Methanol → n-(1-{[3-(Aminomethyl)phenyl]methyl}-4-hydroxy-1h-indazol-3-yl)-5-chloro-2-thiophenesulfonamide formate salt

HRID 1874662Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1874662
Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20]C)[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.B(Br)(Br)Br.CO.[C:38](=O)([OH:40])[O-:39].[Na+]>C(Cl)Cl>[CH:38]([OH:40])=[O:39].[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1

Komponenten

6

Edukt 4

HCID 887MethanolHCID 25134Boron tribromide2×HCID 516892Sodium BicarbonateHCID 66632476HCID 66632476, Verbindung

Produkt 1

HCID 136346357n-(1-{[3-(Aminomethyl)phenyl]methyl}-4-hydroxy-1h-indazol-3-yl)-5-chloro-2-thiophenesulfonamide formate salt

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel2×

Versuchsvorschrift

A suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (266 mg, 0.533 mmol) in anhydrous DCM (7.5 mL) under nitrogen atmosphere was treated dropwise with boron tribromide solution in DCM (1M, 0.533 mL, 0.533 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour (reaction not in solution—sticky orange gum had formed). A further portion of boron tribromide (1M, 0.533 mL) was added and the reaction mixture was stirred at room temperature for 1 hour (reaction still not in solution). Anhydrous methanol was added dropwise until the reaction was in solution. Reaction mixture was then stirred at room temperature for a further 30 min. Saturated aqueous sodium bicarbonate solution (10 mL) was added dropwise with care to quench the reaction, on addition of which both a white precipitate (suspended in the aqueous layer) and a dark green sticky gum (stuck to the side of the flask) formed. The aqueous and organic layers were applied to a hydrophobic frit and the organic layer collected and retained. The remaining green gum in the flask was dissolved in 1:1 methanol-dichloromethane, passed through a hydrophobic frit, combined with the retained organic and evaporated in-vacuo to yield a dark green sticky solid (265 mg). This was dissolved in DMSO (3×1 mL) and purified by MDAP Sunfire C18 column, eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) (25 min run). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a colourless oil (86 mg, 33%). LCMS (System B) RT=1.63 min, ES+ve m/z 449/451 (M+H)+.

Aufarbeitung

  1. customreaction not in solution—sticky orange gum
  2. customhad formed)
  3. stirringthe reaction mixture was stirred at room temperature for 1 hour (
  4. customreaction still not in solution)
  5. customReaction mixture
  6. stirringwas then stirred at room temperature for a further 30 min
  7. customto quench
  8. customthe reaction
  9. additionon addition of which both a white precipitate (
  10. customformed
  11. customthe organic layer collected
  12. dissolutionThe remaining green gum in the flask was dissolved in 1:1 methanol-dichloromethane
  13. customevaporated in-vacuo

Quellen und Nachweise

ORD-Eintrag
ord-a11f45f730364896abbaa88de33fe47b
Quelldatensatz
uspto-grants-2012_11
Patentnummer
US08304446B2

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