KR790001064B1 - Process for preparing unsymmetrical esters of 1,4-dihydropyridine dicarboxylic acid - Google Patents

Abstract

Fifty-three title compds. (I; R = e.g., m-O2-NC6H4, 2,5-Cl(O2N)C6H3, O-NCC6H, or 2-pyridyl; R1, R3 = Me; R2 = e.g., Me or Me2CH; R4 = e.g., Et, CH2; CHCH2, Me OCH2CH2, or cyclohexyl), useful as cornary dilators, antihypotensives, spasmolytics, and drugs against cardiac fibrillation, were prepd. in 24-78% yield by reaction of RCH:C(COMe) CO2R2 with MeCOCH2COOR4 and NH3 in H2O or alcs as thickener.

Description

[Name of invention]

Method for preparing asymmetric 1,4-dihydropyridine dicarboxylic acid ester compound

Detailed description of the invention

The present invention relates to a method for producing a novel asymmetric 1,4-dihydropyridine dicarboxylic acid ester represented by the following general formula (1).

Food,

R is a substituent having at least one nitro, nitrile, azido or -SOn-alkyl group wherein n is 0, 1 or 2 and optionally a phenyl group having at least one alkyl or alkoxy group or halogen atom , In this case, the maximum total number of substituents that R can have is 3); Or a naphthyl, quinolyl, isoquinolyl, pyridyltenyl, furyl or pyryl group which may have at least one alkyl or alkoxy group or a halogen atom as a substituent;

R ¹ and R ³ are the same or different and each represent a hydrogen atom or a linear or branched alkyl group;

R ² and R ⁴ represent different straight, branched or cyclic saturated or unsaturated hydrocarbon groups,

Each carbon chain may be interrupted by one or two oxygen atoms and may have one hydroxyl group as a substituent.

Benzylidene acetoacetic acid ethyl ester is reacted with β-aminocrotonic acid ethyl ester or acetoacetic acid ethyl ester with ammonia to give 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester. It is already known that K can be obtained (Knoevenagel, Ber. 31, 743 (1898)). Symmetric dihydropyridine has been prepared by this method but the asymmetric esters of 1,4-dihydropyridine are not yet known.

Compounds prepared according to the present invention exhibit strong coronary action and anti-hypertension.

The present invention reacts the iriden-β-ketocarboxylic acid ester represented by the general formula (2) with an enaminocarboxylic acid ester represented by the general formula (3) in water or an inert organic solvent as a diluent, or ammonia and general formula (4 It provides a method for producing an asymmetric 1, 4-dihydropyridine dicarboxylic acid ester compound represented by the general formula (1) by reacting with β-ketocarboxylic acid ester represented by the formula (1).

Food,

[R, R ¹ , R ² , R ³ , and R ⁴ are as described above.]

Asymmetric compounds prepared according to the invention surprisingly show higher coronari-extension than the known symmetric 1, 4-dihydropyridine. Therefore, the compounds of the present invention represent an advance in the pharmaceutical field.

The reaction scheme of the process of the present invention using 3′-nitrobenzylideneacetoacetic acid methyl ester and β-aminocrotonic acid isopropyl ester as starting materials is as follows.

In particular in formulas (1), (2), (3) and (4) R is one or more nitro, nitrile, azido and SO _n -alkyl groups (n = O-2), in particular by means of nitro or nitrile groups Phenyl groups which are monosubstituted or double substituted, and in any case additionally one or more alkyl, alkoxy or halogen, preferably halogen, in particular substituted by chlorine, in which case the maximum total number of substituents is 3, 1 or Two are particularly preferred), or naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, tenyl, furyl, or pyryl groups optionally substituted by alkyl, alkoxy or halogen; Alkyl and alkoxy groups substituted in R are suitably containing 1-2 carbon atoms and halogens are fluorine, chlorine, and bromine. The above-mentioned pyridyl, pyryl, tenyl and furyl groups are particularly preferably substituted with alkyl groups having the same 1-2 carbon atoms, and the pyrimidyl group may be optionally substituted with 1-2 methoxy or epoxy groups.

R ¹ and R ³ are the same or different and preferably represent a straight or branched chain alkyl group, especially a methyl group, having hydrogen or 1-4 carbon atoms. R ² and R ⁴ are always different from each other and preferably represent straight, branched or cyclic saturated and unsaturated hydrocarbon groups each having 1-6 carbon atoms, in particular an aliphatic hydrocarbon chain having 1-3 carbons. The chain is in some cases interrupted by 1-2 oxygen atoms, in particular 1 oxygen atom, or substituted by hydroxyl groups.

Starting materials that can be used in the present invention are already known and can be prepared by well-known methods, and the following can be illustrated.

