WO2022036636A1 - 一种1,3,5-三甲氧基苯的制备方法 - Google Patents

一种1,3,5-三甲氧基苯的制备方法 Download PDF

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WO2022036636A1
WO2022036636A1 PCT/CN2020/110265 CN2020110265W WO2022036636A1 WO 2022036636 A1 WO2022036636 A1 WO 2022036636A1 CN 2020110265 W CN2020110265 W CN 2020110265W WO 2022036636 A1 WO2022036636 A1 WO 2022036636A1
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trimethoxybenzene
preparation
reaction
cuprous
reaction substrate
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PCT/CN2020/110265
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刘建明
肖筱
邢久东
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江苏康龙医药有限公司
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring

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  • the invention relates to the technical field of medicines, in particular to a preparation method of 1,3,5-trimethoxybenzene.
  • 1,3,5-Trimethoxybenzene alias trimethylphloroglucinol, etc., CAS registration number: 621-23-8, molecular formula C9H12O3.
  • 1,3,5-trimethoxybenzene is phloroglucinol injection
  • One of the main components in the liquid the latter is widely used in the treatment of smooth muscle spasm, and has the characteristics of rapid antispasmodic effect, significant effect, and no toxic side effects.
  • the methods for preparing 1,3,5-trimethoxybenzene include: phloroglucinol methylation method, trihalogenated anisole method, etc., in trihalogenated anisole method, etc.,
  • these methods often have the disadvantages of complicated operation, difficult to obtain raw materials, high preparation cost, low yield and low purity.
  • Chinese patent (CN1491927A) has disclosed that 1,3,5-tribromobenzene reacts with sodium methoxide to prepare trimethylphloroglucinol under the catalysis of cuprous iodide. The quality of the trimethylphloroglucinol is average and cannot meet the needs of pharmaceutical grades.
  • the technical problem to be solved by the present invention is to provide a preparation method of 1,3,5-trimethoxybenzene, so that the method is easy to operate, has good reproducibility, and the prepared finished product has stable quality and high purity.
  • the present invention proposes the following technical solutions:
  • a method for preparing 1,3,5-trimethoxybenzene characterized in that the method comprises the following steps: reacting a reaction substrate and sodium methoxide under the catalysis of cuprous halide;
  • the reaction substrate is selected from 1,3,5-trichlorobenzene, 1,3,5-tribromobenzene, 1,3,5-triiodobenzene, 1,3,5-trimethylsulfonylbenzene, 1 ,3,5-tris(trifluoromethanesulfonyl) benzene in one.
  • the solvent for the reaction is selected from one or both of N,N-dimethylamide, N,N-diethylamide, methanol, ethanol, isopropanol, and dimethyl sulfoxide.
  • the molar ratio of the reaction substrate to sodium methoxide is 1:3-1:9.
  • the reaction temperature is 60-120°C.
  • the cuprous halide is selected from any one of cuprous chloride, cuprous bromide and cuprous iodide.
  • the molar ratio of the reaction substrate to the cuprous halide is 1:0.02-1:0.1.
  • the method further includes the following purification step: taking the crude 1,3,5-trimethoxybenzene obtained by the reaction, adding water in a proportion corresponding to 10 mL per 1 g of the crude product, and stirring for 2 hours to separate out the solid, and taking the For the solid, add a recrystallization solvent in a ratio of 10 mL per 1 g of the crude product, heat to reflux temperature and stir at this temperature for 3 hours, then drop to room temperature to separate out crystals, filter, take the solid, and vacuum-dry it at 45 ° C for 10 hours. ;
