Hydrochloric Acid → HCID 58999876, compound

To a solution of 2-acetylamino-malonic acid diethyl ester (15.1 g, 70 mmol) and 3-bromo-4-chlorobenzyl chloride (16.7 g, 70 mmol) in EtOH (110 mL) was added a solution of NaOEt (20% in EtOH, 28.7 mL, 73 mmol). The mixture was heated at reflux for 3 h in a flask fitted with a reflux condenser, then was treated with additional 2-acetylamino-malonic acid diethyl ester (3.0 g, 14 mmol) and NaOEt (20% in EtOH, 2.0 mL, 5.1 mmol). The mixture was heated at reflux for an additional 3 h. The mixture was cooled to rt and treated with water (200 mL). The resulting white precipitate was collected by filtration, washed with water, and suspended in a mixture of water (60 mL) and EtOH (60 mL). This mixture was heated to reflux temperature in a flask fitted with a reflux condenser. A solution of KOH (3.3 g, 59 mmol) in water (10 mL) was added dropwise. After 2 h at reflux, more KOH (5.9 g, 105 mmol) in water (20 mL) was added dropwise, and the mixture was heated at reflux for 3 h. The mixture was cooled to 0° C., diluted with water (120 mL), and treated with 50% aq. HCl until pH˜1. The resulting white precipitate was collected by filtration and washed with 0.1 M HCl. The solid was suspended in water (80 mL) and treated with 2 M aq. KOH until pH˜8.0. The solution was filtered. The filtrate was warmed to 40° C., treated with Acylase “Amano” (0.19 g, Amano Enzyme Inc., Japan) and CoCl2 (10 mg), and 2 M aq. KOH was added to keep the pH of solution at 8.0. After 4 d at 40° C., 2 M HCl was added until pH=1. The suspension was filtered and the filtrate was concentrated to 20 mL. The pH was adjusted to 6.0 with 2.0 M KOH. The mixture was kept at 0° C. overnight and the solid was collected by filtration to obtain the title compound as a light tan solid (7.67 g, 40% overall). 1H NMR (400 MHz, DMSO-d6): 7.66 (br s, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 3.39 (dd, J=7.1, 5.3 Hz, 1H), 3.08 (dd, J=14.2, 4.6 Hz, 1H), 2.86 (dd, J=14.0, 7.7 Hz, 1H). To determine the enantiomeric ratio, the product was transformed to the corresponding methyl ester (SOCl2, MeOH, rt) and then to the Mosher's amide (Mosher's acid chloride, iPr2NEt, CH2Cl2). The analysis of 1H-NMR data of the amide showed that the product was a single enantiomer (e.e. >99.5%).

1. temperatureThe mixture was heated
2. temperatureat reflux for 3 h in a flask
3. customfitted with a reflux condenser
4. temperatureThe mixture was heated
5. temperatureat reflux for an additional 3 h
6. filtrationThe resulting white precipitate was collected by filtration
7. washwashed with water
8. additionsuspended in a mixture of water (60 mL) and EtOH (60 mL)
9. temperatureThis mixture was heated
10. temperatureto reflux temperature in a flask
11. customfitted with a reflux condenser
12. temperatureAfter 2 h at reflux
13. temperaturethe mixture was heated
14. temperatureat reflux for 3 h
15. temperatureThe mixture was cooled to 0° C.
16. filtrationThe resulting white precipitate was collected by filtration
17. washwashed with 0.1 M HCl
18. additiontreated with 2 M aq. KOH until pH˜8.0
19. filtrationThe solution was filtered
20. temperatureThe filtrate was warmed to 40° C.
21. additiontreated with Acylase “Amano” (0.19 g, Amano Enzyme Inc., Japan) and CoCl2 (10 mg), and 2 M aq. KOH
22. additionwas added
23. addition2 M HCl was added until pH=1
24. filtrationThe suspension was filtered
25. concentrationthe filtrate was concentrated to 20 mL
26. waitThe mixture was kept at 0° C. overnight
27. filtrationthe solid was collected by filtration

ORD record

ord-b36e3813ba6e4dc1805b87e0d761411d

Source dataset

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07855292B2