Methanol → Thebaine

Temperature

25 °C

To a dried 4-neck 5-liter round bottom flask equipped with a mechanical stirrer, heating mantle, pressure equalizing dropping funnel, and reflux condenser under a nitrogen atmosphere were added 100 g of codeinone, 500 mL of methanol and 73.5 mL of trimethyl orthoformate. The resulting mixture was allowed to stir at a temperature of from about 10° to about 15° C. Methanesulfonic acid (42 g) was then added to the flask at a temperature of about 10° C. to about 20° C. over a time period of about 10 minutes. To the resultant solution was added 500 mL of toluene, and the resulting mixture was allowed to reflux for about 3 h at a temperature of about 62° C. to about 64° C. until at least 93% of the codeinone was consumed. The reflux condenser was replaced with a distillation apparatus, the mixture was heated at a temperature of from about 91° C. to about 93° C., and methanol was allowed to distill from the reaction mixture until substantially all the methanol was removed. At various intervals an aliquot of the reaction mixture was removed, quenched in a phosphate buffer solution having a pH value of about 8, and analyzed using HPLC. The reaction mixture was monitored hourly until HPLC analysis showed that the peak corresponding to thebaine was at least about 95 percent of the total peak area (about 3 to 4 h). Dimethylformamide (22.4 mL) was then added to the reaction mixture, and the reaction mixture was heated at a temperature of from about 90° C. to about 95° C. for from about 3 to about 4 h. The mixture was cooled to about 25° C., deionized distilled water (500 mL) was added, and the resultant biphasic mixture was stirred at 25° C. for 0.5 h. The aqueous phase was collected, and to it was added iso-propanol (166 mL). The resultant mixture was heated to reflux, and treated with 25% NaOH (120 mL). The resultant slurry was slowly cooled with stirring to about 25° C. then further cooled to 0° C. to 5° C. and filtered. The solid was then washed with 3×50 mL of 3:1 (v:v) deionized distilled water:iso-propanol and dried under reduced pressure (40 mm Hg) at a temperature of from about 45° to about 50° C. for about 16 h to provide dry thebaine (67–80 g) as an off-white solid.

1. customTo a dried 4-neck 5-liter round bottom flask equipped with a mechanical stirrer
2. temperatureheating mantle, pressure
3. temperaturereflux condenser under a nitrogen atmosphere
4. customwas consumed
5. temperaturethe mixture was heated at a temperature of from about 91° C. to about 93° C., and methanol
6. distillationto distill from the reaction mixture until substantially all the methanol
7. customwas removed
8. customAt various intervals an aliquot of the reaction mixture was removed
9. customquenched in a phosphate buffer solution
10. customwas at least about 95 percent of the total peak area (about 3 to 4 h)
11. additionDimethylformamide (22.4 mL) was then added to the reaction mixture
12. temperaturethe reaction mixture was heated at a temperature of from about 90° C. to about 95° C. for from about 3 to about 4 h
13. distillationdeionized distilled water (500 mL)
14. additionwas added
15. stirringthe resultant biphasic mixture was stirred at 25° C. for 0.5 h
16. customThe aqueous phase was collected
17. additionto it was added iso-propanol (166 mL)
18. temperatureThe resultant mixture was heated
19. temperatureto reflux
20. additiontreated with 25% NaOH (120 mL)
21. temperatureThe resultant slurry was slowly cooled
22. stirringwith stirring to about 25° C.
23. temperaturethen further cooled to 0° C. to 5° C.
24. filtrationfiltered
25. washThe solid was then washed with 3×50 mL of 3:1 (v:v)
26. distillationdeionized distilled water
27. dry with materialiso-propanol and dried under reduced pressure (40 mm Hg) at a temperature of from about 45° to about 50° C. for about 16 h

ORD record

ord-62cce3c259cd4239b3f10e3b5e10e232

Source dataset

uspto-grants-2005_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06958398B1