KR790001065B1 - Process for preparing unsymmetrical 1,4-dihydropyridin ester - Google Patents

Abstract

Title compds. (I; R = e.g. Ph, Naphthal, quinolyl, isoquinolyl, pyridyl, primidyl, Tenyl, Furyl, pyryl, R1, R3 = same or different of H, Ph, alkyl, R2, R4 = same or different of - OH group contg. hydrocarbon), useful as coronary dilators, spasmolytics, antihypertensives, and drugs against cardiac fibrillation, were prepd. by reaction of I with II and IV in the presence of H2O or in inert solvents.

Description

Method for preparing asymmetric 1, 4-dihydropyridine ester

The present invention relates to a novel process for producing novel asymmetric 1,4-dihydropyridinedicarboxylic acid esters.

The aldehydes represented by the general formula RCHO are reacted with β-ketocarboxylic acid esters represented by the general formula R ¹ COCH ₂ COOR ² and ammonia to form symmetrical 1,4-dihydropyridine derivatives represented by the following general formula (A): Has already been mentioned. Kirchner, Ber. 25, 2786 (1892).

로 표시되는 엔아미노카복실산 에스테르류와 반응시킴으로서 제조되었다.As is known from the literature, the symmetric 1,4-dihydropyridine derivatives described above can be used to convert aldehydes to β-ketocarboxylic acid esters and to the general formula R =.

It was prepared by reacting with the enaminocarboxylic acid esters represented by.

(Fox, Lewis and Wenner, J. Org. Chem 16, 1259 (1951)).

In addition, a method of preparing dihydropyridine derivatives represented by the following general formula (A) by reacting with aldehydes and enaminocarboxylic acid esters is also known.

(Cook, Heilbron and Steger, J. Chem. Soc. [London], 1943, 413)]

In addition, it is also known that the compound of the general formula (A) is prepared by reacting the iriden-β-ketocarboxylic acid ester of the following general formula (B) with the enaminocarboxylic acid ester of the following general formula (C).

(Knoevnagel, Ber. 31, 743 (1898))

However, asymmetric 1, 4-dihydropyridine dicarboxylic acid esters have not been described in the literature to date.

Based on the known methods already mentioned, the following general formula (I) is reacted when reacting the iriden-β-ketocarboxylic acid esters represented by the following general formula (B) with the enaminocarboxylic acid esters represented by the following general formula (C): The assumption that the compound represented by 1) will be made can be made.

However, the drawback of this two-step process is that it is almost impossible to isolate in a pure form the iriden-β-ketocarboxylic acid esters of the following general formula obtained by condensing the β-ketocarboxylic acid ester and the alzehydride in the first step. Is often produced in very low yields.

The present invention is obtained by reacting the aldehyde represented by the following general formula (2) with the β-ketocarboxylic acid ester represented by the following general formula (3) and the enaminocarboxylic acid ester represented by the following general formula (4) in the presence of a diluent. It relates to a method for producing asymmetric 1, 4-dihydropyridine esters represented by the following general formula (1).

Food,

R represents a phenyl group having 1,2 or 3 substituents selected from alkyl, alkoxy, halogen, nitro, nitrile, azido, trifluoromethyl, carvalkoxy and SOn-alkyl groups (n = 0, 1 or 2) or Or a naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, tenyl, furyl, or pyryl group which may have one or more alkyl, alkoxy or halogen groups as substituents;

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

R ² and R ⁴ are different from each other, each having a carbon chain which can be interrupted by a hydrogen atom, and in any case, represent a straight or branched or cyclic saturated or unsaturated hydrocarbon group having the same hydroxyl group as a substituent.

As used herein, the term "hydrocarbon group" includes a methyl group, in addition, a group having the same hydrocarbon chain interrupted by one or more oxygen atoms (eg, an alkoxy alkyl group) and one or more hydrogen atoms are replaced by a hydroxyl group. Containing hydrocarbon groups.

The asymmetric 1, 4-dihydropyridine esters represented by the general formula (1), and the present method and other manufacturing method thereof have also filed the patent applications (A) and (B), which are the same co-applicants with the present application, in Korea. .

(Note: Patent applications (A), (B) and (C) are co-filed on April 10, 1971 in the original filing country (the Federal Republic of Germany) with P21 17 571.3, R21 17 572.4 and P21 17 573.5, respectively. ).

Asymmetric 1,4-dihydropyridine esters of formula (1) have strong coronary-extension and anti-hypertensive properties.

It is quite surprising that asymmetric 1,4-dihydropyridines are produced by the method of the present invention with significantly higher purity and excellent yields. Because of the consensus in the art to date, it has been expected that the reactions according to the invention will produce undesired symmetric 1,4-dihydropyridines at a considerably high rate. This has been pointed out in the following references (see: Wessberger's "Chemistry of Heterocyclic Compounds, Pyridine and Its Derivatives, Part 1, p. 502").