a) iriden-β-ketocarboxylic acid esters

2'-nitrobenzylideneacetoacetic acid methyl ester,

2'-nitrobenzylideneacetoacetic acid ethyl ester,

3'-nitrobenzylideneacetoacetic acid methyl ester,

3'-nitrobenzylideneacetoacetic acid ethyl ester,

3'-nitrobenzylideneacetoacetic acid isopropyl ester,

2'-cyanobenzylideneacetoacetic acid methyl ester,

2'-cyanobenzylideneacetoacetic acid ethyl ester,

2'-cyanobenzylideneacetoacetic acid propyl ester,

2'-cyanobenzylideneacetoacetic acid allyl ester,

4'-nitrobenzylideneacetoacetic acid methyl ester,

3'-cyanobenzylideneacetoacetic acid ethyl ester,

3'-cyanobenzylideneacetoacetic acid propargyl ester,

4'-cyanobenzylideneacetoacetic acid ethyl ester,

3'-nitro-4'-chlorobenzylideneacetoacetic acid tert-butyl ester,

3'-nitro-4'-chlorobenzylideneacetoacetic acid isopropyl ester,

3'-nitro-6'-chlorobenzylideneacetoacetic acid cyclohexyl ester,

3'-nitro-6'-chlorobenzylideneacetoacetic acid ethyl ester,

3'-nitro-4'-methoxybenzylideneacetoacetic acid methyl ester,

2'-nitro-4'-methoxybenzylideneacetoacetic acid methyl ester,

2'-cyano-4'-methylbenzylideneacetoacetic acid ethyl ester,

2'-azidobenzylideneacetoacetic acid methyl ester,

2'-azidobenzylideneacetoacetic acid ethyl ester,

3'-azidobenzylideneacetoacetic acid propargyl ester,

4'-azidobenzylideneacetoacetic acid methyl ester,

4'-methylmethcaptobenzylideneacetoacetic acid ethyl ester,

2'-methylmethcaptobenzylideneacetoacetic acid ethyl ester,

2'-sulfinylmethylbenzylideneacetoacetic acid methyl ester,

2'-sulfonylmethylbenzylideneacetoacetic acid isopropyl ester,

4'-sulfonylmethylbenzylideneacetoacetic acid ethyl ester,

(1'-naphthylidene) -acetoacetic acid methyl ester,

(1'-naphthylidene) -acetoacetic acid ethyl ester,

(2'-naphthylidene) -acetoacetic acid ethyl ester,

2'-ethoxy- (1'-naphthylidene) -acetoacetic acid methyl ester,

2'-methoxy- (1'-naphthylidene) -acetoacetic acid ethyl ester,

5'-bromo- (1'-naphthylidene) -acetoacetic acid methyl ester,

(2'-quinolyl) -methylideneacetoacetic acid ethyl ester,

(3'-quinolyl) -methylideneacetoacetic acid methyl ester,

(4'-quinolyl) -methylideneacetoacetic acid ethyl ester,

(8'-quinolyl) -methylideneacetoacetic acid ethyl ester,

(1'-isoquinolyl) -methylideneacetoacetic acid methyl ester,

(3'-isoquinolyl) -methylideneacetoacetic acid methyl ester,

α-pyridylmethylideneacetoacetic acid methyl ester,

α-pyridylmethylideneacetoacetic acid ethyl ester,

α-pyridylmethylideneacetoacetic acid allyl ester,

α-pyridylmethylideneacetoacetic acid propargyl ester,

α-pyridylmethylideneacetoacetic acid cyclohexyl ester,

β-pyridylmethylideneacetoacetic acid β-methoxy ethyl ester,

β-pyridylmethylideneacetoacetic acid ethyl ester,

-피리딜메틸리덴아세토아세트산 메틸에스테르,

Pyridylmethylideneacetoacetic acid methyl ester,

6'-methyl-α-pyridylmethylideneacetoacetic acid ethyl ester,

4 ', 6'-dimethoxyl- (5'-pyrimidyl) -methylideneacetoacetic acid ethyl ester,

(2'-tenyl) -methylideneacetoacetic acid ethyl ester,

(2'-furyl) -methylideneacetoacetic acid allyl ester,

(2'-pyryl) -methylideneacetoacetic acid methyl ester,

3'-nitro-α-benzylidene propionyl acetic acid ethyl ester and

α-pyridylmethylidene propionyl acetic acid methyl ester,

b) β-ketocarboxylic acid esters,

Formyl acetic acid ethyl ester,

Acetoacetic acid methyl ester,

Acetoacetic acid ethyl ester,

Acetoacetic acid propyl ester,

Acetoacetic acid isopropyl ester,

Acetoacetic acid butyl ester,

Acetoacetic acid tert-butyl ester,

Acetoacetic acid (α-orβ-)-methoxyethyl ester,

Acetoacetic acid (α-orβ-)-ethoxyethyl ester,

Acetoacetic acid (α-or β-)-propoxyethyl ester,

Acetoacetic acid (α-orβ-)-hydroxyethyl ester,

Acetoacetic acid allyl ester,

Acetoacetic acid propargyl ester,

Acetoacetic acid cyclohexyl ester,

Propionyl acetic acid methyl ester,

Propionyl acetic acid ethyl ester,

Propionyl acetic acid isopropyl ester and

Butidyl acetic acid ethyl ester.

