Formaldehyde → (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) 4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine dihydrochloride

HRID 584209Notes

Reaction equation

HRID 584209 reaction equation
[ClH:1].[CH3:2][C:3]1([CH3:12])[CH2:8][O:7][CH2:6][CH2:5][N:4]1[CH2:9][C:10]#[CH:11].C=O.[F:15][C:16]([F:45])([F:44])[C:17]1[CH:18]=[C:19]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][C@H:23]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=1)=[O:21].[I-].[K+].[C:48](=O)([O-])O.[Na+]>O1CCOCC1.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[ClH:1].[ClH:1].[F:45][C:16]([F:15])([F:44])[C:17]1[CH:18]=[C:19]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:48][C:11]#[C:10][CH2:9][N:4]2[CH2:5][CH2:6][O:7][CH2:8][C:3]2([CH3:12])[CH3:2])[CH2:24][C@H:23]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=1)=[O:21]

Participants

8

Reactant 5

HCID 712FormaldehydeHCID 4875Potassium IodideHCID 516892Sodium BicarbonateHCID 223427013,3-Dimethyl-4-(2-propynyl)morpholine hydrochlorideHCID 54478438(2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine

Product 1

HCID 86588519(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) 4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine dihydrochloride

Reagents, catalysts & solvents 2

HCID 24463Copper sulfate pentahydrateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 3,3-dimethyl-4-(2-propynyl)morpholine hydrochloride (0.24 g), 37% aqueous formaldehyde (0.16 ml), (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.57 g), copper(II) sulfate pentahydrate (5 mg) and potassium iodide (20 mg) in 1,4-dioxane (0.7 ml) was stirred at 90° C. for 1 hour. After being cooled to room temperature, the mixture was poured into ice-water and the aqueous mixture was made alkaline with saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound was collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution. The resulting mixture was evaporated under reduced pressure and the residue was recrystallized from a mixture of acetone and water to give colorless crystals of (2R)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethyl-morpholino)-2-butynyl]piperazine dihydrochloride (0.64 g).

Workup

  1. temperatureAfter being cooled to room temperature
  2. extractionThe resulting mixture was extracted with ethyl acetate
  3. washThe extract was washed with brine
  4. dry with materialdried over magnesium sulfate
  5. customevaporated under reduced pressure
  6. customThe residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1)
  7. additionThe fractions containing the objective compound
  8. customwas collected
  9. customevaporated under reduced pressure
  10. additiontreated with 4N hydrogen chloride in ethyl acetate solution
  11. customThe resulting mixture was evaporated under reduced pressure
  12. customthe residue was recrystallized from a mixture of acetone and water

Sources & evidence

ORD record
ord-9369211a5b604872a279de101c3e74f7
Source dataset
uspto-grants-2005_08
Patent number
US06924278B2

Reaction notes

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