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Preparation method of arbidol hydrochloride

A technology of arbidol hydrochloride and molar ratio, which is applied in the field of medicine and chemical industry, can solve the problems of low total reaction yield, low total yield and the like, and avoid the problems of low reaction yield, low production cost and high yield. Effect

Active Publication Date: 2016-11-09
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] 2. Song Yanling, Zhao Yanfang, Gong Ping and others reported in the literature "Synthesis of Arbidol Hydrochloride" that the substitution reaction between thiophenol and ethyl chloroacetoacetate occurred first, and the thiophenyl segment in the molecule was introduced, and then combined with Methylamine is condensed, followed by Nenitzescu reaction with p-benzoquinone, dimethylaminomethyl is introduced through Mannich reaction, bromination reaction is carried out after acetylation protection reaction, then deprotection reaction, and finally Arbidol hydrochloride is obtained through salt formation, The yield of the Nenitzescu reaction of this method has only 33.7%, causes total yield lower (11.2%); Its synthetic route is as follows:
[0010] The above synthetic methods of Arbidol hydrochloride all use the Nenitzescu indole ring synthesis method to synthesize the indole ring of Arbidol hydrochloride, resulting in a low overall reaction yield, about 10-20%.

Method used

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  • Preparation method of arbidol hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1-1

[0039] Example 1-1: Preparation of 4-acetoxyaniline (7)

[0040] P-nitrophenol (9, 1.0mol, 139.1g) was added to 1000mL of acetone, 151.8g (1.5mol) of triethylamine was added, 196.3g of acetyl chloride (2.5mol) was added dropwise at room temperature, the dropwise was completed within 1 hour, and reflux reaction 1 Hours, naturally cooled to room temperature, the reaction solution was poured into 2000g of ice water, stirred, filtered, the filter cake was washed with water, and vacuum-dried to obtain 183.2g of p-nitrophenyl acetate (8) crude product. The next reaction was carried out directly without further purification.

[0041] Add 3000mL of water and 3000mL of ethanol to the reaction flask, add reduced iron powder (139.6g, 2.5mol) and ammonium chloride (133.7g, 2.5mol) under stirring, heat to reflux for 1h, and add the above-prepared p- Nitrophenyl acetate (8, 183.2g), continued to reflux for 2h, and TLC confirmed that the reaction was complete. Stop the reaction, suction fi...

Embodiment 1-2

[0042] Embodiment 1-2: Preparation of 4-acetoxyaniline (7)

[0043] P-nitrophenol (9, 1.0mol, 139.1g) was added to 1000mL of acetone, 158.2g (2mol) of pyridine was added, 196.3g of acetyl chloride (2.5mol) was added dropwise at room temperature, the dripping was completed within 1 hour, and the reaction was refluxed for 3 hours, naturally After cooling to room temperature, the reaction solution was poured into 2000 g of ice water, stirred, filtered, the filter cake was washed with water, and vacuum-dried to obtain 187.5 g of crude p-nitrophenyl acetate (8). The next reaction was carried out directly without further purification.

[0044] Add 3000mL of water and 3000mL of ethanol to the reaction flask, add reduced iron powder (195.5g, 3.5mol) and ammonium chloride (187.2g, 3.5mol) under stirring, heat to reflux for 1h, and add in batches the obtained For p-nitrophenyl acetate (8), the reaction was confirmed to be complete by TLC after continuing to reflux for 2 h. Stop the re...

Embodiment 2-1

[0045] Example 2-1: Preparation of ethyl 5-acetoxy-2-methylindole-3-carboxylate (5)

[0046] Add 2000mL of dichloromethane into the reaction flask, add 4-acetoxyaniline (7, 120.9g, 0.8mol) under stirring, heat to dissolve, add 104.1g of ethyl acetoacetate (6, 0.8mol) and catalyst bromine Indium InBr 3 (8, 2.8g, 0.008mol), after reflux reaction for 2h, TLC confirmed that the reaction was complete. Stop the reaction, suction filter while it is hot, and remove the solvent by rotating the filtrate under reduced pressure to obtain 203.7 g of the enaminone intermediate; the yield is 96.7%. The next reaction was carried out directly without further purification.

[0047] Add 203.7 g of the above-mentioned enaminone intermediate into a reaction flask containing 2000 mL of DMF, and add K respectively under stirring. 2 CO 3 (345.5g, 2.5mol), catalyst Pd(OAc) 2 (9g, 0.04mol), and oxidant Cu(OAc) 2 (480g, 2.4mol), heated to 80°C for 3 hours, TLC confirmed that the reaction was compl...

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Abstract

The invention discloses a preparation method of arbidol hydrochloride. P-nitrophenol which is cheap and easy to obtain is innovatively adopted as the raw material, and through acetylation, nitroreduction, an indole ring reaction, a methylation reaction, bromination, a reaction with thiophenol and deprotection, a Mannich reaction and salification, arbidol hydrochloride is obtained. Reaction conditions of the whole synthesis process are mild, the raw material can be conveniently obtained, the character of the product is good, the yield is high, few by-products are generated, reaction selectivity and purity are high, environmental friendliness is achieved, production cost is low, and the method is suitable for industrial production; the defects that in the prior art, selectivity is low, many by-products are generated, the yield is low, precious catalysts are used, and serious environmental pollution is caused are overcome.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of Arbidol hydrochloride. Background technique [0002] Arbidol hydrochloride, the English name is arbidol hydrochloride, the Chinese chemical name is 1-methyl-4-dimethylaminomethyl-5-hydroxyl-6-bromo-2-phenylthiomethyl-1H-indole-3 - Ethyl carboxylate hydrochloride monohydrate, molecular formula C 22 h 25 BrN 2 o 3 S·HCI·H 2 O, the molecular weight is 531.90. Its chemical structural formula is as follows: [0003] [0004] Arbidol hydrochloride was first listed in Russia in 1993. It is a hydrate for medicinal use, and is suitable for the prevention and treatment of adults and children with influenza A, influenza B, acute viral respiratory infections, severe acute respiratory syndrome, and concurrent bronchitis and pneumonia. Clinical application proves that Arbidol hydrochloride has few side effects and is not easy to produce...

Claims

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Application Information

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IPC IPC(8): C07D209/42
CPCC07D209/42
Inventor 刘新泉蒋燕杰王彦锋
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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