Phosphorus oxychloride → 4-((3-Chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate hydrochloride

HRID 1951993Notes

Reaction equation

HRID 1951993 reaction equation
[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].C(N(C(C)C)C(C)C)C.P(Cl)(Cl)([Cl:29])=O.[Cl:32][C:33]1[C:34]([F:40])=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>C1(C)C=CC=CC=1>[ClH:29].[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:36][C:35]1[CH:37]=[CH:38][CH:39]=[C:33]([Cl:32])[C:34]=1[F:40])(=[O:3])[CH3:2]

Participants

6

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 750143-Chloro-2-fluoroanilineHCID 81531DiisopropylethylamineHCID 1356819606-Acetoxy-7-methoxy-3H-quinazolin-4-one

Product 1

HCID 574768664-((3-Chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate hydrochlorideYield 78%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
70 °C

Procedure

6-Acetoxy-7-methoxyquinazolin-4-one (International Patent Application WO 96/15118, Example 39 thereof; 21.4 kg, 89.3 mol) was suspended in toluene (150 kg). To this was added N-ethyldiisopropylamine (13.3 kg, 103 mol). The brown suspension was heated to 70° C. then phosphorus oxychloride (36.0 kg, 228 mol) was charged. The reaction mixture was stirred at 70° C. for 5 hours. Further toluene (84.0 kg) was added followed by 3-chloro-2-fluoroaniline (14.88 kg, 102 mol). The reaction mixture was stirred at 70° C. for 2 hours during which time a solid precipitated. The suspension was cooled to 25° C. and held at this temperature for 93 hours. The reaction mixture was filtered and the filter cake washed with toluene (2×55.5 kg). The cake was further washed with a mixture of ethanol (24.5 kg) and water (32.0 kg) twice, then ethanol (50.5 kg) twice and the solid then dried under vacuum to give the title product as a beige solid (33.4 kg, 78%); 1H NMR: 2.37 (s, 3H), 4.00 (s, 3H), 7.34 (ddd, 1H), 7.48 (s, 1H), 7.52 (ddd, 1H), 7.61 (ddd, 1H), 8.62 (s, 1H), 8.86 (s, 1H); Mass Spectrum: 362.4, 364.4.

Workup

  1. stirringThe reaction mixture was stirred at 70° C. for 2 hours during which time a solid
  2. customprecipitated
  3. temperatureThe suspension was cooled to 25° C.
  4. waitheld at this temperature for 93 hours
  5. filtrationThe reaction mixture was filtered
  6. washthe filter cake washed with toluene (2×55.5 kg)
  7. washThe cake was further washed with a mixture of ethanol (24.5 kg) and water (32.0 kg) twice
  8. dry with materialethanol (50.5 kg) twice and the solid then dried under vacuum

Sources & evidence

ORD record
ord-060505c638cf4a6e905bfc87ca9f43d6
Source dataset
uspto-grants-2013_03
Patent number
US08404839B2

Reaction notes

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