c). Enaminocarboxylic acid esters

β-amino crotonic acid methyl ester,

β-amino crotonic acid ethyl ester,

β-amino crotonic acid isopropyl ester,

β-amino crotonic acid propyl ester,

β-amino crotonic acid allyl ester,

α-pyridylmethylideneacetoacetic acid cyclohexyl ester,

β-pyridylmethylideneacetoacetic acid β-methoxy ethyl ester,

β-pyridylmethylideneacetoacetic acid ethyl ester,

γ-pyridylmethylideneacetoacetic acid methyl ester,

6'-methyl-α-pyridylmethylideneacetoacetic acid ethyl ester,

4 ', 6'-dimethoxy- (5' --- pyrimidyl) -methylideneacetoacetic acid ethyl ester,

(2'-tenyl) -methylideneacetoacetic acid ethyl ester,

(2'-furyl) -methylideneacetoacetic acid allyl ester,

(2'-pyryl) -methylideneacetoacetic acid methyl ester,

3'-nitro-α-benzylidene propionyl acetic acid ethyl ester and

α-pyridylmethylidene propionyl acetic acid methyl ester,

b) β-ketocarboxylic acid esters

Formyl acetic acid ethyl ester,

Acetoacetic acid ethyl ester,

Acetoacetic acid methyl ester,

Acetoacetic acid propyl ester,

Acetoacetic acid isopropyl ester,

Acetoacetic acid butyl ester,

Acetoacetic acid tert-butyl ester,

Acetoacetic acid (α-or β-)-methoxyethyl ester,

Acetoacetic acid (α-or β-)-ethoxyethyl ester,

Acetoacetic acid (α-or β-)-propoxyethyl ester,

Acetoacetic acid (α-or β-)-hydroxyethyl ester,

Acetoacetic acid allyl ester,

Acetoacetic acid propargyl ester,

Acetoacetic acid cyclohexyl ester,

Propionyl acetic acid methyl ester,

Propionyl acetic acid ethyl ester,

Propionyl acetic acid isopropyl ester,

Butidyl acetic acid ethyl ester,

c). Enaminocarboxylic acid esters

β-aminochromic acid methyl ester,

β-aminochromic acid ethyl ester,

β-aminochromic acid isopropyl ester,

β-aminochromic propyl ester,

β-aminochromic allyl ester,

β-aminochromic acid butyl ester,

β-aminochromic β-methoxy ethyl ester,

β-aminochromic β-ethoxy ethyl ester,

β-aminochromic β-propoxyethyl ester,

β-aminochromic acid tert-butyl ester,

β-aminochromic cyclohexyl ester, and

β-amino β-ethylacrylic acid ethyl ester,

Diluents which can be used in the process of the invention are water and all inert organic solvents, suitable organic solvents include alcohols such as ethanol and methanol; Ethers such as dioxane and diethyl ether, glacial acetic acid, pyridine, dimethylformamide, dimethyl sulfoxide and acetonitrile.

The reaction temperature can vary widely and is generally carried out at about 20-200 ° C., but preferably at the boiling point of the solvent. The reaction can be carried out at normal pressure, but also under high pressure, generally atmospheric pressure is used. The substances involved in the reaction in carrying out the process of the present invention were generally used in molar amounts and ammonia was adequately added to the excess.

The following are new active substances.

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

2, 6-dimethyl-4- (2'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester-5-isopropyl ester,

2, 6-dimethyl-4- (2'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester-5-methylester,

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

2, 6-dimethyl-4- (2'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester-5-β-methoxy ethyl ester,

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

2, 6-dimethyl-4- (2'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-allyl ester-5-isopropyl ester,

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

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

2, 6-dimethyl-4- (3'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester-5-isopropyl ester,

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

2, 6-methyl-6-isopropyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester-5-isopropyl ester,

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

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

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

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

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

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

2, 6-dimethyl-4- (3'-nitrophenyl-6'-chlorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester-5-isopropyl ester.

The new compounds prepared according to the invention can be used as drugs, which have a wide variety of pharmacological activity spectrum. Animal testing has demonstrated the following main effects:

1) The novel compounds of the present invention are uniquely expanded in coronary tubes and are long-lived when administered parenterally and orally, especially sublingually. This action on the coronary tract has been enhanced by the simultaneous effect of nitrite amounts, which reduce the burden on the heart. With regard to the absolute intensity of action and sublingual absorption, the novel compounds of the present invention are far superior to known symmetric dihydropyridinecarboxylic acid esters and affect or change cardiac metabolism in terms of energy accumulation.

2). Decreases the shock and excitability of the stimulus delivery system in the heart to produce a detectable anti-fibrillation effect in therapeutic dosing.

3). Under the action of the compounds of the present invention, the tension of vascular muscles is greatly reduced.

4). The novel compounds of the invention usually reduce the tension and blood pressure of hypertensive animals. Therefore, it can be used as a blood pressure lowering agent.

5). The novel compounds of the present invention had strong muscle-nervous action in the muscles of the stomach, intestines, urinary and respiratory systems.

The new compounds prepared in the Examples have a coronary effect which can be seen at the following doses.

The following table shows the toxicity and minimum doses (expressed as DL ₅₀ as mg of active compound administered orally per kg body weight) of the new compounds according to the invention prepared by the process described in the Examples (orally administered per kg body weight). Blood pressure drop shown in mg of active compound) and hypertension.

As mentioned above, the novel asymmetric 1,4-dihydropyridinecarboxylic acid ester compounds according to the invention can be used for human and veterinary medicine.

It is possible to prepare a pharmaceutical composition by containing the compound according to the present invention as an active ingredient and mixing with a liquid diluent having a molecular weight of 200 or more (preferably smaller than 350) in addition to the presence of a surfactant, as well as sterile the compound of the present invention as an active ingredient. It is also possible to make pharmaceutical compositions containing in the form of an isotonic aqueous solution. It is also possible to make drugs in the form of tablets, sugars, capsules, pills, ampoules and suppositories which are formed alone or in admixture with a diluent.

