WO2022117071A1 - 从多羟基酚合成苄基醚的方法 - Google Patents

从多羟基酚合成苄基醚的方法 Download PDF

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WO2022117071A1
WO2022117071A1 PCT/CN2021/135325 CN2021135325W WO2022117071A1 WO 2022117071 A1 WO2022117071 A1 WO 2022117071A1 CN 2021135325 W CN2021135325 W CN 2021135325W WO 2022117071 A1 WO2022117071 A1 WO 2022117071A1
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polyhydric phenol
benzyl ether
benzyl
organic solvent
trihydroxyacetophenone
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PCT/CN2021/135325
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English (en)
French (fr)
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黄培培
陈锦辉
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福建海创医药科技有限公司
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Priority to CN202180003988.5A priority Critical patent/CN114867708A/zh
Publication of WO2022117071A1 publication Critical patent/WO2022117071A1/zh

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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
    • 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
    • C07C41/09—Preparation of ethers by dehydration of compounds containing hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring

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  • the present application relates generally to the field of organic chemical synthesis, and more particularly to methods for protecting polyhydric phenols with benzyl groups.
  • benzyl is a commonly used protecting group.
  • the synthesis of benzyl ethers can be prepared by a basic organic solution of phenol (eg DMF) and a benzylation reagent such as benzyl chloride or benzyl bromide.
  • phenol eg DMF
  • benzylation reagent such as benzyl chloride or benzyl bromide.
  • the phenolic hydroxyl group contains a carbonyl group in the ortho-position, it can form an intramolecular hydrogen bond with the phenolic hydroxyl group, which reduces the reactivity of the phenolic hydroxyl group and makes the benzylation of the phenolic hydroxyl group difficult.
  • the present disclosure provides a method for synthesizing benzyl ethers from polyhydric phenols, wherein the method comprises catalyzing the polyhydric alcohol in an organic solvent to which water is added in the presence of a base and a catalyst The phenol is reacted with a benzylating reagent to obtain a fully benzylated benzyl ether.
  • the benzylation reagent is selected from benzyl chloride, benzyl bromide, or a combination thereof.
  • the base is selected from carbonate, potassium bicarbonate, or a combination thereof.
  • the catalyst is selected from potassium iodide, sodium iodide, and combinations thereof.
  • the organic solvent is selected from the group consisting of N-methylpyrrolidone, N,N-dimethylformamide, acetone, acetonitrile, and any combination thereof.
  • the polyhydric phenol contains a carbonyl group in the ortho position to at least one phenolic hydroxyl group
  • the polyhydric phenol is a polyhydric C1-C10 alkyl phenyl ketone, such as a trihydric or dihydric C1- C10 alkyl phenyl ketones, such as trihydroxyacetophenones such as 2,3,4-trihydroxyacetophenone, 2,3,5-trihydroxyacetophenone, and 2,4,5-trihydroxyacetophenone ; or dihydroxyacetophenones such as 2,3-dihydroxyacetophenone, 2,4-dihydroxyacetophenone, and 2,5-dihydroxyacetophenone.
  • the molar ratio of the polyhydric phenol to the benzylating reagent is from 1:3.1 to 1:4.0.
  • the molar ratio of the polyhydric phenol to base is from 1:3.0 to 1:5.8.
  • the molar ratio of the polyhydric phenol to catalyst is from 1:0.1 to 1:1.0.
  • the volume ratio of the organic solvent to water is from 1:0.1 to 1:1.0.
  • the reaction is carried out at a temperature ranging from 15°C to 60°C.
  • the reaction is continued for a period of 1 to 10 hours.
  • the method further comprises extracting the benzyl ether with an organic solvent such as ethyl acetate or dichloromethane.
  • the method further comprises recrystallizing the benzyl ether using an organic solvent such as ethanol or methanol.
  • the benzyl ether obtained comprises at least 80% fully benzylated benzyl ether, eg at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% , at least 99% or more fully benzylated benzyl ethers.
  • Figure 1 shows the HPLC results of the product benzyl ether obtained by the method according to one embodiment of the present invention. It can be seen from the results that the benzyl ethers obtained by the exemplary method of the present invention are all benzyl ether I (the peak position of HPLC is at 40.1 minutes), no other benzyl ethers exist, and there are few impurities.
