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

HRID 1473543Notes

Reaction equation

HRID 1473543 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[S:42]1[C:46]([NH2:47])=[N:45][CH:44]=[N:43]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:47][C:46]4[S:42][N:43]=[CH:44][N:45]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1

Participants

4

Reactant 3

HCID 10796Cesium carbonateHCID 2902745-Amino-1,2,4-thiadiazoleHCID 86687601Perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate

Product 1

HCID 866876021-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamideYield 64.4%

Procedure

A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 71.85 mg, 0.118 mmol), 1,2,4-thiadiazol-5-amine (13.10 mg, 0.130 mmol), and cesium carbonate (115 mg, 0.353 mmol). The vial was flushed with Ar (g), and then acetonitrile (589 μl) was added. After 2 h, the mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from DCM/MeOH. The residue was then taken up in MeOH and filtered. The collected solid was washed with MeOH (1×), dried under a stream of N2 (g), then dried under vacuum to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (40 mg, 0.076 mmol, 64.4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.60 (d, J=1.7 Hz, 1H), 8.48 (s, 1H), 8.16 (d, J=5.7 Hz, 1H), 7.95-7.90 (m, 1H), 7.88-7.81 (m, 1H), 7.63-7.54 (m, 2H), 7.50-7.41 (m, 2H), 7.36-7.29 (m, 1H), 7.27 (s, 1H), 3.71 (s, 3H). m/z (ESI) 527.2 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. additionacetonitrile (589 μl) was added
  3. additionthe mixture was diluted with EtOAc and 0.5 N aq. HCl
  4. customThe layers were separated
  5. extractionthe aq. layer was extracted with EtOAc (2×)
  6. dry with materialThe combined organic extracts were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. concentrationThe residue was concentrated from DCM/MeOH
  10. filtrationfiltered
  11. washThe collected solid was washed with MeOH (1×)
  12. dry with materialdried under a stream of N2 (g)
  13. customdried under vacuum

Sources & evidence

ORD record
ord-82a94390c84d4e32861c916e8d81d443
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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