이하)량을 함유하는 약제투여용으로 적합한 산재입자 응집체를 의미하는 것이다. 약물이 1일 용량을 함유하느냐 아니면 예컨대 1일 용량의

을 함유하느냐의 여부는 약물이 1회 투여용이냐 아니면 2회, 3회 또는 4회 투여용이냐에 따라 각각 결정될 것이다.As used herein, "drug" refers to an industrial coagulant suitable for administration, and "dose unit form" means a daily dose or multiples (up to four times) of the daily dose and distilled water (

It means a scattering particle aggregate suitable for drug administration containing the amount). Does the drug contain a daily dose or, for example, a daily dose

Whether or not it will be determined depending on whether the drug is for single administration or for two, three or four administrations, respectively.

Pharmaceutical compositions according to the invention may be formulated in the form of ointments, gel pastes, creams, sprays, lotions, suspensions, solutions and emulsions, syrups, granules or powders of the active ingredient with an aqueous or non-aqueous diluent. Illustrative diluents suitable for use in pharmaceutical compositions (eg granules) to form tablets, sugars, capsules and pills are as follows.

(a) fillers and extenders; Starch, sugar, mannitol and silicic acid;

(b) binders; Such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone;

(c) wetting agents; For example glycerol;

(d) swelling agent; Agar-agar, calcium carbonate and sodium bicarbonate;

(e) dissolution retardants; For example paraffin;

(f) absorption accelerators; Tetravalent ammonium compounds, for example;

(g) surfactants; Cetyl alcohol, monostearine glycerol;

(h) adsorptive carriers; Such as kaolin and bentonite;

(i) lubricants; Such as talc, stearin magnesium and calcium and solid polyethylene glycols

Tablets, sugars, capsules and pills formed from the pharmaceutical compositions of the present invention may have conventional coatings, envelopes, protective matrices, and the like, which may contain milky agents. They may be formulated such that only the active ingredient is released over a period of time as much as possible or as effective as possible to the actual part of the intestine after administration. Coatings, envelopes and protective matrices and the like can be prepared, for example, as polymeric materials or waxes.

The active ingredient may be prepared in the form of a microcapsule together with one or several of the aforementioned diluents. Diluents used in pharmaceutical compositions suitable for formation into suppositories include, for example, demanded or non-aqueous diluents such as polyethylene glycol and fats (e.g. cocoa butter and higher esters such as C ₁₄ -alcohols and C ₁₆ -fatty acids) or diluents thereof. Pharmaceutical compositions such as ointments, pastes, creams and gels include animal and vegetable fats, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and It may contain conventional diluents such as zinc oxide or mixtures of these materials.

Pharmaceutical compositions such as powders and sprays may contain conventional diluents such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders or mixtures of these materials, and the aerosol sprays may, for example, be chlorofluoro hydrocarbons. Conventional propenerants such as Pharmaceutical compositions such as pharmaceuticals and emulsions are conventional diluents, for example solvents, disintegrating agents and emulsifiers (other than those mentioned above having a molecular weight of less than 200 in addition to the presence of surfactants), ie water, ethyl alcohol, isopropyl alcohol, carbonic acid. Ethyl, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethyl formamide, oils (e.g. peanut oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol Diluents such as fatty acid esters or mixtures thereof. For parenteral administration, solutions and emulsions must be sterile and, in certain cases, isotonic with blood. Pharmaceutical compositions of suspensions are usually diluents such as liquid diluents such as water, ethyl alcohol, propylene glycol, surfactants (such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitan and sorbitan esters), microcrystalline cellulose, aluminum Conventional diluents such as etahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.

All pharmaceutical compositions according to the present invention may include colorants and preservatives, as well as flavoring agents (eg peppermint oil and ekalie oil) and flavoring agents (eg saccharin) and the like.

Pharmaceutical compositions according to the present invention contain about 0.1-99.5% active ingredient based on the total weight of the composition, and particularly suitably 0.5-95%. The pharmaceutical composition according to the present invention may include a pharmaceutical friendly compound according to the present invention in addition to the compound of the present invention, and may also include a series of compounds of the present invention. Any of the dilution systems exemplified above with respect to the pharmaceutical composition of the present invention can be used in the drug of the present invention. The drug may contain a solvent having a molecular weight of 200 or less as a single diluent. The scattered particle populations that comprise the drug of the present invention, whether in the form of a dosage unit or not, may be any of tablets, pills, sugars, capsules, suppositories, and ampoules (including pastilles and granules). . While some of these forms may be made to delay release of the active ingredient, such as a casing includes a protective sheath that provides some of the drug as interspersed and aggregated.

A suitable daily dosage for intravenous administration of a medicament of the invention is 0.0001-1 mg of active ingredient per kg of body weight, more preferably 0.0005-0.1 mg. A suitable daily dosage for oral administration is 0.005-10 mg / kg body weight, more appropriate 0.05-5 mg.

The preparation of the pharmaceutical compositions and drugs described above is carried out by methods known in the art, for example by mixing the oily ingredients with diluents to form pharmaceutical compositions (eg granules) and then forming the compositions into drugs (eg tablets). It became. The present invention also provides a method for lowering blood pressure in humans and non-human animals, comprising administering the compound of the invention alone or in admixture with a diluent or in the form of a drug according to the invention to the animal.

The active compounds may be administered orally or parenterally (eg intramuscularly, intraperitoneally or intravenously), particularly sublingually and intravenously. Therefore, particularly suitable pharmaceutical compositions and drugs are suitable for sublingual and oral administration. The actual dosage will vary depending on the human or animal nature and weight to be treated, the individual response to the treatment, the form of the active ingredient to be administered and the method of administration, and the course of the disease or the interval at which it is administered. May be out of the dose range. Therefore, in some cases, the at least one dose described above may be less than sufficient, while in other cases it may exceed the above limits to achieve the desired result. If higher doses are given, it may be advisable to divide the dose several times a day. Hereinafter, the present invention will be described in detail with reference to the following Examples.

