NO133712B - - Google Patents

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NO133712B
NO133712B NO119272A NO119272A NO133712B NO 133712 B NO133712 B NO 133712B NO 119272 A NO119272 A NO 119272A NO 119272 A NO119272 A NO 119272A NO 133712 B NO133712 B NO 133712B
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ester
acid
ethanol
dihydropyridine
theoretical
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NO119272A
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Norwegian (no)
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NO133712C (en
Inventor
H Meyer
F Bossert
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Bayer Ag
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Publication of NO133712C publication Critical patent/NO133712C/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

Oppfinnelsens gjenstand er en ny kjemisk fremgangsmåte til fremstilling av nye usymmetriske 1,4-dihydropyridindikarboksylsyreestere. The object of the invention is a new chemical process for the production of new unsymmetrical 1,4-dihydropyridine dicarboxylic acid esters.

Det er allerede kjent at omsetningen av aldehyder med den generelle formel It is already known that the turnover of aldehydes with the general formula

med fS-ketokarboksylsyreestere med den generelle formel og ammoniakk fører til de symmetriske 1,4-dihydropyridinderivater med den generelle formel (II<*>): with fS-ketocarboxylic acid esters of the general formula and ammonia leads to the symmetrical 1,4-dihydropyridine derivatives of the general formula (II<*>):

(Litteratur: Kirchner, Ber. 25, 2786 (1892)) (Literature: Kirchner, Ber. 25, 2786 (1892))

De samme 1,4-dihydropyridinderivater får man ifølge litteraturen ved reaksjon av aldehyder med $-ketokarboksylsyreestere og enaminkarboksylsyreestere med den generelle formel According to the literature, the same 1,4-dihydropyridine derivatives are obtained by reaction of aldehydes with $-ketocarboxylic acid esters and enamine carboxylic acid esters with the general formula

(Litteratur: Fox, Lewis, Wenner, J. Org. Chem. _16 1259 (1951)). (Literature: Fox, Lewis, Wenner, J. Org. Chem. _16 1259 (1951)).

Det er videre kjent at også omsetningen av aldehyder med enaminokarboksylsyreestere fører til dihydropyridinderivater med den generelle formel (II<*>): It is also known that the reaction of aldehydes with enaminocarboxylic acid esters leads to dihydropyridine derivatives with the general formula (II<*>):

(Litteratur: Cook, Heilbron, Steger, J. Chem. Soc. I_ London/, 1943, 413). Det er videre fra litteraturen kjent varianter til fremstilling av forbindelser med den generelle-formel (II<*>) som endelig består i at man bringer yliden-g<->ketokarboksylsyreestere med den generelle formel til reaksjon med enaminokarboksylsyreestere med den generelle struktur (Literature: Cook, Heilbron, Steger, J. Chem. Soc. I_ London/, 1943, 413). There are also variants known from the literature for the preparation of compounds with the general formula (II<*>) which finally consist in bringing ylidene-g<->ketocarboxylic acid esters with the general formula to reaction with enaminocarboxylic acid esters with the general structure

(Litteratur: Knoevenagel, Ber. 31, 743 (I898)). (Literature: Knoevenagel, Ber. 31, 743 (I898)).

Hittil er det imidlertid i litteraturen ikke omtalt usymmetriske 1,4-dihydropyridindikarboksylsyreestere. So far, however, unsymmetrical 1,4-dihydropyridinedicarboxylic acid esters have not been mentioned in the literature.

Ved tilgrunnlegging av de oppførte kjente fremgangs-måter er det å anta at omsetningen av yliden-g-ketokarboksylsyreestere med formel On the basis of the listed known methods, it is assumed that the reaction of ylidene-g-ketocarboxylic acid esters with formula

med enaminokarboksylsyreestere med formel gir forbindelser med formel (I): Ulempen ved denne totrinns-fremgangsmåte består imidlertid i at de i første trinn ved kondensasjon av en (3-keto-karboksylsyreester med et aldehyd oppnåelig yliden-B-ketokarbok-sylsyreester med den generelle formel with enaminocarboxylic acid esters of formula give compounds of formula (I): The disadvantage of this two-step process, however, consists in that in the first step by condensation of a (3-ketocarboxylic acid ester with an aldehyde obtainable ylidene-B-ketocarboxylic acid ester with the general formula

er meget vanskelig og ofte bare er å isolere i ren form med små is very difficult and is often only isolated in its pure form with small

- utbytter. - dividends.

Det er nå funnet at man får de nye usymmetriske 1,4-dihydropyridiner med formel (I) It has now been found that the new unsymmetrical 1,4-dihydropyridines of formula (I) are obtained

hvori in which

R betyr en fenylrest som inneholder 1-3 like eller forskjellige substituenter fra gruppene alkyl, alkoksy, halogen, nitro,. cyano, trifluormetyl, karbalkoksy eller alkylmerkapto eller betyr en eventuelt med alkyl, alkoksy eller haloger: substituert naftyl-, kinolyl-, isokinolyl-, pyridyl-, pyrimidyl-, tenyl-, furyl-. eller pyrrolylrest og R means a phenyl radical containing 1-3 identical or different substituents from the groups alkyl, alkoxy, halogen, nitro,. cyano, trifluoromethyl, carbalakoxy or alkyl mercapto or means an optionally with alkyl, alkoxy or halogens: substituted naphthyl-, quinolyl-, isoquinolyl-, pyridyl-, pyrimidyl-, thenyl-, furyl-. or pyrrolyl residue and

R"^ og R^ er like eller forskjellige og betyr hydrogen, fenyl eller en rettlinjet eller forgrenet alkylrest og 2 4 . R"^ and R^ are the same or different and mean hydrogen, phenyl or a straight or branched alkyl residue and 2 4 .

R og R er forskjellige fra hverandre og betyr en rettlinjet,forgrenet eller cyklisk mettet eller umettet hydrokarbonrest som eventuelt er avbrutt med 1 eller 2 oksygenatomer i kjeden og/eller er substituert med en hydroksygruppe, R and R are different from each other and mean a linear, branched or cyclic saturated or unsaturated hydrocarbon residue which is optionally interrupted by 1 or 2 oxygen atoms in the chain and/or is substituted with a hydroxy group,

i ett reaksjonstrinn og med utmerkede utbytter når man i nærvær av vann eller inerte organiske oppløsningsmidler ved temperaturer mellom 30 og 200°C omsetter aldehydet med formel in one reaction step and with excellent yields when, in the presence of water or inert organic solvents at temperatures between 30 and 200°C, the aldehyde is reacted with the formula

(II) (II)

hvori in which

R har overnevnte betydning, R has the above meaning,

med 3-ketokarboksylsyreestere med formel (III) with 3-ketocarboxylic acid esters of formula (III)

hvori in which

12 .. R og R har overnevnte betydning og enaminokarboksylsyreestere med formel (IV) 12 .. R and R have the above meaning and enaminocarboxylic acid esters of formula (IV)

hvori in which

3 4 3 4

R og R har overnevnte betydning. R and R have the above meaning.

De usymmetriske 1,4-dihydropyridiner med formel (I) har sterke koronarutvidende og antihypertensive egenskaper. The unsymmetrical 1,4-dihydropyridines of formula (I) have strong coronary dilating and antihypertensive properties.