  • the recrystallization solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol and toluene;
  • the recrystallization solvent is methanol.
  • the method of the invention has the advantages of simple operation and good reproducibility, and the prepared finished product has stable quality and high purity.
  • Contrast 2 of refined products self-made according to Comparative Example 2, namely, purifying according to the prior art.
  • the yield of each refined product was calculated by weighing method.
  • the chromatographic conditions use octadecyl silane bond and silica gel as filler (Waters SPHERISORB 5 ⁇ m, 250mm*4.0mm or its equivalent chromatographic column); use potassium dihydrogen phosphate solution (1.36g/L potassium dihydrogen phosphate solution, Phosphoric acid was adjusted to pH 3.0) as mobile phase A, and acetonitrile was used as mobile phase B; the volume ratio of A and B was 2:8.
  • the test results are shown in Table 1.
  • the results show that nitrogen filling protection in the purification process can not only improve the yield of the product, but also improve the purity of the refined product. The mechanism is unclear and needs to be further explored.
  • the results also show that, using the purification process of the present invention, the yield is basically the same as the existing purification technology, but the purity of the finished product is higher, and the operation is simpler, the distillation operation is abandoned, the energy consumption is lower, and the operation is safer.
  • 1,3,5-trimethoxybenzene crude product (20g, 0.012mol) was prepared by the reaction, 200mL of water was added, the solid was filtered after stirring for 2 hours, 180mL of methanol was added to the solid, heated to reflux temperature and at this temperature After stirring at low temperature for 3 hours, the crystals were precipitated at room temperature, and the solid was filtered out, and the obtained solid was vacuum-dried at 45° C. for 10 hours to obtain 16.7 g of an off-white solid with a purity of 98.6%. In the purification step, except for vacuum drying, other operations are carried out under nitrogen protection.
  • the crude product of 1,3,5-trimethoxybenzene (20g, 0.012mol) was obtained by taking the reaction, adding 100ml distilled water, heating to a boiling state, and then performing steam distillation until no product was produced, and the distillation was terminated.
  • the obtained distillate was cooled to below 10°C, and then filtered. After the filter cake was suction-dried, it was vacuum-dried at 30°C to obtain 16.4 g of a white solid with a purity of 95.5%.
  • the catalyst is selected from cuprous iodide (the molar ratio of the catalyst to the reaction substrate is the same as that in Example 1), and the rest are the same as in Example 1.
  • the reaction substrate is selected from 1,3,5-triiodobenzene
  • the catalyst is selected from cuprous iodide (the molar ratio of the catalyst to the reaction substrate is the same as that in Example 1), and the rest are the same as in Example 1.
  • the reaction substrate is selected from 1,3,5-trichlorobenzene
  • the catalyst is selected from cuprous chloride (the molar ratio of the catalyst to the reaction substrate is the same as that in Example 1), and the rest are the same as those in Example 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

