Imidazole → (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-6-phenyl-2-(4-pyridin-2-ylbenzyl)hexanoic acid

Participants

Reaction Conditions

Reaction Steps

A solution of the product of Example 111-8 (250 g, 529 mmol) in N-methylpyrrolidinone (2L) under N2 was treated with milled lithium hydroxide monohydrate (33.3 g, 793.5 mmol, 1.5equivalents) and N,N-(dimethylamino)pyridine (6.5 g, 53 mmol, 0.1 equivalent) and stirred at 40° C. for 10 hrs. The reaction mixture was cooled to about 22° C., treated with imidazole (827.5 g, 12.2 mol, 23 equivalents) over 15 minutes, stirred at 22° C. for 30minutes, cooled to 6° C., and treated with t-butyldimethylsilyl chloride (876.94 g, 5.819 mol, 11 equivalents) over 45 minutes. This mixture was warmed to 22° C., stirred at 20° C. for 1.5 hours, and stirred at 40° C. overnight. The reaction mixture was cooled to 22° C., charged with 1.25 L of distilled water over 10 minutes and mixed for 2 hrs. The reaction mixture was charged with 1.25 L of brine, 1.25 L of ethyl acetate and 1.25 L of heptanes. The aqueous layer was extracted with 1.25 L of ethyl acetate and 1.25 L of heptanes. The combined organic layer was washed with brine (2×1.2 L), concentrated and chased with heptanes (1.4 L). The resulting oil was dissolved in N,N-dimethylformamide (812 mL), partitioned between heptanes (5.25 L) and 10% aqueous K2CO3 (1.25 L). The heptane layer was extracted with 10% K2CO3 (2×400 mL) and N,N-dimethylformamide (260 mL). The combined aqueous layer (DMF/K2CO3) was washed with 4×5L heptanes. The aqueous layer was cooled to 5° C., charged with 2.5L of toluene, adjusted to pH 5 with 5% HCl, and extracted with 1.6 L of toluene. The combined toluene layer was washed with brine (2×1.75 L), and water (2×1.75 L), concentrated to oil and chased with toluene (2×800 mL) to give the title compound. 1H NMR (CDCl3): δ 8.50(m, 1H), 7.5-7.8(m, 4H), 7.0-7.2 (m, 8H), 4.6 (m, 1H), 3.6-4.0(m, 2H), 2.5-2.9(m, 4H), 2.25(s, residual toluene), 1.5-2.0(m, 2H), 1.0-1.3 (s+d, boc), 0.85(s, t-butyl), 0 (m, 6H).

Provenance & Evidence