反应详情

Triethylamine (1.7 mL, 12.1 mmol) was added dropwise to a cooled (0° C.) solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 1.00 g, 4.66 mmol) in dichloromethane (10 mL), yielding a thick slurry. Dichloromethane (5 mL) was added to facilitate stirring. The reaction mixture was stirred at 0° C. for 5 min and then N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 936 mg, 3.85 mmol) was added in small portions over 2-3 min. The reaction mixture was allowed to warm to room temperature and stir overnight, then it was cooled again to 0° C. and triethylamine (0.5 mL, 3.6 mmol) and a solution of N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 241 mg, 1.12 mmol) in dichloromethane (1 mL) were added. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 6 h. Again triethylamine (0.8 mL, 5.7 mmol) and a solution of N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 431 mg, 2.0 mmol) in dichloromethane (1 mL) were added at 0° C. and the reaction mixture was allowed to warm to room temperature and stir over the weekend. The solvent was evaporated and the residue was taken up in ethyl acetate and washed with water (25 mL), 1 M HCl (50 mL), and brine (2×50 mL). The organic layer was dried (sodium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc. Burlington, Wis.) with a RediSep-40 g silica gel column, eluting with 5-50% ethyl acetate/hexanes, to give N′-(2-chloro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (1.275 g, 79%) as a pale yellow foam.

1. customyielding a thick slurry
2. stirringThe reaction mixture was stirred at 0° C. for 5 min
3. stirringstir overnight
4. temperatureit was cooled again to 0° C.
5. stirringThe reaction mixture was stirred at 0° C. for 30 min
6. temperatureto warm to room temperature
7. stirringstir over the weekend
8. customThe solvent was evaporated
9. washwashed with water (25 mL), 1 M HCl (50 mL), and brine (2×50 mL)
10. dry with materialThe organic layer was dried (sodium sulfate)
11. filtrationfiltered
12. customevaporated
13. custompurified
14. washeluting with 5-50% ethyl acetate/hexanes