Reaktion #1865604

Reaktionsgleichung

3-[(3R)-3-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-3-oxo-propanenitrile

pyrrolidine

3-[tert-butyl(dimethyl)silyl]oxy-2,2-dimethyl-propanal

Dess-Martin periodinane

3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropan-1-ol

TMS-Cl

→

(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

Ausbeute 104.5%

Lösungsmittel

—

hexanes

DCM

Reaktionsbedingungen

Aufarbeitung

1. 1
   Filtrationfiltered over a plug of silica
2. 2
   EinengenThe residue was concentrated to a thick oil
3. 3
   workup.DISSOLUTIONdissolved in DCM (10 mL)
4. 4
   Sonstigethe reaction by LCMS
5. 5
   workup.WAITAfter 16 h
6. 6
   Sonstigethe mixture was partitioned between water and DCM
7. 7
   Waschenthe organic phase was washed with brine
8. 8
   Trocknendried over sodium sulfate
9. 9
   FiltrationFiltration and removal of solvents
10. 10
    Sonstigeafforded a colorless oil that
11. 11
    Sonstigewas purified by silica gel choromatography (9:1 to 90:10 methylene chloride:MeOH gradient)

Vorschrift

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 (10 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 choromatography (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.

Quelle