Water → HCID 21902000, compound

HRID 1160372Notes

Reaction equation

HRID 1160372 reaction equation
OS([O-])(=O)=O.[Na+].O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:41])[CH2:20][CH2:19][CH:18]([C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[CH2:24]3)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOC(C)=O.CCCCCC.CCOCC>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:41])[CH2:16][CH2:17][CH:18]([CH2:21][N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([CH2:29][O:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=4)[CH2:24]3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1

Participants

8

Reactant 4

HCID 962WaterHCID 516919Sodium BisulfateHCID 21226445Aluminium lithium hydrideHCID 21902058HCID 21902058, compound

Product 1

HCID 21902000HCID 21902000, compound

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×HCID 21226206Ethyl acetate hexaneSolvent

Conditions

Temperature
0 °C

Procedure

A portion of this ketone (105 mg, 0.27 mmol) amide mixture was dissolved in 2 mL of THF at 0° C. and p-C1-phenyl magnesium bromide (0.68 mL of a 1M solution, 2.5 equivalents) was added via syringe. After 30 minutes, 2 mL of 1M NaHSO4 solution was added, followed by 15 mL of water and 15 mL of ether. Extractive workup gave, after concentration of the organic layers in vacuo and chromatography on silica gel using a EtOAc-hexane gradient column, the desired Grignard adduct [4-(4-Chloro-phenyl)-4-hydroxy-cyclohexyl]-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-methanone (88 mg, 65%; MS 478=M+1 minus water). A portion of this material (41 mg, 0.083 mmol) was dissolved in 2 mL of THF and excess lithium aluminum hydride (31 mg, ca 10 equivalents) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 1 mL 1M NaOH. Additional THF (10 mL) was added, and the suspension was stirred at room temperature for 30 minutes and then filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 1-(4-Chloro-phenyl)-4-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-ylmethyl]-cyclohexanol (187) was obtained (28 mg, 70%). MS 482 (M++1), 464 (M++1 minus water).

Workup

  1. customExtractive workup gave
  2. temperatureThe solution was heated
  3. temperatureto reflux for 5 minutes
  4. customquenched by dropwise addition of 1 mL 1M NaOH
  5. additionAdditional THF (10 mL) was added
  6. filtrationfiltered though a plug of sodium sulfate
  7. customThe solution thus obtained
  8. concentrationwas concentrated in vacuo
  9. customthe residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide

Sources & evidence

ORD record
ord-346123f5f17541d2932f5dfec2293d5d
Source dataset
uspto-grants-2010_10
Patent number
US07816375B2

Reaction notes

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