反应详情

温度

-10 °C

A 2-L, 3-neck jacketed round-bottomed flask equipped with an overhead mechanical stirrer, N2-inlet, temperature probe and addition funnel was charged with sodium triacetoxyborohydride (93.0 g, 0.44 mol), isopropyl acetate (100 g) and an isopropyl acetate solution obtained from Example 1 (27.8 wt %, 410 g, 0.33 mol). The resulting mixture was chilled to −10° C. (internal temperature). Trifluoroacetic acid (170 g, 1.5 mol) was added dropwise by addition funnel over a 2-hour period. The internal temperature was adjusted to 10° C. and the mixture was stirred until HPLC analysis indicated complete consumption of starting material (about 15 hours). The reaction was poured into 750 g of 25% K2HPO4 (prepared by dissolving 250 g of K2HPO4 in 750 g of water). The pH of the mixture was adjusted to 6.6 using 20% KOH (prepared by dissolving 100 g of KOH in 400 g of water). The layers were separated. The organic layer was washed with 25% K2HPO4 (250 g) and with water (250 g). The organic layer was distilled to remove isopropyl acetate, which was chased with ethanol to a final volume of about 250 mL. The solution was cooled to 0° C. and 3.5 M LiOH solution (prepared by dissolving 37 g of LiOH—H2O in 250 g of water) was added such that the temperature remained below 20° C. The reaction progress was followed by HPLC until no ester remained (typically about 2 hours). The ethanol was removed by distillation under vacuum and the resulting aqueous layer was extracted with methyl tert-butyl ether (190 g). The methyl tert-butyl ether layer was extracted with water (100 g) and discarded. The combined aqueous layers was cooled to 0° C. and neutralized to pH 7 with concentrated HCl. Isopropyl acetate (220 g) was added and the pH was adjusted to 3 with concentrated HCl. The layers were separated and the aqueous layer was extracted with isopropyl acetate (220 g). The combined organic layers were washed with water (100 g). The organic solution was distilled under vacuum to a total volume of about 180 mL, and cooled to 0° C. Crystals formed over a 30-minute period. Heptanes (50 g) was added dropwise over a 2-hour period and the resulting mixture was stirred for 2 hours at 0° C. The mixture was filtered and the solid was washed with cold 1:1 isopropyl acetate/heptanes (50 mL) and dried under vacuum to afford the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.24 (s, 9H) 1.45 (s, 9H) 1.87-2.04 (m, 1H) 2.11-2.28 (m, 1H) 2.57-2.81 (m, 2H) 3.75 (s, 3H) 4.23-4.40 (m, 1H) 4.99-5.14 (m, 1H).

1. additiontemperature probe and addition funnel
2. customwas adjusted to 10° C.
3. customconsumption of starting material (about 15 hours)
4. additionThe reaction was poured into 750 g of 25% K2HPO4 (prepared by dissolving 250 g of K2HPO4 in 750 g of water)
5. customThe layers were separated
6. washThe organic layer was washed with 25% K2HPO4 (250 g) and with water (250 g)
7. distillationThe organic layer was distilled
8. customto remove isopropyl acetate, which
9. temperatureThe solution was cooled to 0° C.
10. addition3.5 M LiOH solution (prepared by dissolving 37 g of LiOH—H2O in 250 g of water) was added such that the temperature
11. customremained below 20° C
12. customtypically about 2 hours
13. customThe ethanol was removed by distillation under vacuum
14. extractionthe resulting aqueous layer was extracted with methyl tert-butyl ether (190 g)
15. extractionThe methyl tert-butyl ether layer was extracted with water (100 g)
16. temperatureThe combined aqueous layers was cooled to 0° C. and neutralized to pH 7 with concentrated HCl
17. additionIsopropyl acetate (220 g) was added
18. customThe layers were separated
19. extractionthe aqueous layer was extracted with isopropyl acetate (220 g)
20. washThe combined organic layers were washed with water (100 g)
21. distillationThe organic solution was distilled under vacuum to a total volume of about 180 mL
22. temperaturecooled to 0° C
23. customCrystals formed over a 30-minute period
24. stirringthe resulting mixture was stirred for 2 hours at 0° C
25. filtrationThe mixture was filtered
26. washthe solid was washed with cold 1:1 isopropyl acetate/heptanes (50 mL)
27. customdried under vacuum