Cyanoacetic acid → 3-[(2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile

HRID 1529888Notes

Reaction equation

HRID 1529888 reaction equation
FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:15][C:16]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[N:31][C:32]=3[NH2:34])[N:27]([CH2:35][C@H:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)[N:26]=2)=[CH:21][CH:20]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:58]([CH2:60][C:61](O)=[O:62])#[N:59]>ClCCl>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([CH2:35][C@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[C:61](=[O:62])[CH2:60][C:58]#[N:59])[N:26]=[C:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C:17]4[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:16]=4[F:15])=[CH:24][CH:23]=3)[C:33]=12

Participants

5

Reactant 3

HCID 9740Cyanoacetic acidHCID 682631,1'-CarbonyldiimidazoleHCID 867144733-[4-(2,3-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetic acid)

Product 1

HCID 867144753-[(2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrileYield 72%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

Into a 100 mL, round-bottom flask, was placed a solution of 3-[4-(2,3-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetic acid) salt (200 mg, 0.31 mmol, 1.00 equiv) in dichloromethane (10 mL), CDI (324 mg, 2.00 mmol, 6.50 equiv), and 2-cyanoacetic acid (170 mg, 2.00 mmol, 6.50 equiv). The resulting solution was stirred for 12 h at 25° C. and the resulting mixture was washed with water and brine. The organics were dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 109 mg (72%) of 3-[(2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a white solid.

Workup

  1. washthe resulting mixture was washed with water and brine
  2. dry with materialThe organics were dried over anhydrous magnesium sulfate
  3. concentrationconcentrated under vacuum
  4. washeluted with dichloromethane/methanol (20/1)

Sources & evidence

ORD record
ord-98b05182402743649bf7d5824ab069f1
Source dataset
uspto-grants-2015_07
Patent number
US09090621B2

Reaction notes

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