Det er å betegne som meget overraskende, at ved omsetningen ifølge oppfinnelsen oppstår de usymmetriske 1,4-dihydropyridiner i så høy renhet og så gode utbytter, fordi man med hen-syn til teknikkens stand måtte vente at ved omsetningen ifølge oppfinnelsen, skulle det oppstå en høy mengde av uønskede, symmetriske 1,4-dihydropyridiner, en oppfatning som også støttes av litteraturen(WEISSBERGER, "Chemistry of Heterocyclic Compounds", Pyridine and Derivatives, Part I, side 502). It is to be described as very surprising that in the reaction according to the invention the unsymmetrical 1,4-dihydropyridines occur in such high purity and in such good yields, because in view of the state of the art one had to expect that in the reaction according to the invention, a high amount of undesired, symmetrical 1,4-dihydropyridines, an opinion also supported by the literature (WEISSBERGER, "Chemistry of Heterocyclic Compounds", Pyridine and Derivatives, Part I, page 502).

Således betyr fremgangsmåten ifølge oppfinnelsen overvinnelse av en fordom. Thus, the method according to the invention means overcoming a prejudice.

En vesentlig fordel ved fremgangsmåten ligger ved siden av de utmerkede utbytter og den høye renhet av det ønskede produkt i, at en kan gjennomføre som entrinns-prosess med enkelt teknikk og høy økonomi. A significant advantage of the method lies alongside the excellent yields and the high purity of the desired product in that it can be carried out as a one-step process with simple technique and high economy.

Anvender man 3-nitro-benzaldehyd, aceteddiksyre-isopropylester og amino-krotonsyre-metylester som utgangsstoffer, så kan reaksjonsforløpet gjengis ved følgende formelskjema: If 3-nitro-benzaldehyde, acetoacetic acid isopropyl ester and amino-crotonic acid methyl ester are used as starting materials, the course of the reaction can be reproduced by the following formula:

I formel (II) betyr In formula (II) means

R fortrinnsvis en fenylrest som kan være substituert med 1-3 like eller forskjellige substituenter fra gruppen alkyl eller alkoksy med 1-4, fortrinnsvis 1-2 karbonatomer, halogen, som fluor, klor eller brom, nitro, cyano, karbalkoksy med fortrinnsvis 1-4 karbonatomer i alkoksyresten eller alkylmerkapto eller betyr en naftyl-, kinolyl-, pyridyl-, pyrimidyl-, tenyl-, furyl- eller pyrrolylrest, idet naftyl-, kinolyl- og isokinolylresten kan være substituert med halogen, som fluor eller brom, alkyl- og/eller alkoksygrupper med 1-2 karbonatomer, de overnevnte pyridyl-, pyrroly1-, tenyl- eller furylrester med en alkylrest med 1-2 karbonatomer og pyrimi-dylresten i tillegg med 1-2 metoksy- eller etoksygrupper og R preferably a phenyl radical which can be substituted with 1-3 identical or different substituents from the group alkyl or alkoxy with 1-4, preferably 1-2 carbon atoms, halogen, such as fluorine, chlorine or bromine, nitro, cyano, carbolicoxy with preferably 1- 4 carbon atoms in the alkoxy residue or alkyl mercapto or means a naphthyl, quinolyl, pyridyl, pyrimidyl, thenyl, furyl or pyrrolyl residue, the naphthyl, quinolyl and isoquinolyl residue may be substituted with halogen, such as fluorine or bromine, alkyl and/or alkoxy groups with 1-2 carbon atoms, the above-mentioned pyridyl, pyrroly-1, thenyl or furyl residues with an alkyl residue with 1-2 carbon atoms and the pyrimidyl residue additionally with 1-2 methoxy or ethoxy groups and

R<1> og Fr som er like eller forskjellige betyr hydrogen eller en rettlinjet eller forgrenet alkylgruppe med 1-4 karbonatomer eller fenyl og R<1> and Fr which are the same or different mean hydrogen or a straight or branched alkyl group with 1-4 carbon atoms or phenyl and

R 2 og R 4 som alltid må være forskjellige fra hverandre hver gang betyr en rettlinjet, forgrenet eller cyklisk mettet eller umettet hydrokarbonrest, fortrinnsvis med 1-6 karbonatomer, spesielt en alifatisk hydrokarbonkjede med 1-3 karbonatomer idet hydrokarbonkjeden kan være avbrutt med 1 eller 2 oksygenatomer, fortrinnsvis med et oksygenatom og/eller være substituert med en hydroksylgruppe. R 2 and R 4 which must always be different from each other each time means a linear, branched or cyclic saturated or unsaturated hydrocarbon residue, preferably with 1-6 carbon atoms, especially an aliphatic hydrocarbon chain with 1-3 carbon atoms, the hydrocarbon chain may be interrupted by 1 or 2 oxygen atoms, preferably with an oxygen atom and/or be substituted with a hydroxyl group.

De ifølge oppfinnelsen anvendbare utgangsstoffer The starting materials which can be used according to the invention

er allerede kjent og kan fremstilles etter kjente metoder. is already known and can be produced by known methods.

Som fortynningsmiddel kommer det på tale vann og alle inerte organiske oppløsningsmidler. Hertil hører fortrinnsvis alkoholer som metanol, etanol, propanol, etere som dioksan, dietyleter eller iseddik, pyridin, dimetylformamid, dimetyl-sulfoksyd eller acetonitril. Diluents include water and all inert organic solvents. These preferably include alcohols such as methanol, ethanol, propanol, ethers such as dioxane, diethyl ether or glacial acetic acid, pyridine, dimethylformamide, dimethyl sulfoxide or acetonitrile.

Reaksjonstemperaturene kan varieres innen et stort område. Vanligvis arbeider man mellom 30 og 200°C, fortrinnsvis ved oppløsningsmidlets temperatur. The reaction temperatures can be varied within a large range. Usually one works between 30 and 200°C, preferably at the temperature of the solvent.

Omsetningen kan gjennomføres ved normaltrykk-, The turnover can be carried out at normal pressure,

men også ved forhøyet trykk. Vanligvis arbeider man ved normaltrykk . but also at elevated pressure. Usually you work at normal pressure.

Ved gjennomføring av fremgangsmåten ifølge oppfinnelsen anvendes de i reaksjonen deltagende stoffer hver gang omtrent i molare mengder. When carrying out the method according to the invention, the substances participating in the reaction are used each time in approximately molar quantities.

De nye forbindelser som fremstilles er stoffer anvendbare som legemidler. De har et bredt og mangesidig"The new compounds that are produced are substances that can be used as medicines. They have a broad and versatile"

■farmakologisk virkningsspektrum. ■pharmacological spectrum of action.

I detalj kunne det i dyreeksperiment påvises følgende hovedvirkninger: 1) Forbindelsene bevirker ved parenteral, oral og perlingual inngivning en tydelig og langvarig utvidelse av koronarkarene. Denne virkning på koronarkarene forsterkes ved en samtidig nitrit-lignende hjerteavlastende effekt. In detail, the following main effects could be demonstrated in animal experiments: 1) When administered parenterally, orally and perlingually, the compounds cause a clear and long-lasting dilation of the coronary vessels. This effect on the coronary vessels is enhanced by a simultaneous nitrite-like heart-relieving effect.

