Potassium Carbonate → HCID 117737172, compound

HRID 1504430Notes

Reaction equation

HRID 1504430 reaction equation
Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([F:38])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>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:25]1[CH:26]=[CH:27][C:23]([NH:22][S:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:9]([C:5]2[C:4]([O:29][CH3:30])=[CH:3][C:2]([C:34]4[CH:33]=[C:32]([F:31])[CH:37]=[C:36]([F:38])[CH:35]=4)=[C:7]([F:8])[CH:6]=2)[C:10](=[O:28])[CH:11]=[CH:12]3)(=[O:21])=[O:20])=[N:24]1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 2734338(3,5-Difluorophenyl)boronic acidHCID 117737112HCID 117737112, compound

Product 1

HCID 117737172HCID 117737172, compound

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
90 °C

Procedure

A RBF was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (272 mg, 0.550 mmol), (3,5-difluorophenyl)boronic acid (130 mg, 0.825 mmol), potassium carbonate (228 mg, 1.651 mmol), and Pd(Ph3P)4 (63.6 mg, 0.055 mmol). The vial was sealed with a septum cap and flushed with N2 (g), then Dioxane (2064 μl) and Water (688 μl) were added via syringe. The mixture was heated at 90° C. for 40 min. The mixture was diluted with HCl (8 mL, 1M aq) then extracted with EtOAc (2×20 mL). The organic layers were combined and concentrated. The residue was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0%-3% MeOH in DCM, to provide N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide. The racemic N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide was subjected to chiral separation by SFC on an AS-H column (25% MeOH/75% CO2) to give (P)—N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide as peak 1 and (M)-N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide as peak 2. Data for peak 1: 1H NMR (500 MHz, DMSO-d6) δ 11.65 (br. s., 1H), 8.72 (d, J=1.66 Hz, 1H), 8.38 (d, J=1.98 Hz, 1H), 8.16-8.31 (m, 1H), 7.86 (dd, J=2.08, 8.98 Hz, 1H), 7.56 (d, J=10.47 Hz, 1H), 7.47 (t, J=6.79 Hz, 3H), 7.33-7.43 (m, 1H), 6.84-6.91 (m, 1H), 6.77-6.84 (m, 1H), 6.41-6.49 (m, 1H), 3.70-3.83 (s, 3H). m/z (ESI) 528.0 (M+H)+. Data for peak 2: 1H NMR (500 MHz, DMSO-d6) δ 11.65 (br. s., 1H), 8.72 (d, J=1.66 Hz, 1H), 8.38 (d, J=1.98 Hz, 1H), 8.16-8.31 (m, 1H), 7.86 (dd, J=2.08, 8.98 Hz, 1H), 7.56 (d, J=10.47 Hz, 1H), 7.47 (t, J=6.79 Hz, 3H), 7.33-7.43 (m, 1H), 6.84-6.91 (m, 1H), 6.77-6.84 (m, 1H), 6.41-6.49 (m, 1H), 3.70-3.83 (s, 3H). m/z (ESI) 528.0 (M+H)+.

Workup

  1. customThe vial was sealed with a septum
  2. customcap
  3. customflushed with N2 (g)
  4. additionDioxane (2064 μl) and Water (688 μl) were added via syringe
  5. additionThe mixture was diluted with HCl (8 mL, 1M aq)
  6. extractionthen extracted with EtOAc (2×20 mL)
  7. concentrationconcentrated
  8. customThe residue was absorbed onto a plug of silica gel
  9. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  10. washeluting with a gradient of 0%-3% MeOH in DCM

Sources & evidence

ORD record
ord-a9b39c6f36e14078a609b3939470a700
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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