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New synthesis method of gefitinib

A synthetic method, the technology of gefitinib, is applied in the new synthetic field of gefitinib, which can solve the problems of lengthy reaction steps and serious environmental pollution, and achieve the effect of less steps, simple post-processing and cheap raw materials

Inactive Publication Date: 2018-01-16
JIANGSU QINGJIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction steps are lengthy, and halogenated reagents, such as thionyl chloride, phosphorus oxychloride, etc., need to be used in the reaction. Such reagents cause serious environmental pollution and have been listed as national banned products

Method used

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  • New synthesis method of gefitinib
  • New synthesis method of gefitinib
  • New synthesis method of gefitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1: Synthesis of 3-hydroxyl-4-methoxybenzonitrile (II)

[0025] 10.0g (65.8mmol) of 3-hydroxy-4-methoxybenzaldehyde (compound 1), 15mL (362mmol) of formic acid, 4.5g (65.8mmol) of sodium formate were placed in a 100mL three-necked flask, and the The temperature rose to 85°C, slowly added 22.9g (329mmol) of hydroxylamine sulfate to the reaction system within two hours, continued the reaction at this temperature for 5 hours after the addition, then stopped heating, cooled to room temperature, and poured into the reaction bottle Add 25 mL of distilled water, stir for 1 hour, filter with suction, wash with 20 mL of ice water, and dry to obtain 8.8 g (89.7%) of powdery solid.

Embodiment 2

[0026] Example 2: Synthesis of 4-methoxy-3-(3-morpholine propoxy)benzonitrile (Ⅲ)

[0027] Add 8.0g (53.6mmol) 3-hydroxy-4-methoxybenzonitrile, 10.5g (64.3mmol) 4-(3-chloropropoxy)morpholine and 56mL acetonitrile into a 100mL three-necked flask, stir, and wait for 3 After -hydroxy-4-methoxybenzonitrile is dissolved, add 14.8g (107mmol) of anhydrous potassium carbonate, heat to 85°C, react for 11 hours, cool to room temperature, remove salt by suction filtration, wash with acetonitrile, and concentrate the filtrate , precipitated a white solid, washed 3 times, weighed 14.0g after drying (yield 94.5%).

Embodiment 3

[0028] Example 3: Synthesis of 4-methoxy-5-(3-morpholine propoxy)-2-nitrobenzonitrile (Ⅳ)

[0029] Mix 13.0g (47.0mmol) of 4-methoxy-3-(3-morpholinepropoxy)benzonitrile, 17mL concentrated nitric acid (65%) (376mmol) and 17mL glacial acetic acid into a 250mL single-necked flask , Stir at room temperature for about 2 hours to precipitate a large amount of solids, continue to stir for 1 hour, stop the reaction, add 52g of ice water, stir for 30min, filter with suction, wash the filter cake with ice water to about pH 7, and dry to obtain 14.4g of white solid (95.3 %).

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Abstract

The invention relates to a new synthetic method of an anti-tumor drug 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholinylpropoxy)quinazoline (gefitinib, I). According to the synthesis method,synthesis is performed through a novel synthetic intermediate. Before a quinazoline mother ring is synthesized, hydroxy of 3-hydroxy-4-methoxybenzonitrile is reacted with 3-morpholinopropyl chloride firstly, so that the steps of adding protecting groups and removing the protecting groups are reduced, the synthesis route is shortened, the step number of synthesis is lowered, raw materials are cheapand easily obtained, the use of chlorinated reagents which heavily pollute the environment is avoided, the purification process is simplified, the pH (potential of hydrogen) value does not need to berepeatedly adjusted, the operation is safe and simple, and the reaction yield exceeds 60%.

Description

technical field [0001] The present invention relates to a new synthesis of gefitinib (I) 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline method. Background technique [0002] Gefitinib (Gefitinib, ZD1839, trade name Iressa), chemical name is 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinoline Azoline, the structural formula is as follows: [0003] [0004] Gefitinib is an oral epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor (a small molecule compound). Inhibition of EGFR-TK can hinder tumor growth, metastasis and angiogenesis, and increase tumor cell apoptosis. Gefitinib was developed by AstraZeneca in the United Kingdom and first launched in Japan in 2002. In May 2003, it was approved as a third-line monotherapy in the United States and Australia for the treatment of advanced non-small cell lung cancer. Gefitinib is not only effective against advanced non-small cell lung cancer, but also has antitumor...

Claims

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Application Information

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IPC IPC(8): C07D239/94
CPCY02P20/55
Inventor 孙占奎冯玲玲
Owner JIANGSU QINGJIANG PHARMA
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