WO2021056324A1 - Green chemical preparation method for alpha-tri-o-acetyl glucuronic acid methyl ester bromo compound - Google Patents

Green chemical preparation method for alpha-tri-o-acetyl glucuronic acid methyl ester bromo compound Download PDF

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WO2021056324A1
WO2021056324A1 PCT/CN2019/108115 CN2019108115W WO2021056324A1 WO 2021056324 A1 WO2021056324 A1 WO 2021056324A1 CN 2019108115 W CN2019108115 W CN 2019108115W WO 2021056324 A1 WO2021056324 A1 WO 2021056324A1
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tri
alpha
methyl ester
bromide
glucuronic acid
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PCT/CN2019/108115
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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
    • 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

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  • the invention belongs to the field of sugar chemical synthesis, and specifically relates to a chemical preparation method of methyl alpha-tri-O-acetylglucuronate bromide.
  • Alpha-tri-O-acetylglucuronic acid methyl ester bromide is an important synthetic building block for glucuronic acid sugar derivatives or modifications, and has important uses in the development and production of related carbohydrate drugs and diagnostic reagents, such as Preparation of tofacitinib glycosylation prodrug for the treatment of gastroenteritis (WO 2018217700A1), preparation of natural drug scutellarin (CN 107759472A), diagnostic reagent Beta-glucuronidase for trichomonas vaginitis Preparation of materials (CN 108129530A).
  • the existing method for preparing Alpha-tri-O-acetylglucuronate methyl bromide generally uses beta-tetra-O-acetylglucuronic acid methyl ester as raw material and hydrobromic acid (A Mechanism-Based Approach to Screening Metagenomic Libraries for Discovery of Unconventional Glycosidases, Angew Chem Int Edit 2018, 57, 11359-11364) or Titanium tetrabromide (Design, synthesis and in vitro evaluation of ⁇ -glucuronidase-sensitive prodrug of 5-aminolevulinic acid for photo diagnosis for cell Bioorganic Chemistry, 2018, 78, 372-380).
  • the biggest disadvantage of these methods is that the process produces a large amount of acidic or metal-containing wastewater, which is easy to cause environmental pollution and difficult industrialization.
  • the present invention provides a chemical synthesis of methyl alpha-tri-O-acetylglucuronate bromide
  • the method has high yield, the mother liquor can be used in a similar manner, and is suitable for industrial production.
  • the present invention adopts the following technical solutions.
  • a method for synthesizing methyl alpha-tri-O-acetylglucuronate bromide comprising the following steps:
  • Beta-tetra-O-acetylglucuronic acid methyl ester and sodium bromide are dissolved in methyl tertiary ether, concentrated sulfuric acid is added dropwise to keep the reaction, the reaction liquid is cooled to room temperature and filtered to obtain filtrate and sodium sulfate;
  • step (2) Concentrate the filtrate of step (1) to obtain a concentrated solution, and return to step (1) by concentrating and distilling methyl tertiary ether.
  • the concentrated solution is cooled and crystallized, and filtered to obtain methyl bromide alpha-tri-O-acetyl glucuronate. Substitutes and mother liquor, the mother liquor returns to step (1).
  • step (1) the molar ratio of beta-tetra-O-acetylglucuronic acid methyl ester, sodium bromide and concentrated sulfuric acid is 1.0:1.0 ⁇ 1.05:1.05 ⁇ 1.2.
  • step (1) the reaction temperature is 40-50°C.
  • step (2) the volume of the concentrated solution is 1/4 to 1/3 of the reaction solution.
  • step (2) the crystallization temperature is -5 to 5°C.
  • the synthetic route is as follows:
  • the synthesis method of the present invention replaces the traditional hydrobromic acid or titanium bromide method with the inorganic salt sodium bromide, sulfuric acid and methyl tertiary ether system, the system reaction is clean, the product can be directly separated from the system by crystallization, and the product yield is high.
  • the purity is high, the by-product sodium sulfate can be recycled, the distilled methyl tertiary ether and the concentrated mother liquor after crystallization can be recycled, achieving zero emission, no pollution, and large-scale alpha-tri-O-acetyl glucaldehyde.
  • the preparation of methyl acid bromide is conducive to the development and production of glucuronic acid-related drugs and functional compounds.
  • step (2) Concentrate the filtrate obtained in step (1) to about 3L under normal pressure, collect the distilled methyl tertiary ether and continue to use it in the next batch of reactions, then stir and lower the temperature to 0°C for 3 hours to keep and crystallize, and filter to obtain The product and the mother liquor; the mother liquor can be directly put into the next batch of reaction without concentration.
  • the product alpha-tri-O-acetylglucuronate methyl bromide has a dry mass of 971g, a yield of 92%, and a purity of 99.5 by HPLC %.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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Abstract