Therefore, the manufacturing method of this invention surrenders this conventional bias.

The practical advantage of the process lies in the fact that in addition to the fact that the desired product with high purity is produced in a significantly higher yield, the process can be carried out in a single step to achieve high economics with less technical effort.

If 3-nitro-benzaldehyde, acetoacetic acid isopropyl ester and amino crotonic acid methyl ester are used as starting materials, the reaction process can be represented by the following scheme.

In the above general formula 1-4, R is in particular 1-4, preferably 1-2 alkyl, alkoxy, halogen, such as fluorine, chlorine or cancellation, nitro, nitrile, azido, alkoxy, Or a naphthyl, quinolyl, pyridyl, pyrimidyl group which represents a phenyl group which may be substituted by 1 to 3 identical or different substituents from among 4 carbon atom carboalkoxy or SOn-alkyl (n = 0-2) groups , Natril, quinolyl and isoquinolyl groups, optionally substituted with halogen, such as fluorine or cancellation, alkyl and / or alkoxy groups of 1-2 carbon atoms, and with pyridyl, pyryl, tenyl The furyl group may be optionally substituted with an alkyl group having 1-2 carbon atoms, and the pyrimidyl group may be optionally substituted with 1-2 methoxy or ethoxy groups.

R ¹ and R ³ are the same as or different from each other, and represent a straight and branched chain alkyl group or a phenyl group having a hydrogen atom or 1-4 carbon atoms.

R ² and R ⁴ must be different from each other and represent a straight, branched or cyclic, saturated or unsaturated hydrocarbon group of 1-6 carbon atoms, in particular an aliphatic hydrocarbon chain of 1-3 carbon atoms. Always a hydrocarbon chain is a hydrocarbon chain optionally interrupted by one or two oxygens, in particular by one oxygen atom or optionally substituted by a hydroxyl group.

Starting materials used in the present invention are already known or can be prepared by known methods.

Examples of starting materials that can be used in the process of the present invention are as follows.

Aldehydes (Formula 2):-

Benzaldehyde,

2-, 3- or 4-methoxybenzaldehyde,

2-, 3- or 4-methylbenzaldehyde,

3, 4, 5-trimethoxybenzaldehyde,

2-isopropoxybenzaldehyde,

Fluorobenzaldehyde,

2, 4- 2, 6-dichlorobenzaldehyde,

2, 4-dimethylbenzaldehyde,

2-, 3- or 4-nitrobenzaldehyde,

2, 4- or 2, 6-dinitrobenzaldehyde,

2-nitro-6-bromobenzaldehyde,

2-nitro-3-methoxy-6-chlorobenzaldehyde,

2-nitro-4-chlorobenzaldehyde,

2-nitro-4-methoxybenzaldehyde,

2-, 3- or 4-trifluoromethylbenzaldehyde,

Benzaldehyde-2-carboxylic acid ethyl ester,

Benzaldehyde-3-carboxylic acid methyl ester,

Benzaldehyde-4-carboxylic acid butyl ester,

3-nitrobenzaldehyde-4-carboxylic acid ethyl ester,

α, β- or γ-pyridinealdehyde,

6-methylpyridine-2-aldehyde,

Pyrimidine-5-aldehyde,

4, 6-dimethoxy-pyrimidine-5-aldehyde,

2-, 3- or 4-cyanobenzaldehyde,

2-, 3- or 4-cyanobenzaldehyde,

2-, 3- or 4-azidobenzaldehyde,

2-methyl mercaptobenzaldehyde,

4-methylmercaptobenzaldehyde,

2-methylsulfonylbenzaldehyde,

2-methylsulfinylbenzaldehyde,

1- or 2-naphthaldehyde,

5-bromo-1-naphthaldehyde,

2-ethoxy-1-naphthaldehyde,

4-methyl-1-naphthaldehyde,

Quinolyl-2, 3-, 4-, 5-, 6-, 7- or 8-aldehyde,

Furan-2-aldehyde,

Thiophene-2-aldehyde and pyrrole-2-aldehyde,

β-ketocarboxylic acid ester (formula 3):

Formyl acetic acid ethyl ester,

Formyl acetic acid butyl ester,

Acetoacetic acid methyl ester,

Acetoacetic acid ethyl ester,

Acetoacetic acid propyl ester,

Acetoacetic acid isopropyl ester,

Acetoacetic acid butyl ester,

Acetoacetic acid 6-butyl ester,

Acetoacetic acid (α- or β-)-hydroxy-ethyl ester,

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

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

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

Acetoacetic acid allyl ester,

Acetoacetic acid propargyl ester,

Acetoacetic acid cyclohexyl ester,

Propionyl acetic acid ethyl ester,

Butyryl acetic acid ethyl ester,

Isobutyryl acetic acid ethyl ester and benzoyl acetic acid ethyl ester,

Enaminocarboxylic acid ester (General formula 4)

