Imidazole → 4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1H-isochromen-1-one

HRID 634514Notes

Reaction equation

HRID 634514 reaction equation
[C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]=2[CH:21]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31]([NH2:32])=[C:26]3[C:25]([C:33]3[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([F:40])[CH:34]=3)=[N:24]2)[CH3:22])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:41][C:42]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])[CH3:43].N1C=CN=C1>CN(C)C=O.C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]=2[CH:21]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31]([NH2:32])=[C:26]3[C:25]([C:33]3[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([O:39][Si:45]([C:42]([CH3:44])([CH3:43])[CH3:41])([CH3:47])[CH3:46])[CH:38]=3)=[N:24]2)[CH3:22])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]

Participants

6

Reactant 3

HCID 795Imidazole2×HCID 28928tert-Butyldimethylsilyl chloride2×HCID 1181312574-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1H-isochromen-1-one

Product 1

HCID 1231689484-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1H-isochromen-1-oneYield 72.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1H-isochromen-1-one (Example 72, 726 mg, 1.343 mmol) was dissolved in N,N-Dimethylformamide (7.5 ml), followed by the addition of TBDMSCl (405 mg, 2.69 mmol) and imidazole (366 mg, 5.37 mmol). The mixture stirred for 3 hrs at rt, then further 0.3 eq of TBDMSCl and imidazole were added to achieve full reaction completion The reaction was diluted with DCM (100 ml) and washed twice with 0.5M HClaqueous (50 ml), filtered through a phase separator, and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel using a Biotage 100G SNAP with a gradient of DCM and EtOH to give the title compound (635 mg, 72.2%) as pinky foam.

Workup

  1. washwashed twice with 0.5M HClaqueous (50 ml)
  2. filtrationfiltered through a phase separator
  3. concentrationconcentrated under reduced pressure
  4. customThe residue was purified via flash chromatography on silica gel using a Biotage 100G SNAP with a gradient of DCM and EtOH

Sources & evidence

ORD record
ord-cfcd48a6190041c4a690acd118022b94
Source dataset
uspto-grants-2016_04
Patent number
US09321776B2

Reaction notes

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