WO2012136108A1 - 一种1-羟基-3,5-二甲基-4-氯苯的制备方法 - Google Patents

一种1-羟基-3,5-二甲基-4-氯苯的制备方法 Download PDF

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WO2012136108A1
WO2012136108A1 PCT/CN2012/073112 CN2012073112W WO2012136108A1 WO 2012136108 A1 WO2012136108 A1 WO 2012136108A1 CN 2012073112 W CN2012073112 W CN 2012073112W WO 2012136108 A1 WO2012136108 A1 WO 2012136108A1
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copper
reaction
hydroxy
dimethylbenzene
copper salt
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PCT/CN2012/073112
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French (fr)
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吴飞
张新波
李培骏
胡汉忠
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湖南利洁生物化工有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms

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  • the invention relates to a preparation method of 1-hydroxy-3,5-dimethyl-4-chlorobenzene, in particular to a 1-hydroxy-3,5 compound with a chlorine-containing compound in the presence of a catalyst and an oxidant.
  • 1-hydroxy-3,5-dimethyl-4-chlorobenzene (aka: 4-chloro-3,5-dimethylphenol, CAS number: 88-04-0, English abbreviation: PCMX) is a kind An important microbicide, widely used in the industrial and cosmetic industries as an antibacterial, antifungal, and disinfectant, it has excellent inhibitory effects against bacteria, mold, and most fungi. In recent years, with the ravages of epidemic diseases, people's health awareness has become stronger and stronger. As a traditional low-toxic disinfectant, 1-hydroxy-3,5-dimethyl-4-chlorobenzene will also have more The great development potential is as follows:
  • the proportion of the para- ortho-chloro product obtained according to the patented method is very limited.
  • the para-monochlorinated product has a larger industrial use, so it is generally The reaction takes the para-monochlorinated compound as the target product.
  • some undesired isomers and polychlorinated by-products are produced in the reaction, which not only affects the purification of the product, but also increases the disposal cost.
  • U.S. Patent 4,245,127 focuses on the use of organosulfides and metal chlorides as co-catalysts for the reaction of 1-hydroxy-3,5-dimethylbenzene.
  • This patent discusses the use of thiophene and dodecyl mercaptan as organic sulfides; ferric chloride, aluminum trichloride, and titanium tetrachloride as a metal chloride co-catalyst system, with sulfuryl chloride and 1- The effect of hydroxy-3,5-dimethylbenzene on the synthesis of 1-hydroxy-3,5-dimethyl-4-chlorobenzene.
  • the maximum product selectivity can be obtained with titanium tetrachloride and dodecanethiol as co-catalysts, ie 1-hydroxy-3,5-dimethyl-4-chlorobenzene reaches 91.5 %.
  • Chinese patent CN101085722A mentions an improved method based on US 4245127, in which one or more alkyl ether compounds are added as a co-catalyst during the reaction, which greatly improves the selectivity of the para-product.
  • the two by-products produced are all highly corrosive gases, which are difficult to handle; in particular, the recovery value of sodium sulfite produced by the absorption of soda sulphur dioxide by soda ash is low, and most manufacturers adopt direct discharge method for treatment, not only for process equipment.
  • the infrastructure causes corrosion and causes serious pollution to the environment.
  • Japanese Patent Laid-Open No. 59-5132 discloses oxychlorinated 1-hydroxy-3,5- using divalent copper salt as a catalyst, hydrogen peroxide as an oxidizing agent, and hydrochloric acid as a chlorine source in an organic solvent system.
  • a method of synthesizing 1-hydroxy-3,5-dimethyl-4-chlorobenzene from dimethylbenzene are very low, and the highest theoretical yield (conversion rate* selectivity) obtained is only 79.3%, which does not have the value of commercialization.
  • an organic solvent is required.
  • 200910044035.4 proposes a process for oxidative chlorination to obtain 1-hydroxy-3,5-dimethyl-4-chlorobenzene using a divalent copper salt and a lower fatty acid as a catalytic system.
  • a lower fatty acid or a lower fatty acid and a chlorinated aliphatic compound are mixed as an organic solvent for the reaction.
  • organic solvents not only causes certain pollution to the environment, but also increases production costs.
  • the object of the present invention is to provide a preparation method of 1-hydroxy-3,5-dimethyl-4-chlorobenzene which is environmentally friendly, has high product yield, low cost and simple operation.
  • Method for preparing 1-hydroxy-3,5-dimethyl-4-chlorobenzene using divalent copper salt as catalyst, in the absence of organic solvent, 1-hydroxy-3,5-dimethyl
  • the reaction of benzene, an oxidizing agent and a chlorine-containing inorganic substance is carried out at a reaction temperature of 50-150 ° C; the divalent copper salt accounts for 0.5%-200% by weight of 1-hydroxy-3,5-dimethylbenzene; the oxidizing agent
  • the molar ratio of available oxygen, chlorine-containing compound and 1-hydroxy-3,5-dimethylbenzene is from 1-2:1 to 1.5:1.