β-aminocrotonic acid methyl ester,

β-aminocrotonic acid ethyl ester,

β-aminocrotonic acid propyl ester,

β-aminocrotonic acid isopropyl ester,

β-aminocrotonic acid butyl ester,

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

β-aminocrotonic acid allyl ester,

β-aminocrotonic acid propargyl ester,

β-aminocrotonic acid cyclohexyl ester,

β-ethyl-β-aminocrylic acid ethyl ester and

β-aminocinnamic acid ethyl ester,

The process of the present invention has generally been carried out in diluents, where water and all inert organic solvents can be used. Suitable organic solvents include alcohols such as methanol, ethanol and propanol, ethers such as dioxane or diethyl ether or glacial acetic acid, pyridine, dimethyl formamide, dimethyl sulfoxide or acetonitrile.

The reaction temperature can be carried out over a wide range, generally at about 20-250 ° C., preferably at 30-200 ° C., and most preferably at the boiling point of the liquid diluent.

The reaction can be carried out at atmospheric pressure, but can also be carried out under high pressure, generally using atmospheric pressure.

The compounds used in the reaction in carrying out the process according to the invention were generally used in molar amounts.

Esters prepared by the process of the invention can be used as medicaments and have a broad and varied spectrum of pharmacological activity.

In fact, animal testing can demonstrate the following main effects:

(One). On parenteral and oral (particularly sublingual) administration, the present esters significantly extended coronary vessels. This action on coronary vessels has been enhanced by the simultaneous effect of nitrite amounts, which alleviate the burden on the heart. The esters affect or change heart metabolism in terms of energy saving.

(2). Shock formation and excitability of the stimulus conduction system in the heart were reduced, resulting in a therapeutically detectable anti-defibrillation action.

(3). The action of the compound significantly reduced the tension of vascular smooth muscle. This vasculoskeletal action may occur in the entire vasculature, or in some isolated way (such as the central nervous system) in a range of vasculature.

(4). The compound lowered blood pressure in normal and hypertensional animals and thus can be used as an anti-solids agent.

(5). The compound had potent muscle-nerve action on the gastrointestinal, intestinal, urinary and respiratory system smooth muscles and the like.

As described above, novel asymmetric 1,4-dihydropyridine ester compounds prepared according to the method of the present invention can be used as human and veterinary medicines.

The present invention is a pharmaceutical prepared by mixing a compound prepared according to the method of the present invention as an active ingredient with a liquid diluent (except when using a surfactant) in addition to a solvent having a molecular weight of less than 200 (particularly less than 350). It provides a composition.

Furthermore, the present invention provides a pharmaceutical composition containing the compound of the present invention as an active ingredient in the form of a sterile or isotonic aqueous solution.

The present invention also provides a drug in dosage unit form which is a compound of the present invention alone or as a mixture with a diluent.

In addition, the present invention provides tablets, sugars, capsules, pills (containing cookie tablets and granules) which are formed alone or as a mixture with a diluent. Provides ampoules and suppositories

As used herein, the term "drug" refers to agglomerate aggregates suitable for drug administration, and "drug unit drug" means a daily dose or multiple of up to four times the daily dose of the compound, respectively. B or an intergranular particle aggregate suitable for drug administration containing a dilution (up to 1/40 or less). Whether the drug contains a daily dose or, for example, 1/2, 1/3 or 1/4 of the daily dose, is for the single dose or for example for two, three or four doses. It will be decided depending on whether it is.

Pharmaceutical compositions according to the present invention include ointments from active ingredients and aqueous or non-aqueous diluents, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions or syrups, granules and powders. It can be reshaped in form.

Illustrative diluents suitable for use in pharmaceutical species (eg granules) to form tablets, sugars, capsules and pills are as follows.

(a). Fillers and extenders such as starch, sugar, mannitol and silicic acid;

(b). Binders such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone;

(c). Wetting agents such as glycerol;

(d). Swelling agents such as agar-agar, calcium carbonate and sodium bicarbonate;

(e). Dissolution retardants such as paraffin;

(f). Absorption accelerators such as quaternary ammonium compounds;

(g). Surfactants such as cetyl alcohol, monostearic acid glycerol;

(h). Adsorbent carriers such as kaolin and bentonite;

(i). Lubricants, yttertal talc, magnesium stearate and calcium and solid polyethylene glycols.

Tablets, sugars, capsules and pills formed in pharmaceutical compositions according to the present invention may have conventional coatings, envelopes and protective matrices, which may contain milky agents. They may be formulated to release over a period of time as long as possible only the active ingredient, particularly in the intestinal tract, after administration. Coatings, envelopes and protective matrices and the like may be made of, for example, polymeric materials or waxes.

The active ingredient may be prepared in the form of a microcapsule together with one or several of the above-described diluents.

Diluents for use in pharmaceutical compositions suitable for formation as suppositories are usually water soluble, such as polyethylene glycol and fats (e.g., cocoa butter and higher esters (e.g., C ₁₄ -alcohols and C ₁₆ -fatty acids)) or mixtures of these diluents; Water-insoluble diluents and the like are suitable.

Pharmaceutical compositions such as ointments, pastes, creams and gels include animal and vegetable fats, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols; May contain conventional diluents such as silicon, bentonite, silicic acid, talc and zinc oxide or mixtures of these materials

Pharmaceutical compositions in powder and spray form may contain conventional diluents such as, for example, lactose, dalc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these materials.

Pharmaceutical compositions in the form of powders and sprays may contain diluents in the total, such as, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders or mixtures of these materials, and aerosol sprays may be conventionally formulated, for example, chlorofluorohydrocarbons. It may contain propane.

Pharmaceutical compositions such as liquids and emulsions may be prepared by conventional diluents, such as solvents, solubilizers and emulsifiers (of course, the above-mentioned solvents having a lower weight than 200 in addition to the presence of surfactants are not applicable), ie water, ethyl alcohol, iso Propyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethyl formamide, oils (such as peanut oil), glycerol, tetrahydrofurfuryl alcohol, poly And diluents such as solvents, solubilizers and emulsifiers, such as fatty acid esters of styrene glycol and sorbitol or mixtures thereof.

For parenteral administration, solutions and emulsions must be annihilated and, in certain cases, isotonic with blood.

Suspensions include pharmaceutical compositions such as conventional diluents such as liquid diluents such as water, ethyl alcohol, propylene glycol, surfactants (e.g., isostearyl alcohol, polyoxyethylene sorbitan and sorbitan esters), microcrystalline cellulose, Aluminum meta hydroxide, bentonite, agar-agar and tragaganth or mixtures thereof.

All pharmaceutical compositions prepared according to the present invention may contain colorants and preservatives, perfumes and odorants (eg peppermint oil, eucalyptus oil) and sweeteners (eg saccharin).

The present pharmaceutical compositions contain 0.5-90% active ingredient based on the total weight of the composition.

In addition to the compounds of the invention, the pharmaceutical compositions according to the invention may contain other pharmaceutically effective compounds and may also contain a number of compounds of the invention.

The diluent of the drug using the compound prepared in the present invention as an active ingredient may use any of the above-mentioned compounds related to the pharmaceutical composition. Such drugs may include solvents of less than 200 molecular weight as a single diluent.

The powdered particle aggregates constituting the drug according to the present invention may be any one of tablets, pills, sugars, capsules, suppositories, orally decomposed capsules and ampoules. Any of these forms may be removed to delay release of the active ingredient, such as capsules, which include a protective sheath that provides some of the drug as interspersed and aggregated.

A suitable daily dosage for the drug of the present invention to be administered intravenously is preferably in the range of 0.005-90 mg, especially in the range of 2.5-450 mg, based on the weight of the active ingredient.

The pharmaceutical compositions and drug preparations described above are known methods such as mixing the active ingredient (s) with diluent (s) to form pharmaceutical compositions (eg granules) and then forming the compositions into drugs (eg tablets). As is done by known methods.

Compounds prepared by the method of the present invention alone or in combination with a diluent or in the form of drugs can be administered to humans and animals to inhibit (prevent, rescue, treat) the above-mentioned diseases.

The active compounds can be administered orally, parenterally, rectally or locally, especially in the sublingual vein. Therefore, suitable pharmaceutical compositions and drugs should be made in a form suitable for sublingual administration and intravenous administration, and intravenous and sublingual administration are suitable among various administration methods.

In general, in order to achieve an effective result for intravenous administration, it is recommended to administer 0.0001-1mg per kg body weight per day, especially 0.0005-0.1mg, whereas in oral administration, the range of 0.005-10mg per day, especially 0.05-5mg Is good.

However, it may be necessary to deviate from the above-mentioned amounts because of the weight of the test animal or the method of administration, or the animal's individual adaptability to the form and drug, or the form and time and interval of administration of the drug. Therefore, in some cases it may be sufficient to use less than the above-mentioned minimum amount, while in other cases, the above upper limit must be exceeded. When administering larger doses, it is best to divide the dose several times throughout the day. The same dosage ranges as described above apply to the case of human medicaments, and again with respect to the human medicament the general idea of the above-described illustration.

Hereinafter, the present invention will be described in more detail with reference to the following examples.

Example 1

A solution of 5.3 g of benzaldehyde, 5, 8 g of β-aminoxtonic acid methyl ester and 6.5 g of acetoacetic acid ethyl ester in 50 ml methanol was heated for 8 hours, and the melting point was 153 DEG C (from ethanol). -Dimethyl-4-phenyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester 5-ethyl ester was produced. Yield: 74% of theory

Example 2

A solution of 7, 6 g 3-nitrobenzaldehyde, 5, 8 g acetoacetic acid methyl ester and 6.5 g β-aminocrotonic acid ethyl ester in 40 ml of ethanol was boiled for 6 hours and the melting point was 158 ° C. (from ethanol ), 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester 5-ethylester. Yield: 75% of theory

Example 3

A solution of 7.6 g of 3-nitrobenzaldehyde, 5, 8 g of β-aminocrotonic acid methyl ester and 7.0 g of acetoacetic acid propargyl ester in 40 ml of ethanol was heated for 10 hours, and the melting point was 112-113 占 폚 ( 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine3, 5-dicarboxylic acid 3-methyl ester 5-propargyl ester, from petroleum ether / ethyl acetate . Yield: 68% of theory

Example 4

A solution of 7.8 g 3-nitrobenzaldehyde, 6.5 g β-aminocrotonic acid ethyl ester and 9.4 g acetoacetic acid β-propoxyethyl ester in 40 ml of ethanol was boiled for 10 hours, and the melting point was 75 ° C. (petroleum). Ether, from ethyl acetate), 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-β-propoxyethyl ester Generated. Yield: 51% of theory

Example 5

A solution of 6.0 g of 2-methyl benzaldehyde, 6 and 5 g of β-aminocrotonic acid ethyl ester and 7.1 g of acetoacetic allyl ester in 40 ml of ethanol was heated for 10 hours, and the melting point was 105 캜 (ethyl acetate / petroleum). 2, 6-dimethyl-4- (2'-methylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-allyl ester.

Yield: 52% of theory

Example 6

8.7 g of 2-trifluoro-methylbenzaldehyde, 5, 8 g of aceto acetic acid methyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 50 ml of ethanol were boiled for 8 hours, and the melting point was 117-118 ° C. From 2, 6-dimethyl-4- (2'-trifluoro-methylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester 5-ethyl ester .

Yield: 65% of theory

Example 7

8.7 g of 2-trifluoro methylbenzaldehyde, 6 and 5 g of acetoacetic acid ethyl ester and 7.2 g of β-aminocrotonic acid isopropyl ester in 50 ml of methanol were heated for 8 hours, and the melting point was 106-107 DEG C. 2, 6-dimethyl-4- (2'-trifluoro-methylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-isopropyl ester which is petroleum ether / ethyl acetate) Was created.

Yield: 59% of theory

Example 8

8.7 g of 2-trifluoromethylbenzaldehyde, 6.5 g of β-aminocrotonic acid ethyl ester and 7.1 g of aceto acetic acid allyl ester in 50 ml of isopropanol were boiled for 6 hours and the melting point was 128 ° C. (from ethanol / water ), 2, 6-dimethyl-4- (2'-trifluoro-methylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethylester 5-allyl ester.

Yield: 57% of theory

Example 9

7.0 g of 2-chloro benzaldehyde, 5, 8 g of β-aminocrotonic acid methyl ester and 6.5 g of acetoacetic acid ethyl ester in 40 ml of ethanol were heated for 10 hours, and the melting point was 122-123 ° C. (from ethanol). 2, 6-dimethyl-4- (2'-chlorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methylester 5-ethyl ester was produced.

Yield: 69% of theory

Example 10

7.6 g of 4-methylmercaptobenzaldehyde, 5, 8 g of acetoacetic acid methyl ester and 6.5 g of beta-aminocrotonic acid ethyl ester in 40 ml of ethanol were boiled for 10 hours and the melting point was 163 DEG C (from ethanol). 2, 6-dimethyl-4- (4'-methylmercaptophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethylester 5-methyl ester were produced.

Yield: 67% of theory

Example 11

5.3 g of pyridine-2-aldehyde, 5, 8 g of acetoacetic acid methyl ester and 7.1 g of beta-aminocrotonic isopropyl ester in 50 ml of ethanol were boiled for 6 hours and the melting point was 188 ° C. (from ethanol). 2, 6-dimethyl-4- (0-pyridyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester 5-isopropyl ester were produced.

Yield: 70% of theory

Example 12

5.3 g of pyridine-3-aldehyde, 5, 8 g of acetoacetic acid methyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 40 ml of ethanol were boiled for 12 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-methyl ester 5-ethyl ester.

Yield: 72% of theory

Example 13

7.8 g of 1-naphthaldehyde, 5, 8 g of acetoacetic acid methyl ester and 6.5 g of acetoacetic acid ethyl ester in 50 ml of methanol were heated for 10 hours, and the melting point was 196-197 ° C. (petroleum ether / ethyl acetate). 2), 6-dimethyl-4- (1'-naphthyl) -1, 4-dihydro pyridine3, 5-dicarboxylic acid 3-methyl ester 5-ethyl ester.

