1-Chloro-4-(chloromethyl)benzene → HCID 53361740, compound

HRID 1023378Notes

Reaction equation

HRID 1023378 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][N:10]=1.[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49]Cl)=[CH:47][CH:46]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:49][C:48]2[CH:51]=[CH:52][C:45]([Cl:44])=[CH:46][CH:47]=2)=[CH:11][N:10]=1

Participants

5

Reactant 3

HCID 77231-Chloro-4-(chloromethyl)benzeneHCID 24758Sodium hydrideHCID 67354960HCID 67354960, compound

Product 1

HCID 53361740HCID 53361740, compoundYield 87.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (E)-3-{3-chloro-4-[(5-hydroxypyridin-2-yl)oxy]-5-methylphenyl}-1-(4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (479 mg) and p-chlorobenzyl chloride (129 mg) in DMF (5.0 mL) was added NaH (41.6 mg, 60% in mineral oil) at 0° C. Then the reaction mixture was stirred over night at room temperature. The reaction mixture was quenched by addition of saturated aqueous NH4Cl, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/0 to 9/1) to afford (E)-3-[3-chloro-4-({5-[(4-chlorobenzyl)oxy]pyridin-2-yl}oxy)-5-methylphenyl]-1-(4-{4-[2-(4-methylphenoxy)-ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (507 mg) as a colorless amorphous. To a solution of that amorphous (507 mg) in EtOH (10 mL) was added 6 M aqueous HCl (0.129 mL) at room temperature, then the reaction mixture was stirred for 3 hours. The reaction mixture was filtered off, and the precipitate was dried at 50° C. under reduced pressure to afford (E)-3-[3-chloro-4-({5-[(4-chlorobenzyl)oxy]pyridin-2-yl}oxy)-5-methylphenyl]-1-(4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one hydrochloride (486 mg) as a colorless crystal.

Workup

  1. customThe reaction mixture was quenched by addition of saturated aqueous NH4Cl
  2. extractionextracted with AcOEt
  3. washThe organic layer was washed with water and saturated aqueous NaCl
  4. dry with materialdried over anhydrous Na2SO4
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/0 to 9/1)

Sources & evidence

ORD record
ord-e00c0e32dce74f4e948a4ff6b76d5d58
Source dataset
uspto-grants-2014_05
Patent number
US08722663B2

Reaction notes

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