阅读说明：本技术 2-溴-4-氟-6-甲基苯酚的制备方法 (Preparation method of 2-bromo-4-fluoro-6-methylphenol ) 是由 赵雪 于 2019-12-12 设计创作，主要内容包括：2-溴-4-氟-6-甲基苯酚的制备方法,具体涉及精细化工产品制备技术领域。2-溴-4-氟-6-甲基苯酚的制备方法,所述方法包括如下步骤：①硝化反应：间氟甲苯经硝化反应制备4-氟-2-甲基硝基苯；②还原反应：将步骤①制备的4-氟-2-甲基硝基苯经还原反应制得4-氟-2-甲基苯胺；③重氮化水解反应：将步骤②制备的4-氟-2-甲基苯胺经重氮化水解反应制得4-氟-2-甲基苯酚。④溴化反应：将步骤③制备的4-氟-2-甲基苯酚经溴化反应制得2-溴-4-氟-6-甲基苯酚。本发明优点提出了一条由间氟甲苯为原料合成2-溴-4-氟-6-甲基苯酚的完整工艺路线,工艺简单,工业化生产易实现。(The preparation method of the 2-bromo-4-fluoro-6-methylphenol comprises the steps of ① nitration reaction of m-fluorotoluene to prepare 4-fluoro-2-methylnitrobenzene through nitration reaction, ② reduction reaction of 4-fluoro-2-methylnitrobenzene prepared in the step ① to prepare 4-fluoro-2-methylaniline, ③ diazotization hydrolysis reaction of 4-fluoro-2-methylaniline prepared in the step ② to prepare 4-fluoro-2-methylphenol through diazotization hydrolysis reaction, and ④ bromination reaction of 4-fluoro-2-methylphenol prepared in the step ③ to prepare 2-bromo-4-fluoro-6-methylphenol through bromination reaction.)

A process for the preparation of 2-bromo-4-fluoro-6-methylphenol, characterized in that it comprises the following steps:

① nitration reaction, wherein m-fluorotoluene is subjected to nitration reaction to prepare 4-fluoro-2-methyl nitrobenzene;

② reduction reaction, namely, the 4-fluoro-2-methyl nitrobenzene prepared in the step ① is subjected to reduction reaction to prepare 4-fluoro-2-methylaniline;

③ diazotization hydrolysis reaction, namely diazotization hydrolysis reaction of the 4-fluoro-2-methylaniline prepared in step ② to prepare 4-fluoro-2-methylphenol;

④ bromination reaction, the 4-fluoro-2-methylphenol prepared in step ③ is made into 2-bromo-4-fluoro-6-methylphenol by bromination reaction.

2. The method according to claim 1, characterized in that the nitration reaction step is as follows: and (3) dropwise adding fuming nitric acid into the m-fluorotoluene at the temperature of 20-30 ℃, and reacting for 8-12 hours at the temperature of 20-30 ℃ to obtain the 4-fluoro-2-methyl nitrobenzene, wherein the molar ratio of the m-fluorotoluene to the fuming nitric acid is 1: 1.9-2.3.

3. The method according to claim 1, wherein the reduction reaction comprises the step of dropwise adding a prepared solution of the 4-fluoro-2-methylnitrobenzene prepared in the step ① and ethanol into a mixed solution of water, iron powder and ammonium chloride at a temperature of 70-80 ℃, and carrying out reduction reaction for 1 hour at a temperature of 70-80 ℃ to obtain the 4-fluoro-2-methylaniline.

4. The method as claimed in claim 1, wherein the diazotization hydrolysis reaction comprises the steps of salifying 4-fluoro-2-methylaniline prepared in the step ② in sulfuric acid aqueous solution at 50-60 ℃, cooling to 0-5 ℃ after salification, dropwise adding sodium nitrite aqueous solution to prepare diazonium salt, dropwise adding the diazonium salt into aqueous solution of sulfuric acid and copper sulfate prepared in advance at 103-105 ℃, dropwise adding a water vapor distillation product while dropwise adding, extracting and rectifying the distillate to obtain the 4-fluoro-2-methylphenol.

5. The method according to claim 1, wherein the bromination reaction comprises the steps of dissolving the 4-fluoro-2-methylphenol prepared in the step ③ in chloroform, dropwise adding a mixture of bromine and chloroform at a temperature of-10 to 5 ℃, and carrying out bromination reaction to generate the 2-bromo-4-fluoro-6-methylphenol, wherein the molar ratio of the 4-fluoro-2-methylphenol to the bromine is 1: 1.01 to 1.1.

Technical Field

The invention belongs to the field of preparation of fine chemical products, and particularly relates to a preparation method of 2-bromo-4-fluoro-6-methylphenol.

