Water → HCID 44548961, compound

HRID 2069831Notes

Reaction equation

HRID 2069831 reaction equation
[CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:33].C([SiH2][O:39][C:40](C)(C)[C:41]1[C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=[CH:43][C:42]=1[N:56]1[CH:65]=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[C:61]([CH:66]3[CH2:68][CH2:67]3)[CH:62]=2)[C:57]1=[O:69])(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O.ClCCl>CN(C=O)C.O1CCOCC1>[CH:66]1([C:61]2[CH:62]=[C:63]3[C:58](=[CH:59][CH:60]=2)[C:57](=[O:69])[N:56]([C:42]2[CH:43]=[CH:44][CH:45]=[C:46]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([C:24]([N:26]6[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]6)=[O:25])=[CH:20][N:19]=5)[C:3](=[O:33])[N:2]([CH3:1])[CH:7]=4)[C:41]=2[CH2:40][OH:39])[CH:65]=[CH:64]3)[CH2:68][CH2:67]1

Participants

8

Reactant 5

HCID 962WaterHCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 67136110HCID 67136110, compoundHCID 131727998HCID 131727998, compound

Product 1

HCID 44548961HCID 44548961, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Procedure

Methyl-3-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (104 mg, 0.256 mmol), 2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-6-cyclopropyl-2H-isoquinolin-1-one (124 mg, 0.233 mmol), 2 mL dioxane, 200 μL DMF, and a 0.86 mg/μL solution of cesium carbonate in water (450 μL, 1.2 mmol) were charged into a 4 mL reaction vial fitted with a stir bar and septum. Sparged mixture with nitrogen for 5 min. Added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane (10 mg, 0.012 mmol). The reaction was sparged with nitrogen for 5 min. Sealed the vial and stirred at 90° 16 hr. Cooled to room temperature and filtered the reaction mixture through a 300 mg C18 cartridge. Washed the cartridge with 4 mL EtOAc, 4 mL water, and 4 mL EtOAc. Separated filtrate phases and washed the organic phase with 5 mL of water and 5 mL of brine. Dried the solution over Na2SO4 and concentrated in vacuo. Purified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile +0.1% TFA/water +0.1% TFA). Added 1 mL of saturated NaHCO3 to the pooled product fractions and concentrated in vacuo. Extracted the remaining aqueous mixture with 2×10 mL CH2Cl2, dried over Na2SO4, and concentrated in vacuo to obtain 6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one as an off-white solid. (80 mg, 0.13 mmol). MS (ESI) 617 (M+H)+.

Workup

  1. customvial fitted with a stir bar
  2. customSparged mixture with nitrogen for 5 min
  3. customThe reaction was sparged with nitrogen for 5 min
  4. customSealed the vial and
  5. filtrationfiltered the reaction mixture through a 300 mg C18 cartridge
  6. washWashed the cartridge with 4 mL EtOAc, 4 mL water, and 4 mL EtOAc
  7. washSeparated filtrate phases and washed the organic phase with 5 mL of water and 5 mL of brine
  8. dry with materialDried the solution over Na2SO4
  9. concentrationconcentrated in vacuo
  10. customPurified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile +0.1% TFA/water +0.1% TFA)
  11. additionAdded 1 mL of saturated NaHCO3 to the pooled product fractions
  12. concentrationconcentrated in vacuo
  13. extractionExtracted the remaining aqueous mixture with 2×10 mL CH2Cl2
  14. dry with materialdried over Na2SO4
  15. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-81458a570c394779892bf73394aa8875
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Reaction notes

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