反应详情

1,3,3-Trimethoxybutane (145.4 g, 0.98 mol) is combined with 1 N aqueous hydrochloric acid (50.0 mL, 0.05 mol) and stirred for 1-2 h at RT under a nitrogen atmosphere. THF (1.5 L) is added and the solvent is evaporated at standard atmospheric pressure below 70° C. twice. THF (1.5 L) is added to prepare a solution of 4-methoxybutan-2-one in THF. (S)-(−)-2-Methyl-2-propanesulfinamide (124.4 g, 1.03 mol) and titanium (IV) ethoxide (447.0 g, 1.96 mol) are added and the reaction heated to 65-70° C. for 16-17 h. The reaction mixture is cooled to −10 to 0° C. Sodium borohydride (37.0 g, 0.98 mol) is added in portions, and then the mixture is stirred for 1-2 h at the same temperature. The reaction mixture is warmed to RT and stirred for 1-2 h. It is then cooled to 10-20° C. and methanol (100 mL) is added dropwise over 1-2 h. 25% Aqueous sodium chloride (300 mL) is added and the mixture is warmed to RT. Ethyl acetate (500 mL) is added. The mixture is stirred for 1-2 h at RT and then filtered. The filtercake is rinsed with additional ethyl acetate (807 mL). The layers are separated and the organic phase is washed with 25% aqueous sodium chloride (1.0 L). The aqueous phase is extracted with ethyl acetate (500 mL). The organic portions are combined, and the solvent is distilled at atmospheric pressure (no vacuum) below 75° C. to arrive at a solution of 300-500 mL total volume. Ethyl acetate (600 mL) and sodium thiosulfate (150.0 g) are added and the mixture is stirred for 1-2 h at 20-30° C. The mixture is filtered and the filtrate is concentrated. The diastereomers are separated by supercritical fluid chromatography to afford the title compound as a yellow oil (205.0 g, 65%). Column. ChiralPak® AD 10 μm, 50×300 mm; Elution mode: Isocratic; Mobile phase: CO2/ethanol; Flow rate: 280 mL/min; UV detection: 215.16 nm; Loading: 300 mg/mL. The first eluting peak is the minor diastereomer, TR=15.17 min. The second eluting peak is the major diastereomer representing the title compound, TR=17.11 min.

1. customthe solvent is evaporated at standard atmospheric pressure below 70° C. twice
2. additionTHF (1.5 L) is added
3. customto prepare a solution of 4-methoxybutan-2-one in THF
4. temperaturethe reaction heated to 65-70° C. for 16-17 h
5. temperatureThe reaction mixture is cooled to −10 to 0° C
6. stirringthe mixture is stirred for 1-2 h at the same temperature
7. temperatureThe reaction mixture is warmed to RT
8. stirringstirred for 1-2 h
9. temperatureIt is then cooled to 10-20° C.
10. temperaturethe mixture is warmed to RT
11. stirringThe mixture is stirred for 1-2 h at RT
12. filtrationfiltered
13. washThe filtercake is rinsed with additional ethyl acetate (807 mL)
14. customThe layers are separated
15. washthe organic phase is washed with 25% aqueous sodium chloride (1.0 L)
16. extractionThe aqueous phase is extracted with ethyl acetate (500 mL)
17. distillationthe solvent is distilled at atmospheric pressure (no vacuum) below 75° C.
18. additionEthyl acetate (600 mL) and sodium thiosulfate (150.0 g) are added
19. stirringthe mixture is stirred for 1-2 h at 20-30° C
20. filtrationThe mixture is filtered
21. concentrationthe filtrate is concentrated
22. customThe diastereomers are separated by supercritical fluid chromatography