Triethylamine → 4-[4-(3-Chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cyclohexanone

HRID 455910Notes

Reaction equation

HRID 455910 reaction equation
P(Cl)(Cl)(Cl)=O.O1[C:10]2([CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:26]=3[O:27][CH3:28])[N:23]=[CH:22][NH:21][C:20]4=O)[CH2:12][CH2:11]2)[O:9]CC1.C(N(CC)CC)C.[Cl:37][C:38]1[C:39]([F:45])=[C:40]([CH:42]=[CH:43][CH:44]=1)[NH2:41]>C(#N)C>[Cl:37][C:38]1[C:39]([F:45])=[C:40]([NH:41][C:20]2[C:19]3[C:24](=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH:13]4[CH2:12][CH2:11][C:10](=[O:9])[CH2:15][CH2:14]4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:42]=[CH:43][CH:44]=1

Participants

6

Reactant 4

HCID 8471Triethylamine2×HCID 24813Phosphorus oxychlorideHCID 750143-Chloro-2-fluoroaniline2×HCID 1359917776-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-7-methoxy-3H-quinazolin-4-one

Product 1

HCID 581572644-[4-(3-Chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cyclohexanone

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent3×

Conditions

Temperature
40 °C

Procedure

3.25 ml phosphorus oxychloride are added dropwise to 6.50 g 6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-7-methoxy-3H-quinazolin-4-one in 65 ml acetonitrile under an argon atmosphere. Then the reaction mixture is heated to 40° C., combined dropwise with 5.00 ml triethylamine and refluxed for 2 h. After cooling to ambient temperature 1.40 ml triethylamine and 2.60 ml 3-chloro-2-fluoro-aniline, dissolved in 5 ml acetonitrile, are added and the reaction mixture is stirred overnight at 40° C. Then a further 0.70 ml of 3-chloro-2-fluoro-aniline dissolved in 2 ml acetonitrile are added dropwise and the reaction mixture is stirred for a further 10 h. After cooling to ambient temperature the precipitate formed is suction filtered, taken up in 1 N hydrochloric acid, combined with 6 N isopropanolic hydrochloric acid and stirred at ambient temperature until the ketal cleaving is complete. The precipitate formed is suction filtered and combined with methylene chloride and 1 N sodium hydroxide solution. The aqueous phase is separated off and extracted with methylene chloride, the combined extracts are evaporated down and the flask residue is brought to crystallisation with diisopropylether.

Workup

  1. temperaturerefluxed for 2 h
  2. additionare added
  3. additionare added dropwise
  4. stirringthe reaction mixture is stirred for a further 10 h
  5. temperatureAfter cooling to ambient temperature the precipitate
  6. customformed
  7. filtrationfiltered
  8. stirringstirred at ambient temperature until the ketal cleaving
  9. customThe precipitate formed
  10. filtrationfiltered
  11. customThe aqueous phase is separated off
  12. extractionextracted with methylene chloride
  13. customthe combined extracts are evaporated down
  14. customthe flask residue is brought to crystallisation with diisopropylether

Sources & evidence

ORD record
ord-3b8cdb950e7542f186bd59fcbcd25e7c
Source dataset
uspto-grants-2013_07
Patent number
US08497369B2

Reaction notes

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