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 409074Notes

Reaction equation

HRID 409074 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-19e04453d4e34e9d862c14372e09c991
Source dataset
uspto-grants-2014_06
Patent number
US08759358B1

Reaction notes

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