Methanesulfonic Acid → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol

Temperature

-78 °C

4-bromo-1-chloro-2-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]benzene 7d (6.15 g, 16.2 mmol) was dissolved in 150 mL of mixed solution (THF and n-hexane, v:v=2:3) and cooled to −78° C., followed by dropwise addition of a solution of nBuLi in n-hexane (10 mL, 24.3 mmol). The reaction was stirred for 1 hour at −78° C. before a solution (35 mL) of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyl-oxymethyl)tetrahydropyran-2-one 2f (8.32 g, 17.8 mmol) in n-hexane was dropwise added. Then, the reaction mixture was stirred for 2 hours at −78° C. before 50 mL methanol and 3.2 mL methylsulfonic acid were added. The reaction mixture was warmed and stirred for 16 hours at room temperature. Thereafter, the reaction mixture was concentrated under reduced pressure and was partitioned after 30 mL saturated sodium bicarbonate solution and 10 mL water were added. The aqueous phase was extracted with ethyl acetate (100 mL×3) and the organic extract was washed with saturated sodium chloride solution (20 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 7e (3.93 g, white solid), yield: 49.2%. 1H NMR (400 MHz, CD3OD): δ 7.57 (d, 1H), 7.49 (dd, 1H), 7.38 (d, 1H), 7.18 (d, 2H), 6.99-6.88 (m, 2H), 4.49 (q, 2H), 4.19-4.01 (m, 3H), 3.99-3.91 (m, 1H), 3.89-3.71 (m, 2H), 3.66-3.55 (m, 1H), 3.49-3.39 (m, 1H), 3.14-3.04 (s, 3H).

1. additionwas dropwise added
2. additionwere added
3. temperatureThe reaction mixture was warmed
4. concentrationThereafter, the reaction mixture was concentrated under reduced pressure
5. customwas partitioned after 30 mL saturated sodium bicarbonate solution and 10 mL water
6. additionwere added
7. extractionThe aqueous phase was extracted with ethyl acetate (100 mL×3)
8. extractionthe organic extract
9. washwas washed with saturated sodium chloride solution (20 mL)
10. dry with materialdried over anhydrous magnesium sulfate
11. filtrationfiltered
12. concentrationThe filtrate was concentrated under reduced pressure
13. customthe resulting residue was purified by silica gel chromatography with elution system D

ORD record

ord-7dd10bbe7e7c4f06b431133cdc0d23d1

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08609622B2