WO2023134406A1 - 一种藜芦醚的制备方法 - Google Patents

一种藜芦醚的制备方法 Download PDF

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WO2023134406A1
WO2023134406A1 PCT/CN2022/140231 CN2022140231W WO2023134406A1 WO 2023134406 A1 WO2023134406 A1 WO 2023134406A1 CN 2022140231 W CN2022140231 W CN 2022140231W WO 2023134406 A1 WO2023134406 A1 WO 2023134406A1
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lithium hydroxide
preparation
reaction
solution
temperature
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French (fr)
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吴华强
李兰花
裘月南
刘志远
张洪圆
姜立军
蔺珍
盖树强
孙宽宽
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山东泓瑞医药科技股份公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/34—Separation; Purification; Stabilisation; Use of additives
    • C07C41/40—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation
    • C07C41/42—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation by distillation

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  • the invention relates to the technical field of organic synthesis, in particular to a preparation method of veratrole.
  • Heart disease is a disease that seriously endangers human health. According to statistics, there are about 370 million heart disease patients in my country, and hundreds of thousands of people die of heart disease every year. At the same time, there are about 3 million new heart disease patients every year. In my country, the age of onset of heart disease patients is also younger, which makes the types of drugs for the treatment of various heart diseases increase year by year.
  • Veratrole whose chemical name is 1,2-dimethoxybenzene, has a melting point of 22-23°C, and its pure product is a colorless transparent liquid, which is solid at low temperature.
  • the existing synthetic method of veratrole mainly uses catechol as raw material, and dimethyl sulfate is a methylating agent, and a methylation reaction occurs in NaOH solution to obtain a crude product, which is then separated by water washing, alkali washing and distillation to obtain Final product.
  • the reaction temperature of this synthesis method needs to reach at least 99° C., and the reaction time is long, requiring at least 8 hours of reaction under reflux, which is not conducive to the stability and safety of the synthesis reaction.
  • the present invention provides a preparation method of veratrole, the preparation method has low reaction temperature, short reaction time, improved reaction stability and safety, and high product yield.
  • a method for preparing veratrole comprising the following steps: mixing catechol, dimethyl sulfate and lithium hydroxide for methylation reaction to obtain veratrole; the temperature of the methylation reaction is ⁇ 80°C ; The time of the methylation reaction ⁇ 6h.
  • the temperature of the methylation reaction is 60-80° C.; the time of the methylation reaction is 2-6 hours.
  • the mass ratio of catechol, dimethyl sulfate and lithium hydroxide is 1:1-1.3:0.92-1.3.
  • the mixing of catechol, dimethyl sulfate and lithium hydroxide includes: mixing catechol and dimethyl sulfate to obtain a reaction solution, and adding lithium hydroxide solution dropwise to the reaction solution .
  • the mass fraction of lithium hydroxide in the lithium hydroxide solution is 30%-50%.
  • the lithium hydroxide solution is prepared from lithium hydroxide monohydrate, and the solvent of the lithium hydroxide solution is water.
  • the lithium hydroxide solution is added dropwise in two drops.
  • the dropwise addition of the lithium hydroxide solution is as follows: heating the reaction solution to raise the temperature, and starting to add the lithium hydroxide solution dropwise when the temperature of the reaction solution is 10°C to 40°C; When the temperature required for the alkylation reaction, the dropwise amount of the lithium hydroxide solution is not less than 50% of the total amount added; then continue to drop the remaining lithium hydroxide solution, and the dropwise addition of the remaining lithium hydroxide solution The time is 1.5 ⁇ 4.0h.
  • the method further includes: sequentially washing the product liquid obtained from the methylation reaction with water, washing with alkali and distilling.
  • the water washing is: after the methylation reaction stops, the obtained product feed liquid is allowed to stand for stratification, and the obtained oil layer is washed with water.
  • the alkaline cleaning reagent is LiOH solution, NaOH solution, KOH solution or NaCO 3 solution.
