WO2010057406A1 - Method for preparing 3-bromo-5-chlorophenol - Google Patents

Method for preparing 3-bromo-5-chlorophenol Download PDF

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WO2010057406A1
WO2010057406A1 PCT/CN2009/074490 CN2009074490W WO2010057406A1 WO 2010057406 A1 WO2010057406 A1 WO 2010057406A1 CN 2009074490 W CN2009074490 W CN 2009074490W WO 2010057406 A1 WO2010057406 A1 WO 2010057406A1
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compound
acid
reaction
preparation
bromo
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王萍
潘强彪
李杨州
廖承志
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联化科技股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/20—Diazonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
    • C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
    • C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
    • 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
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/045—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of a group bound to the ring by nitrogen

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  • the invention relates to a preparation method of an organic synthesis intermediate, in particular to a preparation method of 3-bromo-5-chlorophenol. Background technique
  • Patent WO 2006010545 describes a process for preparing 3-bromo-5-chlorophenol by using 3-chloro-5-fluorobromobenzene as a starting material, first performing a methoxy-substituted fluoro functional group, and then demethylating under acidic conditions.
  • the method yield is low, and the synthesis of 3-chloro-5-fluorobromobenzene is cumbersome.
  • the above three synthetic routes all have certain limitations, which brings certain difficulties to the industrial production of 3-bromo-5-chlorophenol. Summary of the invention
  • the technical problem to be solved by the invention is to overcome the high cost, the side reaction, the complicated operation, the high energy consumption, the low raw material and the low yield of the existing 3-bromo-5-chlorophenol synthesis route.
  • the defect provides a preparation method of 3-bromo-5-chlorophenol, which has the advantages of low cost, easy availability of raw materials, convenient operation, easy purification of products and easy scale-up production, and can also achieve relatively high yield.
  • the present invention relates to a process for the preparation of 3-bromo-5-chlorophenol as shown in Formula 1, which comprises the following steps: Compound 3 is hydrolyzed in an acidic medium to obtain Compound 1;
  • the method and conditions of the hydrolysis reaction may be the conventional methods and conditions for the hydrolysis reaction of the diazonium salt in the field, and the following conditions are particularly preferred in the present invention:
  • the acid in the acidic medium is preferably used in an amount of from 1 to 20 times, more preferably from 8 to 12 times, the molar amount of the compound 3; the acidic medium may be selected from various ratios of sulfuric acid aqueous solution or sulfuric acid. a mixed solution of an aqueous solution and an organic inert solvent;
  • the mass percentage of the aqueous sulfuric acid solution is preferably 5% to 90%, more preferably 30% to 60%; and the organic inert solvent is preferably selected from the group consisting of aromatic hydrocarbons, ethers and halogenated anthracene hydrocarbons.
  • aromatic hydrocarbon is preferably toluene and/or xylene
  • the ether is preferably one or more of tetrahydrofuran, ethylene glycol dimethyl ether and dioxan
  • the halogenated hydrocarbon is preferably one or more of dichloromethane, chloroform and 1,2-dichloroacetam.
  • the temperature of the hydrolysis reaction is preferably from 60 ° C to 150 ° C, more preferably from 80 ° C to 120 ° C.
  • the reaction time is until the reaction is completed.
  • the reactants are consumed by HPLC. until.
  • pure compound 1 can be obtained by a simple post-treatment such as extraction, concentration, filtration, and drying.
  • the compound 3 is a diazonium salt compound, and is generally used without isolation and purification according to a conventional operation method in the art, and therefore, in the preparation method of the above compound 1, the amount of the reagent related to the compound 3 is prepared by The amount of the raw material obtained after the complete conversion of the raw material is calculated.
  • the starting material for preparing the compound 3 is preferably the following compound 2.
  • the compound 3 can be obtained by the following method: Compound 2 can be subjected to diazotization reaction under acidic conditions;
  • the method and conditions of the diazotization reaction can be a conventional method and condition for preparing a diazonium salt reaction in the art.
  • the preferred methods and conditions are as follows:
  • the compound 2 is subjected to a diazotization reaction with sodium nitrite or n-butyl nitrite to form a diazonium salt compound 3; wherein a method of reacting with sodium nitrite is a preferred method.
  • the molar ratio of the compound 2 to the sodium nitrite is preferably 1:1 to 1:3, more preferably 1:1 to 1:2;
  • the conditions are favorable for the progress of the reaction and ensure the stability of the diazonium salt.
  • the strong acid is preferably one or more of hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid, preferably sulfuric acid;
  • the molar amount of the compound 2 is from 1 to 100 times, more preferably from 8 to 20 times;
  • the temperature of the reaction is preferably from -5 ° C to 50 ° C, preferably from 0 ° C to 10 °. C ;
  • the reaction time is determined until the reaction is completed, and it is preferred to detect the consumption of the reactants by HPLC.
  • the compound 2 can be obtained by the following method:
  • the compound 4 can be subjected to a reduction reaction.
  • the method and conditions of the reduction reaction may be the methods and conditions for the conventional nitro reduction reaction in the art, and the preferred methods and conditions are as follows:
  • the reducing agent is preferably one or more of reduced iron powder, zinc powder, sodium dithionite, stannous chloride dihydrate, sodium borohydride and lithium aluminum hydride, and most preferably reduced iron powder
  • the reducing agent is preferably used in an amount of from 1 to 20 times, more preferably from 5 to 10 times, the molar amount of the compound;
  • the catalyst is preferably palladium carbon (Pd-C) or platinum carbon ( One or more of Pt-C) and Raney-Ni, preferably Raney-Ni; the amount of the catalyst is preferably 0.01 to 1 times the molar amount of the compound 4,
  • the hydrogen source is preferably one or more of hydrogen, hydrazine hydrate, sodium formate, formic acid, ammonium formate and triethylamine formate, and most preferably hydrazine hydrate;
  • the organic inert solvent is preferably a lower alcohol and/or a lower acid, more preferably a lower acid; the lower acid is preferably one or more of
  • the temperature of the reduction reaction is preferably from 0 ° C to 80 ° C, more preferably from 10 ° C to 30 ° C; the time of the reduction reaction is detected until the reaction is completed, preferably by TLC. The reactants are consumed.
  • the compound 4 can be synthesized by the method of Gazz. Chim. Ital., 1874, 4, 341.
  • the positive effect of the invention is that: the preparation method of the invention can avoid expensive reagents or raw materials, thereby reducing the cost, and the raw materials are easy to obtain, the operation method is simple and convenient, the product is easy to be purified, and is not only suitable for laboratory preparation, but also suitable for industrialization. Mass production; it also achieves higher yields and purity. detailed description
  • 3-bromo-5-chloronitrobenzene (23.6 g, 0.1 mol) was added to 200 mL of glacial acetic acid. After cooling to 0 ° C, reduced iron powder (33.6 g, 0.6 mol) was added. After stirring at 0 ° C for 2 h, the temperature was raised to room temperature. After stirring for 16 h, celite was filtered and washed with ethyl acetate (100 mL), and the filtrate was concentrated, and then filtered and evaporated to ethyl acetate (200 mL).
  • 3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 10 mL of anhydrous acetonitrile and 5 mL of water, then sodium dithionite (6.96 g, 0.04 mol) was added and the mixture was warmed to 80 ° C for 2 h. After adding 10 mL of water and extracting with 3 X 15 mL of ethyl acetate, the organic layer was dried and concentrated to give 1.16 g of a tan solid.
  • 3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 30 mL of absolute ethanol, then dihydrate was added.
  • the stannous chloride (6.78 g, 0.03 mol) was heated to 80 ° C for 2 h, concentrated, and then added with ethyl acetate and refluxed for 30 min, filtered, and the filtrate was concentrated to give 1.63 g of a brownish brown liquid.
  • 3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 30 mL of ethyl acetate, and then added with 1% palladium carbon (0.03 mol), hydrogenated at room temperature for 1 h under normal pressure, filtered, and concentrated to give 2.06 g of a black liquid. , yield 99%.
  • 3-bromo-5-chloronitrobenzene (23.6 g, Ol mol) was added to 472 mL of propionic acid. After cooling to 0 ° C, reduced iron powder (0.5 mol) was added. After stirring at 0 ° C for 2 h, the temperature was raised to room temperature and stirred for 16 h. The celite was filtered and washed with ethyl acetate (100 mL), and the filtrate was concentrated and then filtered and evaporated to ethyl ether.