Yield: 48% of theory

Example 14

5.8 g of thiophene-2-aldehyde, 5.8 g of beta-aminocrotonic acid methyl ester and 7.2 g of acetoacetic acid propyl ester in 50 ml of methanol were boiled for 8 hours, and Jungjung was 121-122 ° C (ethanol). 2,6dimethyl-4- (2'-tenyl) 1,4-dihydropyridine 3,5-dicarboxylic acid 3-methyl ester 5-isopropyl ester.

Yield: 53% of theory

Example 15

7.6 g of 3-nitrobenzaldehyde, 6, 5 g of acetoacetic acid ethyl ester and 9.1 g of beta-aminocrotonic acid cyclohexyl ester in 40 ml of ethanol were boiled for 10 hours, and the melting point was 135 캜 (petroleum ether / ethyl acetate). 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine3, 5-dicarboxylic acid 3-ethyl ester 5-cyclohexyl ester.

Yield: 43% of theory

Example 16

6.5 g of 2-cyanobenzaldehyde, 6 and 5 g of acetoacetic acid ethyl ester and 7.1 g of beta-aminocrotonic acid isopropyl ester in 50 ml of methanol were heated for 12 hours, and the melting point was 152 DEG C (from ethanol). Phosphorous 2, 6-dimethyl-4- (2'-cyanophenyl) -1, 4-dihydropyridine3, 5-dicarboxylic acid 3-ethyl ester 5-isopropyl ester was produced.

Yield: 51% of theory

Example 17

12 g of 6.5 g of 2-cyanobenzaldehyde, β-aminocrotonic acid ethyl ester and 7, 1 g of acetoacetic allyl ester in 40 ml of isopropanol resulted in boiling at 148 ° C. (from ethanol) 2, 6 -Dimethyl-4- (2'-cyanophenyl) -1, 4-dihydropyridine3, 5-dicarboxylic acid 3-ethylester 5-allyl ester was produced.

Yield: 42% of theory

Example 18

6.8 g of 2-methoxybenzaldehyde, 6.5 g of acetoacetic acid ethyl ester and 7, 1 g of beta-aminocrotonic acid isopropyl ester in 50 ml of ethanol were heated for 10 hours and the melting point was 130 ° C. (from ethanol / water ), 2, 6-dimethyl-4- (2'-methoxyphenyl) -1, 4-dihydro pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-isopropyl ester.

Yield: 61% of theory

Example 19

7.6 g 2-nitrobenzaldehyde, 5.8 g acetoacetic acid methyl ester and 7, 1 g β-aminocrotonic isopropyl ester in 50 ml of ethanol were boiled for 10 hours and the melting point was 174 DEG C (from ethanol). 2, 6-dimethyl-4- (2'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester 5-isopropyl ester were produced.

Yield: 52% of theory

Example 20

7.6 g 2-nitrobenzaldehyde, 5.8 g β-aminocrotonic acid methyl ester and 7, 2 g acetoacetic acid propyl ester in 50 ml of ethanol were heated for 8 hours and the melting point was 127-128 ° C. (ethyl acetate / petroleum oil). 2, 6-dimethyl-4- (2'-nitrophenyl) -1, 4-dihydropyridine3, 5-dicarboxylic acid 3-methyl ester 5-propyl ester.

Yield: 54% of theory

Example 21

A solution of 7.6 g of 3-nitrobenzaldehyde, 7.2 g of acetoacetic acid propyl ester and 7.1 g of β-aminocrotonic acid isopropyl ester in 40 ml of ethanol was boiled for 10 hours, and the melting point was 109-110 ° C. (ethanol 2), 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine3, 5-dicarboxylic acid 3-propylester 5-isopropyl ester.

Yield: 59% of theory

Example 22

A solution of 7.6 g of 3-nitrobenzaldehyde, 7.1 g of β-aminocrotonic acid isopropyl ester and 7, 1 g of acetoacetic acid allyl ester in 50 ml of isopropanol was boiled for 8 hours and the melting point was 96-97 ° C. (isopropanol 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydro pyridine3, 5-dicarboxylic acid 3-isopropyl ester-5-allyne ester.

Yield: 64% of theory

Example 23

A solution of 9.3 g of 3-nitro-6-chlorobenzaldehyde, 5.8 g of β-aminocrotonic acid methyl ester and 6, 5 g of acetoacetic acid ethyl ester in 50 ml of ethanol was heated for 6 hours, and the melting point was 163-164. 2, 6-dimethyl-4- (3'-nitro-6'-chlorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester 5-ethyl ester at ° C (from ethanol) Was created.

