GB808046A - Novel substituted pyridone-acetic acid derivatives and process for the manufacture thereof - Google Patents

Abstract

The invention comprises [1-(31,41-dimethoxyphenylethyl) - 2 - keto - 1,2 - dihydropyridyl-(4)]-acetic acid and 5-alkyl derivatives thereof having the general formula <FORM:0808046/IV (b)/1> wherein - - R denotes the optional presence of an alkyl group. They may be prepared by reacting a 2-(31,41-dimethoxyphenyl)-ethyl halide, preferably iodide, with 4-methyl-pyridone-(2) or a 4 - methyl - 5 - alkyl - pyridone - (2) in the presence of an alkaline agent, e.g. alkali metal alkoxide or hydroxide, conveniently in benzene or an alcohol, treating the resulting 1-(31,41-dimethoxyphenylethyl) - 2 - keto - 4 - methyl - 1,2-dihydropyridine or 5-alkyl derivative thereof with an alkyl oxalate in the presence of alkalimetal alkoxide under anhydrous conditions conveniently in a solvent such as a mixture of diethyl ether and ethanol, and, finally treating the pyruvic acid derivative so formed (after treatment with dilute acid if desired) first with an alkali, preferably in the cold, and then with hydrogen peroxide. The process may be varied by using 4-methyl-2-bromopyridine or a 4-methyl-5-alkyl-2-bromopyridine instead of the pyridone-(2), and submitting the resulting quaternary salt to a treatment with alkali, e.g. aqueous alcoholic alkali-metal hydroxide, under mild conditions to form the 1-(31,41-dimethoxyphenylethyl) - 2 - keto - 4 - methyl - 1,2 - dihydropyridine or 5-alkyl derivative thereof. A further variation involves treating the pyruvic acid derivative, after treatment with dilute acid if desired, with hydroxylamine (hydrochloride) and submitting the resulting oximino-ester successively to alkaline hydrolysis, decarboxylation-cum-dehydration to give a nitrile, e.g. by heat or a dehydrating agent such as acetic anhydride, and treatment with alkali or acid. The product may be catalytically reduced to [1-(31,41-dimethoxyphenylethyl) - 2 - ketopiperidyl - (4)]-acetic acid or a 5-alkyl derivative and then esterified with methanol or treated (in the form of a salt) successively with ethyl chloroformate and homoveratryl amine to give the [1-(31,41-dimethoxyphenylethyl) - 2 - ketopiperidyl-(4)] - acetic acetic acid (311,411 - dimethoxyphenylethyl)-amide or a 5-alkyl derivative. These may be converted in known manner to bisnoremetine or emetine (from the 5-ethyl derivative). The 4 - methyl - 5 - alkyl - pyridone - (2) starting materials may be prepared by treating the appropriate 3 - alkyl - 4 - methyl - pyridines with sodamide followed by nitrous acid or by the method disclosed in Specification 808,045. In examples: (1) 2-(31,41-dimethoxyphenyl) ethyl chloride is prepared by the action of thionyl chloride in benzene on the corresponding alcohol in the presence of diethyl aniline, converted into the iodide by means of sodium iodide in dry methyl ethyl ketone or acetone and this reacted with 4-methylpyridone-(2) or 4-methyl - 2 - bromopyridine to give 1 - (31,41-dimethoxyphenylethyl) - 2 - keto - 4 - methyl-1,2-dihydropyridine; this is converted to the potassio derivative of 1-(31,41-dimethoxyphenylethyl) - 2 - keto - 1,2 - dihydropyridyl - (4)-pyruvic acid ethyl ester by the action of potassium ethoxide and ethyl oxalate in benzene and the product converted by various routes to 1-(31,41 - dimethoxyphenylethyl) - 2 - keto - 1,2-dihydropyridyl - (4) - acetic acid; this is hydrogenated using Adams' catalyst to 1-(31,41-dimethoxyphenylethyl) - 2 - ketopiperidyl - (4)-acetic acid from which are prepared the methyl ester and the (311,411-dimethoxyphenylethyl) amide, the latter by reaction with ethyl chloroformate and homoveratrylamine in dry dimethylformamide in the presence of triethylamine; (2) 4 - methyl - 5 - ethyl - pyridone - (2) is prepared by reacting b -collidine in dimethylaniline or xylene solution with sodamide to give a crude mixture of 5-ethyl-4-methyl-2- and 6-aminopyridines which is reacted with nitrous acid to give a mixture of pyridones from which 5 - ethyl - 4 - methyl - pyridone - (2) and 3-ethyl - 4 - methyl pyridone - (2) are isolated by fractional crystallization or chromatography; from the former product are prepared 1-(31,41-dimethoxyphenylethyl) - 2 - keto - 4 - methyl-5 - ethyl - 1,2 - dihydropyridine, 1 - (31,41 - dimethoxyphenylethyl) - 2 - keto - 5 - ethyl - 1,2-dihydropyridyl - (4) - pyruvic acid ethyl ester and its potassio derivative, and 1-(31,41-dimethoxyphenylethyl) - 2 - keto - 5 - ethyl - 1,2 - dihydropyridyl - (4) - acetic acid, all by methods analogous to those of Example 1. The Provisional Specification refers to the use of alkali agents in general, e.g. alkali-metal hydroxides, in the formation of the pyruvic acid derivative.