反应详情

温度

45 °C

To a mechanically stirred suspension of O-desmethylvenlafaxine (200.0 g, 0.759 mol in 2-propanol (1000 mL) at 70–75° C. under a nitrogen atmosphere was added dropwise a solution of 96% formic acid (40 ml, d=1.22, 46.85 g, 1.018 mol., 1.34 molar excess) over a period of 1 hour. The resulting, hazy solution was kept for a further 10 min. at 70–75° C. and then filtered through a pad of Celite filter aid (40 g, prewashed with hot 2-propanol). The filter pad was washed with hot (70–80° C.) 2-propanol (2×162 mL). The filtrate and washings (temperature 48–49° C.) were stirred slowly under a nitrogen atmosphere and allowed to cool to 45° C. The solution was seeded with crystals of O-desmethylvenlafaxine formate and allowed to cool at a rate of about 1° C. per 4 minutes. The solution became cloudy at 40.5° C. The stirred, cloudy solution was allowed to cool to 34–35° C., then maintained at that temperature for a period of 1.5 hours. Most of the product crystallized during this period. The stirred slurry of crystals was allowed to cool to 25° C. over a period of 1 hour and then cooled in an ice bath over a period of 1 hour to 5–10° C. The slurry was chilled to −10° C. in 40 min. and kept at that temperature for 30 min. The crystals were collected on a filter and washed with chilled (0 to −10° C.) acetone (3×400 mL). Drying in a vacuum oven at 47–48° C., for 36 hours at 80 mm Hg, under a nitrogen stream, (with intermediate crushing after 13 hours) furnished 203.1 g (86%) of the product, O-desmethylvenlafaxine formate. The product had a mp=145–147° C. and residue on ignition 0.1% (as sulfated ash). It was characterized by DSC (sharp endotherm at 151.8° C.

1. filtrationfiltered through a pad of Celite
2. filtrationfilter aid (40 g, prewashed with hot 2-propanol)
3. washThe filter pad was washed with hot (70–80° C.) 2-propanol (2×162 mL)
4. temperatureto cool at a rate of about 1° C. per 4 minutes
5. customat 40.5° C
6. temperatureto cool to 34–35° C.
7. temperaturemaintained at that temperature for a period of 1.5 hours
8. customMost of the product crystallized during this period
9. temperatureto cool to 25° C. over a period of 1 hour
10. temperaturecooled in an ice bath over a period of 1 hour to 5–10° C
11. temperatureThe slurry was chilled to −10° C. in 40 min.
12. waitkept at that temperature for 30 min
13. customThe crystals were collected on
14. filtrationa filter
15. washwashed
16. temperaturewith chilled (0 to −10° C.) acetone (3×400 mL)
17. customDrying in a vacuum oven at 47–48° C., for 36 hours at 80 mm Hg, under a nitrogen
18. customstream, (with intermediate crushing after 13 hours)