[Example of manufacturing]

Example 1

A solution of 13.4 g of 3'-nitrobenzylidene acetoacetic acid ethyl ester and 5.8 g of beta-amino-crotonic acid methyl ester in 50 ml of ethanol was stirred for 10 hours and had a melting point of 158 ° C. (from ethanol). 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethyl ester were produced. Yield: 67% of theory

Example 2

A solution of 12.7 g of 3'-nitrobenzylidene-acetoacetic acid methyl ester and 7.2 g of β-amino-crotonic acid propyl ester in 50 ml of methanol was heated for 8 hours, and a melting point of 147 DEG C (from ethanol) was obtained. With 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester-5-isopropyl ester. Yield: 70% of theory

Example 3

A solution of 14.0 g of 3'-nitro-benzylideneacetoacetic acid allyl ester and 5.8 g of β-amino-crotonic acid methyl ester in 50 ml of ethanol was boiled for 8 hours, resulting in a melting point of 110 ° C. (ethyl acetate / petroleum ether). 2), 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester-5-allyl ester. Yield: 63% of theory

Example 4

A solution of 12.7 g of 3'-nitro-benzylideneacetoacetic acid methyl ester, 7.0 g acetoacetic acid propargyl ester and 6 ml of concentrated ammonia in 50 ml of ethanol was boiled for 8 hours to find a melting point of 111-113 DEG C. 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester-5-propargyl ester with petroleum ether / ethyl acetate Was created. Yield: 70% of theory

Example 5

A solution of 13.4 g of 3'-nitrobenzylidene-acetoacetic acid ethyl ester and 7.2 g of β-aminocrotonic acid isopropyl ester in 50 ml of isopropanol was heated for 10 hours to give a melting point of 148 DEG C (from ethanol). With 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester-5-isopropyl ester. Yield: 60% of theory

Example 6

A solution of 13.4 g of 3'-nitrobenzylidene acetoacetic acid ethyl ester in 50 ml of ethanol, 9.2 g of acetoacetic acid β-propoxyethyl ester and 6 ml of concentrated ammonia was heated for 10 hours to find a melting point of 75 DEG C. 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester-5-β-propoxy with petroleum ether / ethyl acetate Ethyl ester was produced. Yield: 46% of theory

Example 7

A solution of 14.9 g of 3'-nitrobenzylideneacetoacetic acid β-methoxyethyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 50 ml of methanol was heated for 10 hours, and the melting point was 108 캜 (ethanol / From water) yielded 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester-5-β-methoxyethylester . Yield: 51% of theory

Example 8

A solution of 13.4 g of 3'-nitrobenzylideneacetoacetic acid ethyl ester, 7.1 g of acetoacetic allyl ester and 6 ml of concentrated ammonia in 50 ml of ethanol was heated and boiled for 10 hours. Phosphorus (from ethyl acetate / petroleum ether) 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-allyl ester It became. Yield: 55% of theory

Example 9

A solution of 13.4 g of 3'-nitrobenzylideneacetoacetic acid ethyl ester, 7.0 g of acetoacetic acid propargyl ester and 6.0 ml of ammonia in 50 ml of ethanol was boiled for 8 hours and the melting point was 132-133. 2,6-dimentyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethylester-5-propargyl ester is produced It became. Yield: 54% of theory

Example 10

A solution of 13.4 g of 3'-dinitrobenzylideneacetoacetic acid ethyl ester and 9.2 g of β-aminocrotonic acid cyclohexyl ester in 50 ml of methanol was boiled for 8 hours, and the melting point was 135 ° C (ethanol / water From 2), 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethylester-5-cyclohexyl ester. Yield: 44% of theory

Example 11

A solution of 14.2 g of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 7.1 g of β-aminocrotonic acid allyl ester in 50 ml of ethanol was heated for 10 hours, and the melting point was 96-97 占 폚 (ethanol / 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-isopropyl-5-allyl-ester. Yield: 58% of theory

Example 12

A solution of 14.1 g of 3'-nitrobenzylideneacetoacetic acid isopropyl ester, 7.0 g of acetoacetic acid probargyl ester and 6 ml of concentrated ammonia in 50 ml of ethanol was boiled for 10 hours. 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-isopropyl ester-5-propargyl ester Generated. Yield: 59% of theory

Example 13

A solution of 14.1 g of 3'-nitrobenzylideneacetoacetic acid isopropyl ester, 7.2 g of acetoacetic acid propyl ester and 6 ml of concentrated ammonia in 50 ml of ethanol was boiled for 8 hours. From 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-isopropyl ester). Yield: 54% of theory

Example 14

A solution of 12.7 g of 2'-nitrobenzylideneacetoacetic acid methyl ester and 7.1 g of β-aminocrotonic acid isopropyl ester in 50 ml of ethanol was boiled for 10 hours, and the melting point was 174 캜 (from ethanol). 2, 6-dimethyl-4- (2'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-isopropyl ester were produced. Yield: 48% of theory

Example 15

A solution of 12.7 g of 2'-nitrobenzylideneacetoacetic acid methyl ester and 7.2 g of acetic acid propyl ester and 6 ml of concentrated ammonia in 50 ml of ethanol was heated for 8 hours, and the melting point was 127-128 deg. From isopropanol) 2, 6-dimethyl-4- (2'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-propylester. Yield: 54% of theory