  • the divalent copper salt is copper sulfate, copper nitrate, copper carbonate, copper hydroxide, copper halide or a copper salt of a fatty acid having 1 to 6 carbon atoms.
  • the copper halide is copper chloride, copper bromide or copper iodide; the copper salt of a fatty acid having 1 to 6 carbon atoms is copper formate, copper acetate or copper propionate.
  • the divalent copper salt is anhydrous or a copper salt with crystal water.
  • the divalent copper salt is preferably used in an amount of from 10% to 60% by weight based on the weight of the 1-hydroxy-3,5-dimethylbenzene.
  • the catalyst may be replaced by a monovalent copper salt (such as cuprous chloride, etc.) corresponding to the above-mentioned divalent copper salt; and an oxidizing agent for oxidizing and chlorinating the monovalent copper salt to a divalent copper salt may be added to the reaction system. And the amount of inorganic chloride.
  • a monovalent copper salt such as cuprous chloride, etc.
  • an oxidizing agent for oxidizing and chlorinating the monovalent copper salt to a divalent copper salt may be added to the reaction system. And the amount of inorganic chloride.
  • the oxidizing agent is oxygen, air or hydrogen peroxide.
  • the chlorine-containing inorganic substance is hydrogen chloride or hydrochloric acid.
  • the reaction temperature is preferably 80-110 ° C; further preferably 90-100 ° C,
  • the reaction is preferably carried out at a pressure of 1-5 atm.
  • Water may be added during the reaction so that the total amount of water accounts for 5% to 200% by weight of the 1-hydroxy-3,5-dimethylbenzene.
  • the effective oxygen amount of the oxidizing agent is a portion of the oxidizing agent capable of participating in the oxidation reaction (ie, the content of oxygen element). For example, when 30% hydrogen peroxide is used as the oxidizing agent, the O released in the hydrogen peroxide water (ie, the content of oxygen element in the hydrogen peroxide) is The amount of oxygen available.
  • the above reaction system can be completed in one reaction vessel, or can be first reacted with 1-hydroxy-3,5-dimethylbenzene with a sufficient amount of copper chloride (not applicable to other copper salts) to produce chlorine.
  • the cuprous copper is regenerated by using an oxidizing agent and hydrogen chloride or hydrochloric acid, but from the economical point of view, the one-step reaction is effective.
  • the divalent copper salt has significant catalytic activity for the chlorination of 1-hydroxy-3,5-dimethylbenzene.
  • the divalent copper salt used in the present invention includes copper sulfate, copper nitrate, copper carbonate, copper hydroxide, copper chloride, copper bromide, copper iodide, copper formate, copper acetate or copper propionate, and the like.
  • the effect of the amount of divalent copper salt on the reaction rate is positively correlated, that is, the larger the amount of catalyst used, the higher the conversion rate of the reactant per unit time.
  • the first use amount is preferably controlled from 0.5% to 200% (based on the weight of 1-hydroxy-3,5-dimethylbenzene); 10% to 60% is optimal.
  • the divalent copper salt catalyst used can be repeatedly applied during the reaction without affecting the reaction rate. It is also possible to add a monovalent copper salt corresponding to the divalent copper salt to the above reaction system instead of the divalent copper salt, which is produced by reacting with the oxidizing agent and the inorganic chloride added in the reaction system, but correspondingly increasing the reaction therewith. The amount of oxidant and inorganic chloride is only.
  • the oxidizing agent used in the present invention includes oxygen, air and hydrogen peroxide; the amount of oxidizing agent (in terms of available oxygen) and 1-hydroxy-3,5-dimethylbenzene are in a molar ratio of 1:1 to 2:1. between.
  • the use of hydrogen peroxide can significantly increase the reaction speed, but the selectivity is not high; and the use of oxygen or air can obtain a higher alignment ability.
  • the raw material which can be used as a chlorine source in the present invention includes hydrogen chloride or hydrochloric acid.
  • the molar ratio of the chlorine-containing inorganic substance to 1-hydroxy-3,5-dimethylbenzene used in the present invention is between 1:1 and 1.5:1.
  • the reaction pressure has no obvious effect on the reaction; when oxygen or air is used as the oxidant, the reaction pressure and the reaction rate are positively correlated and can be controlled at 1-5 atm. Considering the economics of the reaction, a suitable pressure range can be controlled between 1-2 atm.
  • the water in the reaction system can be brought in by the industrial hydrochloric acid added during the reaction; if hydrogen chloride is used as the chlorine source, a certain amount of water can be added before the reaction to increase the solubility of hydrogen chloride in the system, thereby improving the reaction effect.
  • the reaction itself produces an equimolar amount of water with the product (see Equations 1 and 2).
  • a catalyst with water of crystallization When a catalyst with water of crystallization is used, part of the water can also be brought in.
  • 30% hydrogen peroxide is used as the oxidant, it will also be carried.
