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2-(3-(Trifluoromethyl)benzyl)malonic acid → (2,4-Dichloro-8-methyl-3-(3-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone

HRID 1507315
Notes
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Reaction equation

HRID 1507315 reaction equation
[Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](S(C)(=O)=O)=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[F:33][C:34]([F:50])([F:49])C1C=C(C=CC=1)CC(C(O)=O)C(O)=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:34]([F:50])([F:49])[F:33])[CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

4

Reactant 2

HCID 665199072-(3-(Trifluoromethyl)benzyl)malonic acid2×HCID 86715618(2,4-dichloro-8-methyl-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone2×

Product 1

HCID 118005810(2,4-Dichloro-8-methyl-3-(3-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone

Reagents, catalysts & solvents 1

HCID 24813Phosphorus oxychloride
Solvent

Conditions

Temperature
105 °C

Procedure

A heterogeneous mixture of (4-amino-3-methylphenyl)(1-methyl-1H-imidazol-5-yl)methanone (1.3 g, 6.04 mmol, Intermediate 13: step c), 2-(3-(trifluoromethyl)benzyl)malonic acid (2.06 g, 7.85 mmol, Intermediate 15: step b) and POCl3 (10 mL) was heated at 105° C. for 4 hours. The mixture was cooled to room temperature and concentrated to remove excess POCl3. Ice water was then added and the mixture treated with aqueous NH4OH (kept adding ice during addition) to a basic pH 8-9. The aqueous mixture was extracted with EtOAc (2×). The EtOAc extracts were dried over Na2SO4, evaporated in vacuo and chromatographed (DCM/EtOAc, gradient) to provide the title compound as an off-white solid.

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. concentrationconcentrated
  3. customto remove excess POCl3
  4. additionIce water was then added
  5. additionthe mixture treated with aqueous NH4OH (kept adding ice during addition) to a basic pH 8-9
  6. extractionThe aqueous mixture was extracted with EtOAc (2×)
  7. dry with materialThe EtOAc extracts were dried over Na2SO4
  8. customevaporated in vacuo
  9. customchromatographed (DCM/EtOAc, gradient)

Sources & evidence

ORD record
ord-805e275fc19243b892081fa3c867e471
Source dataset
uspto-grants-2015_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09221804B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes