Veratryl alcohol → N-[1-{[3,4-Bis(methyloxy)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide

Temperature

60 °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) (150 mg, 0.286 mmol), triphenylphosphine (150 mg, 0.572 mmol) and [3,4-bis(methyloxy)phenyl]methanol (Aldrich) (96 mg, 0.57 mmol) in THF (3 mL) was added at room temperature di-iso-propyl azodicarboxylate (0.113 mL, 0.572 mmol). The resulting mixture was stirred at 60° C. for 3 hours. DCM (3 mL) and water (3 mL) were added and the organic phase was separated. The aqueous layer was further extracted with 3 mL of DCM. The combine organic solutions were dried over an hydrophobic frit and concentrated under a nitrogen stream in a blowdown unit. The residue was purified by chromatography on silica 50 g cartridge on Flashmaster II using a gradient of 0-100% EtOAc in DCM over 60 min. The appropriate fractions were combined and evaporated in vacuo and the residue was dissolved in methanol (5 mL) and treated with a solution of sodium hydroxide (2M, 1.43 mL, 2.86 mmol). The resulting mixture was stirred at 60° C. for 2 hours. The solvents were evaporated off under reduced pressure, and the residue was partitioned between 2 mL of DCM, 3 mL of water. A solution of dilute HCl solution was added 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 from appropriate fractions under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (52.6 mg, 37%). LCMS (System A) RT=1.17 min, ES+ve m/z 494/496 (M+H)+.

1. customthe organic phase was separated
2. extractionThe aqueous layer was further extracted with 3 mL of DCM
3. customThe combine organic solutions were dried over an hydrophobic frit
4. concentrationconcentrated under a nitrogen stream in a blowdown unit
5. customThe residue was purified by chromatography on silica 50 g cartridge on Flashmaster II
6. customover 60 min
7. customevaporated in vacuo
8. dissolutionthe residue was dissolved in methanol (5 mL)
9. stirringThe resulting mixture was stirred at 60° C. for 2 hours
10. customThe solvents were evaporated off under reduced pressure
11. customthe residue was partitioned between 2 mL of DCM, 3 mL of water
12. additionA solution of dilute HCl solution was added until the pH of the aqueous layer
13. customThe organic phase was separated
14. extractionthe aqueous layer was further extracted with 2 mL of DCM
15. customThe combined organic solutions were dried over an hydrophobic frit
16. concentrationconcentrated under a stream of nitrogen in a blowdown unit
17. dissolutionThe residue was dissolved in 1:1 MeOH-DMSO (1 mL)
18. custompurified by MDAP (supelcosil ABZ+Plus column)
19. washeluting with solvents A/B (A: Water+0.1% Formic acid, B
20. customThe solvent was removed from appropriate fractions under a stream of nitrogen in the Radleys blowdown apparatus

ORD record

ord-ffe358f527ab4073bd5eb239cb8d8da9

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08304446B2