Thioanisole → N-[2-[(4R)-4-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N-methylpyridine-2-sulfonamide

Temperature

0 °C

To a solution of triphenylphosphine oxide (2.7 g) in dichloromethane (6 mL) was added dropwise trifluoromethanesulfonic anhydride (1.2 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min. The obtained suspension was diluted with dichloromethane (19 mL), and a solution of S-benzyl-N-({5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}carbonyl)-L-cysteine methyl ester (1.0 g) and thioanisole (1.5 mL) in dichloromethane (25 mL) was added. The reaction mixture was stirred at 0° C. for 1 hr, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was concentrated. The residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1, volume ratio) to give a mixture of methyl (4R)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-4-carboxylate and triphenylphosphine oxide. The obtained mixture of the ester and triphenylphosphine oxide was dissolved in tetrahydrofuran (5 mL), sodium borohydride (0.053 mg) was added at 0° C., and methanol (2.5 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, and then at room temperature for 3 hr. Water was added, the mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-0:1, volume ratio) to give the title compound (0.27 g, yield 36%) as a colorless amorphous solid. MS: 477 (MH+).

1. stirringThe reaction mixture was stirred at 0° C. for 1 hr
2. concentrationthe mixture was concentrated
3. extractionThe residue was extracted with ethyl acetate
4. washThe ethyl acetate layer was washed with water and saturated brine
5. dry with materialdried (MgSO4)
6. concentrationconcentrated
7. washeluted with hexane-ethyl acetate (1:1, volume ratio)
8. customto give
9. stirringThe reaction mixture was stirred at 0° C. for 1 hr
10. waitat room temperature for 3 hr
11. concentrationthe mixture was concentrated
12. extractionthe residue was extracted with ethyl acetate
13. washThe ethyl acetate layer was washed with water and saturated brine
14. dry with materialdried (MgSO4)
15. concentrationconcentrated
16. washeluted with hexane-ethyl acetate (4:1-0:1, volume ratio)

ORD record

ord-09a98f189db943189a16a51c99f2ec3c

Source dataset

uspto-grants-2010_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07652133B2