CS243590B1 - Process for preparing 4-aryl-2,2-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters - Google Patents
Process for preparing 4-aryl-2,2-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters Download PDFInfo
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Abstract
Vynález spadá do odboru syntetických liečiv. Jeho predmetom je spósob přípravy diesterov 4-aryl-2,6-dimetyl-l,4-dihydropyrldín-3,5-dikarboxylovej kyseliny vzorca I v ktorom R představuje priamy alebo rozvětvený alkylový zvyšok s počtom atómov uhlíka 1 až 5, pričom alkylový zvyšok móže byť přerušený v reťazci atómom kyslíka a X představuje nitroskupinu v o-, m- alebo p-polohe. Tieto zlúčeniny majú antianginózny a antihypertenzný účinok. Příprava sa uskutečňuje reakciou esteru 2-amínokrotónovej kyseliny s nitrobenzaldehyddiacetátom.The invention belongs to the field of synthetic drugs. Its subject is a method for preparing diesters of 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid of formula I in which R represents a straight or branched alkyl radical with a number of carbon atoms from 1 to 5, the alkyl radical being able to be interrupted in the chain by an oxygen atom and X represents a nitro group in the o-, m- or p-position. These compounds have antianginal and antihypertensive effects. The preparation is carried out by reacting 2-aminocrotonic acid ester with nitrobenzaldehyde diacetate.
Description
Vynález spadá do odboru syntetických liečiv. Jeho predmetom je spósob přípravy diesterov 4-aryl-2,6-dimetyl-l,4-dlhydropyrldín-3,5-dikarboxylovej kyseliny vzorca IThe invention falls within the field of synthetic drugs. It relates to a process for the preparation of 4-aryl-2,6-dimethyl-1,4-dihydropyrldine-3,5-dicarboxylic acid diesters of the formula I
v ktoromin which
R představuje priamy alebo rozvětvený alkylový zvyšok s počtom atómov uhlíka 1 až 5, pričom alkylový zvyšok móže byť přerušený v reťazci atómom kyslíka aR represents a straight or branched alkyl radical having a carbon number of 1 to 5, wherein the alkyl radical may be interrupted in the chain by an oxygen atom; and
X představuje nitroskupinu v o-, m- alebo p-polohe.X represents a nitro group at the o-, m- or p-position.
Tieto zlúčeniny majú antianginózny a antihypertenzný účinok. Příprava sa uskutečňuje reakciou esteru 2-amínokrotónovej kyseliny s nitrobenzaldehyddiacetátom.These compounds have an antianginal and antihypertensive effect. The preparation is carried out by reacting the 2-aminocrotonic acid ester with nitrobenzaldehyde diacetate.
Vynález sa týká spósobu přípravy diesterov 4-aryl-2,6-dlmetyl-l,4-dihydropyridín-3,5-dikarboxylovej kyseliny všeobecnéhoThe present invention relates to a process for preparing 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters of general formula
v ktoromin which
R představuje priamy alebo rozvětvený alkylový zvyšok s počtom atómov uhlíka 1 až 5, pričom alkylový zvyšok móže byť přerušený v reťazci atómom 'kyslíka aR represents a straight or branched alkyl radical having 1 to 5 carbon atoms, wherein the alkyl radical may be interrupted in the chain by an oxygen atom; and
X predsavuje nitroskupinu v o-, m- alebo p-polohe.X represents a nitro group in the o-, m- or β-position.
Tieto zlúčeniny sa používajú ako antianginózne látky a antihypertenzíva.These compounds are used as antianginal agents and antihypertensives.
Doposial' sa tieto zlúčeniny připravovali reakciou nitrobenzaldehydov s estermi acetoctovej kyseliny a amoniakem v inertnom rozpúšťadle (F. Bossert, W. Vater: US pat. č. 3 644 627 /1972/, ger. pat č. 1 670 827 /1967/, S. Afričan pat. č. 6 801 482 /1982/, brit pat. č. 1 173 104 /1968/).To date, these compounds have been prepared by reacting nitrobenzaldehydes with acetic acid esters and ammonia in an inert solvent (F. Bossert, W. Vater: US Pat. No. 3,644,627 (1972), Ger. Pat No. 1,670,827 (1967)). S. African Pat No. 6,801,482 (1982), British Pat No. 1,173,104 (1968)).
