Piperidine → tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate

HRID 1187664Notes

Reaction equation

HRID 1187664 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.[CH:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=O.N1CCCCC1>C(O)C>[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])[C:32]([C:33]#[N:34])=[CH:36][C@@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[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 2734674tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate2×HCID 71015721(2R)-2-((4-Amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo(3,4-d)pyrimidin-1-yl)methyl)-beta-oxo-1-pyrrolidinepropanenitrile

Product 1

HCID 86714560tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylateYield 57%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
100 °C

Procedure

To a sealed tube was added 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (507 mg, 1.07 mmol), tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (0.2, mL, 1.1 mmol), piperidine (0.05 mL, 0.54 mmol) and ethanol (3 mL). The tube was capped and heated to 100° C. for 16 hrs. The reaction was not complete so an additional amount of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (732 mg, 3 eq) was added and heating was continued for 4 hrs at 110° C. The reaction was cooled and concentrated then dissolved in DCM (50 mL) and washed with water (50 mL) and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting material was purified by Isolera (250 g column; 2%-3% MeOH/DCM) to provide 403 mg (57%) of tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate as a solid.

Workup

  1. customThe tube was capped
  2. additionwas added
  3. temperatureheating
  4. temperatureThe reaction was cooled
  5. concentrationconcentrated
  6. dissolutionthen dissolved in DCM (50 mL)
  7. washwashed with water (50 mL) and brine
  8. dry with materialThe organic layer was dried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe resulting material was purified by Isolera (250 g column; 2%-3% MeOH/DCM)

Sources & evidence

ORD record
ord-f632dc273fc940c085d93de5656cfa7f
Source dataset
uspto-grants-2014_03
Patent number
US08673925B1

Reaction notes

Loading…