Trifluoroacetic acid → HCID 117737193, compound

HRID 1504520Notes

Reaction equation

HRID 1504520 reaction equation
[NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.[CH:7]1([C:10]2[CH:11]=[C:12]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=3)[CH:13]=[CH:14][C:15]=2[N:16]2[C:25]3[C:20](=[CH:21][C:22]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:30])[CH2:9][CH2:8]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[CH:7]1([C:10]2[CH:11]=[C:12]([C:31]3[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=3)[CH:13]=[CH:14][C:15]=2[N:16]2[C:25]3[C:20](=[CH:21][C:22]([S:26]([NH:1][C:2]4[CH:6]=[CH:5][O:4][N:3]=4)(=[O:28])=[O:27])=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:30])[CH2:9][CH2:8]1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 18102163-IsoxazolamineHCID 2733832Lithium HexamethyldisilazideHCID 117737111HCID 117737111, compound

Product 1

HCID 117737193HCID 117737193, compoundYield 36.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 3-aminoisoxazole (0.070 ml, 0.954 mmol) and 1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (0.150 g, 0.318 mmol) in 3 mL THF was cooled to 0° C. and was treated with LiHMDS 1N in THF (0.636 ml, 0.636 mmol). The cooling bath was removed and the reaction mixture was allowed to stir for one hour. TFA (0.122 ml, 1.589 mmol) was then added, and the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.06, 0.115 mmol, 36.3% yield). m/z (ESI) 520.1 (M+H)+. The atropisomers were separated using supercritical fluid chromatography (SFC). The column used was Chiralpak OJ-H. The mobile phase was run under isocratic conditions; CO2 with 25% Methanol to afford product as an off-white solid. First atropisomer (peak 1): (M)-1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.015 g, 0.029 mmol, 9.08% yield). NMR (ACETONITRILE-d3) □: 8.22 (d, J=2.1 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.80 (dd, J=8.9, 2.1 Hz, 1H), 7.65 (dd, J=8.2, 2.2 Hz, 1H), 7.35-7.42 (m, 3H), 7.30 (d, J=8.2 Hz, 1H), 6.95-7.04 (m, 1H), 6.76 (d, J=9.6 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 6.30 (d, J=1.8 Hz, 1H), 1.42-1.53 (m, 1H), 0.69-0.88 (m, 2H), 0.51-0.65 (m, 2H). m/z (ESI) 472.0 (M+H)+. Second atropisomer (peak 2): (P)-1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.016 g, 0.031 mmol, 9.69% yield). NMR (ACETONITRILE-d3) □: 8.22 (d, J=2.1 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.80 (dd, J=8.9, 2.1 Hz, 1H), 7.65 (dd, J=8.2, 2.2 Hz, 1H), 7.35-7.42 (m, 3H), 7.30 (d, J=8.2 Hz, 1H), 6.95-7.04 (m, 1H), 6.76 (d, J=9.6 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 6.30 (d, J=1.8 Hz, 1H), 1.42-1.53 (m, 1H), 0.69-0.88 (m, 2H), 0.51-0.65 (m, 2H). m/z (ESI) 520.2 (M+H)+.

Workup

  1. customThe cooling bath was removed
  2. concentrationthe reaction mixture was concentrated
  3. customPurification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)]

Sources & evidence

ORD record
ord-12315a6415e54fc0839eda506a5beaf3
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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