  • the total amount of water is preferably between 5% and 200% by weight based on the weight of 1-hydroxy-3,5-dimethylbenzene. Too much water will reduce the economics of the reaction.
  • the present invention utilizes a divalent copper salt as a catalyst, 1-hydroxy-3,5-dimethylbenzene, an oxidizing agent, and a chlorine-containing inorganic substance to react to form 1-hydroxy-3,5-dimethyl-4-chlorobenzene. All of them are reacted at low temperature using an organic solvent, the main purpose of which is to dissolve the substrate 1-hydroxy-3,5-dimethylbenzene in the organic phase, which is beneficial to the catalyst, oxidant and chlorine in the aqueous phase.
  • the compound reacts sufficiently because the solid 1-hydroxy-3,5-dimethylbenzene at low temperature is difficult to react sufficiently with the catalyst, oxidant, and chlorine-containing compound in the aqueous phase, and has a great influence on the efficiency of the reaction, so in the research field A mindset is formed in which the substrate is dissolved in an organic solvent in order to proceed smoothly.
  • the inventors have found through research that it is possible to ensure that the substrate reacts with the aqueous phase in a molten state by heating without adding an organic solvent.
  • the temperature at the start of the reaction is preferably 50 ° C or higher.
  • the melting point of the substrate will first decrease and then gradually increase.
  • the reaction temperature should be gradually increased to ensure that the reaction substrate is in a molten state, which is more advantageous for improving the product. Yield.
  • the melting point of the substrate in the aqueous system is increased to above 90 °C.
  • the higher the temperature the faster the reaction rate, but if the temperature is too high and exceeds the boiling point of the water phase in the system, vaporization of the aqueous phase occurs, and the reaction substrate is a phenolic substance, which is easy to sublimate.
  • the reaction temperature is preferably controlled at 80 to 110 ° C, more preferably 90 to 100 ° C.
  • the present invention provides a novel method for synthesizing 1-hydroxy-3,5-dimethyl-4-chlorobenzene, using a divalent copper salt as a catalyst, hydrogen chloride or hydrochloric acid as a chlorine source, and an oxidizing agent.
  • the desired product is synthesized by oxychlorination under the conditions present.
  • the method has the advantages of simple operation, mild reaction conditions, good selectivity of the target product, high conversion rate, almost no toxic gas in the reaction process, no need to use any organic solvent, and can significantly reduce environmental pollution, and is suitable for large-scale Process for the preparation of 1-hydroxy-3,5-dimethyl-4-chlorobenzene for industrial applications.
  • Example 1 The lower aqueous phase of Example 1 was subjected to atmospheric distillation to concentrate, and about 80 g of water was distilled off. 122 g of 1-hydroxy-3,5-dimethylbenzene and 102 g of concentrated hydrochloric acid were added to the bottom liquid; then, a condenser, magnetic stirring, a thermometer, and an oxygen tube were installed. The reaction was heated to 90 ° C and oxygen was introduced at a constant rate with stirring. The reaction temperature is controlled between 90 and 98 ° C, and the reaction pressure is normal pressure. After the reaction was completed, the lower layer material was separated, and the content was measured by GC. The results are shown in Table 1.
  • Example 1 The test procedure was the same as in Example 1, except that hydrochloric acid was changed to 1 mol of HCl, and 50 g of tap water was additionally added. The reaction pressure was controlled at 2 atm, and the reaction results are shown in Table 1: Table 1 Analysis results of oxychlorination project Reaction time MX % OC% DC% PC% Selectivity Conversion rates Yield Example 1 6 hours 0.38 1.98 1.2 96.44 96.80% 99.62% 96.43%
  • Example 2 8 hours 0.45 2.15 1.04 96.36 96.79% 99.55% 96.35%
  • Example 3 8 hours 0.65 2.05 1.15 96.15 96.77% 99.35% 96.14%
  • MX 1-hydroxy-3,5-dimethylbenzene
  • OC 1-hydroxy-3,5-dimethyl-2-chlorobenzene
  • DC 1-hydroxy-3,5-dimethyl- 2,4-dichlorobenzene
  • PC 1-hydroxy-3,5-dimethyl-4-chlorobenzene
  • Example 2 The test procedure was the same as in Example 1-2 except that the oxygen was replaced with air.
