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Preparation method of afatinib and maleate thereof

A technology of afatinib and afatinib maleate, which is applied in the field of drug synthesis, can solve problems such as hidden dangers of drug safety for patients, excessive content of impurity I, and impact on drug quality, and achieves simple operation, mild reaction conditions, and high purity. high effect

Pending Publication Date: 2018-08-03
NORTHEAST PHARMA GRP
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, there are two major defects in the second preparation method of Afatinib maleate: 1. In the process of synthesizing Afatinib, the impurity I (i.e. raw material IV) content is too high due to the presence of a vacuum distillation concentration step in the post-treatment (0.40-0.50%, HPLC), finally causing the content of impurity I in the final product afatinib maleate to exceed the standard (limit regulation≤0.10%, HPLC); The content of impurity II (formula V) in the final product afatinib maleate exceeds the standard (limit regulation ≤0.20%, HPLC)
Exceeding the standard of impurity I and impurity II will seriously affect the quality of the drug and bring hidden dangers to the safety of patients

Method used

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  • Preparation method of afatinib and maleate thereof
  • Preparation method of afatinib and maleate thereof
  • Preparation method of afatinib and maleate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: Preparation of crude afatinib

[0021] Add 3.76kg of (E)-4-dimethylaminocrotonic acid hydrochloride and 36kg of N-methylpyrrolidone to a 100L reaction kettle, stir and cool to -5°C, and slowly add chlorine to the stirring solution. 2.56kg of sulfoxide to ensure that the temperature of the reaction solution is between 0 and -5°C, and stir for 20 minutes in the above temperature range after the dripping. Dissolve 4.85 kg of N-4-[(3-chloro-4-fluorophenyl)]-7-{[(3S)-tetrahydrofuran-3-yl]oxy}-4,6-quinazoline diamine in 24kg of N-methylpyrrolidone is used as a dropping liquid. Add this solution slowly to the above stirring liquid and ensure that the temperature is between 0~-5℃. After the dropping, stir for 15 minutes in the above temperature range to obtain the acylation reaction liquid. . Then add 10 kg of water dropwise, control the temperature not to exceed 15°C, transfer the above reaction liquid to a 500L reactor, slowly add 29 kg of water to the reaction solu...

Embodiment 2

[0022] Example 2: Preparation of crude afatinib

[0023] Add 19.3 g of (E)-4-dimethylamino crotonic acid hydrochloride and 185 g of N-methylpyrrolidone into a 1000 ml four-necked flask, stir and cool to -5°C, and slowly add dropwise to the stirring liquid 13.2g of thionyl chloride to ensure that the temperature of the reaction solution is between 0 and -5°C, and stir for 20 minutes in the above temperature range after the dripping is completed. Dissolve 24.9 g of N-4-[(3-chloro-4-fluorophenyl)]-7-{[(3S)-tetrahydrofuran-3-yl]oxy}-4,6-quinazoline diamine in 123g of N-methylpyrrolidone was used as a dropping solution, slowly adding this solution to the above stirring solution and ensuring that the temperature was between 0 to -5°C, and stirring within the above temperature range for 15 minutes after dropping to obtain an acylation reaction solution. Then, 200 g of water was slowly added dropwise to the above reaction solution and the temperature was controlled to not exceed 15°C, a...

Embodiment 3

[0026] Example 3: Preparation of crude afatinib

[0027] Add 9.65 g of (E)-4-dimethylamino crotonic acid hydrochloride and 93 g of N-methylpyrrolidone in a 500ml four-necked flask, stir and cool to -5°C, slowly add dropwise to the stirring solution 6.6 g of thionyl chloride to ensure that the temperature of the reaction solution is between 0 and -5°C, and stir for 20 minutes in the above temperature range after the dropping. Dissolve 12.45 g of N-4-[(3-chloro-4-fluorophenyl)]-7-{[(3S)-tetrahydrofuran-3-yl]oxy}-4,6-quinazoline diamine in 62g of N-methylpyrrolidone was used as a dropwise addition solution. The solution was slowly added dropwise to the above-mentioned stirring solution and the temperature was ensured to be between 0 and -5°C. After the dropping, the solution was stirred in the above-mentioned temperature range for 15 minutes to obtain an acylation reaction solution. Then, 100 g of water was slowly added dropwise to the above reaction solution and the temperature wa...

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Abstract

The invention belongs to the technical field of synthesis of compounds, and relates to a preparation method of afatinib and maleate thereof. The preparation method comprises the following steps: in the presence of a first organic solvent, adopting N-4-[(3-chloro-4-fluorophenyl)]-7-{[(3S)-tetrahydrofuran-3-group]oxo}-4,6-quinazoline diamine as a raw material to have the acylation reaction with (E)-4-dimethyl amino crotonate hydrochloride to obtain an acylation reaction solution under the effect of thionyl chloride, water and alkaline water are added into the acylation reaction solution, the water phase is extracted by virtue of butyl acetate, an organic phase is collected, after the organic phase is washed, the organic phase is directly stirred and precipitated to obtain an afatinib crude product, then the afatinib crude product is refined to obtain a competitive product, and the competitive product reacts with maleic acid to obtain maleic acid afatinib. The method has the characteristics of being high in product yield, high in purity, low in impurity content, mild in reaction conditions, simple in operation, suitable for industrialized production and the like.

Description

Technical field [0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a method for preparing afatinib and its maleate. Background technique [0002] Afatinib Dimaleate, chemical name (2E)-N-{4-(3-chloro-4-fluoroanilino)-7-[(3S)-3-tetrahydrofuranoxy]- 6-quinazolinyl}-4-dimethylamino-2-butenamide, (2Z)-2-butenedioic acid (1:2), the structural formula is as formula I: [0003] [0004] Developed by Boehringer Ingelheim, Germany, it was approved by the U.S. FDA in July 2013 for the treatment of metastatic non-small cell lung cancer with EGFR exon 19 deletion mutations or exon 21 substitution mutations. The drug is the world's first irreversible dual inhibitor of human epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinase, and it can treat non-small cells with EGFR and HER2 overexpression. Lung cancer tissue has a strong inhibitory effect. [0005] At present, there are two main methods f...

Claims

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Application Information

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IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 孙冰赵会王玉军杨亚圣吴静
Owner NORTHEAST PHARMA GRP
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