Anisole → 7-(Benzyloxy)-4-chloro-6-methoxyquinazoline

HRID 407269Notes

Reaction equation

HRID 407269 reaction equation
[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22].C(N(CC)CC)C.C1(OC)C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 7519AnisoleHCID 11130Triethylamine hydrochlorideHCID 81531DiisopropylethylamineHCID 1354047187-Benzyloxy-6-methoxy-3H-quinazolin-4-one

Product 1

HCID 106619987-(Benzyloxy)-4-chloro-6-methoxyquinazoline

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
15 °C

Procedure

7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (28 kg) and triethylamine hydrochloride (2.7 kg) were added to anisole (244 kg). N,N-Diisopropylethylamine (19.2 kg) was added, followed by a line wash of anisole (20 kg). The mixture was cooled to 15° C. and phosphorus oxychloride (19.8 kg) added over 5 minutes, followed by a line wash of anisole (13.9 kg). After stirring for 15 minutes the mixture was heated to 80° C. over 90 minutes and held at 80° C. for 1 hour. When the reaction was complete the batch was transferred to a new reactor, followed by a line wash of anisole (39.7 kg). The mixture was cooled to 40° C. and 16.19% w/w aqueous sodium hydroxide solution (132 kg) added over 15 minutes, allowing the temperature to rise to 50° C., followed by a line wash of water (5 kg). The mixture was held at 50° C. for 30 minutes, then heated to 80° C. The batch was filtered through a Gaf filter, followed by a line-wash of anisole (10 kg). The lower aqueous layer was separated and the upper organic layer washed at 80° C. with 20.9% w/w aqueous sodium chloride solution (98.2 kg). The mixture was distilled under reduced pressure (80 mbar) to leave a residual volume of 224 l. 1-Methyl-2-pyrrolidinone (28.9) was added and the mixture heated to 80° C. to give a solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline.

Workup

  1. washwash of anisole (20 kg)
  2. additionphosphorus oxychloride (19.8 kg) added over 5 minutes
  3. washwash of anisole (13.9 kg)
  4. temperaturewas heated to 80° C. over 90 minutes
  5. waitheld at 80° C. for 1 hour
  6. customwas transferred to a new reactor
  7. washwash of anisole (39.7 kg)
  8. temperatureThe mixture was cooled to 40° C.
  9. addition16.19% w/w aqueous sodium hydroxide solution (132 kg) added over 15 minutes
  10. customto rise to 50° C.
  11. washwash of water (5 kg)
  12. waitThe mixture was held at 50° C. for 30 minutes
  13. temperatureheated to 80° C
  14. filtrationThe batch was filtered through a Gaf
  15. filtrationfilter
  16. washa line-wash of anisole (10 kg)
  17. customThe lower aqueous layer was separated
  18. washthe upper organic layer washed at 80° C. with 20.9% w/w aqueous sodium chloride solution (98.2 kg)
  19. distillationThe mixture was distilled under reduced pressure (80 mbar)
  20. customto leave a residual volume of 224 l
  21. temperaturethe mixture heated to 80° C.

Sources & evidence

ORD record
ord-c044101d16034f98b91808d0c5fc5795
Source dataset
uspto-grants-2014_06
Patent number
US08754240B2

Reaction notes

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