Benzyl 4-oxopiperidine-1-carboxylate → Benzyl 4-[(4-fluorophenyl)methyl]-4-hydroxypiperidine-1-carboxylate

HRID 1710664Notes

Reaction equation

HRID 1710664 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][Mg]Cl)=[CH:21][CH:20]=1>CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:23][C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 643496Benzyl 4-oxopiperidine-1-carboxylateHCID 178505759HCID 178505759, compound

Product 1

HCID 68502893Benzyl 4-[(4-fluorophenyl)methyl]-4-hydroxypiperidine-1-carboxylateYield 25%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
-40 °C

Procedure

To a round bottom flask equipped with a magnetic stirring bar was added 2.94 g of 4-oxo-piperidine-1-carboxylic acid benzyl ester (12.6 mmol, 1.0 equiv) and 25 mL of ether. The flask was fitted with a septum and a nitrogen inlet and cooled to −40° C. A 0.25 M solution of (4-fluoro)benzylmagnesium chloride (50 mL, 12.5 mmol, 1.0 equiv.) was added via syringe over 10 minutes to the reaction solution. After 1 h, the mixture was warmed to room temperature and stirred for 20 h. Then the solution was cooled to 0° C. and quenched with 30 mL of saturated aqueous ammonium-chloride. The aqueous layer was extracted with 100 mL of EtOAc. The combined organic layers were washed with saturated aqueous NaCl (3×25) and dried over MgSO4. The resultant yellow oil was purified by flash chromatography to afford 1.058 g of 4-(4-Fluoro-benzyl)-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (3.08 mmol, 25% yield). The crude product was diluted in methanol (12 mL) and added to a round bottom flask containing a magnetic stirring bar and 200 mg of 10% Pd/C. The flask was evacuated, and back-filled with hydrogen (1 atm). After 24 h of vigorous stirring under nitrogen atmosphere, the solution was filtered through celite and concentrated in vacuo to afford 4-(4-fluoro-benzyl)-piperidin-4-ol (67) in quantitative yield (644 mg): HPLC retention time=0.26 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected=210.1, found 210.1.

Workup

  1. customTo a round bottom flask equipped with a magnetic stirring bar
  2. customThe flask was fitted with a septum and a nitrogen inlet
  3. temperaturethe mixture was warmed to room temperature
  4. temperatureThen the solution was cooled to 0° C.
  5. customquenched with 30 mL of saturated aqueous ammonium-chloride
  6. extractionThe aqueous layer was extracted with 100 mL of EtOAc
  7. washThe combined organic layers were washed with saturated aqueous NaCl (3×25)
  8. dry with materialdried over MgSO4
  9. customThe resultant yellow oil was purified by flash chromatography

Sources & evidence

ORD record
ord-a66e0ae66204441dbe4d75fe55680209
Source dataset
uspto-grants-2010_09
Patent number
US07790726B2

Reaction notes

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