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.