Method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester

A technology of ethyl indole carboxylate and acetoxy, which is applied in the field of preparation of intermediates, can solve the problems of many by-products, increase costs, and high prices, and achieve the effects of reducing the generation of three wastes, mild reaction conditions, and simple equipment

Active Publication Date: 2012-11-21
ZHEJIANG GENEBEST PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 1. In the paper "Synthesis of Arbidol Hydrochloride" (Journal of China Pharmaceutical Industry, 2004, 35 (8), 457-458), it is mentioned that p-benzoquinone and ethyl 3-aminocrotonate are used as raw materials. The key intermediate 1-methyl-2-bromomethyl-5-acetoxy-6-bromo-3-indole carboxylic acid ethyl ester is prepared by reactions such as oxidation, protection, alkylation and bromination, and the method operation is relatively It is simple and convenient, and the yield is also good, but the raw material 3-aminocrotonate ethyl ester used in it is more irritating, which has certain hidden dangers to production safety and workers' health, and the domestic price is relatively expensive, and the three wastes produced by the process are more. The processing cost is high, which directly leads to the high production cost of the product
[0005] 2. Paper "1-methyl-2-bromomethyl-5-acetoxy-6-bromo-1H-indole-3-carboxylic acid ethyl ester" (Fine and Specialty Chemicals, 2007, 15 (13) , 14-16) mentioned that 3-methylamino-2-butenoic acid ethyl ester and p-benzoquinone can also be used as raw materials to obtain the key intermediate 1-methyl-2 -Bromomethyl-5-acetoxy-6-bromo-3-indole carboxylic acid ethyl ester, the method uses easy-to-get raw materials to prepare 3-methylamino-2-butenoic acid ethyl ester in advance, which can effectively Reduce costs, but the yield of the cyclization step is too low, only 52%, resulting in more by-products, difficult post-processing and separation and purification, which also affects product quality while increasing costs

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] A. Preparation of 2-chloro-4-acetoxynitrobenzene

[0032] Add 3-chloro-4-nitrophenol (173.5g, 1.0mol) and acetone (1735g) into the reaction flask, stir evenly, then continue to add potassium carbonate (151.8g, 1.1mol), and heat up to 40°C after the addition , after stirring for 10 minutes, slowly add acetyl chloride (86.3g, 1.1mol) dropwise to it, the temperature of the reaction mixture does not exceed 50°C during the dropwise addition, remove the heating device after the dropwise addition, continue to stir the reaction for 6 hours, after the end of the reaction The mixed solution was poured into ice water, and the solid was precipitated, collected by filtration, and dried to obtain the crude product 2-chloro-4-acetoxynitrobenzene. The crude product was recrystallized with 347 g of anhydrous methanol to obtain a light yellow solid, which was 2-chloro-4- The refined product of 4-acetoxynitrobenzene (207.9g), the yield is about 96.5%.

[0033] Melting point: 67-68°C, 1...

Embodiment 2

[0043] Other steps are identical with embodiment 1, just the preparation method of the 2-chloro-4-acetoxynitrobenzene of A step is as follows:

[0044] Add 3-chloro-4-nitrophenol (173.5g, 1.0mol) and acetone (350g) into the reaction flask, stir evenly, continue to add potassium carbonate (138g, 1.0mol), and heat up to 40°C after the addition is complete. After stirring for 10 minutes, slowly add acetyl chloride (78.5g, 1.0mol) dropwise to it. During the dropwise addition, the temperature of the reaction mixture does not exceed 50°C. After the dropwise addition, remove the heating device and continue stirring for 4 hours. After the reaction, mix The solution was poured into ice water, and the solid was precipitated, collected by filtration, and dried to obtain the crude product 2-chloro-4-acetoxynitrobenzene. The crude product was recrystallized with 347g of anhydrous methanol to obtain a light yellow solid, which was 2-chloro-4 -Acetoxynitrobenzene fine product (188.3g), the y...

Embodiment 3

[0046] Other steps are identical with embodiment 1, just the preparation method of the 2-chloro-4-acetoxynitrobenzene of A step is as follows:

[0047] Add 3-chloro-4-nitrophenol (173.5g, 1.0mol) and acetone (1000g) into the reaction flask, stir evenly, continue to add potassium carbonate (145g, about 1.05mol), and heat up to 40°C after the addition , after stirring for 10 minutes, slowly add acetyl chloride (82.5g, about 1.05mol) dropwise, the temperature of the reaction mixture does not exceed 50°C during the dropwise addition, remove the heating device after the dropwise addition, continue stirring for 5 hours, and the reaction ends Afterwards, the mixed solution was poured into ice water, and the solid was precipitated, collected by filtration, and dried to obtain the crude product 2-chloro-4-acetoxynitrobenzene. The crude product was recrystallized with 347 g of anhydrous methanol to obtain a light yellow solid, which was 2-chloro -4-Acetoxynitrobenzene fine product (195....

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Abstract

A method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester. The invention relates to a method for preparing the 5-acetoxyl-3-indole carboxylic acid ethyl ester which is a key intermediate of a widely-used antiviral drug Arbidol Hydrochloride. The method successively comprises the following steps that, by using 3-chlorine-4-nitrophenol as raw materials, phenolic hydroxyl groups are reacted with an acetylation reagent, then products obtained are subjected to a substitution reaction with sodium salt of malonate, and at last a hydrogenated cyclization reaction is carried out under pressurized conditions to get the 5-acetoxyl-3-indole carboxylic acid ethyl ester. The method provides a novel synthesizing route, and has advantages of concise steps, simple technology and cheap and easily-available raw materials. Each reaction step is relatively conventional operations and production cost can be effectively reduced.

Description

technical field [0001] The invention relates to a method for preparing an intermediate of antiviral drug Arbidol hydrochloride, in particular to a method for preparing ethyl 5-acetoxy-3-indolecarboxylate. Background technique [0002] Arbidol Hydrochloride is a kind of broad-spectrum antiviral drug developed by the former Soviet Medicinal Chemistry Research Center. Its chemical name is 6-bromo-4-dimethylaminomethyl-5-hydroxy-1-methyl Ethyl-2-(phenylthiomethyl)-1H-indole-3-carboxylate hydrochloride, the drug was first listed in Russia in 1993, and it is a monohydrate for medicinal purposes. The drug not only has immunomodulatory effects In addition to the induction of interferon, it also has good antiviral activity and is clinically used to prevent and treat influenza and other acute viral respiratory infections. [0003] The main production process of the drug is similar at present, the main difference lies in the preparation method of its key intermediate 1-methyl-2-bromom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/42
CPCY02P20/584
Inventor 宋苗根王金银
Owner ZHEJIANG GENEBEST PHARMA
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