反应详情

温度

0 °C

To a reactor was charged N-benzyl-L-serine (1.0 eq) and THF (6.1 volumes). The resulting solution was cooled to 0±5° C. and a pre-cooled solution (0–5° C.) of potassium carbonate (3.0 eq) in water (6.1 volumes) was added. Chloroacetyl chloride (1.4 eq) then was added via addition funnel while maintaining the internal temperature below 5° C. The biphasic reaction mixture was aged for approximately 30 min at 0±5° C. After aging, the mixture was sampled for HPLC analysis. If >6 area percent remaining N-benzyl-L-serine was present, additional chloroacetyl chloride was added. Once the reaction completeness specification has been met, 50 wt % sodium hydroxide is charged while keeping the internal temperature between 5 and 10° C. until the pH remains constant >13.5. The reaction was deemed complete when HPLC analysis showed <1 area percent (combined) intermediates. The mixture was warmed to 25° C., and heptane (2.03 volumes) was added. The mixture was stirred rapidly for 10 min, and then the phases were allowed to separate. The organic upper phase was discarded, and the rich aqueous phase was treated again with heptane (3.04 volumes). After stirring rapidly for 10 min, the phases were allowed to settle, and the organic upper phase was discarded. The rich aqueous portion was cooled to −5–0° C. and 37 wt % hydrochloric acid was added while maintaining a batch temperature <10° C. until pH <2. The resulting slurry was kept at −10–0° C. for a minimum of 4 h. The slurry was filtered over Whatman 1 filter paper, or equivalent, and washed with pre-cooled (3–7° C.) water (2×4.57 volumes). The wet cake was dried in vacuo at 40–45° C. After drying, 1.475 kg (84.9%, uncorrected) of 4-benzyl-5-oxo-morpholine-3-carboxylic acid was obtained. HPLC Ret Time: 1.82 min (YMC S5 ODS column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm); Chiral HPLC Ret Time: 7.94 min, e.e. 100%, (Chiralcel OJ-R, 150×4.6 mm, 5 μM, eluent: MeOH:0.2% aq. H3PO4 [50:50], flow rate 1 mL/min, 210 nm).

1. temperaturewhile maintaining the internal temperature below 5° C
2. customThe biphasic reaction mixture
3. aliquotthe mixture was sampled for HPLC analysis
4. customthe internal temperature between 5 and 10° C.
5. temperatureThe mixture was warmed to 25° C.
6. customto separate
7. additionthe rich aqueous phase was treated again with heptane (3.04 volumes)
8. stirringAfter stirring rapidly for 10 min
9. temperatureThe rich aqueous portion was cooled to −5–0° C.
10. addition37 wt % hydrochloric acid was added
11. temperaturewhile maintaining a batch temperature <10° C. until pH <2
12. customwas kept at −10–0° C. for a minimum of 4 h
13. filtrationThe slurry was filtered over Whatman 1
14. filtrationfilter paper
15. washequivalent, and washed
16. temperaturewith pre-cooled (3–7° C.) water (2×4.57 volumes)
17. customThe wet cake was dried in vacuo at 40–45° C
18. customAfter drying