阅读说明：本技术 一种利用废料制备10-脱乙酰基巴卡亭ⅲ的方法 (Method for preparing 10-deacetylbaccatin III from waste materials ) 是由 杨青春 滕院 赵晓怡 赵泽熙 胡倩 马秋丽 于 2020-07-08 设计创作，主要内容包括：本发明公开了一种利用废料制备10-脱乙酰基巴卡亭Ⅲ的方法,该方法以生产天然紫杉醇或10-脱乙酰基巴卡亭Ⅲ过程中产生的废料为原料,通过高碘酸钠对废料中含木糖基成分的化合物氧化脱去木糖基后得到不含木糖基成分的化合物的混合物,该混合物再用水合肼水解还原得到10-脱乙酰基巴卡亭Ⅲ粗品,继而经纯化后得到10-脱乙酰基巴卡亭Ⅲ成品；该方法操作简单,生产成本低,生产条件不苛刻,节能环保,进一步充分有效利用红豆杉资源,适于工业化生产和市场推广。(The invention discloses a method for preparing 10-deacetyl baccatin III by utilizing waste materials, which takes the waste materials generated in the process of producing natural paclitaxel or 10-deacetyl baccatin III as raw materials, compounds containing xylosyl components in the waste materials are oxidized and deacidized by sodium periodate to obtain a mixture of compounds without xylosyl components, the mixture is hydrolyzed and reduced by hydrazine hydrate to obtain a 10-deacetyl baccatin III crude product, and then the 10-deacetyl baccatin III finished product is obtained after purification; the method has the advantages of simple operation, low production cost, non-harsh production conditions, energy conservation and environmental protection, further fully and effectively utilizes the taxus chinensis resources, and is suitable for industrial production and market popularization.)

1. A method for preparing 10-deacetylbaccatin III by utilizing waste materials is characterized by comprising the following steps:

(1) taking natural paclitaxel or waste materials generated in the production process of 10-deacetylbaccatin III as raw materials, drying the raw materials, dissolving the dried raw materials by using methanol or ethanol, adding water-soluble sodium periodate into a dissolved solution according to the proportion of the raw materials of sodium periodate to water =1g: 0.5-2 g: 10-15 mL, uniformly mixing, reacting for 20-48 h, adding water for diluting after the reaction is finished, concentrating and recovering an organic solvent, extracting the concentrated solution for 3 times by using chloroform or ethyl acetate, combining organic extraction solutions, and carrying out rotary evaporation under reduced pressure and draining to obtain a concentrate for later use;

(2) dissolving the concentrate obtained in the step (1) by using methanol or ethanol, adding an acetic acid solution with the mass concentration of 50-60% and hydrazine hydrate with the mass concentration of more than or equal to 80%, stirring while adding, and reacting for 2-4 h at the temperature of 50-60 ℃; after the reaction is finished, adding water for dilution, and concentrating and recovering the organic solvent; extracting the concentrated solution with chloroform or ethyl acetate for 2-3 times, combining organic extraction solutions, and performing rotary evaporation under reduced pressure for draining for later use;

(3) dissolving the concentrate obtained in the step (2) with methanol or ethanol, adding hydrazine hydrate at room temperature, stirring and reacting for 2-3 h, and adding dilute hydrochloric acid or dilute sulfuric acid to adjust the pH value to 6.5-7.5 after the reaction is finished;

(4) concentrating the reaction solution obtained in the step (3) under reduced pressure to remove the organic solvent, extracting the concentrated solution with chloroform or ethyl acetate for 2-3 times, combining organic extracts, concentrating under reduced pressure and drying; dissolving the dried concentrate with acetonitrile, filtering, concentrating the filtrate until attachments appear on the inner wall of a concentrating pan, stopping concentrating, standing and crystallizing for 4-6 h at the temperature of 0-minus 5 ℃, carrying out vacuum filtration under reduced pressure, continuously crystallizing the crystals for 2-3 times with acetonitrile-methanol mixed solution, and collecting the crystals to obtain a finished product of 10-deacetylbaccatin III, wherein the content of the 10-deacetylbaccatin III in the finished product is more than or equal to 95%.