  • 3-bromo-5-chloronitrobenzene (23.6 g, Ol mol) was added to 200 mL of absolute ethanol, cooled to 0 ° C, then reduced Raney-Ni (O.lmol) was added, and 20 ml of formic acid was added with stirring at 0 ° C. After stirring at 0 ° C for 2 h, the temperature was raised to 80 ° C for 1 h, and the filtrate was concentrated to give a tan liquid, yield 95%.
  • 3-bromo-5-chloronitrobenzene (23.6 g, Ol mol) was added to 200 mL of isopropyl acid, cooled to 0 ° C, then reduced iron powder (1 mol) was added, stirred at 0 ° C for 2 h, then warmed to room temperature and stirred for 16 h. Diatomaceous earth filtered After washing with 100 mL of ethyl acetate, the combined filtrate was concentrated and then filtered and evaporated to ethyl ether.
  • the yellow diazonium salt solution obtained in Example 13 was slowly dropped into a mixed solution of 5% sulfuric acid (0.05 mol) and 200 mL of diethyl ether at 60 ° C, stirred at 60 ° C for 30 minutes, and allowed to stand for separation.
  • the organic layer was added to 50 mL of 4N. Stir the sodium hydroxide for 10 minutes, separate the layers and wash the organic layer with 50 mL of water.
  • the combined aqueous layer was acidified with 4N hydrochloric acid to pH 4, extracted with 3 X 50 mL of diethyl ether, and dried and concentrated to 10 mL.
  • the gadolinium was completely precipitated, filtered and washed with n-glycol to give a white solid, yield 72%.
  • Compound 2 (10. 3 g, 0.05 mol) was added to 100 mL of 50% nitric acid, heated to 100 °C, stirred until dissolved, cooled to 0 ° C, controlled temperature below 10 ° C, and added sodium nitrite solid (4.14 g, 0.15 mol) The mixture was further stirred at 50 ° C for 30 minutes to obtain a yellow diazonium salt solution.
  • the yellow diazonium salt solution obtained in Example 15 was slowly dropped into a mixed solution of 90% sulfuric acid (1 mol) and 200 mL of toluene at 150 ° C, stirred at 150 ° C for 30 minutes, and allowed to stand for separation, and the organic layer was added to 50.
  • the mixture was stirred for 10 minutes with mL 4N sodium hydroxide, and the organic layer was separated and washed with 50 mL of water.
  • the aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3 X 50 mL of toluene, and the organic layer was dried and concentrated to 10 mL. Add n-glum to all solids, filter and wash with n-glycol to dry a white solid, yield 70%
  • the yellow diazonium salt solution obtained in Example 17 was slowly dropped into a mixed solution of 90% sulfuric acid (0.4 mol) and 200 mL of chloroform at 80 ° C, stirred at 80 ° C for 30 minutes, and allowed to stand for separation.
  • the organic layer was added to 50 mL of 4N. Stir the sodium hydroxide for 10 minutes, separate the layers and wash the organic layer with 50 mL of water.
  • the combined aqueous layer was acidified with 4N hydrochloric acid to pH 4, extracted with 3 X 50 mL chloroform, and dried and concentrated to 10 mL.
  • the gadolinium was completely precipitated, filtered and washed with n-glycol to give a white solid, yield 7.5%.
  • Example 20 Preparation of 3-bromo-5-chlorophenol
  • the yellow diazonium salt solution obtained in Example 19 was slowly dropped into a mixed solution of 40% sulfuric acid (0.6 mol) and 200 mL of chloroform at 120 ° C, stirred at 120 ° C for 30 minutes, and allowed to stand for separation.
  • the organic layer was added to 50 mL of 4N. Stir the sodium hydroxide for 10 minutes, separate the layers and wash the organic layer with 50 mL of water.
  • the combined aqueous layer was acidified with 4N hydrochloric acid to pH 4, extracted with 3 X 50 mL chloroform, and dried and concentrated to 10 mL.
  • the gadolinium was completely precipitated from the solid, filtered and washed with n-heptane to give a white solid, yield 71%.
  • the yellow diazonium salt solution obtained in Example 21 was slowly dropped into 50 ml of a mixed solution of 30% sulfuric acid and 200 mL of toluene at 90 ° C, stirred at 90 ° C for 30 minutes, and allowed to stand for separation.
  • the organic layer was added with 50 mL of 4N sodium hydroxide. After stirring for 10 minutes, the organic layer was separated and washed with 50 mL of water.
  • the aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3 ⁇ 50 mL of toluene, and dried and concentrated to 10 mL. The solid was all precipitated, filtered and washed with n-glycol to give a white solid 7.78 g, yield 75%.
  • the yellow diazonium salt solution obtained in Example 21 was slowly dropped into 100 mL of 100 mL of 50% sulfuric acid, stirred at 90 ° C for 30 minutes, extracted with 2 X 50 mL of toluene, and the organic layer was added with 50 mL of 4 N oxyhydrogen.
  • the sodium salt was stirred for 10 minutes, and the organic layer was separated and washed with 50 mL of water.
  • the aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3 ⁇ 50 mL of toluene, and then dried and concentrated to 10 mL. The solid was completely precipitated, filtered and washed with n-glycol to give a white solid, 6.73 g, yield 65%.
  • the yellow diazonium salt solution obtained in Example 24 was slowly dropped into 200 mL of 50% sulfuric acid at 90 ° C, stirred at 90 ° C for 30 minutes, extracted with 2 X 50 mL of toluene, and the organic layer was added with 50 mL of 4N sodium hydroxide and stirred for 10 minutes.
  • the organic layer was separated and washed with 50 mL of water, and the aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3 ⁇ 50 mL of toluene, and dried and concentrated to 10 mL of organic layer. Filtered and washed with n-glycol to give a white solid 5.11 g, yield 49%.

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Abstract

Disclosed is a method for preparing 3-bromo-5-chlorophenol showed as formula (1), which includes the following step: hydrolyzing compound (3) in acidic medium to obtain compound (1), in which X- is Cl-, Br-, HSO4 - or NO3 -. The preparing method has advantage of low cost, easy obtained raw material, convenient handling, easy purified product, and the method is easy to be scale up. Further more, higher yield and purity can be obtained.

Description

一种 3-溴 -5-氯苯酚的制备方法 技术领域  Method for preparing 3-bromo-5-chlorophenol
本发明涉及一种有机合成中间体的制备方法， 具体的涉及一种 3-溴 -5- 氯苯酚的制备方法。 背景技术  The invention relates to a preparation method of an organic synthesis intermediate, in particular to a preparation method of 3-bromo-5-chlorophenol. Background technique
3-溴 -5-氯苯酚， 英文名称为 3-Bromo-5-chlorophenol， CAS 为 56962-04-0, 其结构式如式 1所示。  3-bromo-5-chlorophenol, English name is 3-Bromo-5-chlorophenol, CAS is 56962-04-0, and its structural formula is shown in Formula 1.
Figure imgf000003_0001
Figure imgf000003_0001
1 化合物 1作为一种重要的有机合成中间体， 专利 US2006025462描述了 将其用于制备一种治疗由免疫缺陷病毒引起的疾病的药物，专利 2007078128 描述了将其用于制备一种非核苷类逆转录酶抑制剂，专利 WO2007145569描 述了将其用于制备治疗阿尔茨海默病轻度认知功能障碍疾病的一种药物， 市 场需求潜力非常大， 但其合成方法均存在一定的局限性。 目前， 3-溴 -5-氯苯 酚几条主要的合成路线如下：  1 Compound 1 as an important organic synthesis intermediate, the patent US2006025462 describes its use in the preparation of a medicament for the treatment of diseases caused by immunodeficiency virus, and patent 2007078128 describes its use in the preparation of a non-nucleoside reversal. The enzyme inhibitor, patent WO2007145569 describes a drug for the treatment of mild cognitive impairment of Alzheimer's disease. The market demand potential is very large, but its synthesis methods have certain limitations. At present, several main synthetic routes for 3-bromo-5-chlorophenol are as follows:
1. 文献 J. Am. Chem. Soc, 2003, 125, 7792描述了以间氯溴苯为原料，经 过硼酸酯化再进行臭氧化反应得到 3-溴 -5-氯苯酚的方法，所用硼试剂价格昂 贵， 臭氧化反应的副反应较多， 且需投入新型设备， 耗能较高。
Figure imgf000004_0001
1. Document J. Am. Chem. Soc, 2003, 125, 7792 describes the use of m-chlorobromobenzene as a starting material, followed by boronation and ozonation to give 3-bromo-5-chlorophenol. The reagents are expensive, the side reactions of the ozonation reaction are many, and new equipment is required, which consumes a lot of energy.
