5-bromo-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrimidin-2-amine → (E)-6-(2-(2-(3-chloro-4-(difluoromethoxy)phenylamino)pyrimidin-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one

HRID 77485Notes

Reaction equation

HRID 77485 reaction equation
Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[C:11]([Cl:19])[CH:10]=2)=[N:6][CH:7]=1.[CH3:20][Si:21]([CH3:40])([CH3:39])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[C:35]2[C:30](=[CH:31][C:32]([CH:36]=[CH2:37])=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]1=[O:38]>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[CH:3][C:2](/[CH:37]=[CH:36]/[C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:20])([CH3:40])[CH3:39])[C:27](=[O:38])[CH:28]=[CH:29]4)=[CH:7][N:6]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH:16]([F:18])[F:17]

Participants

5

Reactant 2

HCID 866797715-bromo-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrimidin-2-amineHCID 866797751-((2-(trimethylsilyl)ethoxy)methyl)-6-vinylquinolin-2(1H)-one

Product 1

HCID 86679777(E)-6-(2-(2-(3-chloro-4-(difluoromethoxy)phenylamino)pyrimidin-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-oneYield 49.1%

Reagents, catalysts & solvents 2

HCID 70681Tetrabutylammonium ChlorideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 5-bromo-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrimidin-2-amine (0.3 g, 0.856 mmol) in DMF (5 mL), were added 1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinylquinolin-2(1H)-one (0.258 g, 0.856 mmol) triethylamine (0.358 mL, 2.57 mmol), tetrabutylammonium chloride, hydrate (0.380 g, 1.284 mmol) and PdOAc2 (0.019 g, 0.086 mmol). The reaction mixture was heated at 120° C. for 12 h. The reaction mixture was concentrated, dissolved in ethyl acetate, filtered through celite, and washed with water. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography on silica gel using 15% ethyl acetate in petroleum ether to give (E)-6-(2-(2-(3-chloro-4-(difluoromethoxy)phenylamino)pyrimidin-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (0.24 g, 49%). LCMS (ES-API), RT: 2.56 m/z 571.2 (M+H).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. dissolutiondissolved in ethyl acetate
  3. filtrationfiltered through celite
  4. washwashed with water
  5. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  6. concentrationconcentrated
  7. custompurified by flash chromatography on silica gel using 15% ethyl acetate in petroleum ether

Sources & evidence

ORD record
ord-3b60ffbaf417475496752e89f24121e9
Source dataset
uspto-grants-2014_09
Patent number
US08841301B2

Reaction notes

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