  • the reaction results are shown in Table 2: Table 2 Analysis results of oxychlorination project Reaction time MX % OC% DC% PC% Selectivity Conversion rates Yield Example 4 20 hours 1.04 2.58 2.25 94.16 95.14% 98.96% 94.15% Example 5 24 hours 1.18 2.89 2.19 93.74 94.86% 98.82% 93.74%
  • Example 6 4 hours 0.99 6.78 7.54 86.69 85.53% 99.01% 84.68%
  • Example 7 4 hours 1.08 5.99 7.55 85.38 86.31% 98.82% 85.38%
  • Example 4 Analysis results of oxychlorination project catalyst Reaction time MX % OC% DC% PC% Selectivity Conversion rates Yield Example 8 Copper bromide 10 hours 1.14 2.79 2.34 93.73 94.81% 98.86% 93.73%
  • Example 9 Copper iodide 10 hours 1.28 2.88 2.55 93.29 94.50% 98.72% 93.29%
  • Example 10 Copper formate 10 hours 1.13 2.89 2.21 93.77 94.84% 98.87% 93.77%
  • Example 11 Copper acetate 10 hours 1.19 2.43 2.38 94 95.13% 98.81% 94%
  • Example 12 Copper propionate 10 hours 1.23 2.59 2.44 93.74 94.91% 98.77% 93.74%
  • Example 13 Copper sulfate 10 hours 1.
  • the test procedure is the same as in the first embodiment except that the reaction temperature is controlled between 110 and 115 ° C. During the reaction, the reflux phenomenon of the condenser is very obvious, and white materials accumulate in the condensation tube. After 8 hours of reaction, the sample is taken and detected by GC. The result was MX: 0.98%; OC: 3.25%; DC: 2.98%; PC: 92.79%.
  • test procedure was the same as in Example 1, except that the amount of copper chloride dihydrate added was increased to 102.4 g, and after 8 hours of reaction, a sample was taken and detected by GC, and the result was MX: 1.08%; OC: 2.25%; DC: 1.95%; PC: 94.72%.

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Abstract

本发明公开了一种1-羟基-3,5-二甲基-4-氯苯的制备方法。由二价铜盐作催化剂，在无有机溶剂的条件下，以1-羟基-3,5-二甲基苯、氧化剂和含氯无机物进行反应得到，反应温度为50-150℃；所述二价铜盐占1-羟基-3,5-二甲基苯重量的0.5％－200％；所述氧化剂的有效氧量、含氯化合物和1-羟基-3,5-二甲基苯用量的摩尔比为：1-2：1-1.5：1。该方法操作简便、反应条件温和，得到的目的产物选择性好，转化率高，且反应过程中几乎不产生有毒气体，不需要使用任何有机溶剂，能明显减少环境污染，是一种适合大规模工业化应用的1-羟基-3,5-二甲基-4-氯苯制备方法。

Description

一种1-羟基-3,5-二甲基-4-氯苯的制备方法 技术领域
本发明涉及一种1-羟基-3,5-二甲基-4-氯苯的制备方法，具体涉及一种在催化剂和氧化剂存在的条件下，用含氯化合物对1-羟基-3,5-二甲基苯进行氯化反应制备1-羟基-3,5-二甲基-4-氯苯的方法。
背景技术