De påvirker respektivt forandrer hjertestoffskiftet i retning av en energibe-sparelse. 2) Påvirkningen av irritasjons- og stimulerings-systemet innen hjertet nedsettes således at det fremkommer i terapeutiske doser påvisbar anti-flimmervirkning, 3) Tonusen av karenes glatte muskulatur nedsettes sterkt under virkning av forbindelsene. Denne karspasmolytiske virkning kan finne sted i det samlede karsystem eller manifistere seg mer eller mindre isolert i omgivende karområder (som f.eks. They influence or change cardiac metabolism in the direction of energy saving. 2) The influence of the irritation and stimulation system within the heart is reduced so that a detectable anti-fibrillation effect appears in therapeutic doses, 3) The tone of the smooth muscles of the vessels is greatly reduced under the action of the compounds. This vascular spasmolytic effect can take place in the overall vascular system or manifest itself more or less isolated in surrounding vascular areas (such as

sentralnervesystemet). central nervous system).

4) Forbindelsene senker blodtrykket fra normotone og hypertone dyr og kan således anvendes som 4) The compounds lower the blood pressure of normotonic and hypertonic animals and can thus be used as

antihypertensive midler. antihypertensive agents.

5) Forbindelsene har sterk muskulatur-spasmolytiske virkninger som tydeliggjøres på den glatte muskulatur av maven, tarmkanalen, urogenial-kanalen og respirasjonssystemet. 5) The compounds have strong muscle-spasmolytic effects which are evident on the smooth muscles of the stomach, the intestinal tract, the urogenital tract and the respiratory system.

Norsk søknad nr. 1190/72 og nr. 1191/72 ved-rører analogifremgangsmåter til fremstilling av tilsvarende forbindelser. Norwegian application No. 1190/72 and No. 1191/72 relate to analogous methods for the preparation of corresponding compounds.

Eksempel 1. Example 1.

Etter 8 timers oppvarmning av en oppløsning av After 8 hours of heating a solution of

5,3 g benzaldehyd, 5,8 g g-aminokrotonsyremetylester og 6,5 g aceteddiksyreetylester i 50 ml etanol fremkom 2,6-dimetyl-4-fenyl-l,4-dihydropyridin-3,5-dikarb oksylsyre-3-imetylester-5-etylester av smeltepunkt 153°C (etanol). Utbytte 74$ av det teoretiske. 5.3 g of benzaldehyde, 5.8 g of g-aminocrotonic acid methyl ester and 6.5 g of acetoacetic acid ethyl ester in 50 ml of ethanol yielded 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-imethyl ester -5-ethyl ester of melting point 153°C (ethanol). Dividend 74$ of the theoretical.

Eksempel 2, Example 2,

Etter 6 timers kokning av en oppløsning av 7,6 g 3- nitro-benzaldehyd, 5,8 g aceteddiksyremetylester og 6,5 g B-aminokrotonsyreetylester i 40 ml etanol fremkom 2,6-dimetyl-4- (3'-nitrofenyl)-l,4-dihydropyridin-3,5~dikarboksylsyre-3-metylester-5-etylester av smeltepunkt 158°C (etanol). Utbytte 75% av det teoretiske. After boiling a solution of 7.6 g of 3-nitro-benzaldehyde, 5.8 g of acetoacetic acid methyl ester and 6.5 g of B-aminocrotonic acid ethyl ester in 40 ml of ethanol, 2,6-dimethyl-4-(3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester of melting point 158°C (ethanol). Yield 75% of the theoretical.

Eksempel 3. Example 3.

Etter 10 timers oppvarmning av en oppløsning av '7,6 g 3-nitrobenzaldehyd, 5,8 g B-aminokrotonsyremetylester og 7,0 g aceteddiksyrepropargylester i 40 ml etanol, fremkom 2, 6-dimetyl-4- (3 ' -nitrofenyl)-l,4-dihydropyridin-3,5-di-karboksylsyre-3-metylester-5-propargylester av smeltepunkt 112-113°C (petroleter/eddikester). Utbytte 68$ av det teoretiske . After 10 hours of heating a solution of '7.6 g of 3-nitrobenzaldehyde, 5.8 g of B-aminocrotonic acid methyl ester and 7.0 g of acetoacetic acid propargyl ester in 40 ml of ethanol, 2,6-dimethyl-4-(3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-propargyl ester of melting point 112-113°C (petroleum ether/acetic ester). Dividend 68$ of the theoretical .

Eksempel 4. Example 4.

■Ved 10 timers kokning av en oppløsning av 7,8 g 3-nitrobenzaldehyd, 6,5 g B-aminokrotonsyreetylester, 9,4 g aceteddiksyre-B-propoksyetylester i 40 ml etanol, fremkom 2,6-dimetyl-4-(3'-nitrofény1)-l,4-dihydropyridin-3, 5-dikarbok-sylsyre-3-etylester-5-B-propoksyetylester av smeltepunkt 75°C (petroleter/eddikester). Utbytte 51$ av det teoretiske. ■By boiling a solution of 7.8 g of 3-nitrobenzaldehyde, 6.5 g of B-aminocrotonic acid ethyl ester, 9.4 g of acetoacetic acid-B-propoxyethyl ester in 40 ml of ethanol, 2,6-dimethyl-4-(3 -nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-B-propoxyethyl ester of melting point 75°C (petroleum ether/acetic ester). Dividend 51$ of the theoretical.

Eksempel 5* Example 5*

Ved 10 timers oppvarmning av en oppløsning av 6,0 g 2-metylbenzaldehyd, 6,5 g B-aminokrotonsyreetylester og 7,1 g aceteddiksyreallylester i 40 ml etanol fremkom 2,6-dimetyl-4-(2'-metylfenyl)-l,4-dihydropyridin-3,5_dikarboksyl-syre-3-etylester-5-allylester av smeltepunkt 105°C (eddikester/petroleter). Utbytte 52% av det teoretiske. By heating a solution of 6.0 g of 2-methylbenzaldehyde, 6.5 g of B-aminocrotonic acid ethyl ester and 7.1 g of acetoacetic acid allyl ester in 40 ml of ethanol for 10 hours, 2,6-dimethyl-4-(2'-methylphenyl)-1 ,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-allyl ester of melting point 105°C (acetic ester/petroleum ether). Yield 52% of the theoretical.

Eksempel 6. Example 6.

Etter 8 timers kokning av 8,7 g 2-trifluormetyl-benzaldehyd, 5,8 g aceteddiksyremetylester og 6,5 g B-aminokrotonsyreetylester i 50 ml etanol, fremkom 2,6-dimetyl-4-(2'-trifluor-metylfenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-metylester-5-etylester av smeltepunkt 117 - 118°C (etanol/vann). Utbytte 65% av det teoretiske. After 8 hours of boiling 8.7 g of 2-trifluoromethyl-benzaldehyde, 5.8 g of acetoacetic acid methyl ester and 6.5 g of B-aminocrotonic acid ethyl ester in 50 ml of ethanol, 2,6-dimethyl-4-(2'-trifluoro-methylphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester of melting point 117 - 118°C (ethanol/water). Yield 65% of the theoretical.

Eksempel 7. Example 7.

Ved 8 timers oppvarmning av 8,7 g 2-trifluormetylbenzaldehyd, 6,5 g aceteddiksyreetylester og 7, 2 g 3-aminokroton-syre isopropylester i 50 ml metanol, fremkom 2,6-dimetyl-4-(2'-trifluormetylfenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-etylester-5-isopropylester av smeltepunkt 106-107°C (petroleter/eddikester). Utbytte 59% av det teoretiske. Eksempel 8. By heating 8.7 g of 2-trifluoromethylbenzaldehyde, 6.5 g of acetoacetic acid ethyl ester and 7.2 g of 3-aminocrotonic acid isopropyl ester in 50 ml of methanol for 8 hours, 2,6-dimethyl-4-(2'-trifluoromethylphenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-isopropyl ester of melting point 106-107°C (petroleum ether/acetic ester). Yield 59% of the theoretical. Example 8.