Example 16

A solution of 13.4 g of 4'-nitrobenzylidene acetoacetic acid ethyl ester and 5.8 g of β-aminocrotonic acid methyl ester in 50 ml of ethanol was boiled for 8 hours, and the melting point was 150 DEG C (from ethanol). , 6-dimethyl-4- (4'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethylester were produced. Yield: 85% of theory

Example 17

A solution of 15.2 g of 3'-nitro-6'-chlorobenzylideneacetoacetic acid ethyl ester in 50 ml of methanol and 5.8 g of β-aminocrotonic acid methyl ester was boiled for 10 hours, and the melting point was 163-164 占 폚. 2, 6-dimethyl-4- (3'-nitro-6'-chlorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethyl (from ethanol / water) Ester was produced. Yield: 40% of theory

Example 18

A solution of 15.2 g of 3'-nitro-6'-chlorobenzylideneacetoacetic acid ethyl ester and 7.2 g of β-aminocrotonic isopropyl ester in 50 ml of methanol was heated for 8 hours, and the melting point was 152 占 폚 ( 2, 6-dimethyl-4- (3'-nitro-6'-chlorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester-5- which is petroleum ether / ethyl acetate) Isopropyl ester was produced. Yield: 41% of theory

Example 19

A solution of 14.5 g of 3'-nitro-6'-chlorobenzylideneacetoacetic acid methyl ester and 7.2 g of β-aminocrotonic isopropyl ester in 50 ml of methanol was heated for 10 hours, and the melting point was 163 占 폚. 2, 6-dimethyl-4- (3'-nitro-6'-chlorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-isopropyl ester were produced. Yield: 54% of theory

Example 20

A solution of 13.4 g of 3'-nitrobenzylideneacetoacetic acid ethyl ester, 7.2 g acetoacetic acid propyl ester and 6 ml of concentrated ammonia in 50 ml of ethanol was boiled for 8 hours, and the melting point was 131-133 ° C (petroleum). 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethylester-5-propylester, from ether / ethyl acetate). Yield: 49% of theory

Example 21

A solution of 12.2 g of 2'-cyanobenzylideneacetoacetic acid ethyl ester and 5.8 g of β-aminocrotonic acid methyl ester in 50 ml of ethanol was boiled for 10 hours, and the melting point was 178 DEG C (from ethanol). , 6-dimethyl-4- (2'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethylester were produced. Yield: 65% of theory

Example 22

A solution of 12.2 g of 2'-cyanobenzylideneacetoacetic acid ethyl ester and 7.2 g of β-aminocrotonic acid isopropyl ester in 50 ml of ethanol was heated for 8 hours, and the melting point was 152 DEG C (from ethanol). 2, 6-dimethyl-4- (2'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethylester-5-isopropyl ester were produced. Yield: 49% of theory

Example 23

A solution of 12.2 g of 2'-cyanobenzylideneacetoacetic acid ethyl ester, 7.1 g of acetoacetic allyl ester, and 6 ml of concentrated ammonia in 50 ml of ethanol was boiled for 10 hours, and the melting point was 148 DEG C (ethyl acetate / 2, 6-dimethyl-4- (2'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethylester-5-allyl ester. Yield: 24% of theory

Example 24

A solution of 12.9 g of 2'-cyanobenzylideneacetoacetic acid propyl ester and 5.8 g of β-aminocrotonic acid methyl ester in 50 ml of methanol was boiled for 8 hours, and the melting point was 188 DEG C (from ethanol). , 6-dimethyl-4- (2'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-propylester was produced. Yield: 51% of theory

Example 25

A solution of 11.5 g of 3'-cyanobenzylideneacetoacetic acid methyl ester, 6.5 g acetoacetic acid ethyl ester and 6 ml of concentrated ammonia in 50 ml of ethanol was heated for 8 hours, and the melting point was 150 DEG C (from ethanol). Phosphorous 2, 6-dimethyl-4- (3'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethylester was produced. Yield: 68% of theory

Example 26

A solution of 12.2 g of 3'-cyanobenzylideneacetoacetic acid ethyl ester and 7.1 g of β-aminocrotonic acid isopropyl ester in 50 ml of ethanol was boiled for 8 hours, and the melting point was 133-134 ° C (petroleum ether). 2, 6-dimethyl-4- (3'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethylester-isopropylester were produced. Yield: 55% of theory

Example 27

A solution of 12.5 g of 4'-methylmercaptobenzylideneacetoacetic acid methyl ester, 6.5 g of acetoacetic acid ethyl ester and 6 ml of concentrated ammonia in 50 ml of ethanol was heated for 10 hours, and the melting point was 163 占 폚 (from ethanol ), 2, 6-dimethyl-4- (4'-methylmercaptophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethylester were produced. Yield: 60% of theory

Example 28

A solution of 10.5 g of 2'-tenylmethylideneacetoacetic acid methyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 50 ml of ethanol was boiled for 10 hours, and the melting point was 142 DEG C (from methanol). 6-dimethyl-4- (2'-tenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethylester was produced. Yield: 45% of theory

Example 29

A solution of 10.5 g of 2'-tenylmethylideneacetoacetic acid methyl ester and 7.2 g of β-aminocrotonic isopropyl ester in 50 ml of methanol was heated for 8 hours, and the melting point was 121-122 ° C. -Dimethyl-4- (2'-tenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-isopropylester were produced. Yield: 41% of theory

