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Chemical semi-synthetic process for high-purity 10-hydroxy-camptothecin

A semi-synthetic technology of hydroxycamptothecin, which is applied in the fields of chemical industry and medicine, can solve the problems of unstable product yield, solvent waste environment, and many influencing factors, and achieve considerable economic benefits, save a lot of reagents, and improve production efficiency. Effect

Inactive Publication Date: 2008-06-04
上海中城生物工程有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] However, there are still some deficiencies in this process, which limit its industrial application, such as: the recovery of the solvent is not considered, resulting in a large amount of waste of solvent and environmental pollution; there are many factors affecting the second step reaction, the product yield is unstable, and it will Formation of a by-product that is difficult to separate from 10-hydroxycamptothecin (see image 3 Compound c), greatly increasing the difficulty and cost of separation

Method used

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  • Chemical semi-synthetic process for high-purity 10-hydroxy-camptothecin
  • Chemical semi-synthetic process for high-purity 10-hydroxy-camptothecin
  • Chemical semi-synthetic process for high-purity 10-hydroxy-camptothecin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Dissolve camptothecin (10, 15 or 20 g) in 1000 ml solution (36% acetic acid; or glacial acetic acid: water = 70:30, V: V; or the adjusted solution after recovery) at 30° C. Slowly add 200ml of 30% hydrogen peroxide dropwise at 40°C, rapidly raise the temperature to 70°C, and react for 3h under stirring. Concentrate under reduced pressure and distill off acetic acid (about 50ml remaining), pour the residue into 500ml ice water to precipitate, and let it stand in the refrigerator for 12h. Filter, dry in a vacuum desiccator, and weigh. The product yield and HPLC purity of each reaction are shown in Table 1.

[0045] The acetic acid aqueous solution collected under reduced pressure concentration was measured by acid-base titration (0.5M NaOH as standard solution, phenolphthalein indicator) to measure the concentration of acetic acid, and then an appropriate amount of acetic acid or water was added to adjust the concentration of acetic acid for the next reaction.

[0046] ...

Embodiment 2

[0050] 2.50 g of the yellow product obtained in Example 1 was added to a quartz cup equipped with 2500 ml of dioxane, acetonitrile or water mixed solution, stirred and dissolved, and concentrated H was added dropwise. 2 SO 4 5ml, irradiated by a high-pressure mercury lamp (the distance between the lamp tube and the cup wall is 2-5cm) for 30min to obtain a brownish-yellow solution. Concentrate under reduced pressure until solids appear, and pour the residue into 4500ml of ice water to precipitate for 12h. Filter, vacuum dry, and weigh. Mass spectrometric identification of 10-hydroxycamptothecin see figure 1 , the yield and HPLC purity of each reaction product are shown in Table 2, and the HPLC analysis spectrum of the corresponding product is shown in image 3 .

[0051] The specific gravity of the dioxane and acetonitrile solution with a volume ratio of 50:50 is 0.875, and the solvent collected by concentrating under reduced pressure can be added with an appropriate amoun...

Embodiment 3

[0055] Take 2500g of dry silica gel (200-300 mesh) and put it into a φ150×700mm glass chromatography column with a packing height of 20cm. Weigh 48.49 g of the 10-hydroxycamptothecin crude product obtained in Example 2, apply the dry method, rinse with 5% methanol-chloroform solution, collect the eluate with a 500ml reagent bottle, and number it sequentially from 1 to 298. These fractions were first tested by TLC to roughly determine the peak order and distribution range of each substance. After detection, it was found that the unreacted 1-oxocamptothecin, camptothecin and reaction by-products were eluted first, followed by 10-hydroxycamptothecin, and the fractions with numbers greater than 30 were mainly 10-hydroxycamptothecin . In order to illustrate the content change trend of each substance in the fractions, the fractions numbered 9~15, 16~18, 19~23, 24~25, 26~31, 32~35 were respectively combined and marked as I, U, III, IV, V, VI. After concentrating the combined solu...

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Abstract

The present is a seimsynthesis process for high purity 10-hydroxy camptothecin, which begin with the raw materials 20(S)-camptothecin, followed by optimized N-oxidation and photochemistry rearrangement reaction, then subject the resulting product to silica gel chromatography, thereby obtain said 10-hydroxy camptothecin with high purity. Said process is simple to handle, the reaction reagents therein could the recovered for further process is sipmle to handle, the reaction reagents therein could be recovered for further use, and the product is easy to isolate, thus having a low production cost. Moreover, both the yields and purity of 10-hydroxy camptothecin is very high, whith a purity degree of 98.5%, which meets the requirement of National Drug Testing Standard.

Description

technical field [0001] The invention belongs to the technical fields of chemical industry and medicine, and in particular relates to a production process for semi-synthesizing 10-hydroxycamptothecin with 20(s)-camptothecin as raw material. Background technique [0002] Camptothecin (CPT), light yellow needle crystal, molecular formula: C 20 h 16 N 2 o 4 , molecular weight: 348.3, the structural formula is shown in the figure below: [0003] [0004] camptothecin [0005] Camptothecin is an alkaloid extracted from Camptotheca acuminata, a unique tree species in my country, by American scholar Wall et al. in 1966. It has a unique anticancer effect, but its toxic and side effects limit the clinical application of camptothecin. . Therefore, camptothecin derivatives that not only maintain the anticancer activity of camptothecin but also have lower toxicity have always been the focus of attention. [0006] 10-Hydroxycamptothecin (10-Hydroxycamptothecin, HCPT), yellow pris...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22C07D221/00C07D209/00C07D311/00
CPCY02P20/582
Inventor 陈建民陆华吴蓓莉陈明兴
Owner 上海中城生物工程有限公司