tert-Butyl methyl ether → Sufentanil

To a suitably sized reaction flask (e.g., a jacketed glass reactor with stirring, nitrogen blanket, internal temperature recorder, and reflux capabilities) is charged 4-[(1-oxopropyl)phenylamino]-4-methoxymethyl piperidine nosylate (100.0 g), 2-(2-thiophenylethyl) 4-nitro-benzene sulfonate (79.2 g), tert-butyl methyl ether (MTBE, 333 mL), and triethylamine (TEA, 666 mL). The reaction mixture is warmed to 55°±5° C. and allowed to react at that temperature for not less than 24 hours. As the reaction progresses, a slurry is formed. The extent of the reaction can be followed by HPLC until most of the initial reactants are consumed. At that point, the reaction mixture is cooled to 20°±5° C. and charged with MTBE (400 mL) and water (400 mL). The diluted slurry is mixed for at least 10 minutes and then aqueous and organic phases are allowed to separate in a separatory funnel. The aqueous phase is discarded and then the organic phase is washed with water two additional times. Carbon (20 g) is then added to the resultant organic phase, mixed for at least 10 minutes and the carbon is filtered from the organic phase through a CELITE® diatomaceous earth bed. The CELITE® diatomaceous earth bed is washed with 200 ml of MTBE, the organic phases are combined and then solvent exchanged with ethanol under vacuum distillation conditions (by concentrating the organic phase to minimum stir volume three times and thereafter adding 400 mL of ethanol following each step of concentrating). The final volume should be about 600 mL. The solution is warmed to 45°±5° C. and then water (834 mL) is added slowly to give a turbid system. The hazy slurry is cooled slowly to 5°±5° C., and held at that temperature for at least 16 hours. The resultant slurry is filtered, washed with 30% aqueous ethanol and then dried in a vacuum oven at 50° C. to yield 67.9 g of the desired sufentanil product (expected yield 84%; expected purity 99.7%).

1. customTo a suitably sized reaction flask (e.g., a jacketed glass reactor with stirring, nitrogen blanket, internal temperature recorder, and reflux capabilities)
2. temperatureThe reaction mixture is warmed to 55°±5° C.
3. customto react at that temperature for not less than 24 hours
4. customAs the reaction progresses
5. customa slurry is formed
6. customThe extent of the reaction
7. customare consumed
8. temperatureAt that point, the reaction mixture is cooled to 20°±5° C.
9. additioncharged with MTBE (400 mL) and water (400 mL)
10. additionThe diluted slurry is mixed for at least 10 minutes
11. customto separate in a separatory funnel
12. washthe organic phase is washed with water two additional times
13. additionCarbon (20 g) is then added to the resultant organic phase
14. additionmixed for at least 10 minutes
15. filtrationthe carbon is filtered from the organic phase through a CELITE® diatomaceous earth bed
16. washThe CELITE® diatomaceous earth bed is washed with 200 ml of MTBE
17. distillationsolvent exchanged with ethanol under vacuum distillation conditions (
18. concentrationby concentrating the organic phase to minimum stir volume three times
19. additionadding 400 mL of ethanol following each step
20. concentrationof concentrating)
21. temperatureThe solution is warmed to 45°±5° C.
22. additionwater (834 mL) is added slowly
23. customto give a turbid system
24. temperatureThe hazy slurry is cooled slowly to 5°±5° C.
25. waitheld at that temperature for at least 16 hours
26. filtrationThe resultant slurry is filtered
27. washwashed with 30% aqueous ethanol
28. customdried in a vacuum oven at 50° C.

ORDレコード

ord-40ec2175b6f24841ad720244a5eff5f5

出典データセット

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08299258B2