  • the vacuum degree of the distillation is -0.09998MPa ⁇ -0.0998MPa.
  • the invention provides a preparation method of veratrole, comprising the following steps: mixing catechol, dimethyl sulfate and lithium hydroxide for methylation reaction to obtain veratrole;
  • the temperature is ⁇ 80°C; the time of the methylation reaction is ⁇ 6h.
  • lithium hydroxide is used to replace sodium hydroxide
  • catechol is used as a raw material
  • dimethyl sulfate is used as a methylating agent to prepare veratrole.
  • the preparation method provided by the invention reduces the reaction temperature, shortens the reaction time, and improves the stability and safety of the reaction and the product yield.
  • the experimental data of the embodiment of the present invention shows that the highest yield of veratrole is 95%.
  • the preparation method provided by the present invention does not need to be carried out under the condition of reflux, the operation is simpler, and the safety and stability of the reaction are further improved.
  • the invention provides a kind of preparation method of veratrol, comprising the following steps:
  • preparation raw materials used in the present invention are all commercially available.
  • the methylation reaction is preferably carried out in a methylation reaction tank; the temperature of the methylation reaction is ⁇ 80°C, preferably 60°C-80°C, more preferably 70°C-75°C, Most preferably 75°C.
  • the time of the methylation reaction is calculated after the catechol, dimethyl sulfate and lithium hydroxide are mixed, and the methylation time is ⁇ 6h, preferably 2-6h, It is more preferably 3 to 5 hours, more preferably 4 to 5 hours, and most preferably 5 hours.
  • the invention mixes catechol, dimethyl sulfate and lithium hydroxide to carry out methylation reaction.
  • the mass ratio of catechol, dimethyl sulfate and lithium hydroxide is preferably 1:1-1.3:0.92-1.3, more preferably 1:1-1.20:0.95-1.25, and even more preferably 1:1 to 1.15:0.95 to 1.2, most preferably 1:1.14:1.2.
  • the proportions of catechol, dimethyl sulfate and lithium hydroxide are preferably limited within the above range, which is beneficial to improving the catalytic effect of lithium hydroxide and increasing the yield of veratrole.
  • the mixing of catechol, dimethyl sulfate and lithium hydroxide includes: mixing catechol and dimethyl sulfate to obtain a reaction solution, and then adding hydrogen dropwise to the reaction solution Lithium oxide solution.
  • the mass fraction of lithium hydroxide in the lithium hydroxide solution is preferably 30% to 50%, more preferably 40% to 50%, further preferably 40% to 45%, most preferably 40%;
  • the solvent of the lithium hydroxide solution is water.
  • the present invention preferably adopts lithium hydroxide monohydrate to prepare lithium hydroxide solution.
  • the price of lithium hydroxide monohydrate is lower than that of anhydrous lithium hydroxide, and the use of lithium hydroxide monohydrate is beneficial to reduce the cost of the reaction.
  • the present invention has no special requirements on the configuration method of the lithium hydroxide monohydrate solution, preferably dissolving lithium hydroxide monohydrate in deionized water to prepare the lithium hydroxide solution.
  • the dropping method of the lithium hydroxide solution is preferably divided into two drops, and the dropping method is preferably: heating the reaction solution, when the temperature of the reaction solution is 10° C. to 40° C. , start to drop the lithium hydroxide solution; when the temperature of the reaction solution reaches the temperature required for the methylation reaction, the dropwise amount of the lithium hydroxide solution is not less than 50% of the total amount added; then continue The remaining lithium hydroxide solution is added dropwise, and the time for adding the remaining lithium hydroxide solution is 1.5-4.0 h.
  • the temperature of the reaction solution is preferably 10°C to 40°C, more preferably 15°C to 35°C, further preferably 20°C to 30°C, most preferably is 25°C.
