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

Temperature

0 °C

To a mixture of triphenylphosphine oxide (557 mg) and dichloromethane (1 mL) was added trifluoromethanesulfonic anhydride (0.17 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min, followed by an addition of dichloromethane (3 mL). A mixture of N-[2-(benzylthio)-3-thiomorpholinopropyl]-7-[(cyclopropylmethyl)(pyridin-2-ylsulfonyl)amino]-5-(2-methoxyethoxy)-1H-indole-2-carboxamide (355 mg), thioanisole (0.12 mL) and dichloromethane (3 mL) was added thereto at 0° C., and the mixture was stirring at 0° C. for 10 min. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was extracted with concentrated hydrochloric acid, and after basified with the aqueous layer with potassium carbonate, the whole mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the amorphous solid from a fraction eluted with ethyl acetate. To the mixture of the obtained amorphous solid, tetrahydrofurane (5 mL), ethanol (5 mL) and water (5 mL) was added OXONE (registered trade mark, 369 mg) at room temperature, and the mixture was stirred at room temperature for 1 hr. To the resulting mixture was added 10% aqueous sodium sulfite solution, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give amorphous solid, which was crystallized from diisopropyl ether to give the title compound (146 mg, yield 47%) as colorless crystals.

1. additionwas added
2. stirringat 0° C., and the mixture was stirring at 0° C. for 10 min
3. customthe organic layer was separated
4. extractionThe organic layer was extracted with concentrated hydrochloric acid
5. extractionthe whole mixture was extracted with ethyl acetate
6. washThe extract was washed with saturated brine
7. dry with materialdried over anhydrous sodium sulfate
8. filtrationfiltered
9. concentrationthe filtrate was concentrated under reduced pressure
10. customto give the amorphous solid from a fraction
11. washeluted with ethyl acetate
12. additionTo the mixture of the obtained amorphous solid, tetrahydrofurane (5 mL), ethanol (5 mL) and water (5 mL)
13. additionwas added OXONE (registered trade mark, 369 mg) at room temperature
14. stirringthe mixture was stirred at room temperature for 1 hr
15. additionTo the resulting mixture was added 10% aqueous sodium sulfite solution
16. extractionthe mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran
17. washThe organic layer was washed with saturated brine
18. dry with materialdried over anhydrous sodium sulfate
19. filtrationfiltered
20. concentrationthe filtrate was concentrated under reduced pressure
21. customThe residue was purified by preparative HPLC
22. customto give amorphous solid, which
23. customwas crystallized from diisopropyl ether

ORD record

ord-5b05a2d53112412eb824b96ef10973fe

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08410087B2