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

Abstract

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 (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. . The key intermediate N-(tert-butyloxycarbonyl)-2(S)-amino-1-phenyl-3(R)-3,4-epoxy-butane

Synthesis of13C6-labeled Reyataz? (BMS-232632)

“…The route used to synthesize 13 C 6 -labeled Reyataz TM ([ring- 3,4 The key to the synthesis was the use of [ring-13 C 6 ]-l-phenylalanine as the starting material. This 13 C 6 -labeled compound is commercially available with high enantiomeric and isotopic purity.…”

“…4 All experimental procedures were optimized using unlabeled materials. All glassware was dried and purged with nitrogen or argon before use.…”

“…4 The mixture was heated to 758C and stirred for 12 h under argon. At that time the solution was cooled to room temperature and concentrated under reduced pressure to give a yellow wax.…”

“…4 The solution was heated to 608C and stirred for 3 h. Gas evolution was observed during the first 30 min. The reaction mixture was cooled to room temperature and concentrated to give crude 10 as a yellow oil.…”

“…4 Crude 10 (assume 1.94 mmol) and diisopropylethylamine (1.55 g, 2.10 ml, 12.03 mmol) were dissolved in anhydrous CH 2 Cl 2 (5 ml) and added to the solution prepared above. The mixture was stirred at room temperature under argon for 17 h. At that time the reaction mixture was diluted CH 2 Cl 2 (75 ml) and then washed with water (25 ml), saturated NaHCO 3 (25 ml), and brine (25 ml).…”