Piperidine → 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-(1-piperidyl)pent-2-enenitrile

HRID 1855011Notes

Reaction equation

HRID 1855011 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12

Participants

5

Reactant 3

HCID 8082PiperidineHCID 125429402-Methyl-2-(piperidin-1-yl)propanalHCID 86714506(S)-3-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile

Product 1

HCID 867145522-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(1-piperidyl)pent-2-enenitrileYield 18%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
160 °C

Procedure

To a microwave vial was added 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 (139.3 mg, 0.30 mmol), piperidine (0.04 mL, 0.35 mmol), 2-methyl-2-(1-piperidyl)propanal (68.8 mg, 0.4400 mmol) and toluene (3 mL). The vial was heated under microwave conditions at 160° C. for 3 hrs. The reaction was cooled and concentrated, then dissolved in ethyl acetate (30 mL) and washed with 2M HCl. The aqueous layer was basified to pH˜7.5 with sat. NaHCO3 and washed with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated and the crude material was purified by Isolera (1%-10% MeOH/ethyl acetate) to obtain 32 mg (18%) of the title compound. MS (pos. ion) m/z: 609 (M+1).

Workup

  1. temperatureThe reaction was cooled
  2. concentrationconcentrated
  3. dissolutiondissolved in ethyl acetate (30 mL)
  4. washwashed with 2M HCl
  5. washwashed with ethyl acetate
  6. dry with materialThe organic layer was dried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customthe crude material was purified by Isolera (1%-10% MeOH/ethyl acetate)

Sources & evidence

ORD record
ord-f5e446eefb894c38b8833adce87dcadd
Source dataset
uspto-grants-2015_02
Patent number
US08962831B2

Reaction notes

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