  • FIG. 2 shows the HPLC results of Comparative Example 1.
  • FIG. 2 shows the HPLC results of Comparative Example 1.
  • the product system is relatively complex, including the remaining raw materials (the peak position of HPLC is at 23.1 minutes), the presence of benzyl ether II and III (the peak positions of HPLC are at 30.7 minutes and 34.4 minutes, respectively), and only A small amount of benzyl ether I was produced (HPLC peak position at 41.5 minutes).
  • FIG. 3 shows the HPLC results of Comparative Example 2.
  • FIG. 3 shows the HPLC results of Comparative Example 2.
  • benzyl ether III and benzyl ether I were present in the product (the HPLC peak positions were at 33.5 minutes and 39.4 minutes, respectively).
  • the present disclosure provides a method for forming benzyl ethers from polyhydric phenols.
  • the method has mild reaction conditions, simple operation, low preparation cost and high yield, and is favorable for realizing industrialized production.
  • the present disclosure provides a method for improving benzyl-protected polyhydric phenols to form benzyl ethers, which in conventional methods usually uses an organic solvent alone as an organic solvent, and additionally adds water to the solvent system, Taking polyhydric phenol such as 2,3,4-trihydroxyacetophenone as raw material, reacting it with benzylation reagent under the action of base and catalyst, the desired form of benzyl ether can be obtained.
  • the benzyl ether obtained comprises at least 80% fully benzylated benzyl ether, eg, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% , at least 99% or more fully benzylated benzyl ethers.
  • the term "fully benzylated benzyl ether” means that all of the phenolic hydroxyl groups on the polyhydric phenol are reacted with a benzylating reagent to form a benzyl ether.
  • polyhydric phenol is a substituted or unsubstituted phenol protecting at least 2 hydroxyl groups, eg, 3 hydroxyl groups.
  • the polyhydric phenol contains a carbonyl group in an ortho position to at least one phenolic hydroxyl group.
  • the polyhydric phenol comprises a carbonyl group at the ortho position to at least one phenolic hydroxyl group
  • the polyhydric phenol is a polyhydric C1-C10 (eg, C2, C3, C4, C5, C6, C7, C8, C9 or C10) alkyl phenyl ketones, such as trihydroxy or dihydroxy C1-C10 (eg C2, C3, C4, C5, C6, C7, C8, C9 or C10) alkyl phenyl ketones, such as trihydroxyphenethyl Ketones such as 2,3,4-trihydroxyacetophenone, 2,3,5-trihydroxyacetophenone, and 2,4,5-trihydroxyacetophenone; or dihydroxyacetophenone such as 2,3- Dihydroxyacetophenone, 2,4-dihydroxyacetophenone, and 2,5-dihydroxyacetophenone.
  • benzylation reagent includes benzylation reagents known in the art that can be used to protect hydroxyl groups (eg, phenolic hydroxyl groups), including, but not limited to, benzyl chloride, benzyl bromide, or combinations thereof.
  • the base is selected from weak bases, which provide alkalinity to the reaction system, eg, a weak base, such as a pH greater than 7.0-8.5.
  • the base may be selected from carbonates, bicarbonates, or combinations thereof, such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or any combination thereof.
  • the reaction solvent is an organic solvent, including conventional organic solvents known in the art useful for benzylation protection of phenolic hydroxyl groups, preferably water-miscible organic solvents such as N-methylpyrrolidone , N,N-dimethylformamide, acetone, acetonitrile, or any combination thereof.
  • organic solvent including conventional organic solvents known in the art useful for benzylation protection of phenolic hydroxyl groups, preferably water-miscible organic solvents such as N-methylpyrrolidone , N,N-dimethylformamide, acetone, acetonitrile, or any combination thereof.
  • the catalyst may include catalysts known in the art useful for catalyzing benzylation protection of phenolic hydroxyl groups, including, but not limited to, potassium iodide, sodium iodide, and combinations thereof.
  • the molar ratio of polyhydric phenol to benzylating reagent may be 1:3.1 to 1:4.0, eg, 1:3.2 to 1:3.9, 1:3.3 to 1:3.8, 1:3.4 to 1:3. 3.7 or 1:3.5 to 1:3.6.