  • the dropwise addition of the lithium hydroxide solution is preferably started at the above temperature, which is beneficial to prevent the temperature from rising too quickly and is easier to control, so that the reaction temperature is relatively stable so that the reaction proceeds smoothly, while ensuring the stability of the final product yield.
  • the dropwise amount of the lithium hydroxide solution is preferably not less than 50% of the total amount to be added, more preferably 50% of the total amount to be added. 50% to 60%, more preferably 55% to 60% of the total amount to be added dropwise, most preferably 60%.
  • the exothermic reaction can be used to increase the temperature of the reaction solution so that the temperature of the reaction solution reaches the temperature required for the methylation reaction.
  • the dropping time of the remaining lithium hydroxide solution is preferably 1.5 to 4.0 h, more preferably 1.5 to 3.0 h, further preferably 1.5 to 2.5 h, and most preferably 1.5 to 2.5 h. Preferably 2.0h. Since the methylation reaction carried out by the remaining lithium hydroxide solution has less exothermic heat, the present invention preferably limits the dropwise addition time of the remaining lithium hydroxide solution within the above range, which is beneficial to avoid artificial waste during the dropwise addition.
  • the methylation reaction after the methylation reaction, it further includes: sequentially washing the product liquid obtained from the methylation reaction with water, washing with alkali and distilling.
  • the obtained product liquid is allowed to stand for stratification, and the obtained oil layer is washed with water; the water for washing is preferably process water.
  • the present invention preferably samples and detects the organic phase until the water washing is qualified.
