Hydrochloric Acid → 8-[3-(4-piperidinyl)propanoyl]1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one

Temperature

85 °C

A mixture of 3.95 kg of 8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one and 19.8 L of 2 N HCl was stirred at about 85° C. for about 10 hours. After cooled to about 35° C., 12 L of toluene was added to the reaction mixture, the layers were separated, and pH was adjusted to about 13 by adding 30% NaOH (about 10 L) to the aqueous layer while maintaining about 30° C. Further, 20 L of a mixture of toluene-acetonitrile (1:1) was added thereto, and the layers were separated. To the aqueous layer was added 12 L of a mixture of toluene-acetonitrile (1:1), and the layers were separated. The organic layers were combined, 12 L of 30% brine was added thereto, and the layers were separated. To the organic layer were added 346 g of active carbon and 346 g of silica gel, followed by stirring for about 15 minutes. The insolubles were filtered off, and washed with 6 L of a mixture of toluene-acetonitrile (1:1). The filtrate was concentrated to a volume of the solution of about 7 L. To the residue was added 3 L of toluene, and the mixture was stirred at about 40° C. Under nitrogen, 666 g of acetic acid was added at about 30° C. over about 15 minutes. The mixture was stirred at about 25° C. for 1.5 hours and then at about 5° C. for 1 hour. Precipitated crystals were separated, and washed with 28 L of a mixture of toluene-acetonitrile (1:1) cooled to about 5° C. The wet crystals were suspended in 65 L of a mixture of toluene-acetonitrile (1:1), 30% NaOH was added (about 10 L) thereto, pH was adjusted to 13.5, and the layers were separated. To the aqueous layer was added 8 L of a mixture of toluene-acetonitrile (1:1), and the layers were separated. The organic layers were combined, and washed with 12 L of 30% brine. The organic layer was washed again with 12 L of 30% brine. To the organic layer were added 346 g of active carbon and 346 g of silica gel, the mixture was stirred for about 15 minutes. The insolubles were filtered off, and washed with 6 L of a mixture of toluene-acetonitrile (1:1). The same procedures were repeated twice. The organic layer was concentrated, and 5 L of water was added to the residue, followed by re-concentration. The same procedures were repeated twice. Under nitrogen, 5 L of water was added to the residue, and 5 L of 30% brine was added at about 20° C. over about 15 minutes. Seed crystals were added, and the mixture was stirred at about 20° C. for 1.5 hours and then at about 5° C. for 1 hour. The desired compound was separated under nitrogen, washed with 4 L of 30% brine cooled to about 5° C., and dried to give 1.78 kg (yield 51%) of the desired compound as crystals.

1. temperatureAfter cooled to about 35° C.
2. customthe layers were separated
3. additionby adding 30% NaOH (about 10 L) to the aqueous layer
4. temperaturewhile maintaining about 30° C
5. additionFurther, 20 L of a mixture of toluene-acetonitrile (1:1) was added
6. customthe layers were separated
7. additionTo the aqueous layer was added 12 L of a mixture of toluene-acetonitrile (1:1)
8. customthe layers were separated
9. addition12 L of 30% brine was added
10. customthe layers were separated
11. additionTo the organic layer were added 346 g of active carbon and 346 g of silica gel
12. stirringby stirring for about 15 minutes
13. filtrationThe insolubles were filtered off
14. washwashed with 6 L of a mixture of toluene-acetonitrile (1:1)
15. concentrationThe filtrate was concentrated to a volume of the solution of about 7 L
16. additionTo the residue was added 3 L of toluene
17. stirringthe mixture was stirred at about 40° C
18. additionUnder nitrogen, 666 g of acetic acid was added at about 30° C. over about 15 minutes
19. stirringThe mixture was stirred at about 25° C. for 1.5 hours
20. waitat about 5° C. for 1 hour
21. customPrecipitated crystals
22. customwere separated
23. washwashed with 28 L of a mixture of toluene-acetonitrile (1:1)
24. temperaturecooled to about 5° C
25. additionwas added (about 10 L)
26. customthe layers were separated
27. additionTo the aqueous layer was added 8 L of a mixture of toluene-acetonitrile (1:1)
28. customthe layers were separated
29. washwashed with 12 L of 30% brine
30. washThe organic layer was washed again with 12 L of 30% brine
31. additionTo the organic layer were added 346 g of active carbon and 346 g of silica gel
32. stirringthe mixture was stirred for about 15 minutes
33. filtrationThe insolubles were filtered off
34. washwashed with 6 L of a mixture of toluene-acetonitrile (1:1)
35. concentrationThe organic layer was concentrated
36. addition5 L of water was added to the residue
37. concentrationfollowed by re-concentration
38. additionUnder nitrogen, 5 L of water was added to the residue, and 5 L of 30% brine
39. additionwas added at about 20° C. over about 15 minutes
40. additionSeed crystals were added
41. stirringthe mixture was stirred at about 20° C. for 1.5 hours
42. waitat about 5° C. for 1 hour
43. customThe desired compound was separated under nitrogen
44. washwashed with 4 L of 30% brine
45. temperaturecooled to about 5° C.
46. customdried

ORD record

ord-02fb4cd16f8348ca8f81d84dee70f036

Source dataset

uspto-grants-2005_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06881842B2