反应详情

Into a dry flask under N2 is added 4-cyano-3-hydroxy-5-methylthioisothiazole (8.6 g., 0.05 m.), DMF (120 ml.) and NaH (50% mineral oil, 2.5 g., 0.052 m.). After stirring at room temperature for 15 minutes, the tosylate of (S) 2-phenyl-3-tert. butylamino-5-hydroxymethyloxazolidine (0.05 m.) in DMF (80 ml.) is added and the solution heated at 80° C. with stirring. After 15 hours, the solution is cooled to 0°-10°, poured into H2O (600 ml.) and extracted with ether (4×100 ml.). The organic layer is washed with H2O (2×100 ml.) and 1N HCl (3×100 ml.). The acid layer is poured into NaOAc.3H2O (41 g., 0.3 m.) and the solution stirred at room temperature. After 5 hours, the solution is extracted with ether (2×100 ml.). The aqueous layer is neutralized with saturated Na2CO3 and extracted with CHCl3 (4×150 ml.). The organic layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product eluted with CHCl3 saturated with ammonia. There is obtained 6.3 g. (42%) of (S) 4-cyano-3-(tert.-butylamino-2-hydroxypropoxy)-5-methylthioisothiazole, which on treatment with maleic yields the (S) 4-cyano-3-(3-tert. butylamino-2-hydroxypropoxy(-5-methylthioisothiazole hydrogen maleate salt hemihydrate, m.p. 199°-200° C.

1. temperaturethe solution heated at 80° C.
2. stirringwith stirring
3. waitAfter 15 hours
4. temperaturethe solution is cooled to 0°-10°
5. extractionextracted with ether (4×100 ml.)
6. washThe organic layer is washed with H2O (2×100 ml.) and 1N HCl (3×100 ml.)
7. additionThe acid layer is poured into NaOAc.3H2O (41 g., 0.3 m.)
8. stirringthe solution stirred at room temperature
9. waitAfter 5 hours
10. extractionthe solution is extracted with ether (2×100 ml.)
11. extractionextracted with CHCl3 (4×150 ml.)
12. dry with materialThe organic layer is dried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated to dryness
15. customThe residue is chromatographed on silica gel 60
16. washthe product eluted with CHCl3 saturated with ammonia
17. customThere is obtained 6.3 g