Methanol → Tert-butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2-fluorophenyl)piperidine-1-carboxylate

HRID 391462Notes

Reaction equation

HRID 391462 reaction equation
[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH2:34][OH:35])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.CC(C)([O-])C.[K+].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:35][CH2:34][C:21]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1

Participants

6

Reactant 4

HCID 887Methanol2×HCID 223242723-Bromo-5-(trifluoromethyl)benzyl bromideHCID 23665647Potassium tert-butoxide2×HCID 58993673Tert-butyl 4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate

Product 1

HCID 58993612Tert-butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2-fluorophenyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A flask was charged with 1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (0.149 g, 0.47 mmol) and tert-butyl 4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.112 g, 0.36 mmol) in tetrahydrofuran (2 mL) at 0° C. The reaction was treated with potassium tert-butoxide (0.41 mg, 0.36 mmol), stirred at 0° C. for 20 min, and treated with another aliquot of potassium tert-butoxide (0.41 mg, 0.36 mmol). The reaction was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was evaporated in vacuo and the crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→30% ethyl acetate/70% hexanes) to afford 0.138 g (70%) of the desired ether. Mass spec.: 546.03 (MH)+ LC tr=4.501 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).

Workup

  1. temperatureto warm to room temperature
  2. stirringwas stirred for 16 h
  3. customThe reaction mixture was evaporated in vacuo
  4. customthe crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→30% ethyl acetate/70% hexanes)
  5. customto afford 0.138 g (70%) of the desired ether

Sources & evidence

ORD record
ord-e57606b6137d413cac4ff10b1abd9223
Source dataset
uspto-grants-2013_02
Patent number
US08383821B2

Reaction notes

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