2. The method for preparing 10-deacetylbaccatin iii from waste according to claim 1, characterized in that: in the step (2), the concentrate is acetic acid solution, hydrazine hydrate =1g, 8-10 mL and 0.2-0.5 mL.

3. The method for preparing 10-deacetylbaccatin iii from waste according to claim 1, characterized in that: the addition amount of hydrazine hydrate in the step (3) is based on the pH value of the reaction liquid being 8-9.

4. The method for preparing 10-deacetylbaccatin iii from waste according to claim 1, characterized in that: the acetonitrile-methanol mixed solution is prepared by mixing acetonitrile and methanol according to the volume ratio of 25-35: 1.

Technical Field

The invention belongs to the technical field of chemistry, and particularly relates to a method for preparing 10-deacetylbaccatin III by recycling waste materials in the production process of natural paclitaxel and 10-deacetylbaccatin III.

Background

Paclitaxel (trade name Taxol) is a unique diterpenoid compound with anticancer activity extracted from the bark or needle leaf of taxus plant, and after approved to market by the U.S. Food and Drug Administration (FDA) in 1992, the Taxol (trade name Taxol) is considered to be one of the most effective anticancer drugs discovered by human beings so far. At present, taxol is mainly extracted from taxus branch and leaf, but the content of taxol in taxus branch and leaf is extremely low, the extraction difficulty is high, and the production period is long; however, the increase of patients with tumor is high, and the natural paclitaxel is unable to meet the supply requirements of medical treatment and pharmaceutical industry. Although the total synthesis of paclitaxel has been successful, the total synthesis method is unlikely to provide a drug source because the synthesis route is complicated and the steps are complicated, and about 30 steps exist; in addition, the tissue culture method for producing paclitaxel is still in the research and development stage, is still far away from the industrial production, and a plurality of problems still need to be solved when paclitaxel is obtained from the fungus culture solution.

To date, the chemical semi-synthesis method, which utilizes 10-deacetylbaccatin III obtained from Taxus chinensis needle leaves as a raw material to semi-synthesize taxol and its analog taxol, remains a major approach to expand the taxol source in reality from the viewpoint of feasibility of operation and economy. Therefore, one way to alleviate the resource shortage problem is to convert the available taxanes into 10-deacetylbaccatin III to ultimately increase the production of paclitaxel.

In the production process of natural paclitaxel, except obtaining paclitaxel, baccatin III and 10-deacetylbaccatin III, some compounds with similar structure to paclitaxel, namely compounds containing paclitaxel mother ring, including cephalomannine, paclitaxel C, 10-deacetyl paclitaxel and the like, can be obtained, and the components are discarded as waste materials because of high single purification cost and no commercial value, thereby wasting resources and polluting the environment. Thus, if these compounds can be converted into 10-deacetylbaccatin III, precious resources can be fully utilized.

In the existing preparation method, people usually utilize single taxane compounds to prepare 10-deacetylbaccatin III, so that the single taxane compounds need to be obtained by continuous separation and purification, the production cost is high, and the method is not suitable for industrial production and market popularization.

Disclosure of Invention

The invention aims to provide an industrial production method for preparing 10-deacetylbaccatin III by taking waste materials generated in the process of producing natural paclitaxel and 10-deacetylbaccatin III as raw materials, which can omit the traditional process of separating and purifying to obtain taxane single substances, directly takes the waste materials generated in the process of producing natural paclitaxel or 10-deacetylbaccatin III as the raw materials, obtains a mixture of compounds without xylosyl groups by oxidizing and deacidizing the compounds containing xylosyl groups in the waste materials by sodium periodate, obtains a crude product of 10-deacetylbaccatin III by hydrolyzing and reducing the mixture by hydrazine hydrate, and then obtains a finished product of 10-deacetylbaccatin III by purification; the method has the advantages of simple operation, low production cost, non-harsh production conditions, energy conservation and environmental protection, and is suitable for industrial production and market popularization.

