Chlorotrimethylsilane → HCID 131732371, compound

HRID 1778430Notes

Reaction equation

HRID 1778430 reaction equation
[CH3:1][C:2]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)([CH3:5])[CH:3]=O.N1CCCC1.[Si](Cl)(C)(C)C.[NH2:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([CH2:53][C@@H:54]3[CH2:58][CH2:57][CH2:56][N:55]3[C:59](=[O:63])[CH2:60][C:61]#[N:62])[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:41][C:40]=3[F:52])[C:31]=12>C(Cl)Cl.O>[NH2:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([CH2:53][C@@H:54]3[CH2:58][CH2:57][CH2:56][N:55]3[C:59](=[O:63])[C:60]([C:61]#[N:62])=[CH:3][C:2]([N:6]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)([CH3:1])[CH3:5])[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[CH:41][C:40]=3[F:52])[C:31]=12

Participants

7

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 31268PyrrolidineHCID 86714506(S)-3-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrileHCID 90003016HCID 90003016, compound

Product 1

HCID 131732371HCID 131732371, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of tert-butyl 4-(1,1-dimethyl-2-oxo-ethyl)piperazine-1-carboxylate (326.2 mg, 1.27 mmol) in DCM (6 mL), was added pyrrolidine (0.17 mL, 2.04 mmol). The reaction mixture was cooled to 0° C., followed by the addition TMS-Cl (0.13 mL, 1.02 mmol). The ice bath was removed and the mixture stirred for 10 min before adding 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (120 mg, 0.250 mol). The mixture was stirred for 4 h at room temperature, at which point TLC and LC-MS showed the reaction was finished. To the mixture was added 30 ml water, the layers separated and the aq. layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed in vacuo. The residue was dissolved in minimum CH2Cl2, loaded on a silica gel column and purified by MeOH/CH2Cl2(1/4):EtOAc 20-30% gradient to get pure product tert-butyl 4-[4-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-cyano-1,1-dimethyl-4-oxo-but-2-enyl]piperazine-1-carboxylate as light yellow oil

Workup

  1. customThe ice bath was removed
  2. stirringThe mixture was stirred for 4 h at room temperature, at which point TLC and LC-MS
  3. customthe layers separated
  4. extractionthe aq. layer was extracted with CH2Cl2
  5. washThe combined organic layer was washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. customthe solvent removed in vacuo
  9. dissolutionThe residue was dissolved in minimum CH2Cl2
  10. custompurified by MeOH/CH2Cl2(1/4)

Sources & evidence

ORD record
ord-126d958a793a4267819168fd4e879441
Source dataset
uspto-grants-2016_02
Patent number
US09266895B2

Reaction notes

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