2-Aminopyrimidine → N-(pyrimidin-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 roundbottom 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, 48.52 mg, 0.069 mmol), pyrimidin-2-amine (7.84 mg, 0.082 mmol), and THF (343 μl) to give a clear, lightly-colored solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (144 μl, 0.144 mmol) was added dropwise over 30 s to give a light-yellow solution. After 5 min, the cooling bath was removed. After 20 min, the mixture was diluted with TFA (0.5 mL), then concentrated. The residue was taken up in DCM (1 mL) and TFA (0.5 mL) and stirred for 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, eluting with 5 to 10% MeOH/DCM, then with 20 to 40% of 2N ammonia in methanol solution dissolved in DCM). The fractions containing product were combined and concentrated. The residue was taken up in DCM and filtered through cotton. The filtrate was concentrated, and the residue was taken up in 10% MeOH/DCM and filtered through cotton. The filtrate was concentrated to give N-(pyrimidin-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 (13.66 mg, 0.026 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (d, J=4.7 Hz, 2 H), 7.69 (d, J=8.5 Hz, 1 H), 7.59-7.48 (m, 2 H), 7.33 (s, 1 H), 7.25 (dd, J=1.8, 8.6 Hz, 1 H), 6.83 (t, J=4.6 Hz, 1 H), 6.41 (d, J=8.6 Hz, 1 H), 5.83 (br. s., 1 H), 4.25 (br. s., 2H), 3.59 (br. s., 2 H), 3.38 (br. s., 2 H), 2.87 (br. s., 2 H), 2.33 (br. s., 1 H), 2.23 (br. s., 1 H). m/z (ESI) 518.4 (M+H)+.

Provenance & Evidence