3-Fluorophenol → HCID 44600362, compound

Participants

Reaction Steps

To a heterogeneous mixture of (2R,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidin-1-yl]-ethanone (139 g, 448.5 mmol), 3-fluoro-phenol (52 mL, 462 mmol), and triphenylphosphine resin (1.52 mmol/g loading, 339 g, 516 mmol) in CH2Cl2 (4.3 L) was slowly added DIAD (91 mL, 462 mmol) over 15 min. The mixture was stirred at rt for 15 h. The resin was filtered off and washed with CH2Cl2 (4 L). The filtrate was concentrated and partitioned between methyl tert-butyl ether (MTBE; 2 L) and water (2 L). The aqueous layer was extracted with additional MTBE (2×1.8 L). The combined organic layers were concentrated to a volume of 2 L and extracted with 1 N HCl(aq) (2 L). The acidic aqueous layer was washed with MTBE (1 L) and then basified to pH>12 with 50% NaOH(aq) (118 mL). The basic aqueous layer was extracted with CH2Cl2 (2×1.5 L) and the combined organics were dried with MgSO4, filtered, and concentrated to an oil. The oil was optionally purified by FCC (0 to 5% 2 M NH3 in MeOH/95% CH2Cl2) to provide the title compound (89 g, 49%). MS (ESI): mass calcd. for C22H30FN3O3, 403.2; m/z found, 404.3 [M+H]+. 1H NMR (CDCl3): 7.28-7.19 (m, 1H), 6.74-6.54 (m, 3H), 5.12-5.05 (m, 0.91H), 5.02-4.95 (m, 0.91H), 4.93-4.79 (m, 0.18H), 4.13-4.02 (m, 1H), 3.88-3.60 (m, 5H), 2.96-2.82 (m, 1H), 2.70-2.27 (m, 6H), 2.1-1.55 (m, 11H).

Provenance & Evidence