Triethylamine → N-(4-Fluorophenyl)-N'-(2-fluoro-4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide

HRID 2265681Notes

Reaction equation

HRID 2265681 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:54]=1[F:60]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:52][C:53]3[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:54]=3[F:60])=[O:16])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 448869124-Amino-3-fluorophenol hydrochloride

Product 1

HCID 59596967N-(4-Fluorophenyl)-N'-(2-fluoro-4-hydroxyphenyl)cyclopropane-1,1-dicarboxamideYield 39%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.02 g) in N,N-dimethylformamide (5.0 ml) were added triethylamine (1.28 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.03 g), followed by stirring at room temperature for 5 min. To this was added 4-amino-3-fluorophenol hydrochloride (500 mg), followed by stirring at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with a 1N aqueous solution of sodium hydroxide. To the aqueous layer was added 5N hydrochloric acid to make it acidic, this was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as a pale red solid (395 mg, 39%).

Workup

  1. stirringby stirring at room temperature for 3 days
  2. customThe reaction mixture was partitioned between ethyl acetate
  3. washThe organic layer was washed with a 1N aqueous solution of sodium hydroxide
  4. additionTo the aqueous layer was added 5N hydrochloric acid
  5. extractionthis was extracted with ethyl acetate
  6. washThe organic layer was washed with brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. customThe solvent was removed
  9. customthe residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2)
  10. additionFractions containing the target compound
  11. concentrationwere concentrated under reduced pressure

Sources & evidence

ORD record
ord-0005aa4d3b064fb9acc31f8747e2cdf1
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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