Hydrochloric Acid → HCID 86721085, compound

Temperature

82.5 °C

3-Chlorobenzaldehyde (5 mL, 44.1 mmol), methyl 3-oxobutanoate (9.53 mL, 88 mmol), piperidine (0.654 mL, 6.62 mmol) in MeOH (14.71 mL) were stirred at rt. Over time, the yellow solution turned cloudy, and finally too thick to stir. The solid-like reaction mixture was kept at rt overnight. MeOH (20 mL) was then added, and the yellow solid was broken apart using a spatula, chilled in an ice-water bath and filtered. The solid was washed with cold MeOH (2×10 mL) and then air-dried. A yellowish solid was obtained and the solid was suspended in MeOH (10 mL), then NaOMe (41 mL, 179 mmol, 25% wt in MeOH), followed by water (3.4 mL, 189 mmol) were added. The reaction was warmed to reflux (80-85° C.). During the course of reaction, the suspension became very hard to stir, and additional MeOH (40 mL) was added. After 7 h, the reaction was cooled to rt, and left at rt for 2 days. Water was added to the solid-like reaction mixture to give a brown solution. The reaction mixture was concentrated to remove MeOH, and the residue extracted with EtOAc. The aqueous layer was acidified with concentrated HCl to pH<3, then extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The orange oil obtained was dissolved in MeOH (50 mL), then concentrated HCl (0.63 mL) was added, and the mixture was heated at reflux (80° C. in an oil bath). After 6 h, the reaction was cooled to rt and then the reaction was concentrated to remove ⅔ of the MeOH. Water was then added, and a brown oil separated out. The solution was concentrated to remove all organics. The brown oil at the bottom solidified overnight. The solid was filtered, washed with water, air-dried and then dried in a vacuum oven (50° C.) for 2 h, to give a brown solid. The crude solid was purified by silica gel chromatography to give the desired product as a yellow oil (6.23 g, 52%). MS (ESI) m/z: 292.9 (M+Na)+.

1. customThe solid-like reaction mixture
2. temperaturechilled in an ice-water bath
3. filtrationfiltered
4. washThe solid was washed with cold MeOH (2×10 mL)
5. customair-dried
6. customA yellowish solid was obtained
7. additionwere added
8. temperatureThe reaction was warmed
9. customDuring the course of reaction
10. stirringto stir
11. waitAfter 7 h
12. temperaturethe reaction was cooled to rt
13. waitleft at rt for 2 days
14. customto give a brown solution
15. concentrationThe reaction mixture was concentrated
16. customto remove MeOH
17. extractionthe residue extracted with EtOAc
18. extractionextracted with EtOAc (3×)
19. dry with materialThe combined organic layers were dried over Na2SO4
20. filtrationfiltered
21. concentrationconcentrated
22. customThe orange oil obtained
23. temperaturethe mixture was heated
24. temperatureat reflux (80° C. in an oil bath)
25. waitAfter 6 h
26. temperaturethe reaction was cooled to rt
27. concentrationthe reaction was concentrated
28. customto remove ⅔ of the MeOH
29. additionWater was then added
30. customa brown oil separated out
31. concentrationThe solution was concentrated
32. customto remove all organics
33. customat the bottom solidified overnight
34. filtrationThe solid was filtered
35. washwashed with water
36. customair-dried
37. customdried in a vacuum oven (50° C.) for 2 h
38. customto give a brown solid
39. customThe crude solid was purified by silica gel chromatography

ORD record

ord-1a142a1cd8ec45258e2d0a9191d8d9be

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08901115B2