  • the molar ratio of polyhydric phenol to base may be 1:3.0 to 1:5.8, eg, 1:3.5 to 1:5.5, 1:4.0 to 1:5.0, 1:4.2 to 1:4.8, 1 :4.4 to 1:5.5, or about 1:4.5.
  • the molar ratio of polyhydric phenol to catalyst may be 1:0.1 to 1:1.0, eg, 1:0.2 to 1:0.8, 1:0.4 to 1:0.6, or about 1:0.5.
  • the volume ratio of organic solvent to water may be 1:0.1 to 1:1.0, eg, 10 1:0.2 to 1:0.8, 1:0.4 to 1:0.6, or about 1:0.5.
  • the reaction is carried out at a temperature ranging from 15°C to 60°C, eg, at 20°C to 50°C, 25°C to 40°C, 25°C to 30°C, or room temperature.
  • the reaction is continued for a period of 1 to 10 hours, eg, 2 to 8 hours, 3 to 7 hours, 4 to 6 hours, or 5 hours.
  • the method further comprises extracting the benzyl ether with an organic solvent such as ethyl acetate or dichloromethane.
  • the method further comprises recrystallizing the benzyl ether using an organic solvent such as ethanol or methanol.
  • the method of the present disclosure includes the steps of: adding a polyhydric phenol such as 2,3,4-trihydroxyacetophenone, a base, a catalyst to an organic solvent at room temperature, adding water with stirring and benzylation reagent, after the reaction, extraction, concentration under reduced pressure and recrystallization give the desired product.
  • the benzylation reagent is benzyl bromide in a molar ratio of 3.1 : 1.0 to a polyhydric phenol such as 2,3,4-trihydroxyacetophenone.
  • the base is potassium carbonate in a molar ratio of 3.1 : 1.0 to a polyhydric phenol such as 2,3,4-trihydroxyacetophenone.
  • the catalyst is potassium iodide in a molar ratio of 0.15:1.0 to a polyhydric phenol such as 2,3,4-trihydroxyacetophenone.
  • the organic solvent is N-methylpyrrolidone, and its volume ratio to water is 1.0:0.5.
  • the temperature of the reaction was 25°C.
  • the reaction time was 3 hours.
  • reaction process of the method of the present disclosure is shown in the following formula:
  • the present invention provides a method for improving the synthesis of benzyl ether, which surprisingly has one or more of the following advantages: 1) Compared with the prior art, the The reaction temperature is relatively low, and can be carried out at room temperature, avoiding the disadvantage that the prior art needs to be heated to carry out the reaction, and reducing the consumption of energy; 2) It is ensured that all hydroxyl groups can be protected by benzyl groups to form benzyl ethers, preventing The situation that the reaction is not complete occurs, thereby improving the utilization rate of atoms; 3) It is not necessary to use a large excess of alkali to promote the reaction, which reduces the material cost and is conducive to environmental protection; 4) When adding water in the preparation process, reducing It reduces the use of organic solvents, reduces waste emissions, and is also environmentally friendly.
  • the preparation method of the invention is simple, the production cost is low, the product yield is high, the use of the solvent and the pollution to the environment are reduced, and it is easy to implement in the process
  • the present embodiment provides different implementation conditions, and steps, extraction and recrystallization conditions are all the same as in Example 1, and some of the results are shown in the following table:
  • Example 2 The same procedure and conditions as in Example 1 were used, except that the solvent was only 7.75 L of N-methylpyrrolidone. When the reaction was carried out at 25°C, only a small amount of fully benzylated benzyl ether (not more than 10%) was obtained, as shown in FIG. 2 .
  • Example 3 The same procedure and conditions as in Example 1 were used, except that the solvent was only 7.75 L of N-methylpyrrolidone and the reaction was carried out at 120°C. The yield is below 80%.
  • the high performance liquid chromatography data in Figure 3 shows that the proportion of fully benzylated benzyl ether in the final product is higher than that of Comparative Example 1, but still not more than 65%.

