Phenol → 1-Benzhydryl-3-phenoxyazetidine

HRID 72399

Reaction equation

HRID 72399 reaction equation
[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH:15]1[CH2:18][N:17]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1)(=O)=O>C1(C)C=CC=CC=1>[CH:19]([N:17]1[CH2:18][CH:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16]1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1

Participants

5

Reactant 3

HCID 996PhenolHCID 24758Sodium hydrideHCID 27587161-(Diphenylmethyl)azetidin-3-yl methanesulfonate

Product 1

HCID 28175781-Benzhydryl-3-phenoxyazetidineYield 40%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
60 °C

Procedure

Phenol (2.2 g, 23.4 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 937 mg, 23.4 mmol) in toluene (40 ml) and the mixture was heated at 60° C. for 2 hours. The temperature was then increased to 80° C. and a solution of 1-benzhydrylazetidin-3-yl methanesulfonate (D19) (4.78 g, 14.6 mmol) in toluene (80 ml) was added dropwise. After stirred at 80° C. for 2 hours, the resulting mixture was cooled to room temperature, then washed with water (100 ml) and brine (100 ml), dried over Na2SO4, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate from 30:1 to 20:1. Collected fractions after solvent evaporation were further purified by preparative HPLC to afford the title compound (D20) (1.84 g) as a white solid.

Workup

  1. temperatureThe temperature was then increased to 80° C.
  2. temperaturethe resulting mixture was cooled to room temperature
  3. washwashed with water (100 ml) and brine (100 ml)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. customevaporated in vacuo
  7. customThe crude residue was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate from 30:1 to 20:1
  8. customCollected fractions after solvent evaporation
  9. customwere further purified by preparative HPLC

Sources & evidence

ORD record
ord-bf882239aee74feb95c3fe1051f93979
Source dataset
uspto-grants-2014_09
Patent number
US08828987B2

Linked notes

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