Patent GB-737758-A (GB)
Title: Novel 2-methyl-pyridine-4-carboxylic acid derivatives and process for the manufacture thereof
IPC: C07D213/81
Filed: 1953-06-26
Abstract: The invention comprises 2-methyl-pyridine-4-carboxylic acid hydrazides of the general formula <FORM:0737758/IV (b)/1> wherein X is a hydrogen or halogen atom and R1, R2 and R3 may each be a hydrogen atom or an alkyl, aralkyl or alkenyl group containing not more than 7 carbon atoms, and salts thereof.  They may be prepared by reacting compounds of the general formula <FORM:0737758/IV (b)/2> wherein X is hydrogen or halogen and R represents a halogen atom or an alkoxy group, or a hydrohalide salt thereof, with a hydrazine <FORM:0737758/IV (b)/3> the Rs being as defined above, or a hydrate or salt thereof; if desired, when X is a halogen, the halogen in the 6-position in the resulting product may be replaced by hydrogen according to methods known per se.  The unsubstituted hydrazine or a hydrate or salt thereof is preferably condensed with an ester of the methylpyridine carboxylic acid, the hydrate being normally used with a solvent.  The substituted hydrazines and salts thereof are preferably reacted with the acid halide or its hydrohalide salt, desirably in presence of an acid-binding agent.  Hydrazides formed which still contain hydrogen attached to hydrazido-nitrogen may be further substituted by treating them with an alkali metal dissolved in an alkanol and then reacting the mixture with an alkyl, aralkyl or alkenyl halide containing up to 7 carbon atoms or an alkyl sulphate containing not more than 7 carbon atoms in each of its alkyl groups. The products and their salts include compounds having therapeutic uses, especially for combating tuberculosis, or compounds useful for the preparation of such chemotherapeutically active substances.  The bases form salts with such acids as hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, tartaric and oxalic acids.  The 2-methyl-6-halogeno-pyridine-4-carboxylic acid alkyl esters or halides used as starting materials may be prepared by condensing cyanoacetic amide with an acetyl-pyruvic acid ester, converting the resulting 2-methyl-5-cyano-6-hydroxy-pyridine-4-carboxylic acid ester into 2-methyl-6-hydroxypyridine-4-carboxylic acid by means of concentrated hydrochloric acid and reacting the product with a phosphorous halide to yield 2-methyl-6-halogenopyridine-4-carboxylic acid halide; the latter may be reacted with an alkanol to form a desired ester.  Halogen - free 2 - methyl - pyridine - 4 - carboxylic acid esters may be prepared by esterification of the corresponding acid; these esters may also be prepared by catalytic hydrogenolysis of the corresponding 6-halogeno compounds in the present of a hydrogenation catalyst and a hydrogen-halide binding agent having no hydrolysing action on the ester.  In examples (1) 2-methyl-6 - chloro - pyridine - 4 - carboxylic acid methyl ester is reacted with hydrogen in methanol containing potassium acetate and a palladium catalyst and the resulting 2-methyl-pyridine-4-carboxylic acid methyl ester is converted into its hydrazide by heating with hydrazine hydrate in methanol; (2) the starting material of (1) is reacted with hydrazine hydrate in methanol and the resulting hydrazide catalytically hydrogenolysed in aqueous caustic soda yielding the same product as in (1); (3)-(5) 2-methyl pyridine-4-carboxylic acid chloride hydrochloride, prepared from the free carboxylic acid and thionyl chloride is reacted in dry pyridine with N1N1-dimethyl, -diethyl and di-allyl-hydrazine hydrochlorides respectively yielding the corresponding N2,N2-disubstituted hydrazides.  Many other such compounds are mentioned including the N1-2-methyl-pyridine-4-carboxylic acid hydrazides of N1-isopropyl hydrazine, N1,N2-di-iso propyl hydrazine, N1,N2-dibenzyl hydrazine, N2,N2-dimethyl hydrazine, N1-methyl-N2,N2-dibenzyl hydrazine and N1-allyl-N2,N2-diethyl hydrazine.  Specification 720,787 is referred to.