Benzyl Bromide → Methyl 2-Benzyl-3-[4-(4-Chlorophenyl)-4-fluoropiperidin-1-yl]propionate Hydrochloride

HRID 537206Notes

Reaction equation

HRID 537206 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:20])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[ClH:1].[CH2:31]([CH:15]([CH2:14][N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([F:20])[CH2:13][CH2:12]1)[C:16]([O:18][CH3:19])=[O:17])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1

Participants

5

Reactant 3

HCID 7498Benzyl BromideHCID 2733832Lithium HexamethyldisilazideHCID 67462732Methyl 3-[4-(4-Chlorophenyl)-4-fluoropiperidin-1-yl]propionate

Product 1

HCID 67460614Methyl 2-Benzyl-3-[4-(4-Chlorophenyl)-4-fluoropiperidin-1-yl]propionate HydrochlorideYield 44%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A solution of methyl 3-[4-(4-chlorophenyl)-4-fluoropiperidin-1-yl]propionate (75 mg, 0.23 mmol) in toluene (5 mL) was placed under a dry nitrogen atmosphere and cooled in a dry ice acetone bath. A 1M solution of lithium hexamethyldisilazide (0.28 mL, 0.28 mmol) was then added drop-wise over 10 minutes. The resulting bright yellow solution was stirred for 1 hour then benzyl bromide (43 mg, 0.25 mmol) added in one portion. The reaction was then allowed to warm to room temperature with stirring over a 16 hour period then quenched by the addition of 25% aqueous ammonium chloride solution (10 mL). The resulting mixture was extracted with ethyl acetate (2×10 mL) and the combined extracts dried over magnesium sulfate, filtered and stripped to a viscous yellow oil. This oil was treated with 10% methanolic hydrogen chloride (5 mL) and the solution re-concentrated. The resulting oil was triturated with 1:1 ethyl acetate/heptanes (10 mL) to afford a light yellow solid which was collected by filtration. After drying under vacuum for 12 hours methyl 2-benzyl-3-[4-(4-chlorophenyl)-4-fluoropiperidin-1-yl]propionate hydrochloride was obtained as a light yellow solid in 44% yield.

Workup

  1. temperaturecooled in a dry ice acetone bath
  2. stirringwith stirring over a 16 hour period
  3. customthen quenched by the addition of 25% aqueous ammonium chloride solution (10 mL)
  4. extractionThe resulting mixture was extracted with ethyl acetate (2×10 mL)
  5. dry with materialthe combined extracts dried over magnesium sulfate
  6. filtrationfiltered
  7. additionThis oil was treated with 10% methanolic hydrogen chloride (5 mL)
  8. concentrationthe solution re-concentrated
  9. customThe resulting oil was triturated with 1:1 ethyl acetate/heptanes (10 mL)
  10. customto afford a light yellow solid which
  11. filtrationwas collected by filtration
  12. dry with materialAfter drying under vacuum for 12 hours methyl 2-benzyl-3-[4-(4-chlorophenyl)-4-fluoropiperidin-1-yl]propionate hydrochloride
  13. customwas obtained as a light yellow solid in 44% yield

Sources & evidence

ORD record
ord-ca3429c7248e464d9367625879536743
Source dataset
uspto-grants-2014_10
Patent number
US08859777B2

Reaction notes

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