1-[(3-Methoxyphenyl)methyl]piperidin-4-one → 4-(3-Chloro-4-fluorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol

HRID 2167516Notes

Reaction equation

HRID 2167516 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[CH2:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]2([OH:23])[CH2:19][CH2:18][N:17]([CH2:16][C:15]3[CH:24]=[CH:25][CH:26]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:22][CH2:21]2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

4

Reactant 2

HCID 119595401-[(3-Methoxyphenyl)methyl]piperidin-4-oneHCID 178505834HCID 178505834, compound

Product 1

HCID 667642824-(3-Chloro-4-fluorophenyl)-1-(3-methoxybenzyl)piperidin-4-olYield 26%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To (3-chloro-4-fluorophenyl)magnesium bromide (6.8 ml of a 0.5 M solution in tetrahydrofuran, 3.4 mmol) was added a solution of 1-(3-methoxybenzyl)piperidin-4-one (500 mg, 2.28 mmol) from Step B of Example 12 in tetrahydrofuran (10 mL). The reaction mixture was stirred at ambient temperature for 3 h and then was quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate (2×) and the combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (10% ethyl acetate/methylene chloride to ethyl acetate) gave 4-(3-chloro-4-fluorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol (209 mg, 26%): 1H NMR (CDCl3, 500 MHz) δ 7.59-7.55 (m, 1H), 7.39-7.33 (m, 1H), 7.27-7.22 (m, 1H), 7.13-7.07 (m, 1H), 6.95-6.93 (m, 2H), 6.83-6.80 (m, 1H), 3.84 (s, 3H), 3.60-3.55 (m, 2H), 2.82-2.73 (m, 2H), 2.48-2.40 (m, 2H), 2.18-2.02 (m, 2H), 1.72-1.68 (m, 2H), 1.59-1.56 (m, 1H).

Workup

  1. customwas quenched with saturated ammonium chloride
  2. extractionThe mixture was extracted with ethyl acetate (2×)
  3. washthe combined organics were washed with brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customPurification by silica gel chromatography (10% ethyl acetate/methylene chloride to ethyl acetate)

Sources & evidence

ORD record
ord-deaca81e80f349ea937622da5a413070
Source dataset
uspto-grants-2015_06
Patent number
US09045468B2

Reaction notes

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