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Abstract

公开了一种从多羟基酚合成苄基醚的方法，其特征在于，所述方法包括在碱和催化剂的存在下，在添加水的有机溶剂中使所述多羟基酚与苄基化试剂反应，从而获得完全苄基化的苄基醚。公开的的方法简单，生产成本低，产物收率高，减少了溶剂的使用以及对环境造成的污染，从而在工业放大的过程中，易于实施。

Description

从多羟基酚合成苄基醚的方法 技术领域
本申请一般性涉及有机化学合成领域，更具体涉及利用苄基保护多羟基酚的方法。
背景技术
直接合成是有机合成发展的方向和愿景，而使用保护基策略实属无奈之举。尽管在大量的新兴的有机合成方法中，传统的保护基策略在逐渐地被抛弃。但毋庸置疑的是，在目前以及可期的未来中，对于有机化合物合成，特别是天然产物和药物化学的合成，选择保护基保护特有官能团仍是合成工作成功与否的关键，因此对于官能团的保护策略还在快速地发展中。
在众多的保护基中，苄基是一种常用的保护基。一般情况下，苄基醚的合成可以通过酚的碱性有机溶液(例如DMF)和苄基化试剂例如氯化苄或溴化苄制备。但当酚羟基邻位含有羰基时，由于其可以与酚羟基形成分子内氢键，降低了酚羟基的反应活性，导致该酚羟基的苄基化困难。特别是对于有多个羟基存在的酚来说，在羟基邻位存在羰基的情况下，在该羟基处形成苄基醚更加困难。在下列反应中，在放大生产中发现，很难实现全部羟基均形成苄基醚，大部分是形成一个或者两个苄基醚的化合物Ⅱ和Ⅲ，只有少部分形成了全部苄基化的化合物Ⅰ。
Figure PCTCN2021135325-appb-000001
为了解决这个问题，通常需要采用更高的合成温度、增加苄基化试剂或碱的量，或者采用碱性更强的碱溶液，这可以在一定程度上改善这种现状。但是，这些方式将使得能耗增加、所用原料繁多、原子利用率降低，从而不利于绿色和可持续发展理念的实行。
在本领域中，存在改进多羟基酚的苄基保护的需求。
发明内容
在一个方面中，本公开提供了一种从多羟基酚合成苄基醚的方法，其特征在于，所述方法包括在碱和催化剂的存在下，在添加水的有机溶剂中使所述多羟基酚与苄基化试剂反应，从而获得完全苄基化的苄基醚。
在一个实施方案中，所述苄基化试剂选自氯化苄、溴化苄或其组合。
在一个实施方案中，所述碱选自碳酸盐、碳酸氢盐钾或其组合。
在一个实施方案中，所述催化剂选自碘化钾、碘化钠和其组合。
在一个实施方案中，述有机溶剂选自N-甲基吡咯烷酮、N,N-二甲基甲酰胺、丙酮、乙腈和其任何组合。
在一个实施方案中，所述多羟基酚在至少一个酚羟基邻位处包含羰基，优选地，所述多羟基酚是多羟基C1-C10烷基苯基酮，例如三羟基或二羟基C1-C10烷基苯基酮，诸如三羟基苯乙酮例如2,3,4-三羟基苯乙酮、2,3,5-三羟基苯乙酮、和2,4,5-三羟基苯乙酮；或二羟基苯乙酮例如2,3-二羟基苯乙酮、2,4-二羟基苯乙酮、和2,5-二羟基苯乙酮。
在一个实施方案中，所述多羟基酚与苄基化试剂的摩尔比为1:3.1至1:4.0。
在一个实施方案中，所述多羟基酚与碱的摩尔比为1:3.0至1:5.8。
在一个实施方案中，所述多羟基酚与催化剂的摩尔比为1:0.1至1:1.0。
在一个实施方案中，所述有机溶剂与水的体积比为1:0.1至1:1.0。
在一个实施方案中，所述反应在15℃至60℃的温度范围下进行。
在一个实施方案中，所述反应持续1至10小时的时间。
在一个实施方案中，所述方法进一步包括使用有机溶剂例如乙酸乙酯或二氯甲烷萃取所述苄基醚。
在一个实施方案中，所述方法进一步包括使用有机溶剂例如乙醇或甲醇重结晶所述苄基醚。