The purpose of the invention is realized by the following technical scheme:

1. taking natural paclitaxel or waste materials generated in the production process of 10-deacetylbaccatin III as raw materials, drying the raw materials, dissolving the dried raw materials by using methanol or ethanol, adding water-soluble sodium periodate into a dissolved solution according to the proportion of the raw materials of sodium periodate to water =1g: 0.5-2 g: 10-15 mL, uniformly mixing, reacting for 20-48 h, adding water for diluting after the reaction is finished, concentrating and recovering an organic solvent, extracting the concentrated solution for 3 times by using chloroform or ethyl acetate, combining organic extraction solutions, and carrying out rotary evaporation under reduced pressure and draining to obtain a concentrate for later use;

the waste material generated in the process of producing natural taxol or 10-deacetylbaccatin III is: the production process of natural taxol or 10-deacetylbaccatin III produces waste containing other taxanes, the waste contains taxanes with C-7, C-10 and C-13 in the structural formula having xylosyl, acetyl, chiral side chain and other groups, such as cephalomannine, taxol C, 10-deacetyltaxol, 7-xylosyl-10-deacetylcephalomannine, 7-xylosyl-10-deacetyltaxol C and the like;

2. dissolving the concentrate obtained in the step (1) by using methanol or ethanol, adding an acetic acid solution with the mass concentration of 50-60% and hydrazine hydrate with the mass concentration of more than or equal to 80%, stirring while adding, and reacting for 2-4 h at the temperature of 50-60 ℃; after the reaction is finished, adding water for dilution, and concentrating and recovering the organic solvent; extracting the concentrated solution with chloroform or ethyl acetate for 2-3 times, combining organic extraction solutions, and performing rotary evaporation under reduced pressure for draining for later use;

the concentrate is acetic acid solution, namely hydrazine hydrate =1g, 8-10 mL and 0.2-0.5 mL;

3. dissolving the concentrate obtained in the step (2) with methanol or ethanol, adding hydrazine hydrate at room temperature, stirring and reacting for 2-3 h, and adding dilute hydrochloric acid or dilute sulfuric acid to adjust the pH value to 6.5-7.5 after the reaction is finished;

the addition amount of the hydrazine hydrate is based on the condition that the pH value of the hydrazine hydrate added into the reaction liquid is 8-9;

4. concentrating the reaction solution obtained in the step (3) under reduced pressure to remove the organic solvent, extracting the concentrated solution with chloroform or ethyl acetate for 2-3 times, combining organic extracts, concentrating under reduced pressure and drying; dissolving the dried concentrate with acetonitrile, filtering, concentrating the filtrate until attachments appear on the inner wall of a concentrating pan, stopping concentrating, standing and crystallizing for 4-6 h at the temperature of 0-minus 5 ℃, carrying out vacuum filtration under reduced pressure, continuously crystallizing the crystals for 2-3 times with acetonitrile-methanol mixed solution, and collecting the crystals to obtain a 10-deacetylbaccatin III finished product, wherein the content of 10-deacetylbaccatin III in the finished product is more than or equal to 95%;

the acetonitrile-methanol mixed solution is prepared by mixing acetonitrile and methanol according to the volume ratio of 25-35: 1.

The invention has the following advantages and technical effects:

1. the method does not need to separate and purify a single taxane compound used for preparing 10-deacetylbaccatin III from waste materials, and can directly use the mixture as a raw material to carry out synthetic reaction;

2. the method has the advantages of low cost, mild production conditions, energy conservation and environmental protection, further fully and effectively utilizes the taxus chinensis resource, and is suitable for industrial production and market popularization.

Detailed Description

The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention; the waste materials used in the following examples are derived from yew, specifically by-products other than the target product generated in the production process of extracting natural paclitaxel and 10-deacetylbaccatin III from yew raw materials, and by-products obtained in the separation and purification method adopted for obtaining the target product with high purity;