DE1008739B - Process for the preparation of monoacyl derivatives of maleic acid hydrazide - Google Patents

Description

GERMAN

It is known that maleic acid hydrazide reacts with carboxylic acid halides !! reacts in a ratio of 1: 1 and this creates monoacyl compounds for which the following four structures are up for discussion:

OH

OH

O — C —R

R = organic residue.

A number of these compounds are known from the literature, e.g. B. the reaction products of cyclic maleic acid hydrazide with the halides of acetic acid, acrylic acid, valeric acid, triehloroacetic acid, a-naphthylacetic acid, 2,4-dichlorophenoxyacetic acid, Benzoic acid, p-toluic acid, chlorobenzoic acid, Salicylic acid and picolinic acid. Compounds of this type, those with p-nitrogenous aromatic Carboxylic acid halides are produced, but are not yet known.

It has now been found that aminoacyl derivatives of maleic acid hydrazide which are effective as cytostatics can be obtained by reacting in a molar ratio of about 1: \ maleic acid hydrazide with a benzoyl chloride which has an NO ₂ -, NH-CO- in the p-position to the COCl group. Has alkyl or NH-CO — aryl group, or with those heterocyclic carboxylic acid chlorides which have a nitrogen atom in the p-position of the —COCl group, the process being carried out in the presence of a hydrogen chloride-binding agent and, optionally, the substituent in p-position to the COCl group is converted in a known manner into an amino group or a hydroxylamino group.

According to the invention, processes for production are expediently used

of mono acy oil derivatives

of maleic hydrazide

Paint factories Bayer Aktiengesellschaft, Leverkusen-Bayerwerk

Dr. Engelbert Kühle, Cologne-Stammheim,

Dr. Richard Wegler, Leverkusen,

and Dr. Dr. H. c. Gerhard Domagk, Wuppertal-Elberfeld,

have been named as inventors

The place of the maleic hydrazide is its alkali metal or alkaline earth metal salt. These are preferably in indifferent organic solvents, e.g. B. benzene or chlorobenzene, or in the aqueous phase, with implemented the carboxylic acid chlorides. But you can also use maleic hydrazide with the carboxylic acid halides react with the addition of tertiary amines or alkali metal carbonates or bicarbonates.

The following overview shows the cytostatic effectiveness of the compounds mentioned in contrast to other acyl derivatives of cyclic maleic hydrazide:

Compounds According to the Invention Ehrlich carcinoma
in vivo p-Nitrobenzoyl maleic hydrazide ...
p-aminobenzoyl maleic hydrazide ..
p-hydroxylaminobenzoyl
maleic hydrazide
Isonicotinoyl maleic hydrazide effect
effect
little effect
effect

Known connections

m-Nitrobenzoyl maleic hydrazide ... 3,5-Dinitrobenzoyl maleic hydrazide m-nitro-p-chlorobenzoyl-

maleic hydrazide

p-chlorobenzoyl maleic hydrazide ... 2, 4-dichlorobenzoyl maleic hydrazide o-chlorobenzoyl maleic hydrazide ... p-methoxybenzoyl maleic hydrazide

Ehrlich carcinoma in vivo

without effect without effect

no effect no effect no effect no effect no effect

709 510/405

example 1

To a mixture of 43.8 g of maleic hydtrazide and 72.5 g of p-nitrobenzoyl chloride in 200 ml of boiling Benzene is added dropwise to 32 g of pyridine. The mixture is stirred overnight on the water bath and this is sucked off precipitated reaction product together with the pyridine chlorohydrate from cold. To remove the The pyridine chlorohydrates are washed with warm water. 45 g of p-nitrobenzoyl maleic hydrazide are obtained from 246 to 247 °.

Example 2

50 g of p-nitrobenzoyl maleic hydrazide are dissolved in 300 ml of dimethylformamide and hydrogenated with the addition of Raney nickel at 60 ° in the autoclave until the _{amount of hydrogen required to reduce the NO 2} to the NH ₂ group has been absorbed. This gives the p-aminobenzoyl-maleic acid hydrazide with a temperature of 260 ° (Kofier bench). Yield: 17.5 g from dimethylformamide / water.

Example 3

21 g of sodium maleic acid hydrazide are slurried in 100 ecm of absolute toluene and reduced to 90 heated to 100 °. The solution of 22.1 g of isonicotinic acid chloride is slowly left at this temperature in 30 ml of absolute toluene and stir on the steam bath for 2 hours. You vacuum cold, wash with warm water and after recrystallization from methanol, 18 g of the isonicotinoyl maleic hydrazide are obtained from the F. 196 °.

Example 4

10g of sodium maleic acid hydrazide will be used at about 90 ° in 50 ml of absolute toluene and stirred dropwise with the solution of 14.5 g of quinoline-4-carboxylic acid chloride (Cinchoninic acid chloride) in 70 ml of toluene. The mixture is stirred on the steam bath for about an hour and then sucks off. After the usual work-up, the yield is satisfactory the cinchoninoyl maleic hydrazide with a temperature of 218 °.

Claims (2)

Patent claims: 1. A process for the preparation of ■ monoacyl derivatives of maleic acid hydrazide, characterized in that one reacts in a molar ratio of about 1: 1 maleic acid hydrazide either with a benzoyl chloride which has a NO ₂ -, NH — CO as a substituent in the p-position to the COCl group —Alkyl or NH-CO-aryl group, or with those heterocyclic carboxylic acid chlorides which have a nitrogen atom in the p-position of the carboxylic acid chloride group, the process being carried out in the presence of a hydrogen chloride-binding agent and the substituent in the p-position of the COCl -Group is converted in a known manner into an amino group or a hydroxylamino group. 2. The method according to claim 1, characterized in that instead of maleic acid hydrazide whose alkali or alkaline earth salts are used for the reaction. Considered publications:
German patent specification No. 886 147. © 709 510/405 5.