Triethylamine → 3-[(2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile

HRID 409078Notes

Reaction equation

[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][NH:24]3)[N:13]=2)=[CH:8][CH:7]=1.[C:32]([CH2:34][C:35](O)=[O:36])#[N:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:35](=[O:36])[CH2:34][C:32]#[N:33])[N:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:28]=[C:29]([F:31])[CH:30]=[C:2]([F:1])[CH:3]=4)=[CH:11][CH:10]=3)[C:20]=12

Participants

Conditions

Temperature: 25 °C

Procedure

Into a 100 mL, round-bottom flask, was placed 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (185 mg, 0.44 mmol, 1.00 equiv), 2-cyanoacetic acid (30.7 mg, 0.36 mmol, 0.80 equiv), HATU (138 mg, 0.36 mmol, 0.80 equiv), triethylamine (91 mg, 0.90 mmol, 2.00 equiv), and N,N-dimethylformamide (50 mL). The resulting solution was stirred for 3 h at 25° C. and then extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 101 mg (47%) of 3-[(2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a off-white solid.

Workup

extractionextracted with ethyl acetate
concentrationconcentrated under vacuum
washeluted with dichloromethane/methanol (50/1)

Sources & evidence

ORD record: ord-37f4e74f29c04e40ad3b73dc745c4d82
Source dataset: uspto-grants-2014_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08759358B1

Reaction notes

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