under reduced pressure. The obtained oily substance (201 female) was dissolved in an elution solvent (benzene: ethyl acetate = 5
:1) was purified by silica gel column chromatography, and the obtained oily substance (9 of 172.4) was treated with n-hexane to yield 2-methyl-4-(2-trifluoromethylphenyl). -6-cyano-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester powder (11 & 9) is obtained. This substance was identified using a standard specimen. [4,2-Methyl-4-(2-chloro-5-nitrophenyl)-6-formyl-1,4-dihydropyridine-315-dicarboxylic acid diethyl ester (3.70
After heating a mixture of sodium acetate (1.436 mm), hydroxylamine hydrochloride (695 grade) and acetic acid (36 [)] at room temperature for 2.5 hours, acetic anhydride (2 [
), stirred at room temperature for 30 minutes, and heated under reflux for an additional 1.5 hours.

After distilling off the acetic acid, water and ethyl acetate were added to the remaining bamboo,
After washing twice with dilute aqueous sodium bicarbonate solution and then with aqueous sodium chloride solution, dry over magnesium sulfate and concentrate under reduced pressure. Diethyl ether was added to the residue, and the resulting powder (2.5 hours) was mixed with an elution solvent (benzene: ethyl acetate = 1
0:1) and subjected to silica gel column chromatography. Regarding the eluate, 1
Crystals obtained by concentrating the fraction showing spots (
9) of 450 and the crystals obtained by concentrating the fraction showing multiple spots (1.0 m) were combined and recrystallized from a mixture of benzene and ethyl acetate to obtain mp204.5-20.
Crystals of 2-methyl-4-(2-chloro-5-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarbosic acid diethyl ester of 5.90 (657
9) is obtained. (5'1'1)2-Methyl-4-1(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-
Carboxylic acid 2-(N-benzyl-N-methylamino)
Ethyl ester (0.91 min), N-N'-dicyclohexylcarbodiimide (0.7 min) and pyridine (
The mixture of [) in step 5 is heated under reflux at room temperature for 3 hours.

After removing pyridine under reduced pressure, water was added to the residue and extracted with ethyl acetate. The unfiltered substances are removed from the furnace, and the furnace liquid is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained red oily substance (1.6 days) was purified by silica gel column chromatography using an eluent (benzene: ethyl acetate = 2:1) to give a red oily 2-methyl-4-(
2-(N-penzyl-N-methylamino)ethyl ester (0.Wakita) of 3-nitrophenyl)-5-ethoxycarbonyl-6-cyano 1,4-dihydropyridine-3-carboxylic acid is obtained.

Infrared absorption spectrum (Nujol) 3320, 3250 (sh), 2240, 1708, 1
685, 1525, 1500, 1345, 1293, 1
210, 1100, 103078i73fu700ka-1
Nuclear magnetic resonance absorption spectrum (6, CDC13) 1,25
(Group, t, J=7HZ), 2,15 (thin, s), 2.3
9 (dark blue, s), 2.62 (but, t, J=7HZ), 3.
48 (ga, s), 3.9-4.3 (fly, q (CH2C), t (COOCH2C ratio N)), 5.26 (IH, s
), 7.1-8.2 (1 Cape, m) Add ethyl hydrochloric acid to a solution of the compound obtained above dissolved in diethyl ether and concentrate.

The residual liquid is powdered with n-hexane, and the powder is collected in a furnace. When this is recrystallized from aqueous ethanol, mp228-229
00 2-methyl-4-(3-nitrophenyl)-5-
Yellow crystals (46
0. &9) is obtained. [51 monopod 2-methyl-4-(3
-Nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-benzyl 2-(N-benzyl-N-methylphenylamino)ethyl ester (253.8 p), sodium acetate (82
9) After stirring a mixture of hydroxylamine hydrochloride (40 o) and acetic acid (1) for 30 minutes at room temperature,
Add acetic anhydride (0.1') and stir at room temperature for 1 hour, then heat to reflux for an additional hour. Water was added to the reaction solution, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with an aqueous sodium bicarbonate solution and then with water, dried over magnesium sulfate, and concentrated under reduced pressure to give an oily 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-104-dihydropyridine-3-carpon. The 2-(N-penzyl-N-methylamino)ethyl ester of the acid (250 females) is obtained. This substance was identified using a specimen.