Ďalšou metodou přípravy zlúčenín všeobecného vzorca I je reakcia nitrobenzaldehyddiacetátu s metylesterom acetoctovej kyseliny a amoniakom za přítomnosti organických zásad, napr. pyridinu v inertnom rozpúšťadle.Another method for preparing compounds of formula I is by reacting nitrobenzaldehyde diacetate with acetic acid methyl ester and ammonia in the presence of organic bases, e.g. pyridine in an inert solvent.
Ďalšou známou metodou přípravy zlúčenín všeobecného vzorca I je reakcia nitrobenzaldehydu s estermi amínokrotónovej kyseliny (Murakami M. aspol.: Japan Kokai Tokkyo Koho 8 002 652 /1980/).Another known method for preparing compounds of formula I is by reacting nitrobenzaldehyde with aminocrotonic acid esters (Murakami M. aspol .: Japan Kokai Tokkyo Koho 8 002 652 (1980)).
Ďalšou popísanou metodou přípravy zlúčenín všeobecného vzorca I je reakcia nitrobenzaldehydu s esterom acetoctovej kyseliny a esterom amínokrotónovej kyseliny (Murakami M. a spol.: Japan Kokai Tokkyo Koho 8 004 318 /1980/).Another method described for the preparation of compounds of formula I is the reaction of nitrobenzaldehyde with acetic acid ester and aminocrotonic acid ester (Murakami M. et al., Japan Kokai Tokkyo Koho 8,004,318 (1980)).
Podstatou vynálezu je spósob přípravy zlúčenín všeobecného vzorca I z 2 až 3 molových dielov esteru 3-amínokrotónovej kyseliny všeobecného vzorca IIThe present invention provides a process for the preparation of compounds of the formula I from 2 to 3 moles of a 3-aminocrotonic acid ester of the formula II
CHs—C = CH—COOR nh2 (II) v ktorom má R ten istý význam ako vo vzorci I, z 1 mólového dielu benzaldehyddiacetátu všeobecného vzorca III .OCOCH, ococh5 (iidCH-C = CH-COOR NH2 (II) wherein R has the same meaning as in formula I, 1 mol of the component of formula III benzaldehyddiacetátu .OCOCH, 5 OCOCH (iid
v ktorom má X ten istý význam ako vo vzorci I v prostředí inertného organického rozpúšťadla, napr. chloroformu, dioxanu, dimetylformamidu, dimetylsulfoxidu, kyseliny octovej, alifatických alkoholov s počtom atómov uhlíka 1 až 3 alebo v zmesi uvedených rozpúšťadiel pri teplote 20 až 150 °G. Reakciu možno prevádzať za přítomnosti organickej bázy, napr. pyridinu.wherein X has the same meaning as in Formula I in an inert organic solvent, e.g. chloroform, dioxane, dimethylformamide, dimethylsulfoxide, acetic acid, aliphatic alcohols having a carbon number of 1 to 3 or in a mixture of the solvents mentioned at a temperature of 20 to 150 ° C. The reaction may be carried out in the presence of an organic base, e.g. pyridine.
Ako estery 3-amínokrotónovej kyseliny všeobecného vzorca II možno použit metylester, etylester, izopropylester, metoxyetylester, etoxyetylester, propoxyetylester a pod. Ako substituované benzaldehyddiacetáty možno použit ο-nitro-, m-nitro-, resp. p-nitro-benzaidehyddiacetát.As the 3-aminocrotonic acid esters of formula (II), methyl, ethyl, isopropyl, methoxyethyl, ethoxyethyl, propoxyethyl and the like can be used. As substituted benzaldehyde diacetates, ο-nitro-, m-nitro-, resp. p-nitro-benzaidehyddiacetát.
Postup podfa vynálezu sa uskutočňuje tak, že sa ester 3-amínokrotónovej kyseliny všeobecného vzorca II zahrieva so substituovaným aldehyddiacetátom všeobecného vzorca III v prostředí vyššie uvedených inertných organických rozpúšťadiel na vyššie uvedenú teplotu za tlaku 0,1 až 2,5 MPa. Reakcia sa uskutočňuje výhodné pri teplote spatného toku použitého rozpúšťadla alebo zmesi rozpúšťadiel za normálneho tlaku. Z dovodov malej rozpustnosti produktov reakcie všeobecného vzorca I v metanole je výhodné reakciu prevádzať pri teplote spatného toku v tomto rozpúšťadle.The process according to the invention is carried out by heating a 3-aminocrotonic acid ester of the formula II with a substituted aldehyde diacetate of the formula III in an environment of the above-mentioned inert organic solvents to the above-mentioned temperature under a pressure of 0.1 to 2.5 MPa. The reaction is preferably carried out at the reflux temperature of the solvent or solvent mixture used under normal pressure. Because of the low solubility of the reaction products of formula I in methanol, it is preferable to carry out the reaction at reflux temperature in this solvent.
