Ammonia → HCID 57736428, compound

Temperature

-50 °C

To a solution of 2-bromo-5-[[[tert-butyl(diphenyl)silyl]oxy](2,3,6-trifluoro phenyl)methyl]-4-methylpyridine (75.6 g, 133 mmol) in toluene (1200 ml), a hexane solution of n-butyllithium (1.60 M, 99.4 ml, 159 mmol) was added in an argon atmosphere at −78° C. The reaction mixture was stirred for 30 minutes at −50° C., and then cooled again to −78° C., and carbon dioxide was bubbled therein. After stirring for 30 minutes at the same temperature, the reaction mixture was allowed to warm to 0° C., water and then 1 N hydrochloric acid were added thereto, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (1000 ml), and isobutyl chlorocarbonate (25.3 ml, 195 mmol) and then triethylamine (36.2 ml, 260 mmol) were added thereto at −5° C. After stirring the mixture for 30 minutes at the same temperature, a 7 N methanol solution of ammonia (100 ml, 700 mmol) was added, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the resulting residue. After the organic layer was separated, the organic layer was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, and the organic layer was dried over anhydrous sodium sulfate and filtered. Subsequently, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain the title compound (50.0 g, 93.5 mmol, 70%) as a pale brown oily substance.

1. temperaturecooled again to −78° C.
2. customcarbon dioxide was bubbled
3. stirringAfter stirring for 30 minutes at the same temperature
4. temperatureto warm to 0° C.
5. additionwater and then 1 N hydrochloric acid were added
6. concentrationthe mixture was concentrated under reduced pressure
7. additionEthyl acetate was added to the resulting residue
8. washthe organic layer was washed with saturated brine
9. dry with materialThe organic layer was dried over anhydrous sodium sulfate
10. filtrationfiltered
11. concentrationthe filtrate was concentrated under reduced pressure
12. dissolutionThe resulting residue was dissolved in tetrahydrofuran (1000 ml)
13. customat −5° C
14. stirringAfter stirring the mixture for 30 minutes at the same temperature
15. stirringthe mixture was stirred for 1 hour at room temperature
16. concentrationThe reaction mixture was concentrated under reduced pressure, and ethyl acetate and water
17. additionwere added to the resulting residue
18. customAfter the organic layer was separated
19. washthe organic layer was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate
20. dry with materialsaturated brine, and the organic layer was dried over anhydrous sodium sulfate
21. filtrationfiltered
22. concentrationSubsequently, the filtrate was concentrated under reduced pressure
23. customthe fraction obtained from an elution with hexane
24. concentrationethyl acetate=1:1 was concentrated under reduced pressure

ORD record

ord-c3cd0a38ca3244b4af2082d543fa6870

Source dataset

uspto-grants-2012_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08114886B2