Figure imgf000004_0001
2. 文献 J. Chem. Soc, 1926, 2078描述了以 3-氨基 -5-氯苯酚为原料经桑 德迈耳反应合成 3-溴 -5-氯苯酚的方法， 但所用原料不易得， 且收率较低。  2. Document J. Chem. Soc, 1926, 2078 describes a method for the synthesis of 3-bromo-5-chlorophenol by Sandermeer reaction using 3-amino-5-chlorophenol as a starting material, but the starting materials are not readily available, and The yield is low.
c
Figure imgf000004_0002
Br c
Figure imgf000004_0002
Br
3. 专利 WO 2006010545描述了以 3-氯 -5-氟溴苯为原料， 先进行甲氧基 取代氟官能团，然后在酸性条件下脱甲基制备 3-溴 -5-氯苯酚的方法， 该方法 收率偏低， 且原料 3-氯 -5-氟溴苯合成繁琐。
Figure imgf000004_0003
上述三条合成路线，均存在一定的局限性，给 3-溴 -5-氯苯酚的工业化生 产带来一定的困难。 发明内容 3. Patent WO 2006010545 describes a process for preparing 3-bromo-5-chlorophenol by using 3-chloro-5-fluorobromobenzene as a starting material, first performing a methoxy-substituted fluoro functional group, and then demethylating under acidic conditions. The method yield is low, and the synthesis of 3-chloro-5-fluorobromobenzene is cumbersome.
Figure imgf000004_0003
The above three synthetic routes all have certain limitations, which brings certain difficulties to the industrial production of 3-bromo-5-chlorophenol. Summary of the invention
本发明所要解决的技术问题是为了克服现有的 3-溴 -5-氯苯酚合成路线 中成本较高、 副反应较多、 操作复杂、 耗能较高、 原料不易得及收率较低的 缺陷， 提供了一种 3-溴 -5-氯苯酚的制备方法， 其成本较低、 原料易得、 操作 方便、 产物易纯化和易放大生产， 还可以达到比较高的产率。  The technical problem to be solved by the invention is to overcome the high cost, the side reaction, the complicated operation, the high energy consumption, the low raw material and the low yield of the existing 3-bromo-5-chlorophenol synthesis route. The defect provides a preparation method of 3-bromo-5-chlorophenol, which has the advantages of low cost, easy availability of raw materials, convenient operation, easy purification of products and easy scale-up production, and can also achieve relatively high yield.
本发明涉及一种如式 1所示的 3-溴 -5-氯苯酚的制备方法，其包含下列歩 骤： 化合物 3在酸性介质中进行水解反应即可制得化合物 1 ;
Figure imgf000005_0001
The present invention relates to a process for the preparation of 3-bromo-5-chlorophenol as shown in Formula 1, which comprises the following steps: Compound 3 is hydrolyzed in an acidic medium to obtain Compound 1;
Figure imgf000005_0001
3 1  3 1
其中， X—为 CI—、 Br 、 HS04—或 N03—。 Where X—is CI—, Br, HS0 4 — or N0 3 —.
其中，所述的水解反应的方法和条件可以为本领域重氮盐水解反应的常 规方法和条件， 本发明特别优选下述条件：  Wherein, the method and conditions of the hydrolysis reaction may be the conventional methods and conditions for the hydrolysis reaction of the diazonium salt in the field, and the following conditions are particularly preferred in the present invention:
所述的酸性介质中的酸的用量较佳的为化合物 3的摩尔量的 1〜20倍， 更佳的为 8〜12倍； 所述的酸性介质可选用各种比例的硫酸水溶液、 或硫酸 水溶液与有机惰性溶剂形成的混合溶液；  The acid in the acidic medium is preferably used in an amount of from 1 to 20 times, more preferably from 8 to 12 times, the molar amount of the compound 3; the acidic medium may be selected from various ratios of sulfuric acid aqueous solution or sulfuric acid. a mixed solution of an aqueous solution and an organic inert solvent;
其中， 所述的硫酸水溶液的质量百分比较佳的为 5%〜90%， 更佳的为 30%〜60%； 所述的有机惰性溶剂较佳的选自芳香烃、醚和卤代垸烃中的一种 或多种； 其中所述的芳香烃优选甲苯和 /或二甲苯， 所述的醚优选四氢呋喃、 乙二醇二甲醚和二恶垸中的一种或多种， 所述的卤代垸烃优选二氯甲垸、 氯 仿和 1,2-二氯乙垸中的一种或多种。  Wherein, the mass percentage of the aqueous sulfuric acid solution is preferably 5% to 90%, more preferably 30% to 60%; and the organic inert solvent is preferably selected from the group consisting of aromatic hydrocarbons, ethers and halogenated anthracene hydrocarbons. One or more of the above; wherein the aromatic hydrocarbon is preferably toluene and/or xylene, and the ether is preferably one or more of tetrahydrofuran, ethylene glycol dimethyl ether and dioxan, The halogenated hydrocarbon is preferably one or more of dichloromethane, chloroform and 1,2-dichloroacetam.
所述的水解反应的温度较佳的为 60°C〜150°C， 更佳的为 80°C〜120°C ; 反应的时间以检测反应完全为止， 较佳的以 HPLC检测反应物消耗完为止。  The temperature of the hydrolysis reaction is preferably from 60 ° C to 150 ° C, more preferably from 80 ° C to 120 ° C. The reaction time is until the reaction is completed. Preferably, the reactants are consumed by HPLC. until.
此歩骤在反应完全之后， 只需要简单的后处理如萃取、 浓缩、 过滤、 干 燥等方法即可得到纯的化合物 1。  After the reaction is completed, pure compound 1 can be obtained by a simple post-treatment such as extraction, concentration, filtration, and drying.
本发明中， 化合物 3是重氮盐类化合物， 根据本领域常规操作方法， 一 般不分离纯化而直接使用， 因此在上述化合物 1的制备方法中， 与化合物 3 相关的试剂的用量， 均以制备它的原料完全转化后得到的量来计算， 在本发 明中， 制备化合物 3的原料较佳的为下述的化合物 2。  In the present invention, the compound 3 is a diazonium salt compound, and is generally used without isolation and purification according to a conventional operation method in the art, and therefore, in the preparation method of the above compound 1, the amount of the reagent related to the compound 3 is prepared by The amount of the raw material obtained after the complete conversion of the raw material is calculated. In the present invention, the starting material for preparing the compound 3 is preferably the following compound 2.
本发明中， 所述的化合物 3可由下列方法制得： 化合物 2在酸性条件下 进行重氮化反应即可；
Figure imgf000006_0001
In the present invention, the compound 3 can be obtained by the following method: Compound 2 can be subjected to diazotization reaction under acidic conditions;
Figure imgf000006_0001
2 3 其中， X 为 CI—、 Br 、 HS04—或 N03—。 2 3 where X is CI—, Br, HS0 4 — or N0 3 —.
其中，所述的重氮化反应的方法和条件可为本领域制备重氮盐反应的常 规方法和条件。 优选的方法和条件如下：  Among them, the method and conditions of the diazotization reaction can be a conventional method and condition for preparing a diazonium salt reaction in the art. The preferred methods and conditions are as follows:
在强酸性水溶液中，化合物 2与亚硝酸钠或亚硝酸正丁酯进行重氮化反 应， 形成重氮盐化合物 3; 其中， 与亚硝酸钠反应的方法是较佳的方法。  In a strongly acidic aqueous solution, the compound 2 is subjected to a diazotization reaction with sodium nitrite or n-butyl nitrite to form a diazonium salt compound 3; wherein a method of reacting with sodium nitrite is a preferred method.
