Dichloromethane → 2-[2-(2-Tert-butylsilyloxypropan-2-yl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridinyl]amino]-6-oxo-3-pyridinyl]phenyl]-6-cyclopropylisoquinolin-1-one

HRID 2245730Notes

Reaction equation

HRID 2245730 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][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[C:35]([C:54]([CH3:62])([CH3:61])[O:55][SiH2:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[C:36]([N:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([CH:50]4[CH2:52][CH2:51]4)[CH:46]=3)[C:41]2=[O:53])[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O.O1CCOCC1>[C:57]([SiH2:56][O:55][C:54]([CH3:62])([CH3:61])[C:35]1[C:34]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[CH:20][N:19]=3)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[N:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([CH:50]3[CH2:52][CH2:51]3)[CH:46]=2)[C:41]1=[O:53])([CH3:60])([CH3:58])[CH3:59]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 592164661-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-oneHCID 178455415HCID 178455415, compound

Product 1

HCID 1317279972-[2-(2-Tert-butylsilyloxypropan-2-yl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridinyl]amino]-6-oxo-3-pyridinyl]phenyl]-6-cyclopropylisoquinolin-1-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (99 mg, 0.22 mmol), 2-[3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-cyclopropyl-2H-isoquinolin-1-one (120 mg, 0.248 mmol), 2 mL dioxane, and a solution of cesium carbonate in water (370 mg/420 μL) were charged into a 4 mL reaction vial fitted with a stir bar and septum. Sparged the mixture with nitrogen for 15 min. Added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane (12 mg, 0.015 mmol). The reaction was sparged with nitrogen for 5 min. Sealed the vial and stirred at 90° 16 hr. Cooled to room temperature, partitioned the reaction mixture between 5 mL of 5% NaHCO3 and 10 mL of EtOAc, and separated phases. Washed the organic phase with 5 mL of water and 5 mL of brine, dried 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 2-(2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-cyclopropyl-2H-isoquinolin-1-one as a brittle amber foam. (70 mg, 0.097 mmol). MS (ESI) 718 (M+H)+.

Workup

  1. customvial fitted with a stir bar
  2. customSparged the mixture with nitrogen for 15 min
  3. customThe reaction was sparged with nitrogen for 5 min
  4. customSealed the vial and
  5. custompartitioned the reaction mixture between 5 mL of 5% NaHCO3 and 10 mL of EtOAc
  6. customseparated phases
  7. washWashed the organic phase with 5 mL of water and 5 mL of brine
  8. dry with materialdried 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-49133cffec044dd79d307575077ef96d
Source dataset
uspto-grants-2010_03
Patent number
US07683064B2

Reaction notes

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