Process Research and Development for an Efficient Synthesis of the HIV Protease Inhibitor BMS-232632

Development of an efficient and scalable process for the human immunodeficiency virus (HIV) protease inhibitor BMS-232632 1-[4-(pyridin-2-yl)phenyl]-5( S )-2,5-bis{[ N -(methoxycarbonyl)- l - tert -leucinyl]-amino}-4( S )-hydroxy-6-phenyl-2-azahexane, is described. The key step in the synthesis of the intermediate N -1-( tert -butyloxycarbonyl)- N -2-[4-(pyridin-2-yl)benzylidene]hydrazone ( 11 ) was the Pd-mediated coupling of boronic acid 9 with 2-bromopyridine. An efficient procedure was developed for the chemoselective reduction of hydrazone 11 to hydrazine carbamate 4 . The key intermediate N -( tert -butyloxycarbonyl)-2( S )-amino-1-phenyl-3( R )-3,4-epoxy-butane ( 6 ) was prepared stereoselectively from chiral diol 10 . The subsequent union of 4 and 6 followed by coupling with N -methoxycarbonyl- l - tert -leucine provided the free base BMS-232632 in high yield. Evaluation of a variety of salts and identification of bisulfate salt 19 with enhanced bioavailability are also described.