Preparation method and application of icotinib intermediate

A technology of icotinib and intermediates, which is applied in the field of chemical synthesis and can solve the problems of high environmental pollution, low yield of target product, large pollutant discharge and the like

Pending Publication Date: 2022-04-05
ZHEJIANG TOP MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the production process in the prior art, a large amount of toxic additives, such as phosphorus oxychloride, will be added, the discharge of pollutants is relatively large, the pollution to the environment is large, and the yield of the target product is low

Method used

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  • Preparation method and application of icotinib intermediate
  • Preparation method and application of icotinib intermediate
  • Preparation method and application of icotinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] A preparation method of an icotinib intermediate, comprising the following steps;

[0036] (1) Add triethylene glycol to the alkaline mixed solution, the alkaline mixed solution is added with four

[0037] The mass concentration of hydrofuran is 32% sodium hydroxide solution, and the mixed solution of p-toluenesulfonyl chloride and tetrahydrofuran is added dropwise to carry out esterification reaction. After the reaction is completed, cool, filter, and dry to obtain product 1, the structural formula of product 1 as follows;

[0038]

[0039] (2) Mix the product 1, 3,4 dihydroxybenzonitrile and add dropwise to the mixture of acetonitrile and potassium carbonate

[0040] In the combined solution, carry out cyclization reaction, cool after reaction, filter, dry, obtain product 2, the structural formula of product 2 is as follows;

[0041]

[0042] The reaction equation in this step is as follows;

[0043] The key to this step is ring closure, which has formed ...

Embodiment 2

[0058] A preparation method of an icotinib intermediate, comprising the following steps;

[0059] (1) Add triethylene glycol to the alkaline mixed solution, the alkaline mixed solution is added with four

[0060] The mass concentration of hydrofuran is 33% sodium hydroxide solution, and the mixed solution of p-toluenesulfonyl chloride and tetrahydrofuran is added dropwise to carry out esterification reaction. After the reaction is completed, it is cooled, filtered, and dried to obtain product 1, the structural formula of product 1 as follows;

[0061]

[0062] (2) Mix the product 1, 3,4 dihydroxybenzonitrile and add dropwise to the mixture of acetonitrile and potassium carbonate

[0063] In the combined solution, carry out cyclization reaction, cool after reaction, filter, dry, obtain product 2, the structural formula of product 2 is as follows;

[0064]

[0065] The reaction equation in this step is as follows;

[0066] The key to this step is ring closure, which...

Embodiment 3

[0082] A preparation method of an icotinib intermediate, comprising the following steps;

[0083] (1) Add triethylene glycol to the alkaline mixed solution, the alkaline mixed solution is added with four

[0084] The mass concentration of hydrofuran is 35% sodium hydroxide solution, and the mixed solution of p-toluenesulfonyl chloride and tetrahydrofuran is added dropwise to carry out esterification reaction. After the reaction is completed, cool, filter, and dry to obtain product 1, the structural formula of product 1 as follows;

[0085]

[0086] (2) Mix the product 1, 3,4 dihydroxybenzonitrile and add dropwise to the mixture of acetonitrile and potassium carbonate

[0087] In the combined solution, carry out cyclization reaction, cool after reaction, filter, dry, obtain product 2, the structural formula of product 2 is as follows;

[0088]

[0089] The reaction equation in this step is as follows;

[0090] The key to this step is ring closure, which has formed ...

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PUM

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Abstract

The invention provides a preparation method and application of an icotinib intermediate, and belongs to the technical field of chemical synthesis. The preparation method comprises the following steps: (1) adding triethylene glycol into an alkaline mixed solution, and dropwise adding a mixed solution of paratoluensulfonyl chloride and tetrahydrofuran to obtain a product 1; (2) mixing the product 1, 3, 4-dihydroxybenzonitrile, dropwise adding the mixture into a mixed solution of acetonitrile and potassium carbonate, and carrying out cyclization reaction to obtain a product 2; (3) dissolving the product 2 in glacial acetic acid, and dropwise adding fuming nitric acid and concentrated sulfuric acid to obtain a product 3; (4) dissolving the product 3 in a mixed solution 1 of acetic acid and ethanol, and adding iron powder to generate an icotinib intermediate product BPI-X04; (5) dissolving the icotinib intermediate product BPI-X04 in methylbenzene, and then adding N, N-dimethyl dimethyl acetal, so as to obtain an icotinib intermediate product BPI-X05; the process provided by the invention effectively reduces the discharge amount of pollutants, does not add highly toxic additives such as phosphorus oxychloride, and greatly improves the yield.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method and application of an icotinib intermediate. Background technique [0002] Tumor is a human body affected by various carcinogenic factors, a certain cell in a local tissue loses its normal growth regulation at the genetic level, resulting in abnormal proliferation of cell clones, thereby forming a new organism. Scientific research now generally believes that most tumor cells are monoclonal, that is, all tumor cells in a certain tumor are the offspring of a mutant cell. Tumors are now divided into two categories, benign and malignant. Malignant tumors are collectively referred to as cancer. Tumor cells have abnormal morphology, metabolism and function, and have lost the ability to differentiate and mature to varying degrees. Tumors grow vigorously and are relatively autonomous. Even if the tumorigenic factors no longer exist, they can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D323/00C07D491/056
Inventor 谢再法姚凤鸣郭锋燕
Owner ZHEJIANG TOP MEDICINE
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