2-ethoxycetyl ester of 2-methyl-4-(3-nitrophenyl)-5-ethoxycarponyl-6-formyl-114-dihydropyridine-3-carboxylic acid (3.

00 min), sodium acetate (1.1382 min), hydroxylamine hydrochloride (0.5547 min) and acetic acid (1
A mixture of 0 [)] was stirred at room temperature for 30 minutes, and then acetic anhydride (1.

4) was added, stirred at room temperature for 1 hour, and heated under reflux for an additional hour.

After acetic acid was distilled off under reduced pressure, water was added to the residue, neutralized with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract is washed with water and then with a saturated aqueous solution of sodium chloride, and then concentrated under reduced pressure. The obtained yellow oily substance is subjected to silica gel column chromatography using an elution solvent (benzene:ethyl acetate=5:1) to obtain a yellow oily substance (1.74 yen) from the fraction containing the target substance.

This oily substance becomes a crystal (1.56). When this is recrystallized from benzene, the mp89-2-methyl-4
Yellow powder (1 .5 evening). When this powder was recrystallized from a mixture of diethyl ether and n-hexane, the mpl15 plateli was converted to 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylic acid. Crystals of 2-ethoxychetyl ester are obtained. '
7} 2-methyl-41(3-nitrophenyl)-6-
Formyl-114-dihydropyridine-3,5-dicarboxylic acid diethyl ester (1.9418 mm), sodium acetate (820 females), hydroxylamine hydrochloride (39
After heating a mixture of 9.6 mm) and acetic acid (7.5 mm) at room temperature for 30 minutes, acetic anhydride (1 mm) was added, heated at room temperature for 1 hour, and then heated under reflux for an additional hour.

After removing the acetic acid and adding water to the residue and neutralizing it with a saturated aqueous sodium bicarbonate solution, the precipitated oily substance is extracted with ethyl acetate.The extract is washed with an aqueous sodium chloride solution, dried, and the solvent is removed under reduced pressure. The resulting light yellow oily substance (
2.0103) crystallizes and recrystallizes it from a solution of diethyl ether, ethyl acetate and n-hexane to give a yellow powder. This powder was mixed with benzene (5 parts) and ethyl acetate (1 part) to avoid contamination with a small amount of residual impurities.
The solution is filtered through silica gel and the solution is concentrated. When the obtained crystals (1.02 poly) were recrystallized from a mixture of benzene and diethyl ether, mp1
2-Methyl-4-(3-nitrophenyl)-6-cyano-114-dihydropyridine-3.5 at 74-177°C
- yellow granular crystals of dicarponic acid diethyl ester (0.8
479 evenings).

[8] In the same manner as in Example 4-■, 2-methyl-4-(
2-penzyloxyethyl ester of 1-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid (2.0), sodium acetate (9 of 662.9), hydroxylamine Crystals (767 females) from a mixture of hydrochloride (336.9 pine 9) and acetic acid (15 chloride) and acetic anhydride (1.5')
get.

When this was recrystallized from a mixture of benzene and diethyl ether, the 2-benzyloxyethyl ester of 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylic acid was obtained. Yellow crystals (450 female) (further recrystallized from diethyl ether and n-hexane yielded mp139-140
00) is obtained. ■ Example 4-{2
2-ethoxyshethyl ester of -methyl-4-(2nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid (90
2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl from a mixture of sodium acetate (milk 1), hydroxylamine hydrochloride (9 of 167) and acetic acid (7) and acetic anhydride (1) -6-cyano 1・
Crystals of 2-ethoxy Z ethyl ester of 4-dihydropyridine-3-carboxylic acid (42 product 9) (recrystallized from diethyl ether and n-hexane, mp129.5-13
0.5qo) is obtained.

