反应详情

Triethylamine (440 μL, 3.2 mmol) was added dropwise to a solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 318 mg, 1.5 mmol) in 1,2-dichloroethane (4 mL) over 1 min. Then a solution of N-benzyl-N′-(2-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (242 mg, 0.77 mmol) in 1,2-dichloroethane (8 mL) was added over 2 min. The reaction mixture was stirred at room temperature for 15 min and then heated in an oil bath at 100° C. for 45 min. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 1 h. A further portion of HCl in dioxane (4 M; 2 mL, 8 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 2 h. The reaction mixture was allowed to cool to room temperature and dichloromethane (100 mL) was added. The mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified on an ISCO system using a 40 g column, eluting with 50-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with diethyl ether and petroleum ether, and then dried under high vacuum at 90° C. to give (4R,7S)-1-benzyl-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (40 mg, 14%) as a pale yellow solid. ES(+)-MS (M+H) 377.

1. temperatureheated in an oil bath at 100° C. for 45 min
2. temperaturethe mixture was heated in an oil-bath at 100° C. for 1 h
3. temperaturethe mixture was heated in an oil-bath at 100° C. for 2 h
4. temperatureto cool to room temperature
5. washThe mixture was washed with 1:1 water/brine (20 mL)
6. dry with materialdried (magnesium sulfate)
7. filtrationfiltered
8. customevaporated
9. custompurified on an ISCO system
10. washeluting with 50-100% ethyl acetate/hexanes
11. customFractions homogeneous for the product were evaporated
12. customdried under high vacuum at 90° C.