1,2-Dichloroethane → (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide

Participants

Reaction Steps

To a suspension of 2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetic acid (151 mg, 0.571 mmol) in DCM (25 ml), DMAP (69.8 mg, 0.571 mmol), EDC (274 mg, 1.428 mmol) and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (200 mg, 0.476 mmol) were added in one portion at room temperature, and the resulting mixture was stirred for 4 hours. The solution was diluted with DCM (40 ml) and washed with a saturated solution of NaHCO3 (40 ml), with 1N HCl (30 ml) and finally with brine (30 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The crude was purified by crystallization from ethyl acetate (40 ml) to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a white solid (130 mg, 0.195 mmol, 40.9% yield). MS/ESI+ 667.16 [MH]+; [αD]=−42.80, c=0.25, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.43 (s, 2H), 7.19 (d, 1H), 7.02-7.13 (m, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.37 (s, 2H), 3.96 (s, 6H), 3.92 (d, 2H), 3.39 (dd, 1H), 3.22 (dd, 1H), 1.12-1.34 (m, 1H), 0.52-0.67 (m, 2H), 0.29-0.46 (m, 2H).

Provenance & Evidence