Example 5 (11 2-methyl-4-(2-chlorophenyl)-6
- Formyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (1.5 parts of ethanol (3 parts)
Sodium borohydride (15') solution under rope pestle
Add 5 o) and stir at room temperature for 2 hours.

The reaction solution was made acidic with dilute hydrochloric acid, the solvent was removed, water was added to the residue, and the mixture was extracted twice with ethyl acetate. After washing the extract with water and drying, the solvent was removed under reduced pressure to obtain a red oily substance (1.3
525) was dissolved in diethyl ether and then allowed to stand at room temperature. If the insoluble matter is separated in a furnace and the furnace liquid is left to stand, crystals will gradually precipitate. When this was taken in a furnace and recrystallized from a mixture of diethyl ether and n-hexane, diethyl 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate of mp14y0 was obtained. Obtain crystals of Stell (9 of 92.0). '2)
Methanol (15
Gradually add sodium borohydride (46.9) to the solution in [2] under an ice-cold lamp, and let the lamp stand under the ice for 35 minutes.

The reaction solution was neutralized with hydrochloric acid and heated under reduced pressure for 30 minutes.
The solvent is removed at a temperature below midnight. The residue is adjusted to pH 7-8 by adding water and a small amount of aqueous sodium bicarbonate solution, and upon standing, a white powder is obtained. This was dried in a furnace, and the resulting powder (395.0 female) was added to the powder (395.0 females) containing jethyl ether (20 secretions).
Add and incubate at room temperature for 30 minutes. The precipitated white insoluble matter is filtered out and washed with diethyl ether. When the washing liquid and furnace liquid are combined and the solvent is removed at a relatively low temperature, mp145-14
7q0 2-methyl-4-(2-chlorophenyl)-6
-(1-Hydroxyethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester crystals (1
00.5 evening). [3} 2-methyl-4-(2
-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (2
．． Sodium borohydride (0.1892 mm) was gradually added to an ethanol (29') solution of 0.0881 mm) under clear water and allowed to stand at room temperature for 1 hour.

The reaction solution was made acidic with dilute hydrochloric acid, heated for 30 minutes at room temperature, and then filtered. The white insoluble matter (329.7mc) was separated in a furnace, the furnace liquid was concentrated under reduced pressure and extracted with ethyl acetate, the extract was washed with water and dried, and the solvent was distilled off. The resulting light-colored oily substance (1.8
596 yen) was dissolved in ethanol, and the impregnable matter (337.7 yen) was dissolved in ethanol.
(female) is separated in a furnace, the furnace liquid is concentrated under reduced pressure, and the oily residue is left to stand for 3 days to obtain crystals. When this is recrystallized from diethyl ether, 2-methyl- of mpl12-11 Mori○ is obtained.
4-(2nitrophenyl)-6-hydroxymethyl-
Crystals of 1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are obtained. [4} 2-Methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-, 0-5 in an ethanol (10') solution of 3,5-dicarboxylic acid diethyl ester (233 female)
Add sodium borohydride (22.7M) to the suspension at 0-5°C for 1 hour and 10 minutes.

The reaction solution was adjusted to the size of 4-5 seedlings with 0.1N hydrochloric acid, and the solvent was distilled off under reduced pressure. The residue is extracted with ethyl acetate, the extract is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure.
When Isosasa is treated with a mixture of diethyl ether and n-hexane and the obtained crystals are recrystallized from a mixture of diethyl ether and n-hexane, 2-methyl-4-(3-nitrophenyl)-6-hydroxy with a temperature of mp141-142.5℃ is obtained. Crystals of methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (152c) are obtained. '5
'2-Methyl-4-(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3.
To a solution of 5-dicarboxylic acid diethyl ester (1.0 ml) in ethanol (20 ml) under ice-cold water, gradually add sodium borohydride (Shinobu O) and stir for an additional 25 minutes.