Provided is a green chemical preparation method for alpha-tri-O-acetyl glucuronic acid methyl ester bromo compound. The method uses sodium bromide, sulfuric acid and methyl tertiary ether system to replace the traditional hydrobromic acid or titanium bromide; the systemic reaction is clean; a product can be crystallized and separated directly from the system, the product has a high yield and a high purity; the sodium sulfate as a by-product can be recycled; and the distilled methyl tertiary ether and the concentrated mother liquor after crystallization and separation can be recycled, so as to achieve zero emission and free of pollution. The method can be used for large-scale preparation of alpha-tri-O-acetyl glucuronic acid methyl ester bromo compound, facilitating the development and production of glucuronic acid related drugs and functional compounds.

Description

一种alpha-三-O-乙酰基葡萄糖醛酸甲酯溴代物的绿色化学制备方法Green chemical preparation method of methyl alpha-tri-O-acetylglucuronate bromide 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-三-O-乙酰基葡萄糖醛酸甲酯溴代物的化学制备方法。The invention belongs to the field of sugar chemical synthesis, and specifically relates to a chemical preparation method of methyl alpha-tri-O-acetylglucuronate bromide.
背景技术Background technique
alpha-三-O-乙酰基葡萄糖醛酸甲酯溴代物是葡萄糖醛酸糖衍生物或修饰物的重要合成砌块，在相关糖类药物和诊断试剂研发和生产过程中有重要的用途，例如治疗肠胃炎药物托法替尼糖基化改造前体药物的制备(WO 2018217700A1)、天然药物灯盏花乙素的制备(CN 107759472A)、滴虫性阴道炎诊断试剂Beta-葡萄糖醛酸苷酶底物的制备(CN 108129530A)。Alpha-tri-O-acetylglucuronic acid methyl ester bromide is an important synthetic building block for glucuronic acid sugar derivatives or modifications, and has important uses in the development and production of related carbohydrate drugs and diagnostic reagents, such as Preparation of tofacitinib glycosylation prodrug for the treatment of gastroenteritis (WO 2018217700A1), preparation of natural drug scutellarin (CN 107759472A), diagnostic reagent Beta-glucuronidase for trichomonas vaginitis Preparation of materials (CN 108129530A).
现有制备Alpha-三-O-乙酰基葡萄糖醛酸甲酯溴代物的方法一般以beta-四-O-乙酰基葡萄糖醛酸甲酯为原料和氢溴酸(A Mechanism-Based Approach to Screening Metagenomic Libraries for Discovery of Unconventional Glycosidases,Angew Chem Int Edit 2018,57,11359-11364)或者四溴化钛(Design,synthesis and in vitro evaluation ofβ-glucuronidase-sensitive prodrug of 5-aminolevulinic acid for photodiagnosis of breast cancer cells，Bioorganic Chemistry,2018,78,372-380)反应，这些方法最大的缺点是工艺过程产生大量的酸性或含有金属的废水、容易造成环境污染、产业化困难。The existing method for preparing Alpha-tri-O-acetylglucuronate methyl bromide generally uses beta-tetra-O-acetylglucuronic acid methyl ester as raw material and hydrobromic acid (A Mechanism-Based Approach to Screening Metagenomic Libraries for Discovery of Unconventional Glycosidases, Angew Chem Int Edit 2018, 57, 11359-11364) or Titanium tetrabromide (Design, synthesis and in vitro evaluation of β-glucuronidase-sensitive prodrug of 5-aminolevulinic acid for photo diagnosis for cell Bioorganic Chemistry, 2018, 78, 372-380). The biggest disadvantage of these methods is that the process produces a large amount of acidic or metal-containing wastewater, which is easy to cause environmental pollution and difficult industrialization.
发明内容Summary of the invention
针对现有alpha-三-O-乙酰基葡萄糖醛酸甲酯溴代物生产工艺废水难处理的问题，本发明提供了一种alpha-三-O-乙酰基葡萄糖醛酸甲酯溴代物的化学合成方法，收率高、母液可以套用，适于工业化生产。Aiming at the problem of difficult treatment of wastewater from the existing production process of methyl alpha-tri-O-acetylglucuronate bromide, the present invention provides a chemical synthesis of methyl alpha-tri-O-acetylglucuronate bromide The method has high yield, the mother liquor can be used in a similar manner, and is 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-三-O-乙酰基葡萄糖醛酸甲酯溴代物的合成方法，包括以下步骤：A method for synthesizing methyl alpha-tri-O-acetylglucuronate bromide, comprising the following steps:
(1)beta-四-O-乙酰基葡萄糖醛酸甲酯和溴化钠溶解于甲叔醚中，滴加浓硫酸保温反应，反应液冷至常温后过滤获得滤液和硫酸钠；(1) Beta-tetra-O-acetylglucuronic acid methyl ester and sodium bromide are dissolved in methyl tertiary ether, concentrated sulfuric acid is added dropwise to keep the reaction, the reaction liquid is cooled to room temperature and filtered to obtain filtrate and sodium sulfate;
