A Facile Approach for the Synthesis of Highly Pure Immunomodulator Drugs-Leflunomide and Teriflunomide: A Robust Strategy to Control Impurities

Abstract

A facile synthesis of immunomodulator drugs, Leflunomide (10) and its active metabolite, Teriflunomide (1) is described. The synthesis is sequential and comprises N-acylation of 4-trifluoromethyl aniline (9) with 5-methylisoxazole-4-carboxylic acid chloride (8) in dimethoxyethane as a solvent to yield leflunomide (10) with an overall yield of 68% and 99.8% purity by HPLC. Sodium hydroxide mediated isoxazole ring scission of leflunomide (10) in aqueous methanol furnished teriflunomide with 81% yield and 99.9% purity by HPLC. The work further describes raw material and process attributes which are critical to control the process related, degradation and carryover impurities in both 10 and 1.