Preparation method of Gefitinib

A technology of gefitinib and triphenylphosphine, applied in the field of chemical drug preparation, can solve problems such as the yield of only 50%

Inactive Publication Date: 2011-08-17
JIANGSU FARMTEC RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Including the method for obtaining gefitinib by reacting 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7

Method used

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  • Preparation method of Gefitinib
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  • Preparation method of Gefitinib

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[0032] As far as the preparation method of the present invention is concerned, the reactant formula (II) compound and 4-(3-hydroxypropyl)-morpholine (i.e. 3-morpholinopropanol) are commercially available, or can be Preparation by methods known per se to the skilled person.

[0033] In a preferred embodiment of the method of the present invention, the molar ratio of 4-(3-hydroxypropyl)-morpholine to the compound of formula (II) is 1:1-10:1.

[0034] In a preferred embodiment of the method of the present invention, diisopropyl azodicarboxylate and triphenylphosphine are used as reaction accelerators.

[0035] In a preferred embodiment of the method of the present invention, the molar ratio of triphenylphosphine to diisopropyl azodicarboxylate is 1:1-10:1 or 1:1-1:10.

[0036] In a preferred embodiment of the method of the present invention, the molar ratio of triphenylphosphine to the compound of formula (II) is 1:1-10:1.

[0037] In the reaction of the method of the present i...

Embodiment

[0043] Embodiment: the preparation of gefitinib

[0044]

[0045] To a solution of triphenylphosphine (2.01 g, 7.66 mmol) in THF (13 mL) was added diisopropyl azodicarboxylate (1.5 mL, 7.66 mmol) in THF (2 mL). The color of the clear solution turned to yellow. After 1 hour, a solution of 4-(3-hydroxypropyl)morpholine (0.23 mL, 1.69 mmol) in THF (2 mL) was added dropwise to the yellow solution at room temperature over 20 minutes. Then, under nitrogen, 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (0.50 g, 1.53 mmol) of formula (II) was added to the reaction in solution. The resulting mixture was stirred at room temperature for 4 hours, then a solution of 4-(3-hydroxypropyl)morpholine (0.19 mL, 1.38 mmol) in THF (2 mL) was added dropwise to the yellow reaction over 20 minutes. in solution. The resulting mixture was stirred for an additional 1 hour at room temperature. The reaction was terminated, and the solvent was removed by evaporation. The residue w...

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Abstract

The invention relates to a preparation method of 4-(3-chloro-4-fluorophenylamido)-7-methoxy-6-(3-morpholinylpropoxy)quinazoline (Gefitinib, I). The preparation method of Gefitinib is characterized in that etherification reaction is carried out on a Gefitinib intermediate 4-(3-chloro-4-fluorophenylamido)-6-hydroxy-7-methoxy-quinazoline and 4-(3-hydroxypropyl)-morpholine under proper conditions to obtain the target product Gefitinib. Gefitinib (I).

Description

technical field [0001] The invention belongs to the technical field of preparation of chemical medicines, in particular to 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholine propoxy)quinazoline ( The preparation method of gefitinib (Gefitinib). Background technique [0002] Gefitinib is a small molecule inhibitor of EGFR tyrosine kinase developed by Astra Zeneca. It was first launched in Japan in 2002 for the treatment of locally advanced or recurrent non-small cell lung cancer that was ineffective or unsuitable for chemotherapy. In May 2003, it was approved as a third-line monotherapy for advanced non-small cell lung cancer in the United States and Australia. It is The first targeted small molecule tyrosine kinase inhibitor for the treatment of solid tumors. [0003] Gefitinib was approved by the State Food and Drug Administration (SFDA) on February 25, 2005 to be officially launched in China (trade name: Gefitinib) for the treatment of locally advanced or metasta...

Claims

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Application Information

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IPC IPC(8): C07D239/94
Inventor 赵长阔刘赟王先桓
Owner JIANGSU FARMTEC RES
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