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A new method for microwave synthesis of gefitinib and its derivatives

A technology for microwave synthesis and gefitinib, which is applied in the new field of microwave synthesis of gefitinib and its derivatives, can solve the problems of low total yield and many reaction steps, and achieve simple operation, reduced product cost, and high production efficiency. high rate effect

Inactive Publication Date: 2016-03-30
FUJIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The chlorination reaction in this route needs to use highly polluting halogenation reagents, and there are many reaction steps and the overall yield is low, so it is not an economical and environmentally friendly synthetic route

Method used

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  • A new method for microwave synthesis of gefitinib and its derivatives
  • A new method for microwave synthesis of gefitinib and its derivatives
  • A new method for microwave synthesis of gefitinib and its derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The first step: the preparation of 6-methoxy-7-hydroxyquinazolin-4-one

[0035]

[0036] Weigh 1 mmol of 2-iodo(bromo)-4-methoxy-5-hydroxybenzonitrile, 1.5 mmol of formamidine hydrochloride in 10 mL of water phase, add 0.1 mmol of CuI catalyst, base K 2 CO 3 3mmol, 80 ° C microwave heating reflux 0.5h, microwave power 150W. After the reaction was completed, it was cooled to room temperature and filtered to obtain solid powder.

[0037] The second step: the preparation of 7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazolin-4-one

[0038]

[0039] Weigh 1 mmol of 7-methoxy-7-hydroxyquinazolin-4-one and 1.2 mmol of 4-(3-bromopropyl)morpholine, add 0.1 mmol of CuI catalyst to 10 mL of water phase, base K 2 CO 3 3mmol, heated to reflux in microwave at 90°C for 0.5h, microwave power 150W. After the reaction was completed, it was cooled to room temperature and filtered to obtain solid powder.

[0040] The third step: the preparation of 4-chloro-7-methoxy-6-[3-(4-morph...

Embodiment 2

[0047] Preparation of 4-(3-chloro-4-fluoroanilino)-7-methyl-6-(3-morpholinopropoxy)quinazoline

[0048]

[0049] Weigh 1 mmol of 4-chloro-7-methyl-6-[3-(4-morpholinyl)propoxy]quinazoline and 1.2 mmol of 3-fluoro-4-chloroaniline in 10 mL of aqueous phase, add CuI Catalyst 0.1mmol, base K 2 CO 3 2mmol, 100°C microwave heating and reflux for 0.5h, microwave power 150W. After the reaction solution was cooled to room temperature, excess reaction raw materials were removed by filtration, and the filtrate was distilled under reduced pressure to precipitate a solid, which was recrystallized from ethyl acetate to obtain a white solid, which was a gefitinib derivative.

Embodiment 3

[0051] Preparation of 4-chloro-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline

[0052]1mmol 7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazolin-4-one with 2mmol chlorination reagent phosphorus trichloride and 2mmol base Na 2 CO 3 Microwave reaction in the presence of intermediate 4-chloro-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline. The reaction temperature was 80°C, and the microwave power was 150W. After the reaction was completed, it was cooled to room temperature and filtered to obtain solid powder.

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Abstract

The invention discloses a new method for performing microwave synthesis on gefitinib and a derivative thereof. The method comprises the following steps of: at first, synthesizing 6-methoxyl-7-hydroxyl quinazoline-4-one from 2-iodo (bromo)-4-methoxyl-5-hydroxyl cyanophenyl used as an initial raw material and formamidine hydrochloride in a microwave mode; then performing reaction with 4-(3-bromo propyl) morpholine to introduce an alkyl side chain so as to obtain 7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline-4-ketone; in the presence of a catalyst, performing reaction on the obtained product and a chlorination reagent to obtain 4-chloro-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline; finally, performing reaction on 4-chloro-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline and 3-chloro-4-fluoroaniline to obtain a final product 4-(3-chloro-4-fluoroanilino)-7-methoxyl-6-(3-morpholinyl propoxy) quinazoline (gefitinib). The whole route steps are simplified into four steps, the yield is high, the method is convenient to carry out, the dangerousness is low, and the application of high-pollution reagents is reduced; moreover, the whole route is high in economy and suitable for industrial production, and the product cost is reduced. The reaction formula is as shown in the specification.

Description

technical field [0001] The invention relates to a method for synthesizing gefitinib, a drug with anti-tumor effect, and derivatives thereof, and belongs to the technical field of drugs. Background technique [0002] Gefitinib (Gefitinib), the chemical name is 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, which is derived from A protein tyrosine kinase inhibitor developed by AstraZeneca. Gefitinib is an epidermal growth factor receptor and molecular targeted therapy drug, targeting (EGFR), inhibiting EGFR activation and blocking the EGFR activation process by competing with ATP to bind to the extracellular ligand binding site. Thereby inhibiting cell proliferation and promoting tumor cell apoptosis. Studies have shown that it has obvious curative effect on the treatment of advanced lung cancer, and it is mainly used to treat locally advanced or recurrent non-small cell lung cancer that is ineffective or unsuitable for chemotherapy. very importa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 柯方许建华刘彩琴吴丽贤林媚李鹏周孙英
Owner FUJIAN MEDICAL UNIV
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