反应详情

温度

-12 °C

A clean, dry and nitrogen gas purged flask was charged with (3R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid amide (20.11 g, 77.27 mmol) and isopropyl ether (100 mL) and the mixture was cooled to −12° C. Benzyl chloroformate (13.25 mL, 92.8 mmol) was then added followed by the slow addition of 1.0 M lithium tert-butoxide in THF solution (185.5 mL). The lithium tert-butoxide solution was added at such a rate that the internal temperature remained below 0° C. Fifteen minutes after the completion of base addition, the reaction was quenched by adding the mixture to isopropyl ether (100 mL) and 1.5 M hydrochloric acid (130 mL). The phases were separated and the organic layer was washed with saturated aqueous sodium chloride solution (130 mL). The phases were separated, the organic layer was dried (MgSO4), filtered, and concentrated under partial vacuum (at 40° C.) to a total volume of 100 mL. Additional isopropylether (200 mL) was added and the solution was again concentrated under partial vacuum (at 40° C.) to a total volume of 100 mL. After cooling, the solution was seeded with (3R)-[3-(4-trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid benzyl ester and allowed to stir at room temperature overnight. The remaining solvent was displaced with cyclohexane using partial vacuum distillation (45° C. bath, 200 mL followed by 100 mL), the resultant slurry was cooled and stirred for 40 minutes, filtered, and dried to provide 25.8714 g (85%) of the title compound.

1. customA clean, dry
2. customnitrogen gas purged flask
3. customremained below 0° C
4. additionFifteen minutes after the completion of base addition
5. customthe reaction was quenched
6. additionby adding the mixture to isopropyl ether (100 mL) and 1.5 M hydrochloric acid (130 mL)
7. customThe phases were separated
8. washthe organic layer was washed with saturated aqueous sodium chloride solution (130 mL)
9. customThe phases were separated
10. dry with materialthe organic layer was dried (MgSO4)
11. filtrationfiltered
12. concentrationconcentrated under partial vacuum (at 40° C.) to a total volume of 100 mL
13. additionAdditional isopropylether (200 mL) was added
14. concentrationthe solution was again concentrated under partial vacuum (at 40° C.) to a total volume of 100 mL
15. temperatureAfter cooling
16. distillationThe remaining solvent was displaced with cyclohexane using partial vacuum distillation (45° C. bath, 200 mL followed by 100 mL)
17. temperaturethe resultant slurry was cooled
18. stirringstirred for 40 minutes
19. filtrationfiltered
20. customdried