Methyl iodide → 1-[(Benzyloxy)carbonyl]-3-methylpiperidine-3-carboxylic acid

HRID 218234Notes

Reaction equation

HRID 218234 reaction equation
C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)=[O:5])C.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]([CH3:22])([C:4]([OH:3])=[O:5])[CH2:7]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 2733832Lithium HexamethyldisilazideHCID 17999271Benzyl ethyl piperidine-1,3-dicarboxylate

Product 1

HCID 532493621-[(Benzyloxy)carbonyl]-3-methylpiperidine-3-carboxylic acid

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a −78° C. solution of the product of Example 45A (6.0 g, 20.6 mmoles) in THF (50 mL) was added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 22.7 mmoles). After 35 min, iodomethane (1.4 mL, 22.7 mmoles) was added and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with aqueous sat. ammonium chloride and extracted with Et2O. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→65:35 hexane:EtOAc). The resulting ester was hydrolyzed overnight at room temperature in THF (15 mL), H2O (10 mL), and EtOH (15 mL) with NaOH (2.5 g). The solution was concentrated under vacuum; the residue was dissolved in saturated ammonium chloride; and, the solution was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated under vacuum to yield the title compound as a white solid.

Workup

  1. customThe reaction was quenched with aqueous sat. ammonium chloride
  2. extractionextracted with Et2O
  3. washThe organic layer was then rinsed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified by silica gel chromatography
  8. waitThe resulting ester was hydrolyzed overnight at room temperature in THF (15 mL)
  9. concentrationThe solution was concentrated under vacuum
  10. dissolutionthe residue was dissolved in saturated ammonium chloride
  11. extractionand, the solution was extracted with ethyl acetate (3×)
  12. dry with materialThe combined ethyl acetate extracts were dried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-26fa4b15182240339379626f5ad01ff9
Source dataset
uspto-grants-2012_06
Patent number
US08198331B2

Reaction notes

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