Tetrahydrofuran → HCID 117737278, compound

HRID 1504445Notes

Reaction equation

HRID 1504445 reaction equation
[CH2:1]([O:3][C:4]1[C:5]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:30])=[O:29])=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:43])=[CH:6][C:7]([F:17])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:9]=1)[CH3:2].[O:44]1[CH:48]=[CH:47][C:46]([NH2:49])=[N:45]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]1[C:5]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28]([NH:49][C:46]4[CH:47]=[CH:48][O:44][N:45]=4)(=[O:29])=[O:30])=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:43])=[CH:6][C:7]([F:17])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:9]=1)[CH3:2]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 18102163-IsoxazolamineHCID 2733832Lithium HexamethyldisilazideHCID 117737253HCID 117737253, compound

Product 1

HCID 117737278HCID 117737278, compoundYield 81%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of perfluorophenyl 1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (398 mg, 0.638 mmol), isoxazol-3-amine (66.0 pdr, 0.894 mmol) and THF (6383 μl) was cooled in an ice-bath for 15 min, then lithium bis (trimethylsilyl)amide (1M in THF) (1596 μl, 1.596 mmol) was added dropwise. After 1.5 h, the mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the organic layer was washed with 1N aq. HCl. The aq. layers were combined and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (270 mg, 81% yield) as light-yellow solid. m/z [M+H]+=524.0. NMR (400 MHz, DMSO-d6) δ ppm 0.97 (t, J=6.99 Hz, 2 H) 4.01-4.13 (m, 2 H) 6.42 (s, 1 H) 6.82 (d, J=9.68 Hz, 1 H) 6.88 (d, J=9.10 Hz, 1 H) 7.27-7.37 (m, 1 H) 7.43 (d, J=6.94 Hz, 1 H) 7.50-7.67 (m, 4 H) 7.86 (dd, J=8.95, 2.20 Hz, 1 H) 8.24 (d, J=9.59 Hz, 1 H) 8.37 (d, J=2.05 Hz, 1 H) 8.69 (s, 1 H) 11.66 (br. s., 1H).

Workup

  1. customThe layers were separated
  2. washthe organic layer was washed with 1N aq. HCl
  3. extractionextracted with EtOAc (2×)
  4. dry with materialThe combined organic extracts were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was absorbed onto a plug of silica gel
  8. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (40 g)
  9. washeluting with a gradient of 0% to 70% EtOAc in heptane

Sources & evidence

ORD record
ord-4909c9a36f7b4826b2bc42cfc565987c
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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