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Preparation method and application of bicyclol

A bicyclic alcohol and bicyclic alkyd technology, applied in the field of medicine, can solve the problems of cumbersome process, high standards, production accidents, etc., and achieve the effect of stable process yield and simple process operation

Pending Publication Date: 2020-05-29
北京鑫开元医药科技有限公司
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  • Abstract
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Problems solved by technology

[0003] However, in the current synthetic route for preparing bicyclic alcohols, the methylating reagents used in the key step of methylation are usually dimethyl sulfate and nitrosomethyl urea, wherein dimethyl sulfate is a genotoxic impurity , is a highly toxic chemical substance, and the process of purchasing in large quantities is very cumbersome; nitrosomethyl urea is decomposed into diazomethane, which is very easy to cause an explosion
In this way, not only the standard for methylation reagent residues in the final product of bicyclic alcohol is high, the refining process is harsh, and a lot of manpower and material resources are wasted, but also because of its high toxicity and easy explosive production, it is easy to cause production accidents, which poses a threat to industrial production. bring inconvenience

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  • Preparation method and application of bicyclol
  • Preparation method and application of bicyclol
  • Preparation method and application of bicyclol

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preparation example Construction

[0021] In the first aspect, the embodiments of the present invention provide a method for preparing bicyclic alcohol, comprising the following steps:

[0022] Step S10, adding bicyclic alkyd and base to the reaction solvent;

[0023] Step S20, adding methyl p-toluenesulfonate solution for reaction to obtain bicyclic alcohol.

[0024] In the preparation method of the bicyclic alcohol provided in this example, a new methylating reagent, methyl p-toluenesulfonate, is used to avoid the use of methyl p-toluenesulfonate, which is prone to poisoning and explosion, is not suitable for commercial purchase, and is very likely to produce dangerous formazan during use. base reagents, thereby overcoming the disadvantages of harsh post-treatment and low yields caused by the use of methylation reagents that are prone to poisonous and explosive production. Through simple process operations, mild experimental conditions, and high yields The raw material medicine meeting the quality requiremen...

Embodiment 1

[0049] Step S1, at 0°C~5°C, add 10.0g (26.6mmol) of bicyclic alkyd and 0.96g (39.9mmol, 1.5eq) of sodium hydride into 80ml of acetonitrile, and stir for about 20min.

[0050] In step S2, 20ml of acetonitrile solution dissolved with 5.9g (31.9mmol, 1.2eq) of methyl p-toluenesulfonate was added dropwise, the addition time was about 30min, and the reaction was stirred at 0°C~5°C for about 6h.

[0051] Step S3, TLC monitors the completion of the reaction, filters, collects the filtrate, adds 300ml of water dropwise under stirring at 0°C~5°C, keeps stirring at room temperature for 2 hours after the dropwise addition, filters, and dries the filter cake to obtain 7.9g of crude bicycloalcohol, bicycloalcohol The crude product yield was 76.2%.

[0052] Step S4, reflux the crude product of bicyclic alcohol with 80ml of toluene to dissolve it, add 0.5g of activated carbon for decolorization for 30min, heat filter, stir the filtrate at room temperature for 1h, precipitate a solid, filter,...

Embodiment 2

[0055] Step S1, at 45°C~50°C, add 10.0g (26.6mmol) of bicyclic alkyd and 0.64g (26.6mmol, 1.0eq) of sodium hydride into 15ml of dichloromethane, and stir for about 20min.

[0056] Step S2, 5ml of dichloromethane solution dissolved with 5.0g (26.6mmol, 1.0eq) of methyl p-toluenesulfonate was added dropwise, the dropwise addition time was about 30min, and the reaction was stirred at 45°C~50°C for about 3h.

[0057] Step S3, TLC monitors the completion of the reaction, filters, collects the filtrate, adds 100ml of water dropwise under stirring at 45°C~50°C, keeps stirring at room temperature for 2 hours after the dropwise addition, filters, and dries the filter cake to obtain 7.8g of crude bicycloalcohol, bicycloalcohol The crude product yield was 75.2%.

[0058] Step S4, reflux the crude product of bicyclic alcohol with 80ml of toluene to dissolve it, add 0.5g of activated carbon for decolorization for 30min, heat filter, stir the filtrate at room temperature for 1h, precipitate...

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Abstract

The invention belongs to the field of medicines, and particularly relates to a preparation method and application of bicyclol. The preparation method comprises the following steps: adding bicyclol acid and alkali into a reaction solvent; adding a methyl p-toluene sulfonate solution; and carrying out reactions to obtain bicyclol. According to the provided preparation method, a new methylation reagent namely methyl p-toluene sulfonate is adopted; and a methylation reagent, which is toxic and explosive, is difficult to buy, and is dangerous during the application process, is not used. The defectssuch as difficult post-treatment, low yield and the like caused by adopting a methylation reagent which is toxic and explosive are overcome. Prodrugs meeting the quality requirements can be preparedthrough simple process operation and mild experimental conditions, and the yield is high. The method is stable in process yield, has reproducibility and reliability and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a preparation method and application of bicyclic alcohol. Background technique [0002] The chemical name of Bicyclol is 4,4,-dimethoxy-5,6,5,6,-bis(methylenedioxy)-2-hydroxymethyl-2-methoxycarbonylbiphenyl , is a product developed by the Chinese Academy of Medical Sciences and the Chinese Union Medical University. It is the first class of anti-hepatitis innovative drug with independent intellectual property rights in my country. Bicyclol has comparative effects on various clinical and experimental liver injuries. The significant protective effect on liver function may have the following mechanisms: first, it inhibits lipid peroxidation caused by chemical poisons and drugs; second, it has a better maintenance effect on the fluidity of mitochondrial membrane; third, it improves Intrahepatic antioxidant thiol transferase level; fourth, reduce liver cell damage, inhibit apoptosis ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/68G01N30/06
CPCC07D317/68G01N30/06
Inventor 蒋兴凯孟月垒许秀荣段晓峰戴信敏
Owner 北京鑫开元医药科技有限公司
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