Thioanisole → N-(5-(2-methoxyethoxy)-2-{5-[(1-oxidothiomorpholino)methyl]-4,5-dihydro-1,3-thiazol-2-yl}-1H-indol-7-yl)pyridine-2-sulfonamide

HRID 1994974Notes

Reaction equation

HRID 1994974 reaction equation
C1(P(=[O:20])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:73][N:74]1[CH2:79][CH2:78][S:77][CH2:76][CH2:75]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:53][C:52]=2[NH:63][S:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=1)(=[O:66])=[O:65])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1.OOS([O-])=O.[K+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O1CCCC1.O.C(O)C>[CH3:62][O:61][CH2:60][CH2:59][O:58][C:54]1[CH:55]=[C:56]2[C:51](=[C:52]([NH:63][S:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=3)(=[O:66])=[O:65])[CH:53]=1)[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:73][N:74]3[CH2:75][CH2:76][S:77](=[O:20])[CH2:78][CH2:79]3)[CH2:45][N:46]=1)=[CH:57]2

Participants

11

Reactant 6

HCID 7520ThioanisoleHCID 13097Triphenylphosphine OxideHCID 24437Sodium SulfiteHCID 67749Trifluoromethanesulfonic anhydrideHCID 23707502Potassium hydroxy sulfiteHCID 59303541N-[2-(benzylthio)-3-thiomorpholinopropyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide

Product 1

HCID 59356796N-(5-(2-methoxyethoxy)-2-{5-[(1-oxidothiomorpholino)methyl]-4,5-dihydro-1,3-thiazol-2-yl}-1H-indol-7-yl)pyridine-2-sulfonamideYield 6.1%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of triphenylphosphine oxide (470 mg) in dichloromethane (3 mL) was added trifluoromethanesulfonic anhydride (480 mg) under ice-cooling, and the mixture was stirred for 30 min. A solution of N-[2-(benzylthio)-3-thiomorpholinopropyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (570 mg) and thioanisole (210 mg) in dichloromethane (20 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred for 3 hr under ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:9, volume ratio) to give colorless crystals. To a mixture of the obtained crystals, ethanol (20 mL), water (10 mL) and tetrahydrofuran (10 mL) was added OXONE (registered trade mark, 43 mg) at room temperature, and the mixture was stirred at room temperature for 2 hr. Aqueous sodium sulfite solution was added to the reaction mixture, the mixture was stirred for 30 min, and the organic solvent was evaporated under reduced pressure. The residue was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-90:10, volume ratio) to give colorless crystals. The obtained crystals was further purified by preparative HPLC, and recrystallized from acetone-methanol to give the title compound (30 mg, yield 6.1%) as colorless prism crystals. melting point 235-236° C.

Workup

  1. temperaturecooling
  2. temperaturecooling
  3. stirringthe mixture was stirred for 3 hr under ice-
  4. temperaturecooling
  5. extractionthe mixture was extracted with ethyl acetate
  6. washThe ethyl acetate layer was washed with saturated brine
  7. dry with materialdried (MgSO4)
  8. concentrationconcentrated
  9. washeluted with hexane-ethyl acetate (1:1-1:9, volume ratio)
  10. customto give colorless crystals
  11. stirringthe mixture was stirred at room temperature for 2 hr
  12. stirringthe mixture was stirred for 30 min
  13. customthe organic solvent was evaporated under reduced pressure
  14. extractionThe residue was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran
  15. washThe organic layer was washed with saturated brine
  16. dry with materialdried (MgSO4)
  17. concentrationconcentrated
  18. washeluted with ethyl acetate-methanol (100:0-90:10, volume ratio)
  19. customto give colorless crystals
  20. customThe obtained crystals was further purified by preparative HPLC
  21. customrecrystallized from acetone-methanol

Sources & evidence

ORD record
ord-58f1236a03c74060a0fd9369aa883539
Source dataset
uspto-grants-2010_01
Patent number
US07652133B2

Reaction notes

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