Hydrochloric Acid → Erlotinib Hydrochloride

HRID 1016388Notes

Reaction equation

HRID 1016388 reaction equation
[ClH:1].[CH3:2][O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[N:13]=[CH:12][N:11]=[C:10]2[NH:22][C:23]1[CH:24]=[C:25]([C:29]#[C:30]C(C)(O)C)[CH:26]=[CH:27][CH:28]=1.O.[OH-].[Na+].Cl>C(O)CCC>[ClH:1].[C:29]([C:25]1[CH:24]=[C:23]([NH:22][C:10]2[C:9]3[C:14](=[CH:15][C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:7]([O:6][CH2:5][CH2:4][O:3][CH3:2])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:28]=[CH:27][CH:26]=1)#[CH:30]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 14798Sodium Hydroxide2×HCID 9913356HCID 9913356, compound

Product 1

HCID 176871Erlotinib Hydrochloride

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent3×

Procedure

4-[3-[[6,7-Bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, monohydrochloride, prepared as described above (32.34 g, 66.3 mmol), water (300 mL) and butan-1-ol (600 mL) were stirred together at room temperature to form a mixture. The pH of the mixture was adjusted to pH 10-12 with 50% aqueous sodium hydroxide solution to give two clear layers. The organic layer was separated from the aqueous layer and concentrated under atmospheric pressure, so that water was azeotropically removed from the butan-1-ol solution. The final volume of butan-1-ol solution was ˜300 mL. Anhydrous solid sodium hydroxide (0.13 g, 3.3 mmol) was added to the azeotropically dried butan-1-ol solution and the resultant mixture was heated under reflux at 115-120° C. for 24 hours. Butan-1-ol (150 mL) was removed by distillation and the concentrated reaction mixture cooled to 15-25° C. Concentrated hydrochloric acid (6.1 mL) and butan-1-ol (60 mL) were added to the cooled concentrate and the mixture was granulated overnight at 20-25° C. to establish crystallization. The title product crystals were isolated by filtration and dried under vacuum at 45-50° C. to remove butan-1-ol. Yield (21.0 g, 73.7%). Purity by HPLC 96.5%.

Workup

  1. customto form a mixture
  2. customto give two clear layers
  3. customThe organic layer was separated from the aqueous layer
  4. concentrationconcentrated under atmospheric pressure, so that water
  5. customwas azeotropically removed from the butan-1-ol solution
  6. temperatureunder reflux at 115-120° C. for 24 hours
  7. customButan-1-ol (150 mL) was removed by distillation
  8. customthe concentrated reaction mixture
  9. temperaturecooled to 15-25° C
  10. concentrationconcentrate
  11. customcrystallization

Sources & evidence

ORD record
ord-bf9ccf405e3c46ec9435f635f1cb76eb
Source dataset
uspto-grants-2002_11
Patent number
US06476040B1

Reaction notes

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