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Preparation method of neratinib

A neratinib and ethoxy technology, which is applied in the field of preparation of neratinib, can solve the problems of high temperature and long time reflux, high cost, waste of energy, etc., and achieve improved safety, reduced industrial cost, and simple process Effect

Active Publication Date: 2015-11-25
HARBIN ZHENBAO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic route has a classic reaction, but the condensation and cyclization reaction requires high temperature and long-term reflux, which wastes energy and is costly

Method used

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  • Preparation method of neratinib
  • Preparation method of neratinib
  • Preparation method of neratinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The present embodiment is the preparation method of Neratinib, which specifically includes the following steps:

[0035] (1) Add 2.5 L of tetrahydrofuran into a three-necked flask, add 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-chloro-3- Quinolinecarbonitrile (I) (358.82g, 1mol, 1.00eq) and 2-chloro-4-aminophenol (II) (143.57g, 1moL, 1eq) were replaced with nitrogen three times, and the temperature of the reaction system was raised to 65°C. Dichloromethylpyridine hydrochloride (Ⅲ) (237.70g, 1.46moL, 1.05eq) dissolved in 1L tetrahydrofuran was added dropwise for a total of 4 hours. After the 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%;

[0036] (2) Cool the reaction system to room temperature, add potassium carbonate (553.48g, 4moL, 4eq) and potassium iodide (16.69g, 0.1moL, 0.1eq), raise the temperature of the reaction system to 60 ° C, ...

Embodiment 2

[0039] The present embodiment is the preparation method of Neratinib, which specifically includes the following steps:

[0040] (1) Add 3.0 L of dimethyl sulfoxide to a three-necked flask, add 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-chloro -3-quinolinecarbonitrile (I) (358.72g, 1mol, 1.00eq) and 2-chloro-4-aminophenol (II) (143.62g, 1moL, 1eq), nitrogen replacement three times, the reaction system was heated to 60 ℃, add dichloromethylpyridine hydrochloride (Ⅲ) (172.23g, 1.05moL, 1.05eq) dissolved in 1L of dimethyl sulfoxide dropwise at a constant speed, add dropwise for a total of 4 hours, and keep warm for 2 hours after the dropwise addition is completed. HPLC monitoring 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-chloro-3-quinolinecarbonitrile (I)≤0.3%;

[0041] (2) The reaction system was cooled to room temperature, sodium hydroxide (168.91g, 4moL, 4eq) and sodium iodide (14.89g, 0.1moL, 0.1eq) were added, the temperature of the reaction system was raised ...

Embodiment 3

[0044] The difference between the present embodiment and Example 1 lies in the following two points: the dropwise addition time of dichloromethylpyridine hydrochloride (Ⅲ) dissolved in 1L tetrahydrofuran in step (1) is 5 hours; in step (2), the reaction The temperature of the system was raised to 55°C.

[0045] In this example, the yield of neratinib was 80.14%.

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Abstract

The invention relates to the field of pharmaceuticals, in particular to a preparation method of neratinib. The preparation method specifically includes: successively condensing 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-chloro-3-cyanoquinoline (I) with 2-chloro-4-aminophenol (II) and 2-(chloromethyl)pyridine hydrochloride (III) through an intermediate (E)-N-{4-[3-chloro-4-hydroxyanilino]3-cyano-7-ethoxy-6-quinoline}-4-dimethylamino-2-butenamide (IV). The materials in the preparation method are easy to obtain, and the preparation method is simple, green and economical and has greatly worthy of application.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a preparation method of Neratinib. Background technique [0002] Neratinib is an irreversible epidermal growth factor receptor (EGFR) inhibitor developed by Wyeth Pharmaceuticals, a subsidiary of Pfizer, which can selectively inhibit HER-1 and HER- 2. It can be used in the treatment of cancers, especially those cancers affected by the kinases of the epidermal growth factor receptor family. Such cancers include, but are not limited to, pancreatic, melanoma, lymphatic, parotid, Barrett's esophagus, esophagus, head and neck, ovary, breast, epithelioid tumors, major organs such as kidney, bladder, Cancers of the larynx, stomach, and lungs, colon polyps and colorectal cancers, and prostate cancers. [0003] The chemical name of neratinib is: (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7 -Ethoxyquinolin-6-yl]-4-(dimethylamino)-2-butenamide, its structural formula is:...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 方同华高丽马丽梅王天晔韩杰葛一萌周广红范玉奇
Owner HARBIN ZHENBAO PHARMA
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