Phosphorus oxychloride → 4-[(2-Fluoro-5-methyl-phenyl)amino]-6-(4-oxo-cyclohexyloxy)-7-methoxy-quinazoline

HRID 1672123Notes

Reaction equation

HRID 1672123 reaction equation
P(Cl)(Cl)(Cl)=O.O=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:27][CH2:26][C:21]4(OCC[O:22]4)[CH2:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][NH:8]1.ClC1C2C(=CC(OC)=C(OC3CCC4(OCCO4)CC3)C=2)N=CN=1.[F:54][C:55]1[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][C:56]=1[NH2:57]>C(#N)C.C(N(CC)CC)C>[F:54][C:55]1[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][C:56]=1[NH:57][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:19][CH2:20][C:21](=[O:22])[CH2:26][CH2:27]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1

Participants

7

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 2629702-Fluoro-5-methylanilineHCID 591582254-Chloro-6-(1,4-dioxa-spiro[4,5]decan-8-yl-oxy)-7-methoxy-quinazolineHCID 1359917776-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-7-methoxy-3H-quinazolin-4-one

Product 1

HCID 581572534-[(2-Fluoro-5-methyl-phenyl)amino]-6-(4-oxo-cyclohexyloxy)-7-methoxy-quinazoline

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 8471TriethylamineSolvent

Conditions

Temperature
40 °C

Procedure

6 ml phosphorus oxychloride are added dropwise to 12.1 g 3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4,5]decan-8-yl-oxy)-7-methoxy-quinazoline in 120 ml acetonitrile and the mixture is heated to an internal temperature of 40° C. Then 9.3 ml triethylamine are added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is cooled to ambient temperature and after standing overnight half the solution of the intermediate product (4-chloro-6-(1,4-dioxa-spiro[4,5]decan-8-yl-oxy)-7-methoxy-quinazoline, see Example IX) is combined dropwise with 2.7 ml of 2-fluoro-5-methylaniline in 5 ml acetonitrile. The reaction mixture is heated to 40° C. for 3 hours, then cooled and evaporated down. The residue is mixed with water and stirred. The precipitate formed is suction filtered and divided between 1M sodium hydroxide solution and dichloromethane. The organic phase is separated off, dried, evaporated down and stirred with diisopropylether. The solid is suction filtered and dried.

Workup

  1. temperaturethe reaction mixture is refluxed for 3 hours
  2. temperatureThe mixture is cooled to ambient temperature
  3. temperatureThe reaction mixture is heated to 40° C. for 3 hours
  4. temperaturecooled
  5. customevaporated down
  6. additionThe residue is mixed with water
  7. customThe precipitate formed
  8. filtrationfiltered
  9. customThe organic phase is separated off
  10. customdried
  11. customevaporated down
  12. stirringstirred with diisopropylether
  13. filtrationfiltered
  14. customdried

Sources & evidence

ORD record
ord-f58dfd88eb564c4db3a52f6672fd5dee
Source dataset
uspto-grants-2011_08
Patent number
US07998949B2

Reaction notes

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