An Improved Synthesis of Teriflunomide and Identification, Synthesis and Characterization of Its Critical Process Impurities

Abstract

Teriflunomide has an impeccable drug used to treat multiple sclerosis. Ample of literature is available for its synthesis, however, it does not reveals the potential impurities formation during synthesis, The chief intent of the article is to highlight the key impurities formation in Teriflunomide synthesis that yet to have to be documented in the literature and are not mentioned in any monograph. It also provides an overview of the process flow for the formation of new contaminants and their fate in the carryover study. The generation of corresponding impurities from impurity-I, i.e. ((Z)-4-Amino- N, N'-bis[(4-(trifluoromethyl)phenyl] benzimidamide, which generates in starting material (4-TFMA) and has a genotoxic alert, is discussed in every stage of Teriflunomide (I) synthesis, and a characterization study is carried out for corresponding impurities. The paper also provides a brief overview of the development of isomeric impurities from the beginning material 4-TFMA and equivalent impurities from the precursor of another starting material, cyano acetic acid. All of the impurities were identified, and the data is presented in this publication. The primary goal of the invention is to reveal the crucial impurity creation and elimination from the process, resulting in a highly efficient and scalable method. Also the invention introduces the new concept for amidation process to well-optimized reaction conditions. The synthesis avoids the use of unsafe chemicals and pyrophoric bases, and new the boric acid concept is introduced for amidation in Teriflunomide synthesis.