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A novel preparation method of epidermal growth factor receptor (EGFR) inhibitor neratinib

A technology of epidermal growth factor and neratinib, applied in the field of organic synthesis, can solve the problems of poor solubility of intermediates, large amount of solvent and high production cost

Active Publication Date: 2018-12-04
SHANGHAI STEPPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the above synthetic routes, due to the poor solubility of intermediates, there is a problem that the amount of solvent used in the last three-step reaction is relatively large, which will generate a large amount of waste liquid, and the production cost is very high. It is also very unfavorable for environmental protection and greatly limits Prospects for industrialization

Method used

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  • A novel preparation method of epidermal growth factor receptor (EGFR) inhibitor neratinib
  • A novel preparation method of epidermal growth factor receptor (EGFR) inhibitor neratinib
  • A novel preparation method of epidermal growth factor receptor (EGFR) inhibitor neratinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add 0.4L of dimethyl sulfoxide to a 2L three-necked flask, add 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-chloro- 3-quinolinecarbonitrile (I) (43.06g, 0.12mol, 1eq) and 2-chloro-4-aminophenol (II) (17.23g, 0.12moL, 1eq), nitrogen replacement three times, the reaction system was heated to 90 ℃, add dichloromethylpyridine hydrochloride (Ⅲ) (29.53g, 0.18moL, 1.50eq) dissolved in tetrahydrofuran 0.15L dropwise at a constant speed, add dropwise for 1 hour, keep warm for 2 hours after the dropwise addition, monitor by HPLC 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-chloro-3-quinolinecarbonitrile (Ⅰ)≤0.2%, the reaction system is cooled To room temperature, potassium carbonate (66.34g, 0.48moL, 4eq) and sodium iodide (1.80g, 0.01moL, 0.1eq) were added, the temperature of the reaction system was raised to 90°C, and the reaction was kept for 16 hours, and the intermediate state (E) was monitored by HPLC -N-{4-[3-chloro-4-hydroxyanilino]3-cyano-7-ethoxy-6-quinoline}...

Embodiment 2

[0025] Add 300 mL of tetrahydrofuran into a 2L three-necked flask, add 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-chloro-3-quinoline Nitrile (I) (28.70g, 0.08mol, 1eq) and 2-chloro-4-aminophenol (II) (11.49g, 0.08mol, 1eq), replaced by nitrogen three times, the reaction system was heated to 65 ° C, and added dropwise Dichloromethylpyridine hydrochloride (Ⅲ) (13.78g, 0.08moL, 1.05eq) dissolved in 100mL of tetrahydrofuran was added dropwise for 1 hour. After the addition was completed, the reaction was incubated for 2 hours. HPLC monitored 6-[(E) -4-(dimethylamino)-2-butenylamino]-7-ethoxy-4-chloro-3-quinolinecarbonitrile (Ⅰ)≤0.5%, the reaction system was cooled to room temperature, and potassium carbonate was added (44.23g, 0.32moL, 4eq) and potassium iodide (1.99g, 0.01moL, 0.1eq), the temperature of the reaction system was raised to 60°C, and the reaction was kept for 16 hours. The intermediate state (E)-N-{4-[3 -Chloro-4-hydroxyanilino]3-cyano-7-ethoxy-6-quinoline}-4...

Embodiment 3

[0027] Add 300 mL of tetrahydrofuran into a 2L three-necked flask, add 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-chloro-3-quinoline Nitrile (I) (35.88g, 0.1mol, 1eq) and 2-chloro-4-aminophenol (II) (14.36g, 0.1moL, 1eq), replaced by nitrogen three times, the temperature of the reaction system was raised to 60°C, and the Dichloromethylpyridine hydrochloride (Ⅲ) (17.22g, 0.11moL, 1.05eq) dissolved in 100mL of tetrahydrofuran was added dropwise for 1 hour. After the dropwise addition was completed, the reaction was incubated for 2 hours. HPLC monitored 6-[(E) -4-(dimethylamino)-2-butenamido]-7-ethoxy-4-chloro-3-quinolinecarbonitrile (Ⅰ)≤0.3%, the reaction system was cooled to room temperature, and sodium methoxide was added (10.80g, 0.20moL, 2eq) and sodium iodide (1.5g, 0.01moL, 0.1eq), the temperature of the reaction system was raised to 60°C, and the reaction was kept for 16 hours. The intermediate state (E)-N-{4- [3-Chloro-4-hydroxyanilino]3-cyano-7-ethoxy-6-quinolin...

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Abstract

The invention relates to a preparation method of an epidermal growth factor receptor (EGFR) inhibitor neratinib. The method is characterized in that 6-[(E)-4-(dimethylamino)-2-butenylamido]-7-ethoxy-4-chloro-3-quinolylmethylnitrile (I) continuously reacts with 2-chloro-3-aminophenol (II) and dichloromethylpyridine hydrochloride (III) to temporarily obtain an intermediate (E)-N-{4-[3-chloro-4-hydroxyanilino]3-cyno-5-ethoxy-6-quinolyl}-4-dimethylamino-2-butenylamide (IV) in order to finally obtain neratinib. The preparation method adopts a continuous reaction process, and dichloromethylpyridine hydrochloride (III) is a catalyst in the first stage of the continuous reaction and is a reaction reagent in the second stage of the continuous reaction, so the method has the advantages of simple and easily available raw materials, high yield, mild reaction conditions, extremely small amount of a generated waste liquid, and high facilitation of industrial production of the above raw medicine.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of an epidermal growth factor receptor (EGFR) inhibitor (neratinib). Background technique [0002] An epidermal growth factor receptor (EGFR) inhibitor (neratinib), an irreversible EGFR inhibitor developed by Wyeth Pharmaceuticals, a subsidiary of Pfizer, can selectively inhibit the EGFR family HER-1 and HER-2 are useful in the treatment of cancers, especially those cancers affected by epidermal growth factor receptor family kinases, including but not limited to, pancreatic cancer, melanoma, lymphatic carcinoma, parotid tumor , Barrett's esophagus, esophageal cancer, head and neck cancer, ovarian cancer, breast cancer, epithelioid tumor, cancer of major organs such as kidney, bladder, larynx, stomach and lung, colon polyps and colorectal cancer, and prostate cancer. [0003] Existing (neratinib) preparation routes mainly contain two: Route 1 uses 3-cyano-6-a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12A61K31/4709A61P35/00
CPCC07D401/12
Inventor 张巍吴水长唐飞宇廖文胜
Owner SHANGHAI STEPPHARM CO LTD
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