Trifluoroacetic acid → 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1, 1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

HRID 1050171Notes

Reaction equation

HRID 1050171 reaction equation
[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC(OC)=CC=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[O:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:28])=[C:22]([F:42])[CH:21]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[O:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:38])([F:39])[F:37])[CH:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 904224232-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1, 1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

Product 1

HCID 784268852-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1, 1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamideYield 36.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

To a suspension of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (1.5 g, 2.55 mmol) in DCM (20 mL) was added TFA (2 mL, 26.9 mmol) dropwise. The mixture was stirred at 25° C. for 2 h. The mixture was then concentrated. To the residue was added H2O (50 mL) dropwise and then neutralized with saturated Na2CO3 solution to adjust pH=7.5. The precipitate was filtered, washed with H2O (50 mL×3) and dried in vacuo. To the solid was added PE/EA (3:1, v/v, 30 mL) and stirred for 0.5 h. The solid was filtered, washed with PE/EA (3:1, v/v, 30 mL×2). The solid was redissolved in DCM/MeOH (20:1, v/v, 50 mL) and then concentrated in vacuo to a minimal amount of solvent (about 10 mL). The solid was filtered, washed with CH3CN (10 mL×2) and dried in vacuo. The residue was redissolved in DCM/MeOH (10:1, v/v, 50 mL) and concentrated in vacuo to give a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (440 mg, 0.938 mmol, 36.7% yield): 1H NMR (400 MHz, CD3OD): δ 7.39-7.36 (m, 1H), 7.36-7.30 (m, 1H), 7.25-7.18 (m, 2H), 6.37 (s, 1H), 5.99 (s, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.82 (s, 2H), 1.53 (s, 6H), 1.37 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 468 (M+H); CHN analytical report: average (%): N, 8.717; C, 55.32; H, 4.672.

Workup

  1. concentrationThe mixture was then concentrated
  2. additionTo the residue was added H2O (50 mL) dropwise
  3. filtrationThe precipitate was filtered
  4. washwashed with H2O (50 mL×3)
  5. customdried in vacuo
  6. additionTo the solid was added PE/EA (3:1, v/v, 30 mL)
  7. stirringstirred for 0.5 h
  8. filtrationThe solid was filtered
  9. washwashed with PE/EA (3:1, v/v, 30 mL×2)
  10. dissolutionThe solid was redissolved in DCM/MeOH (20:1, v/v, 50 mL)
  11. concentrationconcentrated in vacuo to a minimal amount of solvent (about 10 mL)
  12. filtrationThe solid was filtered
  13. washwashed with CH3CN (10 mL×2)
  14. customdried in vacuo
  15. dissolutionThe residue was redissolved in DCM/MeOH (10:1, v/v, 50 mL)
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0d883648beef4ca781a884daa952a274
Source dataset
uspto-grants-2016_07
Patent number
US09382238B2

Reaction notes

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