反应详情

温度

50 °C

To a mechanically stirred suspension of O-desmethylvenlafaxine (100.0 g, 0.380 mol) in 2-propanol (500 mL) at 70–75° C. under a nitrogen atmosphere was added dropwise a solution of 96% formic acid (20 ml, d=1.22, 23.42 g, 0.509 mol., 1.34 molar excess) over a period of 45 min. 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 (20 g, prewashed with hot 2-propanol). The filter pad was washed with hot (70–75° C.) 2-propanol (2×81 mL). The filtrate and washings (temperature 44–45° C.) were warmed to 50° C., under a nitrogen atmosphere, using slow mechanical stirring. The solution was seeded with crystals of O-desmethylvenlafaxine formate and allowed to cool. After further seeding at 45° C. the solution was allowed to cool to 40–41° C. whereupon the solution became cloudy. The stirred, cloudy solution was maintained at 40–42° C. for 25 min. and then cooled quickly (using cold water) to 35° C. It was then maintained at 34–35° C. for 1.5 h. Copious crystallization occurred during this latter period. The stirred thick slurry of crystals was allowed to cool to 25° C. over a period of 50 min. and then cooled to 7° C. (using ice) over a period of 1 h. and 40 min. The slurry was chilled to −10° C. in 10 min. and kept at that temperature for 30 min. The crystals were collected on a filter and washed with chilled (−5 to −10° C.) acetone (3×200 mL). After drying in a vacuum oven at 46–47° C., for 47 h. at 80 mm Hg, under a nitrogen stream, the product, O-desmethylvenlafaxine formate, weighed 101.59 g (86% yield) and it had mp=146.5–148° C. It was characterized by DSC (sharp endotherm at 152.4° C.).

1. filtrationfiltered through a pad of Celite
2. filtrationfilter aid (20 g, prewashed with hot 2-propanol)
3. washThe filter pad was washed with hot (70–75° C.) 2-propanol (2×81 mL)
4. temperatureto cool
5. customAfter further seeding at 45° C.
6. temperatureto cool to 40–41° C. whereupon the solution
7. temperatureThe stirred, cloudy solution was maintained at 40–42° C. for 25 min.
8. temperaturecooled quickly (using cold water) to 35° C
9. temperatureIt was then maintained at 34–35° C. for 1.5 h
10. customCopious crystallization
11. waitoccurred during this latter period
12. temperatureto cool to 25° C. over a period of 50 min.
13. temperaturecooled to 7° C. (using ice) over a period of 1 h.
14. custom40 min
15. temperatureThe slurry was chilled to −10° C. in 10 min.
16. waitkept at that temperature for 30 min
17. customThe crystals were collected on
18. filtrationa filter
19. washwashed
20. temperaturewith chilled (−5 to −10° C.) acetone (3×200 mL)
21. customAfter drying in a vacuum oven at 46–47° C., for 47 h. at 80 mm Hg, under a nitrogen stream
22. customwas characterized by DSC (sharp endotherm at 152.4° C.)