The reaction solution was adjusted to a speck of 4-5 with 0.1N hydrochloric acid, and the solvent was removed under reduced pressure at a relatively low temperature. Water was added to the remaining groove, the obtained crystals (1.2 hours) were collected in a furnace, and recrystallized from a solution of diethyl ether and n-hexane, resulting in mp147-14.
8.5 square crystals of 2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are obtained. {6} 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1
・To a solution of 2-ethoxyethyl ester of 4-dihydropyridine-3-carboxylic acid (1.132) in ethanol (above 15) was added sodium borohydride (80 Ng) under ice for 1 hour. Worship flies.

The reaction solution was adjusted to pH 6 with diluted hydrochloric acid under ice cooling, and the solvent was distilled off under reduced pressure. Water is added to the residue, extracted with diethyl ether, and the extract is washed with water and dried over magnesium sulfate. The solvent was removed, and the resulting oil was crystallized by treatment with n-hexane, and then recrystallized from a mixture of diethyl ether and n-hexane to give 2-methyl-4- with mp99-100q0.
(3-nitrophenyl)-5-ethoxycarbonyl-6
-Hydroxymethyl-114-dihydropyridine-3-
Crystals of 2-ethoxychetyl ester of carboxylic acid (90
0 copies). (71 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-
2-(N of 1,4-dihydropyridine-3-carboxylic acid
-Methyl-N-benzylamino)ethyl ester (1.
Sodium borohydride (112-2) was added to the ethanol (15 liters) solution of 20 minutes under ice and soaked under ice for 20 minutes.

The reaction solution was covered with 0.1N hydrochloric acid under ice cooling and concentrated under reduced pressure. Water and ethyl acetate are added to the residue, and the aqueous solution is further washed twice with ethyl acetate. Combine the extract and washing liquid,
After washing with water and drying with magnesium sulfate, the solvent was removed under reduced pressure to obtain oily 2-methyl-4-(3-nitrophenyl).
-5-ethoxycarponyl-6-hydroxymethyl-1
2-(N-) of 14-dihydropyridine-3-carboxylic acid
Methyl-N-benzylamino)ethyl ester (1.4
8 evenings). Infrared absorption spectrum (film) 3390, 1730, 1680, 1650, 1600,
1520, 14601345, 1200, 1100, 1
025, 900, 780,? 40700 Ka-1 nuclear magnetic resonance absorption spectrum (6, CDC130D20) 1.2 (
Spot, t, Ji7HZ), 2.2 (thin, s), 2.38 (
3 days, s), 2.66 (2 days, t, J=6HZ), 3,
53 (ga, s) "3.97-4,26 (4th, m),
5.14 (IH, s), 7.28-815 (1 plate, m)
Dissolve the oily substance obtained above in diethyl ether,
Add 21% ethanolic hydrochloric acid (9 of 225).

The precipitated oily substance is washed several times with diethyl ether and powdered using the gentle method, resulting in 2-(N-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-114-dihydropyridine-3-carboxylic acid). The hydrochloride of N-benzylamino)ethyl ester is obtained. This stuff starts to decompose at 8pm and turns brown. Example 6 {112-methyl-4-(2-chlorophenyl)-6-
Hydroxymethyl-114-dihydropyridine-305
A dry pyridine solution of dicarboxylic acid diethyl ester (759.7 o) was added with acetic acid chloride (313 o) under an ice-cooled slurry.
．． Add the methylene chloride solution of 5-9) dropwise, and leave at room temperature overnight.

