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Preparation method of 10-acetyl paclitaxel

A technology of paclitaxel and 10-DAB, which is applied in the field of preparation of 10-acetylpaclitaxel, and achieves the effects of low cost, being beneficial to large-scale industrial production and easy to judge.

Pending Publication Date: 2021-12-10
无锡紫杉药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Through searching, it is found that there are basically no synthetic methods reported in the literature using accessible compounds as raw materials, so it is of great significance to develop feasible preparation methods

Method used

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  • Preparation method of 10-acetyl paclitaxel
  • Preparation method of 10-acetyl paclitaxel
  • Preparation method of 10-acetyl paclitaxel

Examples

Experimental program
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Effect test

Embodiment 1

[0037] S1: 10g precursor 10-deacylated baccatin III (10-DAB), followed by 10-DAB instead, 10-DAB was dissolved in 130g dichloromethane and 49g pyridine, and 12g chloroformic acid-2,2,2 was added dropwise -Trichloroethyl ester, stirred and reacted under ice bath (0°C) for 2h, after the reaction was completed, quenched the reaction with water, washed with hydrochloric acid and salt water respectively, collected and concentrated the organic phase, added 15g of toluene to make a slurry, and dried by suction to obtain 15.1g of IMJ- 1;

[0038] S2: Dissolve 15.1g IMJ-1 in 150g toluene, add 6.0g paclitaxel side chain acid and 0.91g 4-dimethylaminopyridine, add dropwise 6.0g N,N'-dicyclohexylcarbodiimide (with a small amount of dilute with toluene), stir the reaction at room temperature around 20°C for 2h, after the reaction is over, add water to quench the reaction, filter with suction, add ethyl acetate to the filtrate, then extract with saline, concentrate the organic phase, dissol...

Embodiment 2

[0048] S1: Dissolve 10g of 10-DAB in 180g of dichloromethane and 50g of pyridine, add 12g of 2,2,2-trichloroethyl chloroformate dropwise, stir at room temperature (around 5°C) for 1 hour, add water to quench the reaction after completion of the reaction , washed with hydrochloric acid and salt water respectively, collected and concentrated the organic phase, added 15g of toluene to make a slurry, and dried by suction to obtain 14.8g of IMJ-1;

[0049] S2: Dissolve 14.8g IMJ-1 in 135g toluene, add 7.4g paclitaxel side chain acid and 0.90g 4-dimethylaminopyridine, add dropwise 7.4g N,N'-dicyclohexylcarbodiimide (with a small amount of dilute with toluene), stir the reaction at room temperature around 23°C for 4h, after the reaction is over, add water to quench the reaction, filter with suction, add ethyl acetate to the filtrate, then extract with saline, concentrate the organic phase, dissolve it in 30ml ethyl acetate, add dropwise 60ml Recrystallized from n-heptane, filtered an...

Embodiment 3

[0055] S1: Dissolve 100g of 10-DAB in 2600g of dichloromethane and 500g of pyridine, add 125g of 2,2,2-trichloroethyl chloroformate dropwise, stir and react at 0-10°C for 0.5h, add water to quench the reaction after completion of the reaction, Wash with hydrochloric acid and brine respectively, collect and concentrate the organic phase, add 150 g of toluene to make a slurry, and filter and dry to obtain 149.1 g of IMJ-1;

[0056] S2: Dissolve 148g IMJ-1 in 1480g toluene, add 68g paclitaxel side chain acid and 11.8g 4-dimethylaminopyridine, add dropwise 74g N,N'-dicyclohexylcarbodiimide (diluted with a small amount of toluene) , Stir the reaction at about 23°C for 3.5h. After the reaction is over, add water to quench the reaction, filter with suction, add ethyl acetate to the filtrate, then extract with saline, concentrate the organic phase, dissolve it in 300ml ethyl acetate, add dropwise 600ml n-heptane Recrystallized, filtered and dried to obtain 187g IMJ-2;

[0057] S3: Di...

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Abstract

According to the technical scheme, the preparation method comprises the following steps: S1, dissolving 10-DAB in dichloromethane and pyridine, dropwise adding chloroformic acid-2, 2, 2-trichloroethyl ester, carrying out a quenching reaction, and treating to obtain IMJ-1; S2, dissolving IMJ-1 in toluene, adding paclitaxel side chain acid and 4-dimethylaminopyridine, adding N, N '-dicyclohexylcarbodiimide, carrying out a quenching reaction, and treating to obtain IMJ-2; S3, dissolving IMJ-2 in methanol and acetic acid, adding zinc powder, stirring for reaction, adding diluted hydrochloric acid into filtrate, stirring for reaction, extracting with dichloromethane, and adding n-heptane for crystallization to obtain IMJ-3; S4, dissolving the IMJ-3 in N, N-dimethylformamide, adding 2-methylimidazole, adding triethyl chlorosilane, carrying out a stirring reaction, and carrying out treatment so as to obtain IMJ-4; S5, dissolving and clarifying the IMJ-4 with tetrahydrofuran, adding sodium carbonate, adding diketene, concentrating filtrate, pulping with methyl tert-butyl ether, and performing suction filtration to obtain IMJ-5; and S6, dissolving and clarifying the IMJ-5 with acetonitrile, adding hydrochloric acid, dichloromethane and a saturated sodium bicarbonate solution for extraction, and concentrating to obtain a target product. The method has the advantages that the reaction conditions are mild, and the purity of the target product is high.

Description

technical field [0001] The invention relates to the field of taxane natural products, in particular to a preparation method of 10-acetylpaclitaxel. Background technique [0002] Paclitaxel, a natural anticancer drug, has been widely used clinically in the treatment of breast cancer, ovarian cancer, some head and neck cancers and lung cancer. As a diterpene alkaloid compound with anticancer activity, paclitaxel has attracted botanists and chemists due to its novel and complex chemical structure, extensive and significant biological activities, new and unique mechanism of action, and scarce natural resources. The great favor of scientists, pharmacologists, and molecular biologists made it a world-renowned anti-cancer star and research focus in the second half of the 20th century. [0003] The structure of paclitaxel is shown in formula 1, and the structure of 10-acetyl paclitaxel is shown in formula 2. The difference between the two is mainly that the 10-position group is dif...

Claims

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Application Information

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IPC IPC(8): C07D305/14
CPCC07D305/14
Inventor 王莉佳黄春陆叶梦王旭阳
Owner 无锡紫杉药业股份有限公司
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