Aminopyrazine → N-(pyrazin-2-yl)-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

Participants

Reaction Steps

A round-bottom flask was charged with tert-butyl 4-(2-(7-((perfluorophenoxy)sulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE AA, 37.7 mg, 0.053 mmol), pyrazin-2-amine (7.61 mg, 0.080 mmol, TCI America, Portland, Oreg.), and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (112 μL, 0.112 mmol) was added dropwise over 30 s to give a light-yellow solution. After 20 min, the flask was lowered into an ice bath. After another 30 min, TFA (3 drops) was added via syringe, and the mixture was concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 20 min, the mixture was concentrated, and the residue was dissolved in MeOH and loaded onto a 500 mg SCX-2 ion exchange column. The column was eluted with MeOH then with 2N ammonia in methanol. The basic fraction was concentrated. The residue was further purified by chromatography on silica gel (12 g column, 10% MeOH/DCM, then 20% of a 2N ammonia in methanol solution dissolved in DCM) to give N-(pyrazin-2-yl)-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (13.49 mg, 0.026 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (s, 1 H), 8.02 (s, 1 H), 7.86 (br. s., 1 H), 7.72 (dd, J=1.7, 8.6 Hz, 2 H), 7.59 (d, J=1.9 Hz, 1 H), 7.54 (d, J=8.1 Hz, 1 H), 6.43 (d, J=8.5 Hz, 1 H), 5.87 (br. s., 1 H), 4.27 (br. s., 2 H), 3.61-3.53 (m, J=6.1 Hz, 5 H), 3.09 (br. s., 2 H), 2.39-2.30 (m, 1 H). m/z (ESI) 518.4 (M+H)+.

Provenance & Evidence