Toluene → 3-[(4-Fluorophenyl)methylidene]piperidin-2-one

HRID 1744403Notes

Reaction equation

HRID 1744403 reaction equation
[C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O[C:13](=O)[C:14]([F:17])(F)F)=O.[C:21]1([CH3:27])[CH:26]=CC=[CH:23][CH:22]=1>>[F:17][C:14]1[CH:13]=[CH:26][C:21]([CH:27]=[C:2]2[CH2:3][CH2:4][CH2:5][NH:6][C:1]2=[O:7])=[CH:22][CH:23]=1

Participants

4

Reactant 3

HCID 1140TolueneHCID 9845Trifluoroacetic anhydrideHCID 126652-Piperidone

Product 1

HCID 573514463-[(4-Fluorophenyl)methylidene]piperidin-2-oneYield 87.5%

Conditions

Temperature
60 °C

Procedure

This example illustrates the preparation of the compound of formula II (n=2, R1=p-fluorophenyl) at a multi-kilogram scale. A 30 gallon (120 L) glass-lined reactor was charged with valerolactam (18.0 kg) and toluene (42.0 kg). Trifluoroacetic anhydride (42.0 kg) was added over 30 min and the mixture was stirred for an additional 60 min. Volatiles were distilled off at 60-70° C. at 140 torr. Toluene (50.0 kg) was added and the mixture was further distilled until approximately 27 L remained in the pot and this process was repeated twice. To the residue was added tert-butanol (18.8 kg) and 4-fluorobenzaldehyde (20.3 kg). The resultant solution was slowly transferred to 100 gallon (400 L) glass-lined reactor containing potassium tert-butoxide in tetrahydrofuran (122 kg of a 20% solution). The mixture was warmed to 60° C. for 1 h. Volatiles were distilled at 40-50° C. at 250 torr to a volume of approximately 100 L. Water (180 L) was added to the slurry at 40° C. and the mixture was cooled to 5° C. for 2 h and collected by filtration. The wet cake was washed and reslurried with water (3×200 L) and dried in a tray dryer (50° C., 50 torr) to afford crude 3-p-fluorobenzylidene-2-piperidone (32.6 kg) whose purity by HPLC was 70.3 wt % (95.4 area %).

Workup

  1. distillationVolatiles were distilled off at 60-70° C. at 140 torr
  2. additionToluene (50.0 kg) was added
  3. distillationthe mixture was further distilled until approximately 27 L
  4. additionTo the residue was added tert-butanol (18.8 kg) and 4-fluorobenzaldehyde (20.3 kg)
  5. customThe resultant solution was slowly transferred to 100 gallon (400 L) glass-lined reactor
  6. additioncontaining potassium tert-butoxide in tetrahydrofuran (122 kg of a 20% solution)
  7. distillationVolatiles were distilled at 40-50° C. at 250 torr to a volume of approximately 100 L
  8. additionWater (180 L) was added to the slurry at 40° C.
  9. temperaturethe mixture was cooled to 5° C. for 2 h
  10. filtrationcollected by filtration
  11. washThe wet cake was washed
  12. customdried in a tray dryer (50° C., 50 torr)

Sources & evidence

ORD record
ord-51db6c49181e4b46b5c3ccb7f66e2f0c
Source dataset
uspto-grants-2006_03
Patent number
US07015320B2

Reaction notes

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