Diisopropylethylamine → N-(2,5-difluoro-4-((2-(2-methoxyacetamido)pyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476379Notes

Reaction equation

HRID 476379 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:42][O:43][CH2:44][C:45](Cl)=[O:46]>C1COCC1.C(OCC)(=O)C>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][O:43][CH3:42])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 96623Methoxyacetyl chlorideHCID 59596940N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 54576301N-(2,5-difluoro-4-((2-(2-methoxyacetamido)pyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 50.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (130 mg, 0.29 mmol) in 10 mL, of anhydrous tetrahydrofuran was added diisopropylethylamine (75 mg, 0.58 mmol). A solution of methoxyacetyl chloride (34.5 mg, 0.32 mmol) in THF (1 mL) was added drop wise at 0° C. The resultant reaction mixture was stirred at R.T. for 0.5 h. It was diluted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by prep-TLC to give N-(2,5-difluoro-4-((2-(2-methoxyacetamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (75 mg, 50% yield). 1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.30 (dd, J=12.0, 7.2 Hz, 1H), 8.17 (d, J=5.6 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.49-7.45 (m, 2H), 7.07-6.99 (m, 3H), 6.64 (dd, J=5.6, 2.4 Hz 1H), 3.98 (s, 2H), 3.49 (s, 3H), 1.78-1.66 (m, 4H); MS (ESI): m/z 515.2 [M+H]+.

Workup

  1. customThe resultant reaction mixture
  2. washwashed with brine
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified by prep-TLC

Sources & evidence

ORD record
ord-849cbaca24aa42e4b6d319c0fab028ec
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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