反应详情

Methyltriphenylphosphonium bromide (MTPPB, 25.8 Kg) was suspended in 2-methyltetrahydrofuran (MTHF, 56 liters). Keeping the temperature in the range 20-25° C., KO-t-Bu (8.8 kg) was charged in portions under inert atmosphere in one hour. The suspension turned yellow and was stirred further for two hours. An anhydrous solution of naltrexone (8.0 Kg) in MTHF (32 liters) was then added over a period of one hour at 20-25° C. The suspension was maintained under stirring for a few hours to complete the reaction. The mixture was then treated with a solution of ammonium chloride (4.2 Kg) in water (30.4 liters) and then further diluted with water (30.4 liters). The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water (16 liters). The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (40 liters) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 2 liters) was added over one hour at 20-25° C. The suspension was stirred for at least three hours at the same temperature, and then filtered and washed with dichloromethane (8 liters) and then with acetone (16 liters). The solid was then re-suspended in dichloromethane (32 liters) at 20-25° C. for a few hours and then filtered and washed with dichloromethane (16 liters), affording 9.20 Kg of nalmefene hydrochloride, corresponding to 7.76 kg of nalmefene hydrochloride (99.7% pure by HPLC). Molar yield 89%.

1. additionwas charged in portions under inert atmosphere in one hour
2. temperatureThe suspension was maintained
3. stirringunder stirring for a few hours
4. customthe reaction
5. customThe phases were separated
6. washthe organic phase was washed twice with water (16 liters)
7. concentrationThe organic phase was concentrated to residue under vacuum
8. additiondiluted with dichloromethane (40 liters)
9. customto give a clear solution
10. stirringThe suspension was stirred for at least three hours at the same temperature
11. filtrationfiltered
12. washwashed with dichloromethane (8 liters)
13. waitThe solid was then re-suspended in dichloromethane (32 liters) at 20-25° C. for a few hours
14. filtrationfiltered
15. washwashed with dichloromethane (16 liters)