反应详情

温度

3.5 °C

To a cooled vessel containing (4aS,5S,7aS)-7a-(2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (184.1 g, 574.8 mmol) was added trifluoroacetic acid (0.954 kg) in portions while the temperature was maintained below 20° C. The mixture was cooled to 3.5° C. and sulfuric acid (146 mL, 2.73 mol) was added over 20 min while the temperature was maintained below 5° C. Fuming nitric acid (39.8 mL, 0.948 mol) was added over 30 min, while the temperature was maintained below 10° C. After 1.5 h at 0-10° C., the reaction mixture was slowly quenched by transferring into an aq. solution of NaOH (575 g, 14.4 mol) in water (4.6 L) cooled to 5° C. The resulting suspension was stirred for 1 h at 21° C. The suspension was then filtered and the solid rinsed with cold water (920 mL). The solid was dried under vacuum until constant weight, and then dissolved into ethanol (1.05 L). The solution was heated to 35° C., and conc. HCl (55.6 mL, 0.690 mol) was added while maintaining temperature below 40° C. The suspension was then cooled to −5° C., held for 1 hr and filtered. The solid was rinsed with cold ethanol (420 mL) and dried until constant weight to obtain the title compound (185.0 g, 87.3%). 1H NMR (500 MHz, DMSO) δ ppm 11.80 (s, 2H), 8.45-8.36 (m, 1H), 8.31 (dd, J=6.6, 2.5 Hz, 1H), 7.66 (dd, J=11.1, 9.3 Hz, 1H), 4.96-4.72 (m, 1H), 4.58 (d, J=10.0 Hz, 1H), 4.27 (d, J=9.9 Hz, 1H), 3.76-3.66 (m, 1H), 3.39 (dd, J=14.9, 3.6 Hz, 1H), 3.24 (dd, J=14.3, 4.6 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 168.34, 163.33 (d, JCF=257.8 Hz), 144.58, 127.61 (d, JCF=11.6 Hz), 125.84, 124.10, 119.28 (d, JCF=26.5 Hz), 77.38 (q, JCF=31.5 Hz), 75.99, 65.88 (d, JCF=4.8 Hz), 40.36, 23.98.

1. temperaturewas maintained below 20° C
2. temperaturewas maintained below 5° C
3. temperaturewas maintained below 10° C
4. customthe reaction mixture was slowly quenched
5. temperaturecooled to 5° C
6. filtrationThe suspension was then filtered
7. washthe solid rinsed with cold water (920 mL)
8. customThe solid was dried under vacuum until constant weight
9. dissolutiondissolved into ethanol (1.05 L)
10. temperatureThe solution was heated to 35° C.
11. temperaturewhile maintaining temperature below 40° C
12. temperatureThe suspension was then cooled to −5° C.
13. waitheld for 1 hr
14. filtrationfiltered
15. washThe solid was rinsed with cold ethanol (420 mL)
16. customdried until constant weight