Thioanisole → 4-Chloro-7-fluoro-6-hydroxy-3-quinolinecarbonitrile

HRID 1837336Notes

Reaction equation

HRID 1837336 reaction equation
C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]=[CH:14][C:13]([C:20]#[N:21])=[C:12]2[Cl:22])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O.CO.C(OCC)(=O)C>[Cl:22][C:12]1[C:11]2[C:16](=[CH:17][C:18]([F:19])=[C:9]([OH:8])[CH:10]=2)[N:15]=[CH:14][C:13]=1[C:20]#[N:21]

Participants

6

Reactant 2

HCID 7520ThioanisoleHCID 234981164-Chloro-7-fluoro-6-(phenylmethoxy)-3-quinolinecarbonitrile

Product 1

HCID 234980764-Chloro-7-fluoro-6-hydroxy-3-quinolinecarbonitrileYield 49.9%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6422Trifluoroacetic acidSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 6-benzyloxy-4-chloro-7-fluoro-3-quinolinecarbonitrile (733 mg, 2.34 mmol) and 1 mL of thioanisole in 12 mL of trifluoroacetic acid is heated at reflux for 9 hours then concentrated in vacuo. The residue is treated with ice water and then basified to pH 9-10 by the addition of aqueous ammonium hydroxide. The resultant solid is collected by filtration and washed with diethyl ether. The filtrate is extracted with 10% methanol in ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is combined with the solid obtained initially, and this material is dissolved in 5% methanol in ethyl acetate and absorbed onto silica gel. Purification by flash column chromatography eluting with a gradient of hexane to increasing amounts of ethyl acetate in hexane to 5% methanol in ethyl acetate provides 260 mg of 4-chloro-7-fluoro-6-hydroxy-3-quinolinecarbonitrile, mp>250° C.

Workup

  1. temperatureis heated
  2. temperatureat reflux for 9 hours
  3. concentrationthen concentrated in vacuo
  4. additionThe residue is treated with ice water
  5. additionbasified to pH 9-10 by the addition of aqueous ammonium hydroxide
  6. filtrationThe resultant solid is collected by filtration
  7. washwashed with diethyl ether
  8. extractionThe filtrate is extracted with 10% methanol in ethyl acetate
  9. dry with materialThe organic layer is dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customobtained initially
  13. customabsorbed onto silica gel
  14. customPurification by flash column chromatography
  15. washeluting with a gradient of hexane
  16. temperatureto increasing amounts of ethyl acetate in hexane to 5% methanol in ethyl acetate

Sources & evidence

ORD record
ord-d12f57bd227344fe8aa23f49c77d2d8d
Source dataset
uspto-grants-2004_08
Patent number
US06780996B2

Reaction notes

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