Synthetic development of Mitapivat via improved route

Mitapivat, a pyruvate kinase activator used to treat hemolytic anemia, is prepared via a concise and efficient route starting from the inexpensive and commercially available p-aminobenzoic acid (PABA). The synthetic sequence features a mild reaction condition to form the amide linkage with piperazine and p-aminobenzoic acid, followed by N-alkylation using cyclopropyl bromide as the electrophile. The overall transformation proceeds with a 40 % isolated yield over three steps, exhibiting good atom economy and step efficiency. Notably, the mitapivat was obtained without the use of column chromatography. This streamlined protocol offers operational simplicity, cost-efficiency, and scalability, making it a compelling alternative to existing synthetic approaches for mitapivat.