在所述的化合物 2与亚硝酸钠的反应中，化合物 2与亚硝酸钠的摩尔比 较佳的为 1:1〜1:3， 更佳的为 1:1〜1:2； 反应在强酸酸性条件下有利于反应的 进行并保证重氮盐的稳定性， 所述的强酸较佳的为盐酸、 氢溴酸、 硝酸和硫 酸中的一种或多种， 优选硫酸； 所述的硫酸的用量较佳的为化合物 2的摩尔 量的 1〜100倍， 更佳的为 8〜20倍； 所述的反应的温度较佳的为 -5°C〜50°C， 优选 0°C〜10°C ; 所述的反应的时间以检测反应完全为止， 较佳的为以 HPLC 检测反应物消耗完为止。 In the reaction of the compound 2 with sodium nitrite, the molar ratio of the compound 2 to the sodium nitrite is preferably 1:1 to 1:3, more preferably 1:1 to 1:2; The conditions are favorable for the progress of the reaction and ensure the stability of the diazonium salt. The strong acid is preferably one or more of hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid, preferably sulfuric acid; Preferably, the molar amount of the compound 2 is from 1 to 100 times, more preferably from 8 to 20 times; the temperature of the reaction is preferably from -5 ° C to 50 ° C, preferably from 0 ° C to 10 °. C ; The reaction time is determined until the reaction is completed, and it is preferred to detect the consumption of the reactants by HPLC.
本发明中， 所述的化合物 2可由下列方法制得：
Figure imgf000006_0002
In the present invention, the compound 2 can be obtained by the following method:
Figure imgf000006_0002
4 2  4 2
将化合物 4进行还原反应即可。 The compound 4 can be subjected to a reduction reaction.
其中，所述的还原反应的方法和条件可以为本领域常规的硝基还原反应 的方法和条件， 优选的方法和条件如下：  Wherein, the method and conditions of the reduction reaction may be the methods and conditions for the conventional nitro reduction reaction in the art, and the preferred methods and conditions are as follows:
在有机惰性溶剂中， 在还原剂、 或者催化剂和氢源的作用下， 化合物 4 进行还原反应， 形成化合物 2。 In an organic inert solvent, under the action of a reducing agent, or a catalyst and a hydrogen source, Compound 4 A reduction reaction is carried out to form Compound 2.
其中， 所述的还原剂较佳的为还原铁粉、 锌粉、 连二亚硫酸钠、 二水合 氯化亚锡、 硼氢化钠和氢化铝锂的一种或多种， 最佳的为还原铁粉； 所述的 还原剂的用量较佳的为化合物 4摩尔量的 1〜20倍， 更佳的为 5〜10倍； 所述 的催化剂较佳的为钯碳（Pd-C)、 铂碳（Pt-C)和兰尼镍（Raney-Ni) 中的一 种或多种， 优选兰尼镍 （Raney-Ni); 催化剂的用量较佳的为化合物 4的摩 尔量的 0.01〜1倍， 更佳的为 0.1〜0.2倍； 所述的氢源较佳的为氢气、水合肼、 甲酸钠、 甲酸、 甲酸铵和甲酸三乙胺盐中的一种或多种， 最佳的为水合肼； 所述的有机惰性溶剂较佳的为低级醇和 /或低级酸，更佳的为低级酸；所述低 级酸优选甲酸、 乙酸、 丙酸、 异丙酸和正丁酸中的一种或多种， 更佳的为乙 酸； 所述的有机惰性溶剂与化合物 4的体积质量比较佳为 l〜100ml/g， 更佳 的为 8〜20ml/g。  Wherein, the reducing agent is preferably one or more of reduced iron powder, zinc powder, sodium dithionite, stannous chloride dihydrate, sodium borohydride and lithium aluminum hydride, and most preferably reduced iron powder The reducing agent is preferably used in an amount of from 1 to 20 times, more preferably from 5 to 10 times, the molar amount of the compound; the catalyst is preferably palladium carbon (Pd-C) or platinum carbon ( One or more of Pt-C) and Raney-Ni, preferably Raney-Ni; the amount of the catalyst is preferably 0.01 to 1 times the molar amount of the compound 4, Preferably, the hydrogen source is preferably one or more of hydrogen, hydrazine hydrate, sodium formate, formic acid, ammonium formate and triethylamine formate, and most preferably hydrazine hydrate; The organic inert solvent is preferably a lower alcohol and/or a lower acid, more preferably a lower acid; the lower acid is preferably one or more of formic acid, acetic acid, propionic acid, isopropyl acid and n-butyric acid, Preferably, it is acetic acid; the volume of the organic inert solvent and the compound 4 is preferably from 1 to 100 ml/g, more preferably 8~20ml / g.
所述的还原反应的温度较佳的为 0°C〜80°C， 更佳的为 10°C〜30°C ; 所述 的还原反应的时间以检测反应完全为止， 较佳的以 TLC检测反应物消耗完 为止。  The temperature of the reduction reaction is preferably from 0 ° C to 80 ° C, more preferably from 10 ° C to 30 ° C; the time of the reduction reaction is detected until the reaction is completed, preferably by TLC. The reactants are consumed.
本发明中， 所述的化合物 4可参照文献 Gazz. Chim. Ital.， 1874， 4， 341 的方法合成获得。  In the present invention, the compound 4 can be synthesized by the method of Gazz. Chim. Ital., 1874, 4, 341.
除特殊说明外， 本发明涉及的试剂和原料均市售可得。  Unless otherwise stated, the reagents and starting materials of the present invention are commercially available.
本发明的积极进歩效果在于： 本发明的制备方法可避免昂贵的试剂或原 料， 从而降低成本， 且原料易得、 操作方法简单方便、 产物易纯化， 不仅适 合实验室少量制备， 也适合工业化大规模生产； 其还可以达到较高的产率和 纯度。 具体实施方式  The positive effect of the invention is that: the preparation method of the invention can avoid expensive reagents or raw materials, thereby reducing the cost, and the raw materials are easy to obtain, the operation method is simple and convenient, the product is easy to be purified, and is not only suitable for laboratory preparation, but also suitable for industrialization. Mass production; it also achieves higher yields and purity. detailed description
下面用实施例来进一歩说明本发明， 但本发明并不受其限制。  The invention will be further illustrated by the following examples, but the invention is not limited thereto.
其中所述的常温为 20〜40°C， 常压为 0.8atm〜1.2atm。 实施例 1 3-溴 -5-氯苯胺的制备 The normal temperature is 20 to 40 ° C, and the normal pressure is 0.8 to 1.2 atm. Example 1 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 （23.6 g， 0.1 mol) 加入 200 mL冰醋酸， 冷却到 0°C后 加入还原铁粉 （33.6 g， 0.6 mol), 0°C搅拌 2h后升温至室温搅拌 16h， 硅藻 土过滤并以 100 mL乙酸乙酯洗涤，合并滤液浓缩后再以 200 mL乙酸乙酯溶 解过滤， 滤液浓缩得褐色液体 19.2 g， 收率 93 %。  3-bromo-5-chloronitrobenzene (23.6 g, 0.1 mol) was added to 200 mL of glacial acetic acid. After cooling to 0 ° C, reduced iron powder (33.6 g, 0.6 mol) was added. After stirring at 0 ° C for 2 h, the temperature was raised to room temperature. After stirring for 16 h, celite was filtered and washed with ethyl acetate (100 mL), and the filtrate was concentrated, and then filtered and evaporated to ethyl acetate (200 mL).
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 3.80 (br, 2H, NH 2 ), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 ( t, J=1.40Hz, 1H, Ph).
HPLC: 91.5%  HPLC: 91.5%
实施例 2 3-溴 -5-氯苯胺的制备  Example 2 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 （23.6 g， 0.1 mol) 加入 200 mL无水乙醇， 冷却到 0°C 后加入还原 Raney-Ni (0.59 g， 0.01 mol), 0°C搅拌下滴入水合肼 23 mL， 0°C 搅拌 2h后升温至 80°C反应 lh， 过滤滤液浓缩后得 20.9 g黄褐色液体， 收率 98%。  3-bromo-5-chloronitrobenzene (23.6 g, 0.1 mol) was added to 200 mL of absolute ethanol, cooled to 0 ° C, then reduced Raney-Ni (0.59 g, 0.01 mol) was added, and the mixture was added dropwise with stirring at 0 °C. 23 mL of hydrazine hydrate, stirred at 0 ° C for 2 h, then heated to 80 ° C for 1 h, and the filtrate was concentrated to give 20.9 g of a brownish brown liquid, yield 98%.
