Trifluoroacetic acid → N-(4-(2-(azetidine-3-carboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476382Notes

Reaction equation

HRID 476382 reaction equation
[F:1][C:2]1[CH:28]=[C:27]([NH:29][C:30]([C:32]2([C:35](=[O:44])[NH:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:34][CH2:33]2)=[O:31])[C:26]([F:45])=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([CH:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[O:13])[CH:6]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH:16]1[CH2:17][CH:14]([C:12]([NH:11][C:7]2[CH:6]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:28][C:27]([NH:29][C:30]([C:32]4([C:35]([NH:36][C:37]5[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=5)=[O:44])[CH2:34][CH2:33]4)=[O:31])=[C:26]([F:45])[CH:25]=3)[CH:10]=[CH:9][N:8]=2)=[O:13])[CH2:15]1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 66604062Tert-butyl 3-(4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamoyl)azetidine-1-carboxylate

Product 1

HCID 54576511N-(4-(2-(azetidine-3-carboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 8.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl 3-(4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamoyl)azetidine-1-carboxylate (220 mg, 0.35 mmol) in CH2Cl2 (4 mL) was added TFA (0.2 mL) at 0° C. and the reaction was stirred at room temperature overnight. Saturated NaHCO3 solution was added drop wise until pH>7 and the mixture with extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by HPLC separation to give N-(4-(2-(azetidine-3-carboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (16 mg, yield 8.7%). 1H-NMR (400 MHz, MeOH-d4): δ 9.50 (s), 8.46 (d, J=7.2 Hz, 1H), 8.33 (dd, J=7.2 Hz, 12.4 Hz, 1H), 7.53-7.43 (m, 3H), 7.26 (dd, J=7.2 Hz, 2.4 Hz, 1H), 7.10 (t, J=8.4 Hz, 2H), 6.75 (d, J=2.4 Hz, 1H), 4.61-4.54 (m, 1H), 3.63-3.58 (m, 1H), 3.49-3.44 (m, 1H), 3.31-3.29 (m, 1H), 3.27-3.25 (m, 1H), 1.75-1.73 (m, 4H); MS (ESI): m/z 443.2 [M+H]+.

Workup

  1. extractionthe mixture with extracted with CH2Cl2 (2×50 mL)
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by HPLC separation

Sources & evidence

ORD record
ord-01c25d19fae7437c97b18bbe74524adb
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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