1-羟基-3,5-二甲基-4-氯苯（又名：4-氯-3，5-二甲基苯酚，CAS编号：88-04-0，英文缩写：PCMX）是一种重要的微生物杀灭剂，作为抗菌剂、防霉剂、消毒剂，广泛应用于工业和化妆品行业,它对细菌，霉菌和大多数真菌有着优良的抑制作用。近年来，随着流行性疾病的肆虐，人们的健康意识越来越强烈，作为一种传统的低毒消毒剂，1-羟基-3,5-二甲基-4-氯苯也将有着更大的发展潜力，其结构式如下：
Figure PCTCN2012073112-appb-C000001
传统的1-羟基-3,5-二甲基-4-氯苯是采用硫酰氯和1-羟基-3,5-二甲基苯进行亲电取代反应制备的。1866年，从Dubois用等摩尔的硫酰氯和熔融的苯酚进行反应开始，人类就知道了用硫酰氯选择性合成一氯苯酚类化合物（Z.F.Chem.705 (1866)）。但是，现代分析技术表明，上述反应的选择性与Dubois当时的想法并不一致，即在上述反应过程中，他认为对氯苯酚的选择性占主导地位。上个世纪中期，这个反应的催化剂体系，包括二价硫化物和金属卤化物，在美国专利3920757中进行了介绍。该专利中提供了一种最优的有机硫化合物作为催化剂——二苯醚，并与三氯化铝进行共催化。这个催化剂体系同时也被应用于其他许多用硫酰氯作为氯化剂的氯化反应中。该催化反应所获得的主产物是对位氯代的烷基苯酚化合物。但是，这个催化剂体系存在一些缺点，特别是将这个体系应用于工业化生产过程中更是如此。例如，产品的收率很难达到预想的程度，另外，按照专利方法所获得的对/邻位氯代产品的比例非常有限，（对位单氯代产品因为具有更大的工业用途，所以一般的反应以对位单氯代化合物作为目的产品。）而且在反应中还会产生一些不需要的异构体和多氯化副产物，不但影响产品的提纯，同时增加了处置成本。
美国专利4245127重点介绍了使用有机硫化物和金属氯化物作为共催化剂，氯化1-羟基-3,5-二甲基苯的反应。该专利分别讨论了用噻酚和十二硫醇作为有机硫化物；三氯化铁、三氯化铝，以及四氯化钛作为金属氯化物组成共催化剂的体系，对用硫酰氯和1-羟基-3,5-二甲基苯进行反应合成1-羟基-3,5-二甲基-4-氯苯的影响。根据该专利中所提到的实例，用四氯化钛和十二硫醇作为共催化剂可以获得最大的产品选择性，即1-羟基-3,5-二甲基-4-氯苯达到91.5%。
中国专利CN101085722A中提到一种基于US4245127的改进方法，即在反应过程中加入了一种或多种烷基醚类化合物作为共催化剂，较大的提高了对位产品的选择性。
然而，随着可持续发展、生态化学和绿色化学等观念的不断深入，人类对化工生产过程产生的环境污染问题越来越重视，控制也越来越严格。由于传统的工艺合成1-羟基-3,5-二甲基-4-氯苯采用硫酰氯作为氯源，在生产过程中产生等摩尔的氯化氢和二氧化硫副产品，因此其原子经济性极低，仅为26.3%。所产生的这两种副产品均为具有强腐蚀性的气体，处理困难；特别是二氧化硫用纯碱吸收后产生的亚硫酸钠回收价值低，绝大多数的厂家采用直接排放的方法进行处理，不但对工艺设备、基础设施造成腐蚀，而且对环境造成严重污染。
鉴于上述问题，日本专利特开昭59-5132中提到了用二价铜盐作为催化剂，双氧水作为氧化剂，在有机溶剂的体系中用盐酸作为氯源的氧氯化1-羟基-3,5-二甲基苯合成1-羟基-3,5-二甲基-4-氯苯的方法。但是从发明人提供的实验数据来看，使用该方法的转化率和选择性均很低，所得的最高理论收率（转化率*选择性）仅为79.3%，不具备商业化推广的价值，而且需要使用有机溶剂。中国专利申请200910044035.4提出了用二价铜盐和低级脂肪酸作为催化体系，氧化氯化得1-羟基-3,5-二甲基-4-氯苯的工艺。该发明中将低级脂肪酸，或者低级脂肪酸与氯代脂肪族化合物两者混合作为反应的有机溶剂。但是有机溶剂的使用不但会对环境造成一定的污染，而且增加了生产成本。
 技术问题
本发明的目的是提供一种对环境无污染、产品得率高、成本低、操作简单的1-羟基-3,5-二甲基-4-氯苯的制备方法。
技术解决方案
本发明的目的是通过以下方式实现的：
一种1-羟基-3,5-二甲基-4-氯苯的制备方法：由二价铜盐作催化剂，在无有机溶剂的条件下，以1-羟基-3,5-二甲基苯、氧化剂和含氯无机物进行反应得到，反应温度为50-150℃；所述二价铜盐占1-羟基-3,5-二甲基苯重量的0.5％－200％；所述氧化剂的有效氧量、含氯化合物和1-羟基-3,5-二甲基苯用量的摩尔比为：1-2：1-1.5：1。
所述二价铜盐为硫酸铜、硝酸铜、碳酸铜、氢氧化铜、卤化铜或含1-6个碳原子的脂肪酸铜盐。
所述卤化铜为氯化铜、溴化铜或碘化铜；所述含1-6个碳原子的脂肪酸铜盐为甲酸铜、乙酸铜或丙酸铜。
所述的二价铜盐为无水的或是带有结晶水的铜盐。
所述二价铜盐的用量优选占1-羟基-3,5-二甲基苯重量的10％－60％。
所述的催化剂可以由上述二价铜盐相对应的一价铜盐（如：氯化亚铜等）代替；同时在反应体系中增加将一价铜盐氧化和氯化成二价铜盐的氧化剂和无机氯化物的量。
所述氧化剂为氧气、空气或双氧水。
所述含氯无机物是氯化氢或者盐酸。
所述的反应温度优选为80-110℃；进一步优选为90-100℃，
反应最好在压强1-5atm条件下进行。
反应时可以加入水，使得水的总量占1-羟基-3,5-二甲基苯重量的5%-200%。
所述氧化剂的有效氧量为氧化剂中能够参与氧化反应的部分（即氧元素的含量），例如采用30%双氧水为氧化剂时，以双氧水中释放出的O（即双氧水中氧元素的含量）为有效氧量。