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 3.80 (br, 2H, NH 2 ), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 ( t, J=1.40Hz, 1H, Ph).
HPLC: 93.2%  HPLC: 93.2%
实施例 3 3-溴 -5-氯苯胺的制备  Example 3 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 (2.36 g， 0.01 mol) 加入 10 mL无水乙腈和 5 mL水， 再加入连二亚硫酸钠 （6.96 g， 0.04 mol) 升温至 80°C反应 2h， 浓缩后加入 10 mL水， 以 3 X 15 mL乙酸乙酯萃取， 有机层干燥浓缩后得 1.16 g黄褐色 固体， 收率 56%。  3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 10 mL of anhydrous acetonitrile and 5 mL of water, then sodium dithionite (6.96 g, 0.04 mol) was added and the mixture was warmed to 80 ° C for 2 h. After adding 10 mL of water and extracting with 3 X 15 mL of ethyl acetate, the organic layer was dried and concentrated to give 1.16 g of a tan solid.
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 3.80 (br, 2H, NH 2 ), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 ( t, J=1.40Hz, 1H, Ph).
HPLC: 86.4%  HPLC: 86.4%
实施例 4 3-溴 -5-氯苯胺的制备  Example 4 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯（2.36 g， 0.01 mol)加入 30 mL无水乙醇， 再加入二水 合氯化亚锡 （6.78 g， 0.03 mol) 升温至 80°C反应 2h， 浓缩后加入乙酸乙酯 回流 30分钟过滤， 滤液浓缩后得 1.63 g黄褐色液体， 收率 79 %。 3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 30 mL of absolute ethanol, then dihydrate was added. The stannous chloride (6.78 g, 0.03 mol) was heated to 80 ° C for 2 h, concentrated, and then added with ethyl acetate and refluxed for 30 min, filtered, and the filtrate was concentrated to give 1.63 g of a brownish brown liquid.
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 3.80 (br, 2H, NH 2 ), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 ( t, J=1.40Hz, 1H, Ph).
HPLC: 90.2%  HPLC: 90.2%
实施例 5 3-溴 -5-氯苯胺的制备  Example 5 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 （2.36 g， 0.01 mol) 加入 30 mL乙酸乙酯， 再加入 1% 钯碳 0.03 mol, 室温下常压氢化 lh， 过滤， 滤液浓缩后得 2.06 g黑色液体， 收率 99%。  3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 30 mL of ethyl acetate, and then added with 1% palladium carbon (0.03 mol), hydrogenated at room temperature for 1 h under normal pressure, filtered, and concentrated to give 2.06 g of a black liquid. , yield 99%.
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 3.80 (br, 2H, NH 2 ), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 ( t, J=1.40Hz, 1H, Ph).
HPLC: 83.9%  HPLC: 83.9%
实施例 6 3-溴 -5-氯苯胺的制备  Example 6 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 （2.36 g， 0.01 mol) 加入 2.36mL无水乙醇， 再加入硼 氢化钠（O.Olmol)升温至 30°C反应 2h， 浓缩后加入 lO mL水， 以 3 X 15 mL 乙酸乙酯萃取， 有机层干燥浓缩后得黄褐色固体， 收率 53 %。 HPLC: 90% 实施例 7 3-溴 -5-氯苯胺的制备  3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 2.36 mL of absolute ethanol, and sodium borohydride (O.Olmol) was added to raise the temperature to 30 ° C for 2 h. After concentration, 10 mL of water was added to 3 X 15 mL of ethyl acetate was extracted, and the organic layer was dried and concentrated to give a brown solid. HPLC: 90% Example 7 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 (2.36 g， 0.01 mol) 加入 236mL无水乙醇， 再加入硼 氢化钠（0.2mol)在 10°C反应 2h， 浓缩后加入 lO mL水， 以 3 X 15 mL乙酸 乙酯萃取， 有机层干燥浓缩后得黄褐色固体， 收率 50%。 HPLC: 90.2%  3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 236 mL of absolute ethanol, then sodium borohydride (0.2 mol) was added and reacted at 10 ° C for 2 h. After concentration, 10 mL of water was added to 3 X 15 The mixture was extracted with EtOAc (EtOAc)EtOAc. HPLC: 90.2%
实施例 8 3-溴 -5-氯苯胺的制备  Example 8 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 （23.6 g， 0.1 mol) 加入 189mL无水乙醇， 冷却到 0°C 后加入还原 Raney-Ni ( 0.001 mol) , 0°C搅拌下加入甲酸铵 0.3mol， 0°C搅拌 2h后升温至 80°C反应 lh， 过滤滤液浓缩后得黄褐色液体， 收率 93 %。  3-bromo-5-chloronitrobenzene (23.6 g, 0.1 mol) was added to 189 mL of absolute ethanol, cooled to 0 ° C, then reduced Raney-Ni (0.001 mol) was added, and 0.3 mol of ammonium formate was added with stirring at 0 ° C. After stirring at 0 ° C for 2 h, the temperature was raised to 80 ° C for 1 h, and the filtrate was concentrated to give a brownish brown liquid, yield 93%.
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph). HPLC: 93.2% 3⁄4 NMR (300MHz, CDC1 3 ) δ: 3.80 (br, 2H, NH 2 ), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 ( t, J=1.40Hz, 1H, Ph). HPLC: 93.2%
实施例 9 3-溴 -5-氯苯胺的制备  Example 9 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 （23.6 g， O.l mol) 加入 472mL丙酸， 冷却到 0°C后加 入还原铁粉（0.5mol)， 0°C搅拌 2h后升温至室温搅拌 16h， 硅藻土过滤并以 100 mL乙酸乙酯洗涤， 合并滤液浓缩后再以 200 mL乙酸乙酯溶解过滤， 滤 液浓缩得褐色液体， 收率 90%。  3-bromo-5-chloronitrobenzene (23.6 g, Ol mol) was added to 472 mL of propionic acid. After cooling to 0 ° C, reduced iron powder (0.5 mol) was added. After stirring at 0 ° C for 2 h, the temperature was raised to room temperature and stirred for 16 h. The celite was filtered and washed with ethyl acetate (100 mL), and the filtrate was concentrated and then filtered and evaporated to ethyl ether.
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 3.80 (br, 2H, NH 2 ), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 ( t, J=1.40Hz, 1H, Ph).
HPLC: 92.2%  HPLC: 92.2%
实施例 10 3-溴 -5-氯苯胺的制备  Example 10 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 （23.6 g， O.l mol) 加入 200 mL无水乙醇， 冷却到 0°C 后加入还原 Raney-Ni (O.lmol), 0°C搅拌下加入甲酸 20ml， 0°C搅拌 2h后升 温至 80°C反应 lh， 过滤滤液浓缩后得黄褐色液体， 收率 95 %。  3-bromo-5-chloronitrobenzene (23.6 g, Ol mol) was added to 200 mL of absolute ethanol, cooled to 0 ° C, then reduced Raney-Ni (O.lmol) was added, and 20 ml of formic acid was added with stirring at 0 ° C. After stirring at 0 ° C for 2 h, the temperature was raised to 80 ° C for 1 h, and the filtrate was concentrated to give a tan liquid, yield 95%.
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 3.80 (br, 2H, NH 2 ), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 ( t, J=1.40Hz, 1H, Ph).
HPLC: 93.2%  HPLC: 93.2%
实施例 11 3-溴 -5-氯苯胺的制备  Example 11 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 （23.6 g， O.l mol) 加入 200 mL无水乙醇， 冷却到 0°C 后加入还原 Raney-Ni (0.02mol)， 0°C搅拌下加入水合肼 23ml， 0°C搅拌 2h 后升温至 80°C反应 lh， 过滤滤液浓缩后得黄褐色液体， 收率 95 %。  3-bromo-5-chloronitrobenzene (23.6 g, Ol mol) was added to 200 mL of absolute ethanol, cooled to 0 ° C, then reduced Raney-Ni (0.02 mol) was added, and 23 ml of hydrazine hydrate was added with stirring at 0 ° C. After stirring at 0 ° C for 2 h, the temperature was raised to 80 ° C for 1 h, and the filtrate was concentrated to give a tan liquid, yield 95%.