Background

2-bromo-4-fluoro-6-methylphenol is a very important bactericide and a medical intermediate, so far, almost no information and data exist for synthesizing the compound, and in order to meet market demands, the company researches and develops a preparation method of 2-bromo-4-fluoro-6-methylphenol, which has the advantages of readily available raw materials, simple industrial process and low cost.

Disclosure of Invention

The invention aims to provide a preparation method of 2-bromo-4-fluoro-6-methylphenol, which has the advantages of easily obtained raw materials, simple industrial process and lower cost. The reaction route of the invention is as follows:

① nitration reaction, wherein m-fluorotoluene is subjected to nitration reaction to prepare 4-fluoro-2-methyl nitrobenzene with the yield of 68%;

② reduction reaction, namely, the 4-fluoro-2-methyl nitrobenzene prepared in the step ① is subjected to reduction reaction to prepare 4-fluoro-2-methyl aniline with the yield of 90 percent;

③ diazotization hydrolysis reaction, namely diazotization hydrolysis reaction of the 4-fluoro-2-methylaniline prepared in step ② to prepare 4-fluoro-2-methylphenol, wherein the yield is 40.9%;

④ bromination reaction, the 4-fluoro-2-methylphenol prepared in step ③ is made into 2-bromo-4-fluoro-6-methylphenol by bromination reaction, the yield is 90%.

The oxidation reaction comprises the following steps: adding fuming nitric acid into m-fluorotoluene, carrying out nitration reaction at the temperature of 20-30 ℃ to obtain 4-fluoro-2-methylnitrobenzene, and carrying out layering, washing and rectification to obtain the 4-fluoro-2-methylnitrobenzene, wherein the content is more than or equal to 93%.

The reduction reaction comprises the following steps of dropwise adding a prepared solution of the 4-fluoro-2-methylnitrobenzene prepared in the step ① and ethanol into a mixed solution of water, iron powder and ammonium chloride at the temperature of 70-80 ℃ to prepare 4-fluoro-2-methylaniline, and filtering, desolventizing and layering the 4-fluoro-2-methylaniline to obtain the 4-fluoro-2-methylaniline.

The ammonium chloride is used as a catalyst, and the desolventizing and layering treatment refers to that the solvent ethanol is evaporated after the reaction is finished so as to only leave water and 4-fluoro-2-methylaniline in the system, and the water is removed in a layering manner to obtain crude 4-fluoro-2-methylaniline which is directly subjected to the next reaction without purification.

The diazotization hydrolysis step comprises the steps of salifying the 4-fluoro-2-methylaniline prepared in the step ② in sulfuric acid aqueous solution, dropwise adding sodium nitrite aqueous solution into the salt to prepare diazonium salt, finally dropwise adding the diazonium salt into the prepared aqueous solution of sulfuric acid and copper sulfate, and performing steam distillation, extraction and rectification to obtain the 4-fluoro-2-methylphenol with the content being more than or equal to 99%.

The diazotization hydrolysis reaction refers to that 4-fluoro-2-methylaniline diazonium salt is prepared by using sodium nitrite, then the diazonium salt is dripped into water for hydrolysis reaction, and the diazotization salt is dripped while the water vapor distillation product is distilled.

The bromination reaction comprises the following steps of dissolving the 4-fluoro-2-methylphenol prepared in the step ③ in chloroform, dropwise adding a mixed solution of bromine and chloroform at the temperature of-10-5 ℃, carrying out bromination reaction to generate 2-bromo-4-fluoro-6-methylphenol, washing, layering, distilling and recrystallizing to obtain the 2-bromo-4-fluoro-6-methylphenol, wherein the content is more than or equal to 99%.

Further explaining that washing is to remove bromine which is a reaction, the steps of adding product purification after each reaction step of nitration reaction, reduction reaction, diazotization hydrolysis reaction and bromination reaction, such as liquid separation, washing, filtering, drying and the like, are all conventional operations in the art, are well known to the skilled person, and are not described herein.

The invention has the beneficial effects that: compared with the prior art, the invention provides a complete process route for synthesizing 2-bromo-4-fluoro-6-methylphenol by taking m-fluorotoluene as a raw material, and overcomes the defects of difficult acquisition of raw materials, high price, unsuitability for industrial production and the like in the prior art. The method provided by the invention has the advantages of easily available raw materials, availability in China, simple process, convenience in operation, high product purity (more than or equal to 99%), low cost, safety, high efficiency, energy conservation and consumption reduction, thereby being more suitable for industrial large-scale production.

Detailed Description

The following non-limiting examples are presented to enable those of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way.

The test methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.

The embodiment of the invention adopts the following main instruments and types: gas chromatography-mass spectrometer, Agilent model 7890A/5975C and nuclear magnetic resonance spectrometer, Brucker model AM-400.