Potassium Carbonate → N-(isoxazol-3-yl)-1-(4-methoxy-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

HRID 1504440Notes

Reaction equation

Br[C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:27])[CH:7]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:24]1[CH:25]=[CH:26][C:22]([NH:21][S:18]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[N:8]([C:6]2[CH:7]=[C:2]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=4)[CH:3]=[CH:4][C:5]=2[O:28][CH3:29])[C:9](=[O:27])[CH:10]=[CH:11]3)(=[O:20])=[O:19])=[N:23]1

Participants

Conditions

Temperature: 90 °C

Procedure

1-(5-Bromo-2-methoxy phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.300 g, 0.630 mmol), (3-(trifluoromethyl)phenyl)boronic acid (0.179 g, 0.945 mmol), potassium carbonate (0.261 g, 1.890 mmol), and Pd(PPh3)4 (0.073 g, 0.063 mmol) were combined in 1,4-dioxane (2.362 ml) and water (0.787 ml). The reaction was heated to 90° C. for 3 h. The reaction was cooled to RT and quenched with NH4Cl (saturated aqueous solution), and extracted with DCM (×3) and the organics were then dried via phase separator and concentrated in vacuo. The material was purified via MPLC, eluting with 0-100% ethyl acetate in heptanes to yield N-(isoxazol-3-yl)-1-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.149 g, 0.275 mmol, 43.7% yield) as a light yellow solid. MS (ESL pos. ion) m/z: [M+1] 542.2 NMR (400 MHz, DMSO-d6) □ ppm 3.74 (s, 3 H) 6.44 (d, J=1.76 Hz, 1 H) 6.82 (dd, J=9.24, 3.77 Hz, 2H) 7.42 (d, J=8.80 Hz, 1 H) 7.66-7.70 (m, 2 H) 7.84 (dd, J=9.05, 2.20 Hz, 1 H) 7.89 (d, J=2.45 Hz, 1 H) 7.97-8.07 (m, 3 H) 8.23 (d, J=9.49 Hz, 1 H) 8.38 (d, J=2.35 Hz, 1 H) 8.72 (d, J=1.76 Hz, 1 H) 11.65 (s, 1 H). N-3-Isoxazolyl-1-(4-methoxy-3′-(trifluoromethyl)-3-biphenylyl)-2-oxo-1,2-dihydro-6-quinolinesulfonamide was separated by chiral SFC on a Chiralpak AD with 35% MeOH to give (P)—N-3-isoxazolyl-1-(4-methoxy-3′-(trifluoromethyl)-3-biphenylyl)-2-oxo-1,2-dihydro-6-quinolinesulfonamide as peak 1 and (M)-N-3-isoxazolyl-1-(4-methoxy-3′-(trifluoromethyl)-3-biphenylyl)-2-oxo-1,2-dihydro-6-quinolinesulfonamide as peak 2, both as white solids. Data for peak 1: NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 6.16-6.27 (m, 1 H) 6.66-6.72 (m, 1 H) 6.72-6.77 (m, 1 H) 7.35-7.45 (m, 1 H) 7.64-7.69 (m, 2 H) 7.73-7.79 (m, 1 H) 7.83-7.87 (m, 1 H) 7.96-8.06 (m, 3 H) 8.13-8.20 (m, 1 H) 8.20-8.24 (m, 1 H) 8.35-8.43 (m, 1 H). MS (ESI, pos. ion) m/z: [M+1] 542.2; Data for peak 2: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 6.08-6.18 (m, 1 H) 6.58-6.67 (m, 1 H) 6.68-6.75 (m, 1 H) 7.36-7.44 (m, 1 H) 7.61-7.74 (m, 3 H) 7.80-7.86 (m, 1 H) 7.96-8.06 (m, 3 H) 8.11-8.18 (m, 2 H) 8.20-8.25 (m, 1 H); MS (ESL pos. ion) m/z: [M+1] 542.0.

Workup

temperatureThe reaction was cooled to RT
customquenched with NH4Cl (saturated aqueous solution)
extractionextracted with DCM (×3)
customthe organics were then dried via phase separator
concentrationconcentrated in vacuo
customThe material was purified via MPLC
washeluting with 0-100% ethyl acetate in heptanes

Sources & evidence

ORD record: ord-6f9bb33e340b48378ba83ff1544addb4
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09212182B2

Reaction notes

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