An Efficient Large-Scale Process for the Human Leukocyte Elastase Inhibitor, DMP 777¹

This report describes a new convergent, selective, and economical synthesis of DMP 777,1 ending with the coupling of the chiral β-lactam half of the molecule (1) to the chiral amine as the isocyanate (2). Other steps involve the coupling of the β-lactam 3 to the phenolic moiety under phase-transfer conditions, followed by resolution of the resulting piperazine derivative using a chiral acid, and recycling of the undesired enantiomer also under phase-transfer conditions. The chiral amine 4 was produced efficiently starting from (R)-α-methylbenzylamine and the corresponding butyrophenone.