Hydrochloric Acid → 1-Benzyl 4-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate

To a solution of 3.00 g of piperazine-2-carboxylic acid in 100 mL of 1:1 dioxane-water at pH 11 was added dropwise a solution of 4.0 g of 2-(tert-butyloxycarbonyloxyimino)-2-phenylacetonitrile in 25 mL of dioxane, maintaining the pH of the solution at 11 during the addition with the use of 5 N NaOH. The mixture was stirred for 6 h at room temperature, then cooled to 0° C. The pH was adjusted to 9.5 with the use of 1 N HCl. Benzyl chloroformate (2.8 g) was added dropwise, maintaining the pH of the solution at 9.5 during the addition with the use of 5 N NaOH. The mixture was allowed to warm to room temperature and stirred for 20 h, then extracted with 2×75 mL of Et2O, acidified to pH≦2 with 1 N HCl, and extracted with 4×50 mL of EtOAc. The combined EtOAc extracts were washed with 50 mL of brine, dried over MgSO4, and concentrated to a pale yellow oil. This oil was dissolved in 150 mL of acetone. Dimethyl sulfate (2.25 g) and potassium carbonate (2.89 g) were added. The mixture was heated to reflux and stirred at this temperature for 6 h, then cooled, filtered, and concentrated. The residue was dissolved in 125 mL of Et2O and washed with 50 mL each of saturated NaHCO3, water, and brine. The organic phase was dried over MgSO4 and concentrated to yield 6.06 g of the title compound, which was used without further purification.

1. temperaturemaintaining the pH of the solution at 11
2. temperaturecooled to 0° C
3. temperaturemaintaining the pH of the solution at 9.5
4. temperatureto warm to room temperature
5. stirringstirred for 20 h
6. extractionextracted with 2×75 mL of Et2O
7. extractionextracted with 4×50 mL of EtOAc
8. washThe combined EtOAc extracts were washed with 50 mL of brine
9. dry with materialdried over MgSO4
10. concentrationconcentrated to a pale yellow oil
11. dissolutionThis oil was dissolved in 150 mL of acetone
12. additionDimethyl sulfate (2.25 g) and potassium carbonate (2.89 g) were added
13. temperatureThe mixture was heated
14. temperatureto reflux
15. stirringstirred at this temperature for 6 h
16. temperaturecooled
17. filtrationfiltered
18. concentrationconcentrated
19. dissolutionThe residue was dissolved in 125 mL of Et2O
20. washwashed with 50 mL each of saturated NaHCO3, water, and brine
21. dry with materialThe organic phase was dried over MgSO4
22. concentrationconcentrated

ORD record

ord-e70366d872c54f7f869ee89380bfb9a9

Source dataset

uspto-grants-2002_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06498165B1