tert-Butyl 4-oxopiperidine-1-carboxylate → 1-(4-[1-(Tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]phenyl}cyclopropanecarboxylic acid

HRID 969124Notes

Reaction equation

HRID 969124 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Mg]CCCC)CCC.C([Li])CCC.[O:28]=[C:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1>CCCCCCC.CCCCCC.C1COCC1>[C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)([OH:28])[CH2:30][CH2:31]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]

Participants

8

Reactant 4

HCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 162279661-(4-Bromophenyl)cyclopropane-1-carboxylic acidHCID 178418339ButyllithiumHCID 178448196HCID 178448196, compound

Product 1

HCID 666615921-(4-[1-(Tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]phenyl}cyclopropanecarboxylic acid

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolventHCID 8900HeptaneSolvent

Procedure

A solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (1000.0 mg, 0.0041480 mol) in tetrahydrofuran (30 mL, 0.4 mol) was cooled below −20° C. under a N2 atmosphere and dibutylmagnesium in heptane (1.0 M, 2.2 mL) was slowly added to the solution while the reaction temperature was maintained below −20° C. Then 2.5 M of n-butyllithium in hexane (1.8 mL) was slowly added to the mixture below −20° C. under effective stirring. After stirring below −20° C. for 1 h, a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (0.909 g, 0.00456 mol) in THF (20.0 mL) was added to the mixture below −20° C. After stirring below −20° C. for 1 h, the reaction was quenched with ammonium chloride. The product was extracted with EtOAc and the combined extract was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and then purified by Combiflash, eluting with 5% methanol in methylene chloride.

Workup

  1. temperaturewas maintained below −20° C
  2. stirringAfter stirring below −20° C. for 1 h
  3. customthe reaction was quenched with ammonium chloride
  4. extractionThe product was extracted with EtOAc
  5. extractionthe combined extract
  6. washwas washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated
  10. custompurified by Combiflash
  11. washeluting with 5% methanol in methylene chloride

Sources & evidence

ORD record
ord-e1d2cfed3d6b4fd29a5995317846153f
Source dataset
uspto-grants-2007_12
Patent number
US07304081B2

Reaction notes

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