2-Bromo-1,4-difluorobenzene → Tert-butyl 4-[(2,5-difluorophenyl)(hydroxy)methyl]piperidine-1-carboxylate

HRID 1373363

Reaction equation

HRID 1373363 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1Br.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:28]([OH:29])[CH:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][CH2:24]1

Participants

5

Reactant 3

HCID 678622-Bromo-1,4-difluorobenzeneHCID 1514430tert-Butyl 4-formylpiperidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 69344572Tert-butyl 4-[(2,5-difluorophenyl)(hydroxy)methyl]piperidine-1-carboxylateYield 34%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 2,5-difluoro-1-bromobenzene (24.5 g, 127 mmol) in anhydrous tetrahydrofuran (400 ml) at −78° C. was added n-butyllithium (1.6M, 80 ml, 128 mmol). The solution was stirred for 15 minutes tert-butyl-4-formyl-piperidine-1-carboxylate (27.0 g, 127 mmol) added slowly in THF (50 ml). The mixture was allowed to warm to room temperature and stirred for 16 hours, quenched with water (200 ml) and extracted with ethyl acetate (3×150 ml). The combined organics were washed with water (50 ml), dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 3 to 10% ethyl acetate in iso hexanes to yield (RS)-tertbutyl 4-[(2,5-difluorophenyl)-hydroxymethyl]-piperidine-1-carboxylate as a colourless oil (14 g, 34%).

Workup

  1. customquenched with water (200 ml)
  2. extractionextracted with ethyl acetate (3×150 ml)
  3. washThe combined organics were washed with water (50 ml)
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. customThe residue was purified by flash chromatography
  7. washeluting with 3 to 10% ethyl acetate in iso hexanes

Sources & evidence

ORD record
ord-203eaa1b5f8c4c2393b62ec513ff30f7
Source dataset
uspto-grants-2007_01
Patent number
US07161006B2

Linked notes

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