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Method for synthesizing 1-methylindole as Tagrisso intermediate

A technology of methyl indole and synthetic method, which is applied in the field of organic synthesis, can solve the problems of being prone to danger, unsuitable for laboratory and industrial production, etc., and achieves the effects of simple post-processing, stable product quality and simple operation

Inactive Publication Date: 2017-06-20
SHANDONG GREEN BIO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This method uses highly toxic dimethyl sulfate, and the preparation process is prone to danger, so it is not suitable for laboratory and industrial production

Method used

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  • Method for synthesizing 1-methylindole as Tagrisso intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 140.6g of cyclopentanone, 20g of indole, 10g of potassium carbonate, and 10.3g of dimethyl carbonate into the reaction flask, stir, and raise the temperature to 120°C for a reflux reaction. After 2 hours of reaction, stop heating and wait for no reflux , Sampling detection, the purity of the intermediate state is above 99%; add 5.1g of dimethyl carbonate, heat up to 115°C to reflux, and react for 4 hours; then drop to room temperature and add 3.3g of dimethyl carbonate, heat up to 115°C to Reflux and continue to react for 2 hours; then drop to room temperature and add 3.3 g of dimethyl carbonate, raise the temperature to 115°C to reflux and continue to react for 12 hours; About 90% of the solvent is distilled under high pressure, the pressure is about 0.1MP, and the temperature is about 50-70°C. It must be slow at the beginning, otherwise, add 200g of water to the remaining product, stir for 30 minutes, and stand at 30-35°C Place for 2 hours, separate layers, the lo...

Embodiment 2

[0034] Add 100.4g of cyclopentanone, 16g of indole, 8g of potassium carbonate, and 8.4g of dimethyl carbonate into the reaction flask, stir, and raise the temperature to 120°C for a reflux reaction. Stop heating after 2 hours of reaction, and wait for no reflux. Sampling and testing. The purity of the intermediate state is above 99%; add 4.1g of dimethyl carbonate, raise the temperature to 116°C to reflux, and react for 4 hours; then cool down to room temperature, add 3.1g of dimethyl carbonate, raise the temperature to 116°C to reflux to continue the reaction 2 hours; then lowered to room temperature and added 3.1 g of dimethyl carbonate, raised the temperature to 116°C to reflux and continued to react for 12 hours; stopped heating, waited for no reflux, took a sample for detection, the remaining raw materials were less than 2%, stopped the reaction, and distilled out under reduced pressure About 90% of the solvent, the pressure is about 0.1MP, the temperature is about 50-55°C...

Embodiment 3

[0036] Add 160.7g of cyclopentanone, 22g of indole, 12g of potassium carbonate, and 11.24g of dimethyl carbonate into the reaction flask, stir, and raise the temperature to 120°C for a reflux reaction. Stop heating after 2 hours of reaction, and wait for no reflux. Sampling and testing. The purity of the intermediate state is above 99%; add 6.2g of dimethyl carbonate, raise the temperature to 120°C to reflux, and react for 4 hours; then lower the temperature to room temperature and add 4.1g of dimethyl carbonate, raise the temperature to 120°C to reflux to continue the reaction 2 hour; then drop to room temperature and add 4.1g of dimethyl carbonate, heat up to 120°C to reflux and continue to react for 12 hours; stop heating, wait for no reflux, take a sample for detection, the remaining raw material is less than 2%, stop the reaction, and distill out about 90% solvent, the pressure is about 0.1MP, the temperature is about 65-70°C, it should be slow at the beginning, otherwise,...

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Abstract

The invention relates to the field of organic synthesis, and in particular to a method for synthesizing 1-methylindole as a Tagrisso intermediate. The method for synthesizing 1-methylindole as a Tagrisso intermediate is characterized in that solvent, indole, alkali and dimethyl carbonate are adopted as materials, operation is simple, the reaction materials are easy to obtain, the price is reasonable, reaction conditions are mild, control is easy, post-processing is simple, the usage of the highly toxic product, dimethyl sulfate, is avoided, 1-methylindole is nontoxic and harmless, the method belongs to a green synthesis process, moreover, the quality of the product is stable, the purity is high, yield is high, and the method is suitable for lab and industrialized production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for synthesizing a Tagres intermediate 1-methylindole. Background technique [0002] 1-Methylindole is a key intermediate in the synthesis of Targreese. On January 7, 2016, the FDA approved the official launch of AstraZeneca's new drug Targres, which is a drug for the treatment of advanced non-small cell lung cancer. Non-small cell lung cancer accounts for about 80% of all lung cancers, and about 75% of patients are in the middle and advanced stages when they are discovered. In recent decades, the incidence and mortality of lung cancer have risen rapidly in countries all over the world, especially in industrialized countries. Lung cancer is the leading cause of death among various cancers in men, and the second only to breast cancer in women. 1-Methylindole is also an important intermediate in other organic synthesis, mainly used in pharmaceutical intermediates, and ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08
CPCC07D209/08
Inventor 陈成文方金印颜猛
Owner SHANDONG GREEN BIO PHARMA CO LTD
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