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 3.80 (br, 2H, NH 2 ), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 ( t, J=1.40Hz, 1H, Ph).
HPLC: 93.2%  HPLC: 93.2%
实施例 12 3-溴 -5-氯苯胺的制备  Example 12 Preparation of 3-bromo-5-chloroaniline
3-溴 -5-氯硝基苯 （23.6 g， O.l mol) 加入 200 mL异丙酸， 冷却到 0°C后 加入还原铁粉 （lmol), 0°C搅拌 2h后升温至室温搅拌 16h， 硅藻土过滤并 以 100 mL乙酸乙酯洗涤， 合并滤液浓缩后再以 200 mL乙酸乙酯溶解过滤， 滤液浓缩得褐色液体， 收率 90%。 3-bromo-5-chloronitrobenzene (23.6 g, Ol mol) was added to 200 mL of isopropyl acid, cooled to 0 ° C, then reduced iron powder (1 mol) was added, stirred at 0 ° C for 2 h, then warmed to room temperature and stirred for 16 h. Diatomaceous earth filtered After washing with 100 mL of ethyl acetate, the combined filtrate was concentrated and then filtered and evaporated to ethyl ether.
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 3.80 (br, 2H, NH 2 ), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 ( t, J=1.40Hz, 1H, Ph).
HPLC: 92.2%  HPLC: 92.2%
实施例 13 化合物 3 (X—为 Br ) 的制备  Example 13 Preparation of Compound 3 (X- is Br)
化合物 2 ( 10.3 g， 0.05 mol)加入 100 mL 50%氢溴酸升温至 100°C搅拌 至溶解， 冷却至 0°C， 控制温度 10°C以下， 分批加入亚硝酸钠固体（4.14 g， 0.05mol) , -5°C继续搅拌 30分钟， 得黄色重氮盐溶液。  Compound 2 (10. 3 g, 0.05 mol) was added to 100 mL of 50% hydrobromic acid to 100 ° C, stirred until dissolved, cooled to 0 ° C, controlled temperature below 10 ° C, and added sodium nitrite solid (4.14 g, Stirring was continued for 30 minutes at -5 ° C to obtain a yellow diazonium salt solution.
实施例 14 3-溴 -5-氯苯酚的制备  Example 14 Preparation of 3-bromo-5-chlorophenol
将实施例 13所得黄色重氮盐溶液缓慢滴入 60°C的 5 %硫酸 （0.05mol) 和 200 mL***混合溶液中， 60°C搅拌 30分钟，静至分液，有机层加入 50 mL 4N氢氧化钠搅拌 10分钟， 分液并以 50 mL水洗涤有机层， 合并水层并以 4N盐酸酸化至 pH为 4左右， 以 3 X 50 mL***萃取， 有机层干燥浓缩至 10 mL滴加正庚垸至固体全部析出， 过滤并以正庚垸洗涤干燥得白色固体， 收 率 72%。  The yellow diazonium salt solution obtained in Example 13 was slowly dropped into a mixed solution of 5% sulfuric acid (0.05 mol) and 200 mL of diethyl ether at 60 ° C, stirred at 60 ° C for 30 minutes, and allowed to stand for separation. The organic layer was added to 50 mL of 4N. Stir the sodium hydroxide for 10 minutes, separate the layers and wash the organic layer with 50 mL of water. The combined aqueous layer was acidified with 4N hydrochloric acid to pH 4, extracted with 3 X 50 mL of diethyl ether, and dried and concentrated to 10 mL. The gadolinium was completely precipitated, filtered and washed with n-glycol to give a white solid, yield 72%.
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph)， 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph), 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t , J=1.46Hz, 1H, Ph).
HPLC: 99.1%  HPLC: 99.1%
实施例 15 化合物 3 (X—为 N03— ) 的制备 Example 15 Preparation of Compound 3 (X—N0 3 — )
化合物 2 ( 10.3 g， 0.05 mol)加入 100 mL 50%硝酸升温至 100 °C搅拌至 溶解， 冷却至 0°C， 控制温度 10°C以下， 分批加入亚硝酸钠固体 （4.14 g， 0.15mol) , 50°C继续搅拌 30分钟， 得黄色重氮盐溶液。  Compound 2 (10. 3 g, 0.05 mol) was added to 100 mL of 50% nitric acid, heated to 100 °C, stirred until dissolved, cooled to 0 ° C, controlled temperature below 10 ° C, and added sodium nitrite solid (4.14 g, 0.15 mol) The mixture was further stirred at 50 ° C for 30 minutes to obtain a yellow diazonium salt solution.
实施例 16 3-溴 -5-氯苯酚的制备  Example 16 Preparation of 3-bromo-5-chlorophenol
将实施例 15所得黄色重氮盐溶液缓慢滴入 150°C的 90%硫酸 （lmol) 和 200 mL甲苯混合溶液中， 150°C搅拌 30分钟， 静至分液， 有机层加入 50 mL 4N氢氧化钠搅拌 10分钟， 分液并以 50 mL水洗涤有机层， 合并水层并 以 4N盐酸酸化至 pH为 4左右， 以 3 X 50 mL甲苯萃取， 有机层干燥浓缩至 10 mL滴加正庚垸至固体全部析出， 过滤并以正庚垸洗涤干燥得白色固体， 收率 70% The yellow diazonium salt solution obtained in Example 15 was slowly dropped into a mixed solution of 90% sulfuric acid (1 mol) and 200 mL of toluene at 150 ° C, stirred at 150 ° C for 30 minutes, and allowed to stand for separation, and the organic layer was added to 50. The mixture was stirred for 10 minutes with mL 4N sodium hydroxide, and the organic layer was separated and washed with 50 mL of water. The aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3 X 50 mL of toluene, and the organic layer was dried and concentrated to 10 mL. Add n-glum to all solids, filter and wash with n-glycol to dry a white solid, yield 70%
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph)， 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph), 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t , J=1.46Hz, 1H, Ph).
HPLC: 99.1%  HPLC: 99.1%
实施例 17 化合物 3 (X—为 N03— ) 的制备 Example 17 Preparation of Compound 3 (X—N0 3 — )
化合物 2 ( 10.3 g， 0.05 mol)加入 100 mL 50%硝酸升温至 100 °C搅拌至 溶解， 冷却至 0°C， 控制温度 10°C以下， 分批加入亚硝酸钠固体 （4.14 g， 0.15mol) , 30°C继续搅拌 30分钟， 得黄色重氮盐溶液。  Compound 2 (10. 3 g, 0.05 mol) was added to 100 mL of 50% nitric acid, heated to 100 °C, stirred until dissolved, cooled to 0 ° C, controlled temperature below 10 ° C, and added sodium nitrite solid (4.14 g, 0.15 mol) The mixture was stirred at 30 ° C for 30 minutes to obtain a yellow diazonium salt solution.
实施例 18 3-溴 -5-氯苯酚的制备  Example 18 Preparation of 3-bromo-5-chlorophenol
将实施例 17所得黄色重氮盐溶液缓慢滴入 80°C的 90%硫酸 （0.4mol) 和 200 mL氯仿混合溶液中， 80°C搅拌 30分钟，静至分液，有机层加入 50 mL 4N氢氧化钠搅拌 10分钟， 分液并以 50 mL水洗涤有机层， 合并水层并以 4N盐酸酸化至 pH为 4左右， 以 3 X 50 mL氯仿萃取， 有机层干燥浓缩至 10 mL滴加正庚垸至固体全部析出， 过滤并以正庚垸洗涤干燥得白色固体， 收 率 70.5 %。  The yellow diazonium salt solution obtained in Example 17 was slowly dropped into a mixed solution of 90% sulfuric acid (0.4 mol) and 200 mL of chloroform at 80 ° C, stirred at 80 ° C for 30 minutes, and allowed to stand for separation. The organic layer was added to 50 mL of 4N. Stir the sodium hydroxide for 10 minutes, separate the layers and wash the organic layer with 50 mL of water. The combined aqueous layer was acidified with 4N hydrochloric acid to pH 4, extracted with 3 X 50 mL chloroform, and dried and concentrated to 10 mL. The gadolinium was completely precipitated, filtered and washed with n-glycol to give a white solid, yield 7.5%.
