Dimethylformamide → N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-cyano-pyridine-2-carboxamide hydrochloride

Participants

Reaction Conditions

Reaction Steps

Scheme 2, step K (amide formation): Oxalyl chloride (60.0 μL, 692 mmol) is added to a solution of dimethylformamide (60.0 μL, 776 mmol) in acetonitrile (4.0 mL), and the resulting reaction is stirred for 16 min. 5-Cyanopyridine-2-carboxylic acid (106 mg, 715 mmol) is added to the resulting solution. The reaction is stirred for 33 minutes, and 2.0 mL of this solution is removed via syringe and added drop wise to a solution of (4aR,7aS)-7a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-2-amine (110 mg, 347 mmol) in ethanol (2.0 mL) and water (2.0 mL) at 50° C. The resulting solution is heated at 50° C. for 44 minutes followed by purification by SCX columns (methanol to 7 M ammonia in methanol) to give a residue, which is purified again by silica gel flash chromatography, eluting with 7 M ammonia in methanol/dichloromethane (0/10) to 7 M ammonia in methanol/dichloromethane (1/10) to give a residue as the free base of the desired product (120 mg, 83%). This material is dissolved in 5 mL of dichloromethane/methanol (1/1) and is treated with 1 M HCl in ether (300 μL, 0.30 mmol). The sample is concentrated to give the title compound (128 mg, 81.6%). ES/MS (m/e): 416.1 (M+1).

Provenance & Evidence