Sodium Chloride → 3-(2-Chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine

HRID 547492Notes

Reaction equation

HRID 547492 reaction equation
C(=O)([O-])[O-].[Na+].[Na+].O.[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.[Cl:18][C:19]1[N:28]=[C:27](Cl)[C:26]2[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([O:30][CH3:31])[CH:25]=2)[N:20]=1.[Cl-].[Na+]>O1CCCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:18][C:19]1[N:28]=[C:27]([C:13]2[CH:14]=[C:9]([NH2:8])[CH:10]=[CH:11][CH:12]=2)[C:26]2[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([O:30][CH3:31])[CH:25]=2)[N:20]=1

Participants

9

Reactant 4

HCID 5234Sodium ChlorideHCID 10340Sodium CarbonateHCID 5203272,4-Dichloro-6,7-dimethoxyquinazolineHCID 143894233-Aminophenylboronic acid monohydrate

Product 1

HCID 576095393-(2-Chloro-6,7-dimethoxyquinazolin-4-yl)phenylamineYield 99.7%

Reagents, catalysts & solvents 4

HCID 11776TriphenylphosphineCatalystHCID 24290Palladium ChlorideCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
25 °C

Procedure

To 634 g of sodium carbonate (5.98 mol) was added 2.91 kg of water under a nitrogen atmosphere, followed by stirring for dissolution. To the solution were added 3.0 L of tetrahydrofuran, 431 g of 3-aminophenyl boronic acid monohydrate (2.78 mol), 30.4 g of triphenylphosphine (0.116 mol) and 26.0 g of dichloropalladium (0.116 mol) in this order. To the mixture was dropwise added a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (600 g; 2.32 mol) in tetrahydrofuran (12.0 L) over 2 hours while stirring at 60° C., followed by stirring at the same temperature for 16 hours. To the mixture were added 3.0 kg of a 5% sodium chloride solution and 12.0 L of tetrahydrofuran in this order, and the mixture was stirred at 50° C. for 1 hour and allowed to cool down to 25° C. The mixture was filtered through celite to remove the insoluble matter, and the filtrate was transferred to separatory funnel and the organic layer was separated. To the separated organic layer were added 150 g of anhydrous magnesium sulfate and 60.0 g of activated carbon, and the mixture was stirred at 50° C. for 1 hour and allowed to cool down to 25° C. The mixture was filtered through celite to remove the insoluble matter, and the filtrate was concentrated under reduced pressure. To the residue was added 6.0 L of water, and the mixture was stirred at room temperature for 1 hour, and precipitated crystals were collected by filtration. The collected crystals were dried at 50° C. under reduced pressure to yield 730 g of a product of interest. Yield: 62.1%

Workup

  1. stirringwhile stirring at 60° C.
  2. stirringby stirring at the same temperature for 16 hours
  3. stirringthe mixture was stirred at 50° C. for 1 hour
  4. filtrationThe mixture was filtered through celite
  5. customto remove the insoluble matter
  6. customthe filtrate was transferred to separatory funnel
  7. customthe organic layer was separated
  8. additionTo the separated organic layer were added 150 g of anhydrous magnesium sulfate and 60.0 g of activated carbon
  9. stirringthe mixture was stirred at 50° C. for 1 hour
  10. temperatureto cool down to 25° C
  11. filtrationThe mixture was filtered through celite
  12. customto remove the insoluble matter
  13. concentrationthe filtrate was concentrated under reduced pressure
  14. additionTo the residue was added 6.0 L of water
  15. stirringthe mixture was stirred at room temperature for 1 hour
  16. customprecipitated crystals
  17. filtrationwere collected by filtration
  18. customThe collected crystals were dried at 50° C. under reduced pressure

Sources & evidence

ORD record
ord-837d432d853c4f0d9ecd42573c3b6b5d
Source dataset
uspto-grants-2011_05
Patent number
US07939540B2

Reaction notes

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