反应详情

To 6-[2-amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine (0.250 g, 0.918 mmol) in TFA (8.7 mL) at 0° C. was added aqueous H2O2 (0.375 mL, 3.67 mmol, 30% (w/w)) dropwise over 3 minutes. Upon completion of addition, the reaction was allowed to warm to room temperature. After 2 hours, LCMS showed complete conversion to the sulfone. The reaction was cooled to 0° C. and quenched with dimethyl sulfide (0.54 mL, 7.34 mmol). The reaction was allowed to warm to room temperature and stirred for 10 minutes. The mixture was cooled to 0° C. and diluted with Et2O (10 mL) and hexane (5 mL). The resulting orange precipitate was filtered, washed with hexane and placed into a 25 mL sealable tube. 1,4-Dioxane (5.83 mL) and triethylamine (0.51 mL, 3.67 mmol) were added followed by 2-methylpyrrolidine (0.12 mL, 1.19 mmol). The tube was sealed, and the reaction mixture was stirred overnight at 95° C. LCMS analysis of the reaction mixture showed 60% desired product and 30% unreacted sulfone. More 2-methylpyrrolidine (0.1 mL) was added and the reaction mixture was stirred for 2 additional hours at 95° C. The reaction was cooled to room temperature and decanted. The solution was concentrated, and the resulting residue was dissolved in 3 mL of 50/50 CH3CN/H2O w/0.1% TFA. Purification on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA) afforded a TFA salt of the title compound (105 mg, 20%) as a yellow solid as a mixture of rotamers. LC-MS (ES) m/z=310 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.22-1.26 (m, 3H), 1.65-1.87 (m, 1H), 1.93-2.16 (m, 3H), 3.47-3.64 (m, 1H), 3.65-3.87 (m, 1H), 4.31-4.54 (m, 1H), [6.54 (s) and 6.63 (s)] (1H), 7.36 (d, J=8.6 Hz, 1H), 7.72 (s, 1H), 7.91 (m, 1H), 11.99 (bs, 2H).

1. additionUpon completion of addition
2. temperatureThe reaction was cooled to 0° C.
3. temperatureto warm to room temperature
4. temperatureThe mixture was cooled to 0° C.
5. filtrationThe resulting orange precipitate was filtered
6. washwashed with hexane
7. customplaced into a 25 mL sealable tube
8. customThe tube was sealed
9. stirringthe reaction mixture was stirred overnight at 95° C