Piperidine → (R)-2-(2-((4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile

HRID 1854903Notes

Reaction equation

HRID 1854903 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[CH2:33][C:34]#[N:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:42][CH2:41][CH2:40][CH2:39]C1>CO.C1(C=O)CC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([C:33](=[CH:39][CH:40]3[CH2:42][CH2:41]3)[C:34]#[N:35])=[O:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12

Participants

5

Reactant 2

HCID 8082PiperidineHCID 867144673-[(2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile

Product 1

HCID 86714468(R)-2-(2-((4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrileYield 23%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 123114CyclopropanecarboxaldehydeSolvent

Conditions

Temperature
25 °C

Procedure

Into a 10 mL sealed tube, was placed a solution of 3-[(2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (100 mg, 0.20 mmol, 1.00 equiv) in methanol (3 mL), cyclopropanecarbaldehyde (1 mL), and piperidine (1 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with 10 mL of dichloromethane, washed with saturated aqueous NH4Cl, water and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum and the residue was purified via column chromatograpy using dichloromethane/methanol (20/1) to give 26 mg (23%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H]. H-NMR: (CDCl3, ppm): δ8.38 (s, 1H); δ7.66 (d, 2H); δ7.26 (d, 1H); δ7.11 (d, 4H); δ6.77 (d, 1H); δ5.51 (s, 2H); δ4.81 (m, 1H); δ4.65 (d, 2H); δ3.51˜δ3.70 (m, 2H); δ1.91˜δ2.01 (m, 4H); δ1.81 (m, 1H); δ0.83˜1.25 (m, 4H).

Workup

  1. customInto a 10 mL sealed tube
  2. concentrationconcentrated under vacuum
  3. additionThe resulting solution was diluted with 10 mL of dichloromethane
  4. washwashed with saturated aqueous NH4Cl, water and brine
  5. dry with materialThe organics were dried over anhydrous sodium sulfate
  6. concentrationconcentrated under vacuum
  7. customthe residue was purified via column chromatograpy

Sources & evidence

ORD record
ord-c25dfa468b0742e6bca6050d68fca36e
Source dataset
uspto-grants-2015_02
Patent number
US08962831B2

Reaction notes

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