(2)步骤(1)的滤液浓缩获得浓缩液，浓缩蒸出的甲叔醚返回步骤(1)，浓缩液降温析晶，过滤后得alpha-三-O-乙酰基葡萄糖醛酸甲酯溴代物和母液，母液返回步骤(1)。(2) Concentrate the filtrate of step (1) to obtain a concentrated solution, and return to step (1) by concentrating and distilling methyl tertiary ether. The concentrated solution is cooled and crystallized, and filtered to obtain methyl bromide alpha-tri-O-acetyl glucuronate. Substitutes and mother liquor, the mother liquor returns to step (1).
步骤(1)中，beta-四-O-乙酰基葡萄糖醛酸甲酯、溴化钠和浓硫酸的摩尔比为1.0:1.0～1.05:1.05～1.2。In step (1), the molar ratio of beta-tetra-O-acetylglucuronic acid methyl ester, sodium bromide and concentrated sulfuric acid is 1.0:1.0~1.05:1.05~1.2.
步骤(1)中，反应温度为40～50℃。In step (1), the reaction temperature is 40-50°C.
步骤(2)中，浓缩液的体积为反应液的1/4～1/3。In step (2), the volume of the concentrated solution is 1/4 to 1/3 of the reaction solution.
步骤(2)中，析晶温度为-5～5℃。In step (2), the crystallization temperature is -5 to 5°C.
合成路线如下：The synthetic route is as follows:
Figure PCTCN2019108115-appb-000001
Figure PCTCN2019108115-appb-000001
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无机盐溴化钠、硫酸和甲叔醚体系代替了传统的氢溴酸或溴化钛方法，体系反应干净，产物可以直接从体系中析晶分离，产物收率高、纯度高，副产物硫酸钠可以回收利用，蒸馏出的甲叔醚和析晶后的浓缩母液可以循环利用，做到零排放、无污染，可以进行大规模alpha-三-O-乙酰基葡萄糖醛酸甲酯溴代物制备，有利于葡萄糖醛酸相关药物和功能化合物的研发和生产。The synthesis method of the present invention replaces the traditional hydrobromic acid or titanium bromide method with the inorganic salt sodium bromide, sulfuric acid and methyl tertiary ether system, the system reaction is clean, the product can be directly separated from the system by crystallization, and the product yield is high. The purity is high, the by-product sodium sulfate can be recycled, the distilled methyl tertiary ether and the concentrated mother liquor after crystallization can be recycled, achieving zero emission, no pollution, and large-scale alpha-tri-O-acetyl glucaldehyde. The preparation of methyl acid bromide is conducive to the development and production of glucuronic acid-related drugs and functional compounds.
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10L甲叔醚(MTBE)溶剂中加入1000g bBeta-四-O-乙酰基葡萄糖醛酸甲酯，体系搅拌溶清后加入273g溴化钠，加料完毕体系升温至45℃，然后在搅拌下往体系中滴加266g浓硫酸，滴加过程控制体系温度在40℃至50℃范围内；滴加完毕体系保温45±5℃反应，HPLC跟踪反应，约24小时后原料消失，反应完毕，将体系温度降至25℃，体系过滤得到硫酸钠晶体；(1) Add 1000g of beta-tetra-O-acetylglucuronic acid methyl ester to 10L of methyl tertiary ether (MTBE) solvent under stirring. After the system is stirred and dissolved, 273g of sodium bromide is added. After the addition, the system is heated to 45°C. Then 266g of concentrated sulfuric acid was added dropwise to the system under stirring, and the temperature of the dropping process was controlled within the range of 40°C to 50°C; after the dropping, the system was kept at 45±5°C for reaction, and the reaction was followed by HPLC. The raw materials disappeared after about 24 hours. After the reaction is completed, the temperature of the system is reduced to 25°C, and the system is filtered to obtain sodium sulfate crystals;
(2)将步骤(1)中获得的滤液常压浓缩至约3L，收集蒸馏出的甲叔醚继续用于下一批反应，然后在搅拌下降温至0℃保温析晶3h，过滤后得产物与母液；母液不经浓缩可以直接投入下一批反应，产物alpha-三-O-乙酰基葡萄糖醛酸甲酯溴代物，干燥后质量为971g，收率92％，经HPLC检测纯度为99.5％。(2) Concentrate the filtrate obtained in step (1) to about 3L under normal pressure, collect the distilled methyl tertiary ether and continue to use it in the next batch of reactions, then stir and lower the temperature to 0°C for 3 hours to keep and crystallize, and filter to obtain The product and the mother liquor; the mother liquor can be directly put into the next batch of reaction without concentration. The product alpha-tri-O-acetylglucuronate methyl bromide has a dry mass of 971g, a yield of 92%, and a purity of 99.5 by HPLC %.
按照步骤(1)和(2)的投料量和反应条件，经5批连续投料和溶剂及母液套用，平均每批获得产物955g，收率90.5-92.3％，经HPLC检测纯度为98.7％～99.6％，溶剂和母 液的套用并显著影响产品的收率与纯度。According to the feeding amount and reaction conditions of steps (1) and (2), after 5 batches of continuous feeding and solvent and mother liquor, 955g of product was obtained per batch on average, with a yield of 90.5-92.3%, and a purity of 98.7%-99.6 by HPLC %, the use of solvent and mother liquor will significantly affect the yield and purity of the product.

