Reaction Steps
{1-Benzyl-2-hydroxy-3-[isobutyl-(2-methanesulfonyl-benzothiazole-6-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester (1)1,2 (10 g, 15 mmol, 1 equiv), 1-cyclopentyl-piperidin-4-yl-ammonium chloride (4) (6.02 g, 25 mmol, 1.67 equiv) and triethylamine (6.10 g, 60 mmol, 4 equiv) were dissolved in tetrahydrofurane (200 mL), followed by the addition of 10% Na2CO3 in water (50 mL). The solution was stirred at room temperature for 48 hours. The organic layer was separated and washed with saturated NaHCO3 solution. The organic layer was dried on MgSO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on elution with dichloromethane:ammonia in methanol (7N) (100 to 95:5) to yield the title compound (4.45 g, 15 mmol, 39%). LRMS (ES+): m/z 756 [M+H]+; HPLC (system 1) (290 nm) tR 4.16 min, 97.11%; 1H-NMR (CDCl3) 0.87 (d, 3H, J=6.48, CH3), 0.92 (d, 3H, J=6.50, CH3), 1.33-1.51 (m, 4H, CH2 (2×) (cyclopentyl)), 1.51-1.77 (m, 6H, CH2 (2×) (piperidine) and CH2, H4), 1.77-1.96 (m, 5H, CH2 (2×) (cyclopentyl) and CH (isobutyl)), 2.09-2.28 (m, 4H, CH2 (2×) (piperidine)), 2.43-2.59 (m, 1H, CH (cyclopentyl)), 2.72-2.85 (m, 1H, OH), 2.85-2.92 (m, 1H, CH, H3a), 2.92-3.12 (m, 5H, CH (piperidine) and CH2—N and CH2 (isobutyl)), 3.20 (dd, 2H, J=8.63 and J=15.16, CH2 of C6H5CH2), 3.58-3.79 (m, 3H, CH2, H5 and CH2, H2), 3.79-3.91 (m, 3H, CH2, H2 and CH—NH and CH—OH), 4.90-5.10 (m, 2H, CH, H3 and NH), 5.42-5.59 (m, 1H, NH), 5.62 (d, 1H, J=5.04, CH, H6a), 7.12-7.32 (m, 5H, C6H5), 7.52 (d, 1H, J=8.54, CH (benzthiazole)), 7.67 (dd, 1H, J=0.99 and J=8.47, CH (benzthiazole)), 7.95-8.02 (brs, 1H, CH (benzthiazole)). 1 Surleraux, D. L. N. G. et al. Broad spectrum 2-(substituted-amino)-benzothiazolesulfonamide HIV protease inhibitors/PCT Int. Apl. 2002, WO2002083657.2 Surleraux, D. L. N. G. et al. Design of HIV-1 Protease Inhibitors Active on Multidrug-Resistant Virus.; J. Med. Chem. 2005, 48, 1965-1973.