在一个实施方案中，所获得的苄基醚包含至少80％的完全苄基化的苄基醚，例如至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或更高的完全苄基化的苄基醚。
附图说明
图1显示出根据本发明的一个实施方案的方法获得的产物苄基醚的HPLC结果。从结果中可以看出，本发明的示例性方法得到的苄基醚都是苄基醚I(HPLC的出峰位置在40.1分钟)，无其他苄基醚存在，且杂质少。
图2显示出对比实施例1的HPLC结果。从结果中可以看出，产物体系比较复杂，包括原料剩余(HPLC的出峰位置在23.1分钟)、苄基醚II和III存在(HPLC的出峰位置分别在30.7分钟和34.4分钟)，而只有少量苄基醚I产生(HPLC的出峰位置在41.5分钟)。
图3显示出对比实施例2的HPLC结果。从结果中可以看出，产物中存在苄基醚III和苄基醚I(HPLC的出峰位置分别在33.5分钟和39.4分钟)。
具体实施方式
为了促进对本发明原理的理解的目的，现参考在附图中举例说明的实施方案，并且将具体描述所述实施方案。然而，将理解的是，这些描述并不旨在对本发明的范围进行任何限制。
为了解决上述出现的技术问题的至少一个，本公开提供了一种从多羟基酚形成苄基醚的方法。该方法的反应条件温和，操作简单，制备成本低，收率高，有利于实现工业化生产。
在一个方面，本公开提供了一种改善苄基保护多羟基酚而形成苄基醚的方法，其在常规方法中通常单独使用有机溶剂作为有机溶剂的基础上，向溶剂体系中额外添加水，以多羟基酚例如2,3,4-三羟基苯乙酮为原料，将其与苄基化试剂在碱和催化剂的作用下反应，获得期望形式的苄基醚。
在一些实施方案中，所获得的苄基醚包含至少80％的完全苄基化的苄基醚，例如至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或更高的完全苄基化的苄基醚。如本文所 使用，术语“完全苄基化的苄基醚”是指多羟基酚上的全部酚羟基均与苄基化试剂反应而形成苄基醚。
如本文所使用，术语“多羟基酚”取代或未取代的保护至少2个羟基例如3个羟基的苯酚。在一些实施方案中，多羟基酚在至少一个酚羟基的邻位处包含羰基。在一些实施方案中，所述多羟基酚在至少一个酚羟基邻位处包含羰基，优选地，多羟基酚是多羟基C1-C10(例如C2、C3、C4、C5、C6、C7、C8、C9或C10)烷基苯基酮，例如三羟基或二羟基C1-C10(例如C2、C3、C4、C5、C6、C7、C8、C9或C10)烷基苯基酮，诸如三羟基苯乙酮例如2,3,4-三羟基苯乙酮、2,3,5-三羟基苯乙酮、和2,4,5-三羟基苯乙酮；或二羟基苯乙酮例如2,3-二羟基苯乙酮、2,4-二羟基苯乙酮、和2,5-二羟基苯乙酮。
如本文所使用，术语“苄基化试剂”包括本领域中已知的可用于保护羟基(例如酚羟基)的苄基化试剂，包括但不限于氯化苄、溴化苄或其组合。
在一些实施方案中，碱选自弱碱，其为反应体系提供碱性，例如弱碱性，诸如大于7.0-8.5的pH。在一些实施方案中，碱可以选自碳酸盐、碳酸氢盐或其组合，例如碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾或其任何组合。
在一些实施方案中，反应溶剂是有机溶剂，包括本领域中已知的可用作酚羟基的苄基化保护的常规有机溶剂，优选能与水混溶的有机溶剂，例如N-甲基吡咯烷酮、N,N-二甲基甲酰胺、丙酮、乙腈或其 任何组合。
在一些实施方案中，催化剂可包括本领域中已知的可用于催化酚羟基的苄基化保护的催化剂，包括但不限于碘化钾、碘化钠和其组合。
在一些实施方案中，多羟基酚与苄基化试剂的摩尔比可以为1:3.1至1:4.0，例如1:3.2至1:3.9、1:3.3至1:3.8、1:3.4至1:3.7或1:3.5至1:3.6。
