Water → HCID 59216410, compound

HRID 2069832Notes

Reaction equation

HRID 2069832 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]([CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:20][N:19]=2)[C:3]1=[O:31].C([SiH2][O:37][C:38](C)(C)[C:39]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=[CH:41][C:40]=1[N:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([CH:64]3[CH2:66][CH2:65]3)[CH:60]=2)[C:55]1=[O:67])(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O.ClCCl>O1CCOCC1>[CH:64]1([C:59]2[CH:60]=[C:61]3[C:56](=[CH:57][CH:58]=2)[C:55](=[O:67])[N:54]([C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([CH2:24][N:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[CH:20][N:19]=5)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=4)[C:39]=2[CH2:38][OH:37])[CH:63]=[CH:62]3)[CH2:66][CH2:65]1

Participants

7

Reactant 5

HCID 962WaterHCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 67137637HCID 67137637, compoundHCID 131727998HCID 131727998, compound

Product 1

HCID 59216410HCID 59216410, compound

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

Methyl-3-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (96 mg, 0.25 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, 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-morpholin-4-ylmethyl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one as an off-white solid. (73 mg, 0.12 mmol). MS (ESI) 590 (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-7e045c4ee00d461a8851bb435fdc0e0a
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Reaction notes

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