Trifluoroacetic anhydride → 3-fluoro-6-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl acetate

HRID 2281921Notes

Reaction equation

HRID 2281921 reaction equation
[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)=[N:6]1.OO.NC(N)=O.F[C:33](F)(F)[C:34]([O:36]C(=O)C(F)(F)F)=[O:35]>C(Cl)Cl.C(OC(=O)C)(=O)C>[C:34]([O:36][C:17]1[C:18]([F:21])=[CH:19][CH:20]=[C:15]([C:7]2[CH:8]=[C:9]([C:10]3[CH:14]=[CH:13][O:12][N:11]=3)[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:16]=1)(=[O:35])[CH3:33]

Participants

6

Reactant 3

HCID 9845Trifluoroacetic anhydrideHCID 31294Carbamide PeroxideHCID 716222933-(1-(2-fluorobenzyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-5-yl)isoxazole

Product 1

HCID 896573383-fluoro-6-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl acetate

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 7918Acetic AnhydrideSolvent

Conditions

Temperature
25 °C

Procedure

To a cold mixture of 3-(1-(2-fluorobenzyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-5-yl)isoxazole (1 equiv.) and urea compound with hydrogen peroxide (1:1) (3 equiv.) in DCM (1.7 ml) at 0° C., was added trifluoroacetic anhydride (3 equiv.). The mixture was allowed to warm to 25° C. and stirred for 3 days. The mixture was quenched with saturated solution of sodium bisulfate and extracted with dichloromethane (50 ml×3). The organic layers were combined, filtered and evaporated to give solid. The solid was dissolved in acetic anhydride (1.4 ml) and heated to 145° C. for 4 h. The mixture was cooled to 25° C., diluted with dichloromethane (100 ml) and washed with saturated solution of sodium bicarbonate (50 ml). The organic layer was dried (MgSO4), filtered and evaporated to give an oil. Purification of the oil by column chromatography (0 to 30% ethyl acetate in hexanes) gave 3-fluoro-6-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl acetate as an yellow oil. The yellow oil was combined with methanol (1.7 ml) and potassium carbonate (1 equiv.). The mixture was heated to 65° C. for 30 min. The mixture was concentrated under vacuum. The resulting residue was diluted with dichloromethane (100 ml) and washed with 1N HCl (30 ml). The organic layer was dried (MgSO4), filtered and evaporated to give a solid. Purification of the solid by column chromatography (0 to 5% methanol in dichloromethane) gave 3-fluoro-6-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyridin-2(1H)-one as a yellow solid (7% overall yield).

Workup

  1. customThe mixture was quenched with saturated solution of sodium bisulfate
  2. extractionextracted with dichloromethane (50 ml×3)
  3. filtrationfiltered
  4. customevaporated
  5. customto give solid
  6. temperatureheated to 145° C. for 4 h
  7. temperatureThe mixture was cooled to 25° C.
  8. washwashed with saturated solution of sodium bicarbonate (50 ml)
  9. dry with materialThe organic layer was dried (MgSO4)
  10. filtrationfiltered
  11. customevaporated
  12. customto give an oil
  13. customPurification of the oil by column chromatography (0 to 30% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-da730e48a68b40d5a957a890a8fb372f
Source dataset
uspto-grants-2015_09
Patent number
US09139564B2

Reaction notes

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