反应详情

Triethylamine (1.2 mL, 8.6 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 880 mg, 4.1 mmol) in 1,2-dichloroethane (8 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(2,5-dichloro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (751 mg, 2.58 mmol) in 1,2-dichloroethane (14 mL) was added over 2 min. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 30 min, and then in an oil bath at 50° C. for 30 min. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated at reflux for 1 h and then allowed to cool to room temperature. Dichloromethane (150 mL) was added and the mixture was washed with 1:1 water/brine (30 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 120 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and co-evaporated successively with methanol and diethyl ether. The residue was dried overnight under high vacuum at 70° C. to give (4S,7R)-2-(2,5-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (400 mg, 44%) as a white solid. ES(+)-MS (M+H) 351.

1. stirringThe reaction mixture was stirred at 0° C. for 15 min, at room temperature for 30 min
2. waitin an oil bath at 50° C. for 30 min
3. temperaturethe mixture was heated
4. temperatureat reflux for 1 h
5. washthe mixture was washed with 1:1 water/brine (30 mL)
6. dry with materialdried (magnesium sulfate)
7. filtrationfiltered
8. customevaporated
9. custompurified
10. washeluting with 20-100% ethyl acetate/hexanes
11. customFractions homogeneous for the product were evaporated
12. customThe residue was dried overnight under high vacuum at 70° C.