Bromide ion → benzyl 4-((5-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate

HRID 634489Notes

Reaction equation

HRID 634489 reaction equation
O[CH:2]([C:4]1[O:5][C:6](=[O:36])[C:7]2[C:12]([C:13]=1[C:14]1[S:18][C:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH2:21]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].BrP(Br)Br.C(Cl)Cl.[F:44][C:45]1[CH:46]=[C:47]([C:53]2[C:61]3[C:56](=[N:57][CH:58]=[N:59][C:60]=3[NH2:62])[NH:55][N:54]=2)[CH:48]=[C:49]([O:51][CH3:52])[CH:50]=1.C(=O)([O-])[O-].[K+].[K+].[Br-]>CN(C=O)C.CO.C(#N)C>[NH2:62][C:60]1[N:59]=[CH:58][N:57]=[C:56]2[N:55]([CH:2]([C:4]3[O:5][C:6](=[O:36])[C:7]4[C:12]([C:13]=3[C:14]3[S:18][C:17]([CH2:19][N:20]5[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)=[O:27])[CH2:24][CH2:25]5)=[CH:16][CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:54]=[C:53]([C:47]3[CH:48]=[C:49]([O:51][CH3:52])[CH:50]=[C:45]([F:44])[CH:46]=3)[C:61]=12

Participants

10

Reactant 6

HCID 259Bromide ionHCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 24614Phosphorus tribromideHCID 118131376benzyl 4-((5-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate2×HCID 178492931HCID 178492931, compound

Product 1

HCID 118131178benzyl 4-((5-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylateYield 34.5%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolvent

Procedure

benzyl 4-((5-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate (Intermediate B38, 903 mg, 1.790 mmol) was dissolved in 20 ml of dry then tribromophosphine 1M in DCM (2684 μl, 2.68 mmol) was slowly added. The mixture was stirred at r.t. The reaction was quenched by addition of 60 ml of NaHCO3 sat. sol. and extracted with DCM (100 ml). Phases were separated to leave a milky organic phase. 30 ml of ACN were added and the solution became clear. The mixture was concentrated to dryness to leave an off white solid. In a separate 30 ml vial, 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 510 mg, 1.969 mmol) and potassium carbonate (742 mg, 5.37 mmol) were suspended in 10 ml DMF and the mixture heated at 60 C for 15 min prior addition of the bromide dissolved in 5 ml of dry DMF. The reaction was stirred for a further hour at r.t. then the reaction was quenched with NaHCO3aq (40 ml) and extracted with DCM (80 ml) then concentrated to leave a brown solid that was purified by chromatography eluting with DCM:MeOH to give benzyl 4-((5-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate (460 mg, 0.617 mmol, 34.5% yield) as a brown solid.

Workup

  1. customof dry
  2. customThe reaction was quenched by addition of 60 ml of NaHCO3 sat. sol.
  3. extractionextracted with DCM (100 ml)
  4. customPhases were separated
  5. customto leave a milky organic phase
  6. concentrationThe mixture was concentrated to dryness
  7. customto leave an off white solid
  8. temperaturethe mixture heated at 60 C for 15 min
  9. stirringThe reaction was stirred for a further hour at r.t.
  10. customthe reaction was quenched with NaHCO3aq (40 ml)
  11. extractionextracted with DCM (80 ml)
  12. concentrationthen concentrated
  13. customto leave a brown solid that
  14. customwas purified by chromatography
  15. washeluting with DCM

Sources & evidence

ORD record
ord-d2059bafd7dc4b959d6a16737ba68cf4
Source dataset
uspto-grants-2016_04
Patent number
US09321776B2

Reaction notes

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