Claims (5)

  1. 一种alpha-三-O-乙酰基葡萄糖醛酸甲酯溴代物的合成方法，其特征在于，包括以下步骤：A method for synthesizing methyl alpha-tri-O-acetylglucuronate bromide, which is characterized in that it comprises the following steps:
    (1)beta-四-O-乙酰基葡萄糖醛酸甲酯和溴化钠溶解于甲叔醚中，滴加浓硫酸保温反应，反应液冷至常温后过滤获得滤液和硫酸钠；(1) Beta-tetra-O-acetylglucuronic acid methyl ester and sodium bromide are dissolved in methyl tertiary ether, concentrated sulfuric acid is added dropwise to keep the reaction, the reaction liquid is cooled to room temperature and filtered to obtain filtrate and sodium sulfate;
    (2)步骤(1)的滤液浓缩获得浓缩液，浓缩蒸出的甲叔醚返回步骤(1)，浓缩液降温析晶，过滤后得alpha-三-O-乙酰基葡萄糖醛酸甲酯溴代物和母液，母液返回步骤(1)。(2) Concentrate the filtrate of step (1) to obtain a concentrated solution, and return to step (1) by concentrating and distilling methyl tertiary ether. The concentrated solution is cooled and crystallized, and filtered to obtain methyl bromide alpha-tri-O-acetyl glucuronate. Substitutes and mother liquor, the mother liquor returns to step (1).
  2. 根据权利要求1所述的合成方法，其特征在于，步骤(1)中，beta-四-O-乙酰基葡萄糖醛酸甲酯、溴化钠和浓硫酸的摩尔比为1.0:1.0～1.05:1.05～1.2。The synthesis method according to claim 1, wherein in step (1), the molar ratio of beta-tetra-O-acetylglucuronic acid methyl ester, sodium bromide and concentrated sulfuric acid is 1.0:1.0～1.05: 1.05～1.2.
  3. 根据权利要求1所述的合成方法，其特征在于，步骤(1)中，反应温度为40～50℃。The synthesis method according to claim 1, wherein in step (1), the reaction temperature is 40-50°C.
  4. 根据权利要求1所述的合成方法，其特征在于，步骤(2)中，浓缩液的体积为反应液的1/4～1/3。The synthesis method according to claim 1, wherein in step (2), the volume of the concentrated solution is 1/4 to 1/3 of the reaction solution.
  5. 根据权利要求1所述的合成方法，其特征在于，步骤(2)中，析晶温度为-5～5℃。The synthesis method according to claim 1, wherein in step (2), the crystallization temperature is -5 to 5°C.
PCT/CN2019/108115 2019-09-23 2019-09-26 Green chemical preparation method for alpha-tri-o-acetyl glucuronic acid methyl ester bromo compound WO2021056324A1 (en)

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