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph)， 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph), 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t , J=1.46Hz, 1H, Ph).
HPLC: 99.1%  HPLC: 99.1%
实施例 19 化合物 3 (X—为 N03— ) 的制备 Example 19 Preparation of Compound 3 (X—N0 3 — )
化合物 2 ( 10.3 g， 0.05 mol)加入 100 mL 50%硝酸升温至 100 °C搅拌至 溶解， 冷却至 0°C， 控制温度 10°C以下， 分批加入亚硝酸钠固体 （4.14 g， 0.15mol) , 30°C继续搅拌 30分钟， 得黄色重氮盐溶液。  Compound 2 (10. 3 g, 0.05 mol) was added to 100 mL of 50% nitric acid, heated to 100 °C, stirred until dissolved, cooled to 0 ° C, controlled temperature below 10 ° C, and added sodium nitrite solid (4.14 g, 0.15 mol) The mixture was stirred at 30 ° C for 30 minutes to obtain a yellow diazonium salt solution.
实施例 20 3-溴 -5-氯苯酚的制备 将实施例 19所得黄色重氮盐溶液缓慢滴入 120 °C的 40%硫酸 （0.6mol) 和 200 mL氯仿混合溶液中， 120°C搅拌 30分钟， 静至分液， 有机层加入 50 mL 4N氢氧化钠搅拌 10分钟， 分液并以 50 mL水洗涤有机层， 合并水层并 以 4N盐酸酸化至 pH为 4左右， 以 3 X 50 mL氯仿萃取， 有机层干燥浓缩至 10 mL滴加正庚垸至固体全部析出， 过滤并以正庚垸洗涤干燥得白色固体， 收率 71 %。 Example 20 Preparation of 3-bromo-5-chlorophenol The yellow diazonium salt solution obtained in Example 19 was slowly dropped into a mixed solution of 40% sulfuric acid (0.6 mol) and 200 mL of chloroform at 120 ° C, stirred at 120 ° C for 30 minutes, and allowed to stand for separation. The organic layer was added to 50 mL of 4N. Stir the sodium hydroxide for 10 minutes, separate the layers and wash the organic layer with 50 mL of water. The combined aqueous layer was acidified with 4N hydrochloric acid to pH 4, extracted with 3 X 50 mL chloroform, and dried and concentrated to 10 mL. The gadolinium was completely precipitated from the solid, filtered and washed with n-heptane to give a white solid, yield 71%.
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph): 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph) : 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t , J=1.46Hz, 1H, Ph).
HPLC: 99.1%  HPLC: 99.1%
实施例 21 化合物 3 (X—为 HS04— ) 的制备 Example 21 Preparation of Compound 3 (X—HS0 4 — )
化合物 2 ( 10.3 g， 0.05 mol)加入 100 mL 50%硫酸升温至 100 °C搅拌至 溶解， 冷却至 0°C， 控制温度 10°C以下， 分批加入亚硝酸钠固体 （4.14 g， 0.06 mol), 0°C继续搅拌 30分钟， 得黄色重氮盐溶液。  Compound 2 (10. 3 g, 0.05 mol) was added to 100 mL of 50% sulfuric acid, heated to 100 °C, stirred until dissolved, cooled to 0 ° C, controlled temperature below 10 ° C, and added sodium nitrite solid (4.14 g, 0.06 mol) The stirring was continued for 30 minutes at 0 ° C to obtain a yellow diazonium salt solution.
实施例 22 3-溴 -5-氯苯酚的制备  Example 22 Preparation of 3-bromo-5-chlorophenol
将实施例 21所得黄色重氮盐溶液缓慢滴入 90°C50 mL的 30%硫酸和 200 mL甲苯混合溶液中， 90°C搅拌 30分钟，静至分液，有机层加入 50 mL 4N 氢氧化钠搅拌 10分钟， 分液并以 50 mL水洗涤有机层， 合并水层并以 4N 盐酸酸化至 pH为 4左右， 以 3 X 50 mL甲苯萃取，有机层干燥浓缩至 10 mL 滴加正庚垸至固体全部析出， 过滤并以正庚垸洗涤干燥得白色固体 7.78 g， 收率 75 %。  The yellow diazonium salt solution obtained in Example 21 was slowly dropped into 50 ml of a mixed solution of 30% sulfuric acid and 200 mL of toluene at 90 ° C, stirred at 90 ° C for 30 minutes, and allowed to stand for separation. The organic layer was added with 50 mL of 4N sodium hydroxide. After stirring for 10 minutes, the organic layer was separated and washed with 50 mL of water. The aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3×50 mL of toluene, and dried and concentrated to 10 mL. The solid was all precipitated, filtered and washed with n-glycol to give a white solid 7.78 g, yield 75%.
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph): 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph) : 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t , J=1.46Hz, 1H, Ph).
HPLC: 99.1%  HPLC: 99.1%
实施例 23 3-溴 -5-氯苯酚的制备  Example 23 Preparation of 3-bromo-5-chlorophenol
将实施例 21所得黄色重氮盐溶液缓慢滴入 100°C 100 mL的 50%硫酸 中， 90°C搅拌 30分钟， 以 2 X 50 mL甲苯萃取， 有机层加入 50 mL 4N氢氧 化钠搅拌 10分钟， 分液并以 50 mL水洗涤有机层， 合并水层并以 4N盐酸 酸化至 pH为 4左右， 以 3 X 50 mL甲苯萃取， 有机层干燥浓缩至 10 mL滴 加正庚垸至固体全部析出， 过滤并以正庚垸洗涤干燥得白色固体 6.73 g， 收 率 65 %。 The yellow diazonium salt solution obtained in Example 21 was slowly dropped into 100 mL of 100 mL of 50% sulfuric acid, stirred at 90 ° C for 30 minutes, extracted with 2 X 50 mL of toluene, and the organic layer was added with 50 mL of 4 N oxyhydrogen. The sodium salt was stirred for 10 minutes, and the organic layer was separated and washed with 50 mL of water. The aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3×50 mL of toluene, and then dried and concentrated to 10 mL. The solid was completely precipitated, filtered and washed with n-glycol to give a white solid, 6.73 g, yield 65%.
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph) 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph). 3⁄4 NMR (300MHz, CDC1 3 ) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph) 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph).
HPLC: 98.6%  HPLC: 98.6%
实施例 24 化合物 3 (X—为 CD 的制备  Example 24 Compound 3 (X-Preparation of CD)
化合物 2 ( 10.3 g, 0.05 mol) 加入 80 mL浓盐酸， 冷却至 0°C， 控制温 度 10°C以下， 分批加入亚硝酸钠固体 （4.14 g， 0.06 mol), 0°C继续搅拌 30 分钟， 得黄色重氮盐溶液。  Compound 2 (10. 3 g, 0.05 mol) was added to 80 mL of concentrated hydrochloric acid, cooled to 0 ° C, controlled temperature below 10 ° C, sodium nitrite solid (4.14 g, 0.06 mol) was added in portions, and stirring was continued for 30 minutes at 0 °C. , a yellow diazonium salt solution is obtained.
实施例 25 3-溴 -5-氯苯酚的制备  Example 25 Preparation of 3-bromo-5-chlorophenol
将实施例 24所得黄色重氮盐溶液缓慢滴入 90°C 200 mL的 50%硫酸， 90°C搅拌 30分钟， 以 2 X 50 mL甲苯萃取， 有机层加入 50 mL 4N氢氧化钠 搅拌 10分钟， 分液并以 50 mL水洗涤有机层， 合并水层并以 4N盐酸酸化 至 pH为 4左右， 以 3 X 50 mL甲苯萃取， 有机层干燥浓缩至 10 mL滴加正 庚垸至固体全部析出， 过滤并以正庚垸洗涤干燥得白色固体 5.11 g， 收率 49%。  The yellow diazonium salt solution obtained in Example 24 was slowly dropped into 200 mL of 50% sulfuric acid at 90 ° C, stirred at 90 ° C for 30 minutes, extracted with 2 X 50 mL of toluene, and the organic layer was added with 50 mL of 4N sodium hydroxide and stirred for 10 minutes. The organic layer was separated and washed with 50 mL of water, and the aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3×50 mL of toluene, and dried and concentrated to 10 mL of organic layer. Filtered and washed with n-glycol to give a white solid 5.11 g, yield 49%.
