Methanol → tert-Butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluorophenyl)piperidine-1-carboxylate

HRID 391372Notes

Reaction equation

HRID 391372 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:22][OH:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([CH2:35]Br)[CH:26]=1.CC(C)([O-])C.[Na+].CO>O1CCCC1.C(=O)(O)[O-].[Na+]>[Br:24][C:25]1[CH:26]=[C:27]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:35][O:23][CH2:22][C:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]1

Participants

7

Reactant 4

HCID 887Methanol2×HCID 223242723-Bromo-5-(trifluoromethyl)benzyl bromideHCID 23676156Sodium t-butoxide2×HCID 58993620Tert-butyl 4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate

Product 1

HCID 58993590tert-Butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluorophenyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
0 °C

Procedure

tert-Butyl 4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (220 mg, 0.67 mmol) and 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (450 mg, 1.41 mmol) were combined in tetrahydrofuran (2 mL) and cooled to 0° C. The reaction was treated with sodium tert-butoxide (75 mg, 0.355 mmol) and stirred at 0° C. for 20 min. The reaction was treated with another aliquot of sodium tert-butoxide (75 mg, 0.355 mmol), allowed to warm to room temperature, and stirred for 30 min. The reaction was diluted with 10% sodium bicarbonate and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (1×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (0%→25% ethyl acetate/hexanes) gave 200 mg (50%). Mass spec.: 586.04 (MH)+ LC tr=2.552 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 30 min
  3. extractionextracted with ethyl acetate (2×)
  4. washwashed with brine (1×)
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated
  7. customColumn chromatography on silica gel (0%→25% ethyl acetate/hexanes) gave 200 mg (50%)

Sources & evidence

ORD record
ord-dc02d44b7738430d8a12db7e6355492c
Source dataset
uspto-grants-2013_02
Patent number
US08383821B2

Reaction notes

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