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Preparing method of Avitinib

A technology of avitinib and tinib, applied in the field of preparation of avitinib, can solve problems such as toxicity and poor effect of T790M mutation, and achieve the effects of simple operation, high yield and optimized reaction route

Inactive Publication Date: 2019-11-05
重庆化工职业学院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second-generation EGFR inhibitors can irreversibly bind to EGFR, but are not effective against the T790M mutation, and can still bind to wild-type to produce toxicity
However, only a small amount of literature has reported the preparation method of Avitinib

Method used

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  • Preparing method of Avitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] A preparation method of Avitinib, the reaction scheme is as follows:

[0021]

[0022] Include the following steps:

[0023] A. Combine 2,4-dichloropyrrolopyrimidine with XPhos and Pd 2 (dba) 3 and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline were dissolved in a propanol solvent, and reacted to obtain intermediate I;

[0024] B, the 3-nitrophenol that tBu protects is dissolved in ethanol solvent, add iron powder and ammonium chloride, obtain the 3-aminophenol of tBu protection;

[0025] C. Dissolve tBu-protected 3-aminophenol and diisopropylethylamine in dichloromethane, add isopentenyl chloride dropwise, and react to obtain intermediate II;

[0026] D, intermediate II is refluxed in a trifluoroacetic acid solvent, and tBu is removed to obtain intermediate III;

[0027] E. Mixing and reacting intermediate I, intermediate III and dimethylformamide to obtain a final product. The final product is isolated and purified by preparative HPLC or preparative LC / MS, or by o...

Embodiment 2

[0029] This embodiment is on the basis of embodiment 1:

[0030] In the described A step and E step, all add Na 2 CO 3 Participate in the reaction, and Na 2 CO 3 The added mass is the same as intermediate I. The yield was 72%.

Embodiment 3

[0032] This embodiment is on the basis of embodiment 1:

[0033] In the described A step and E step, all add Na 2 CO 3 Participate in the reaction, and Na 2 CO 3 The added mass is the same as intermediate I.

[0034] In the step A, the reaction was stirred under nitrogen protection at 100°C. The yield was 71%.

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Abstract

The invention discloses a preparing method of Avitinib. The method includes the following steps of A, dissolving 2,4-dichloropyrimidine, XPhos, Pd2(dba)3 and 3-floro-4-(4-methyl piperazine-1-yl)aniline in a propyl alcohol solvent for reaction to obtain an intermediate I; B, dissolving tBu-protected 3-nitrophenol in an ethyl alcohol solvent, and adding iron powder and ammonium chloride to obtain tBu-protected 3-amino-phenol; C, dissolving the tBu-protected 3-amino-phenol and diisopropylethylamine in dichloromethane, and dropwise adding isopentyl chloride for reaction to obtain an intermediate II; D, making the intermediate II flow backwards in a rifluoroacetic acid solvent, and removing tBu protection to obtain an intermediate III; E, mixing the intermediate I, the intermediate III and dimethylformamide for reaction to obtain the end product. The method is simple in operation and high in yield.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of Avitinib. Background technique [0002] Lung cancer is divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), of which NSCLC accounts for 85% of the incidence of lung cancer, and most NSCLC patients are in unresectable locally advanced or distant metastasis when they are diagnosed. Epidermal growth factor receptor (EGFR) is currently one of the most attractive targets in the field of non-small cell lung cancer drugs. There are three generations of EGFR inhibitors on the market. The first generation of EGFR inhibitors, such as gefitinib and erlotinib, irreversibly bind to EGFR and specifically target sensitive mutations in exons 19 and 21 of EGFR, but also bind to wild-type EGFR, causing toxic side effects such as diarrhea and rash. Patients using the first-generation EGFR usually develop drug resistance with...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 王元忠曾祥燕
Owner 重庆化工职业学院
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