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Method of producing 10-hydroxy camptothein

A technology of hydroxycamptothecin and its production method, which is applied in the fields of chemical recovery and organic chemistry, can solve the problems of environmental pollution caused by glacial acetic acid, large recrystallization loss, equipment corrosion, etc., and achieve good product purity, shortened production cycle, and over- The effect of high column efficiency

Inactive Publication Date: 2006-09-20
JUNJIE BIOTECH SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the loss of recrystallization is relatively large, and the pollution of the environment and the corrosion of equipment by glacial acetic acid are also very serious, so this method is not an ideal method.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Synthesis of 1,2,6,7-tetrahydrocamptothecin

[0033] 200 grams of camptothecin and 100 grams of 5% platinum carbon were charged into a 5-liter stainless steel high-pressure stirred tank, and then 3 liters of glacial acetic acid and 10 ml of DMSO were added. Close the reactor, after washing the reaction container with hydrogen, charge the hydrogen of 5Kg pressure in the reactor again, and keep this pressure in the following reaction process. The reaction vessel was gradually heated to 65°C, and the reaction absorbed hydrogen relatively quickly within 6 hours after starting the reaction. After 12 hours, there was basically no hydrogen absorption, and the reaction was maintained for 24 hours. The reaction was cooled to below 30°C, and after the hydrogen pressure was released, the reaction solution was exported, and the reaction vessel was washed with 500ml of glacial acetic acid. Filter out the reaction catalyst, put it into the next hydrogenation reaction directly after ...

Embodiment 2

[0035] Synthesis of 10-Hydroxycamptothecin

[0036] Transfer the tetrahydrocamptothecin solution (3.6 liters) obtained above to a 20 liter hard plastic reaction vessel, add an equal amount of water (3.6 liters), and stir vigorously at room temperature (about 20°C) to obtain a light green clear solution. Under vigorous stirring, 320 g of iodobenzene diacetate (1.75 equivalents) was uniformly added to the solution, and the addition was completed within one minute. And after every one hour, 80 grams (0.44 equivalents) and 60 grams (0.33 equivalents) of iodobenzene diacetate were successively added. After the oxidizing agent was added, continue to stir for 12 hours to obtain a yellow suspension, which was filtered by suction, dried after obtaining the product, and weighed about 171 grams (85% yield, HPLC analysis containing 93% 10-hydroxycamptothecin and 5% camptothecin).

Embodiment 3

[0038] Purification of Hydroxycamptothecin

[0039] The 93% hydroxycamptothecin obtained in 100 grams of embodiment 2 and 2 liters of n-hexane-dimethyl sulfoxide (51: 49) solution are placed in the injection tank, heated to 40 ° C and stirred to make it dissolve completely, cooled to When the temperature is below 30°C, the sample is injected into the column, and 100ml of solution is injected each time. The mobile phase is n-hexane-dimethyl sulfoxide (51:49) solution, the flow rate is 300ml / min, and the detector is set at a UV detection wavelength of 254nm. The peaks of camptothecin and hydroxycamptothecin overlap, and the retention time is about 15 minutes. From the peak to 1 / 3 of the main peak, it was connected as component A, and a total of 1000ml was obtained for 20 times, and then it was connected as component B until the end of the next injection peak, and a total of 2000ml was obtained for 20 times. Component A detected by HPLC was 0.096mol / L, wherein the content of hyd...

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Abstract

This invention discloses a method to produce 10-hydroxycamptothecin, that is, camptothecin adopted as raw materials is catalytic hydrogenised and oxidized in turn at pressures to obtain 10-hydroxycamptothecin. It has the characteristics that steps such as catalyst recycling are modified and that high-pressure liquid phase preparation column and recrystallization are combined for product purification. Conventional large-dosage and low-efficient column separation method or repeated acetic acid recrystallization method is abandoned and composite solvent with high solubility is adopted as mobile phase. The mixture is separated in high-pressure liquid phase column and the consequent substance is decolorized with active carbon and recrystallized by adding poor solvent. Compared to convention purification method, this method has the advantages of high yield, little pollution, simple procedure and economical solvent consumption. For the whole procedure, hydroxycamptothecin with a yield of over 60% and purity of over 99% can be obtained, and this method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a production method of 10-hydroxycamptothecin. Background of the invention [0002] Camptothecin (Camptothecin) is a water-soluble cytotoxic alkaloid extracted from Camptotheca japonica growing in China and Nothapodytes foetida native to India, which can be used as a topoisomerase inhibitor. [0003] However, due to the lack of clinical effect and high toxicity, camptothecin has not been able to be developed as an antitumor drug. 10-Hydroxycamptothecin (10-Hydrocamptothecin) and 10-Hydroxycamptothecin derivatives idinotecan and topotecan have shown good antitumor activity and low toxicity, and have become widely favored antitumor drugs. In 1977, 10-Hydroxycamptothecin passed domestic identification as an anti-tumor clinical drug for the treatment of liver cancer, gastric cancer, head and neck cancer and leukemia. [0004] 10-Hydroxycamptothecin was originally obtained from camptothecin extract, and its content in natural camp...

Claims

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Application Information

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IPC IPC(8): C07D491/22C07D221/00C07D209/00C07D311/00
CPCY02P20/584
Inventor 徐宁陶凤岗张黎王全瑞康立涛蒋文泉
Owner JUNJIE BIOTECH SHANGHAI
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