反应详情

温度

0 °C

2-tert-Butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (5.0 g; 17.7 mmol) was dissolved in dry tetrahydrofuran. Iodomethane (8.8 mL; 141 mmol) was added and the reaction mixture was cooled to 0° C. Sodium hydride (2.1 g; 53.0 mmol) was slowly added and the reaction mixture was stirred for 12 hours at room temperature. Ethyl acetate (50 mL) was added and water (20 mL) was added dropwise to the reaction mixture. The ethyl acetate was removed in vacuo and the residue was diluted with diethyl ether (30 mL) and water (100 mL). The organic phase was extracted with a saturated aqueous solution of sodium hydrogen carbonate (50 mL). Citric acid (5%) was added to the combined aqueous phases until pH 3, which were then extracted with ethyl acetate (2×50 mL) and the phases were separated. The organic phase was washed with water (2×50 mL), an aqueous solution of sodium thiosulfate (5%; 2×50 mL) and water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was dissolved in diethyl ether (10 mL). Dicyclohexylamine (10 mL) was added. Methylene chloride (30 mL) was added and the mixture was heated until the precipitate was dissolved. Diethyl ether (20 mL) and heptane (20 mL) were added and the reaction mixture was left 12 hours without stirring. The reaction mixture was filtered to afford 5.7 g of (R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(4-fluorophenyl)propionic acid as a dicyclohexylammonium salt.

1. customThe ethyl acetate was removed in vacuo
2. additionthe residue was diluted with diethyl ether (30 mL) and water (100 mL)
3. extractionThe organic phase was extracted with a saturated aqueous solution of sodium hydrogen carbonate (50 mL)
4. additionCitric acid (5%) was added to the combined aqueous phases until pH 3, which
5. extractionwere then extracted with ethyl acetate (2×50 mL)
6. customthe phases were separated
7. washThe organic phase was washed with water (2×50 mL)
8. dry with materialan aqueous solution of sodium thiosulfate (5%; 2×50 mL) and water (50 mL) and dried (magnesium sulfate)
9. customThe solvent was removed in vacuo
10. dissolutionthe residue was dissolved in diethyl ether (10 mL)
11. additionDicyclohexylamine (10 mL) was added
12. additionMethylene chloride (30 mL) was added
13. temperaturethe mixture was heated until the precipitate
14. dissolutionwas dissolved
15. additionDiethyl ether (20 mL) and heptane (20 mL) were added
16. waitthe reaction mixture was left 12 hours
17. stirringwithout stirring
18. filtrationThe reaction mixture was filtered