The solvent is distilled off, water is added to the remaining bamboo, made weakly acidic with dilute hydrochloric acid, and then extracted with diethyl ether. The extract is washed with a saturated aqueous sodium chloride solution and then with water, dried, and the solvent is removed. The resulting viscous oily substance crystallizes when left to stand, and is washed with n-hexane to give the resulting crystals (0
．． Recrystallization of 2-methyl-41 of mp98qo from a mixture of diethyl ether and n-hexane
2-chlorophenyl)-6-acetoxymethyl-114
-Dihydropyridine-3,5-dicarboxylic acid diethyl ester crystals are obtained. ■ To a mixture of 3-(N-methyl-N-pendylamino)propionate sodium salt (2.0 minutes) and diethyl ether (40 minutes) was added thionyl chloride (10 points) under an ice-cold lamp, and the mixture was stirred at room temperature for 3 hours. After heating and refluxing for 2 hours, the mixture is concentrated under reduced pressure.

The resulting suspension of 3-(N-methyl-N-benzylamino)propionic acid chloride in methylene chloride (5') was added to 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine. -3,5-dicarboxylic acid diethyl ester (0.76 m) was dissolved in pyridine (
Add to the solution in step 5 () under an ice-cold rope pestle and keep the rope under ice for 1 hour. The solvent was removed under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract is washed with water, dried, and then the solvent is distilled off. The obtained brown oil (1.55%) was subjected to silica gel column chromatography using an eluent (benzene: ethyl acetate; 2:1), and the obtained oil was left overnight to obtain crystals. This was washed with n-hexane and recrystallized from a mixture of diethyl ether and n-hexane to give 2-methyl-41 (mp 86-87°C).
2-chlorophenyl)-6-[3-(N-methyl-N-benzylamino)propionyloxymethyl]-1,4
-Dihydropyridine-3,5-dicarboxylic acid diethyl ester crystals are obtained. [3} 2-Methyl-4-(2nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (2.352) in a solution of pyridine (30) under ice-cooling. Over a period of 7 minutes, a solution of acetic acid chloride (942-2) in methylene chloride (5) was added dropwise, and the mixture was allowed to stand at room temperature for 70 minutes.

The solvent was evaporated under reduced pressure, ethyl acetate was added to the residue, and the residue was washed twice with water, washed with hydrochloric acid, washed with an aqueous sodium chloride solution, and dried. The solvent is removed under reduced pressure and the resulting oil is crystallized by treatment with a solution of diethyl ether and a small amount of n-hexane. Next, the crystals collected in the furnace (2.5 nights) were washed with n-hexane and recrystallized from diethyl ether to yield 2-methyl-4-(2-nitrophenyl)-6-acetoxymethyl-1,4-dihydropyridine with mp89-90CO. -3,5-dicarboxylic acid diethyl ester crystals (1.78 min.) were obtained.

(41 2-methyl-4-(3nitrophenyl)-6
-Hydroxymethyl-1,4-dihydropyridine-3.
A solution of 5-dicarboxylic acid diethylester (1.95 μm) in dry pyridine (25 μm) was added to a solution of acetic acid chloride (785 μm) in methylene chloride (5 μm) under ice-cold water.
Add the solution dropwise and let stand at room temperature for 50 minutes.

The solvent is removed, and the residual light is dissolved in ethyl acetate, washed five times with water and then with an aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was distilled off, and the resulting red oil (2.47 nights) was crystallized by treatment with diethyl ether, washed with n-hexane, and the crystals (2 nights) were collected in a furnace.
This is dissolved in diethyl ether, treated with silica gel, and the solution is concentrated under reduced pressure. When the crystalline residue is recrystallized from a solution of diethyl ether and n-hexane, mp1 is obtained.
Crystals of 2-methyl-4-(3-nitrophenyl)-6-acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of 33-1360 (1
．． 45 evenings). [5] Pyridine of 2-(N-methyl-N-benziamino)ethyl ester (630M) of 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylic acid (630M) Add acetic acid chloride (9 of 146) to methylene chloride (9 of 146) in ice-cooled solution of [10].
Add the solution of step 3) and incubate at 50-60°C for 2 hours.