Ved 8 timers kokning av 8,7 g 2-trifluormetylbenzaldehyd, 6,5 g B-aminokrotonsyreetylester og 7, 1 g aceteddiksyreallylester i 50 ml isopropanol, fremkom 2,6-dimetyl-4-(2'-trifluormetyl-fenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-etylester-5-allylester av smeltepunkt 128°C (etanol/vann). Utbytte 575? av det teoretiske. By boiling 8.7 g of 2-trifluoromethylbenzaldehyde, 6.5 g of B-aminocrotonic acid ethyl ester and 7.1 g of acetoacetic acid allyl ester in 50 ml of isopropanol, 2,6-dimethyl-4-(2'-trifluoromethyl-phenyl)-l ,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-allyl ester of melting point 128°C (ethanol/water). Dividend 575? of the theoretical.

Eksempel 9. Example 9.

Etter 10 timers oppvarmning av 730 g 2-klorbenzalde-hyd, 5,8 g B-aminokrotonsyremetylester, 6,5 g aceteddiksyreetylester og 40 ml etanol , fremkom 2,6-dimetyl-4-(2'-klorfenyl)-l,4-dihydro-pyridin-3,5-dikarboksylsyre-3-metylester-5-etylester av smeltepunkt 122-123°C (etanol). Utbytte 69% av det teoretiske. After 10 hours of heating 730 g of 2-chlorobenzaldehyde, 5.8 g of B-aminocrotonic acid methyl ester, 6.5 g of acetoacetic acid ethyl ester and 40 ml of ethanol, 2,6-dimethyl-4-(2'-chlorophenyl)-1,4 -dihydro-pyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester of melting point 122-123°C (ethanol). Yield 69% of the theoretical.

Eksempel 10. Example 10.

Etter lo timers kokning av 756 g 4-metylmerkapto-benzaldehydy 5,8 g aceteddiksyremetylester og 6,5 g B-aminokrotonsyreetylester i 40 ml etanol, fremkom 2,6-dimetyl-4-(4'-metylmer-kaptofenyl)-l,4-dihydropyridin-3j 5-dikarboksylsyre-3~etylester-5-metylester av smeltepunkt 163°C (etanol). Utbytte 67% av det teoretiske. After boiling for 10 hours 756 g of 4-methylmercapto-benzaldehyde and 5.8 g of acetoacetic acid methyl ester and 6.5 g of B-aminocrotonic acid ethyl ester in 40 ml of ethanol, 2,6-dimethyl-4-(4'-methylmer-captophenyl)-1 was obtained, 4-dihydropyridine-3j 5-dicarboxylic acid-3-ethyl ester-5-methyl ester of melting point 163°C (ethanol). Yield 67% of the theoretical.

Eksempel 11. Example 11.

Ved 6 timers kokning av 5j3 g pyridin-2-aldehyd, 5S8 g aceteddiksyremetylester og 7jl g B-aminokrotonsyreisopropylester i 50 ml etanol, fremkom 2,6-dimetyl-4-pyridyl-l,4-dihydro-pyridin-3j 5-dikarboksylsyre-3-metylester-5-isopropylester av smeltepunkt 188°C (etanol). Utbytte 70$ av det teoretiske. By boiling for 6 hours 5j3 g of pyridine-2-aldehyde, 5S8 g of acetoacetic acid methyl ester and 7jl g of B-aminocrotonic acid isopropyl ester in 50 ml of ethanol, 2,6-dimethyl-4-pyridyl-1,4-dihydro-pyridine-3j 5-dicarboxylic acid appeared -3-methyl ester-5-isopropyl ester of melting point 188°C (ethanol). Dividend 70$ of the theoretical.

Eksempel 12. Example 12.

Etter 12 timers kokning av 5S3 g pyridin-3-aldehyd, 5,8 g aceteddiksyremetylester og 6,5 g B-aminokrotonsyreetylester- After 12 hours of boiling 5S3 g of pyridine-3-aldehyde, 5.8 g of acetoacetic acid methyl ester and 6.5 g of B-aminocrotonic acid ethyl ester-

i 40 ml (etanol), fremkom 2,6-dimetyl-4-B-pyridyl-l,4-dihydropyri-din-3,5-dikarboksylsyre-3~nietylester-5-etylester av smeltepunkt 191-192°C (etanol). Utbytte 72% av det teoretiske. in 40 ml (ethanol), 2,6-dimethyl-4-B-pyridyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3~niethyl ester-5-ethyl ester of melting point 191-192°C (ethanol ). Yield 72% of the theoretical.

Eksempel 13- Example 13-

Etter 10 timers oppvarmning av 7,8 g 1-naftaldehyd, 5,8 g B-aminokrotonsyremetylester og 6,5 g aceteddiksyreetylester i 50 ml metanol, fremkom §,6-dimetyl-4-(l'-naftyl)-l,4-dihydro-pyridin-3,5-dikarboksylsyre-3-metylester-5-etylester av smeltepunkt 196-197°C (petroleter/eddikester). Utbytte 48$ av det teoretiske. Eksempel 14. After 10 hours of heating 7.8 g of 1-naphthaldehyde, 5.8 g of B-aminocrotonic acid methyl ester and 6.5 g of acetoacetic acid ethyl ester in 50 ml of methanol, §,6-dimethyl-4-(1'-naphthyl)-1,4 appeared -dihydro-pyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester of melting point 196-197°C (petroleum ether/acetic ester). Dividend 48$ of the theoretical. Example 14.

Ved 8 timers kokning av 5,8 g tiofen-2-aldehyd, 5,8 g B-aminokrotonsyremetylester og 7,2 g aceteddiksyrepropylester i 50 ml metanol fremkom 2,6-dimetyl-4-(2'-tenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-metylester-5-isopropylester av smeltepunkt 121-122°C (etanol/vann). Utbytte 537» av det teoretiske. By boiling for 8 hours 5.8 g of thiophene-2-aldehyde, 5.8 g of B-aminocrotonic acid methyl ester and 7.2 g of acetoacetic acid propyl ester in 50 ml of methanol resulted in 2,6-dimethyl-4-(2'-thenyl)-1, 4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-isopropyl ester of melting point 121-122°C (ethanol/water). Yield 537” of the theoretical.

Eksempel 15. Example 15.

Etter 10 timers kokning av 7,6 g 3-nitrobenzaldehyd, 6,5 g aceteddiksyreetylester og 9,1 g B-aminokrotonsyrecykloheksyl-ester i 40 ml etanol fremkom 2,6-dimetyl-4-(3'-nitrofenyl)-l,4-dihydropyridin-3,5_dikarboksylsyre-3-etylester-5-cykloheksylester av smeltepunkt 135°C (petroleter/eddikester). Utbytte 43% av det teoretiske. After boiling for 10 hours 7.6 g of 3-nitrobenzaldehyde, 6.5 g of acetoacetic acid ethyl ester and 9.1 g of B-aminocrotonic acid cyclohexyl ester in 40 ml of ethanol resulted in 2,6-dimethyl-4-(3'-nitrophenyl)-1, 4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-cyclohexyl ester of melting point 135°C (petroleum ether/acetic ester). Yield 43% of the theoretical.

Eksempel 16. Example 16.

