Hydrochloric Acid → [2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophen-3-yl]methanol

Temperature

-78 °C

To a solution of ethyl 5-bromo-2-ethylthiophene-3-carboxylate (5.28 g) synthesized in Example 69 (4) in tetrahydrofuran (60 mL) was added dropwise 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (24.1 mL) at −45° C., and the mixture was stirred for 1 hr under an argon atmosphere. A solution of tetrahydro-4H-thiopyran-4-one (7.01 g) in tetrahydrofuran (15 mL) was added dropwise, and the mixture was stirred at −45° C. for 2 hr, and then at room temperature for 1.5 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give a pale-yellow oil. A mixture of the obtained oil, triethylsilane (4.82 mL), methylene chloride (25 mL) and chloroform (50 mL) was cooled to −78° C., trifluoroacetic acid (10 mL) was added, and, under a nitrogen atmosphere, the mixture was stirred −78° C. for 1 hr, and then at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to give colorless oil. The obtained oil in tetrahydrofuran solution (60 was added 1.5M diisobutylaluminum hydride-toluene solution (23.2 mL) at 0° C., and the mixture was stirred for 1 hr. 1.5M Diisobutylaluminum hydride in toluene solution (15.5 mL) was added again, and the mixture was further stirred at 0° C. for 1 hr. 1N Hydrochloric acid was added to quench the reaction, the organic solvent was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (2.76 g, 57%) as a colorless oil.

1. stirringthe mixture was stirred at −45° C. for 2 hr
2. waitat room temperature for 1.5 hr
3. customto quench
4. customthe reaction, tetrahydrofuran
5. customwas evaporated
6. customevaporator
7. extractionthe mixture was extracted with ethyl acetate
8. washThe extract was washed with saturated brine
9. dry with materialdried over magnesium sulfate
10. concentrationconcentrated under reduced pressure
11. customThe residue was purified by silica gel column chromatography (20% ethyl acetate/hexane)
12. customto give a pale-yellow oil
13. stirringunder a nitrogen atmosphere, the mixture was stirred −78° C. for 1 hr
14. waitat room temperature for 3 hr
15. concentrationThe reaction mixture was concentrated under reduced pressure
16. customthe residue was purified by silica gel column chromatography (10% ethyl acetate/hexane)
17. customto give colorless oil
18. stirringthe mixture was stirred for 1 hr
19. stirringthe mixture was further stirred at 0° C. for 1 hr
20. customto quench
21. customthe reaction
22. customthe organic solvent was evaporated
23. customevaporator
24. extractionthe mixture was extracted with ethyl acetate
25. washThe extract was washed with saturated brine
26. dry with materialdried over magnesium sulfate
27. concentrationconcentrated under reduced pressure

ORD record

ord-d537403e9f404d2e90b74c798c361d4c

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08309580B2