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HomeNewsSynthesis of anti tumor drug erlotinib hydrochloride

Synthesis of anti tumor drug erlotinib hydrochloride

2021-01-29
In the traditional synthesis process of Erlotinib Hydrochloride, the synthesis environment is not friendly, there are many by-products and the yield is low, which seriously affects the long-term development of the pharmaceutical industry of the synthesis of erlotinib hydrochloride, and then can not give full play to the value of erlotinib hydrochloride.

Anti tumor drugs

With the deepening of life science research, cell proliferation, apoptosis, regulation, signal transduction, extracellular matrix changes and other aspects of tumor cells are being solved, and the corresponding research and development of anti-tumor drugs are also in constant progress. At present, erlotinib hydrochloride as a specific target with high efficiency and low side effects of anti-cancer drugs is an important development direction in the current medical anti-tumor drug research.

Among the traditional anti-tumor drugs, the drugs have certain toxicity. Although they can kill cancer cells, they also pose a certain threat to other normal working cells of the human body. At present, the research and development of anti-tumor drugs can only avoid the harm of traditional cytotoxic drugs to human normal cells, mainly focus on the signal transduction pathways in tumor cells, and actively develop new anti-tumor drugs. The research and development of targeted anti-tumor drugs is a new kind of drugs for cell receptors, key genes and patients' feelings. At present, there are many researches on anti-tumor drugs targeting protein tyrosine kinase in the market.

Protein tyrosine kinase (PTK) as the main target of anti-tumor drugs (PTK inhibitors, the main PTK in the market) Inhibitors (imatinib, gefitinib, erotinib, etc.) can react with ATP binding sites, thus interfering with the actual binding between tyrosine kinase and ATP, which has been the actual activity of tyrosine kinase, and finally tyrosine autophosphorylation, blocking the downward transmission pathway of epidermal growth factor receptor signal, and ultimately killing tumor cells .

Erlotinib hydrochloride

The chemical name of erlotinib hydrochloride is n - (3-ethynylphenyl) - [6,7-bis (2-methoxyethoxy)] - quinazoline-4-amine hydrochloride, and its chemical structure is shown in Fig. 1. Erlotinib hydrochloride is a 4-anilinoquinazoline oral anticancer drug. It is used in the treatment of advanced pancreatic cancer in the early stage, and has been applied in more than 80 countries all over the world.

Erlotinib hydrochloride is a molecular targeted drug. Its main function is to inhibit EGFR-TK by combining ATP and TK in cells, and then block the growth of tumor cells and induce their death. In addition, erlotinib hydrochloride can also effectively inhibit its growth rate and survival probability due to its anticancer activity [1].

Main synthesis of erlotinib hydrochloride

1) Ethyl 3,4-bis (2-methoxyethoxy) benzoate was synthesized from ethyl 3,4-dihydroxybenzoate and 2-chloroethyl methyl ether. Ethyl 2-amino-4,5-bis (2-methoxyethoxy) benzoate was synthesized by selective nitration and nitro reduction. Quinazoline was obtained by cyclization with formamide and formamide, and then chlorinated with dichlorosulfoxide to give 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline, the intermediate of erlotinib. The chlorinated product reacted with 3-aminophenylacetylene to obtain erlotinib. In this way, the total yield can reach 30%. In the whole synthesis process, selective nitrification and ring closing are the key points in the reaction, which will produce impurities, but the overall synthesis reaction is not demanding, and the process can be enlarged.

2) 2-amino-4,5-dimethoxybenzoic acid was synthesized by the reaction of 3,4-dimethoxyaniline with chloral hydrate and hydroxylamine hydrochloride, closed-loop reaction in concentrated sulfuric acid and treatment with hydrogen peroxide. Subsequently, quinazolinone was obtained by cyclization of N, n '- carbonyldiimidazole with 1-hydroxybenzotriazole using formamide. After chlorination, quinazolinone reacted with m-aminophenylacetylene, aluminum trichloride was demethylated, hydroxyl group was etherified by ethylene glycol p-toluenesulfonate monomethyl ether, and subsequent salification to obtain erlotinib hydrochloride. This method opens up a new way of thinking, but the reaction of the whole synthesis step is longer, the cost of raw materials is higher, compared with 3.1 synthesis method, there is no advantage of actual scale-up production.

4 overall analysis

Among the above synthetic processes, the main problems are as follows: ① incomplete etherification reaction; ② room for improvement in catalytic reaction; ③ obvious exothermic nitrification, which brings risks to scale-up production; ④ climbing rod phenomenon in chlorination reaction. In view of the above problems, mainly through the control of raw material ratio, reaction temperature, time and other aspects in the synthesis of erlotinib hydrochloride, the process can be optimized and improved, and the production of reaction by-products in different steps can be controlled, so as to optimize the synthesis process of erlotinib hydrochloride.

5 Conclusion

To sum up, as an effective measure for the treatment of lung cancer and advanced pancreatic cancer, the corresponding synthesis process of erlotinib hydrochloride has some shortcomings, which leads to the high cost of synthesis and low total yield of erlotinib hydrochloride, which can not play the real value of erlotinib hydrochloride. Through the analysis of the synthesis methods of erlotinib hydrochloride, the optimization of the synthesis of erlotinib hydrochloride was studied, in order to lay a solid foundation for giving full play to the real value of erlotinib hydrochloride and expanding the commercial production of erlotinib hydrochloride.

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