Reakčná doba je závislá na reakčnej teplote a na použitom estere 3-amínokrotónovej kyseliny všeobecného vzorca II. Pri teplote spatného toku použitého rozpúšťadla alebo zmesi rozpúšťadiel je reakčná doba 4 až 10 hod. Izolácia zlúčenín všeobecného vzorca I sa uskutoční odfiltrováním alebo odstředěním vykrystalizovaného produktu po vychladnutí reakčnej zmesi. Surové produkty sa čistia prekryštalizovaním z vhodného rozpúšťadla.The reaction time depends on the reaction temperature and the 3-aminocrotonic acid ester of formula II used. At the reflux temperature of the solvent or solvent mixture used, the reaction time is 4 to 10 hours. The isolation of the compounds of formula I is effected by filtering or centrifuging the crystallized product after cooling the reaction mixture. The crude products are purified by recrystallization from a suitable solvent.
Výhodou postupu podfa vynálezu oproti váčšine doposial' popísaných postupov je použitie podstatné lacnejšieho o-, resp. p-nitrobenzaldehyddiacetátu, namiesto o-, resp. p-nitrobenzaldehydu a mierne zvýšené výtažky oproti postupu založenom na reakcii metylesteru acetoctovej kyseliny, nitrobenzaldehyddiacetátu a amoniaku, respektive za přítomnosti pyridinu.An advantage of the process according to the invention over most of the processes described hitherto is the use of a substantially cheaper o- resp. p-nitrobenzaldehyde diacetate, instead of o- and resp. p-nitrobenzaldehyde and slightly increased yields compared to the procedure based on the reaction of methyl acetate, nitrobenzaldehyde diacetate and ammonia, respectively in the presence of pyridine.
V dalšom je predmet vynálezu objasněný na príkladoch bez toho, že by sa na tieto výlučné obmedzoval.In the following, the invention is illustrated by way of example without being limited thereto.
Příklad 1Example 1
Dimetylester kyseliny 2,6-dimetyl-4-(2‘-nitrofenyl)-l,4-dihydropyridín-3,5-dikarboxylovej2,6-Dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester
7,54 g 2-nitrobenzaldehyddiacetátu sa spolu s 8 g metylesteru kyseliny 3-amínokrotónovej zahrieva v 10 ml metanolu 7 hodin pri teplote varu. Po ochladení a odfiltrovaní sa surový produkt prekryštalizuje z etylesteru kyseliny octovej. Získajú sa jasno243590 žité krystaly (6,7 g) s teplotou topenia 172 až 174 °C v 65 % výtažku.7.54 g of 2-nitrobenzaldehyde diacetate, together with 8 g of 3-aminocrotonic acid methyl ester, are heated at boiling point in 10 ml of methanol for 7 hours. After cooling and filtering, the crude product is recrystallized from ethyl acetate. Clear crystals (6.7 g) with a melting point of 172-174 ° C in 65% yield are obtained.
