反应详情

温度

9 °C

A 500 mL flask was charged with 2-bromobenzene sulfonyl chloride (153.3 g) and dimethylaminopyridine (7.37 g, 0.1 equiv), purged with argon and cooled in an ice-brine bath. Pyridine (300 mL) was added, and the mixture stirred. A separate flask containing 3-amino-4,5-dimethyl isoxazole, (73.95 g) in anhydrous pyridine3 (300 mL) under argon was cooled in an ice bath. When the internal temperature of the pyridine-bromobenzenesulfonyl chloride solution was ˜−3° C., the isoxazole-pyridine solution was added dropwise by cannula. The addition required ˜90 min. Quantitative transfer of the isoxazole was achieved with a 10 mL pyridine rinse. Upon completion of addition, the ice was removed from the brine-ice bath, and the internal temperature of the reaction vessel warmed to approximately 8-10° C. over 1 h. The reaction vessel was then immersed in a preheated oil bath at 42° C. and maintained at this temperature for 24.5 h. The warm solution was cannulated dropwise into ice cold 6N HCl (8 L) with vigorous stirring over approximately 90 min. Immediate precipitation occurred. The mixture was stirred in the ice-water bath for approximately 1 h, and the yellow solid collected by suction filtration on a medium porosity glass frit. The filter cake was washed with cold deionized water (4×0.5 L), taking care to mix the filter cake with each wash. The solid was air suction dried for 24 h affording a yellow powder: 185.5 g, 93.4%, HPLC area percent 97.7. The solid was dissolved in ethyl acetate (3.7 L or 20 mL/g), charcoal (46.1 g, Darco KB, lot 1F-074) added, the mixture heated briefly to 58° C., cooled to RT and stirred for 12 h, filtered through celite, the celite pad rinsed with ethyl acetate (5×200 mL) and evaporated to dryness.

1. custompurged with argon
2. temperaturecooled in an ice-brine bath
3. additionPyridine (300 mL) was added
4. additionA separate flask containing 3-amino-4,5-dimethyl isoxazole, (73.95 g) in anhydrous pyridine3 (300 mL) under argon
5. temperaturewas cooled in an ice bath
6. customwas ˜−3° C.
7. additionthe isoxazole-pyridine solution was added dropwise by cannula
8. additionThe addition required ˜90 min
9. washrinse
10. additionUpon completion of addition
11. customthe ice was removed from the brine-ice bath
12. customThe reaction vessel was then immersed in a preheated oil bath at 42° C.
13. temperaturemaintained at this temperature for 24.5 h
14. stirringwith vigorous stirring over approximately 90 min
15. customImmediate precipitation
16. stirringThe mixture was stirred in the ice-water bath for approximately 1 h
17. filtrationthe yellow solid collected by suction filtration on a medium porosity glass frit
18. washThe filter cake was washed with cold deionized water (4×0.5 L)
19. additionto mix the filter cake with each wash
20. customdried for 24 h
21. customaffording a yellow powder
22. temperaturethe mixture heated briefly to 58° C.
23. temperaturecooled to RT
24. stirringstirred for 12 h
25. filtrationfiltered through celite
26. washthe celite pad rinsed with ethyl acetate (5×200 mL)
27. customevaporated to dryness