Sulfuric Acid → HCID 11733165, compound

Temperature

70 °C

A nitrogen atmosphere was applied to a reaction vessel containing 109.3 L of sulfuric acid (96% w/w) which was warmed to 70° C. with stirring. Heating was discontinued, and 89.2 kg of α-(2-chlorophenyl)-α-[2-[(1-methylethyl)(phenylmethyl)amino]ethyl]-1-piperidinebutanenitrile (product of Example 4) was added at a rate such that the temperature was maintained at 80°-85° C. The reaction mixture was stirred at 80°-85° C. for 2.5 h and cooled to 75° C. The reaction mixture was added to a cooled and stirred mixture of 322 L of water and 219 L of toluene at 5° C. at a rate such that the temperature did not exceed 30° C. An additional 127 L of water was added to rinse the reactor. The mixture was cooled to 5° C. and basified to pH>12 with 219 L of sodium hydroxide solution (50% w/w) while maintaining the temperature below 35° C. Near the end of the base addition, the mixture was allowed to warm to 45° C. and stirred for 15 min. After separation of the layers, the aqueous phase was maintained at 45° C. and extracted with two 126-L portions of toluene. The organic phases were combined using 126 L of toluene. The combined organic phase was washed with 126 L of water at 45° C. The solution was cooled to 25° C. and stirred with 64.3 kg of neutral alumina for 1 h. The slurry was filtered through a layer of diatomaceous earth, and the filter cake was washed with 126 L of toluene. Alternatively, the solution may be passed through a bed of neutral alumina followed by a toluene wash of the bed. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 322 L of heptane by heating to reflux. The solution was allowed to cool to 25° C. with stirring, and the resulting slurry was cooled to less than 10° C. The solid was collected by filtration and washed twice with 200 L of heptane. The solid was dried under vacuum at 35 to 40° C. to give 65.0 kg (70.0%) of the title product α-(2-chlorophenyl)-α-[ 2-[(1-methylethyl)(phenylmethyl) amino]ethyl]-1-piperidinebutanamide. Analysis calcd for C27H38ClN3O: C,71.11; H,8.40; Cl,7.77; N,9.21. Found C,71.09; H,8.50; Cl,7.94; N,9.17. mp 104°-111° C. The purity of the title compound was estimated to be >95% based on TLC Method A.

1. customA nitrogen atmosphere was applied to a reaction vessel
2. temperatureHeating
3. temperaturewas maintained at 80°-85° C
4. stirringThe reaction mixture was stirred at 80°-85° C. for 2.5 h
5. temperaturecooled to 75° C
6. additionThe reaction mixture was added to
7. temperaturea cooled
8. stirringstirred
9. customdid not exceed 30° C
10. washto rinse the reactor
11. temperatureThe mixture was cooled to 5° C. and basified to pH>12 with 219 L of sodium hydroxide solution (50% w/w)
12. temperaturewhile maintaining the temperature below 35° C
13. additionNear the end of the base addition
14. temperatureto warm to 45° C.
15. stirringstirred for 15 min
16. customAfter separation of the layers
17. temperaturethe aqueous phase was maintained at 45° C.
18. extractionextracted with two 126-L portions of toluene
19. washThe combined organic phase was washed with 126 L of water at 45° C
20. temperatureThe solution was cooled to 25° C.
21. stirringstirred with 64.3 kg of neutral alumina for 1 h
22. filtrationThe slurry was filtered through a layer of diatomaceous earth
23. washthe filter cake was washed with 126 L of toluene
24. washwash of the bed
25. customThe solvent was removed by distillation under reduced pressure
26. dissolutionthe residue was dissolved in 322 L of heptane
27. temperatureby heating to reflux
28. temperatureto cool to 25° C.
29. stirringwith stirring
30. temperaturethe resulting slurry was cooled to less than 10° C
31. filtrationThe solid was collected by filtration
32. washwashed twice with 200 L of heptane
33. customThe solid was dried under vacuum at 35 to 40° C.

ORD record

ord-2fd36060ce734cccae7f440337104bf1

Source dataset

uspto-grants-1995_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05432284