Chlorotrimethylsilane → 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile

HRID 1778437Notes

Reaction equation

HRID 1778437 reaction equation
[CH3:1][C:2]([N:6]([CH3:11])[CH:7]1[CH2:10][O:9][CH2:8]1)([CH3:5])[CH:3]=O.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C@@H:36]3[CH2:41][CH2:40][CH2:39][N:38]([C:42](=[O:46])[CH2:43][C:44]#[N:45])[CH2:37]3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:24][C:23]=3[F:35])[C:14]=12.N1CCCC1.[Si](Cl)(C)(C)C>>[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C@@H:36]3[CH2:41][CH2:40][CH2:39][N:38]([C:42]([C:43](=[CH:3][C:2]([CH3:1])([N:6]([CH3:11])[CH:7]4[CH2:10][O:9][CH2:8]4)[CH3:5])[C:44]#[N:45])=[O:46])[CH2:37]3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:24][C:23]=3[F:35])[C:14]=12

Participants

5

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 31268PyrrolidineHCID 867144983-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrileHCID 900007442-Methyl-2-[methyl(oxetan-3-yl)amino]propanal

Product 1

HCID 1236435392-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrileYield 92.4%

Procedure

The mixture of 2-methyl-2-[methyl(oxetan-3-yl)amino]propanal (66.69 mg, 0.42 mmol), 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-3-oxo-propanenitrile (100 mg, 0.2100 mmol) and pyrrolidine (0.1 mL, 1.27 mmol) was stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C., followed by addition of TMS-Cl (0.11 mL, 0.85 mmol). The ice bath was removed and the reaction mixture was stirred for another 1 hour at room temperature, checking process by TLC and LC-MS. The solvent was removed and the resultant residue purified by column chromatography (MeOH, CH2Cl2, MeOH gradient from 0 to 10% to get 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile (118.5 mg) as a white powder. LC-MS (ES, m/z): 612 [M+H]

Workup

  1. temperatureThe reaction mixture was cooled to 0° C.
  2. customThe ice bath was removed
  3. stirringthe reaction mixture was stirred for another 1 hour at room temperature
  4. customThe solvent was removed
  5. customthe resultant residue purified by column chromatography (MeOH, CH2Cl2, MeOH gradient from 0 to 10%

Sources & evidence

ORD record
ord-3ec1dbb5ede746f697d5be8315874f87
Source dataset
uspto-grants-2016_02
Patent number
US09266895B2

Reaction notes

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