Cyclobutanecarboxylic acid → N-(4-(2-(cyclobutanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476383Notes

Reaction equation

HRID 476383 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[CH2:17]OC)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:29])[CH2:27][CH2:26]1)=[O:24].[CH:38]1(C(O)=O)[CH2:41]C[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:17]1([C:16]([NH:15][C:11]2[CH:10]=[C:9]([O:8][C:6]3[C:5]([F:21])=[CH:4][C:3]([NH:22][C:23]([C:25]4([C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)=[O:29])[CH2:26][CH2:27]4)=[O:24])=[C:2]([F:1])[CH:7]=3)[CH:14]=[CH:13][N:12]=2)=[O:20])[CH2:41][CH2:38][CH2:39]1

Participants

6

Reactant 4

HCID 19494Cyclobutanecarboxylic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 54576301N-(2,5-difluoro-4-((2-(2-methoxyacetamido)pyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 54576512N-(4-(2-(cyclobutanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 41.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.45 mmol) (as prepared in Example 9) and cyclobutanecarboxylic acid (90 mg, 0.9 mmol) in DMF (3 ml) was added HATU (513 mg, 1.35 mmol), followed by DIEA (516 mg, 4 mmol). The mixture was sparged with nitrogen and stirred overnight at 60° C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N-(4-(2-(cyclobutanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (97 mg, yield 41.1%). 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 10.42 (s, 1H), 9.80 (s, 1H), 8.18 (d, J=6.0 Hz, 1H), 8.08 (dd, J=12.4, 6.8 Hz, 1H), 7.68 (s, 1H), 7.60-7.54 (m, 3H), 7.17 (t, J=8.8 Hz, 2H), 6.73 (dd, J=5.6, 2.4 Hz, 1H), 2.18-2.02 (m, 4H), 1.92-1.83 (m, 1H), 1.76-7.69 (m, 1H), 1.62-1.55 (m, 4H); MS (ESI): m/z 525.1 [M+H]

Workup

  1. customThe mixture was sparged with nitrogen
  2. customThe reaction mixture was partitioned between ethyl acetate and water
  3. washThe organic layer was washed with brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-75c8cefb5df14d35ac4bc8aae30fc73f
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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