Cesium carbonate → 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamide

HRID 1504420Notes

Reaction equation

HRID 1504420 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[C:5]([O:34][CH3:35])=[CH:4][C:3]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1.[NH2:43][C:44]1[S:45][CH:46]=[N:47][N:48]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:43][C:44]4[S:45][CH:46]=[N:47][N:48]=4)(=[O:21])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[C:5]([O:34][CH3:35])=[CH:4][C:3]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1

Participants

4

Reactant 3

HCID 10796Cesium carbonateHCID 199091,3,4-Thiadiazol-2-amineHCID 117737251Perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate

Product 1

HCID 1177369851-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamideYield 102.8%

Procedure

A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.140 g, 0.224 mmol), 2-amino-1,3,4-thiadiazole (0.027 g, 0.268 mmol), and cesium carbonate (0.219 g, 0.671 mmol). The vial was flushed with Ar (g), then acetonitrile (2.2 mL) was added. The reaction was stirred overnight at RT. The mixture was diluted with EtOAc and NH4Cl (sat.). The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g SNAP Ultra column, 0-50% EtOAc/Heptane) to give 125 mgs of 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamide as an off-white solid. This material was purified by chiral SFC on Chiralpak AS-H column (40% MeOH/60% CO2) to give (P)-1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamide as peak 1 and (M)-1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamide as peak 2, both as off-white solids. Data for peak 1: NMR (400 MHz, DMSO-d6) δ=14.36 (br. s., 1H), 8.77 (s, 1H), 8.31 (d, J=2.15 Hz, 1H); 8.24 (d, J=9.59 Hz, 1H), 7.84 (dd, J=2.15, 8.90 Hz, 1H), 7.68 (s, 1H), 7.60 (dt, J=6.36, 8.07 Hz, 1H), 7.41-7.48 (m, 2H), 7.36 (s, 1H), 7.29-7.34 (m, 1H), 6.78-6.85 (m, 2H), 3.74 (s, 3H). m/z (ESI) 544.0 (M+H)+. Data for peak 2: 1H NMR (400 MHz, DMSO-d6) δ=14.36 (br. s., 1H), 8.77 (s, 1H), 8.31 (d, J=2.25 Hz, 1H), 8.24 (d, J=9.49 Hz, 1H); 7.84 (dd, J=2.20, 8.95 Hz, 1H), 7.68 (s, 1H), 7.59 (dt, J=6.36, 8.07 Hz, 1H), 7.41-7.48 (m, 2H), 7.36 (s, 1H), 7.30-7.35 (m, 1H), 6.81 (dd, J=6.80, 9.24 Hz, 2H), 3.74 (s, 3H). m/z (ESI) 544.0 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. additionacetonitrile (2.2 mL) was added
  3. additionThe mixture was diluted with EtOAc and NH4Cl (sat.)
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with EtOAc (2×)
  6. dry with materialThe combined organic extracts were dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by chromatography on silica gel (25-g SNAP Ultra column, 0-50% EtOAc/Heptane)

Sources & evidence

ORD record
ord-427221ec25b04c1b84b397b75ef95391
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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