Etter 12 timers oppvarmning av 6,5 g 2-cyanbenzaldehyd, 6,5 g aceteddiksyreetylester og 7,1 g B-aminokrotonsyreisopropylester i 50 ml metanol fremkom 2,6-dimetyl-4-(2'-cyanfenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-etylester-5_isopropylester av smeltepunkt 152°C (etanol). Utbytte 51% av det teoretiske. After 12 hours of heating 6.5 g of 2-cyanobenzaldehyde, 6.5 g of acetoacetic acid ethyl ester and 7.1 g of B-aminocrotonic acid isopropyl ester in 50 ml of methanol, 2,6-dimethyl-4-(2'-cyanophenyl)-1,4- dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-isopropyl ester of melting point 152°C (ethanol). Yield 51% of the theoretical.

Eksempel 17. Example 17.

Ved 12 timers kokning av 6,5 g 2-cyanbenzaldehyd, 6,5 g B-aminokrotonsyreetylester og 7,1 g aceteddiksyreallylester og 40 ml isopropanol, fremkom 2,6-dimetyl-4-(2'-cyanfenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-etylester-5-allylester av smeltepunkt 148°C (etanol). Utbytte .42$ av det teoretiske. " Eksempel 18. By boiling 6.5 g of 2-cyanobenzaldehyde, 6.5 g of B-aminocrotonic acid ethyl ester and 7.1 g of acetoacetic acid allyl ester and 40 ml of isopropanol for 12 hours, 2,6-dimethyl-4-(2'-cyanophenyl)-1,4 -dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-allyl ester of melting point 148°C (ethanol). Yield .42$ of the theoretical. " Example 18.

Ved 10 timers oppvarmning av 6., 8 g 2-metoksybenzaldehyd, 6,5 g aceteddiksyreetylester og 7,1 g B-aminokrotonsyreisopropylester i 50 ml etanol, fremkom 2,6-dimetyl-4-(2'-metoksyfenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-etylester-5-isopropylester av smeltepunkt 130°C (etanol/vann). Utbytte 61% av det teoretiske. By heating for 10 hours 6., 8 g of 2-methoxybenzaldehyde, 6.5 g of acetoacetic acid ethyl ester and 7.1 g of B-aminocrotonic acid isopropyl ester in 50 ml of ethanol, 2,6-dimethyl-4-(2'-methoxyphenyl)-1 appeared, 4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-isopropyl ester of melting point 130°C (ethanol/water). Yield 61% of the theoretical.

Eksempel 19♦ Example 19♦

Etter 10 timers kokning av 7,6 g 2-nitrobenzaldehyd, 5,8 g aceteddiksyremetylester og 7,1 g B-aminokrotonsyreisopropylester i 50 ml etanol fremkom 2,6-dimetyl-4-(2'-nitrofenyl)-l,4-dihydropyridin-3j 5-dikarboksylsyre-3-metylester-5-isopropylester av smeltepunkt 174°C (etanol). Utbytte 52% av det teoretiske. Eksempel 20. After 10 hours of boiling 7.6 g of 2-nitrobenzaldehyde, 5.8 g of acetoacetic acid methyl ester and 7.1 g of B-aminocrotonic acid isopropyl ester in 50 ml of ethanol, 2,6-dimethyl-4-(2'-nitrophenyl)-1,4- dihydropyridine-3j 5-dicarboxylic acid-3-methyl ester-5-isopropyl ester of melting point 174°C (ethanol). Yield 52% of the theoretical. Example 20.

Etter 8 timers oppvarmning av 1, 6 g 2-nitrogenzalde-hyd, 5j8 g B-aminokrotonsyremetylester og 7,2 g aceteddiksyrepropylester i 50 ml etanol, fremkom 2,6-dimetyl-4-(2'-nitrofenyl)-1,4-dihydropyridin-3,5-dikarboksylsyre-3-metylester-5-propylester av smeltepunkt 127-128°C (eddikester/petroleter). Utbytte 54% av det teoretiske. After 8 hours of heating 1.6 g of 2-nitrogenaldehyde, 5j8 g of B-aminocrotonic acid methyl ester and 7.2 g of acetoacetic acid propyl ester in 50 ml of ethanol, 2,6-dimethyl-4-(2'-nitrophenyl)-1,4 appeared -dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-propyl ester of melting point 127-128°C (acetic ester/petroleum ether). Yield 54% of the theoretical.

Eksempel 21. Example 21.

Etter 10 timers kokning av en oppløsning av 7,6 g 3- nitrobenzaldehyd, 7,2 g aceteddiksyrepropylester og 7,1 g B-aminokrotonsyreisopropylester i 40 ml metanol, fremkom 2,6-dimetyl-4- (3'-nitrofenyl)-1,4-dihydropyridin-3,5-dikarboksylsyre-3-propylester-5-isopropylester av smeltepunkt 109-110°C (etanol). Utbytte 59% av det teoretiske. After boiling a solution of 7.6 g of 3-nitrobenzaldehyde, 7.2 g of acetoacetic acid propyl ester and 7.1 g of B-aminocrotonic acid isopropyl ester in 40 ml of methanol, 2,6-dimethyl-4-(3'-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid-3-propyl ester-5-isopropyl ester of melting point 109-110°C (ethanol). Yield 59% of the theoretical.

Eksempel 22. Example 22.

Etter 8 timers kokning av en oppløsning av 7,6 g 3- nitrobenzaldehyd, 7,1 g B-aminokrotonsyreisopropylester og 7,1 g aceteddiksyreallylester i 50 ml isopropanol, fremkom 2,6-dimetyl-4- (3_,nitrofenyl)-1,4-dihydropyridin-3,5-dikarboksylsyre-3-isopropylester-5-allylester av smeltepunkt 96-97°C (isopropanol). After 8 hours of boiling a solution of 7.6 g of 3-nitrobenzaldehyde, 7.1 g of B-aminocrotonic acid isopropyl ester and 7.1 g of acetoacetic acid allyl ester in 50 ml of isopropanol, 2,6-dimethyl-4-(3_,nitrophenyl)-1 ,4-dihydropyridine-3,5-dicarboxylic acid-3-isopropyl ester-5-allyl ester of melting point 96-97°C (isopropanol).

Utbytte 64$ av det teoretiske. Dividend 64$ of the theoretical.

Eksempel 23. Example 23.

Ved 6 timers oppvarmning av en oppløsning av 9,3 g 3- nitro-6-klorbenzaldehyd, 5,8 g B-aminokrotonsyremetylester og 6,5 g aceteddiksyreetylester i 50 ml etanol, fremkom 2,6-dimetyl-4- (3'-nitro-61-klorfenyl)-l,4-dihydropyridin-3,5~dikarboksylsyre-3- metylester-5-etylester av smeltepunkt 163-16'4°C (etanol). Utbyt r 65$ av det teoretiske.- By heating for 6 hours a solution of 9.3 g of 3-nitro-6-chlorobenzaldehyde, 5.8 g of B-aminocrotonic acid methyl ester and 6.5 g of acetoacetic acid ethyl ester in 50 ml of ethanol, 2,6-dimethyl-4-(3' -nitro-61-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester of melting point 163-16'4°C (ethanol). Dividend r 65$ of the theoretical.-

Eksempel 24. Example 24.

Etter 8 timers kokning av en oppløsning av 6,0 g 2-metylbenzaldehyd, 6,5 g aceteddiksyreetylester og 7,0 g B-aminokrotonsyrepropargylester i 50 ml metanol, fremkom 2,6-dimety>-4- (2'-metylfenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3~etylester-5-propargylester av smeltepunkt 129°C (petroleter/eddikeste: Utbytte 51$ av det teoretiske. After 8 hours of boiling a solution of 6.0 g of 2-methylbenzaldehyde, 6.5 g of acetoacetic acid ethyl ester and 7.0 g of B-aminocrotonic acid propargyl ester in 50 ml of methanol, 2,6-dimethyl>-4-(2'-methylphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-propargyl ester of melting point 129°C (petroleum ether/acetic acid: Yield 51$ of the theoretical.