The solvent was distilled off, water and ethyl acetate were added to the residue, and the aqueous layer was then adjusted to pH 4. The organic layer is separated, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained oily substance (800 o) was dissolved in an elution solvent (benzene:ethyl acetate=
When purified by silica gel column chromatography using 2:1), an oily 2-methyl-41(3-nitrophenyl)-5-ethoxycarbonyl-6-acetoxymethyl-1,4-dihydropyridine-3-carbonyl was obtained. The 2-(N-methyl-N-benzylamino)ethyl ester (9 of 620) of the acid is obtained. Infrared absorption spectrum (film) 3370, 1747, 1690, 1650, 1615,
1530, 14801350121 1100, 104
Fu 740, 700Nuclear magnetic resonance absorption spectrum (6,
CDC130D20) 1.18 (3 days, t, J = 7H
Z), 2.18 (thin, s), 2.36 (thin, s), 2.
6 (bait, t, J: 6HZ), 3.5 (ga, s), 4.0
6 (bait, q, J!7HZ), 4.15 (2 days, t, J
=6HZ), 5.13 (IH, s), 5.31 (but, s
), 6.7 (IH, m), 7.23-8,08 (bait, m
) A solution of maleic acid in diethyl ether was gradually added to a solution of the oily substance obtained above (580 bars) dissolved in diethyl ether, and the precipitated oily substance was separated and washed twice with diethyl ether using the Rishiya method. When powdered with n-hexane, 2-methyl-41 (
3-nitrophenyl)-5-ethoxycarbonyl-6-
A powder (405M) of maleate of 2-(N-methyl-N-pendylamino)ethyl ester of acetoxymethyl-1,4-dihydropyridine-3-carboxylic acid is obtained.

(6) 2-methyl-4-(2-nitrophenyl)-6
-Hydroxymethyl-1,4-dihydropyridine-3.
A methylene chloride solution of P-chlorophenoxyacetic acid chloride (3.07 yen) was added dropwise to a solution of pyridine (25) of 5-dicarboxylic acid diethyl ester (1.95 yen) over 5 minutes. , cool to 2-0 with water and soak overnight. Remove the solvent, add water to Isotaka, and extract with ethyl acetate. Adjust the extract to pH 4-5 with diluted hydrochloric acid, and then add 30% with water.
It is then washed twice with aqueous sodium bicarbonate solution, dried and the solvent is removed. The obtained oily substance (4.75 minutes) was purified by silica gel column chromatography using an eluent (benzene:ethyl acetate=1031) to give an oily 2-methyl-41(2nitrophenyl)1. 6-
(4-chlorophenoxy)acetoxymethyl-1,4-
Dihydropyridine-3,5-dicarboxylic acid diethyl ester (2.65 hours) is obtained. This crystallizes when left in a cold place, and when recrystallized from a mixture of diisopropyl ether and ethanol, yellow granular crystals with mp86-8 of 0 are obtained. Nuclear magnetic resonance absorption spectrum (8, CDC13020>1
．． 13 (string, t, J=7HZ), 2.2 (spot, s), 4
．． 03, 4.08 (4th, q, J=7Hz), 4.73
(2nd, s), 5.43 (2nd, s) "5. Ori (IH
, s), 6.53 (IH, broad s), 6.76
-7.83 (spots, m) Example 7 '1-2-Allyloxybenzaldehyde (811), 4,4-ditoxyacetoacetic acid ethyl ester (1
Add acetic acid (0.36 mm) to a mixture of 2.00 mm) and benzene (approx. After adding in portions, the mixture was heated under reflux for 2.5 hours.

The reaction solution was cooled to room temperature, benzene (50%) was added thereto, washed with water three times, and dried over magnesium sulfate. The solvent was distilled off, and 3-aminocrotonate ethyl ester (8.56 pm) was added to the red oily residue, and the mixture was heated at 55-60°C for 6. 105-107 for an additional 2 hours at 72-75°C.
0 and 2. Insect Time Toyo.

