反应详情

温度

52.5 °C

To an appropriate flask maintained under a nitrogen atmosphere, 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (189.5 g, 0.58 mol) and methanol (3.8 L) were added. The mixture was heated to 50-55° C. and then D-(−)-tartaric acid (87.0 g , 0.58 mol) was added. The mixture was heated at reflux (˜65° C.) for 5 hours. The slurry was cooled at 30-35° C. and then granulated for 1 hour at 30-35° C. The product was filtered and the cake was washed with fresh methanol (135 mL). The wet cake was sampled for a chiral HPLC assay to determine enantiomeric impurity levels. The wet cake was suspended in methanol (1.6 L), and the resulting slurry was heat at reflux (˜65° C.) under a nitrogen atmosphere for 5 hours. The slurry was cooled to 30-35° C., granulated for 1 hour at 30-35° C. and then filtered. The filter cake was washed with methanol (136 mL) and then dried in vacuo at 40-45° C. for 18-24 hours. A sample was assayed by chiral HPLC. The D-(−)-tartrate salt of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (118.0 g) was obtained in 43% weight yield. At times, as the results show in Table 1 above an additional methanol reslurry is required to decrease the amount of the (1R,2R)-enantiomer impurity below 2.5%.

1. temperatureTo an appropriate flask maintained under a nitrogen atmosphere
2. temperatureThe mixture was heated
3. temperatureat reflux (˜65° C.) for 5 hours
4. temperatureThe slurry was cooled at 30-35° C.
5. filtrationThe product was filtered
6. washthe cake was washed with fresh methanol (135 mL)
7. aliquotThe wet cake was sampled for a chiral HPLC assay
8. temperaturethe resulting slurry was heat
9. temperatureat reflux (˜65° C.) under a nitrogen atmosphere for 5 hours
10. temperatureThe slurry was cooled to 30-35° C.
11. waitgranulated for 1 hour at 30-35° C.
12. filtrationfiltered
13. washThe filter cake was washed with methanol (136 mL)
14. customdried in vacuo at 40-45° C. for 18-24 hours