Eksempel 25. Example 25.

Ved 8 timers kokning av en oppløsning av 6,2 g 2-fluorbenzaldehyd, 5,8 g B-aminokrotonsyremetylester og 7jl g aceteddiksyreallylester i 50 ml etanol, fremkom 2,6-dimetyl-4-(2'-fluorfenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-metylester-5-allylester av smeltepunkt 130°C (etanol/vann). Utbytte 60% av det teoretiske. By boiling for 8 hours a solution of 6.2 g of 2-fluorobenzaldehyde, 5.8 g of B-aminocrotonic acid methyl ester and 7 l g of acetoacetic acid allyl ester in 50 ml of ethanol, 2,6-dimethyl-4-(2'-fluorophenyl)-1 was obtained, 4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-allyl ester of melting point 130°C (ethanol/water). Yield 60% of the theoretical.

Eksempel 26. Example 26.

Etter 10 timers oppvarmning av en oppløsning av 6,5 g 3-cyanbenzaldehydj 5,8 g aceteddiksyremetylester og 6,5 g B-aminokrotonsyreetylester i 40 ml metanol, fremkom 2,6-dimetyl-4-(3'-cyanfenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-metylester-5-etylester av smeltepunkt 150°C (isopropanol). Utbytte 66% av det teoretiske. After 10 hours of heating a solution of 6.5 g of 3-cyanobenzaldehydej 5.8 g of acetoacetic acid methyl ester and 6.5 g of B-aminocrotonic acid ethyl ester in 40 ml of methanol, 2,6-dimethyl-4-(3'-cyanophenyl)-l appeared ,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester of melting point 150°C (isopropanol). Yield 66% of the theoretical.

Eksempel 27. Example 27.

Etter 10 timers oppvarmning av en oppløsning av 6,8 g 2- metoksybenzaldehyd, 6,5 g B-aminokrotonsyreetylester og 9,2 g aceteddiksyre-B-propoksyetylester i 50 ml etanol fremkom 2,6-dimetyl-4-(2'-metoksyfenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3- etylester-5-B~propoksyetylester av smeltepunkt 130°C (petroleter/ eddikester). Utbytte 43% av det teoretiske. After 10 hours of heating a solution of 6.8 g of 2-methoxybenzaldehyde, 6.5 g of B-aminocrotonic acid ethyl ester and 9.2 g of acetoacetic acid-B-propoxyethyl ester in 50 ml of ethanol, 2,6-dimethyl-4-(2'- methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-B~propoxyethyl ester of melting point 130°C (petroleum ether/acetic ester). Yield 43% of the theoretical.

Eksempel 28. Example 28.

Ved 8 timers kokning av en oppløsning av 7,6 g 3~ nitrobenzaldehyd, 6,5 g aceteddiksyreetylester og 7,1 g B-amino-krotonsyrepropylester i 50 ml metanol, fremkom 2,6-dimetyl-4-(3'-nitrofenyl)-1,4-dihydropyridin-3,5~dikarboksylsyre-3-etylester-5-propylester av smeltepunkt 132-133°C (metanol). Utbytte 65% av det teoretiske. By boiling for 8 hours a solution of 7.6 g of 3~ nitrobenzaldehyde, 6.5 g of acetoacetic acid ethyl ester and 7.1 g of B-amino-crotonic acid propyl ester in 50 ml of methanol, 2,6-dimethyl-4-(3'-nitrophenyl) was obtained )-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-propyl ester of melting point 132-133°C (methanol). Yield 65% of the theoretical.

Eksempel 29. Example 29.

Ved 10 timers oppvarmning av en oppløsning av 5,3 g benzaldehyd, 7,1 g aceteddiksyreallylester og 7,1 g B-aminokrotonsyreisopropylester i 50 ml etanol, fremkom 2,6-dimetyl-4-fenyl-l,4-dihydropyridin-3,5-dikarboksylsyre-3-allylester-5-isopropylester av smeltepunkt 117°C (etanol). Utbytte 62% av det teoretiske. Eksempel 30. By heating a solution of 5.3 g of benzaldehyde, 7.1 g of acetoacetic acid allyl ester and 7.1 g of B-aminocrotonic acid isopropyl ester in 50 ml of ethanol for 10 hours, 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3 ,5-dicarboxylic acid-3-allyl ester-5-isopropyl ester of melting point 117°C (ethanol). Yield 62% of the theoretical. Example 30.

Etter 8 timers kokning av en oppløsning av 7,6 g 3-nitrobenzaldehyd, 6,5 g B-aminokrotonsyreetylester og 8,0 g aceteddiksyre-B-metoksyetylester i 50 ml isopropanol, fremkom 2,6-dimetyl-4-(3'-nitrofenyl)-1,4-dihydropyridin-3,5-dikarboksyl-syre-3etylester-5-B-metoksyetylester av smeltepunkt 108°C (petrol- After 8 hours of boiling a solution of 7.6 g of 3-nitrobenzaldehyde, 6.5 g of B-aminocrotonic acid ethyl ester and 8.0 g of acetoacetic acid B-methoxyethyl ester in 50 ml of isopropanol, 2,6-dimethyl-4-(3' -nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-B-methoxyethyl ester of melting point 108°C (petrol-

eter/eddikester). Utbytte 49% av det teoretiske. ether/acetic acid). Yield 49% of the theoretical.

Eksempel 31. Example 31.

Ved 8 timers oppvarmning av en oppløsning av 7>8 g kinolin-4-aldehyd, 6,5 g aceteddiksyreetylester og 5,8 g B-aminokrotonsyremetylester i 40 ml etanol, fremkom 2,6-dimetyl-4-(4'-kinolyl)-!, 4-dihydropyridin-3,5-dikarboksylsyre-3-metylester-5-etylester av smeltepunkt 208°C (etanol). Utbytte 58% av det teoretiske. Eksempel 32. By heating for 8 hours a solution of 7>8 g of quinoline-4-aldehyde, 6.5 g of acetoacetic acid ethyl ester and 5.8 g of B-aminocrotonic acid methyl ester in 40 ml of ethanol, 2,6-dimethyl-4-(4'-quinolyl) was obtained )-!, 4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester of melting point 208°C (ethanol). Yield 58% of the theoretical. Example 32.

Etter 10 timers oppvarmning av en oppløsning av 5,3 g benzaldehyd, 5,8 g B-aminokrotonsyremetylester og 956 g benzoyl-eddiksyreetylester i 50 ml etanol, fremkom 2-metyl-4,6-difenyl-1,4-dihydropyridin-3j5_dikarboksylsyre-3-nietylester-5-etylester av smeltepunkt 152-153°C (etanol. Utbytte 56$ av det teoretiske. Eksempel 33. After 10 hours of heating a solution of 5.3 g of benzaldehyde, 5.8 g of B-aminocrotonic acid methyl ester and 956 g of benzoyl-acetic acid ethyl ester in 50 ml of ethanol, 2-methyl-4,6-diphenyl-1,4-dihydropyridine-3j5_dicarboxylic acid appeared -3-niethyl ester-5-ethyl ester of melting point 152-153°C (ethanol. Yield 56$ of the theoretical. Example 33.