Example 30

A solution of 10.9 g of α-pyridylmethylideneacetoacetic acid ethyl ester and 5.8 g of β-aminocrotonic acid ethyl ester in 50 ml of ethanol was boiled for 10 hours, and the melting point was 199-200 ° C. (from ethanol). 2, 6-dimethyl-4- (α-pyridyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethylester were produced. Yield: 63% of theory

Example 31

A solution of 10.2 g of α-pyridylmethylideneacetoacetic acid methyl ester and 7.2 g of β-aminocrotonic acid isopropyl ester in 50 ml of ethanol was heated for 10 hours, and the melting point was 188 ° C. (from ethanol). , 6-dimethyl-4- (α-pyridyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester-5-isopropyl ester. Yield: 40% of theory

Example 32

A solution of 11.6 g of α-pyridylmethylideneacetoacetic acid isopropyl ester, 7.2 g acetoacetic acid propyl ester and 6 ml of concentrated ammonia in 50 ml of ethanol was boiled for 8 hours, and the melting point was 153-154 ° C. 2, 6-dimethyl-4- (α-pyridyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-propylester-5-isopropylester) which is from ethyl / petroleum ether was produced. : 45% of theory

Example 33

A solution of 10.2 g of α-pyridylmethylideneacetoacetic acid methyl ester and 7.0 g of β-aminocrotonic acid propargyl ester in 50 ml of ethanol was heated for 10 hours, and the melting point was 194-195 ° C. (from ethanol ), 2, 6-dimethyl-4- (α-pyridyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-propargyl ester. Yield: 42% of theory

Example 34

A solution of 13.4 g of α-naphthylideneacetoacetic acid ethyl ester and 7.2 g of β-aminocrotonic acid isopropyl ester in 50 ml of ethanol was heated for 10 hours, and the melting point was 2,6-dimethyl- having a melting point of 167 ° C. 4- (α-naphthyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethylester-5-isopropylester were produced. Yield: 38% of theory

Example 35

A solution of 13.4 g of α-naphthylideneacetoacetic acid ethyl ester and 5.8 g of β-aminocrotonic acid methyl ester in 50 ml of methanol was boiled for 8 hours, and the melting point was 196-197 ° C. (from ethanol). , 6-dimethyl-4- (α-naphthyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethylester-5-methylester was produced. Yield: 45% of theory

Example 36

A solution of 12.7 g of 4'-quinolylmethylideneacetoacetic acid methyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 50 ml of ethanol was heated for 8 hours, and the melting point was 208 DEG C (from ethanol). , 6-dimethyl-4- (4'-quinolyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethylester were produced. Yield: 74% of theory

Example 37

A solution of 9.7 g of 2'-pyrylmethylideneacetoacetic acid methyl ester, 6.5 g of acetoacetic acid ethyl ester and 6 ml of concentrated ammonia in 50 ml of ethanol was boiled for 10 hours, and the melting point was 239 DEG C (from diethyl ether). ), 2, 6-dimethyl-4- (2'-pyryl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethylester. Yield: 36% of theory

Example 38

A solution of 10.2 g of β-pyridylmethylideneacetoacetic acid methyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 50 ml of ethanol was heated for 8 hours, and the melting point was 191-192 ° C. (from ethanol). 2, 6-dimethyl-4- (β-pyridyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-ethylester were produced. Yield: 59% of theory

Example 39

A solution of 11.6 g of β-pyridylmethylideneacetoacetic acid isopropyl ester and 5.8 g of β-aminocrotonic acid methyl ester in 50 ml of ethanol was boiled for 10 hours, and the melting point was 164-165 ° C. (from methanol). Phosphorous 2, 5-dimethyl-4- (β-pyridyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-isopropyl ester was produced. Yield: 52% of theory

Example 40

A solution of 12.8 g of quinolyl-8-methylidene acetoacetic acid methyl ester and 7.2 g of aminocrotonic acid isopropyl ester in 80 ml of ethanol was heated under reflux for 5 hours, and the melting point was 178-179 ° C. (from alcohol ), 2, 6-dimethyl-4- (8'-quinolyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester-5-isopropyl ester. Yield: 69% of theory

Example 41

A solution of 12.8 g of isoquinolyl-3-methylamine acetoacetic acid methyl ester and 6.5 g of amino crotonic acid ethyl ester in 100 ml of ethanol was heated for 8 hours, and the melting point was 206 DEG C (ethanol). -Dimethyl-4- (3'-isoquinolyl) -3,5-dicarboxylic acid 3-methylester-5-ethylester was produced. Yield: 73% of theory

Example 42

A solution of 12.2 g of 3'-cyanobenzylamine acetoacetic acid ethyl ester and 7.0 g of aminocrotonic acid propargyl ester in 80 ml of isopropanol was heated for 10 hours, and the freezing point was 144-145 ° C (acetic acid ester / Petroleum ester), 2, 6-dimethyl-4- (3'-cyanophenyl) -1.4-dihydropyridine 3,5-dicarboxylic acid-3-methylester-5-propargyl ester. Yield: 63% of theory

Example 43

3.8 g of 3'-nitro-benzylidene acetoacetic acid isopropyl ester, 8 g of acetoacetic acid β-methoxyethyl ester and 6 ml of concentrated ammonia in 80 ml of ethanol were heated to reflux for 8 hours. 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine 3-β-methoxyethylester-5-isopropyl ester, which was 125 ° C (petroleum ether / acetic acid ester), were produced . Yield: 49% of theory

