Toluene → HCID 59853008, compound

HRID 1670343Notes

Reaction equation

HRID 1670343 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Li]C.CCOCC.[C:20](Cl)(Cl)=[O:21].C1(C)C=CC=CC=1.[NH2:31][C:32]1[CH:47]=[CH:46][C:35]([O:36][C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]([NH2:45])=[O:44])[CH:38]=2)=[C:34]([F:48])[CH:33]=1.C(OC1C=CC(NC2N=CN=C(OC3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[C:43]([C:39]1[CH:38]=[C:37]([O:36][C:35]2[CH:46]=[CH:47][C:32]([NH:31][C:20](=[O:21])[N:11]([C:9](=[O:10])[CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH3:12])=[CH:33][C:34]=2[F:48])[CH:42]=[CH:41][N:40]=1)(=[O:44])[NH2:45]

Participants

11

Reactant 8

HCID 1140TolueneHCID 3283Diethyl EtherHCID 6371PhosgeneHCID 81531DiisopropylethylamineHCID 231532054-(4-Amino-2-fluorophenoxy)picolinamideHCID 56919414HCID 56919414, compoundHCID 59853038N-(4-(6-(4-(Benzyloxy)phenylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamideHCID 178418348HCID 178418348, compound

Product 1

HCID 59853008HCID 59853008, compoundYield 33%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 2-(4-fluorophenyl)-N-methylacetamide (89 mg, 0.53 mmol) in 2 mL of THF at −78° C. was added MeLi in Et2O (1.6 M, 0.34 mL, 0.55 mmol). The solution was stirred at −78° C. for 5 min and then 20% phosgene in toluene (1.9 M, 0.29 mL, 0.55 mmol) was introduced quickly. After 2 min, 4-(4-amino-2-fluorophenoxy)picolinamide (Compound B′ of Example 24, 100 mg, 0.40 mmol) was added, followed by the addition of DMF (2 mL) and DIEA (0.4 mL). The reaction mixture was stirred at room temperature for 1 h and quenched with H2O. The solution was then extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the title compound (77 mg, 33%). MS (ESI+) m/z 441 (M+H)+.

Workup

  1. waitAfter 2 min
  2. stirringThe reaction mixture was stirred at room temperature for 1 h
  3. customquenched with H2O
  4. extractionThe solution was then extracted with EtOAc
  5. washthe organic layer was washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationAfter filtration and concentration
  8. customthe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-c77305bfa37c4b1587e50c7a6030db77
Source dataset
uspto-grants-2011_08
Patent number
US07989477B2

Reaction notes

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