WO2021056382A1 - Preparation method for alpha-penta-o-acetyl mannose - Google Patents

Preparation method for alpha-penta-o-acetyl mannose Download PDF

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WO2021056382A1
WO2021056382A1 PCT/CN2019/108395 CN2019108395W WO2021056382A1 WO 2021056382 A1 WO2021056382 A1 WO 2021056382A1 CN 2019108395 W CN2019108395 W CN 2019108395W WO 2021056382 A1 WO2021056382 A1 WO 2021056382A1
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mannose
penta
alpha
acetyl
acetyl mannose
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PCT/CN2019/108395
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French (fr)
Chinese (zh)
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李文举
高健
唐鹏飞
庄永忠
李秀珍
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济南山目生物医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Definitions

  • the invention belongs to the field of sugar chemical synthesis, and specifically relates to a method for synthesizing alpha-penta-O-acetyl mannose.
  • Penta-O-acetyl mannose is an important raw material for the development and preparation of a series of mannose drugs and vaccine oligosaccharide fragments.
  • the traditional method of preparing pentaacetyl mannose from mannose is a mixture of two isomers, 1-alpha and 1-beta, which are oily and difficult to purify and commercialize.
  • the present invention provides a method for synthesizing alpha-penta-O-acetyl mannose with a yield High, mother liquor can be used repeatedly, suitable for industrial production.
  • the present invention adopts the following technical solutions.
  • a method for synthesizing alpha-penta-O-acetyl mannose including the following steps: in the presence of concentrated sulfuric acid, cesium fluoride catalyzes the reaction of mannose and acetic anhydride, and separates and purifies the product alpha-penta-O-acetyl mannose .
  • the separation and purification step is: after the reaction, the system is cooled to 0-10°C and poured into ice water, then filtered, the filter cake is washed with methanol at 0-10°C for 2-3 times, then filtered and dried to obtain the product.
  • the synthetic route is as follows:
  • the synthetic method of the present invention uses natural mannose as a raw material to explore on the basis of the traditional acetic anhydride acetylation process, adds a catalytic amount of cesium fluoride as a catalyst, and inhibits beta-penta-O-acetyl mannose under the action of the catalyst.
  • the formation of sugar can directly crystallize and separate to obtain high-purity solid alpha-penta-O-acetyl mannose, which overcomes the difficulty of crystallization and purification of penta-O-acetyl mannose prepared by traditional methods and the difficulties of large-scale industrialization.
  • the method is simple in process, low in cost, suitable for large-scale production, and can promote the application of mannose in the field of drug and vaccine development.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Saccharide Compounds (AREA)

Abstract

Provided is a preparation method for alpha-penta-O-acetyl mannose. A study is performed using natural mannose as a raw material on the basis of the conventional acetic anhydride acetylation process. A catalytic amount of cesium fluoride is added as a catalyst. The production of beta-penta-O-acetyl mannose is inhibited under the action of the catalyst, such that a high-purity, solid alpha-penta-O-acetyl mannose can be obtained by direct crystallization and separation, overcoming the obstacles in which crystallizing, purifying and large-scale industrialization of penta-O-acetyl mannose prepared using the conventional method is difficult. The method is simple in process, low in cost, suitable for large-scale production, and can promote the application of mannose in the field of drug and vaccine development.

