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Method for purifying neratinib

A technology of neratinib and purification method, applied in the field of purification of neratinib, to achieve the effect of simple operation and high yield

Active Publication Date: 2016-09-21
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the combination of these solvents for the purification of neratinib finished products is difficult to make the impurities in the finished products of neratinib meet the requirements of ICH on the impurity limit of generic drugs, that is, "unknown single impurity ≤ 0.10%, known impurity ≤ 0.15% "

Method used

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  • Method for purifying neratinib
  • Method for purifying neratinib
  • Method for purifying neratinib

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Embodiment 1: Preparation of neratinib (compound of formula 1) crude product

[0033] The preparation of the compound of formula I refers to the preparation method of WO2006127207, specifically as follows:

[0034]

[0035] Add 4-N,N-dimethylaminocroton hydrochloride (72g, 0.44mol), tetrahydrofuran (800ml) and dimethylformamide (0.8ml) into a 2L three-necked flask, cool to 0-5°C , Oxalyl chloride (36ml, 0.42mol) was added dropwise to the reaction solution. Then the temperature was raised to 25-30°C and stirred for 2-3 hours. The reaction solution was cooled to 0-5° C. again, and a solution (800 ml) of compound 3 (100 g, 0.22 mol) in N-methylpyrrolidone (NMP) was added dropwise. After the drop was completed, it was stirred overnight at room temperature. The reaction solution was transferred to a 10L reaction kettle, cooled to 0-5°C, quenched with water (500ml), and kept stirring at 0-5°C for 30min. Then the temperature was raised to 40° C., and 1 mol / L sodium hydr...

Embodiment 2

[0037] Take 10.0g of crude neratinib and add it to a 250ml round bottom flask, add 100ml dimethyl sulfoxide and 50ml tetrahydrofuran, stir and suspend, heat to 60°C, stir for 1.5 hours, then cool the suspension to 20-30°C, and stirred at 20-30°C for 1 hour, filtered through a Buchner funnel under reduced pressure, and washed the filter cake with 300ml of purified water. The obtained solid was vacuum-dried to dryness at 50-60°C to obtain 9.3g of neratinib finished product, with a purity of 99.8%. The content of simple impurities is shown in Table 2, attached figure 2 .

Embodiment 3

[0039] Take 10.0g of crude neratinib and add it to a 250ml round bottom flask, add 100ml dimethyl sulfoxide and 100ml tetrahydrofuran, stir and suspend, heat to 65°C, stir for 1.5 hours, then cool the suspension to 20-30°C, and stirred at 20-30°C for 5 hours, filtered through a Buchner funnel under reduced pressure, and washed the filter cake with 300ml of purified water. The obtained solid was vacuum-dried to dryness at 50-60° C. to obtain 7.8 g of neratinib as a finished product, with a purity of 99.8%. The content of simple impurities is shown in Table 2.

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Abstract

The invention relates to a method for purifying neratinib. The method provided by the invention is capable of effectively reducing the content of impurities in neratinib and preparing high-purity neratinib, and moreover is simple in operation, high in yield and very applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and crystallization, and in particular relates to a purification method of neratinib. Background technique [0002] Neratinib, chemical name: (E)-N-[4-[3-chloro-4-(pyridine-2-methoxy)anilino]-3-cyano-7-ethoxy Quinolin-6-yl]-4-dimethylamino-2-butenamide, the structure of which is shown in Formula 1 below. Neratinib is a drug developed by Puma Biotechnology Company of the United States for the treatment of breast cancer. It is a highly selective human epidermal growth factor receptor (EGFR) and HER-2 inhibitor. Clinical studies have shown that neratinib is significantly more effective than Roche's Herceptin in the treatment of early HER-2 positive breast cancer. [0003] [0004] The impurities of neratinib are very similar to the structure and properties of neratinib, and their solubility in common organic solvents is very small, making it difficult to purify and separate. WO20061...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 汪海波况洪福张伟吴忠伟杨志清
Owner ZHEJIANG HISUN PHARMA CO LTD
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