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, 25.06 g, 76.54 mmol) in toluene (150 ml), hexamethyldisiloxane (48 ml, 225.84 mmol, 2.95 eq), and polymethylhydrosiloxane (27.0 ml, 452 mmol, 5.90 eq) is added a 55° mixture of anhydrous p-toluenesulfonic acid (114.3 g, 664 mmol, 8.68 eq) in toluene (100 ml) while maintaining the temperature from about 15 to about 20°. HPLC shows complete conversion to 2-methylpropyl[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamate. Toluene (50 ml) at 55° is used as a rinse and the mixture warmed to 72° and stirred 5.5 hr. The resultant slurry is poured into a 15° mixture of potassium carbonate (67.60 g, 489 mmol, 6.39 eq) in water (250 ml) while maintaining the temperature less than 35°. The resultant liquid phases are separated at 40° and water (150 ml) is added to the aqueous phase. The aqueous phase is washed with toluene (250 then 150 ml) and the organic phases is dried over magnesium sulfate and concentrated. Methylene chloride (200 ml) is added followed by heptane (700 ml) and the mixture concentrated. Heptane (250 ml) is added and the mixture concentrated again. The resultant slurry is cooled to −2° and the product collected by vacuum filtration, washed with cold heptane and dried in a nitrogen stream to give the title compound, TLC Rf=0.34 (ethyl acetate/hexanes, 10/90); HPLC (method C) RT=7.58 min; NMR (CDCl3, 500 MHz) d 7.28, 7.10, 7.00, 6.78, 3.95, 2.88-2.81, 2.68, 2.09, 1.96 and 0.96; CMR (CDCl3, 125 MHz) d 160.3, 153.6, 137.5, 128.1, 127.8, 114.2, 106.3, 71.5, 36.4, 33.9, 29.3, 28.0 and 19.0; MS (CI, NH3) m/z (relative intensity) 312 (22), 311 (100), 255 (38), 238 (25) and 237 (85).

1. temperaturewhile maintaining the temperature from about 15 to about 20°
2. customat 55°
3. washa rinse
4. temperaturethe mixture warmed to 72°
5. additionThe resultant slurry is poured into a 15°
6. temperaturewhile maintaining the temperature less than 35°
7. customThe resultant liquid phases are separated at 40°
8. additionwater (150 ml) is added to the aqueous phase
9. washThe aqueous phase is washed with toluene (250
10. dry with material150 ml) and the organic phases is dried over magnesium sulfate
11. concentrationconcentrated
12. additionMethylene chloride (200 ml) is added
13. concentrationthe mixture concentrated
14. additionHeptane (250 ml) is added
15. concentrationthe mixture concentrated again
16. temperatureThe resultant slurry is cooled to −2°
17. filtrationthe product collected by vacuum filtration
18. washwashed with cold heptane
19. customdried in a nitrogen stream