Yield: 65% of theory

Example 24

A solution of 6.0 g 2-methylbenzaldehyde, 6.5 g acetoacetic acid ethyl ester and 7.0 g β-aminocrotonic acid propargyl ester in 50 ml of methanol was boiled for 8 hours and the melting point was 129 DEG C (petroleum ether / From 2, 6-dimethyl-4- (2'-methylphenyl) -1, 4-dihydro pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-propargyl ester.

Yield: 51% of theory

Example 25

A solution of 6.2 g 2-fluorobenzaldehyde, 5.8 g β-aminocrotonic acid methyl ester and 7, 1 g acetoacetic acid allyl ester in 50 ml of ethanol was boiled for 8 hours and the melting point was 130 ° C. (ethanol / water). 2), 6-dimethyl-4- (2'-fluorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester 5-allyl ester.

Yield: 60% of theory

Example 26

A solution of 6.5 g of 3-cyanobenzaldehyde, 5.8 g of acetoacetic acid methyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 40 ml of methanol was heated for 10 hours, and the melting point was 150 캜 (from isopropanol). Phosphorous 2, 6-dimethyl-4- (3'-cyanophenyl) -1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-methyl ester 5-ethyl ester was produced.

Yield: 66% of theory

Example 27

A solution of 6.8 g 2-methoxybenzaldehyde, 6.5 g β-aminocrotonic acid ethyl ester and 9.2 g acetoacetic acid β-propoxyethyl ester in 50 ml of ethanol was heated for 10 hours. Petroleum ether / ethyl acetate) 2, 6-dimethyl-4- (2'-methoxyphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-β-propoxy Ethyl ester was produced.

Yield: 43% of theory

Example 28

A solution of 7.6 g of 3-nitrobenzaldehyde, 6.5 g of acetoacetic acid ethyl ester and 7.1 g of β-aminocrotonic acid propyl ester in 50 ml of methanol was boiled for 8 hours and the melting point was 132-133 ° C. (from methanol ), 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydro pyridine3, 5-dicarboxylic acid 3-ethyl ester 5-propyl ester.

Yield: 65% of theory

Example 29

A solution of 5.3 g of benzaldehyde, 7.1 g of acetoacetic acid allyl ester and 7.1 g of β-aminocrotonic isopropyl ester in 50 ml of ethanol was heated for 10 hours, and the melting point was 117 DEG C (from ethanol). -Dimethyl-4-phenyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-allyl ester-5-isopropyl ester was produced.

Yield: 62% of theory

Example 30

A solution of 7.6 g of 3-nitrobenzaldehyde, 6.5 g of β-aminocrotonic acid ethyl ester and 8.0 g of acetoacetic acid β-methoxyethyl ester in 50 ml of isopropanol was boiled for 8 hours. Ether / from ethyl acetate) 2, 6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-β-methoxyethyl ester Was created.

Yield: 49% of theory

Example 31

A solution of 7.8 g quinoline-4-aldehyde, 6.5 g acetoacetic acid ethyl ester and 5.8 g β-aminocrotonic acid methyl ester in 40 ml ethanol was heated for 8 hours and the melting point was 208 DEG C (from ethanol). 2, 6-dimethyl-4- (4'-curolyl) -1, 4-dihydropyridine 3, 5-carboxylic acid 3-methyl ester 5-ethyl ester was produced.

Yield: 58% of theory

Example 32

A solution of 5.3 g of benzaldehyde, 5.8 g of β-aminocrotonic acid methyl ester and 9.6 g of benzoylacetic acid ethyl ester in 50 ml of ethanol was heated for 10 hours to give a melting point of 152-153 ° C. (from ethanol). -Methyl-4, 6-diphenyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester 5-ethyl ester was produced. Yield: 56% of theory

Example 33

A solution of 7.8 g 2-naphthaldehyde, 6.5 g acetoacetic acid ethyl ester and 5.8 g aminocrotonic acid methyl ester in 100 ml ethanol was heated for 10 hours, resulting in a freezing point of 140-142 ° C. (ethanol) 2, 6-dimethyl-4- (2'-naphthyl) -1, 4-dihydropyridine 3, 5-carboxylic acid 3-methyl ester 5-ethyl ester was produced. Yield: 61% of theory

Example 34

A solution of 4.8 g of furan-2-aldehyde, 7.1 g of acetoacetic acid alkyl ester and 5.8 g of aminocrotonic acid methyl ester in 80 ml ethanol was boiled for 8 hours, resulting in a freezing point of 134-135 ° C. (ethanol) 2, 6-dimethyl-4- (2'-furyl) -1, 4-dihydropyridine-3, 5-dicarboxyan 3-allyl ester 5-methyl ester was produced.

