PROCEDURE FOR FACILE SYNTHESIS OF AMINO-ACID N-CARBOXYANHYDRIDES

The preparation of high-molecular-weight homopolypeptides and random copolypeptides is usually accomplished by polymerization of the corresponding .alpha.-amino-acid N-carboxyanhydrides (NCA). These intermediates are also useful in stepwise peptide synthesis in solution. Until now the preparation of NCA has not involved a routine procedure. In the phosgene method the amino acid (with protected side-chain functionalities) is usually suspended in a dry solvent such as dioxane at 50.degree. C, and phosgene is passed through the mixture until the amino acid dissolves, which usually requires several hours. The resulting solution must be evaporated under reduced pressure or purged for prolonged periods with N to remove the enormous excess of phosgene, accumulated during the reaction, before crystallization of the product. This method is potentially dangerous because of the use of large amounts of gaseous phosgene. Typically, several careful recrystallizations under stringent, anhydrous conditions are necessary to obtain pure NCA. A routine and rapid method for preparing NCA is described which is based on a combination of the use of a standard solution of phosgene in benzene and careful monitoring of the progress of the reaction by IR spectroscopy. The use of a benzene solution of phosgene allows careful measuring of the amount of phosgene used without accumulation of the vast excesses, which are normally encountered in the conventional procedure. Monitoring the reaction with IR spectroscopy, following the appearance of the NCA bands at 1780-1790 cm-1 and 1850-1865 cm-1, ensures completion of the reaction with facilitates crystallization of the pure NCA.