Diacerein synthesis method based on anthraquinone medicines

Abstract

The invention belongs to a medicine preparation technology, and particularly relates to a diacerein synthesis method based on anthraquinone medicines. The method comprises that aloe-emodin undergoes an oxidation reaction to obtain aldehyde aloe-emdion, aldehyde aloe-emdion undergoes an acylation reaction to obtain diacetyl aldehyde aloe-emdion, diacetyl aldehyde aloe-emdion undergoes an oxidationreaction to obtain a diacerein crude product, and the diacerein crude product is recrystallized to form the diacerein. The invention provides a process for preparing diacerein with low genotoxic impurity residue, which avoids using a resin adsorption or column chromatography purification means, also avoids using a large amount of solvent for continuous extraction and washing, can achieve the purpose by direct recrystallization, and is easy for industrial large-scale production. The content of aloe-emodin and the content of aldehyde aloe-emdion in the prepared diacerein final product are both lower than 15 ppm, and the total genotoxic impurity content is lower than 20 ppm.

Description

technical field

[0001] The invention belongs to medicine preparation technology, specifically relates to a synthesis method of diacerein, and further relates to a synthesis method of diacerein based on anthraquinone drugs, which is green and economical and has low content of genotoxic impurities. Background technique

[0002] Diacerein (Diacerein), chemical name: 4,5-diacetyl-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid, the drug is used to treat degenerative joint disease (bone arthritis and related diseases). Domestic studies have shown that this product can significantly improve symptoms such as pain and joint dysfunction caused by osteoarthritis and related diseases. After 2-4 weeks of taking it, it will start to be effective, and it will be obvious after 4-6 weeks. If the drug is discontinued after 3 months of continuous treatment, the curative effect can last for at least 1 month (follow-up effect).

[0003] Diacerein is a typical anthraquinone compound. This...

Examples

Embodiment 1

[0051]

[0052] Add 2kg N-methylpyrrolidone and 200g aloe-emodin to the reaction bottle, heat up to 70°C, add 230g IBX, then stir and keep warm for 2h; Wash, drain, and vacuum-dry at 80°C for 12 hours to obtain 181 g of rhein;

[0053] Feed 181g rhubaraldehyde and 2400g dichloromethane into the reaction bottle, add 160g acetyl chloride at 15°C, keep 15°C, add 280g triethylamine dropwise within 30 minutes, stir for 10min after the dropwise addition, and then stir the reaction at room temperature 1h; after the reaction, the feed liquid was rotary evaporated at 35°C, evaporated to dryness, added 350g of methanol and 350g of water, beat at room temperature for 0.5h, filtered with suction, and vacuum-dried the filter cake at 80°C for 8h to obtain 205g of diacetyl rhein as a solid;

[0054] Add 205g of diacetyl rhein, 1900g of acetone, and 570g of DMSO in the reaction flask, and add 450g of NaH dropwise within 30 minutes under stirring. 2 PO 4 2H 2 A solution of O mixed with 1...

Embodiment 2

[0060] On the basis of Example 1, the amount of all raw materials was increased by 100 times, and the rest remained unchanged to obtain a refined product of diacerein with a total yield of 51.6% and a purity of 99.72%; the obtained diacerein sample was tested by a genotoxicity method. The residue of aloe-emodin impurities is 11ppm, and the residue of rhein-type impurities is 8ppm.

technical field

[0001] The invention belongs to medicine preparation technology, specifically relates to a synthesis method of diacerein, and further relates to a synthesis method of diacerein based on anthraquinone drugs, which is green and economical and has low content of genotoxic impurities. Background technique

[0002] Diacerein (Diacerein), chemical name: 4,5-diacetyl-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid, the drug is used to treat degenerative joint disease (bone arthritis and related diseases). Domestic studies have shown that this product can significantly improve symptoms such as pain and joint dysfunction caused by osteoarthritis and related diseases. After 2-4 weeks of taking it, it will start to be effective, and it will be obvious after 4-6 weeks. If the drug is discontinued after 3 months of continuous treatment, the curative effect can last for at least 1 month (follow-up effect).

[0003] Diacerein is a typical anthraquinone compound. This...

Examples

Embodiment 1

[0051]

[0052] Add 2kg N-methylpyrrolidone and 200g aloe-emodin to the reaction bottle, heat up to 70°C, add 230g IBX, then stir and keep warm for 2h; Wash, drain, and vacuum-dry at 80°C for 12 hours to obtain 181 g of rhein;

[0053] Feed 181g rhubaraldehyde and 2400g dichloromethane into the reaction bottle, add 160g acetyl chloride at 15°C, keep 15°C, add 280g triethylamine dropwise within 30 minutes, stir for 10min after the dropwise addition, and then stir the reaction at room temperature 1h; after the reaction, the feed liquid was rotary evaporated at 35°C, evaporated to dryness, added 350g of methanol and 350g of water, beat at room temperature for 0.5h, filtered with suction, and vacuum-dried the filter cake at 80°C for 8h to obtain 205g of diacetyl rhein as a solid;

[0054] Add 205g of diacetyl rhein, 1900g of acetone, and 570g of DMSO in the reaction flask, and add 450g of NaH dropwise within 30 minutes under stirring. 2 PO 4 2H 2 A solution of O mixed with 1...

Embodiment 2

[0060] On the basis of Example 1, the amount of all raw materials was increased by 100 times, and the rest remained unchanged to obtain a refined product of diacerein with a total yield of 51.6% and a purity of 99.72%; the obtained diacerein sample was tested by a genotoxicity method. The residue of aloe-emodin impurities is 11ppm, and the residue of rhein-type impurities is 8ppm.

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