Preparation method of anti-tumour medicine intermediate 10-deacetylbacctin III

A technology for antitumor drugs and intermediates, applied in the field of medicine, can solve the problems of harsh reaction conditions, low product yield and purity, unsuitable for industrial production, etc., and achieve the effects of high product purity and yield and mild reaction conditions.

Active Publication Date: 2013-01-23
SHENYANG TIANFENG BIOLOGICAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current preparation method has low yield and purity of the product, and the reaction conditions are harsh, so it is not suitable for industrial production

Method used

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  • Preparation method of anti-tumour medicine intermediate 10-deacetylbacctin III
  • Preparation method of anti-tumour medicine intermediate 10-deacetylbacctin III
  • Preparation method of anti-tumour medicine intermediate 10-deacetylbacctin III

Examples

Experimental program
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Effect test

Embodiment 1

[0042] The cephalomannine used in the present invention can be isolated from Taxus plants, or is a by-product produced during the paclitaxel extraction process.

[0043] Take 10g of cephalomannine and dissolve it in 100ml of methanol, add 132ml of 80% hydrazine hydrate and stir at 30°C for 1.5 hours, add 150ml of saturated aqueous ammonium chloride solution, stir at 30°C for 3 hours, add 382ml of ethyl acetate, stir, and let stand 2 hours, separate layers, take the organic layer, and extract the aqueous layer twice with 382ml ethyl acetate respectively, combine the ethyl acetate layers, and extract once with 382ml saturated brine to obtain the ethyl acetate extract, and the ethyl acetate extract is reduced Concentrate under reduced pressure, purify the concentrate through a 200-300 mesh silica gel column, and elute with petroleum ether-acetone (v:v=3:1) to obtain the main part of 10-DABIII, which is heated and dissolved with 120ml of acetone at 60°C , add sherwood oil afterwar...

Embodiment 2

[0045] Take 10g of cephalomannine and dissolve it in 150ml of ethanol, add 130ml of 80% hydrazine hydrate, stir at 30°C for 1.5 hours, add 150ml of saturated aqueous ammonium chloride solution, stir at 30°C for 3 hours, add an equal volume of ethyl acetate, stir, and statically Stand for 2 hours, separate layers, take the organic layer, extract the aqueous layer twice with an equal volume of ethyl acetate, combine the ethyl acetate layers, and extract once with 432ml of saturated brine to obtain an ethyl acetate extract, which is extracted with ethyl acetate The liquid was concentrated under reduced pressure, and the concentrate was purified by a 200-300 mesh silica gel chromatography column, and eluted with petroleum ether-acetone (v:v=3:1) to obtain the main part of 10-DABIH, which was washed with 120ml of acetone at 60°C. Heat to dissolve, then add n-hexane until crystals precipitate, let stand for 24 hours, filter, heat and dissolve the filter cake with 95ml chloroform meth...

Embodiment 3

[0047] Take 10g of cephalomannine and dissolve it in 120ml of ethanol, add 135ml of 80% hydrazine hydrate, stir at 30°C for 1.5 hours, add 150ml of saturated aqueous ammonium chloride solution, stir at 30°C for 3 hours, add an equal volume of ethyl acetate, stir, and statically Stand for 2 hours, separate layers, take the organic layer, and extract the aqueous layer twice with equal volume of ethyl acetate, combine the ethyl acetate layers, and extract once with 402ml saturated brine to obtain ethyl acetate extract, and extract with ethyl acetate The liquid was concentrated under reduced pressure, and the concentrate was purified by 200-300 mesh silica gel chromatography, and eluted with petroleum ether-acetone (v:v=3:1) to obtain the main part of I0-DABIII, which was washed with 120ml of acetone at 60°C Heat to dissolve, then add cyclohexane until crystals precipitate, let stand for 24 hours, filter, heat and dissolve the filter cake with 82ml chloroform methanol (1:1) at 60°C...

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Abstract

The invention belongs to the medicine technical field and discloses a preparation method of anti-tumour medicine intermediate, namely a method that cephalomannine is utilized to synthesize taxol and taxotere semisynthesis precursor 10-DAB III. Cephalomannine alcoholic solution is contact with hydrazine hydrate and converts the hydrazine hydrate into 10-DAB III. The method can remove C-10 and C-13ester functional group of cephalomannine and has good selectivity. Synthetic product is separated by silicagel column chromatography, petroleum ether-acetone (3:1) is taken as eluent, so as to obtain10-DAB III main section, and then the main section is subject to secondary recrystallization, thus obtaining high purity 10-DAB III. Primary crystallization system is acetone-petroleum ether or normal hexane; and the secondary crystallization system is chloroform-methyl alcohol-normal hexane or petroleum ether or other low polarity solvent. Cephalomannine can be obtained by separation from taxus plant or is byproduct produced in taxol extraction process. The invention has the characteristics of mild reaction condition and higher product purity and yield.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of an antineoplastic drug intermediate, in particular to 10-deacetylbaccatin III (10-DABIII), which is a compound for synthesizing paclitaxel and docetaxel with cephalomannine Preparation of precursor 10-DABIII. Background technique [0002] Paclitaxel (trade name Taxol) is a diterpenoid isolated from the bark or needles of Taxus genus plants with unique anticancer activity. Paclitaxel is approved for chemotherapy in several different types of tumors, including refractory ovarian cancer and metastatic breast cancer. Clinical trials including lung, head, neck and other cancers have shown that paclitaxel has potent anti-leukemia and tumor suppressive activities, and is considered to be one of the most curative anti-cancer drugs discovered by humans so far. At present, paclitaxel is mainly derived from the bark of Taxus genus, and its content is extremely low, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D305/14
Inventor 李英娜王继文王文泽雷茂林马旭陈鑫刘涛张贵明苏宏伟张爽
Owner SHENYANG TIANFENG BIOLOGICAL PHARMA
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