  • the product washed with water is preferably subjected to alkali washing.
  • the reagent for alkali cleaning is preferably LiOH solution, NaOH solution, KOH solution or NaCO solution, more preferably NaCO solution.
  • the product washed with water is preferably washed with alkali for 1 to 4 times, more preferably 2 to 4 times, and even more preferably 3 to 4 times.
  • the invention neutralizes the product to the above pH value, which can ensure that the metal salt intermediate product formed by alkali washing is completely converted into the final product.
  • the distillation is preferably vacuum distillation, and the vacuum degree of the distillation is preferably -0.09998MPa ⁇ -0.0998MPa, more preferably -0.09997MPa ⁇ -0.0999MPa, further preferably -0.09997MPa ⁇ -0.09993MPa , most preferably -0.09997MPa to -0.09994MPa.
  • the crude oil was obtained by stratification, and the product veratrole was distilled from the crude oil under vacuum conditions.
  • the vacuum degree was -0.099939 MPa to obtain 1500 g of veratrole, the yield was 86%, and the selectivity of veratrole was 87%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

涉及有机合成技术领域，尤其涉及一种藜芦醚的制备方法。以氢氧化锂代替氢氧化钠，以邻苯二酚为原料，硫酸二甲酯为甲基化剂，制备得到藜芦醚。提供的制备方法较现有添加氢氧化钠溶液的方法，降低了反应温度，缩短了反应时间，提高了反应的稳定性和安全性以及产品收率。实施例的实验数据表明，藜芦醚的收率最高为95%。进一步的，提供的制备方法无需在回流的条件下进行，操作更加简单，进一步提高了反应的安全性和稳定性。

Description

一种藜芦醚的制备方法
本申请要求于2022年1月17日提交中国专利局、申请号为CN202210046445.8、发明名称为“一种藜芦醚的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及有机合成技术领域，尤其涉及一种藜芦醚的制备方法。
背景技术
心脏病是严重危害人类健康的疾病。据统计，我国现有各类心脏病患者约3亿7千万人，每年约有几十万人死于心脏病，同时，每年还新增心脏病患者约300万人。在我国，心脏病患者的发病年龄也呈现出年轻化，这都使得治疗各类心脏病的药物种类逐年增加。
藜芦醚，化学名称为1,2-二甲氧基苯，熔点22～23℃，纯品为无色透明液体，低温下为固体，是一种重要的精细化工原料，同时也是医药领域的重要原料之一，它不仅是杀菌剂烯酰吗啉合成中的一个关键中间体，还是合成治疗心脏病药物的重要中间体。
