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Preparation method of afatinib maleate

A technology of afatinib maleate and afatinib acid is applied in the field of pharmaceutical preparation, which can solve the problems of reducing yield and quality, and the existence of impurities in the product afatinib maleate, and achieves no solvent residue, The effect of stable properties and low impurity content

Active Publication Date: 2019-12-13
广东安诺药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in this preparation method, due to the presence of enantiomers in the raw materials, there are impurities in the product Afatinib maleate, which reduces the yield and quality.

Method used

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  • Preparation method of afatinib maleate
  • Preparation method of afatinib maleate
  • Preparation method of afatinib maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1. Preparation of afatinib maleate

[0027] S1) Preparation of Intermediate I

[0028] The chemical reaction equation is:

[0029]

[0030] Take 3.58L of tetrahydrofuran and N,N-carbonyldiimidazole (1433g, 8.84mol) and mix and stir at room temperature. Slowly add 2.43L solution of diethyl phosphoacetic acid (1734g, 8.84mol) in tetrahydrofuran. After 30min, the temperature is controlled 40. Stir at ℃ for 30min until the solution is clear, and obtain reaction solution A; add 7.65L of tetrahydrofuran and N 4 -(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazolindiamine (2550g, 6.8mol) was added to In the reactor A, stir at room temperature, add the above-mentioned reaction solution A, control the temperature at 40° C. and stir for 1 h. After the TLC monitors that the reaction is complete, the temperature is lowered to 8° C., filtered and dried to obtain Intermediate I.

[0031] Among them, thin-layer chromatography monitoring uses dichloromethane:metha...

Embodiment 2～3

[0042] Examples 2~3. Preparation of afatinib maleate

[0043] The difference from Example 1 lies in the fact that the amounts of raw materials in the Examples 2 to 3 are different. See Table 1 for details.

[0044] Table 1 Example 2~3 Formula (AF-I) Afatinib Maleate Intermediate Raw and Auxiliary Materials

[0045]

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PUM

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Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of afatinib maleate. The preparation method of the afatinib maleate comprises thefollowing steps: reacting N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furanyl]oxy]-4-quinazolinediamine with diethyl phosphonoacetic acid to obtain an intermediate I, adding dimethylaminoacetaldehyde diethyl acetal, carrying out a Horner-Wadsworth-Emmons reaction to obtain an intermediate II, and finally salifying the intermediate II and maleic acid to obtain the afatinib maleate. The afatinib maleate prepared in the invention has the advantages of low impurity content, no residual of a solvent used in refining, and stable properties.

Description

Technical field [0001] The invention belongs to the technical field of medicine preparation, and specifically relates to a preparation method of afatinib maleate. Background technique [0002] Afatinib maleate is a potent and irreversible dual inhibitor of skin growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinase developed by Boehringer Ingelheim, Germany Its principle of action is to irreversibly inhibit the activity of the tyrosine kinase through the Michael reaction with the sulfhydryl group of the cysteine ​​797 in EGFR, interrupting downstream information transmission, thereby preventing the growth of cancer cells. And induce cancer cell apoptosis. [0003] At present, Chinese patent CN200480030555 discloses the following synthetic routes: [0004] [0005] The patent uses SM1 as the starting material, reacts with SM2 under the action of carbonyl diimidazole to obtain formula IIIa, then conducts Horner-Wadsworth-Emmons reaction with...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07C57/145C07C51/41
CPCC07C51/412C07C57/145C07D405/12
Inventor 曹祺黄慧云潘翠萍陈锐东陈少帆
Owner 广东安诺药业股份有限公司