Hydrochloric Acid → Tert-butyl 4-(3,4-difluorobenzyl)-4-hydroxypiperidine-1-carboxylate

HRID 240402Notes

Reaction equation

HRID 240402 reaction equation
[Mg].BrCCBr.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:10]Br.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.Cl.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C.C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:10][C:17]1([OH:16])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 78391,2-DibromoethaneHCID 5814364-(Bromomethyl)-1,2-difluorobenzeneHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5462224MagnesiumHCID 9855836Potassium sodium tartarate

Product 1

HCID 86680862Tert-butyl 4-(3,4-difluorobenzyl)-4-hydroxypiperidine-1-carboxylateYield 59.6%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a suspension of magnesium (1.2 g) and 1,2-dibromoethane (0.11 mL) in diethyl ether (30 mL) was added a solution of 3,4-difluorobenzyl bromide (10 g) in diethyl ether (10 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with THF (30 mL), and cooled to −78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g) in THF (10 mL) was added thereto, and the mixture was allowed to warm to room temperature, and was stirred overnight. To the reaction mixture was added a small amount of 1N hydrochloric acid at 0° C. to quench the reaction. Saturated aqueous potassium sodium tartrate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (4.9 g).

Workup

  1. temperatureto warm to room temperature
  2. stirringwas stirred overnight
  3. customto quench
  4. customthe reaction
  5. extractionthe mixture was extracted with ethyl acetate
  6. washThe extract was washed with saturated brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. customThe solvent was evaporated under reduced pressure
  9. customThe residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane)
  10. customrecrystallized from ethyl acetate/hexane

Sources & evidence

ORD record
ord-ae60388cf0d74ed984811a1dad1465ac
Source dataset
uspto-grants-2014_02
Patent number
US08648079B2

Reaction notes

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