Formic Acid → O-Desmethylvenlafaxine Formate

HRID 860920Notes

Reaction equation

HRID 860920 reaction equation
[CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([OH:22])=[O:21]>CC(O)C>[CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([O-:22])=[O:21]

Participants

4

Reactant 2

HCID 284Formic AcidHCID 125017Desvenlafaxine

Product 1

HCID 86603914O-Desmethylvenlafaxine FormateYield 86%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
45 °C

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-1cecd8766c4f4263b1abf871938a23c7
Source dataset
uspto-grants-2006_12
Patent number
US07154001B2

Reaction notes

Loading…