Benzyl Alcohol → Benzyl (3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentylcarbamate

Participants

Reaction Conditions

Reaction Steps

To the product of Example 111-9 (274 g, 453 mmol) in toluene (2.65 L) were added triethylamine (126.5 mL, 906 mmol, 2 equivalents) and DPPA (128.5 g, 453 mmol, 1 equivalent). The mixture was stirred at 40° C. for 1 hour. Additional DPPA (6.3 mL, 17 mmol, 0.04 equivalent) was charged to the reaction mixture and mixed at 40° C. for 3 hours. Benzyl alcohol (147 g, 1.359 mol, 3 equivalents) was added and the mixture was heated at 105° C. for 10 hours then 22° C. for 7 hours. The reaction mixture was washed with 10% Na2CO3 (1.1 L), saturated NaHCO3 (1.1 L), and water (4×3 L). The organic layer was concentrated. The residue was dissolved in tetrahydrofuran (500 mL), cooled to 5° C. and treated with 1M TBAF in tetrahydrofuran (2.5 L, 5.5 equivalents.) and the mixture was stirred at 5° C. for 2 hrs. The reaction mixture was quenched with 5% KH2PO4 (2.6 L) and water (1.1 L), extracted with ethyl acetate (5 L). The aqueous layer was extracted with ethyl acetate (3.2 L). The combined organic layers were washed with water (3×2.7 L) and concentrated. The resulting solid was chased with heptanes and methanol. The solid was dissolved in methanol (1.6 L) at 63° C., cooled to 22° C. and stirred at 22° C. until solids precipitated. The slurry was treated with 800 mL of distilled water, mixed at 22° C. for 3 hours, filtered, washed with 2:1 methanol:water (total volume=600 mL), and heptanes (700 mL). The wet cake was dried in 50° C. vacuum oven under N2 to give the title compound (diastereomeric ratio=1.3:1 as determined by HPLC (Column: Zorbax C-8 25 cm, flow, Gradient system: 0-5 min, 0.1% H3PO4/10% CH3CN/90% water to 0.1% H3PO4/90% CH3CN/10% water, 5-12 hold at 0.1% H3PO4/90% CH3CN/10% water, 12-13 min, 0.1% H3PO4/90% CH3CN/10% water to 0.1% H3PO4/10% CH3CN/90% water, 13-15 min, hold at 0.1% H3PO4/10% CH3CN/90% water). 1H NMR (DMSO-d6): δ 8.64(m, 1H), 7.81-7.97(m, 4H), 7.10-7.33(m, 14H), 6.27(m, 1H), 4.83-4.95(m, 2H), 4.60(d, 1H), 3.95(m, 1H), 3.80(m, 1H), 3.55(m, 1H), 2.57-2.77(m, 4H), 1.55(m, 2H), 1.27(s, 9H).

Provenance & Evidence