Pyrrolidine → HCID 67278301, compound

Participants

Reaction Conditions

Reaction Steps

A 2.5 M solution of n-BuLi in hexanes (4.34 ml, 10.9 mmol) was added over 15 min to a solution of intermediate 18, 1-(4-bromo-2,6-difluoro-benzyl)-pyrrolidine (3.0 g, 10.9 mmol) in absolute THF (20 ml) under a flow of nitrogen at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Then a −78° C. chilled solution of 3-oxocyclobutanecarboxylic acid (0.62 g, 5.43 mmol) in absolute THF (6 ml) was added drop wise at −78° C. The mixture was warmed to RT slowly and left stirring for 18 hrs. Pyrrolidine (0.674 ml, 8.15 mmol) and T3P (3.8 ml, 5.97 mmol, 50% solution in EtOAc) were added and stirred for 30 min and the reaction was then quenched with 1N NaOH (25 ml) and extracted with CH2Cl2 (3×100 ml) to recover 2.8 g of crude product. This was purified by flash column chromatography using a 120 g ISCO™ column and 5% and 8% MeOH/CH2Cl2 with 0.2% NH4OH to obtain the title compound (520 mg, 26% yield). Rf=0.75 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C20H26F2N2O2, 364.2, found, 365.4 (M+H) APCI; 1H-NMR (CDCl3) δ 7.03 (ddd, J=8.7, 3.7, 2.5 Hz, 2H), 3.76 (s, 2H), 3.51 (t, J=6.8 Hz, 2H), 3.47-3.40 (m, 4H), 3.13-3.06 (m, 1H), 2.80-2.73 (m, 2H), 2.60-2.50 (m, 5H), 2.00-1.90 (m, 2H), 1.90-1.83 (m, 2H), 1.76-1.72 (m, 4H).

Provenance & Evidence