Chlorotrimethylsilane → HCID 123337781, compound

HRID 1778433Notes

Reaction equation

HRID 1778433 reaction equation
[CH3:1][C:2]([NH:6][CH:7]1[CH2:10][O:9][CH2:8]1)([CH3:5])[CH:3]=O.N1CCCC1.[Si](Cl)(C)(C)C.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH2:45][C@@H:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51](=[O:55])[CH2:52][C:53]#[N:54])[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][C:32]=3[F:44])[C:23]=12>C(Cl)Cl.CCOC(C)=O>[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH2:45][C@@H:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51]([C:52](=[CH:3][C:2]([CH3:5])([NH:6][CH:7]3[CH2:10][O:9][CH2:8]3)[CH3:1])[C:53]#[N:54])=[O:55])[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:33][C:32]=3[F:44])[C:23]=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 90000654HCID 90000654, compound

Product 1

HCID 123337781HCID 123337781, compoundYield 40.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 2-methyl-2-(oxetan-3-ylamino)propanal (106.3 mg, 0.7400 mmol) in DCM (5 mL) was added pyrrolidine (0.07 mL, 0.890 mmol). The reaction mixture was cooled to 0° C., followed by addition TMS-Cl (0.08 mL, 0.59 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 10 minutes 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 (70 mg, 0.1500 mmol). The mixture was stirred for 50 minutes at which point it was deemed finished by checking TLC and LC-MS. The mixture was washed with saturated Na2HCO3 and the layers separated. The aq. layer was extracted with CH2Cl2, and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed. The residue was loaded on silica gel plate, flashed by [MeOH:CH2Cl2(1:4)}: EtOAc 50%, 60% to get pure product 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(oxetan-3-ylamino)pent-2-enenitrile (35.6 mg, 0.0597 mmol, 40.2% yield) as an off white solid. LC-MS (ES, m/z): 598 [M+H].

Workup

  1. customThe ice bath was removed
  2. stirringThe mixture was stirred for 50 minutes at which point it
  3. washThe mixture was washed with saturated Na2HCO3
  4. customthe layers separated
  5. extractionThe aq. layer was extracted with CH2Cl2
  6. washthe combined organic layer was washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. customthe solvent removed

Sources & evidence

ORD record
ord-c7d0c756633d4b6fb0dcfc4ffac5ae7c
Source dataset
uspto-grants-2016_02
Patent number
US09266895B2

Reaction notes

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