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A kind of 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 lowering yield and quality, the existence of impurities in the product afatinib maleate, and achieving no solvent residue, The effect of stable properties and low impurity content

Active Publication Date: 2020-05-19
GUANGDONG ANNOL PHARM CO LTD
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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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  • A kind of preparation method of afatinib maleate
  • A kind of preparation method of afatinib maleate
  • A kind of preparation method of afatinib maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1, the preparation of Afatinib maleate

[0027] S1) Preparation of Intermediate I

[0028] The chemical reaction equation is:

[0029]

[0030] Take 3.58 L of tetrahydrofuran and N,N-carbonyldiimidazole (1433 g, 8.84 mol) and mix and stir at room temperature, slowly add diethylphosphonoacetic acid (1734 g, 8.84 mol) in 2.43 L of tetrahydrofuran solution, complete the addition in 30 minutes, and control the temperature for 40 ℃ and stirred for 30min until the solution was clear to obtain reaction solution A; 7.65L of tetrahydrofuran and N 4 -(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine (2550g, 6.8mol) was added to In reaction kettle A, stir at room temperature, add the above-mentioned reaction solution A, and stir at 40°C for 1 hour. After the completion of the reaction is monitored by thin-layer chromatography, cool down to 8°C, filter, and dry to obtain intermediate I.

[0031] Among them, thin-layer chromatography...

Embodiment 2～3

[0042] Embodiment 2~3, the preparation of Afatinib maleate

[0043] The difference from Example 1 is that the amount of raw materials used in Examples 2-3 is different, see Table 1 for details.

[0044] Table 1 embodiment 2~3 formula (AF-I) afatinib maleate intermediate raw material feeding amount

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

Claims

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Application Information

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Patent Type & Authority Patents(China)
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 GUANGDONG ANNOL PHARM CO LTD
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