Rovnakým sposobom za použitia příslušných východzích látok sa získajú tieto zlúčeniny:The following compounds are obtained in the same manner, using the appropriate starting materials:
a) dimetylester kyseliny 2,6-dimetyl-4-(3-nitr of enyl) -l,4-dihydropyridín-3,5-dikarboxylovej s teplotou topenia 206 až 208 °C,(a) 2,6-dimethyl-4- (3-nitro-phenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, m.p. 206-208 ° C;
b) dimetylester kyseliny 2,6-dimetyl-4-(4‘-nitr of enyl} -1,4-dihydr opyridín-3,5-dikarboxylovej s teplotou topenia 196 až 197 °C,(b) 2,6-dimethyl-4- (4‘-nitro-phenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, m.p. 196-197 ° C;
c) dietylester kyseliny 2,6-dimetyl-4-(2‘-nitrof enylj -1,4-dihydr opyridín-2,5-dikarboxylovej s teplotou topenia 122 až 124 °C,(c) 2,6-dimethyl-4- (2‘-nitrophenyl) -1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester, m.p. 122-124 ° C;
d) dietylester kyseliny 2,6-dimetyl-4-(3‘-nitrof enyl) -l,4-dihydropyridín-3,5-dikarboxylovej s teplotou topenia 160 až 161 °C, ej dietylester kyseliny 2,6-dimetyl-4-(4‘-nitrof enyl) -l,4-dihydropyridín-3,5-dikarboxylovej s teplotou topenia 132 až 134 °C,d) 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, m.p. 160-161 ° C, 2,6-dimethyl-4 diethyl ester - (4'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid, m.p. 132-134 ° C,
f) diizopropylester kyseliny 2,6-dimetyl-4-(2‘-nitrofenyl)-l,4-dihydropyridín-3,5dikarboxylovej s teplotou topenia 140 až 142 °C,(f) 2,6-dimethyl-4- (2‘-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester, m.p. 140-142 ° C;
g) diizopropylester kyseliny 3,6-dimetyl-4-3‘-nitr of enyl) -1,4-dihydr opyridín-3,5-dikarboxylovej s teplotou topenia 123 °C,(g) 3,6-dimethyl-4-3‘-nitro-phenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester, m.p. 123 ° C;
h) diizopropylester kyseliny 2,6-dimetyl-4- (4‘-nitrof enyl) -l,4-idihydropyridín-3,5-dikarboxylovej s teplotou topenia 151 až 152 °C,(h) 2,6-dimethyl-4- (4‘-nitrophenyl) -1,4-idihydropyridine-3,5-dicarboxylic acid diisopropyl ester, m.p. 151-152 ° C;
i) bis-metoxyetylester kyseliny 2,6-dimetyl-4-(4‘-nitrofenyl)-l,4-dihydropyridín-3,5-dikarboxylovej s teplotou topenia 108 až 112 °C,(i) 2,6-dimethyl-4- (4‘-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid bis-methoxyethyl ester, m.p. 108-112 ° C;
j) bis-etoxyetylester kyseliny 2,6-dimetyl-4- (2‘-nitrof enyl)-l,4-dihydropyridín-3,5dikarboxylovej s teplotou topenia 93 až 96 °C,(j) 2,6-dimethyl-4- (2‘-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid bis-ethoxyethyl ester, m.p. 93-96 ° C;
k) bis-etoxyetylester kyseliny 2,6-dimetyl-4- (3‘-nitrofenyl) -l,4-dihydropyridín-3,5-dikarboxylovej s teplotou topenia 101 až 104 °C,(k) 2,6-dimethyl-4- (3‘-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid bis-ethoxyethyl ester, m.p. 101-104 ° C;
l) bis-propoxyetylester kyseliny 2,6-dimetyl-4- (3‘-nitrof enyl j -1,4-dihydropyridín-3,5-dikarboxylovej s teplotou topenia 83 až 86 °C.l) 2,6-dimethyl-4- (3‘-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid bis-propoxyethyl ester, m.p. 83-86 ° C.
Příklad 2Example 2
Dimetylester kyseliny 2,6-dimetyl-4-(2‘-nitrof enyl) -l,4-dihydropyridín-3,5-dikarboxylovej2,6-Dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester
7,54 g 2-nitrobenzaldehyddiacetátu sa spolu s 8,2 g metylesteru kyseliny 3-amínokrotónovej zahrieva v zmesi 10 ml metanolu a 0,1 ml pyridinu 5 hodin pri teplote varu. Po ochladení a odfiltrovaní sa surový produkt prekryštalizuje zo zmesi fadovej kyseliny octovej a etylacetátu. Získajú sa jasnožlté-kryštály (8,8 g, t. j. 66 %) s teplotou topenia 171 až 173 °C.7.54 g of 2-nitrobenzaldehyde diacetate are heated together with 8.2 g of 3-aminocrotonic acid methyl ester in a mixture of 10 ml of methanol and 0.1 ml of pyridine at reflux for 5 hours. After cooling and filtering, the crude product was recrystallized from a mixture of glacial acetic acid and ethyl acetate. Clear yellow crystals (8.8 g, i.e. 66%) with a melting point of 171-173 ° C are obtained.
Rovnakým sposobom za použitia příslušných východzích látok sa získajú zlúčeniny uvedené v příklade la až 1.In the same manner, using the appropriate starting materials, the compounds of Examples 1a to 1 are obtained.
