Sodium hydride → (3R)-tert-butyl 3-((3-chlorophenyl)(3-ethoxy-3-oxopropoxy)methyl)piperidine-1-carboxylate

HRID 451665Notes

Reaction equation

HRID 451665 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:24])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1.[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30]Br)[CH3:26]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([O:24][CH2:30][CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:32])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 68320Ethyl 3-bromopropionateHCID 59201373(R)-tert-butyl 3-((3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate

Product 1

HCID 59201378(3R)-tert-butyl 3-((3-chlorophenyl)(3-ethoxy-3-oxopropoxy)methyl)piperidine-1-carboxylateYield 41%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

To a slurry of NaH (0.835 g, 0.0348 mol) in DMF (50 mL) was added a solution of (R)-tert-butyl 3-((3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (3.8 g, 0.0116 mol) in DMF (30 mL) dropwise at −15˜−5° C. and the reaction mixture was stirred for about 1 h at rt. A solution of 3-bromopropionic acid ethyl ester (4.2 g, 0.0232 mol) in DMF (30 mL) was added to the reaction mixture dropwise while the temperature was maintained at −15˜−5° C. and the mixture was warmed slowly to rt and stirred overnight. The reaction was cooled in an ice bath and quenched with satd aq NH4Cl (80 mL). The product was extracted with EtOAc, washed with brine, dried over NaSO4 and purified by flash chromatography to afford (3R)-tert-butyl 3-((3-chlorophenyl)(3-ethoxy-3-oxopropoxy)methyl)piperidine-1-carboxylate (2.0 g, 4.71 mmol, 41%). 1H NMR (400 MHz, CDCl3): 1.12-1.37 (m, 4H), 1.45 (s, 9H), 1.47-1.75 (m, 3H), 1.82-1.93 (m, 1H), 2.50-2.58 (m, 4H), 3.43-3.52 (m, 2H), 3.80-4.01 (m, 2H), 4.07-4.17 (m, 3H), 7.13-7.23 (m, 1H), 7.25-7.27 (m, 3H). MS (E/Z): 426 (M+H+).

Workup

  1. temperaturewas maintained at −15˜−5° C.
  2. temperaturethe mixture was warmed slowly to rt
  3. stirringstirred overnight
  4. temperatureThe reaction was cooled in an ice bath
  5. customquenched with satd aq NH4Cl (80 mL)
  6. extractionThe product was extracted with EtOAc
  7. washwashed with brine
  8. dry with materialdried over NaSO4
  9. custompurified by flash chromatography

Sources & evidence

ORD record
ord-b23a6399661f4894854eb541c0115a83
Source dataset
uspto-grants-2013_07
Patent number
US08487108B2

Reaction notes

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