反应详情

To a slurry of 2-methylpropyl [3-fluoro-4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamate (IV, EXAMPLE 2, 64.63 g, 197.4 mmol, 90.1 wt %) in methylere chloride (194 ml) at 22° is added trifluoroacetic acid (28.0 ml, 363.5 mmol, 1.84 eq) yielding a mixture at 17° which is warmed and stirred at 35-37° for 1 hr. The mixture is cooled to 15° and a mixture of potassium carbonate (40.3 g, 292 mmol, 1.48 eq) in water (174 ml) added over 5-10 min, to control foaming, while maintaining the temperature at 15-20°. The phases are separated and the organic washed with water (100 ml). Both aqueous are serial back extracted with methylene chloride (100 ml). Methanol (500 ml) is added to the combined organic phases and the mixture concentrated under reduced pressure to give a slurry. Methanol (970 ml) is added. A mixture of sodium periodate (49.90 g, 233.3 mmol, 1.18 eq) in water (490 ml) is then added over 39 min while maintaining 23°. The slurry is stirred at 23° for 17 hr then warmed to 50° over 1 hr and stirred at 50° for 1.5 hr. The is cooled to 23° and water (733 ml) added. The slurry is cooled to −1° and the product collected by vacuum filtration, washed with water (720 ml) and dried to give the title compound, mp=212-214°; TLC Rf=0.43 (methanol/methylene chloride, 5/95); HPLC (method A) RT=3.58 min; NMR (DMSO-d6, 400 MHz) d 9.88, 7.39,7.29-7.21, 5.78, 3.89, 3.65, 3.39-2.51, 1.93 and 0.94; CMR (DMSO-d6, 100 MHz) d 159.0, 153.4, 140.1, 133.0, 129.3, 122.7, 117.7, 113.8, 105.1, 70.3, 46.2, 42.7, 27.4, 20.7 and 18.8; MS (CI, NH3) m/z (relative intensity) 345 (2.9), 344 (7.9), 343 (51), 328 (13), 327 (53) and 326 (100).

1. customyielding a mixture at 17° which
2. temperatureis warmed
3. temperatureThe mixture is cooled to 15°
4. additionadded over 5-10 min
5. temperaturewhile maintaining the temperature at 15-20°
6. customThe phases are separated
7. washthe organic washed with water (100 ml)
8. extractionBoth aqueous are serial back extracted with methylene chloride (100 ml)
9. additionMethanol (500 ml) is added to the combined organic phases
10. concentrationthe mixture concentrated under reduced pressure
11. customto give a slurry
12. additionis then added over 39 min
13. temperaturewhile maintaining 23°
14. stirringThe slurry is stirred at 23° for 17 hr
15. temperaturethen warmed to 50° over 1 hr
16. stirringstirred at 50° for 1.5 hr
17. temperatureThe is cooled to 23°
18. temperatureThe slurry is cooled to −1°
19. filtrationthe product collected by vacuum filtration
20. washwashed with water (720 ml)
21. customdried