Citric Acid → 5,6-Dihydroimidazo[1,2-a][1]benzazepin-4-one

Temperature

-75 °C

Charge a reactor with 281 kg of 2-MeTHF and 31 kg of Diisopropylamine Cool to −80 to −70° C., and charge 86 kg of n-butyl lithium in n-hexane slowly maintaining the temperature a at −80 to −70° C. and stir for 1 to 3 h. Charge 195.8 kg solution of ethyl 3-(2-(1H-imidazol-1-yl)phenyl)propanoate in 2-MeTHF into the reactor slowly at −80 to −70° C., and stir for 2 to 4 h at −80 to −70° C. (in process HPLC<3%, ethyl 3-(2-(1H-imidazol-1-yl)phenyl)propanoate). Charge 47.8 kg of ethanol into the reactor slowly at −80 to −70° C., and stir for 0.5 to 2 h at −80 to 70° C. Charge 310 kg of MTBE into the reactor slowly, maintaining internal temp below −25° C. Adjust pH to 7.5 with 292 kg of 10% Citric acid aqueous solution. Adjust the temperature to about 0° C. Separate out aqueous layer, and wash organic layer with 202 kg of 25% NaCl aqueous. Separate the layers, concentrate the organic layer under reduced pressure to 41 to 82 L, maintaining the internal temp below 40° C. Extract the aqueous layer with 200 kg of dichloromethane. Combine the organic layers, and stir for 0.5 to 1 h at 15 to 25° C. Filter through a pad of silicon dioxide (20 kg), and wash the pad with 60 kg of dichloromethane. Concentrate the filtrate under reduced pressure to 82 to 123 L, maintaining the internal temperature below 40° C. Charge 170 kg of MTBE to the residue, and concentrate under reduced pressure to 82 to 123 L, maintaining the internal temperature below 50° C. Charge 208 kg of MTBE, and stir for 10 to 15 minutes (in-process control indicated 10.8% 2-MeTHF and 4.6% DCM). Charge 279 kg of MTBE and concentrate under reduced pressure to 82 to 123 L, maintaining an internal temperature below 50° C. (residual 2-MeTHF %=1.6%, residual DCM %=2.7%). Charge 14.5 kg of Methyl acetate into the residue, and heat the mixture to reflux for 30 to 60 minutes. Cool the mixture to 0 to 15° C. and stir for 6 to 8 h at 0 to 15° C. Isolate the solid by centrifugation, and wash the cake with 35 kg of MTBE. Dry the resulting solid to give 15.8 kg of 5,6-dihydroimidazo[1,2-a][1]benzazepin-4-one. LC/MS=199 (M+1), 419 (2M+23).

1. temperatureslowly maintaining the temperature a at −80 to −70° C.
2. stirringstir for 0.5 to 2 h at −80 to 70° C
3. temperaturemaintaining internal temp below −25° C
4. customto about 0° C
5. customSeparate out aqueous layer
6. washwash organic layer with 202 kg of 25% NaCl aqueous
7. customSeparate the layers
8. concentrationconcentrate the organic layer under reduced pressure to 41 to 82 L
9. temperaturemaintaining the internal temp below 40° C
10. extractionExtract the aqueous layer with 200 kg of dichloromethane
11. stirringstir for 0.5 to 1 h at 15 to 25° C
12. filtrationFilter through a pad of silicon dioxide (20 kg)
13. washwash the pad with 60 kg of dichloromethane
14. concentrationConcentrate the filtrate under reduced pressure to 82 to 123 L
15. temperaturemaintaining the internal temperature below 40° C
16. additionCharge 170 kg of MTBE to the residue
17. concentrationconcentrate under reduced pressure to 82 to 123 L
18. temperaturemaintaining the internal temperature below 50° C
19. additionCharge 208 kg of MTBE
20. stirringstir for 10 to 15 minutes (in-process control indicated 10.8% 2-MeTHF and 4.6% DCM)
21. additionCharge 279 kg of MTBE
22. concentrationconcentrate under reduced pressure to 82 to 123 L
23. temperaturemaintaining an internal temperature below 50° C. (residual 2-MeTHF %=1.6%, residual DCM %=2.7%)
24. additionCharge 14.5 kg of Methyl acetate into the residue
25. temperatureheat the mixture
26. temperatureto reflux for 30 to 60 minutes
27. temperatureCool the mixture to 0 to 15° C.
28. stirringstir for 6 to 8 h at 0 to 15° C
29. customIsolate the solid by centrifugation
30. washwash the cake with 35 kg of MTBE
31. customDry the resulting solid

ORD record

ord-f60a7d5db4e54fbfbab7d7abdfc5480f

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08299061B2