Hydrochloric Acid → 4-[4-(4-Ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoyl]piperazin-2-one

HRID 467527Notes

Reaction equation

HRID 467527 reaction equation
[CH2:1]([C:3]1[C:19]([F:20])=[CH:18][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[F:17])=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35].C(N(C(C)C)CC)(C)C.Cl>ClCCl.CN(C)C=O>[CH2:1]([C:3]1[C:19]([F:20])=[CH:18][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:32]3[CH2:33][CH2:34][NH:29][C:30](=[O:35])[CH2:31]3)=[O:14])=[CH:10][C:9]=2[F:17])=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 231360Piperazin-2-oneHCID 671160464-(4-Ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid

Product 1

HCID 671162484-[4-(4-Ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoyl]piperazin-2-one

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (55 mg, 0.18 mmol; which may be prepared as described in D2) in dichloromethane (1.8 mL) under Argon cooled at 0° C. were added oxalyl chloride (2M in dichloromethane, 135 μL, 0.27 mmol) and a drop of N,N-dimethylformamide. The mixture was allowed to come to room temperature over 2 hours, and then piperazin-2-one (20 mg, 0.20 mmol) followed by diisopropylethylamine (93 μL, 0.53 mmol) were added. The reaction mixture was cooled to 0° C. and a solution of 1N HCl was added. After stirring a few minutes, dichloromethane was added and the aqueous layer (pH 7) was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel, using dichloromethane/methanol (95:5) as eluent. The title product was obtained as a yellow oil (38 mg, 55%).

Workup

  1. additionwere added
  2. extractionthe aqueous layer (pH 7) was extracted twice with dichloromethane
  3. dry with materialThe combined organic phases were dried over sodium sulfate
  4. filtrationfiltrated
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by preparative thin layer chromatography on silica gel

Sources & evidence

ORD record
ord-49b84cff2d5c4682a0a8779b96b2d8e4
Source dataset
uspto-grants-2014_01
Patent number
US08623865B2

Reaction notes

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