在一些实施方案中，多羟基酚与碱的摩尔比可以为1:3.0至1:5.8，例如1:3.5至1:5.5、1:4.0至1:5.0、1:4.2至1:4.8、1:4.4至1:5.5、或约1:4.5。
在一些实施方案中，多羟基酚与催化剂的摩尔比可以为1:0.1至1:1.0，例如1:0.2至1:0.8、1:0.4至1:0.6、或约1:0.5。
在一些实施方案中，有机溶剂与水的体积比可以为1:0.1至1:1.0，例如10 1:0.2至1:0.8、1:0.4至1:0.6、或约1:0.5。
在一些实施方案中，反应在15℃至60℃的温度范围下进行，例如在20℃至50℃、25℃至40℃、25℃至30℃、或室温下进行。
在一些实施方案中，反应持续1至10小时的时间，例如2至8小时、3至7小时、4至6小时、或5小时。
在一些实施方案中，所述方法进一步包括使用有机溶剂例如乙酸乙酯或二氯甲烷萃取苄基醚。
在一个实施方案中，所述方法进一步包括使用有机溶剂例如乙醇或甲醇重结晶苄基醚。
在一个具体的实施方案中，本公开的方法包括以下步骤：在室温 下，将多羟基酚例如2,3,4-三羟基苯乙酮、碱、催化剂加入到有机溶剂中，搅拌下加入水和苄基化试剂，在反应结束后，萃取、减压浓缩和重结晶得到期望产物。进一步地，苄基化试剂是溴化苄，其与多羟基酚例如2,3,4-三羟基苯乙酮的摩尔比为3.1:1.0。仍进一步地，碱是碳酸钾，其与多羟基酚例如2,3,4-三羟基苯乙酮的摩尔比为3.1:1.0。仍进一步地，催化剂是碘化钾，其与多羟基酚例如2,3,4-三羟基苯乙酮的摩尔比为0.15:1.0。仍进一步地，有机溶剂为N-甲基吡咯烷酮，其与水的体积比为1.0:0.5。仍进一步地，反应的温度为25℃。仍进一步地，反应时间为3小时。
在一个示例性实施方案中，本公开的方法的反应过程如下式所示：
Figure PCTCN2021135325-appb-000002
与已有的技术相比，本发明提供了一种改善苄基醚合成的方法，该方法令人惊讶地具有以下优点的一个或多个：1)相较于已有的技术，本发明的反应温度较低，在室温就可以进行，避免了已有技术需要加热才能进行反应的缺点，降低了能源的消耗；2)确保了所有的羟基都可以被苄基保护，形成苄基醚，防止了反应不完全的情况出现，从而提高了原子的利用率；3)无需使用大大过量的碱促进反应的进行，降低了物料成本，同时利于环境保护；4)制备过程中加入水的同时，减少了有机溶剂的使用，降低了废弃物的排放量，同样对环境 友好。本发明制备方法简单，生产成本低，产物收率高，减少了溶剂的使用以及对环境造成的污染，在工业放大的过程中，易于实施。
下列实施例仅用于示例性阐述本发明而不是限制本发明。
实施例
实施例1
将4.5L N-甲基吡咯烷酮加入到100L反应釜中，机械搅拌下，依次加入1.54kg 2,3,4-三羟基苯乙酮、4.05kg碳酸钾、228g碘化钾和2.25L水。接着加入3.38L溴化苄，然后在25℃下搅拌反应3小时。通过TLC监控反应，原料2,3,4-三羟基苯乙酮已经反应完，体系中无反应中间体残留。然后加入11L水淬灭反应，再加入9L乙酸乙酯进行萃取。分液后，水相再用9L乙酸乙酯萃取一次。之后，将两次有机相合并，用9L水洗涤一次。将有机相中的溶剂乙酸乙酯减压下蒸出，然后加入10L乙醇进行重结晶。通过过滤并干燥后，得到4.38kg黄色固体，收率为91％。如图1的高效液相色谱数据显示，该黄色固体中基本为完全苄基化的苄基醚(大于99％)。
实施例2
本实施例提供不同的实施条件，步骤、萃取和重结晶条件均和实施例1相同，部分结果见下表：
Figure PCTCN2021135325-appb-000003
Figure PCTCN2021135325-appb-000004
对比实施例1