上述反应体系可以在一个反应釜中完成反应，也可以先用足量的氯化铜（不适用于其他铜盐）先和1-羟基-3,5-二甲基苯进行反应，产生的氯化亚铜再用氧化剂和氯化氢或者盐酸进行再生，但从经济性的角度上来说，采用一步法反应的效果较好。
 有益效果
本发明的技术方案中，二价铜盐对1-羟基-3,5-二甲基苯的氯化具有明显的催化活性。本发明所使用的二价铜盐包括：硫酸铜、硝酸铜、碳酸铜、氢氧化铜、氯化铜、溴化铜、碘化铜、甲酸铜、乙酸铜或丙酸铜等等。二价铜盐的使用量对反应速度的影响呈正相关关系，即一般情况下催化剂使用量越大，单位时间反应物的转化率越高。考虑到反应的经济问题，第一次使用量控制在0.5%-200%为宜（基于1-羟基-3,5-二甲基苯的重量）；10%-60%最佳。所使用的二价铜盐催化剂在反应过程中可以进行反复套用而不会影响反应速度。也可以在上述反应体系中加入二价铜盐相对应的一价铜盐代替二价铜盐，其与反应体系中所加入的氧化剂和无机氯化物进行反应而产生，只是相应的增加与其反应的氧化剂和无机氯化物的量而已。
本发明中所使用的氧化剂包括氧气、空气和双氧水；所使用的氧化剂量（以有效氧计）和1-羟基-3,5-二甲基苯的摩尔比在1：1到2：1之间。在本发明技术方案中，使用双氧水可以明显提高反应速度，但是选择性不高；而使用氧气、或者空气可以得到较高的对位定位能力。
在本发明中可以作为氯源的原料包括氯化氢或者盐酸。本发明中所使用的含氯的无机物和1-羟基-3,5-二甲基苯的摩尔比在1：1到1.5：1之间。
在使用双氧水作为氧化剂时，反应压力对反应影响不明显；而使用氧气、或者空气作为氧化剂时，反应压力和反应速度呈正相关关系，可以控制在1-5atm。考虑到反应的经济性，适宜的压力范围可以控制在1-2atm之间。
反应体系中的水可以通过反应过程中添加的工业盐酸带入；如果使用氯化氢作为氯源，可以在反应前加入一定量的水，以增加氯化氢在体系中的溶解度，从而改善反应效果。另外，反应本身也会产生和产物等摩尔的水分（见反应式1和2），当使用带结晶水的催化剂时，也可以带入部分水分，在使用30%双氧水作为氧化剂时，也会带入一定量的水分。水的总量占1-羟基-3,5-二甲基苯重量的5%-200%之间为宜。水分太多，会降低反应的经济性。
Figure PCTCN2012073112-appb-C000002
反应式1
Figure PCTCN2012073112-appb-C000003
反应式2
现有利用二价铜盐为催化剂，1-羟基-3,5-二甲基苯、氧化剂、含氯无机物反应生成1-羟基-3,5-二甲基-4-氯苯的工艺中都采用了有机溶剂在低温下反应，其目的主要是为了使底物1-羟基-3,5-二甲基苯溶于有机相，利于其与溶于水相中的催化剂、氧化剂和含氯化合物充分反应，因为低温下固态的1-羟基-3,5-二甲基苯很难与水相中的催化剂，氧化剂，含氯化合物充分反应，对反应的效率影响很大，所以在研究领域形成一种思维定势，在该类反应中底物都要溶于有机溶剂中才可能顺利进行。但是本发明人通过研究发现，在不添加有机溶剂的情况下，只要通过加热保证底物在熔化状态下与水相进行反应是完全可以的。鉴于反应底物1-羟基-3,5-二甲基苯的在水相存在的情况下的熔点在50℃以上，因此反应开始时温度在50℃以上为宜。随着反应的进行，底物的熔点会先下降，然后逐渐升高，为了保证底物处于熔化状态，反应温度应该逐步升高，保证反应底物处于熔融状态，这样才更加有利于提高产物的得率。当原料1-羟基-3,5-二甲基苯的转化率达到95%以上时，底物在水体系中的熔点会提高到90℃以上。从另外一个方面来讲温度越高，反应速度越快，但是如果温度太高，超过了体系中水相的沸点，就会产生水相的汽化，而反应底物属于酚类物质，容易升华，因此在回流状态下反应，水的汽化会夹带出大量有机物，在冷凝器、或者管道上析出，堵塞冷凝器和管道，影响操作；而且，在回流状态下反应，水相的汽化会损失大量的热量，对反应总体上来讲也是不经济的。因此，温度太高对反应产率有一定的影响，所以，在保持高产率的同时，反应温度优选控制在80-110℃，更加优选90-100℃。
综上所述，本发明提供了一种新的1-羟基-3,5-二甲基-4-氯苯的合成方法，采用二价铜盐作为催化剂，氯化氢或者盐酸作为氯源，在氧化剂存在的条件下进行氧氯化反应合成目的产品。此方法操作简便、反应条件温和，得到的目的产物选择性好，转化率高，且反应过程中几乎不产生有毒气体，不需要使用任何有机溶剂，能明显减少环境污染，是一种适合大规模工业化应用的1-羟基-3,5-二甲基-4-氯苯制备方法。
 本发明的实施方式
以下结合实施例旨在进一步说明本发明，而非限制本发明。
实施例1
500ml三口反应烧瓶中分别加入122g（1.0mol）1-羟基-3,5-二甲基苯，51.2g二水氯化铜，以及101.3g浓盐酸（HCl1.0mol）；然后装上冷凝器、磁力搅拌、温度计，以及通氧管。将反应物加热到90℃，在搅拌状态下匀速通入氧气。反应温度控制在90-98℃之间，反应压力为常压。反应结束后，取上层有机相用GC检测含量。结果见表1。
实施例2
将实施例1中下层水相常压蒸馏进行浓缩，蒸出80g左右水分。釜底料液中添加122g1-羟基-3,5-二甲基苯，以及102g浓盐酸；然后装上冷凝器、磁力搅拌、温度计，以及通氧管。将反应物加热到90℃，在搅拌状态下匀速通入氧气。反应温度控制在90-98℃之间，反应压力为常压。反应结束后，将下层物料分出，取样用GC检测含量；结果见表1。
