An Alternative Pathway for the Synthesis of Glycerol Phenylbutyrate

Abstract

Hyperammonemia is a life-threatening condition which canaffect patients at any age. In pediatric patients, hyperammonemia can be caused by various acquired or inherited disorderssuch as urea cycle deficiencies or organic acidemias. Glycerolphenylbutyrate (GPB) is an orphan drug used in the treatmentof hyperammonemia. GPB is a triglyceride composed of threephenylbutyric acid (PBA) molecules esterified to a glycerolmolecule, which is synthesized through the acyl chloride routeusing thionyl chloride as an acylating agent. In this work wehave developed an alternative synthesis method to obtain GPBdirectly under ambient conditions and avoiding the use ofchlorinated solvents. Moreover, the use of carbodiimides ascoupling agents, instead of thionyl chloride, allowed theconversion to the GPB in higher yields and with higher purity,without the need for column purification. We present amethodology that allows the production of GPB in a simple,efficient and environmentally and human health friendly way.