Etter 10 timers oppvarmning av en oppløsning av 7j8 g 2-naftaldehyd, 6,5 g aceteddiksyreetylester og 5,8 g aminokrotonsyremetylester i 100 ml etanol, fremkom 2,6-dimetyl-4-(2'-naftyl)-1,4-dihydropyridin-3 5 5-dikarboksy1syre-3-metylester-5-etylester av smeltepunkt l40-l42°C (etanol). Utbytte 61% av det teoretiske. After 10 hours of heating a solution of 7j8 g of 2-naphthaldehyde, 6.5 g of acetoacetic acid ethyl ester and 5.8 g of aminocrotonic acid methyl ester in 100 ml of ethanol, 2,6-dimethyl-4-(2'-naphthyl)-1,4- dihydropyridine-3-5-dicarboxylic acid-3-methylester-5-ethyl ester of melting point 140-142°C (ethanol). Yield 61% of the theoretical.

Eksempel 34. Example 34.

Etter 8 timers kokning av en oppløsning av 4,8 g furan-2-aldehyd, 7,1 g aceteddiksyrealkylester og 5,8 g aminokrotonsyremetylester i 80 ml etanol, fremkom 2,6-dimetyl-4-(2 '-furyl)-l,4~-dihydropyridin-3,5-dikarboksylsyre-3-allylester-5metylester av smeltepunkt 134-135°C (etanol). Utbytte 67% av det teoretiske. After 8 hours of boiling 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 of ethanol, 2,6-dimethyl-4-(2'-furyl)- 1,4~-dihydropyridine-3,5-dicarboxylic acid-3-allyl ester-5-methyl ester of melting point 134-135°C (ethanol). Yield 67% of the theoretical.

Eksempel 35. Example 35.

Etter 10 timers oppvarmning av en oppløsning av 8,4 g 4,6-dimetoksypyrimidin-5-aldehyd, 5,8 g aceteddiksyremetylester og 6,5 g aminokrotonsyreetylester i 80 ml isopropanol, fremkom 2,6-dimetyl-4-(4',6'-dimetoksypyrimidyl-5)-1,4-dihydropyridin-3, 5-dikarboksylsyre-3-metylester-5-etylester av smeltepunkt 245°C (etanol). Utbytte 62% av det teoretiske. After 10 hours of heating 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, 2,6-dimethyl-4-(4' ,6'-dimethoxypyrimidyl-5)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester of melting point 245°C (ethanol). Yield 62% of the theoretical.

Eksempel 36. Example 36.

Ved 8 timers kokning av en oppløsning av 7,8 g isokinolin-l-aldehyd, 5,8 g aceteddiksyremetylester og 7,2 g aminokrotonsyreisopropylester i 80 ml etanol, fremkom 2,6-dimetyl-4-(1'-isokinolyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-isopropylester-5-metylester med smeltepunkt 204°C (etanol). Utbytte 71% av det teoretiske. By boiling for 8 hours a solution of 7.8 g of isoquinoline-1-aldehyde, 5.8 g of acetoacetic acid methyl ester and 7.2 g of aminocrotonic acid isopropyl ester in 80 ml of ethanol, 2,6-dimethyl-4-(1'-isoquinolyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid-3-isopropyl ester-5-methyl ester with melting point 204°C (ethanol). Yield 71% of the theoretical.

Eksempel 37. Example 37.

Ved 6 timers kokning av en oppløsning av 7j5 g 3-nitrobenzaldehyd, 5,8 g aceteddiksyremetylester og 7,2 g g-etyl-g-aminoakrylsyreetylester i 60 ml etanol, fremkom 2-metyl-6-etyl-4-(3'-nitrofenyl)-l,4-dihydropyridin-3,5-dikarboksylsyre-3-metylester-5etylester av smeltepunkt 123°C (eddike.ster). Utbytte 48% av det teoretiske. By boiling for 6 hours a solution of 7j5 g of 3-nitrobenzaldehyde, 5.8 g of acetoacetic acid methyl ester and 7.2 g of g-ethyl-g-aminoacrylic acid ethyl ester in 60 ml of ethanol, 2-methyl-6-ethyl-4-(3' -nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester of melting point 123°C (acetic ester). Yield 48% of the theoretical.

- Eksempel 38. - Example 38.

Etter 8 timers oppvarmning av en oppløsning av 6,1 g 6-metylpyridin-2-aldehyd, 6,5 g aceteddiksyreetylester og 5,8 g aminokrotonsyremetylester i 80 ml etanol, fremkom 2,6-dimetyl-4- After 8 hours of heating 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, 2,6-dimethyl-4-

(6'-metylpyridyl-2')-l,4-dihydropyridin-3,5_dikarboksylsyre-3-metylester-5-etylester av smeltepunkt l62°C (etanol/vann). Utbytte 52% av det teoretiske. (6'-Methylpyridyl-2')-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-ethyl ester of melting point 162°C (ethanol/water). Yield 52% of the theoretical.

Eksempel 39. Example 39.

Ved 8 timers oppvarmning av en oppløsning av 8,7 g 2-trifluormetylbenzaldehyd, 7,0 g aceteddiksyrepropargylester og 5,8 g aminokrotonsyremetylester i 60 ml alkohol, fremkom 2,6-di-metyl-4(2'-trifluormetylfenyl)-l,4-dihydropyridin-3,5-dikarboksyl-syre-3-propargylester-5-metylester av smeltepunkt 111°C (dietyleter). Utbytte 57% av det teoretiske. By heating a solution of 8.7 g of 2-trifluoromethylbenzaldehyde, 7.0 g of acetoacetic acid propargyl ester and 5.8 g of aminocrotonic acid methyl ester in 60 ml of alcohol for 8 hours, 2,6-di-methyl-4(2'-trifluoromethylphenyl)-1 ,4-dihydropyridine-3,5-dicarboxylic acid-3-propargyl ester-5-methyl ester of melting point 111°C (diethyl ether). Yield 57% of the theoretical.

Eksempel 40. Example 40.

Etter 8 timers kokning av en oppløsning av 6,2 g 2-fluorbenzaldehyd, 7, 0 g aceteddiksyrepropargylester og 5, 8 g B-aminokrotonsyremetylester i 80 ml etanol, fremkom 2,6-dimetyl-4-( 2' -f luorf enyl)-l, 4-dihydropyridin-3, S-dikarboksylsyre^-propar-gylester-S-metylester av smeltepunkt 142°C (etanol). Utbytte 73% av det teoretiske. After boiling for 8 hours a solution of 6.2 g of 2-fluorobenzaldehyde, 7.0 g of acetoacetic acid propargyl ester and 5.8 g of B-aminocrotonic acid methyl ester in 80 ml of ethanol, 2,6-dimethyl-4-(2'-fluorophenyl) )-1,4-dihydropyridine-3,S-dicarboxylic acid 3-propargyl ester-S-methyl ester of melting point 142°C (ethanol). Yield 73% of the theoretical.

Eksempel 41. Example 41.

Ved 10 timers oppvarmning av en oppløsning av 8,9 g 4-karboksyetylbenzaldehyd, 7,0 g aceteddiksyrepropargylester og 6,5 g aminokrotonsyreetylester i 80 ml etanol, fremkom 2,6-dimetyl-4-(4<1->karbetoksyfenyl)-1,4-dihydropyridin-3,5-di-karboksylsyre-3-propargylester-5-etylester av smeltepunkt 110°C (etanol/vann). Utbytte 55$ av det teoretiske. By heating a solution of 8.9 g of 4-carboxyethylbenzaldehyde, 7.0 g of acetoacetic acid propargyl ester and 6.5 g of aminocrotonic acid ethyl ester in 80 ml of ethanol for 10 hours, 2,6-dimethyl-4-(4<1->carbethoxyphenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid-3-propargyl ester-5-ethyl ester of melting point 110°C (ethanol/water). Dividend 55$ of the theoretical.