Description

一种alpha-五-O-乙酰基甘露糖的制备方法A kind of preparation method of alpha-penta-O-acetyl mannose 技术领域Technical field
本发明属于糖化学合成领域，具体涉及一种alpha-五-O-乙酰基甘露糖的合成方法。The invention belongs to the field of sugar chemical synthesis, and specifically relates to a method for synthesizing alpha-penta-O-acetyl mannose.
背景技术Background technique
五-O-乙酰基甘露糖是开发制备一系列甘露糖药物和疫苗寡糖片段的重要原料。传统的从甘露糖制备五乙酰基甘露糖的方法得到的是两种异构体1-alpha和1-beta两个产物混合物，这样的混合产物呈油状，难以纯化和商品化。Penta-O-acetyl mannose is an important raw material for the development and preparation of a series of mannose drugs and vaccine oligosaccharide fragments. The traditional method of preparing pentaacetyl mannose from mannose is a mixture of two isomers, 1-alpha and 1-beta, which are oily and difficult to purify and commercialize.
现有可行的制备单一构型固态五-O-乙酰基甘露糖的方法是通过两步法获得：The existing feasible method for preparing solid penta-O-acetylmannose in a single configuration is obtained by a two-step method:
Figure PCTCN2019108395-appb-000001
Figure PCTCN2019108395-appb-000001
但是该方法成本较高，此外反应过程无法完全避免beta异构体的产生，重结晶过程单一alpha构型产品收率较低。目前国内市场alpha-五-O-乙酰基甘露糖还仅限于试剂级，价格较高限制了下游功能产品的开发利用。However, the cost of this method is relatively high. In addition, the production of beta isomers cannot be completely avoided in the reaction process, and the yield of a single alpha configuration product during the recrystallization process is low. At present, alpha-penta-O-acetylmannose in the domestic market is still limited to reagent grade, and the high price limits the development and utilization of downstream functional products.
发明内容Summary of the invention
针对现有固体alpha-五-O-乙酰基甘露糖生产工艺纯化困难、成本高、难以工业化生产的问题，本发明提供了一种alpha-五-O-乙酰基甘露糖的合成方法，收率高、母液可以套用，适于工业化生产。Aiming at the problems of difficulty in purification, high cost, and difficulty in industrial production in the existing solid alpha-penta-O-acetyl mannose production process, the present invention provides a method for synthesizing alpha-penta-O-acetyl mannose with a yield High, mother liquor can be used repeatedly, suitable for industrial production.
为实现上述目的，本发明采用如下技术方案。In order to achieve the above objective, the present invention adopts the following technical solutions.
一种alpha-五-O-乙酰基甘露糖的合成方法，包括以下步骤：浓硫酸存在下，氟化铯催化甘露糖和醋酸酐反应，分离纯化获得产物alpha-五-O-乙酰基甘露糖。A method for synthesizing alpha-penta-O-acetyl mannose, including the following steps: in the presence of concentrated sulfuric acid, cesium fluoride catalyzes the reaction of mannose and acetic anhydride, and separates and purifies the product alpha-penta-O-acetyl mannose .
所述分离纯化步骤为：反应结束后的体系降温至0-10℃倒入冰水中，然后过滤，滤饼用0-10℃甲醇洗涤2-3次后过滤并干燥，获得产物。The separation and purification step is: after the reaction, the system is cooled to 0-10°C and poured into ice water, then filtered, the filter cake is washed with methanol at 0-10°C for 2-3 times, then filtered and dried to obtain the product.
合成路线如下：The synthetic route is as follows:
Figure PCTCN2019108395-appb-000002
Figure PCTCN2019108395-appb-000002
本发明具有以下优点：The present invention has the following advantages:
本发明的合成方法以天然甘露糖为原料在传统的醋酸酐乙酰化工艺基础上进行了探索，添加催化量氟化铯为催化剂，在催化剂的作用下抑制了beta-五-O-乙酰基甘露糖的生成，从而直接析晶分离得到高纯度的固态alpha-五-O-乙酰基甘露糖，克服传统方法制备的五-O-乙酰基甘露糖难以析晶纯化和大规模产业化的困难。该方法工艺简单、成本低、适合大规模生产，能够促进甘露糖在药物和疫苗开发领域的应用。The synthetic method of the present invention uses natural mannose as a raw material to explore on the basis of the traditional acetic anhydride acetylation process, adds a catalytic amount of cesium fluoride as a catalyst, and inhibits beta-penta-O-acetyl mannose under the action of the catalyst. The formation of sugar can directly crystallize and separate to obtain high-purity solid alpha-penta-O-acetyl mannose, which overcomes the difficulty of crystallization and purification of penta-O-acetyl mannose prepared by traditional methods and the difficulties of large-scale industrialization. The method is simple in process, low in cost, suitable for large-scale production, and can promote the application of mannose in the field of drug and vaccine development.
具体实施方式detailed description
下面结合实施例对本发明做进一步说明，但本发明不受下述实施例的限制。The present invention will be further described below in conjunction with examples, but the present invention is not limited by the following examples.
实施例1Example 1
(1)搅拌下往6L醋酸酐中加入10g浓硫酸，体系搅拌均匀后分批加入1000g甘露糖，加料过程控制体系温度低于50℃；待加料完毕温度稳定后往体系加入1g氟化铯，然后继续搅拌反应，经HPLC检测12h后体系反应完全；(1) Add 10g of concentrated sulfuric acid to 6L of acetic anhydride under stirring, add 1000g of mannose in batches after the system is evenly stirred, and control the temperature of the system under 50℃ during the feeding process; add 1g of cesium fluoride to the system after the feeding is completed and the temperature is stable. Then continue to stir the reaction, and the system reaction is complete after 12h detection by HPLC;
(2)将反应后的体系降温至4℃，然后将体系缓慢倒入剧烈搅拌的10L冰水中，目标产物析出，过滤，滤饼用3L甲醇在0℃下搅洗，然后再过滤，滤饼用甲醇充分淋洗，固体产物经干燥得alpha-五-O-乙酰基甘露糖1985g，收率91.6％，HPLC纯度99.2％。(2) Cool the reaction system to 4°C, then slowly pour the system into 10L ice water with vigorous stirring. The target product is precipitated out and filtered. The filter cake is washed with 3L methanol at 0°C, and then filtered again. Fully eluted with methanol, the solid product was dried to obtain 1985 g of alpha-penta-O-acetyl mannose, with a yield of 91.6% and an HPLC purity of 99.2%.

Claims (2)

  1. 一种alpha-五-O-乙酰基甘露糖的合成方法，其特征在于，包括以下步骤：浓硫酸存在下，氟化铯催化甘露糖和醋酸酐反应，分离纯化获得产物alpha-五-O-乙酰基甘露糖。A method for synthesizing alpha-penta-O-acetyl mannose, which is characterized in that it comprises the following steps: in the presence of concentrated sulfuric acid, cesium fluoride catalyzes the reaction of mannose and acetic anhydride, and separates and purifies the product alpha-penta-O- Acetyl mannose.
  2. 根据权利要求1所述的合成方法，其特征在于，所述分离纯化步骤为：反应结束后的体系降温至0-10℃倒入冰水中，然后过滤，滤饼用0-10℃甲醇洗涤2-3次后过滤并干燥，获得产物。The synthesis method according to claim 1, wherein the separation and purification step is: after the reaction, the system is cooled to 0-10°C and poured into ice water, then filtered, and the filter cake is washed with methanol at 0-10°C. -Filter and dry after 3 times to obtain the product.
PCT/CN2019/108395 2019-09-23 2019-09-27 Preparation method for alpha-penta-o-acetyl mannose WO2021056382A1 (en)

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