Water → 1'-Benzyl-5-fluoro-3H-spiro[1-benzofuran-2,4'-piperidine]

HRID 270033Notes

Reaction equation

HRID 270033 reaction equation
[H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2F)([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.O>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1

Participants

6

Reactant 4

HCID 962WaterHCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 598336551-Benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol

Product 1

HCID 598336291'-Benzyl-5-fluoro-3H-spiro[1-benzofuran-2,4'-piperidine]

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
110 °C

Procedure

To a stirring suspension of magnesium strip (763 mg) in diethyl ether (7 mL) was added a crystal of iodine followed by (0.4 mL of 2-(bromomethyl)-1,4-difluorobenzene under nitrogen. The reaction mixture was initiated with a high intensity heat gun, 2-(bromomethyl)-1,4-difluorobenzene 5.0 g, 24.25 mmol) in diethyl ether (7 mL) was added slowly maintaining gentle reflux. After addition was completed the reaction mixture was stirred at reflux for 100 min, cooled to room temperature. To this reaction mixture a solution of 1-benzylpiperidin-4-one (4.57 g, 24.25 mmol) in diethyl ether (12 mL) was added dropwise with vigorous stirring. After addition was completed the reaction mixture was left at room temperature overnight. Aqueous NH4Cl solution was added and stirred at room temperature until hydrolysis was completed, extracted with diethyl ether. The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane, 0.2% NH4OH) to give intermediate 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol (2.74 g) containg large quantities of unknown impurities. To a suspension of NaH (55%, 1.12 g, 26.0 mmol) in toluene (10 mL) was slowly added a solution of 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol in toluene (15 mL). After addition was completed the reaction mixture was stirred at 110° C. (in a pre heated oil bath), after 5 min, DMF (9 mL) was added and stirring was continued at reflux temperature for 2 h. The reaction mixture was cooled to room temperature, H2O (20 mL) was added and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.2% NH4OH) to give the subtitled compound (190 mg).

Workup

  1. additionAfter addition
  2. temperatureheated oil bath), after 5 min
  3. stirringstirring
  4. temperatureat reflux temperature for 2 h
  5. temperatureThe reaction mixture was cooled to room temperature
  6. extractionextracted with ethyl acetate
  7. dry with materialThe organic layer was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.2% NH4OH)

Sources & evidence

ORD record
ord-285c7efed39b4dc4a375aedb112c8d4b
Source dataset
uspto-grants-2008_11
Patent number
US07449475B2

Reaction notes

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