反应详情

(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound VIc) (10 g, 0.0348 moles) in methanol (about 100 mL) is reacted in a reaction vessel with potassium borohydride (about 1.1 g, 0.0207 moles) over about 6 hours while maintaining the temperature below about 60° C. The reaction is cooled to ambient room temperature and about 1N HCl and water (about 25 ml) are added, followed by neutralization with sodium hydroxide (about 25%) to generate (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl) in situ. Next, the methanol is evaporated, followed by the addition of 1,2-dichloroethane (about 200 mL). Next, 2,2-dichloro-ethanimidic acid ethyl ester (Compound IV wherein R2 is dichloromethyl and R4 is ethyl) is added (about 10.9 g, 0.0696 moles) with heating up to about 85° C. for about 6 hours. The reaction is then cooled to below about 25° C. After cooling, glycerin is added (about 50 mL). Next, the 1,2-dichloroethane is distilled by heating to about 85° C., followed by continued heating to about 105° C. to about 110° C. for about 10 hours, then followed by cooling to below about 25° C. Thereafter, water is added (about 100 mL). The resulting solids are filtered and washed with water (about 10 mL) and isopropanol (about 10 mL) to yield (4R,5R)-2-(Dichloromethyl)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl and R2 is dichloromethyl).

1. temperaturewhile maintaining the temperature below about 60° C
2. customNext, the methanol is evaporated
3. additionfollowed by the addition of 1,2-dichloroethane (about 200 mL)
4. additionNext, 2,2-dichloro-ethanimidic acid ethyl ester (Compound IV wherein R2 is dichloromethyl and R4 is ethyl) is added (about 10.9 g, 0.0696 moles)
5. temperaturewith heating up to about 85° C. for about 6 hours
6. temperatureThe reaction is then cooled to below about 25° C
7. temperatureAfter cooling
8. additionglycerin is added (about 50 mL)
9. distillationNext, the 1,2-dichloroethane is distilled
10. temperatureby heating to about 85° C.
11. temperatureby continued heating to about 105° C. to about 110° C. for about 10 hours
12. temperatureby cooling to below about 25° C
13. additionThereafter, water is added (about 100 mL)
14. filtrationThe resulting solids are filtered
15. washwashed with water (about 10 mL) and isopropanol (about 10 mL)