GB653068A - Process for the synthesis of folic acid and intermediates therefor - Google Patents

Abstract

4 - ([2 - acylamino - 4 - hydroxy - 6 - pteridyl) methyl] acylamino) benzoic acid chloride is prepared by reacting 4-([2-acylamino-4-hydroxy-6-pteridyl) methyl] acylamino) benzoic acid with a thionyl halide or a phosphorus halide. The acyl group may be an acetyl group, and the thionyl halide may be thionyl chloride. The acid chloride thus produced is reacted with a dialkyl or diaralkyl ester of 1(+) glutamic acid in the presence of a condensing agent to form N - [4 - ([(2 - acylamino - 4 - hydroxy - 6-pteridyl) - methyl] acylamino) benzoyl] glutamic acid ester, e.g. the diethyl ester. The condensing agent may be an aqueous solution of an alkali-metal hydroxide, e.g. sodium p hydroxide, pyridine, or a mixture of an aqueous solution of an alkali metal hydroxide and pyridine. The condensing agent may be employed in an excess of the quantity required to neutralize the hydrohalic acid formed. The dialkyl or diarylkyl esters thus formed may be hydrolysed to form N[([2-amino-4-hydroxy - 6 - pteridyl) methyl] - amino) benzoyl] glutamic acid. A number of detailed examples are given. The Specification as open to inspection under Sect. 91 refers to the preparation of N-[4-([(2 - acetylamino - 4 - hydroxy - 6 - pteridyl) methyl] acetylamino) benzoyl] glutamic acid ethyl ester by heating N - [4 - ([(2 - amino - 4 - hydroxy - 6 - pteridyl) methyl] amino) benzoyl] glutamic acid ethyl ester with a large excess of acetic anhydride at a reflux temperature. This subject-matter does not appear in the Specification as accepted.