A convenient synthesis of amino acid p-nitroanilides:Synthons in the synthesis of protease substrates

A method is described for the synthesis of N-alpha-protected bi- and trifunctional amino acid p-nitroanilides. The reaction uses phosphorus oxychloride as the condensing agent. The synthesis is simple, rapid, free of racemization and affords yields between 70-90%. The synthesis can be performed not only with amino acid derivatives of the urethane type including acid-labile (Z, Boc) and base-labile (Fmoc, Msc) N(a)lpha-protective functions or allyl-derived protections, but also with N-alpha-trityl amino acids, albeit in lower yield. The reaction runs in pyridine and its mechanism implies carboxyl activation by formation of a mixed anhydride with phosphorodichloridic acid (HOPOCl2)