涉及一种1,3,5-三甲氧基苯的制备方法，其特征在于所述方法为：反应底物与甲醇钠在卤化亚铜的催化下进行反应；所述反应底物选自于1,3,5-三氯苯、1,3,5-三溴苯、1,3,5-三碘苯、1,3,5-三甲磺酰基苯、1,3,5-三(三氟甲磺酰)基苯中的一种。所述反应的溶剂选自于N,N-二甲基酰胺、N,N-二乙基酰胺、甲醇、乙醇、异丙醇、二甲基亚砜中的一种或两种。该方法操作简便，重现性好，制备出来的成品质量稳定、纯度高。

Description

一种1,3,5-三甲氧基苯的制备方法 技术领域
本发明涉及药品技术领域，特别涉及一种1,3,5-三甲氧基苯的制备方法。
背景技术
1,3,5-三甲氧基苯，别名三甲基间苯三酚等，CAS登记号：621-23-8，分子式C9H12O3。1,3,5-三甲氧基苯为间苯三酚注射液中的主要成分之一，后者被广泛运用于治疗平滑肌痉挛的疾病，具有解痉作用迅速、效果显著、以及没有毒副作用等特点。
现有技术中，制备1,3,5-三甲氧基苯的方法包括：间苯三酚甲基化法，三卤代苯甲醚化法等，在三卤代苯甲醚化法等，但这些方法往往存在操作繁琐、原料不易获取、制备成本高、得率低、纯度不高等缺点。如中国专利(CN1491927A)就披露过1,3,5-三溴苯在碘化亚铜的催化下，与甲醇钠反应制备出三甲基间苯三酚，但是该工艺后处理较繁琐，得到的三甲基间苯三酚质量一般，无法满足药用级别的需要。
发明内容
本发明所要解决的技术问题是提供一种1,3,5-三甲氧基苯的制备方法，使得该方法操作简便，重现性好，制备出来的成品质量稳定、纯度高。
为了解决上述技术问题，本发明提出如下技术方案：
一种1,3,5-三甲氧基苯的制备方法，其特征在于所述方法为：反应底物与甲醇钠在卤化亚铜的催化下进行反应；
所述反应底物选自于1,3,5-三氯苯、1,3,5-三溴苯、1,3,5-三碘苯、1,3,5-三甲磺酰基苯、1,3,5-三(三氟甲磺酰)基苯中的一种。
反应式如下：
Figure PCTCN2020110265-appb-000001
优选的，所述反应的溶剂选自于N,N-二甲基酰胺、N,N-二乙基酰胺、甲醇、 乙醇、异丙醇、二甲基亚砜中的一种或两种。
优选的，所述反应底物与甲醇钠的摩尔比为1:3-1:9。
优选的，所述反应温度为60-120℃。
优选的，所述卤化亚铜选自于氯化亚铜、溴化亚铜和碘化亚铜中任一种。
优选的，所述反应底物与卤化亚铜的摩尔比为1:0.02-1:0.1。
优选的，所述方法中还包括如下纯化步骤：取反应制得的1,3,5-三甲氧基苯粗品，按每1g粗品对应10mL的比例加入水，搅拌2小时后分离出固体，取固体，按每1g粗品对应10mL的比例加入重结晶溶剂,加热至回流温度并在该温度下搅拌3小时后,降至室温析出晶体,滤过，取固体，在45℃真空干燥10小时即得；
所述重结晶溶剂选自于甲醇、乙醇、异丙醇、正丁醇和甲苯一种或几种；
所述纯化步骤中除真空干燥外，其余操作均在充氮保护的条件下进行。
优选的，所述的重结晶溶剂为甲醇。
本发明方法操作简便，重现性好，制备出来的成品质量稳定、纯度高。
本发明的有益技术效果主要体现在以下几个方面：
(1)操作简便，尤其是舍弃了现有技术中的蒸馏、精馏工艺，在达到同样效果的情况下，成本更低、操作更安全。
(2)创新性的采用了新的纯化工艺，尤其是在纯化时通入氮气进行保护，使得产品的得率和纯度更高。
本发明的有益效果可以通过以下一系列试验证明。
试验例不同纯化工艺的比较
1.材料
1.1 1,3,5-三甲氧基苯粗品：按实施例1方法自制。
1.2精制品：按实施例1方法自制。
1.3精制品对比1：按对比例1自制，即未充氮进行保护。
1.4精制品对比2：按对比例2自制，即按现有技术进行纯化。
1.5精制品对比3：按对比例3自制，即按现有技术进行纯化。
2方法
2.1得率
采用称重法计算各精制品的得率。
2.2采用高效液相色谱法测定各供试品的纯度
色谱条件以十八烷基硅烷键和硅胶为填充剂(Waters SPHERISORB 5μm， 250mm*4.0mm或与之等效的色谱柱)；以磷酸二氢钾溶液(1.36g/L磷酸二氢钾溶液，磷酸调节pH3.0)为流动相A，以乙腈为流动相B；A和B的体积比为2：8。
