Ethyl Acetate → 1294481-80-3

Temperature

-20 °C

To a 1 liter dry round-bottomed flask was loaded ((2R,3R,4R)-3-(4-chlorobenzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl 4-chlorobenzoate (1b, 50.0 g, 113 mmol) and the solid was dissolved in anhydrous THF (200 mL). The solution was cooled to −20° C. Lithium tri-tert-butoxyaluminohydride (1.0 M in THF) (170 mL, 170 mmol) was added via an addition funnel over 20 min and the resulting mixture was stirred for an additional one hour at −20° C. Ethyl acetate (120 mL) was added and the mixture was allowed to warm up slowly to 0° C. Sat. aq ammonium chloride (4.5 mL) was added. The mixture was concentrated under reduced pressure and then diluted with EtOAc (500 mL). Aqueous HCl (3 N, 300 mL) was added to dissolve all solids. After separation, the organic layer was washed with water (2×200 mL), brine (100 mL), and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to furnish an amorphous solid. The solid was dissolved in methanol (169 mL) heated to reflux. After cooling to room temperature, water was added portionwise (37 mL total) until a slightly turbid mixture formed. After standing, the precipitated β-lactol product was filtered and washed with methanol (2×20 mL) and dried (0.2 mmHg, 50° C., 17 h) to 30.5 g (61%) of an off-white solid with an anomeric ratio of β/α>35:1. 1NMR (DMSO-d6): δ 7.95 (m, 2H, arom.), 7.90 (m, 2H, arom.), 7.61 (m, 2H, arom.), 7.51 (m, 2H, arom.), 7.31 (dd, 1H, C1-H, J=5.2 Hz, J=0.8 Hz), 5.50 (dd, 1H, C3-H, J=24 Hz, J=7.2 Hz), 5.19 (dd, 1H, C4-H, J=10.8 Hz, J=5.6 Hz), 4.56 (m, 1H, C5-Ha), 4.42 (m, 2H, C5-Hb and OH), 1.42 (d, 3H, CH3, J=22.8 Hz).

1. customTo a 1 liter dry round-bottomed flask was loaded
2. temperatureto warm up slowly to 0° C
3. concentrationThe mixture was concentrated under reduced pressure
4. additiondiluted with EtOAc (500 mL)
5. additionAqueous HCl (3 N, 300 mL) was added
6. dissolutionto dissolve all solids
7. customAfter separation
8. washthe organic layer was washed with water (2×200 mL), brine (100 mL)
9. dry with materialdried over sodium sulfate
10. concentrationThe organic layer was concentrated under reduced pressure
11. customto furnish an amorphous solid
12. temperatureheated to reflux
13. temperatureAfter cooling to room temperature
14. customformed
15. filtrationthe precipitated β-lactol product was filtered
16. washwashed with methanol (2×20 mL)
17. dry with materialdried (0.2 mmHg, 50° C., 17 h) to 30.5 g (61%) of an off-white solid with an anomeric ratio of β/α>35:1

ORD record

ord-8c54ce586b274e3db5a2006fd1c54d7a

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09045520B2