The reaction solution was dissolved in an elution solvent (methylene chloride: acetone = 25:1
) to obtain an oily substance (19.38 pm). Part of it (3.0
Further, the elution solvent (benzene: ethyl acetate = 20:
Purification by silica gel column chromatography using 1) yields oily 2-methyl-4-(2-allyloxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid. Obtain Jetilester (1.7W). Infrared absorption spectrum (IJ Kid) 3430, 1695, 1650, 1618, 149
0, 1371, 128 and above 1095930760 Ka-1 nuclear magnetic resonance absorption spectrum (8, CDCWI.0-1.5
(1 is m), 2.28 (spot, s), 3.4-4.3 (
Chihito, m), 5.35 (IH, s), 6.17 (IH,
s), 4. Fu 5-5.05.7-6.4 (group, m),
6.5-7.4 (spot, m) t2) 2-methyl-4-(
2-allyloxyphenyl)-6-diethoxymethyl-
To a solution of 1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (1.5 min) in acetone (15 min), carp-hydrochloric acid (1.5 min) was added by dropping a fly, and the mixture was incubated at room temperature for 1 hour and 48 minutes. do.

When the solvent is distilled off and water is added to the solenoid, a yellow suspension with an oily substance precipitated out is obtained, and this oily substance immediately solidifies.
This was left to stand for 10 minutes, the solid matter was taken out in an oven, washed with water, dried, and recrystallized from a mixture of diisopropyl ether and acetone.
Light yellow granular crystals of diethyl ester of monoallyloxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid are obtained. [31 2-methyl-4-
(2-allyloxyphenyl)-6-formyl-1,4
-Dihydropyridine-3,5-dicarboxylic acid diethyl ester (4.53 evening), hydroxylamine hydrochloride (8
A mixture of 66.9 of 9), sodium acetate (1.2093 m) and acetic acid is stirred at room temperature for 1 hour.

Add acetic anhydride (3.5 kites) to this and make 3
Worship for hours. After distilling off the acetic acid under reduced pressure, the residue is neutralized with aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The extract is washed twice with water and then dried. The solvent is distilled off and the resulting brown oily residue immediately crystallizes. This was powdered with diisopropylether and turned into a yellow powder (3.21 evening).
When recrystallized from 90% meta/-nore, mp143 was obtained.
-1490-2-methyl-4-(2-allyloxyphenyl)-6-cyano1,4-dihydropyridine-3.
Light yellow crystals of 5-dicarboxylic acid diethyl ester are obtained. {41 2-methyl-4-(2-allyloxyphenyl)-6-formyl-1,4-dihydropyridine-3.
Sodium borohydride (4452 female) was gradually added to a solution of 5-dicarboxylic acid diethyl ester (4.70 ml) in ethanol (100 ml) at 4°C under ice-cooling at 4°C.
1.5 hours of rope worship.

The reaction solution was made acidic with 50% acetic acid, ethanol was distilled off, water was added to the residue, and the mixture was heated for 10 minutes. The precipitated powder was collected in a furnace and washed with water to obtain crystals (4.49 yen), which were recrystallized from methanol to yield 2-methyl-4-(2-allyloxyphenyl)-6-hydroxy with mp124-12 of o. Yellow crystals of methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are obtained.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. , R_2 and R_3
are the same or different alkoxycarbonyl group, alkoxyalkoxycarbonyl group, aralkoxyalkoxycarbonyl group or N-alkyl-N-aralkylaminoalkoxycarbonyl group, R_4 is a cyano group or hydroxy, unsubstituted lower alkanoyloxy, lower alkoxyimino, Contains a 1,4-dihydropyridine derivative represented by an alkyl group substituted with oxo, N-alkyl-N-aralkylamino lower alkanoyloxy or monohaloaryloxy lower alkanoyloxy, and R_5 means an alkyl group, respectively. A vasodilator and antihypertensive agent.