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 1473544노트

반응식

HRID 1473544 반응식
[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

참가 물질

4

반응물 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

생성물 1

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

실험 절차

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)+.

후처리

  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

출처 및 근거

ORD 기록
ord-6c76da71b9e54e5d804c05c7e0674859
출처 데이터셋
uspto-grants-2015_04
특허 번호
US09012443B2

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