Novel green and environment-friendly synthetic process for cantharidin

A green, environmentally friendly, synthetic technology, applied in organic chemistry and other directions, can solve problems such as low conversion rate, and achieve the effects of high conversion rate, mild conditions and high yield

Active Publication Date: 2017-05-17
海南亦璞科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Aiming at the very harsh conditions of the existing synthetic cantharidin cycloaddition reaction conditions, such as the need for ultra-high pressure and low conversion rate, the present invention proposes a new green and environmentally friendly synthesis process for cantharidin under normal pressure

Method used

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  • Novel green and environment-friendly synthetic process for cantharidin
  • Novel green and environment-friendly synthetic process for cantharidin
  • Novel green and environment-friendly synthetic process for cantharidin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] (1) Preparation of 3-cyano-3-hydroxy-4-formic acid methyl ester-2,5-tetrahydrothiophene

[0029] Add 315g of NaCN aqueous solution (mass percentage concentration: 23.2%) and 620mL of purified water into a 5L reaction kettle under ice-bath conditions, quickly add sodium bisulfite aqueous solution to adjust the pH of the reaction solution to 7-8, slowly add it dropwise within 40min 132g / 75mL of 3-oxo-4-carboxymethylthiophene / methanol solution, warmed to room temperature and reacted for 16h after dropping. It was extracted three times with dichloromethane, and the dichloromethane was evaporated under vacuum to obtain 197 g of yellow oily substance 3-cyano-3-hydroxy-4-methyl carboxylate-2,5-tetrahydrothiophene, with a yield of 80%.

[0030] (2) Preparation of 3-cyano-4-formic acid methyl ester-2,5-dihydrothiophene

[0031] Add 40g of 3-cyano-3-hydroxy-4-methyl-4-carboxylate-2,5-tetrahydrothiophene, 35.2g of benzene, and 60g of pyridine into a 1L reactor, control the intern...

Embodiment 2

[0040] (1) Preparation of 3-cyano-3-hydroxy-4-formic acid methyl ester-2,5-tetrahydrothiophene

[0041] Add 420g NaCN aqueous solution (mass 23.2%) and 800mL purified water into a 5L reaction kettle under ice-bath conditions, quickly add sodium bisulfite aqueous solution to adjust the pH of the reaction solution to 7-8, slowly add 244g / 100mL of 3 -Oxo-4-methyl carboxylate-thiophene / methanol solution, react for 16 hours after dropping. Dichloromethane was extracted three times, and dichloromethane was evaporated under vacuum to obtain 250 g of yellow oily substance 3-cyano-3-hydroxy-4-methyl-4-carboxylate-2,5-tetrahydrothiophene with a yield of 76%.

[0042] (2) Preparation of 3-cyano-4-formic acid methyl ester-2,5-dihydrothiophene

[0043] Control the internal temperature at 4-6°C, put 80g of 3-cyano-3-hydroxy-4-carboxylic acid methyl ester-2,5-tetrahydrothiophene, 88g of benzene, and 140g of pyridine into a 2L reaction kettle, and slowly add 250g of POCl 3 , after the reac...

Embodiment 3

[0051] (1) Preparation of 3-cyano-3-hydroxy-4-formic acid methyl ester-2,5-tetrahydrothiophene

[0052] Add 500g NaCN aqueous solution (mass 23.2%) and 1000mL purified water into a 10L reaction kettle under ice-bath conditions, quickly add sodium bisulfite aqueous solution to adjust the pH of the reaction solution to 7-8, slowly add 336g / 120mL of 3 -Oxo-4-methyl carboxylate-thiophene / methanol solution, react for 16 hours after dropping. Dichloromethane was extracted three times, and the dichloromethane was evaporated under vacuum to obtain 295 g of yellow oily substance 3-cyano-3-hydroxy-4-methyl-4-carboxylate-2,5-tetrahydrothiophene with a yield of 75%.

[0053] (2) Preparation of 3-cyano-4-formic acid methyl ester-2,5-dihydrothiophene

[0054] Control the internal temperature at 8-10°C, add 160g 3-cyano-3-hydroxy-4-carboxylic acid methyl ester-2,5-tetrahydrothiophene, 176g benzene, 280g pyridine into the 2L reaction kettle, and slowly drop 500g POCl 3 , after the reaction...

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Abstract

The invention relates to a novel green and environment-friendly synthetic process for preparing cantharidin under the condition of normal pressure and belongs to the field of synthesis and preparation of medicines. The process comprises the following steps: preparing 3-cyano-3-hydroxy-4-methyl formate-2,5-tetrahydrothiophene from a NaCN aqueous solution; adding benzene, pyridine and POCl3 into thiophene to prepare 3-cyano-4-methyl formate-2,5-dihydrothiophene; then adding acetic acid and concentrated hydrochloric acid, and carrying out reflux reaction to obtain 2,5-dihydrothiophene-3,4-dicarboxylic acid powder; carrying out stirring and refluxing on the prepared dicarboxylic acid and thionyl chloride to prepare 2,5-dihydrothiophene-3,4-dicarboxylic anhydride; carrying out heating reaction according to the solid-liquid ratio of dicarboxylic anhydride to furfuran to ionic liquid being 1mg:(3.5 to 6[mu]l):(2 to 4[mu]l), extracting and carrying out Raney-Ni reflux to obtain the cantharidin. According to the process, superhigh pressure condition and equipment are not needed, and overnight reaction at the temperature of 20 to 50DEG C is carried out; the process has the advantages of mild conditions, high conversion rate, and high yield of the cantharidin, and provides favorable conditions for industrial production of the cantharidin.

Description

technical field [0001] The invention relates to a method for preparing cantharidin, in particular to an environmentally friendly synthesis process for preparing cantharidin under normal pressure conditions, and belongs to the field of drug synthesis and preparation. Background technique [0002] Cantharidin is mainly derived from the dry body of the southern big cantharidin or the yellow and black small cantharidin. Pharmacological studies have shown that mylabris has anti-tumor activity, and has inhibitory effects on liver cancer, cervical cancer, skin cancer, bone marrow cancer, and leukemia. Cantharidin has less damage to normal cells of cancer patients. At the same time, cantharidin has the advantages of increasing white blood cells and not inhibiting the immune system. Therefore, cantharidin has always been a hot spot in the research and development of anti-tumor drugs. Due to the scarcity of natural resources, tablets and injections such as cantharidin, sodium canthar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/18
CPCC07D493/18
Inventor 刘晓玲谭春斌杜洪飞
Owner 海南亦璞科技有限公司
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