A High-Throughput Process for Valsartan

Abstract

With the redesign of three chemical steps, the throughput of the valsartan manufacturing process could be significantly increased, and with the substitution of chlorobenzene with cyclohexane in the bromination of 4′-methyl-biphenyl-2-carbonitrile (6) to 4′-bromomethyl-biphenyl-2-carbonitrile (5), halogenated solvents are no longer used in the whole valsartan production process. The alkylation of (S)-2-amino-3-methyl-butyric acid benzyl ester (8) with 4′-bromomethyl-biphenyl-2-carbonitrile (5), and the acylation of (S)-2-[(2′-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid benzyl ester (4) to (S)-2-[(2′-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid benzyl ester (3) were thoroughly modified. In the acylation of 4 to 3, N-ethyldiisopropylamine was replaced by aqueous sodium hydroxide by using the conditions of the Schotten–Baumann reaction, leading to a better quality of intermediate 3. In the alkylation of 8 with 5, N-ethyldiisopropylamine was indirectly replaced by aqueous sodium hydroxide. The reaction runs under homogenous conditions with (S)-2-amino-3-methyl-butyric acid benzyl ester (8) acting as acceptor for hydrobromic acid; recycling of 8 is performed by extraction with aqueous sodium hydroxide.