现有藜芦醚的合成方法主要以邻苯二酚为原料，硫酸二甲酯为甲基化剂，在NaOH溶液中发生甲基化反应制得粗品，然后通过水洗、碱洗和蒸馏分离得到最终产品。该合成方法的反应温度至少需要到达到99℃，且反应时间长，需要在回流状态下反应至少8h，不利于合成反应的稳定性和安全性。
发明内容
有鉴于此，本发明提供一种藜芦醚的制备方法，该制备方法反应温度低，反应时间短，提高了反应的稳定性和安全性，并且产物收率高。
为了实现上述发明目的，本发明提供以下技术方案：
一种藜芦醚的制备方法，包括以下步骤：将邻苯二酚、硫酸二甲酯和氢氧化锂混合进行甲基化反应，得到藜芦醚；所述甲基化反应的温度≤80℃；所述甲基化反应的时间≤6h。
优选的，所述甲基化反应的温度为60～80℃；所述甲基化反应的时间为2～6h。
优选的，所述邻苯二酚、硫酸二甲酯和氢氧化锂的质量比为1：1～1.3：0.92～1.3。
优选的，所述将邻苯二酚、硫酸二甲酯和氢氧化锂混合包括：将邻苯二酚和硫酸二甲酯混合，得到反应液，向所述反应液中滴加氢氧化锂溶液。
优选的，所述氢氧化锂溶液中氢氧化锂的质量分数为30％～50％。
优选的，所述氢氧化锂溶液由一水合氢氧化锂制备得到，所述氢氧化锂溶液的溶剂为水。
优选的，所述氢氧化锂溶液的滴加方式为分两次滴加。
优选的，所述滴加氢氧化锂溶液为：将所述反应液加热升温，当反应液的温度为10℃～40℃时，开始滴加所述氢氧化锂溶液；当反应液温度达到甲基化反应所需的温度时，所述氢氧化锂溶液的滴加量不少于滴加总量的50％；之后继续滴加剩余氢氧化锂溶液，所述剩余氢氧化锂溶液的滴加时间为1.5～4.0h。
优选的，所述甲基化反应之后还包括：将甲基化反应所得产物料液依次进行水洗、碱洗和蒸馏。
优选的，所述水洗为：在甲基化反应停止后将所得产物料液静置分层，对所得油层进行水洗。
优选的，所述碱洗用试剂为LiOH溶液、NaOH溶液、KOH溶液或NaCO 3的溶液。
优选的，所述碱洗后，还包括采用盐酸将碱洗后的产物中和至pH＝1。
优选的，所述蒸馏的真空度为-0.09998MPa～-0.0998MPa。
本发明提供了一种藜芦醚的制备方法，包括以下步骤：将邻苯二酚、硫酸二甲酯和氢氧化锂混合进行甲基化反应，得到藜芦醚；所述甲基化反应的温度≤80℃；所述甲基化反应的时间≤6h。本发明以氢氧化锂代替氢氧化钠，以邻苯二酚为原料，硫酸二甲酯为甲基化剂，制备得到藜芦醚。本发明提供的制备方法较现有添加氢氧化钠溶液的方法，降低了反应温度，缩短了反应时间，提高了反应的稳定性和安全性以及产品收率。本发 明实施例的实验数据表明，藜芦醚的收率最高为95％。
进一步的，本发明提供的制备方法无需在回流的条件下进行，操作更加简单，进一步提高了反应的安全性和稳定性。
具体实施方式
本发明提供了一种藜芦醚的制备方法，包括以下步骤：
将邻苯二酚、硫酸二甲酯和氢氧化锂混合进行甲基化反应，得到藜芦醚；所述甲基化反应的温度≤80℃；所述甲基化反应的时间≤6h。
如无特殊说明，本发明使用的制备原料均为市售。
在本发明中，所述甲基化反应优选在甲基化反应釜中进行；所述甲基化反应的温度≤80℃，优选为60℃～80℃，进一步优选为70℃～75℃，最优选为75℃。在本发明中，所述甲基化反应的时间以所述邻苯二酚、硫酸二甲酯和氢氧化锂混合完毕后开始计算，所述甲基化时间≤6h，优选为2～6h，进一步优选为3～5h，更优选为4～5h，最优选为5h。本发明优选在搅拌的方式下将邻苯二酚、硫酸二甲酯和氢氧化锂混合进行甲基化反应。
本发明将邻苯二酚、硫酸二甲酯和氢氧化锂混合进行甲基化反应。在本发明中，所述邻苯二酚、硫酸二甲酯和氢氧化锂的质量比优选为1：1～1.3：0.92～1.3，更优选为1：1～1.20：0.95～1.25，进一步优选为1：1～1.15：0.95～1.2，最优选为1：1.14：1.2。本发明优选将邻苯二酚、硫酸二甲酯和氢氧化锂的比例限定在上述范围内，有利于提高氢氧化锂的催化效果，提高藜芦醚的得率。
在本发明中，所述将邻苯二酚、硫酸二甲酯和氢氧化锂混合包括：将邻苯二酚和硫酸二甲酯混合，得到反应液，然后向所述反应液中滴加氢氧化锂溶液。在本发明中，所述氢氧化锂溶液中氢氧化锂的质量分数优选为30％～50％，更优选为40％～50％，进一步优选为40％～45％，最优选为40％；所述氢氧化锂溶液的溶剂为水。本发明优选采用一水合氢氧化锂制备氢氧化锂溶液。在本发明中，一水合氢氧化锂的价格较无水氢氧化锂的价格更低，采用一水合氢氧化锂有利于降低反应的成本。本发明对一水合氢氧化锂溶液的配置方法没有特别要求，优选将一水合氢氧化锂溶于去离子水中配制氢氧化锂溶液。
