DE833817C - Process for the preparation of nicotinic acid amides - Google Patents

Process for the preparation of nicotinic acid amides

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Publication number
DE833817C
DE833817C DEP25542A DEP0025542A DE833817C DE 833817 C DE833817 C DE 833817C DE P25542 A DEP25542 A DE P25542A DE P0025542 A DEP0025542 A DE P0025542A DE 833817 C DE833817 C DE 833817C
Authority
DE
Germany
Prior art keywords
nicotinic acid
preparation
acid amides
phenyl radical
denotes
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
DEP25542A
Other languages
German (de)
Inventor
Dr Hans Suter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cilag AG
Original Assignee
Cilag AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cilag AG filed Critical Cilag AG
Application granted granted Critical
Publication of DE833817C publication Critical patent/DE833817C/en
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3

Description

Verfahren zur Herstellung von Nicotinsäureamiden Es ist bekannt, daß das Benzylamid der Nicotinsäure eine deutliche spasmolytische Aktivität besitzt. Die Wirksamkeit dieser Verbindung ist aber derart schwach, daß ihre praktische Verwendung als Spasmolytikum kaum in Frage kommt. Außerdem steht die Toxizität der therapeutischen Verwendung dieser Verbindung hinderlich im Wege. Ferner sind in der Patentschrift 54o 697 eine größere Anzahl Verbindungen beschrieben, von denen die meisten spasmolytisch wirken sollen. Unter diesen 1)efindet sich ein Derivat der N icotinsäure, nämlich das Hydrobromid des Pyridin-3-carbonsäurepiperidyl-N-äthylamids. Eigene Versuche haben ergeben, daß die spasmolvtische Wirkung dieser Verbindung unbefriedigend ist.Process for the preparation of nicotinic acid amides It is known that the benzylamide of nicotinic acid has a marked spasmolytic activity. However, the effectiveness of this compound is so weak that its practical use as a spasmolytic is hardly an option. Besides, the toxicity is the therapeutic one Use of this connection obstructive in the way. Furthermore, in the patent 54o 697 a large number of compounds are described, most of which are spasmolytic should work. Among these 1) there is a derivative of nicotinic acid, viz the hydrobromide of pyridine-3-carboxylic acid piperidyl-N-ethylamide. Own attempts have shown that the spasmolvtische effect of this compound is unsatisfactory.

Gegenstand der Erfindung ist ein Verfahren zur Herstellung einer Reihe neuer, therapeutisch wertvoller N-substituierter Nicotinsäureamide, welche sowohl das Nicotinsäurebenzylamid als auch das Nicotinsäurepiperidyl-N-äthylamid an Wirksamkeit um das Vielfache übertreffen und die namentlich zur Behebung neurogener und myogener Spasmen verwendet werden sollen.The invention relates to a method for producing a series new, therapeutically valuable N-substituted nicotinic acid amides, which both the nicotinic acid benzylamide as well as the nicotinic acid piperidyl-N-ethylamide in effectiveness many times over, and in particular for the elimination of neurogenic and myogenic Spasms should be used.

