Process Research and Development of l-Alanyl-l-glutamine, a Component of Parenteral Nutrition

A large-scale manufacturing method of l-alanyl-l-glutamine used for a component of parenteral nutrition has been studied. The method consisted of a reaction of d-2-chloro- or d-2-bromopropionic acid with thionyl chloride and Schotten−Baumann reaction with l-glutamine followed by ammonolysis reaction. The intermediate d-2-chloropropionyl-l-glutamine was found to be more stable than its bromo analogue. In the ammonolysis reaction, the former intermediate needed a higher reaction temperature, but the by-products produced had little effect on the quality of the final product. The structures of the by-products were conjectured mainly by mass spectrometry and they were removed by anion resin treatment and recrystallization.