实施例3
试验过程同实施例1，只是将盐酸改为1molHCl，另外添加50g自来水，反应压力控制在2atm，反应结果见表1： 表1 氧氯化反应分析结果
项目 反应时间 MX % OC% DC% PC% 选择性 转化率 收率
实施例1 6小时 0.38 1.98 1.2 96.44 96.80% 99.62% 96.43%
实施例2 8小时 0.45 2.15 1.04 96.36 96.79% 99.55% 96.35%
实施例3 8小时 0.65 2.05 1.15 96.15 96.77% 99.35% 96.14%
注：MX：1-羟基-3,5-二甲基苯；OC：1-羟基-3,5-二甲基-2-氯苯；DC: 1-羟基-3,5-二甲基-2,4-二氯苯；PC: 1-羟基-3,5-二甲基-4-氯苯；收率计算方式：=转化率*选择性(下同)。
实施例4-5
试验过程分别同实施例1-2，只是将氧气更换为空气，反应结果见表2： 表2 氧氯化反应分析结果
项目 反应时间 MX % OC% DC% PC% 选择性 转化率 收率
实施例4 20小时 1.04 2.58 2.25 94.16 95.14% 98.96% 94.15%
实施例5 24小时 1.18 2.89 2.19 93.74 94.86% 98.82% 93.74%
实施例6-7
试验过程分别同实施例1-2，只是将氧气更换为1.2mol 30% 双氧水，反应结果见表3： 表3 氧氯化反应分析结果
项目 反应时间 MX % OC% DC% PC% 选择性 转化率 收率
实施例6 4小时 0.99 6.78 7.54 86.69 85.53% 99.01% 84.68%
实施例7 4小时 1.08 5.99 7.55 85.38 86.31% 98.82% 85.38%
实施例8-14
试验过程同实施例1，只是将氯化铜分别更换为溴化铜、碘化铜、甲酸酮、醋酸铜、丙酸铜、硫酸铜、硝酸铜，实验结果如下： 表4 氧氯化反应分析结果
项目 催化剂 反应时间 MX % OC% DC% PC% 选择性 转化率 收率
实施例8 溴化铜 10小时 1.14 2.79 2.34 93.73 94.81% 98.86% 93.73%
实施例9 碘化铜 10小时 1.28 2.88 2.55 93.29 94.50% 98.72% 93.29%
实施例10 甲酸铜 10小时 1.13 2.89 2.21 93.77 94.84% 98.87% 93.77%
实施例11 醋酸铜 10小时 1.19 2.43 2.38 94 95.13% 98.81% 94%
实施例12 丙酸铜 10小时 1.23 2.59 2.44 93.74 94.91% 98.77% 93.74%
实施例13 硫酸铜 10小时 1.28 2.39 2.49 93.84 95.01% 98.72% 93.84%
实施例14 硝酸铜 10小时 1.23 2.57 2.54 93.66 94.83% 98.77% 93.66%
实施例15
试验过程同实施例1，只是将反应温度控制在110-115℃之间，反应过程中冷凝器回流现象非常明显，且有白色物料在冷凝管中积聚，反应8小时后取样，用GC进行检测，结果为MX：0.98%；OC：3.25%；DC：2.98%；PC：92.79%。
实施例16
试验过程同实施例1，只是将二水氯化铜的加入量增加到102.4g，反应8小时后取样，用GC进行检测，结果为MX：1.08%；OC：2.25%； DC：1.95%； PC：94.72% 。

Claims (10)

  1. 一种1-羟基-3,5-二甲基-4-氯苯的制备方法，其特征是，由二价铜盐作催化剂，在无有机溶剂的条件下，以1-羟基-3,5-二甲基苯、氧化剂和含氯无机物进行反应得到，反应温度为50-150℃；所述二价铜盐占1-羟基-3,5-二甲基苯重量的0.5％－200％；所述氧化剂的有效氧量、含氯化合物和1-羟基-3,5-二甲基苯用量的摩尔比为：1-2：1-1.5：1。
  2. 根据权利要求1所述的制备方法，其特征是，所述二价铜盐为硫酸铜、硝酸铜、碳酸铜、氢氧化铜、卤化铜或含1-6个碳原子的脂肪酸铜盐。
  3. 根据权利要求2所述的制备方法，其特征是，所述卤化铜为氯化铜、溴化铜或碘化铜；所述含1-6个碳原子的脂肪酸铜盐为甲酸铜、乙酸铜或丙酸铜。
  4. 根据权利要求1或2或3所述的制备方法，其特征是，所述的二价铜盐为无水的或是带有结晶水的铜盐。
  5. 根据权利要求1所述的制备方法，其特征是，所述二价铜盐的用量占1-羟基-3,5-二甲基苯重量的10％－60％。
  6. 根据权利要求4所述，其特征是，所述的催化剂可以由所述的二价铜盐相对应的一价铜盐代替，同时在反应体系中增加将一价铜盐氧化和氯化成二价铜盐的氧化剂和无机氯化物的量。
  7. 根据权利要求1所述的制备方法，其特征是，所述氧化剂为氧气、空气或双氧水。
  8. 根据权利要求1所述的制备方法，其特征是，所述含氯无机物是氯化氢或者盐酸。
  9. 根据权利要求1所述的制备方法，其特征是，所述反应温度为80-110℃。
