反应详情

A crude mixture of 3-[tert-butyl(dimethyl)silyl]oxy-2,2-dimethyl-propanal (1.15 g, 5.31 mmol) was prepared by addition of 1.1 equivalents of Dess-Martin periodinane to a solution of 3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropan-1-ol in 25 mL of DCM at 0° C. After 1 h, the slurry was diluted with hexanes and filtered over a plug of silica. The residue was concentrated to a thick oil and then dissolved in DCM (O1 mL). 3-[(3R)-3-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-3-oxo-propanenitrile (236.79 mg, 0.5000 mmol) was added, then TMS-Cl (0.2 mL, 1.59 mmol), followed by pyrrolidine (0.13 mL, 1.59 mmol). The solution was stirred at rt, monitoring the reaction by LCMS. After 16 h, the mixture was partitioned between water and DCM and then the organic phase was washed with brine and dried over sodium sulfate. Filtration and removal of solvents afforded a colorless oil that was purified by silica gel chromatography (9:1 to 90:10 methylene chloride:MeOH gradient) to afford ˜350 mg of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-5-((tert-butyldimethylsilyl)oxy)-4,4-dimethylpent-2-enenitrile.

1. filtrationfiltered over a plug of silica
2. concentrationThe residue was concentrated to a thick oil
3. dissolutiondissolved in DCM (O1 mL)
4. customthe reaction by LCMS
5. waitAfter 16 h
6. customthe mixture was partitioned between water and DCM
7. washthe organic phase was washed with brine
8. dry with materialdried over sodium sulfate
9. filtrationFiltration and removal of solvents
10. customafforded a colorless oil that
11. customwas purified by silica gel chromatography (9:1 to 90:10 methylene chloride:MeOH gradient)