WO2010057406A1 - Procédé de préparation de 3-bromo-5-chlorophénol - Google Patents

Procédé de préparation de 3-bromo-5-chlorophénol Download PDF

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Publication number
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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Prior art keywords
compound
acid
reaction
preparation
bromo
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PCT/CN2009/074490
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English (en)
Chinese (zh)
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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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Publication of WO2010057406A1 publication Critical patent/WO2010057406A1/fr

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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

Definitions

  • 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%.

Abstract

La présente invention concerne un procédé de préparation de 3-bromo-5-chlorophénol représenté par la formule (1), le procédé comportant l'étape consistant à hydrolyser le composé (3) en milieu acide pour obtenir le composé (1), dans lequel X- est Cl-, Br-, HSO4 - ou NO3 -. Ce procédé de préparation a comme avantages son faible coût, une matière première facile à obtenir, une manipulation commode, un produit facile à purifier, et sa facilité de passage à grande échelle. De plus, il est possible d'obtenir un rendement et une pureté plus élevés.
PCT/CN2009/074490 2008-11-24 2009-10-16 Procédé de préparation de 3-bromo-5-chlorophénol WO2010057406A1 (fr)

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CN200810203240.6 2008-11-24
CN200810203240.6A CN101735023B (zh) 2008-11-24 2008-11-24 一种3-溴-5-氯苯酚的制备方法

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CN104140360B (zh) * 2014-07-10 2015-12-02 四川北方红光特种化工有限公司 制备邻甲基苯酚的方法
CN105218379A (zh) * 2015-10-31 2016-01-06 高大元 一种3-氯-5-溴苯胺的合成方法
CN107400058B (zh) * 2016-05-19 2019-08-09 北京理工大学 2,4,6-三甲基苯-1,3,5-三胺以及n,n,n-三酰化产物的合成方法
CN107488127A (zh) * 2016-06-13 2017-12-19 张家港市锦丰润尔发五金塑料厂 以连二亚硫酸钠为还原剂合成邻氨基苯甲醛的方法
CN106187711A (zh) * 2016-07-06 2016-12-07 浙江工业大学 管式重氮化制备2,5‑二氯苯酚的方法及专用装置
CN108147946A (zh) * 2017-12-04 2018-06-12 华南农业大学 一种制备4-苯基苯酚的方法

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CN1993332A (zh) * 2004-07-27 2007-07-04 弗·哈夫曼-拉罗切有限公司 作为非核苷逆转录酶抑制剂的苄基三唑酮化合物
WO2008099000A2 (fr) * 2007-02-16 2008-08-21 Boehringer Ingelheim International Gmbh Nouvelles arylsulphonylglycines substituées, leur procédé de préparation et leur utilisation en tant que compositions pharmaceutiques

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