反应详情

温度

70 °C

A suspension of benzhydrol (200.00 g, 1.075 mol, 1 equivalent) and thiourea (99.4 g, 1.293 mol, 1.20 equivalents) in monochlorobenzene/water (477 ml/300.5 ml) was heated at 70° C. An aqueous 48% HBr solution (145 ml, 1.29 mol, 1.2 equivalents) was then added over a 5 min period. After 3 h stirring at 70° C., the uronium intermediate was hydrolyzed by addition of an aqueous 9.3N potassium hydroxide solution (321.7 ml, 2.825 mol, 2.63 equivalents) over a 50 min period. After 1.5 h stirring at 70° C., chloroacetamide (152.3 g, 1.612 mol, 1.5 equivalents) in powder form was added for over a 15 min period. After 30 min stirring at 70° C., the reaction mixture was cooled down to 55° C. and the stirring was stopped. The lower aqueous phase was removed, and water (600 ml) was added to the reactor. The reaction mixture was again stirred for 45 min. The lower aqueous phase was then removed. Acetic acid (173.3 ml, 3.000 mol, 2.79 equivalents) was added. Hydrogen peroxide 30% (175.4 ml, 1.718 mol, 1.6 equivalents) was slowly added for 80 min. After 50 minutes of stirring at 55° C., the reaction mixture was quenched with an aqueous sodium bisulfite solution (275 g). The lower aqueous phase was removed and the reaction mixture was cooled 0–5° C. Monochlorobenzene (386 g) was added to dilute the reaction mixture. The resultant suspension was then filtered, and the solid was washed with water and monochlorobenzene, and dried to yield modafinil (216.7 g, global yield 69.3%, strength 93.9 wt. %). The crude modafinil was purified by recrystallization in methanol.

1. stirringAfter 1.5 h stirring at 70° C.
2. stirringAfter 30 min stirring at 70° C.
3. temperaturethe reaction mixture was cooled down to 55° C.
4. customThe lower aqueous phase was removed
5. additionwater (600 ml) was added to the reactor
6. stirringThe reaction mixture was again stirred for 45 min
7. customThe lower aqueous phase was then removed
8. stirringAfter 50 minutes of stirring at 55° C.
9. customthe reaction mixture was quenched with an aqueous sodium bisulfite solution (275 g)
10. customThe lower aqueous phase was removed
11. temperaturethe reaction mixture was cooled 0–5° C
12. additionMonochlorobenzene (386 g) was added
13. additionto dilute the reaction mixture
14. filtrationThe resultant suspension was then filtered
15. washthe solid was washed with water and monochlorobenzene
16. customdried