Sustainable and Integrated Flow-Based Three-Step Synthesis of Sodium Valproate

Abstract

Sodium valproate is a well-established drug in neurology, serving as an antiepileptic, migraine prophylactic, and mood stabilizer. According to the World Health Organization, an estimated 50 million people worldwide are affected by these conditions. Continuous pharmaceutical manufacturing offers significant advantages, including consistent drug quality, cost and time efficiency, and the flexibility to scale production to meet rising patient demand. In this work, we present a compact flow synthesis of sodium valproate using inexpensive diethyl malonate, eliminating the need for solvent exchange and intermediate purification. The process features a novel dipropylation reaction with propyl chloride, a simple deethoxycarbonylation step without relying on corrosive acid-mediated decarboxylation, and sequential basic hydrolysis and salification. After an in-line extraction to remove impurities, sodium valproate was obtained with a total yield of 87% and a purity of over 99%, all achieved within a residence time of just 41 min, resulting in a throughput of 552 g/day. The green metrics for this method, with a process mass intensity of 11.8 and an E-factor of 10.8, are significantly lower than those of the current batch production process, demonstrating a more sustainable approach.