3-(Trifluoromethoxy)aniline → 6-methyl-N5-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-yl)-N1(3-(trifluoromethoxy)phenyl)isoquinoline-1,5-diamine

HRID 1668932Notes

Reaction equation

HRID 1668932 reaction equation
[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[C:14]1[C:23]2[CH:22]=[CH:21][C:20]([CH3:24])=[C:19]([NH:25][C:26]3[C:31]([C:32]4[CH:37]=[C:36]([NH:38][CH3:39])[N:35]=[CH:34][N:33]=4)=[CH:30][CH:29]=[CH:28][N:27]=3)[C:18]=2[CH:17]=[CH:16][N:15]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C:20]1[CH:21]=[CH:22][C:23]2[C:14]([NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)=[N:15][CH:16]=[CH:17][C:18]=2[C:19]=1[NH:25][C:26]1[C:31]([C:32]2[CH:37]=[C:36]([NH:38][CH3:39])[N:35]=[CH:34][N:33]=2)=[CH:30][CH:29]=[CH:28][N:27]=1

Participants

7

Reactant 4

HCID 737533-(Trifluoromethoxy)anilineHCID 2733832Lithium HexamethyldisilazideHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 589422651-chloro-6-methyl-N-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-yl)isoquinolin-5-amine

Product 1

HCID 673414706-methyl-N5-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-yl)-N1(3-(trifluoromethoxy)phenyl)isoquinoline-1,5-diamine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Conditions

Temperature
150 °C

Procedure

3-(Trifluoromethoxy)aniline (13 μL, 96 μmol), 1-chloro-6-methyl-N-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-yl)isoquinolin-5-amine (33 mg, 88 μmol), tris (dibenzylideneacetone)dipalladium (0) (3 mg, 4 μmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (3 mg, 7 μmol) were added to a microwave tube and suspended in THF-DMF (1:1, 1 mL). The tube was flushed with nitrogen and a solution of lithium bis(trimethylsilyl)amide, 1.0 M in hexanes (385 μL, 385 μmol) was added. The tube was heated in a microwave reactor at 150° C. for 15 min. The reaction mixture was partitioned between DCM and saturated aqueous sodium bicarbonate. The DCM layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified via preparative TLC on silica (DCM:EtOAc:EtOH:TEA=5:5:10:10) to give the desired product as a yellow solid. MS (M+H)+ 518.

Workup

  1. customThe tube was flushed with nitrogen
  2. customThe reaction mixture was partitioned between DCM and saturated aqueous sodium bicarbonate
  3. washThe DCM layer was washed with brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. customThe residue was purified via preparative TLC on silica (DCM:EtOAc:EtOH:TEA=5:5:10:10)

Sources & evidence

ORD record
ord-a05ea31ca99645bcbafcf13164a8d392
Source dataset
uspto-grants-2011_08
Patent number
US07989461B2

Reaction notes

Loading…