P r i k 1 a d 3Example 1 and d 3
Dimetylester kyseliny 2,6-dimetyl-4-(2‘-nitrofenyl)-l,4-dihydropyridín-3,5-dikarboxylovej g 2-nitrobenzaldehyddiacetátu sa spolu s 3,2 g 3-ammokrotoňanu metylového zahrieva v 4 ml dioxanu 3 hodiny pri teplote varu. Po ochladení a odfiltrovaní sa surový produkt prekryštalizuje z fadovej kyseliny octovej. Získajú sa žité kryštály s teplotou 171 až 173 C v 36 %-nom výtažku.2,6-Dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester g of 2-nitrobenzaldehyde diacetate together with 3.2 g of methyl 3-aminocrotonate are heated in 4 ml of dioxane for 3 hours at boiling point. After cooling and filtering, the crude product is recrystallized from glacial acetic acid. Rye crystals are obtained having a temperature of 171-173 ° C in a 36% yield.
Rovnakým sposobom sa získajú zlúčeniny uvedené v příklade la až 1.The compounds of Examples 1a to 1 are obtained in the same manner.
P r i k 1 ad 4Example 4
Dimetylester kyseliny 2,6-dimetyl-4-(2‘-nitrof enyl) -l,4-dihydropyridín-3,5-dikarboxylovej2,6-Dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester
7,54 g 2-nitrobenzaldehyddiacetátu sa spolu s 8,3 g metylesteru kyseliny 3-amínokrotónovej zahrieva v 8 ml 2-propanolu 4 hodiny pri teplote varu. Reakčná zmes sa spracuje analogicky ako v příklade 1. Získajú sa žité kryštály s teplotou topenia 172 až 174 °C v 64 %-nom výtažku.7.54 g of 2-nitrobenzaldehyde diacetate, together with 8.3 g of 3-aminocrotonic acid methyl ester, are heated at boiling point in 8 ml of 2-propanol for 4 hours. The reaction mixture is worked up in analogy to Example 1. Obtained crystals having a melting point of 172-174 ° C in 64% yield.
Příklad 5Example 5
Dimetylester kyseliny 2,6-dimetyl-4-(2‘-nitrofenyl j -l,4-dihydropyridín-3,5-dikarboxylovej2,6-Dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester
7,54 g 2-nitrobenzaldehyddiacetátu sa spolu s 8 g metylesteru kyseliny 3-amínokrotónovej zahrieva v 6 ml chloroformu 3 hodiny pri teplote varu. Reakčná zmes sa spracuje analogicky ako v příklade 1. Získajú sa svetložlté kryštály s teplotou topenia 171 až 174 °C v 48 %-nom výtažku.7.54 g of 2-nitrobenzaldehyde diacetate, together with 8 g of 3-aminocrotonic acid methyl ester, are heated in 6 ml of chloroform at reflux for 3 hours. The reaction mixture was worked up analogously to Example 1. Light yellow crystals of m.p. 171-174 ° C were obtained in 48% yield.
Příklad 6Example 6
Dimetylester kyseliny 2,6-dimetyl-4-(2‘-nitrofenyl) -l,4-dihydropyridín-3,5-dikarboxylovej2,6-Dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester
7,54 g 2-nitrobenzaldehyddiacetátu sa spolu s 8,4 g metylesteru kyseliny 3-amínokrotónovej zahrieva v 8 ml N,N-dimetylformamidu 2 hodiny pri teplote varu. Po ochladení a 3-dňovom státí vypadnú kryštály, ktoré sa spracujú analogicky ako v příklade 1. Získajú sa žité kryštály s teplotou topenia 172 až 174 °C v 45 %-nom výtažku.7.54 g of 2-nitrobenzaldehyde diacetate are heated together with 8.4 g of 3-aminocrotonic acid methyl ester in 8 ml of N, N-dimethylformamide at reflux temperature for 2 hours. After cooling and standing for 3 days, crystals precipitated which were treated in analogy to Example 1. Obtained crystals having a melting point of 172-174 ° C in a 45% yield.
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| CS85525A CS243590B1 (en) | 1985-01-25 | 1985-01-25 | Process for preparing 4-aryl-2,2-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters |
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| CS85525A CS243590B1 (en) | 1985-01-25 | 1985-01-25 | Process for preparing 4-aryl-2,2-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters |
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