Dimethylformamide → (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate

HRID 218399Notes

Reaction equation

HRID 218399 reaction equation
[H-].[Na+].CN(C=O)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C@H:15]([OH:29])[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:14]=1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C@H:15]([O:29][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17]2)[CH:14]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 7748Ethyl bromoacetateHCID 24758Sodium hydrideHCID 58011541(R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate

Product 1

HCID 58011572(R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylateYield 40%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a suspension of NaH (5.64 g, 0.141 mol) in the mixed solvent of DMF (70 mL) and THF (70 mL) at −25° C. was added dropwise a solution of (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate (16 g, 47 mmol) in anhydrous THF (100 mL), the reaction mixture was stirred for 1 hr at rt. A solution of ethyl bromoacetate (15.6 g, 94 mmol) in anhydrous THF (70 mL) was added dropwise to the above mixture at −10-−5° C. After addition, the reaction mixture was stirred for 2-3 hr at rt. The reaction was quenched with saturated NH4Cl solution (100 mL) and EtOAc (500 mL) was added. The organic layer was washed with water (5×50 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (8 g, 18.8 mmol).

Workup

  1. additionAfter addition
  2. stirringthe reaction mixture was stirred for 2-3 hr at rt
  3. customThe reaction was quenched with saturated NH4Cl solution (100 mL) and EtOAc (500 mL)
  4. additionwas added
  5. washThe organic layer was washed with water (5×50 mL) and brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by column chromatography

Sources & evidence

ORD record
ord-fbdf6b5147594518bfc88cd2859734f8
Source dataset
uspto-grants-2012_06
Patent number
US08198453B2

Reaction notes

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