Trifluoroacetic acid → HCID 53629540, compound

HRID 1990166Notes

Reaction equation

HRID 1990166 reaction equation
[F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:4][F:5].[N:23]1([C:27]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].N1(C(C2N=CC(OC3C=C(C=C(OC(CF)=C)C=3)C(NC3C=CN(C)N=3)=O)=CC=2)=O)CCC1.C(O)(C(F)(F)F)=O>CC(N(C)C)=O.C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br.O.C(OCC)(=O)C>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:22][C:20]3[CH:19]=[C:9]([CH:8]=[C:7]([O:6][CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH:21]=3)[C:10]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[O:11])=[CH:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1

Participants

11

Reactant 5

HCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 536296172-(Azetidin-1-ylcarbonyl)-5-bromopyridineHCID 53629640HCID 53629640, compoundHCID 591271643-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide

Product 1

HCID 53629540HCID 53629540, compoundYield 8.6%

Reagents, catalysts & solvents 5

HCID 11251615Bromotris(triphenylphosphine)copper(I)CatalystHCID 962WaterSolventHCID 6212ChloroformSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Procedure

A mixture 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg, 0.32 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (86 mg, 0.35 mmol), cesium carbonate (209 mg, 0.64 mmol) and bromotris(triphenylphosphine)copper(I) (150 mg, 0.16 mmol) in DMA (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 3 hours. The reaction mixture was added to ethyl acetate (50 mL) and water (50 mL), the organic layer washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a brown oil. The residue was chromatographed on silica, eluting with 0-100% ethyl acetate in isohexane, to give a colorless oil which appeared to be a mixture of product and eliminated product (3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[1-(fluoromethyl)ethenyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide). This mixture was dissolved in chloroform (5 mL), TFA (0.5 mL) added and the mixture stirred for 2 hours. Complete degradation of eliminated product was observed by LCMS and the mixture concentrated in vacuo then water added. The mixture was neutralised and extracted into ethyl acetate (2×30 mL), washed with brine (30 mL), dried (MgSO4), filtered and reduced to give a yellow oil which was chromatographed on silica, eluting with 0-100% ethyl acetate in isohexane, to give the desired compound (13 mg).

Workup

  1. washthe organic layer washed with brine (50 mL)
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered
  4. customthe solvent removed in vacuo
  5. customto give a brown oil
  6. customThe residue was chromatographed on silica
  7. washeluting with 0-100% ethyl acetate in isohexane
  8. customto give a colorless oil which
  9. additiona mixture of product
  10. concentrationthe mixture concentrated in vacuo
  11. additionwater added
  12. extractionextracted into ethyl acetate (2×30 mL)
  13. washwashed with brine (30 mL)
  14. dry with materialdried (MgSO4)
  15. filtrationfiltered
  16. customto give a yellow oil which
  17. customwas chromatographed on silica
  18. washeluting with 0-100% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-d2b4d2d74f4e42a78239a4a7bc10669e
Source dataset
uspto-grants-2010_01
Patent number
US07642259B2

Reaction notes

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