Tetrabutylammonium Fluoride → 6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one

HRID 2069830Notes

Reaction equation

HRID 2069830 reaction equation
C([SiH2][O:6][C:7](C)(C)[C:8]1[C:13]([C:14]2[CH:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:23][N:22]=3)[C:17](=[O:35])[N:16]([CH3:36])[CH:15]=2)=[CH:12][CH:11]=[CH:10][C:9]=1[N:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH:47]3[CH2:49][CH2:48]3)[CH:43]=2)[C:38]1=[O:50])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:47]1([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:50])[N:37]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]4[CH:19]=[C:18]([NH:20][C:21]5[CH:26]=[CH:25][C:24]([C:27]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[O:28])=[CH:23][N:22]=5)[C:17](=[O:35])[N:16]([CH3:36])[CH:15]=4)[C:8]=2[CH2:7][OH:6])[CH:46]=[CH:45]3)[CH2:48][CH2:49]1

Participants

4

Reactant 2

HCID 2724141Tetrabutylammonium FluorideHCID 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

Product 1

HCID 445466206-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

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 (56 mg, 0.078 mmol) was dissolved in 3 mL anhydrous THF. Added a 1.0 M solution of tetrabutylammonium fluoride (466 μL, 466 mmol) in THF and stirred at room temperature for 15 min. Partitioned the reaction mixture between 8 mL of water and 10 mL of CH2Cl2 and separated phases. Washed the organic phase with 8 mL of 1.0 M KHSO4 and 8 mL of saturated aqueous NaHCO3. 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 6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one as an off-white solid. (29 mg, 0.048 mmol). MS (ESI) 604 (M+H)+.

Workup

  1. customPartitioned the reaction mixture between 8 mL of water and 10 mL of CH2Cl2
  2. customseparated phases
  3. washWashed the organic phase with 8 mL of 1.0 M KHSO4 and 8 mL of saturated aqueous NaHCO3
  4. dry with materialDried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customPurified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile +0.1% TFA/water +0.1% TFA)
  7. additionAdded 1 mL of saturated NaHCO3 to the pooled product fractions
  8. concentrationconcentrated in vacuo
  9. extractionExtracted the remaining aqueous mixture with 2×10 mL CH2Cl2
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-7235da2a821b4bf38d75ce7da532d4c1
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Reaction notes

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