3-Isoxazolamine → US9776995, Example 42

HRID 1504405Notes

Reaction equation

HRID 1504405 reaction equation
[O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:17][C:18]1[CH:23]=[C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26][C:25]2=[O:38])[C:21]([O:39][CH3:40])=[CH:20][C:19]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1>C1COCC1>[F:17][C:18]1[CH:23]=[C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34]([NH:6][C:3]4[CH:4]=[CH:5][O:1][N:2]=4)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26][C:25]2=[O:38])[C:21]([O:39][CH3:40])=[CH:20][C:19]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1

Participants

5

Reactant 3

HCID 18102163-IsoxazolamineHCID 2733832Lithium HexamethyldisilazideHCID 1177371251-(2,3'-Difluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride

Product 1

HCID 117736992US9776995, Example 42Yield 13.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A RBF was charged with isoxazol-3-amine (0.016 g, 0.191 mmol) and THF (1.6 mL), and the vessel was cooled to −78° C. for 15 minutes. Lithium bis(trimethylsilyl)amide (1.0 M in THF) (0.208 ml, 0.208 mmol) was then added dropwise over 1 minute. The reaction was stirred for 10 minutes, and then a solution of 1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (0.080 g, 0.173 mmol) in THF (1.6 mL) was added dropwise. The bath was removed, and the resulting mixture was stirred for 45 minutes. The reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL), and was washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via MPLC (ISCO, 40 g), eluting with 0 to 100% ethyl acetate in heptanes. The solid was dried under reduced pressure to provide 1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.012 g, 0.024 mmol, 13.60% yield) as a mixture of atropisomers. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27 (d, J=1.76 Hz, 1 H) 8.15 (d, J=2.05 Hz, 1 H) 7.97 (br. s., 1 H) 7.74-7.84 (m, 2 H) 7.43-7.53 (m, 1 H) 7.37-7.42 (m, 1 H) 7.33 (d, J=9.98 Hz, 1 H) 7.11-7.18 (m, 2 H) 7.09 (d, J=9.49 Hz, 1 H) 6.86 (dd, J=14.67, 9.29 Hz, 2 H) 6.61 (d, J=1.76 Hz, 1 H) 3.72-3.81 (m, 3 H). m/z (ESI) 510.0 (M+H)+.

Workup

  1. customThe bath was removed
  2. stirringthe resulting mixture was stirred for 45 minutes
  3. additionThe reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL)
  4. washwas washed with ethyl acetate (20 mL×3)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting material was purified via MPLC (ISCO, 40 g)
  9. washeluting with 0 to 100% ethyl acetate in heptanes
  10. customThe solid was dried under reduced pressure

Sources & evidence

ORD record
ord-d97f658e723d48959423d6df52cb7fef
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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