4-Methylmorpholine → 1-Boc-4-(2-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)piperidine

Participants

Reaction Conditions

Reaction Steps

To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.20 equiv; 252.61 mmol; 57.92 g) in THF (400 mL), add NMM (3 equiv; 631.52 mmol; 69.66 mL). Cool to −10° C. with a dry ice-acetone bath. Add isobutyl chloroformate (1.1 equiv; 231.56 mmol; 30.26 mL) dropwise maintaining the temperature below −5° C. After 30 min at from −5 to 10° C., add 2-amino-1-(4-fluoro-3-(trifluoromethyl)-phenyl)-ethanone hydrochloride (54.23 g; 1.00 equiv; 210.51 mmol) suspended in THF (300 mL) and stir the mixture in the bath at −5° C. for 20 min and then 1 h at RT. Partition between water and EA; wash the organic layer with water then saturated NaCl aqueous (brine), dry over anhydrous MgSO4, filter and concentrate in vacuo. Suspend the crude in MTBE and stir for 2 h. Filter the solid and dry in vacuo to give the title compound (64.44 g; 70.79%). 1H NMR (300 MHz, DMSO): 8.37-8.26 (m, 3H), 7.74-7.68 (m, 1H), 4.61 (d, J=5.5 Hz, 2H), 3.91 (d, J=12.9 Hz, 2H), 2.75-2.64 (m, 2H), 2.46-2.37 (m, 1H), 1.69-1.60 (m, 2H), 1.39 (s, 12H).

Provenance & Evidence