反应详情

温度

95 °C

To a solution of 39.2 g (0.13 m) of 2′,3′-O-isopropylidene-5-fluorouridine in 55 ml of methylene chloride and 159 ml (1.98 m) of pyridine, cooled to +5° C., 60 g (0.315 m) of p-toluenesulfonyl chloride are added. The mixture thus obtained is stirred for 5 hours observing the formation of a plentiful precipitate. Then 160 ml of methylene chloride and 160 ml of water are added thereinto, whereby the temperature rises to 40° C. The phases are separated and the organic one is extracted with about 900 ml of N HCl; then the organic phase is washed with 2×100 ml of water. The organic phase, containing 0.117 m of 2′,3′-O-isopropylidene-5′-O-(p-toluenesulfonyl)-5-fluorouridine (yield —90% of the theoretical), is concentrated under vacuum until an oily residue is obtained, which is taken up with 2×100 ml of acetone. The oily residue is dissolved with 600 ml of acetone and 105 g (0.70 m) of sodium iodide are added to the solution. The mixture is heated for 5 hours at reflux, then cooled, concentrated under vacuum and the residue thus obtained is taken up with 2×80 ml of ethyl acetate. The residual oil is treated with 800 ml of ethyl acetate and 100 ml of water. The phases are separated and the aqueous one is treated with 2×80 ml of ethyl acetate. The collected organic phases are washed with 2×100 ml of a 5% aqueous solution of sodium metabisulphite, then with 100 ml of water. The organic phase, containing 0.113 m of 5′-deoxy-5′-iodo-2′,3′-0-isopropylidene-5-fluoro uridine (yield —97% of the theoretical), is concentrated under vacuum to a small volume; to the residue 560 ml of 80% aqueous acetic acid are added and the mixture is heated to 95° C. After 4-hour heating, a check by HPLC is performed (0.34% of residual starting product) After cooling, the mixture is concentrated under vacuum until an oily residue is obtained, which is taken up with 150 ml of ethyl acetate. The mixture is let to stand at 20÷25° C. for 15 ore. The product is filtered, washed with ethyl acetate and dried under vacuum at 45° C. Thus, 44.5 g of 5′-deoxy-5′-iodo-5-fluorouridine are obtained. M.p.=174÷175° C., purity (HPLC)=99.74% and [α]D=÷8.96° C. (c=1, CH3OH). The mother liquors are concentrate under vacuum and the residue is taken up with 50 ml of ethyl acetate; after 15 hours at +5° C., a further amount of 3.3 g of product are obtained. Total yield. 83% of the theoretical.

1. customThe mixture thus obtained
2. customrises to 40° C
3. customThe phases are separated
4. extractionthe organic one is extracted with about 900 ml of N HCl
5. washthen the organic phase is washed with 2×100 ml of water
6. additionThe organic phase, containing 0.117 m of 2′,3′-O-isopropylidene-5′-O-(p-toluenesulfonyl)-5-fluorouridine (yield —90% of the theoretical),
7. concentrationis concentrated under vacuum until an oily residue
8. customis obtained
9. additionare added to the solution
10. temperatureThe mixture is heated for 5 hours
11. temperatureat reflux
12. temperaturecooled
13. concentrationconcentrated under vacuum
14. customthe residue thus obtained
15. customThe phases are separated
16. additionthe aqueous one is treated with 2×80 ml of ethyl acetate
17. washThe collected organic phases are washed with 2×100 ml of a 5% aqueous solution of sodium metabisulphite
18. additionThe organic phase, containing 0.113 m of 5′-deoxy-5′-iodo-2′,3′-0-isopropylidene-5-fluoro uridine (yield —97% of the theoretical),
19. concentrationis concentrated under vacuum to a small volume
20. additionto the residue 560 ml of 80% aqueous acetic acid are added
21. temperatureAfter 4-hour heating
22. temperatureAfter cooling
23. concentrationthe mixture is concentrated under vacuum until an oily residue
24. customis obtained
25. customto stand at 20÷25° C. for 15 ore
26. filtrationThe product is filtered
27. washwashed with ethyl acetate
28. customdried under vacuum at 45° C