反应详情

A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 5.4 g, 25.15 mmol) in 1,2-dichloroethane (60 mL) was added over a period of 1 min to a cooled (0° C.) solution of N-(2,4-difluoro-phenyl)-N′-ethylidene-hydrazine (Intermediate 26; 3.92 g, 23.04 mmol) and pyridine (2.9 mL, 35.9 mmol) in 1,2-dichloroethane (30 mL). The reaction mixture was stirred at room temperature for 15 min and then at 50° C. for 40 min. The reaction mixture was cooled, and a solution of HCl in dioxane (4 M, 18 mL, 72 mmol) was added. The solution was stirred for 5 min at room temperature and then glacial acetic acid (30 mL) was added. The reaction mixture was stirred at 100° C. for 45 min. The solvent was evaporated and dichloromethane (200 mL) was added. The solution was washed with 50% saturated brine (2×50 mL), and the combined aqueous layers were back-extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL), dried (magnesium sulfate), filtered, evaporated and eluted through a plug of silica gel with 30% ethyl acetate/hexanes to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (3.2 g, 45%) as an orange gummy solid.

1. waitat 50° C. for 40 min
2. temperatureThe reaction mixture was cooled
3. stirringThe solution was stirred for 5 min at room temperature
4. stirringThe reaction mixture was stirred at 100° C. for 45 min
5. customThe solvent was evaporated
6. additiondichloromethane (200 mL) was added
7. washThe solution was washed with 50% saturated brine (2×50 mL)
8. extractionthe combined aqueous layers were back-extracted with dichloromethane (2×50 mL)
9. washThe combined organic layers were washed with brine (100 mL)
10. dry with materialdried (magnesium sulfate)
11. filtrationfiltered
12. customevaporated
13. washeluted through a plug of silica gel with 30% ethyl acetate/hexanes