测定法采用面积归一法测定各供试品的纯度。
3结果
试验结果见表1。结果表明对纯化工艺进行充氮保护，不仅能提高产品得率，还能提高精制品的纯度，其机理不明，有待进一步的探讨。结果还表明，采用本发明的纯化工艺，得率与现有纯化技术基本相当，但成品的纯度更高，且操作更简便，舍弃了蒸馏操作，能耗更低，操作更安全。
表1不同纯化工艺的比较
项目 纯度(％) 得量(g) 得率(按粗品计，％)
粗品 81.3 - -
精制品 98.6 16.7 83.5％
精制品对比1 92.1 15.1 75.5％
精制品对比2 95.5 16.4 82.0％
精制品对比3 96.3 16.9 84.5％
为了更好的阐述技术方案，下面结合具体实施方式对本发明作进一步的说明，但本发明所要求的保护范围不限于下列实施例。
具体实施方式
实施例1
1,3,5-三甲氧基苯粗品的合成
将化合物1,3,5-三溴苯(100.0g,0.32mol)中加入N,N-二甲基酰胺150mL，在搅拌条件下加入甲醇300mL，并加入甲醇钠(102.9g,1.91mol)，加完温度升至60-70℃，加入氯化亚铜(1.58g,0.016mol)，升温至90-95℃，反应完毕后冷却至室温，过滤出不溶固体，将滤液加入到硫酸中(0.76mL,0.95mol/L)，搅拌析晶过夜，后过滤出固体，将所得固体在45℃真空干燥8小时，得类白色固体44.3g。
反应式如下：
Figure PCTCN2020110265-appb-000002
1,3,5-三甲氧基苯的纯化
将反应制得1,3,5-三甲氧基苯粗品(20g,0.012mol)中，加入200mL水，搅拌2小时后过滤出固体，将固体中加入甲醇180mL,加热至回流温度并在该温度下搅拌3小时后,降至室温析出晶体,后过滤出固体，将所得固体在45℃真空干燥10小时，得类白色固体16.7g，纯度为98.6％。所述纯化步骤中除真空干燥外，其余操作均在充氮保护的条件下进行。
对比例1
1,3,5-三甲氧基苯粗品的合成
同实施例1。
1,3,5-三甲氧基苯的纯化
除了未在充氮保护下进行操作外，余同实施例1。
对比例2
1,3,5-三甲氧基苯粗品的合成
同实施例1。
1,3,5-三甲氧基苯的纯化
参照对比文件CN1491927A披露的工艺进行，具体操作如下：
取反应制得1,3,5-三甲氧基苯粗品(20g,0.012mol)，加入100ml蒸馏水，加热至沸腾状态，然后进行水蒸汽蒸馏，直至无产品出，结束蒸馏。将所得的馏出液冷却至10℃以下，然后进行过滤，滤饼抽干后，在30℃下进行真空干燥，得白色固体物16.4g，纯度95.5％。
对比例3
1,3,5-三甲氧基苯粗品的合成
同实施例1。
1,3,5-三甲氧基苯的纯化
参照对比文件CN101693649A披露的工艺进行，具体操作如下：
取反应制得1,3,5-三甲氧基苯粗品(20g,0.012mol)，加入100ml蒸馏水，加入水和盐酸，温度控制在10—60℃浸泡1-3小时后点动开搅拌；搅拌0.5-3小时后放入离心机离心，离心后的粗品加入精馏塔，精馏结束得白色固体物 16.9g，纯度96.3％。
实施例2
催化剂选碘化亚铜(催化剂与反应底物的摩尔比同实施例1)，余同实施例1。
Figure PCTCN2020110265-appb-000003
得类白色固体得类白色固体16.2g，纯度为98.5％。
实施例3
反应底物选1,3,5-三碘苯，催化剂选碘化亚铜(催化剂与反应底物的摩尔比同实施例1)，余同实施例1。
Figure PCTCN2020110265-appb-000004
得类白色固体得类白色固体16.1g，纯度为99.0％。
实施例4
反应底物选1,3,5-三氯苯，催化剂选氯化亚铜(催化剂与反应底物的摩尔比同实施例1)，余同实施例1。
Figure PCTCN2020110265-appb-000005
得类白色固体得类白色固体16.5g，纯度为98.6％。
显然，上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。

