Acetic Acid → HCID 58398762, compound

Temperature

20 °C

(R)-Boc-2-methylpiperazine (350 g, 1.71 moles, 98% w/w), which is commercially available from Lanzhou Boc Chemical Co., was dissolved in EtOH (2.75 L) at tjacket=20° C. Acetic acid (1.37 L) was added in one portion followed by the addition of cyclobutanone (184 g, 2.57 moles). The charging vessel was rinsed with EtOH (250 mL) and the light yellow solution was left stirring at tjacket=20° C. for 1 h. NaBH(OAc)3 (497 g, 2.48 moles, 95% w/w) was added in 20 portions over 90 min. EtOH (340 mL) was used for rinsing. The reaction mixture was left stirring for 2 h. A sample was analyzed on GC using HP-5MS column (length 25 m, ID 0.32 mm, Film 0.52 μm) with a gradient method (2 min at 60° C., followed by 25° C./min during 8 min then 2 min at 260° C.). Frontinlet temperature=200° C. using He as gas and a detector temperature=300° C. More NaBH(OAc)3 (30 g, 0.14 moles) was added to complete the reaction within 1 h. The reaction mixture was cooled to tjacket=0° C. before quenching with 5M NaOH (5.5 L). EtOH was distilled off under vacuum at tjacket=50° C. The H2O phase was extracted with toluene (5.5 L) at tjacket=20° C. The organic phase was combined with a second batch, started with (R)-Boc-2-methylpiperazine (300 g, 1.47 moles, 98% w/w). The combined organic phases were concentrated under vacuum at tjacket=50° C. to approximately 2 L. The obtained toluene solution with the intermediate can be stored at 5° C. for several days. The toluene solution was diluted with 2-propanol (2 L) at tjacket=10° C., and HCl in 2-propanol (1.06 L, 6.36 moles, 6M) diluted in 2-propanol (2 L) was added over 30 min. The reaction solution was heated to tjacket=48° C. HCl in 2-propanol (2.12 L, 12.72 moles, 6M) diluted in 2-propanol (2 L) was added over 2 h at tinner=46° C. The reaction solution was kept at tjacket=48° C. for an additional 3 h before being cooled to tjacket=0° C. over 1 h. A seed mixture (0.4 L reaction solution with Example 6 (0.2 g, 0.89 mmoles)) was added. The reaction mixture was left stirring at tjacket=0° C. overnight and the product was filtered off. Drying under vacuum at 40° C. gave Example 6 (620 g, 2.63 moles, 96.3% w/w), 83% yield. 1H-NMR (DMSO-d6): δ 12.46 (s, 1H), 10.13 (s, 2H), 3.35-3.74 (m, 6H), 3.09 (m, 1H), 2.92 (m, 1H), 2.39 (m, 2H), 2.16 (m, 2H), 1.72 (m, 2H), 1.32 (d, 3H, J=6.4 Hz); 13C-NMR (DMSO-d6): δ 58.50, 49.62, 48.13, 44.30, 24.48, 24.38, 15.25, 13.26

1. washThe charging vessel was rinsed with EtOH (250 mL)
2. waitthe light yellow solution was left
3. washfor rinsing
4. waitThe reaction mixture was left
5. stirringstirring for 2 h
6. custom2 min
7. customat 60° C.
8. waitfollowed by 25° C./min during 8 min
9. custom2 min
10. customat 260° C.
11. customFrontinlet temperature=200° C.
12. customa detector temperature=300° C
13. customthe reaction within 1 h
14. temperatureThe reaction mixture was cooled
15. custom=0° C.
16. custombefore quenching with 5M NaOH (5.5 L)
17. distillationEtOH was distilled off under vacuum at tjacket=50° C
18. extractionThe H2O phase was extracted with toluene (5.5 L) at tjacket=20° C
19. concentrationThe combined organic phases were concentrated under vacuum at tjacket=50° C. to approximately 2 L
20. waitThe obtained toluene solution with the intermediate can be stored at 5° C. for several days
21. additionwas added over 30 min
22. temperatureThe reaction solution was heated to tjacket=48° C
23. additionwas added over 2 h at tinner=46° C
24. waitThe reaction solution was kept at tjacket=48° C. for an additional 3 h
25. temperaturebefore being cooled
26. custom=0° C.
27. customover 1 h
28. additionwas added
29. waitThe reaction mixture was left
30. stirringstirring at tjacket=0° C. overnight
31. filtrationthe product was filtered off
32. customDrying under vacuum at 40° C.
33. customgave Example 6 (620 g, 2.63 moles, 96.3% w/w), 83% yield

ORD record

ord-16ecd1a316d846278d374d22ad59b014

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012452B2