Hydrochloric Acid → 7,9-Dimethyl-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one--hydrogen chloride (1/1)

Temperature

50 °C

Charge a 5 L flask equipped, with an overhead stirrer, heating mantle, thermocouple, nitrogen purge and a teflon transfer line, with the mixture of tert-butyl 4-ethyl 7,9-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1,4-dicarboxylate and tert-butyl 4-methyl 7,9-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1,4-dicarboxylate (1286 g, 3.56 moles) dissolved in IPA (2 L) and heat the resulting mixture to 50° C. In a separate 12 L flask, equipped with an overhead stirrer, heating mantle, thermocouple, and nitrogen purge to a scrubber, add 5 N NaOH (1 L) and H2O (3 L). Thereafter add HCl (conc, 1.87 L, 21.8 moles) to the 12 L flask and heat to 50° C. Transfer the contents of the 5 L flask to the 12 L flask via the transfer line while flushing with N2 to remove the off gases from the reaction. After the addition, warm the resulting mixture to 80° C., and continue the N2 flush. After the reaction is complete allow the reaction mixture to cool to less than about 20° C. Add MTBE (4 L), and adjust the pH to neutral with aqueous NaOH. Transfer the resulting reaction mixture to a 22 L flask and separate the layers. Wash the aqueous layer with MTBE (2×2 L). Combine the organic washings and wash with brine (2 L), dry over MgSO4, filter and rinse with MTBE. Concentrate the filtrate to a dark oil. Dissolve in IPA (8 volumes) and transfer to a 12 L flask equipped with an overhead stirrer, thermocouple, 1 L addition funnel and N2 purge. Charge the addition funnel with HCl (conc. 765 mL) and add drop-wise over about 1 hr to the IPA solution. Stir the resulting slurry for about 1-2 hrs, filter, rinse the solids with cold IPA (3×500 mL), and dry the solid over night at about 50° C. to yield 561 g of the title compound.

1. additionCharge a 5 L flask
2. customequipped, with an overhead stirrer
3. temperatureheating mantle
4. customthermocouple, nitrogen purge
5. customIn a separate 12 L flask, equipped with an overhead stirrer
6. temperatureheating mantle
7. customthermocouple, and nitrogen purge to a scrubber
8. additionadd 5 N NaOH (1 L) and H2O (3 L)
9. customwhile flushing with N2
10. customto remove the off gases
11. customfrom the reaction
12. additionAfter the addition
13. temperaturewarm the resulting mixture to 80° C.
14. customflush
15. temperatureto cool to less than about 20° C
16. customthe resulting reaction mixture to a 22 L flask
17. customseparate the layers
18. washWash the aqueous layer with MTBE (2×2 L)
19. washCombine the organic washings and wash with brine (2 L)
20. dry with materialdry over MgSO4
21. filtrationfilter
22. washrinse with MTBE
23. concentrationConcentrate the filtrate to a dark oil
24. dissolutionDissolve in IPA (8 volumes)
25. customtransfer to a 12 L flask
26. customequipped with an overhead stirrer
27. additionthermocouple, 1 L addition funnel
28. customN2 purge
29. additionCharge the addition funnel with HCl (conc. 765 mL)
30. additionadd
31. filtrationfilter
32. washrinse the solids with cold IPA (3×500 mL)
33. customdry the solid over night at about 50° C.

ORD record

ord-32b5f660c45843d781e0ca84768b8cdb

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08329688B2