Potassium Carbonate → 1-t-Butoxycarbonyl-4-{[(methyl)(2-trifluoromethylpyridin-4-yl)amino]methyl}piperidine

HRID 1592857Notes

Reaction equation

HRID 1592857 reaction equation
[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7](O)[CH:6]=[CH:5][N:4]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][CH3:27])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:27])[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:8]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 21934652tert-Butyl 4-((methylamino)methyl)piperidine-1-carboxylateHCID 178516505HCID 178516505, compound

Product 1

HCID 694278541-t-Butoxycarbonyl-4-{[(methyl)(2-trifluoromethylpyridin-4-yl)amino]methyl}piperidineYield 28.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 24813Phosphorus oxychlorideSolvent2×

Conditions

Temperature
90 °C

Procedure

A stirred solution of 2-trifluoromethylpyridin-4-ol (12.5 g, 76.6 mmol) and dimethylformamide (3.00 mL) in phosphorus oxychloride (75 mL) is heated under reflux for 2 hours before excess phosphorus oxychloride is removed in vacuo. The residue is poured onto an ice-water mixture and extracted into ethyl acetate (×5). The combined organic extracts dried (sodium sulfate), filtered and concentrated in vacuo. The non-basic components of the mixture are eluted through a SCX column washing with a 1:1 mixture of methanol-dichloromethane. A stirred suspension of the residue, 1-t-butoxycarbonyl-4-[(methylamino)methyl]piperidine (1.11 g, 4.85 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in dimethylformamide (38 mL) is heated at 90° C. for 13 hours. Excess dimethylformamide is removed in vacuo, the residue is taken into chloroform and washed with 2.5% hydrogen chloride solution. The aqueous layer is extracted into chloroform (×3) and the combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. Flash column chromatography eluting with a gradient of 30% ethyl acetate-hexane to 50% ethyl acetate-hexane provides 1-t-butoxycarbonyl-4-{[(methyl)(2-trifluoromethylpyridin-4-yl)amino]methyl}piperidine (520 mg, 2%).

Workup

  1. customis removed in vacuo
  2. additionThe residue is poured onto an ice-water mixture
  3. extractionextracted into ethyl acetate (×5)
  4. dry with materialThe combined organic extracts dried (sodium sulfate)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. washThe non-basic components of the mixture are eluted through a SCX column
  8. washwashing with a 1:1 mixture of methanol-dichloromethane
  9. customExcess dimethylformamide is removed in vacuo
  10. washwashed with 2.5% hydrogen chloride solution
  11. extractionThe aqueous layer is extracted into chloroform (×3)
  12. dry with materialthe combined organic extracts are dried (sodium sulfate)
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. washFlash column chromatography eluting with a gradient of 30% ethyl acetate-hexane to 50% ethyl acetate-hexane

Sources & evidence

ORD record
ord-ee44e7950a6c41229f8215a9a05129e5
Source dataset
uspto-grants-2007_11
Patent number
US07294627B2

Reaction notes

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