反应详情

温度

65 °C

To a solution of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 10) (120 mg, 0.229 mmol), triphenylphosphine (120 mg, 0.458 mmol) and 3-(hydroxymethyl)benzenesulfonamide (85.8 mg, 0.458 mmol) in THF (3 mL) was added at rt diisopropyl azodicarboxylate (DIAD) (0.090 mL, 0.458 mmol). The resulting mixture was stirred at 65° C. for 7 hours. The mixture was partitioned between DCM (3 mL) and water (3 mL). The organic phase was separated and the aqueous layer was further extracted with 3 mL of DCM. The combined organic solutions were dried over an hydrophobic frit and evaporated under a nitrogen stream in a blowdown unit. The residue was loaded in dichloromethane on a silica cartridge (50 g) and purified by chromatography on Flashmaster using a 0-100% EtOAc in DCM over 40 min. The appropriate fractions were combined and evaporated in vacuo, and the residue was dissolved in methanol (3 mL) and treated with sodium hydroxyde (2M, 1.146 mL, 2.291 mmol). The resulting mixture was stirred at 60° C. for 2 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in DCM (2 mL) and 3 mL of water was added, followed by dilute HCl solution until the pH of the aqueous layer was around 1. The organic phase was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried over an hydrophobic frit and concentrated under a stream of nitrogen in a blowdown unit. The residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound, (51.6 mg, 22%). LCMS (System A) RT=1.02 min, ES+ve m/z 513/515 (M+H)+.

1. customThe mixture was partitioned between DCM (3 mL) and water (3 mL)
2. customThe organic phase was separated
3. extractionthe aqueous layer was further extracted with 3 mL of DCM
4. customThe combined organic solutions were dried over an hydrophobic frit
5. customevaporated under a nitrogen stream in a blowdown unit
6. custompurified by chromatography on Flashmaster
7. customover 40 min
8. customevaporated in vacuo
9. dissolutionthe residue was dissolved in methanol (3 mL)
10. additiontreated with sodium hydroxyde (2M, 1.146 mL, 2.291 mmol)
11. stirringThe resulting mixture was stirred at 60° C. for 2 hours
12. customThe solvents were evaporated under reduced pressure
13. dissolutionThe residue was dissolved in DCM (2 mL)
14. addition3 mL of water was added
15. customThe organic phase was separated
16. extractionthe aqueous layer was further extracted with 2 mL of DCM
17. customThe combined organic solutions were dried over an hydrophobic frit
18. concentrationconcentrated under a stream of nitrogen in a blowdown unit
19. dissolutionThe residue was dissolved in 1:1 MeOH
20. customDMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column)
21. washeluting with solvents A/B (A: Water+0.1% Formic acid, B
22. customThe solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus