反应详情

A solution of tert-butyl-cis-4-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (1.66 g, 4.53 mmol, prepared using A from Preparation #2 and tert-butyl-cis-(4-hydroxymethyl)cyclohexylcarbamate [AMRI]), 5-amino-2-methylbenzenesulfonamide (1.10 g, 5.89 mmol, Waterstone), and sodium tert-butoxide (1.306 g, 13.59 mmol) in 1,4-dioxane (15 mL) was stirred at ambient temperature for about 30 min. In a separate 10 mL nitrogen purged vial charged with Pd2(dibenzylideneacetone)3 (0.415 g, 0.453 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.789 g, 1.86 mmol) was added 1,4-dioxane (2 mL) followed by heating to about 80° C. for about 2 min. The mixture was subsequently cooled to ambient temperature. The catalyst solution was added to the reaction mixture at ambient temperature and the reaction mixture was heated to about 80° C. for about 16 h. The reaction mixture was cooled to ambient temperature then water (100 mL) and EtOAc (50 mL) were added and the organic layer was separated. The aqueous layer was further extracted with EtOAc (2×50 mL) and the combined organic extracts were dried over anhydrous MgSO4, filtered through a silica gel pad, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 50% EtOAc in heptane to provide tert-butyl-cis-4-((6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.58 g, 25%) as a light yellow solid. LC/MS (Table 2, Method a) Rt=1.38 min; MS m/z: 516 (M+H)+.

1. temperatureby heating to about 80° C. for about 2 min
2. temperatureThe mixture was subsequently cooled to ambient temperature
3. additionThe catalyst solution was added to the reaction mixture at ambient temperature
4. temperaturethe reaction mixture was heated to about 80° C. for about 16 h
5. temperatureThe reaction mixture was cooled to ambient temperature
6. customthe organic layer was separated
7. extractionThe aqueous layer was further extracted with EtOAc (2×50 mL)
8. dry with materialthe combined organic extracts were dried over anhydrous MgSO4
9. filtrationfiltered through a silica gel pad
10. concentrationconcentrated under reduced pressure
11. customThe crude residue was purified by silica gel chromatography
12. washeluting with 50% EtOAc in heptane