Chlorotrimethylsilane → (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

HRID 1429724Notes

Reaction equation

HRID 1429724 reaction equation
[Si:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH:11]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Si](OCC(C)(C)CO)(C(C)(C)C)(C)C.[NH2:51][C:52]1[N:57]=[CH:56][N:55]=[C:54]2[N:58]([C@@H:75]3[CH2:80][CH2:79][CH2:78][N:77]([C:81](=[O:85])[CH2:82][C:83]#[N:84])[CH2:76]3)[N:59]=[C:60]([C:61]3[CH:66]=[CH:65][C:64]([O:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[CH:63][C:62]=3[F:74])[C:53]=12.[Si](Cl)(C)(C)C.N1CCCC1>C(Cl)Cl>[NH2:51][C:52]1[N:57]=[CH:56][N:55]=[C:54]2[N:58]([C@@H:75]3[CH2:80][CH2:79][CH2:78][N:77]([C:81]([C:82](=[CH:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:83]#[N:84])=[O:85])[CH2:76]3)[N:59]=[C:60]([C:61]3[CH:66]=[CH:65][C:64]([O:67][C:68]4[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=4)=[CH:63][C:62]=3[F:74])[C:53]=12

Participants

8

Reactant 6

HCID 6397ChlorotrimethylsilaneHCID 31268PyrrolidineHCID 159087TriacetoxyperiodinaneHCID 106563753-((Tert-butyldimethylsilyl)oxy)-2,2-dimethylpropanalHCID 590121383-{[Tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropan-1-olHCID 867144983-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile

Product 1

HCID 131732370(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-enenitrileYield 104.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-a80a6086d5cb4885b3aef243bfa75861
Source dataset
uspto-grants-2015_01
Patent number
US08940744B2

Reaction notes

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