Chemical semi-synthetic process of 10-hydroxycamptothecin

A technology for hydroxycamptothecin and camptothecin, which is applied in the field of chemical semi-synthesis of 10-hydroxycamptothecin, can solve the problems of long time consumption, many final steps, large amount of extraction solvent, etc., and achieves production cost saving, The effect of reducing the risk factor and reducing the production cost

Active Publication Date: 2009-06-10
SHANGHAI LONGXIANG BIO MEDICINE DEV CO LTD
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

This scheme adopts Aspergillus flavus T-419 bacterial strain, has improved biotransformation rate, has certain economic effect and development potentiality, but this technology is not mature enough, there is following shortcoming: (1) the cultivation of bacterial strain needs to spend time long, needs There are many equipments and harsh culture conditions; (2) The concentration of the product in the fermentation broth is low, the extraction process is cumbersome, the amount of extraction solvent is large, and the environment is seriously polluted
Although E.J. Coery had realized the chiral total synthesis of camptothecin in 1975, the synthetic route was as long as 21 steps, and the total synthetic yield was only 0.3%.
After the 1980s, scientific researchers continued to improve the total synthesis method of camptothecin, which increased the total yield. However, due to too many steps, the yield was low, and the cost was too high, so that its industrialization could not be realized.
However, these improved methods still have a series of problems such as expensive precious metal platinum, high cost, high-pressure hydrogenation reaction must be carried out in an autoclave, complex operation, and potential safety hazards.

Method used

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  • Chemical semi-synthetic process of 10-hydroxycamptothecin
  • Chemical semi-synthetic process of 10-hydroxycamptothecin
  • Chemical semi-synthetic process of 10-hydroxycamptothecin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: the preparation of palladium carbon

[0027] Wash 100 g of 4-8 mesh activated carbon with 1 mol / L nitric acid for 5 hours, wash with water until neutral, and dry at 100° C. for 10 hours to obtain a carrier of activated carbon for future use. Take 3.2 g of palladium acetate solution containing 16% palladium, add deionized water to 40 mL, add 10% aqueous sodium hydroxide solution to adjust the pH of the palladium acetate solution to 5-7, and after the palladium acetate solution is stable for 1 hour, the above-mentioned treated Activated carbon was impregnated with palladium acetate solution for 3h to obtain the catalyst precursor. The catalyst precursor was aged for 24 hours, treated with high-purity hydrogen for 5 hours, filtered under the protection of hydrogen, and washed with water until neutral. Catalyst at 180°C and vacuum degree 1.013×10 -3 It was dried under Pa for 72h, then dropped to room temperature under nitrogen protection and released from th...

Embodiment 2

[0029] Add 200 g of camptothecin and 120 g of 5% Pd / C into a 5 L three-necked round bottom flask, and add 3 L of 1,4-dioxane. Under normal pressure and stirring, pass through hydrogen gas and heat to 80°C, and react for 24 hours. After the reaction is finished, the reaction solution is cooled, and the reacted catalyst is removed by filtration, and the reaction solution is directly used for the next oxidation reaction.

[0030] Transfer the above 1,4-dioxane reaction solution (about 3.1L) to a 20L reaction flask, add an equal amount of water to dilute the reaction solution, and stir vigorously at room temperature (about 40°C), and pour into the reaction solution within 2h 320g IBX (2.0eq) was added in 5 batches, and the addition was completed within 2h. Then 158 g (1.0 eq) of IBX were added in three batches one hour apart. After the oxidant was added, the product was filtered after stirring for 12 hours, rinsed with methanol, and dried to obtain about 119 g of the product (wh...

Embodiment 3

[0032] Add 200 g of camptothecin and 100 g of 10% Pd / C into a 5 L three-necked round bottom flask, and add 3 L of tetrahydrofuran. Under normal pressure and stirring, pass through hydrogen and heat to 60°C, and react for 24 hours. After the reaction is finished, the reaction solution is cooled, and the reacted catalyst is removed by filtration, and the reaction solution is directly used for the next oxidation reaction.

[0033] Transfer the above tetrahydrofuran reaction solution (about 3.1L) to a 20L reaction flask, add an equal amount of water to dilute the reaction solution, and stir vigorously at room temperature (about 20°C), add 320g IBX in 5 batches to the reaction solution within 2h (2.0eq), 2h added. 176 g (1.1 eq) of IBX were then added in three batches one hour apart. After the oxidant was added, the product was obtained by filtration after stirring for 12 hours, rinsed with methanol, and dried to obtain about 72 g of the product (wherein the HCPT content of the p...

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PUM

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Abstract

The invention discloses a semisynthesis method for 10-hydroxycamptothecin, which takes camptothecin as a raw material to prepare the 10-hydroxycamptothecin through the combination of catalytic hydrogenation and oxidation. The method is characterized by realizing a process of the combination of hydrogenation and oxidation, saving operation steps, in particular improving a catalyst by using a Pd/C catalyst containing 5 to 10 percent of palladium and recycling the catalyst, improving the manageability of the reaction by changing high-temperature reaction to normal-temperature reaction, and improving the selectivity of oxidation by applying oxidizers such as 2-iodoxybenzoic acid during the oxidation reaction. Compared with the prior art, the method has the advantages of hydrogenation reaction which is simple and convenient in operation and is low in cost, oxidation reaction which is high in selectivity, total yield of the two reactions of the whole production process which is increased to more than 85 percent, and suitability for industrial production.

Description

technical field [0001] The present invention relates to 10-hydroxycamptothecin, more specifically to a chemical semi-synthesis method for 10-hydroxycamptothecin. Background technique [0002] The domestic clinical demand and export volume of camptothecin drugs are increasing year by year because of their less toxic and side effects and high antitumor activity. In order to meet the needs of the market, more and more attention has been paid to the synthesis of such drugs, especially the preparation of hydroxycamptothecin, because it is not only an antitumor drug with better clinical effect, but also the preparation of irinotecan And topotecan and other important intermediates of camptothecin derivatives. Therefore, it is of great practical significance to study the preparation process of hydroxycamptothecin. [0003] The chemical structure of 10-hydroxycamptothecin (10-Hydroxycamptothecin, HCPT) is similar to that of camptothecin, except that the hydrogen on the 10th positio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22
CPCY02P20/584
Inventor 高河勇冯虓韩怡政
Owner SHANGHAI LONGXIANG BIO MEDICINE DEV CO LTD
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