Benzyl Bromide → (SR)-1,4-dibenzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester

HRID 395909Notes

Reaction equation

HRID 395909 reaction equation
CC(C)([O-])C.[K+].Cl.[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:17](=[O:26])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:24]([O:23][C:21]([C:18]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:19][CH2:20][N:15]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:16][C:17]1=[O:26])=[O:22])[CH3:25]

Participants

6

Reactant 4

HCID 7498Benzyl BromideHCID 25517Ammonium ChlorideHCID 2723880Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochlorideHCID 23665647Potassium tert-butoxide

Product 1

HCID 15511748(SR)-1,4-dibenzyl-3-oxo-piperidine-4-carboxylic acid ethyl esterYield 99.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A mixture of 38.3 g (341.0 mmol) potassium tert.-butoxide and 625 ml absolute tetrahydrofuran was stirred at room temperature for 0.5 h. The resulting milky solution was cooled to 0° C. and then 50.0 g (168.0 mmol) ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride were added via a powder dropping funnel. The temperature was kept below 5° C. The mixture was warmed up to room temperature and further stirred for 1 h resulting in a yellow solution. After cooling to 0° C., a solution of 30.2 g (176.0 mmol) benzyl bromide in 20.0 ml of absolute tetrahydrofuran was dropwise added in 0.5 h. A maximum temperature of 2° C. was observed. The reaction mixture was warmed to room temperature and stirred for 4 h. The reaction solution was cooled to 0° C. and 200 ml saturated ammonium chloride solution was slowly added. After extraction and phase separation, the aqueous phase was extracted twice with 100 ml of ethyl acetate. The combined organic phase were washed twice with 100 ml of saturated sodium chloride solution, dried over Na2SO4, the solvent evaporated under reduced pressure and the residue dried to yield 58.3 g (99.3%) crude product. MS (ISP): 352 (100, [M+H]+), 174 (15).

Workup

  1. temperatureThe resulting milky solution was cooled to 0° C.
  2. customwas kept below 5° C
  3. temperatureThe mixture was warmed up to room temperature
  4. stirringfurther stirred for 1 h
  5. customresulting in a yellow solution
  6. temperatureAfter cooling to 0° C.
  7. customA maximum temperature of 2° C.
  8. temperatureThe reaction mixture was warmed to room temperature
  9. stirringstirred for 4 h
  10. temperatureThe reaction solution was cooled to 0° C.
  11. extractionAfter extraction and phase separation
  12. extractionthe aqueous phase was extracted twice with 100 ml of ethyl acetate
  13. washThe combined organic phase were washed twice with 100 ml of saturated sodium chloride solution
  14. dry with materialdried over Na2SO4
  15. customthe solvent evaporated under reduced pressure
  16. customthe residue dried

Sources & evidence

ORD record
ord-b3ef866e5f194c00b932b99a9ea05507
Source dataset
uspto-grants-2003_08
Patent number
US06605723B2

Reaction notes

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