Nitrogen → (S)-2'-(2,2-difluoropropoxy)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-5H-spiro[thiazole-4,9'-xanthen]-2-amine

Participants

Reaction Conditions

Reaction Steps

A glass microwave reaction vessel was charged with (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (230 mg, 0.58 mmol, prepared as described in Method BB26 and Example 2 but using 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one), cesium carbonate (302 mg, 0.93 mmol) and 2,2-difluoropropyl 4-methylbenzenesulfonate (159 mg, 0.64 mmol) in DMF (2.5 mL). The reaction mixture was purged with N2 and finally potassium iodide (192 mg, 1.16 mmol) was added. The reaction mixture was stirred and heated in a Initiator microwave reactor at 160° C. for 1.5 h. Then it was diluted with water and extractd by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc again. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide crude product that was purified by chromatography through a Redi-Sep pre-packed silica gel column (24 g), eluting with a gradient of 15% to 30% to 60% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane to provide (S)-2′-(2,2-difluoropropoxy)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (18 mg, 0.017 mmol, 4.78% yield) as off-white solid. MS m/z=486.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 1.75 (t, J=19.32 Hz, 3 H) 3.34-3.49 (m, 2 H) 4.19-4.43 (m, 2 H) 6.81 (dd, J=2.89, 1.61 Hz, 1 H) 7.05 (s, 2 H) 7.16 (dd, J=12.28, 2.98 Hz, 1 H) 7.36-7.44 (m, 1 H) 7.50 (ddd, J=7.26, 5.01, 1.91 Hz, 1 H) 7.58-7.66 (m, 2 H) 8.09 (ddd, J=10.34, 7.51, 1.91 Hz, 1 H) 8.25 (dt, J=4.82, 1.55 Hz, 1 H)

Provenance & Evidence