Acetic Acid → 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one

HRID 1873787Notes

Reaction equation

HRID 1873787 reaction equation
Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Cl:32][CH2:33][C:34](Cl)=[O:35].C(O)(=O)C>C(Cl)Cl.O>[Cl:32][CH2:33][C:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:35]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 6577Chloroacetyl chloride2×HCID 11430Potassium Carbonate2×HCID 666164065-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride2×

Product 1

HCID 666166092-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
20 °C

Procedure

430 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B1; synthesis alternative 2) and 215 g potassium carbonate are suspended in 6.5 l of DCM. The mixture is heated to reflux and 162 g chloroacetylchlorid is added drop wise during 1 h. The mixture is stirred at reflux temperature for 5 h, then 30 g of potassium carbonate and further 36 g of chloroacetylchlorid are added. After 1 h additional reaction time at reflux the reaction is complete. 116 g of acetic acid is added to the mixture during 10 min, then the mixture is cooled to 20° C. and during cooling 3 l of water is added. The organic layer is separated from the aqueous layer; the organic layer is washed twice with 1.5 l of water. The combined aqueous layers are extracted twice with 0.5 l of DCM. The organic layers are combined and 6 l is distilled off in vacuum. Then 2.5 l of tert. butylmethylether is added and the solution is concentrated in vacuum until crystallization starts (about 0.8 liter is distilled off). The suspension is cooled down and stirred overnight. The suspension is filtered, the solid dried in vacuum by 50° C.

Workup

  1. temperatureThe mixture is heated
  2. temperatureto reflux
  3. temperatureat reflux temperature for 5 h
  4. temperatureAfter 1 h additional reaction time at reflux the reaction
  5. additionis added
  6. customThe organic layer is separated from the aqueous layer
  7. washthe organic layer is washed twice with 1.5 l of water
  8. extractionThe combined aqueous layers are extracted twice with 0.5 l of DCM
  9. distillation6 l is distilled off in vacuum
  10. additionThen 2.5 l of tert. butylmethylether is added
  11. concentrationthe solution is concentrated in vacuum until crystallization
  12. distillation(about 0.8 liter is distilled off)
  13. temperatureThe suspension is cooled down
  14. stirringstirred overnight
  15. filtrationThe suspension is filtered
  16. customthe solid dried in vacuum by 50° C.

Sources & evidence

ORD record
ord-522f392932a54928981842e737369889
Source dataset
uspto-grants-2012_11
Patent number
US08304436B2

Reaction notes

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