Yield: 67% of theory

Example 35

A solution of 8.4 g of 4, 6-dimethoxypyrimidine-5-aldehyde, 5.8 g of acetoacetic acid methyl ester and 6.5 g of aminocrotonic acid ethyl ester in 80 ml of isopropanol was heated for 8 hours, resulting in a freezing point of 245 Produces 2, 6-dimethyl-4- (4 ', 6'-dimethoxypyrimidyl) -1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-methyl ester 5-ethyl ester which is ° C (ethanol) It became.

Yield: 62% of theory

Example 36

A solution of 7.8 g of isoquinolyl-1-aldehyde, 5.8 g of acetoacetic acid methyl ester, and 7.2 g of aminocrotonic acid isopropyl ester in 80 ml of ethanol was boiled for 8 hours, and the freezing point was 204 DEG C (ethanol). , 6-dimethyl-4- (1'-isoquinolyl) -1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-isopropyl ester 5-methyl ester were produced.

Yield: 71% of theory

Example 37

A solution of 7.5 g 3-nitrobenzaldehyde, 5.8 g acetoacetic acid methyl ester and 7.2 g β-ethyl-β-aminoacrylic acid ethyl ester in 60 ml of ethanol was boiled for 6 hours and the freezing point was 123 DEG C (acetic acid ester). ), 2-methyl-6-ethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-methyl ester 5-ethyl ester.

Yield: 48% of theory

Example 38

A solution of 6.1 g of 6-methylpyridine-2-aldehyde, 6.5 g of acetoacetic acid ethyl ester and 5.8 g of aminocrotonic acid methyl ester in 80 ml of ethanol was heated for 8 hours and the freezing point was 160 ° C. (ethanol / water). Phosphorous 2, 6-dimethyl-4- (6'-methylpyridine-2 ')-1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-methyl ester 5-ethyl ester was produced.

Yield: 52% of theory

Example 39

A solution of 8.7 g 2-trifluoromethylbenzaldehyde, 7.0 g acetoacetic acid propargyl ester and 5.8 g aminocrotonic acid methyl ester in 60 ml of alcohol was heated for 8 hours and the freezing point was 110 ° C. (diethyl Ether), 2, 6-dimethyl-4- (2'-trifluoromethylphenyl) -1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-propargyl ester 5-methyl ester.

Yield: 50% of theory

Example 40

A solution of 6.2 g 2-fluorobenzaldehyde, 7.0 g acetoacetic acid propargyl ester and 5.8 g β-aminocrotonic acid methyl ester in 80 ml of ethanol was stirred for 8 hours and the freezing point was 142 ° C. (ethanol). Phosphorous 2, 6-dimethyl-4- (2'-fluorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-propargyl ester 5-methyl ester was produced.

Yield: 73% of theory

Example 41

A solution of 8.9 g of 4-carboxyethyl benzaldehyde, 7.0 g of acetoacetic acid propargyl ester and 6.5 g of aminocrotonic acid ethyl ester in 80 ml of ethanol was heated for 10 hours and the freezing point was 110 ° C. (ethanol / water). Phosphorous 2, 6-dimethyl-4- (4'-carbethoxyphenyl ')-1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-propargyl ester 5-ethyl ester was produced.

Yield: 55% of theory

Example 42

A solution of 9.8 g of 2, 4, 5-trimethoxybenzaldehyde, 7.1 g of acetoacetic acid allyl ester and 5.8 g of aminocrotonic acid methyl ester in 80 ml ethanol was heated for 10 hours, and the freezing point was 98 캜 (acetic acid ester). / Petroleum ether) 2, 6-dimethyl-4- (2 ', 4', 5'-trimethoxyphenyl ')-1, 4-dihydropyridine 3, 5-dicarboxylic acid 3-allyl ester 5-methyl Ester was produced.

Yield: 50% of theory

Claims (1)

As described above in the text, the aldehyde of the following general formula (2) is reacted with the β-ketocarboxylic acid ester of the general formula (3) and the enaminocarboxylic acid ester of the general formula (4) in the presence of a diluent Method for producing asymmetric 1, 4-dihydropyridine ester of formula (1).

Food, R is a phenyl group having 1, 2 or 3 substituents selected from alkyl, alkoxy, halogen, nitro, nitrile, azido, trifluoromethyl, carboalkoxy and SO _n -alkyl (n = 0, 1 or 2) groups Or a naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, tenyl, furyl or pyryl group which may have one or more alkyl, alkoxy or halogen groups as substituents; R ¹ and R ³ are the same as or different from each other, and each represent a hydrogen atom, a phenyl or a linear or branched alkyl group; R ² and R ⁴ are different from each other and represent a straight or branched or cyclic saturated and unsaturated hydrocarbon group having a carbon chain which can be interrupted by one or two oxygen atoms, and optionally having a hydroxyl group as a substituent.