在本发明中，所述氢氧化锂溶液的滴加方式优选为分两次滴加，所述滴加方式优选为：将所述反应液加热，当反应液的温度为10℃～40℃时，开始滴加所述氢氧化锂溶液；当反应液的温度达到甲基化反应所需的温度时，所述氢氧化锂溶液的滴加量不少于滴加总量的50％；之后继续滴加剩氢氧化锂溶液，所述剩余氢氧化锂溶液的滴加时间为1.5～4.0h。在本发明中，开始滴加所述氢氧化锂溶液时，所述反应液的温度优选为10℃～40℃，更优选为15℃～35℃，进一步优选为20℃～30℃，最优选为25℃。本发明优选在上述温度下开始滴加氢氧化锂溶液，有利于使温度不会过快升高而更易控制，使反应温度相对稳定从而使反应平稳进行，同时保证最终产物收率的稳定性。在本发明中，当反应液的温度达到甲基化反应所需温度时，所述氢氧化锂溶液的滴加量优选不少于滴加总量的50％，更优选为滴加总量的50％～60％，进一步优选为滴加总量的55％～60％，最优选为60％。在本发明中，由于甲基化反应为放热反应，因此可以利用该放热反应来提高反应液的温度，使反应液的温度达到甲基化反应所需温度。本发明还优选采用通入循环水的方式来防止反应液的温度超过甲基化反应所需温度。在本发明中，继续滴加剩氢氧化锂溶液时，所述剩余氢氧化锂溶液的滴加时间优选为1.5～4.0h，更优选为1.5～3.0h，进一步优选为1.5～2.5h，最优选为2.0h。由于剩余氢氧化锂溶液进行的甲基化反应放热较少，本发明优选将剩余氢氧化锂溶液的滴加时间限定在上述范围内，有利于避免滴加时的人工浪费。
在本发明中，所述甲基化反应之后还包括：将甲基化反应所得产物料液依次进行水洗、碱洗和蒸馏。本发明优选在甲基化反应停止后将所得产物料液静置分层，对所得油层进行水洗；所述水洗用水优选为工艺水。在水洗过程中，本发明优选对有机相进行取样检测，直至水洗合格。在本发明中，优选将水洗后的产物进行碱洗。在本发明中，碱洗用试剂优选为LiOH溶液、NaOH溶液、KOH溶液或NaCO 3的溶液，更优选为NaCO 3溶液。本发明优选将水洗后的产物碱洗1～4次，更优选为2～4次，进一步优选为3～4次。得到碱洗后的产物后，本发明优选采用盐酸将碱洗后的产物中和至pH＝1，然后将中和后的产物进行蒸馏。本发明将产物中和 至上述pH值，可以保证碱洗形成的金属盐中间产物完全转化为最终产物。在本发明中，所述蒸馏优选为真空蒸馏，所述蒸馏的真空度优选为-0.09998MPa～-0.0998MPa，更优选为-0.09997MPa～-0.0999MPa，进一步优选为-0.09997MPa～-0.09993MPa，最优选为-0.09997MPa～-0.09994MPa。
下面将结合本发明中的实施例，对本发明中的技术方案进行清楚、完整地描述。
实施例1
在甲基化反应釜中加入硫酸二甲酯1800g、邻苯二酚1750g，搅拌混合，将硫酸二甲酯和邻苯二酚混合得到的反应液加热至30℃，开始滴加质量分数为40％的LiOH溶液，滴加2100g后，当反应液温度升至70℃时，开启循环水，继续滴加剩余LiOH溶液，剩余LiOH溶液的滴加时间为1.5小时，滴加完毕后，LiOH溶液共滴加4200g。将反应液在65℃下甲基化反应4小时。甲基化反应结束后，关闭搅拌，静置分层，油层用工艺水洗涤至合格，取样检测，待物料合格后用NaCO 3碱洗水洗涤3次，用盐酸中和至pH值＝1，静置分层得粗油，将粗油在真空条件下蒸出产品藜芦醚，真空度为-0.099935MPa，得到藜芦醚1605g，收率为92％，藜芦醚的选择性为90％。
实施例2
在甲基化反应釜中加入硫酸二甲酯1800g、邻苯二酚1750g，搅拌混合，将硫酸二甲酯和邻苯二酚混合得到的反应液加热至25℃，开始滴加质量分数为40％的LiOH溶液，滴加2310g后，当反应液温度升至70℃时，开启循环水，继续滴加剩余LiOH溶液，剩余LiOH溶液的滴加时间为3小时，滴加完毕后，LiOH溶液共滴加4200g。将反应液在70℃下甲基化反应5小时。甲基化反应结束后，关闭搅拌，静置分层，油层用工艺水洗涤至合格，取样检测，待物料合格后用NaCO 3碱洗水洗涤3次，用盐酸中和至pH值＝1，静置分层得粗油，将粗油在真空条件下蒸出产品藜芦醚，真空度为-0.099934MPa，得到藜芦醚1625g，收率为93％，藜芦醚的选择性为89％。