Example 44

A solution of 3.5 g β-naphthylidene acetoacetic acid ethyl ester and 5.8 g aminocrotonic acid methyl ester in 80 ml of ethanol was boiled for 7 hours, resulting in 2, 6- having a freezing point of 140-142 ° C. (ethanol). Dimethyl-4- (β-naphthyl) -1,4-dihydropyridine-3.5-dicarboxylic acid 3-methylester 5-ethylester was produced. Yield: 47% of theory

Example 45

A solution of 9.7 g of 2'-furfurylidene acetoacetic acid methyl ester, 7.1 g acetoacetic allyl ester and 6 ml of concentrated ammonia in 100 ml of ethanol was heated for 8 hours, and the freezing point was 134-135 占 폚 (ethanol ), 2, 6-dimethyl-4- (2'-furyl) -1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-methyl ester 5-allyl ester. Yield: 59% of theory

Example 46

When a solution of 14.0 g of 4, 6-dimethoxypyrimidine-5-methylideneacetoacetic acid ethyl ester and 5.8 g of aminocrotonic acid methyl ester in 100 ml of ethanol was heated for 10 hours, the freezing point was 245 占 폚 (ethanol 2, 6-dimethyl-4- (4 ', 6'-dimethoxypyridyl-5')-1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-methyl ester 5-ethylester Generated. Yield: 68% of theory

Example 47

A solution of 9.7 g of 2'-furfurylidene acetoacetic acid methyl ester and 6.5 g of aminocrotonic acid ethyl ester in 80 ml of ethanol was boiled for 8 hours. As a result, the freezing point was 154-155 ° C (acetic acid ester). 6-dimethyl-4- (2'-furyl) -1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-methylester 5-ethylester was produced. Yield: 66% of theory

Example 48

A solution of 12.2 g of 2'-cyanobenzylideneacetoacetic acid ethyl ester, 7.2 g of acetoacetic acid n-propyl ester and 6 ml of concentrated ammonia in 80 ml of ethanol was heated under reflux for 10 hours, and the freezing point was 156 deg. Ethyl ether), 2, 6-dimethyl-4- (2'-cyanophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-n-propylester was produced. Yield: 47% of theory

Example 49

A solution of 12.8 g of isoquinolyl-1-methylideneacetoacetic acid methyl ether and 7.2 g of aminochromic acid isopropyl ester in 80 ml of ethanol was heated for 6 hours, and the freezing point was 204 DEG C (ethanol). -Dimethyl-4- (1'-isoquinolyl) -1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-methylester 5-isopropylester were produced. Yield: 78% of theory

Example 50

A solution of 12.5 g of 3'-nitrobenzylidene-acetoacetic acid methyl ester and 7.2 g of β-ethyl-β-aminoacrylic acid ethyl ester in 70 ml of ethanol was agitated for 8 hours, and the freezing point was 123 DEG C (acetic acid ester). / Petroleum ester) to 2-methyl-6-ethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester 5-ethylester. Yield: 71% of theory

Example 51

A solution of 11.7 g 6'-methylpyridyl-2-methylidene-acetoacetic acid ethyl ether and 5.8 g aminochromic acid methyl ester in 80 ml of ethanol was heated for 8 hours, and the freezing point was 162 캜 (ethanol). Phosphorus 2, 6-dimethyl-4- (6'-methylpyridyl-2 ')-1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester 5-ethylester was produced. Yield: 62% of theory

Example 52

A solution of 12.5 g of 3'-nitrobenzylidene acetoacetic acid methyl ester, 8.0 g of acetoacetic acid β-methoxyethyl ester and 6 ml of concentrated ammonia in 80 ml of ethanol was heated for 9 hours. 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-8, 5-dicarboxylic acid 3-β-5-methoxyethyl ester which is (acetic acid ester / petroleum ether) It became. Yield: 51% of theory

Example 53

A solution of 13.2 g of 2'-nitrobenzylideneacetoacetic acid ethyl ester and 5.8 g of aminocrotonic acid methyl ester in 60 ml of ethanol was heated for 8 hours, and the freezing point was 117 DEG C (acetic acid ester / petroleum ether). , 6-dimethyl-4- (2'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester 5-ethylester was produced. Yield: 58% of theory

Claims (1)

As described in the text, the reaction of the iriden-β-ketocarboxylic acid ester of the following general formula (2) with ammonia and the β-keto-carboxylic acid ester of the following general formula (4) in water or an inert organic solvent as a diluent A method for producing an asymmetric 1,4-dihydropyridinecarboxylic acid ester compound of the general formula (1).

Food, R has, as substituents, at least one nitro, nitrile, azido, or —SO _n -alkali group, where n is 0, 1 or 2, and may optionally also have at least one alkyl or alkoxy group or halogen atom Naphthyl, quinolyl, isoquinolyl, or a phenyl group, provided that the maximum number of substituents on R ¹ in this case is three, or which may have at least one alkyl or alkoxy group or a halogen atom as a substituent; Pyridyl, pyrimidyl, tenyl, furyl or pyryl groups, R ¹ and R ³ are the same or different and each represent a hydrogen atom or a linear or branched alkyl group; R ² and R ⁴ represent different straight, branched or cyclic saturated and unsaturated hydrocarbons, with each carbon chain being interrupted by one or two oxygen atoms and having a hydroxyl group as a substituent.