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph) 3⁄4 NMR (300MHz, CDC1 3 ) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph)
6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph). 6.93 (t, J = 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph).
HPLC: 98.2%  HPLC: 98.2%

Claims

权利要求 Rights request
1、 一种如式 1所示的 3-溴 -5-氯苯酚的制备方法， 其特征在于包含下列 歩骤： 将化合物 3在酸性介质中进行水解反应即可制得化合物 1 ; A method for producing 3-bromo-5-chlorophenol as shown in Formula 1, which comprises the following steps: Compound 3 is obtained by subjecting Compound 3 to hydrolysis reaction in an acidic medium;
Figure imgf000015_0001
其中， X—为 CI—、 Br 、 HS04—或 N03—。
Figure imgf000015_0001
Where X—is CI—, Br, HS0 4 — or N0 3 —.
2、 如权利要求 1所述的制备方法， 其特征在于： 所述的酸性介质中酸 的用量为化合物 3的摩尔量的 1〜20倍； 所述的酸性介质为硫酸水溶液、 或 硫酸水溶液与有机惰性溶剂形成的混合溶液； 所述的水解反应的温度为 60°C〜150°C ; 所述的反应的时间以检测反应完全为止。  2. The preparation method according to claim 1, wherein the acid medium is used in an amount of 1 to 20 times the molar amount of the compound 3; and the acidic medium is an aqueous solution of sulfuric acid or an aqueous solution of sulfuric acid. a mixed solution formed of an organic inert solvent; the temperature of the hydrolysis reaction is from 60 ° C to 150 ° C; and the reaction time is determined until the reaction is completed.
3、 如权利要求 2所述的制备方法， 其特征在于： 所述的酸性介质中的 酸的用量为化合物 3摩尔量的 8〜12倍； 所述的硫酸水溶液的质量百分比为 5%〜90%；所述的有机惰性溶剂选自芳香烃、醚和卤代垸烃中的一种或多种； 所述的水解反应的温度为 80°C〜120°C。  3. The preparation method according to claim 2, wherein: the acid in the acidic medium is used in an amount of 8 to 12 times the molar amount of the compound; and the mass percentage of the aqueous sulfuric acid solution is 5% to 90. The organic inert solvent is selected from one or more of an aromatic hydrocarbon, an ether and a halogenated hydrocarbon; and the hydrolysis reaction is carried out at a temperature of from 80 ° C to 120 ° C.
4、 如权利要求 1所述的制备方法， 其特征在于： 所述的化合物 3由下 列方法制得： 化合物 2在酸性条件下进行重氮化反应即可；  The method according to claim 1, wherein the compound 3 is obtained by the following method: the compound 2 is subjected to diazotization under acidic conditions;
Figure imgf000015_0002
其中， X—为 CI—、 Br 、 HSO4—或 N03—。
Figure imgf000015_0002
Where X—is CI—, Br, HSO4—or N0 3 —.
5、 如权利要求 4所述的制备方法， 其特征在于： 所述的化合物 3由下 列方法制得： 在强酸性水溶液中， 化合物 2与亚硝酸钠或亚硝酸正丁酯进行 重氮化反应， 形成化合物 3。 The method according to claim 4, wherein the compound 3 is composed of Column method was prepared: In a strongly acidic aqueous solution, Compound 2 was diazotized with sodium nitrite or n-butyl nitrite to form Compound 3.
6、 如权利要求 5所述的制备方法， 其特征在于： 在所述的化合物 2与 亚硝酸钠的反应中： 所述的化合物 2与亚硝酸钠的摩尔比为 1:1〜1:3; 所述 的强酸性水溶液中的强酸为盐酸、 氢溴酸、 硝酸和硫酸中的一种或多种； 所 述的反应的温度为 -5°C〜50°C ; 所述的反应的时间以检测反应完全为止。 6. The preparation method according to claim 5, wherein in the reaction of the compound 2 with sodium nitrite: the molar ratio of the compound 2 to sodium nitrite is 1:1 to 1:3. ; strongly acidic aqueous solution of the strong acid is hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid one or more; the reaction temperature is -5 ° C~50 ° C; the reaction time To detect the reaction is complete.
7、 如权利要求 4所述的制备方法， 其特征在于： 所述的化合物 2由下 列方法制得：  7. The production method according to claim 4, wherein the compound 2 is obtained by the following method:
Figure imgf000016_0001
Figure imgf000016_0001
4 2  4 2
将化合物 4进行还原反应即可。 The compound 4 can be subjected to a reduction reaction.
8、 如权利要求 7所述的制备方法， 其特征在于： 所述的化合物 2由下 列方法制得： 在有机惰性溶剂中， 在还原剂、 或者催化剂和氢源的作用下， 化合物 4进行还原反应， 形成化合物 2。  The method according to claim 7, wherein the compound 2 is obtained by the following method: in an organic inert solvent, the compound 4 is reduced by a reducing agent, or a catalyst and a hydrogen source. The reaction forms Compound 2.
9、 如权利要求 8所述的制备方法， 其特征在于： 所述的还原剂为还原 铁粉、 锌粉、 连二亚硫酸钠、 二水合氯化亚锡、 硼氢化钠和氢化铝锂的一种 或多种； 所述的还原剂的用量为化合物 4摩尔量的 1〜20倍； 所述的催化剂 为钯碳、 铂碳和兰尼镍中的一种或多种； 所述的催化剂的用量为化合物 4的 摩尔量的 0.01〜1倍； 所述的氢源为氢气、 水合肼、 甲酸钠、 甲酸、 甲酸铵和 甲酸三乙胺盐中的一种或多种； 所述的有机惰性溶剂为低级醇和 /或低级酸； 所述的有机惰性溶剂与化合物 4的体积质量比为 l〜100ml/g; 所述的还原反 应的温度为 0°C〜80°C ; 所述的反应的时间以检测反应完全为止。 9. The preparation method according to claim 8, wherein: the reducing agent is a reduced iron powder, zinc powder, sodium dithionite, stannous chloride dihydrate, sodium borohydride and lithium aluminum hydride. Or a plurality of; the reducing agent is used in an amount of 1 to 20 times the molar amount of the compound 4; the catalyst is one or more of palladium carbon, platinum carbon and Raney nickel; It is 0.01 to 1 times the molar amount of the compound 4; the hydrogen source is one or more of hydrogen, hydrazine hydrate, sodium formate, formic acid, ammonium formate and triethylamine formate; the organic inert solvent is a lower alcohol and/or a lower acid; the volume ratio of the organic inert solvent to the compound 4 is from 1 to 100 ml/g ; the temperature of the reduction reaction is from 0 ° C to 80 ° C ; The reaction was detected to be complete.
10、 如权利要求 9所述的制备方法， 其特征在于： 所述的还原剂的用量 为化合物 4的摩尔量的 5〜10倍； 所述的催化剂的用量为化合物 4的摩尔量 的 0.1〜0.2倍； 所述的低级酸为甲酸、 乙酸、 丙酸、 异丙酸和正丁酸中的 种或多种； 所述的有机惰性溶剂与化合物 4的体积质量比为 8〜20ml/g; 所 的还原反应的温度为 10°C〜30°C。 The preparation method according to claim 9, wherein the reducing agent is used in an amount of 5 to 10 times the molar amount of the compound 4; and the amount of the catalyst is the molar amount of the compound 4. 0.1 to 0.2 times; the lower acid is one or more of formic acid, acetic acid, propionic acid, isopropyl acid and n-butyric acid; the volume ratio of the organic inert solvent to the compound 4 is 8 to 20 ml/ g; The temperature of the reduction reaction is from 10 ° C to 30 ° C.
11、 一种化合物 2的制备方法， 其特征在于包含下列歩骤：
Figure imgf000017_0001
11. A method of preparing a compound 2, comprising the steps of:
Figure imgf000017_0001
4 2  4 2
将化合物 4进行还原反应即可。 The compound 4 can be subjected to a reduction reaction.
PCT/CN2009/074490 2008-11-24 2009-10-16 Method for preparing 3-bromo-5-chlorophenol WO2010057406A1 (en)

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