An Alternative Pathway for the Synthesis of Glycerol Phenylbutyrate

Abstract Hyperammonemia is a life‐threatening condition which can affect patients at any age. In pediatric patients, hyperammonemia can be caused by various acquired or inherited disorders such as urea cycle deficiencies or organic acidemias. Glycerol phenylbutyrate (GPB) is an orphan drug used in the treatment of hyperammonemia. GPB is a triglyceride composed of three phenylbutyric acid (PBA) molecules esterified to a glycerol molecule, which is synthesized through the acyl chloride route using thionyl chloride as an acylating agent. In this work we have developed an alternative synthesis method to obtain GPB directly under ambient conditions and avoiding the use of chlorinated solvents. Moreover, the use of carbodiimides as coupling agents, instead of thionyl chloride, allowed the conversion to the GPB in higher yields and with higher purity, without the need for column purification. We present a methodology that allows the production of GPB in a simple, efficient and environmentally and human health friendly way.