  10. 根据权利要求1或9所述的制备方法，其特征是，所述的反应温度在90-100℃。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111574329A (zh) * 2020-05-18 2020-08-25 万华化学集团股份有限公司 一种用于生产4-氯-3，5-二甲基苯酚的反应精馏装置及方法

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102199075A (zh) * 2011-04-02 2011-09-28 湖南利洁生物化工有限公司 一种1-羟基-3,5-二甲基-4-氯苯的制备方法
CN102775278B (zh) * 2012-07-27 2014-03-05 湖南利洁生物化工有限公司 一种1-羟基-3，5-二甲基-4-氯苯的结晶纯化方法
CN103351282B (zh) * 2013-07-09 2014-12-31 湖南利洁生物化工有限公司 一种4-氯-3,5-二甲基苯酚的制备方法
CN105037104A (zh) * 2015-06-02 2015-11-11 铜陵市恒兴化工有限责任公司 一种4-氯-3,5-二甲基苯酚的制备方法
CN107226775A (zh) * 2016-03-24 2017-10-03 中国石油化工股份有限公司 连续流微管反应器中合成4-氯-3,5-二甲基苯酚的方法
CN111440051A (zh) * 2020-04-03 2020-07-24 安徽中羰碳一工业技术有限责任公司 一种4-氯-3，5-二甲基苯酚的合成方法
CN115611710B (zh) * 2022-09-13 2024-02-20 安徽海华科技集团有限公司 一种用于提高3,5-二甲基苯酚氧化氯化效率的方法
CN115583869B (zh) * 2022-09-13 2024-04-23 安徽海华科技集团有限公司 一种酚类化合物选择性氧化氯化方法
CN115433060A (zh) * 2022-10-31 2022-12-06 青岛科技大学 一种单氯代苯酚化合物的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3916014A (en) * 1972-08-03 1975-10-28 Asahi Denka Kogyo Kk Chlorination of aromatic compounds
JPS595132A (ja) * 1982-06-30 1984-01-12 Hodogaya Chem Co Ltd ４−クロル−３，５−キシレノ−ルの製造法
CN100560554C (zh) * 2007-01-10 2009-11-18 胡汉忠 对氯代烷基苯酚的工业化制备方法
CN101624333A (zh) * 2009-08-05 2010-01-13 湖南利洁生物化工有限公司 一种1-羟基-3,5-二甲基-4-氯苯的制备方法
CN102199075A (zh) * 2011-04-02 2011-09-28 湖南利洁生物化工有限公司 一种1-羟基-3,5-二甲基-4-氯苯的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1240829A (en) * 1967-10-04 1971-07-28 Reckitt & Colmann Prod Ltd Improvements in or relating to the chlorination of phenols

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3916014A (en) * 1972-08-03 1975-10-28 Asahi Denka Kogyo Kk Chlorination of aromatic compounds
JPS595132A (ja) * 1982-06-30 1984-01-12 Hodogaya Chem Co Ltd ４−クロル−３，５−キシレノ−ルの製造法
CN100560554C (zh) * 2007-01-10 2009-11-18 胡汉忠 对氯代烷基苯酚的工业化制备方法
CN101624333A (zh) * 2009-08-05 2010-01-13 湖南利洁生物化工有限公司 一种1-羟基-3,5-二甲基-4-氯苯的制备方法
CN102199075A (zh) * 2011-04-02 2011-09-28 湖南利洁生物化工有限公司 一种1-羟基-3,5-二甲基-4-氯苯的制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111574329A (zh) * 2020-05-18 2020-08-25 万华化学集团股份有限公司 一种用于生产4-氯-3，5-二甲基苯酚的反应精馏装置及方法
CN111574329B (zh) * 2020-05-18 2022-09-20 万华化学集团股份有限公司 一种用于生产4-氯-3，5-二甲基苯酚的反应精馏装置及方法

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