Ammonium Chloride → tert-Butyl 4-(2,4-difluorophenyl)-4-hydroxypiperidine-1-carboxylate

HRID 238255Notes

Reaction equation

HRID 238255 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[F:9])([OH:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]

Participants

5

Reactant 3

HCID 25517Ammonium ChlorideHCID 676741-Bromo-2,4-difluorobenzeneHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylate

Product 1

HCID 49760229tert-Butyl 4-(2,4-difluorophenyl)-4-hydroxypiperidine-1-carboxylateYield 89.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

1-Bromo-2,4-difluoro-benzene (0.67 g, 3.5 mmol) was dissolved in THF (5 mL) and cooled to 0° C. Isopropylmagnesium chloride lithium chloride complex in THF (1.3 M, 2.5 mL, 3.2 mmol) was added. The mixture was stirred for 0.5 hours then added dropwise to a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.5 mmol) in THF (10 mL) that had been cooled to −78° C. The mixture was allowed to warm to room temperature then cooled to −78° C. and a solution of saturated aqueous ammonium chloride was added and the mixture extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 0-50% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.7 g) as a clear, colourless oil. LCMS m/z 314.3 [M+H]+. R.T.=4.65 min (Analytical Method 4).

Workup

  1. temperaturehad been cooled to −78° C
  2. temperatureto warm to room temperature
  3. temperaturethen cooled to −78° C.
  4. extractionthe mixture extracted into ethyl acetate
  5. dry with materialdried over magnesium sulphate
  6. filtrationfiltered
  7. customthe solvent removed by evaporation under vacuum
  8. customThe residue was purified by flash chromatography on silica eluting with 0-50% ethyl acetate/hexane
  9. additionThe fractions containing the desired product
  10. concentrationwere concentrated under vacuum

Sources & evidence

ORD record
ord-ab4ce5e131604b66abd9e392cc7547b0
Source dataset
uspto-grants-2014_02
Patent number
US08642621B2

Reaction notes

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