采用与实施例1相同的步骤和条件，除了溶剂仅仅为7.75L N-甲基吡咯烷酮。该反应在25℃进行时，只获得少量完全苄基化的苄基醚(不大于10％)，如图2所示。
对比实施例2
采用与实施例1相同的步骤和条件，除了溶剂仅仅为7.75L N-甲基吡咯烷酮并且反应在120℃下进行。收率低于80％。如图3的高效液相色谱数据显示，最终产物中完全苄基化的苄基醚的比例高于对比实施例1，但仍不大于65％。
虽然在本文已经非常详细地描述了从多羟基酚合成苄基醚的方法的各种实施方案，但该实施方案仅仅作为本文描述的公开内容的非限制性实例而提供。因此，本领域技术人员将理解，可以对本发明进行各种变化和改变，而不偏离本发明的范围。实际上，本公开内容不旨在是穷尽性的或旨在限制本发明的范围。
进一步，在代表性实施方案的描述中，本公开内容已经以特定步骤顺序给出本发明的方法和/或过程。然而，该方法或过程不应限于所描述的特定步骤顺序。其它步骤顺序是可能的。因此，本文公开的特定步骤顺序不应解释为对本发明的限制。此外，针对方法和/或过程的公开内容不应限于以所描述的顺序进行它们的步骤。这样的顺序可以变化并且仍在本发明的范围内。

Claims (15)

  1. 一种从多羟基酚合成苄基醚的方法，其特征在于，所述方法包括在碱和催化剂的存在下，在添加水的有机溶剂中使所述多羟基酚与苄基化试剂反应，从而获得完全苄基化的苄基醚。
  2. 根据权利要求1所述的方法，其特征在于，所述苄基化试剂选自氯化苄、溴化苄或其组合。
  3. 根据权利要求1或2所述的方法，其特征在于，所述碱选自碳酸盐、碳酸氢盐或其组合。
  4. 根据权利要求1-3任一项所述的方法，其特征在于，所述催化剂选自碘化钾、碘化钠和其组合。
  5. 根据权利要求1-4任一项所述的方法，其特征在于，所述有机溶剂选自N-甲基吡咯烷酮、N,N-二甲基甲酰胺、丙酮、乙腈和其任何组合。
  6. 根据权利要求1-5任一项所述的方法，其特征在于，所述多羟基酚在至少一个酚羟基邻位处包含羰基，优选地，所述多羟基酚是多羟基C1-C10烷基苯基酮，例如三羟基或二羟基C1-C10烷基苯基酮，诸如三羟基苯乙酮例如2,3,4-三羟基苯乙酮、2,3,5-三羟基苯乙酮、和2,4,5-三羟基苯乙酮；或二羟基苯乙酮例如2,3-二羟基苯乙酮、2,4-二羟基苯乙酮、和2,5-二羟基苯乙酮。
  7. 根据权利要求1-6任一项所述的方法，其特征在于，所述多羟基酚与苄基化试剂的摩尔比为1:3.1至1:4.0。
  8. 根据权利要求1-7任一项所述的方法，其特征在于，所述多羟基酚与碱的摩尔比为1:3.0至1:5.8。
  9. 根据权利要求1-8任一项所述的方法，其特征在于，所述多羟基酚与催化剂的摩尔比为1:0.1至1:1.0。
  10. 根据权利要求1-9任一项所述的方法，其特征在于，所述有机溶剂与水的体积比为1:0.1至1:1.0。
  11. 根据权利要求1-10任一项所述的方法，其特征在于，所述反应在15℃至60℃的温度范围下进行。
  12. 根据权利要求1-11任一项所述的方法，其特征在于，所述反应持续1至10小时的时间。
  13. 根据权利要求1-12任一项所述的方法，其特征在于，所述方法进一步包括使用有机溶剂例如乙酸乙酯或二氯甲烷萃取所述苄基醚。
  14. 根据权利要求1-13任一项所述的方法，其特征在于，所述方法进一步包括使用有机溶剂例如乙醇或甲醇重结晶所述苄基醚。
  15. 根据权利要求1-14任一项所述的方法，其特征在于，所获得的苄基醚包含至少80％的完全苄基化的苄基醚，例如至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或更高的完全苄基化的苄基醚。
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