Methyl iodide → (1R,7S)-4-(2,5-dichlorophenyl)-1,3,10,10-tetramethyl-3,4-diazatricyclo[5.2.1.02,6]dec-2(6)-en-5-one

Temperature

100 °C

A mixture of (4S,7R)-2-(2,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 44; 12.55 g, 37.2 mmol) and iodomethane (12 mL, 193 mmol) in dimethylformamide (75 mL) was heated at 100° C. for 3 h and then cooled to room temperature. The solvent was evaporated, dichloromethane (300 mL) was added and the solution was washed with saturated aqueous sodium thiosulfate (100 mL), water (2×100 mL), and brine (100 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by flash column chromatography, eluting with 50-100% ethyl acetate/petroleum ether. Fractions homogeneous for the product were evaporated and ethyl acetate (100 mL) was added. The mixture was stirred at room temperature for 10 min and then hexane (300 mL) was added. The mixture was stirred at room temperature for 10 min and then cooled to 0° C. and filtered. The filter cake was washed with hexane and dried. The solid was dissolved in ethanol (100 mL) and treated with activated charcoal (0.8 g). The mixture was stirred at room temperature for 30 min, filtered through celite, and then evaporated. The residue was dried at 70° C. overnight 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 (9.18 g, 70%) as a white solid. ES(+)-MS (M+H) 351.

1. temperaturecooled to room temperature
2. customThe solvent was evaporated
3. additiondichloromethane (300 mL) was added
4. washthe solution was washed with saturated aqueous sodium thiosulfate (100 mL), water (2×100 mL), and brine (100 mL)
5. dry with materialThe solution was dried (magnesium sulfate)
6. filtrationfiltered
7. customevaporated
8. custompurified by flash column chromatography
9. washeluting with 50-100% ethyl acetate/petroleum ether
10. customFractions homogeneous for the product were evaporated
11. additionethyl acetate (100 mL) was added
12. additionhexane (300 mL) was added
13. stirringThe mixture was stirred at room temperature for 10 min
14. temperaturecooled to 0° C.
15. filtrationfiltered
16. washThe filter cake was washed with hexane
17. customdried
18. dissolutionThe solid was dissolved in ethanol (100 mL)
19. additiontreated with activated charcoal (0.8 g)
20. stirringThe mixture was stirred at room temperature for 30 min
21. filtrationfiltered through celite
22. customevaporated
23. customThe residue was dried at 70° C. overnight

ORD record

ord-bdf281f2f8c247f68ea14951cd82b541

Source dataset

uspto-grants-2009_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07622492B2