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

HRID 1473544Notes

Reaction equation

HRID 1473544 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]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[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[CH:46]=[N:45][N:44]=[C:43]1[NH2:47].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:43]4[S:42][CH:46]=[N:45][N:44]=4)(=[O:21])=[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 199091,3,4-Thiadiazol-2-amineHCID 86687601Perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate

Product 1

HCID 866876031-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamideYield 59.8%

Procedure

A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 68.6 mg, 0.112 mmol), 1,3,4-thiadiazol-2-amine (12.51 mg, 0.124 mmol), and cesium carbonate (110 mg, 0.337 mmol). The vial was flushed with Ar (g), then acetonitrile (562 μl) was added. After stirring overnight, 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 purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-4% MeOH/DCM). Some fractions were discarded, and the remainder containing product were combined and concentrated to 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (35.19 mg, 0.067 mmol, 59.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=14.50 (br. s., 1H), 8.80 (s, 1H), 8.71 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.8 Hz, 1H), 8.14 (d, J=5.6 Hz, 1H), 7.95-7.89 (m, 1H), 7.87-7.79 (m, 1H), 7.62-7.53 (m, 2H), 7.49-7.41 (m, 2H), 7.32 (dt, J=3.0, 8.5 Hz, 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 (562 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. customThe residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-4% MeOH/DCM)
  10. additionthe remainder containing product

Sources & evidence

ORD record
ord-6c76da71b9e54e5d804c05c7e0674859
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

Loading…