Synthesis of Valproic Acid, Sodium Valproate, and Divalproex Sodium in Flow

This study describes the synthesis of three active pharmaceutical ingredients (APIs) used as anticonvulsant agents for treating chronic brain disorders, such as epilepsy. The synthetic strategies involve the saponification of the key starting material using perfluoroalkoxyalkane (PFA)-PFR (plug flow reactor) at 120 °C, followed by pH adjustment to obtain dicarboxylic acid. This acid undergoes selective monodecarboxylation using stainless steel (SS)-PFR at 140 °C, followed by atmospheric distillation to yield valproic acid. Finally, salts of monosodium and semisodium valproic acid are produced in PFA–PFR at ambient temperature, resulting in two additional APIs: sodium valproate and divalproex sodium. The key innovation in this process is the ability to generate three APIs from a single starting material in a flow process, achieving yields of approximately 95% and purities of 99% for each. This approach demonstrates industrial viability, with throughputs of 22, 105, and 98 g/h for valproic acid, sodium valproate, and divalproex sodium, respectively.