反应详情

To a solution of hydrochloric acid (12M, 266 mL, 3.19 mol) in water (272 mL) and MeOH (135 mL) was added a solution of crude [(R)-1-(3,5-dichloro-4-fluoro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (208.6 g, 594 mmol) in MeOH (600 mL) via an addition funnel over 30 min. CH2Cl2 (300 mL) was then added and the reaction mixture was stirred at room temperature overnight. An additional portion of HCl (12M, 100 mL) was added and stirring was continued for another 20 h. The volatile solvents were removed in vacuo and the remaining aqueous mixture was cooled to −15 to −20° C. Toluene (400 mL) was added followed by the addition of NaOH solution (50% aqueous, 300 mL), which was added at a rate to keep the internal temperature below 25° C. The layers were separated and the aqueous layer was extracted with toluene (2×1 L). The combined organic layers were dried with Na2SO4 and concentrated to give 158.3 g of the title compound as a dark brown oil that solidifies slowly in the freezer, m/z 251.1 [M+H]+. This crude material was used without further purification.

1. stirringstirring
2. waitwas continued for another 20 h
3. customThe volatile solvents were removed in vacuo
4. temperaturethe remaining aqueous mixture was cooled to −15 to −20° C
5. additionToluene (400 mL) was added
6. additionfollowed by the addition of NaOH solution (50% aqueous, 300 mL), which
7. additionwas added at a rate
8. customthe internal temperature below 25° C
9. customThe layers were separated
10. extractionthe aqueous layer was extracted with toluene (2×1 L)
11. dry with materialThe combined organic layers were dried with Na2SO4
12. concentrationconcentrated