反应详情

温度

50 °C

(3S,4S)-[4-Amino-1-(5,6-dichloro-pyridin-3-yl)-pyrrolidin-3-yl]-methanol (10 g) was suspended in 1,2-dimethoxyethane (100 mL) and N-methylpyyrolidinone (15 mL). The mixture was heated to 50° C. and then a solution of thionyl chloride (7.9 g) in 1,2-dimethoxyethane (35 mL) was slowly added, while maintaining the temperature below 60° C. The reaction mixture was stirred at 50° C. for about 3 hours and then cooled to room temperature. After adding water (100 mL), the 1,1-dimethoxyethane was removed by distillation. Ethanol (100 mL) and water (100 mL) were added and the pH adjusted to 11-12 with 50% aqueous sodium hydroxide. The resulting mixture was heated at 60° C. for at least 12 hours and then cooled to room temperature. After filtering through a bed of Hy-Flo, the ethanol was removed by vacuum distillation. The pH was adjusted to >12 with 50% aqueous sodium hydroxide and then extracted with isopropyl acetate (2×80 mL). The combined organic extracts were concentrated, and then suspended in isopropyl acetate (˜50 mL). After heating to 80° C., the solution was cooled to room temperature while stirring rapidly. The suspension was cooled to 0° C., filtered, washed with isopropyl acetate and dried in the vacuum oven. 1H NMR (MeOH-d4, 300 MHz) δ 3.04 (dd, J=10.9, 4.8 Hz, 1H), 3.11 (dd, J=10.2, 6.8 Hz, 1H), 3.26 (dd, J=8.8, 4.4 Hz, 1H), 3.38 (m, 1H), 3.73 (t, J=11.2 Hz, 2H), 3.84 (t, J=8.1 Hz, 1H), 4.55 (dd, J=6.8, 4.8 Hz, 1H), 7.37 (d, J=3.1 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H); MS (DCI/NH3) m/z 244/246/248 (M+H)+.

1. temperaturewhile maintaining the temperature below 60° C
2. temperaturecooled to room temperature
3. customthe 1,1-dimethoxyethane was removed by distillation
4. additionEthanol (100 mL) and water (100 mL) were added
5. temperatureThe resulting mixture was heated at 60° C. for at least 12 hours
6. temperaturecooled to room temperature
7. filtrationAfter filtering through a bed of Hy-Flo
8. customthe ethanol was removed by vacuum distillation
9. extractionextracted with isopropyl acetate (2×80 mL)
10. concentrationThe combined organic extracts were concentrated
11. temperatureAfter heating to 80° C.
12. temperaturethe solution was cooled to room temperature
13. stirringwhile stirring rapidly
14. temperatureThe suspension was cooled to 0° C.
15. filtrationfiltered
16. washwashed with isopropyl acetate
17. customdried in the vacuum oven