实施例3
在甲基化反应釜中加入硫酸二甲酯2000g、邻苯二酚1750g，搅拌混合，将硫酸二甲酯和邻苯二酚混合得到的反应液加热至25℃，开始滴加质量分数为50％的LiOH溶液，滴加2520g后，当反应液温度升至70℃时，开启循环水，继续滴加剩余LiOH溶液，剩余LiOH溶液的滴加时间为2小时，滴加完毕后，LiOH溶液共滴加4200g。将反应液在75℃下甲基化反应3小时。甲基化反应结束后，关闭搅拌，静置分层，油层用工艺水洗涤至合格，取样检测，待物料合格后用NaCO 3碱洗水洗涤3次，用盐酸中和至pH值＝1，静置分层得粗油，将粗油在真空条件下蒸出产品藜芦醚，真空度为-0.099937MPa，得到藜芦醚1660g，收率为95％，藜芦醚的选择性为91％。
对比例1
在甲基化反应釜中加入硫酸二甲酯2000g、邻苯二酚1750g，搅拌混合，将硫酸二甲酯和邻苯二酚混合得到的反应液加热至25℃，开始滴加质量分数为30％的NaOH溶液，滴加1500g后，当反应液温度升至70℃时，开启循环水，继续滴加剩余NaOH溶液，剩余NaOH溶液的滴加时间为3小时，滴加完毕后，NaOH溶液共滴加5000g，将反应液在99℃下进行回流反应12小时。待反应结束后，关闭搅拌，静置分层，油层用工艺水洗涤至合格，取样检测，待物料合格后用NaCO 3碱洗水洗涤3次，用盐酸中和至pH值＝1，静置分层得粗油，将粗油在真空条件下蒸出产品藜芦醚，真空度为-0.099939MPa，得到藜芦醚1500g，收率为86％，藜芦醚的选择性为87％。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (13)

  1. 一种藜芦醚的制备方法，其特征在于，包括以下步骤：
    将邻苯二酚、硫酸二甲酯和氢氧化锂混合进行甲基化反应，得到藜芦醚；所述甲基化反应的温度≤80℃；所述甲基化反应的时间≤6h。
  2. 根据权利要求1所述的制备方法，其特征在于，所述甲基化反应的温度为60～80℃；所述甲基化反应的时间为2～6h。
  3. 根据权利要求1所述的制备方法，其特征在于，所述邻苯二酚、硫酸二甲酯和氢氧化锂的质量比为1：1～1.3：0.92～1.3。
  4. 根据权利要求1所述的制备方法，其特征在于，所述将邻苯二酚、硫酸二甲酯和氢氧化锂混合包括：将邻苯二酚和硫酸二甲酯混合，得到反应液，向所述反应液中滴加氢氧化锂溶液。
  5. 根据权利要求4所述的制备方法，其特征在于，所述氢氧化锂溶液中氢氧化锂的质量分数为30％～50％。
  6. 根据权利要求4或5所述的制备方法，其特征在于，所述氢氧化锂溶液由一水合氢氧化锂制备得到，所述氢氧化锂溶液的溶剂为水。
  7. 根据权利要求4或5所述的制备方法，其特征在于，所述氢氧化锂溶液的滴加方式为分两次滴加。
  8. 根据权利要求7所述的制备方法，其特征在于，所述滴加氢氧化锂溶液为：
    将所述反应液加热升温，当反应液的温度为10℃～40℃时，开始滴加所述氢氧化锂溶液；当反应液温度达到甲基化反应所需的温度时，所述氢氧化锂溶液的滴加量不少于滴加总量的50％；之后继续滴加剩余氢氧化锂溶液，所述剩余氢氧化锂溶液的滴加时间为1.5～4.0h。
  9. 根据权利要求1所述的制备方法，其特征在于，所述甲基化反应之后还包括：将甲基化反应所得产物料液依次进行水洗、碱洗和蒸馏。
  10. 根据权利要求9所述的制备方法，其特征在于，所述水洗为：在甲基化反应停止后将所得产物料液静置分层，对所得油层进行水洗。
  11. 根据权利要求9所述的制备方法，其特征在于，所述碱洗用试剂 为LiOH、NaOH、KOH或NaCO 3的溶液。
  12. 根据权利要求9或11所述的制备方法，其特征在于，所述碱洗后，还包括采用盐酸将碱洗后的产物中和至pH＝1。
  13. 根据权利要求9所述的制备方法，其特征在于，所述蒸馏的真空度为-0.09998Mpa～-0.0998Mpa。
PCT/CN2022/140231 2022-01-17 2022-12-20 一种藜芦醚的制备方法 WO2023134406A1 (zh)

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