Claims (8)

  1. 一种1,3,5-三甲氧基苯的制备方法，其特征在于所述方法为：反应底物与甲醇钠在卤化亚铜的催化下进行反应；
    所述反应底物选自于1,3,5-三氯苯、1,3,5-三溴苯、1,3,5-三碘苯、1,3,5-三甲磺酰基苯、1,3,5-三(三氟甲磺酰)基苯中的一种。
  2. 根据权利要求1所述1,3,5-三甲氧基苯的制备方法，其特征在于所述反应的溶剂选自于N,N-二甲基酰胺、N,N-二乙基酰胺、甲醇、乙醇、异丙醇、二甲基亚砜中的一种或两种。
  3. 根据权利要求2所述1,3,5-三甲氧基苯的制备方法，其特征在于所述反应底物与甲醇钠的摩尔比为1:3-1:9。
  4. 根据权利要求3所述1,3,5-三甲氧基苯的制备方法，其特征在于所述反应温度为60-120℃。
  5. 根据权利要求4所述1,3,5-三甲氧基苯的制备方法，其特征在于所述卤化亚铜选自于氯化亚铜、溴化亚铜和碘化亚铜中的任一种。
  6. 根据权利要求5所述1,3,5-三甲氧基苯的制备方法，其特征在于所述反应底物与卤化亚铜的摩尔比为1:0.02-1:0.1。
  7. 根据权利要求1-6任一项所述1,3,5-三甲氧基苯的制备方法，其特征在于，所述方法中还包括如下纯化步骤：取反应制得的1,3,5-三甲氧基苯粗品，按每1g粗品对应10mL的比例加入水，搅拌2小时后分离出固体，取固体，按每1g粗品对应10mL的比例加入重结晶溶剂,加热至回流温度并在该温度下搅拌3小时后,降至室温析出晶体,滤过，取固体，在45℃真空干燥10小时即得；
    所述重结晶溶剂选自于甲醇、乙醇、异丙醇、正丁醇和甲苯一种或几种；
    所述纯化步骤中除真空干燥外，其余操作均在充氮保护的条件下进行。
  8. 根据权利要求7所述1,3,5-三甲氧基苯的制备方法，其特征在于，所述的重结晶溶剂为甲醇。
PCT/CN2020/110265 2020-08-20 2020-08-20 一种1,3,5-三甲氧基苯的制备方法 WO2022036636A1 (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4102933A (en) * 1973-12-11 1978-07-25 Oce-Andeno B.V. Process for preparing a S-trialkoxy benzene
EP0057321A1 (en) * 1980-12-17 1982-08-11 Sterwin Ag. Processes for substitution of aromatic organic compounds
CN1491927A (zh) * 2002-10-23 2004-04-28 浙江新和成股份有限公司 间苯三酚的制备方法
CN101575269A (zh) * 2008-05-05 2009-11-11 华东理工大学 一种芳香族甲醚化合物的制备方法
CN101693649A (zh) * 2009-11-02 2010-04-14 山东海王化工股份有限公司 一种1.3.5-三甲氧基苯的制备方法
CN102476981A (zh) * 2010-11-23 2012-05-30 天津三农金科技有限公司 1,3,5-三甲氧基苯的制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4102933A (en) * 1973-12-11 1978-07-25 Oce-Andeno B.V. Process for preparing a S-trialkoxy benzene
US4102933B1 (zh) * 1973-12-11 1988-07-26
EP0057321A1 (en) * 1980-12-17 1982-08-11 Sterwin Ag. Processes for substitution of aromatic organic compounds
CN1491927A (zh) * 2002-10-23 2004-04-28 浙江新和成股份有限公司 间苯三酚的制备方法
CN101575269A (zh) * 2008-05-05 2009-11-11 华东理工大学 一种芳香族甲醚化合物的制备方法
CN101693649A (zh) * 2009-11-02 2010-04-14 山东海王化工股份有限公司 一种1.3.5-三甲氧基苯的制备方法
CN102476981A (zh) * 2010-11-23 2012-05-30 天津三农金科技有限公司 1,3,5-三甲氧基苯的制备方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
JI YA-FEI , XU XIN , ZONG ZHI-MIN , WEI XIAN-YONG: "Synthesis of 1, 3, 5-Trimethoxybenzene", HUAXUE SHIJIE (CHEMICAL WORLD), 25 July 2001 (2001-07-25), pages 373 - 374, XP055902482, ISSN: 0367-6358, DOI: 10.19500/j.cnki.0367-6358.2001.07.012 *
WANG QIAN, YANG JIAN, ZHENG YANG, LIAO XIALI: "An Alternative Synthesis of 2,6-Dimethoxyl-1,4-Benzoquinone", JOURNAL OF CHEMICAL RESEARCH, vol. 41, no. 4, 1 April 2017 (2017-04-01), GB , pages 193 - 194, XP055902435, ISSN: 1747-5198, DOI: 10.3184/174751917X14894997017379 *
YA-FEI JI , ZHI-MIN ZONG & XAN-YONG WEI: "A High Yield , selective synthesis of 1.3.5- Trimethoxbenzene", ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL, vol. 35, no. 2, 11 February 2009 (2009-02-11), pages 225 - 227, XP055902431 *
ZHANG JI: "Study on the Synthesis of Natural Flavone", CHINESE MASTER'S THESES FULL-TEXT DATABASE, 18 April 2014 (2014-04-18), pages 1 - 78, XP055902439 *
ZHU JIN-TAO, CHEN YING-QI, DAI LI-YAN, SUN LI-WEN ,YAO SAN-JING: "A Convenient Synthesis of Chrysin and Tectochrysin", CHEMICAL RESEARCH IN CHINESE UNIVERSITIES, vol. 17, no. 3, 15 August 2001 (2001-08-15), pages 259 - 263, XP055902423 *

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