4-Aminobenzonitrile → 4-(7-Hydroxy-2-isopropyl-4-oxoquinazolin-3(4H)-yl)benzonitrile

HRID 1801695Notes

Reaction equation

HRID 1801695 reaction equation
[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][C:12](=O)[CH:13]([CH3:15])[CH3:14])[CH:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(C#N)(C)=O.P(Cl)(Cl)Cl.[OH-].[Na+]>O>[OH:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:17]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[C:12]([CH:13]([CH3:15])[CH3:14])=[N:11]2)=[CH:9][CH:10]=1

Participants

7

Reactant 5

HCID 133964-AminobenzonitrileHCID 14798Sodium HydroxideHCID 24387Phosphorus trichlorideHCID 694302-OxopropiononitrileHCID 59438295HCID 59438295, compound

Product 1

HCID 251383634-(7-Hydroxy-2-isopropyl-4-oxoquinazolin-3(4H)-yl)benzonitrileYield 75.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
22 °C

Procedure

A 2-L Argonaut reactor, equipped with pitched-blade impeller, RTD sensor, reflux condenser, addition funnel, and nitrogen inlet-outlet, was charged with 54.90 g (246.0 mmol) of 4-hydroxy-2-isobutyrylamino-benzoic acid (5), 31.96 g (270.6 mmol) of 4-aminobenzonitrile (6) and 919.2 g (1.177 L) of AcCN. The suspension was stirred at 22±3° C. for 30 min with an efficient mixing, and 70.97 g (45.09 mL, 516.7 mmol) of PCl3 were added while maintaining an internal temperature of 22±10° C. The suspension was then warmed to an internal temperature of 60±3° C. over 1 h, and the mixture was stirred at 60±3° C. for 20 h with an efficient mixing. The suspension was cooled to an internal temperature of 15±3° C. over 30 min, and then 54.275 g (1356.87 mmol) of NaOH in 220 g of water were added while maintaining an internal temperature of 15±10° C. The suspension was warmed to an internal temperature of 75±5° C. over 1 h, then the mixture was stirred at this temperature for 30 min. Then the mixture was cooled to an internal temperature of 30±5° C. over 45 min, and the organic layer was separated off. The organic layer was then line-filtered by pressure (300 to 500 mbar) and the solvent was concentrated under vacuum (100-50 torr) at an internal temperature of 20-30° C. to collect ˜950 mL of solvent (batch volume ˜200 mL). 875 mL of water were added to the concentrate. Again the solvent was concentrated under vacuum (200-150 torr) at an internal temperature of 20-30° C. to collect ˜200 mL of solvent (batch volume ˜820 mL). The remaining suspension was stirred at 20±3° C. for 2 h, and the solid was removed by filtration over a polypropylene filter paper in a Büchner funnel with suction. The filter cake was washed with 2×100 mL of H2O. The solid was dried under vacuum (100-150 mbar) at 50±5° C. with nitrogen bleeding until ≦1% LOD (15 h) to obtain 56.5 g of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3-yl)-benzonitrile (7) as a white solid.

Workup

  1. temperaturereflux
  2. additioncondenser, addition funnel, and nitrogen inlet-outlet
  3. additionwere added
  4. temperatureThe suspension was then warmed to an internal temperature of 60±3° C. over 1 h
  5. temperatureThe suspension was cooled to an internal temperature of 15±3° C. over 30 min
  6. temperaturewhile maintaining an internal temperature of 15±10° C
  7. temperatureThe suspension was warmed to an internal temperature of 75±5° C. over 1 h
  8. stirringthe mixture was stirred at this temperature for 30 min
  9. temperatureThen the mixture was cooled to an internal temperature of 30±5° C. over 45 min
  10. customthe organic layer was separated off
  11. filtrationThe organic layer was then line-filtered by pressure (300 to 500 mbar)
  12. concentrationthe solvent was concentrated under vacuum (100-50 torr) at an internal temperature of 20-30° C.
  13. customto collect ˜950 mL of solvent (batch volume ˜200 mL)
  14. addition875 mL of water were added to the concentrate
  15. concentrationAgain the solvent was concentrated under vacuum (200-150 torr) at an internal temperature of 20-30° C.
  16. customto collect ˜200 mL of solvent (batch volume ˜820 mL)
  17. stirringThe remaining suspension was stirred at 20±3° C. for 2 h
  18. customthe solid was removed by filtration over a polypropylene
  19. filtrationfilter paper in a Büchner funnel with suction
  20. washThe filter cake was washed with 2×100 mL of H2O
  21. customThe solid was dried under vacuum (100-150 mbar) at 50±5° C. with nitrogen bleeding until ≦1% LOD (15 h)

Sources & evidence

ORD record
ord-73965566dd804306967f1bddc8fea5b2
Source dataset
uspto-grants-2013_01
Patent number
US08349852B2

Reaction notes

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