Eksempel 42. Example 42.

Etter 10 timers oppvarmning av en oppløsning av After 10 hours of heating a solution of

9,8 g 2,4,5-trimetoksybenzaldehyd, 7,1 g aceteddiksyreallyl- 9.8 g of 2,4,5-trimethoxybenzaldehyde, 7.1 g of acetoacetic acid allyl-

ester og 5,8 g aminokrotonsyremetylester i 80 ml etanol, frem- ester and 5.8 g of aminocrotonic acid methyl ester in 80 ml of ethanol,

kom 2,6-dimetyl-4-(2',4',5'-trimetoksyfenyl)-1,4-dihydropyridin-3,5-dikarboksylsyre-3-allylester-5-metylester av smeltepunkt 98°C (eddikester/petroleter). Utbytte 50$ av det teoretiske. came 2,6-dimethyl-4-(2',4',5'-trimethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-allyl ester-5-methyl ester of melting point 98°C (acetic ester/petroleum ether ). Dividend 50$ of the theoretical.

Claims (2)

1. Fremgangsmåte til fremstilling av nye usymmetriske 1,4-dihydropyridiner med formel1. Process for the preparation of new unsymmetrical 1,4-dihydropyridines of formula hvori R betyr en fenylrest, som inneholder 1-3 like eller forskjellige substituenter fra gruppen alkyl, alkoksy, halogen, nitro, cyano, trifluormetyl, karbalkoksy eller alkylmerkapto, eller betyr en eventuelt med alkyl, alkoksy eller halogen substituert naftyl-, kinolyl-, isokinolyl-, pyridyl-, pyrimidyl-, tenyl-, furyl- eller pyrrolylrest og R"*" og R^ er like eller forskjellige og betyr hydrogen, fenyl eller en rettlinjet eller forgrenet alkylrest og 2 4. R og R er forskjellige fra hverandre og betyr en rettlinjet, forgrenet eller cyklisk mettet eller umettet hydrokarbonrest som eventuelt er avbrutt med 1 eller 2 oksygenatomer i kjeden og/eller er substituert med en hydroksygruppe, karakterisert ved at man i nærvær av vann eller inerte, organiske oppløsningsmidler ved temperaturer mellom 30 og 200°C omsetter aldehyder med formel hvori R har overnevnte betydning med B-ketokarboksylsyreestere med formel hvori 1 2 R og R har overnevnte betydning, og enaminokarboksylsyreestere med formel hvori 4 RJ og R har overnevnte betydning. in which R means a phenyl radical, which contains 1-3 identical or different substituents from the group of alkyl, alkoxy, halogen, nitro, cyano, trifluoromethyl, caralkyloxy or alkylmercapto, or means a naphthyl-, quinolyl-, isoquinolyl optionally substituted with alkyl, alkoxy or halogen -, pyridyl, pyrimidyl, thenyl, furyl or pyrrolyl residue and R"*" and R^ are the same or different and mean hydrogen, phenyl or a straight or branched alkyl residue and 2 4. R and R are different from each other and mean a linear, branched or cyclic saturated or unsaturated hydrocarbon residue which is optionally interrupted by 1 or 2 oxygen atoms in the chain and/or is substituted with a hydroxy group, characterized in that in the presence of water or inert, organic solvents at temperatures between 30 and 200°C, aldehydes with the formula in which R has the above meaning with B-ketocarboxylic acid esters of formula in which 1 2 R and R have the above meaning, and enaminocarboxylic acid esters of formula in which 4 RJ and R have the above meaning. 2. Fremgangsmåte til fremstilling av usymmetriske 1,4-dihydropyridiner med formel (I) ifølge krav 1, karakterisert ved at man gjennomfører omsetningen ved oppløsningsmidlets koketemperåtur.2. Process for the preparation of unsymmetrical 1,4-dihydropyridines of formula (I) according to claim 1, characterized in that the reaction is carried out at the boiling temperature of the solvent.
NO119272A 1971-04-10 1972-04-07 NO133712C (en)

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FR2320750A1 (en) * 1975-08-12 1977-03-11 Hexachimie 1,4-DIHYDRO PYRIDINES AND THEIR THERAPEUTIC APPLICATION
DE2650013C3 (en) * 1976-10-30 1981-04-02 Bayer Ag, 5090 Leverkusen 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid isopropyl (2-propoxy-ethyl) ester, process for its preparation and medicinal products containing it
DE2815578C2 (en) * 1978-04-11 1986-01-16 Bayer Ag, 5090 Leverkusen New pharmaceutical use of nimodipine
SE429652B (en) * 1978-06-30 1983-09-19 Haessle Ab 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5-ethyl ester
DE2841667A1 (en) * 1978-09-25 1980-04-10 Bayer Ag FLUORINE 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT
JPS58159490A (en) * 1982-02-23 1983-09-21 Nikken Kagaku Kk 1,4-dihydropyridne compound
DE3208628A1 (en) * 1982-03-10 1983-09-22 Bayer Ag, 5090 Leverkusen NEW COMPOUNDS, METHOD FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS
JPS58185562A (en) * 1982-04-22 1983-10-29 Taisho Pharmaceut Co Ltd 1,4-dihydropyridine derivative
DE3222367A1 (en) * 1982-06-15 1983-12-15 Bayer Ag, 5090 Leverkusen Use of 1,4-dihydropyridines in antiarteriosclerotics and preparation thereof
US4656181A (en) * 1982-11-24 1987-04-07 Cermol S.A. Esters of 1,4-dihydropyridines, processes for the preparation of the new esters, and medicaments containing the same
US4529733A (en) * 1983-04-06 1985-07-16 Merrell Dow Pharmaceuticals Inc. Antihypertensive 3-furoyl-1,4-dihydropyridines
US4607041A (en) * 1983-04-27 1986-08-19 Fisons Plc Antihypertensive 2-phenyl Hantzsch dihydropyridines
IE57810B1 (en) * 1984-03-27 1993-04-21 Delagrange Lab 1,4-dihydropyridine derivatives,their preparation and their use
EP0311053A3 (en) * 1987-10-06 1991-05-08 Banyu Pharmaceutical Co., Ltd. Ameliorant of cerebral circulation and optical isomer of nb-818, processes for its production and its use
DE3741540A1 (en) * 1987-12-08 1989-06-22 Bayer Ag METHOD FOR PRODUCING UNSYMMETRIC DIHYDROPYRIDINES
ATE234286T1 (en) * 1993-12-10 2003-03-15 Bayer Ag PHENYL-SUBSTITUTED 1,4-DIHYDROPYRIDINES WITH CEREBRAL ACTIVITY
US5977369A (en) * 1995-12-28 1999-11-02 Napp Technologies, Inc. Process to prepare dihydropyridine and derivatives thereof
IT1283793B1 (en) * 1996-08-23 1998-04-30 Lusochimica Spa DIHYDROPYRIDINE PREPARATION PROCESS
WO2000005209A1 (en) * 1998-07-23 2000-02-03 Lin, Tong-Ho GUAIACOXYPROPANOLAMINES WITH α/β-ADRENERGIC BLOCKING ACTIVITY

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