Zur Herstellung der neuen 'Verbindungen nach dem erfindungsgemäßen Verfahren setzt man eine zur Einführung des Nicotinsäurtrestes geeignete Verbindung, z. B. Nicotinsäure, ihr Anhydrid, ein N icotinsäurehalogenid oder -ester, mit einem Amin um von der allgemeinen Formel worin R1 den Phenylrest und R2 den Phenylrest oder einen mit einem Phen_vlrest verbundenen ah= phatischen Rest, der eine Oxygruppe enthalten kann, bedeuten oder worin das mit dem Stickstoff-und dem Wasserstoffatom verbundene Kohlenstoffatom Bestandteil eines Ringes ist, an welchem zwei aromatische 6-Ringe ankondensiert sind. Beispiel i Zu 32,7 g Nicotinsäurechloridchlorhydrat und 42 g Aminodiphenylmethan in 250 ccm absolutem Benzol werden langsam unter Rühren 5i,1 g frisch geglühtes Kaliumcarbonat gegeben. Das Gemisch wird 9 Stunden unter Rückflußkiihlung gekocht, das Ungelöste abfiltriert und aus Äthanol umkristallisiert. Ausbeute 57,3 g = 86,4% der Theorie. Das so erhaltene Nicotinsäurediphenylmethylamid kristallisiert in farblosen, bei 175 bis 18o° schmelzenden Nadeln. Es ist leicht löslich in Chloroform, Aceton und Methanol, mäßig gut in Äthanol, wenig löslich in Benzol und Äther, unlöslich in Wasser. Beispiel e Eine Mischung von 36 g Nicotinsäurie und 57,5 g 1. 2-Diphenyläth#-lamin in 300 ccm Cumol wird auf ihren Kochpunkt erhitzt, so daß Cumol und das bei -der Reaktion sich bildende Wasser langsam in eine Vorlage destillieren, die eine Messung des Volumens des Destillates gestattet. Sobald die untere, wässerige Schicht 5,2 ccm beträgt, wird das restliche Cumol im Vakuum abdestilliert und der aus Nicotitisäure-(a-, ß-diphenyl)-äthylamid bestehende Rückstand aus Äthanol umkristallisiert. Die neue Verbindung bildet farblose Drusen nadelförmiger Kristalle vom Schmelzpunkt 159°. Sie ist leicht löslich in 5 n-Salzsäure, mäßig gut löslich in Methanol, Aceton, Äther und Benzol, wenig löslich in Äthanol und unlöslich in Wasser und in Alkalien. Beispiel 3 Einem Gemisch von 28,44 g N icotinsäurechloridchlorhvdrat, 34,23 g 2-Oxv-1. 2-diphenyläthylamin und 200 ccm absolutem Alkohol werden 44,35 g frisch geglühtes Kaliumcarbonat zugefügt. Das Ganze wird i t Stunden am Rückflußkühler gekocht, dann, nach dem Erkalten, das Ungelöste abfiltriert und aus Äthanol umkristallisiert. Man erhält so 37,8 g Nicot1nsäure-(a-hhen_vl-@-oxy-ß-phenyl)-äthylamid in farblosen Nadeln vom Schmelzpunkt 2ä3°. Die neue Verbindung ist leicht löslich in Aceton und Pvridiri, wenig löslich in Äther, Benzol. Eisessig und Äthanol. unlöslich in Wasser.To prepare the new 'compounds by the process according to the invention, a compound suitable for introducing the nicotinic acid residue is used, e.g. B. nicotinic acid, its anhydride, a nicotinic acid halide or ester, with an amine around of the general formula where R1 denotes the phenyl radical and R2 denotes the phenyl radical or a phatic radical connected to a phenyl radical, which may contain an oxy group, or in which the carbon atom connected to the nitrogen and hydrogen atom is part of a ring on which two aromatic 6-membered rings are condensed. EXAMPLE i To 32.7 g of nicotinic acid chloride chlorohydrate and 42 g of aminodiphenylmethane in 250 cc of absolute benzene are slowly added 51.1 g of freshly calcined potassium carbonate with stirring. The mixture is refluxed for 9 hours, the undissolved material is filtered off and recrystallized from ethanol. Yield 57.3 g = 86.4% of theory. The nicotinic acid diphenylmethylamide thus obtained crystallizes in colorless needles melting at 175 to 180 °. It is easily soluble in chloroform, acetone and methanol, moderately well in ethanol, little soluble in benzene and ether, insoluble in water. EXAMPLE e A mixture of 36 g of nicotinic acid and 57.5 g of 1,2-diphenylethelamine in 300 cc of cumene is heated to its boiling point so that cumene and the water formed during the reaction slowly distill into a receiver which a measurement of the volume of the distillate is allowed. As soon as the lower, aqueous layer is 5.2 ccm, the remaining cumene is distilled off in vacuo and the residue consisting of nicotitic acid (α-, ß-diphenyl) ethylamide is recrystallized from ethanol. The new compound forms colorless drusen of needle-shaped crystals with a melting point of 159 °. It is easily soluble in 5N hydrochloric acid, moderately soluble in methanol, acetone, ether and benzene, slightly soluble in ethanol and insoluble in water and in alkalis. Example 3 A mixture of 28.44 g of nicotinic acid chloride chlorohydrate, 34.23 g of 2-Oxv-1. 2-diphenylethylamine and 200 cc of absolute alcohol are added to 44.35 g of freshly calcined potassium carbonate. The whole thing is refluxed for hours, then, after cooling, the undissolved material is filtered off and recrystallized from ethanol. 37.8 g of nicotinic acid (a-hhen_vl - @ - oxy-ß-phenyl) ethylamide are obtained in colorless needles with a melting point of 2-3 °. The new compound is easily soluble in acetone and pvridiri, not very soluble in ether and benzene. Glacial acetic acid and ethanol. insoluble in water.

In ähnlicher Weise kann auch hergestellt werden das Nicotinsäure-[-fluorenvl-9-]-amid (farblos Kristalle vom Schmelzpunkt 287 bis 288°).Nicotinic acid - [- fluorenvl-9 -] - amide can also be prepared in a similar manner (colorless crystals with a melting point of 287 to 288 °).

Claims (1)

PATENTANSPRUCH: Verfahren zur Herstellung von Nicotinsäureamiden durch Umsetzen von N icotinsäure oder einem reaktionsfähigen Derivat davon, z. B. Nicotinsäureanhydrid, einem Nicotinsäurehalogenid oder ,ester, mit einem Amin, dadurch gekennzeichnet, daß man ein Amin von der allgemeinen Formel verwendet, worin R, den Phenylrest und R2 den Phenylrest oder einen mit einem Phenylrest verbundenen aliphatischen Rest. der eine Oxygruppe enthalten kann, bedeuten oder worin das mit dem Stickstoff- und dein `Vasserstoffatom verbundene Kohlenstoffatom Bestandteil eines Ringes ist, an welchem zwei aromatische 6-Ringe ankon.densiert sind. PATENT CLAIM: Process for the preparation of nicotinic acid amides by reacting nicotinic acid or a reactive derivative thereof, e.g. B. nicotinic anhydride, a nicotinic acid halide or, ester, with an amine, characterized in that an amine of the general formula used, in which R denotes the phenyl radical and R2 denotes the phenyl radical or an aliphatic radical bonded to a phenyl radical, which may contain an oxy group, or in which the carbon atom bonded to the nitrogen and hydrogen atom is part of a ring on which two aromatic 6 - Rings are accumulated.
DEP25542A 1945-09-15 1948-12-19 Process for the preparation of nicotinic acid amides Expired DE833817C (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH833817X 1945-09-15

Publications (1)

Publication Number Publication Date
DE833817C true DE833817C (en) 1952-03-13

Family

ID=4540523

Family Applications (1)

Application Number Title Priority Date Filing Date
DEP25542A Expired DE833817C (en) 1945-09-15 1948-12-19 Process for the preparation of nicotinic acid amides

Country Status (1)

Country Link
DE (1) DE833817C (en)

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