4-Methylmorpholine → ((R)-5-{5-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester

Participants

Reaction Steps

To a mixture of [(R)-5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (636 g, 1.77 mol) and 5-cyano-3-methylpyridine-2-carboxylic acid (301 g, 1.86 mol) was added THF (4.2 L) under N2 atmosphere at ambient temperature. To the stirring mixture was added N-methylmorpholine (428 mL, 3.89 mol) and the mixture was stirred to form a homogeneous solution. The reaction solution was cooled to 0-5° C. before addition of isobutyl chloroformate (256 mL, 1.95 mol) via an addition funnel while keeping the reaction temperature under 10° C. After the addition, the mixture was stirred at 0-10° C. for 1 h before filtration. The filtrate was evaporated in vacuo and the resulting residue was dissolved in the mixture of CH2Cl2 (3 L) and methanol (1 L). The mixture was concentrated in vacuo at 400 mbar/35° C. till no more volatile coming out to give a slurry. The slurry was filtered and the filter cake was washed with methanol till the wash getting colorless. The wet cake was dried in a vacuum oven at 45° C. for 24 h to give title compound as a white solid: ESIMS: 504; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 10.00 (s, 1H), 8.98 (s, 1H), 8.39 (s, 1H), 7.92 (m, 1H), 7.81 (m, 1H), 7.24 (m, 1H), 6.30 (t, 1H), 4.56 (d, 1H), 4.44 (d, 1H), 4.12 (m, 1H), 3.90 (m, 1H), 2.55 (s, 3H), 1.41 (s, 9H).

Provenance & Evidence