Dimethylformamide → 4-(2,5-Difluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide

HRID 2374073Notes

Reaction equation

HRID 2374073 reaction equation
C(OC1C=CC(NC2N=CN=C(OC3C=CC(N[C:30](=O)[CH2:31][C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[O:33])=CC=3F)C=2)=CC=1)C1C=CC=CC=1.[F:44]C(F)(F)C(O)=O.N[C:52]1[C:57](C2C=CC(CC(N)=O)=CC=2)=[C:56]([O:68][C:69]2[CH:74]=[CH:73][C:72]([NH:75][C:76](NC(=O)CC3C=CC(F)=CC=3)=[O:77])=[CH:71][C:70]=2[F:89])[CH:55]=[CH:54][N:53]=1.CCN([CH:96]([CH3:98])C)C(C)C.C[N:100]([CH:102]=[O:103])C>>[F:89][C:70]1[CH:71]=[C:72]([NH:75][C:76]([C:31]2[C:32](=[O:33])[N:34]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH:96]=[CH:98][CH:30]=2)=[O:77])[C:73]([F:44])=[CH:74][C:69]=1[O:68][C:56]1[CH:55]=[CH:54][N:53]=[C:52]([C:102]([NH2:100])=[O:103])[CH:57]=1

Participants

5

Reactant 4

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 251957421-(4-(2-Amino-3-(4-(2-amino-2-oxoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea trifluoroacetic acid salt2×HCID 59853038N-(4-(6-(4-(Benzyloxy)phenylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide2×

Product 1

HCID 598530114-(2,5-Difluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamideYield 22%

Procedure

To a homogeneous mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Compound B of Example 101, 50 mg, 0.21 mmol) and 4-(4-amino-2,5-difluorophenoxy)picolinamide (Compound C of Example 112, 69 mg, 0.26 mmol) in DMF (3 mL) was added DIPEA (0.05 mL, 0.26 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)-uranium hexafluorophosphate (TBTU) (83 mg, 0.26 mmol). The resulting solution was stirred for 18 hours before being quenched with 10% LiCl (aq). The mixture was partitioned between EtOAc and 10% LiCl (aq), the layers separated, and the aqueous layer extracted with EtOAc. The combined organic layers were washed twice with 10% LiCl (aq), then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 1:3 hexane/EtOAc) and the appropriate fractions were concentrated in vacuo to afford the title compound (22 mg, 22%). MS(ESI+) m/z 481 (M+H)+.

Workup

  1. custombefore being quenched with 10% LiCl (aq)
  2. customThe mixture was partitioned between EtOAc and 10% LiCl (aq)
  3. customthe layers separated
  4. extractionthe aqueous layer extracted with EtOAc
  5. washThe combined organic layers were washed twice with 10% LiCl (aq)
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by silica gel chromatography (eluting with 1:3 hexane/EtOAc)
  8. concentrationthe appropriate fractions were concentrated in vacuo

Sources & evidence

ORD record
ord-7699a801d311432db8ea2722ca4a66f6
Source dataset
uspto-grants-2008_12
Patent number
US07459562B2

Reaction notes

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