Preparation method of 1,3,5-trimethoxybenzene_Kain Industrial Additive

Background and overview^[1]

1.3.5-Trimethoxybenzene is a white crystalline powder, insoluble in water, and an important organic synthesis intermediate. It is mainly used in the fields of pharmaceutical manufacturing and pesticide synthesis. It is a new dilation drug for peripheral vascular disorders. An important raw material of Bullomedil. 1.3.5-Trimethoxybenzene was originally developed by a German company. Hu Yimin and others from the Institute of Organic Chemistry of Anhui Normal University conducted research on the two-step reaction of etherification and dechlorination to prepare 1.3.5-trimethoxybenzene using hexachlorobenzene as raw material, and the yield was 67.5%. The yield is low, which is not conducive to industrial production.

Preparation^[1]

Method 1: A preparation method of 1.3.5-trimethoxybenzene, including the following basic steps:

A) First add a quantitative amount of aniline and 5-20 times the mass of aniline to water into the reaction kettle, then add 1-10 times the mass of aniline and hydrobromic acid with a purity of 20-30% dropwise into the kettle, and heat it with steam The method is to raise the temperature in the reaction kettle to 50-75°C and keep it warm for 1-4 hours; when the holding time is up, use cooling water to lower the temperature in the reaction kettle to 10-40°C, and add hydrogen dropwise Bromine diluted with bromic acid, the mass of bromine used here is 5.2-5.3 times the mass of the above-mentioned aniline, the mass of hydrobromic acid used to dilute the bromine is 1-3 times the mass of bromine; dropwise addition of bromine is completed Finally, the temperature in the reaction kettle is raised to 45-65°C, kept for 1-3 hours, and then cooled to room temperature; the materials in the reaction kettle are released, filtered with a suction filter, and the hydrobromic acid is separated and recycled. The remaining materials are washed 3-6 times with water to remove impurities that are easily soluble in water. The water consumption during each washing is 5-10 times the mass of the materials. The remaining water-insoluble materials are dried to obtain 2.4.6-tribromoaniline. The drying temperature is 100-120°C and the drying time is 5-10 hours. The drying can be stopped when the moisture content is less than 0.1%.

B) First, add a quantitative amount of the first component of absolute ethanol into the reaction kettle, and then add the above-mentioned dried 2.4.6-tribromoaniline. The added 2.4.6-tribromoaniline and the first component The mass ratio of absolute ethanol is 1:3-5, start stirring, and then add 20-40% sodium nitrite by mass of 2.4.6-tribromoaniline in the reactor; raise the temperature in the reactor to 50-70°C , incubate for 1-3 hours; then add the mixture of ethanol and sulfuric acid dropwise into the reaction kettle. The mass of absolute ethanol and concentrated sulfuric acid in the mixture of ethanol and sulfuric acid is 2.4.6-tribromo in the reaction kettle. 70-90% of the mass of aniline; concentrated sulfuric acid is sulfuric acid with a concentration of more than 98%. After all the mixture of ethanol and sulfuric acid is added dropwise, control the temperature in the reaction kettle to maintain 60-80°C, maintain reflux for 3-10 hours, lower the temperature in the reaction kettle to room temperature, and release the materials in the reaction kettle. Use a suction filter tank to filter and separate the ethanol for recycling. The remaining material is washed with water 5-6 times to remove impurities that are easily soluble in water. The amount of water used each time during washing is 5-10 times the mass of the material. The material in water can be dried to obtain 1.3.5-tribromobenzene.

Step C), first vacuum the methanol solution of sodium methanol with a purity of 27.5-31% into the pressure cooker, and start stirring. The methanol solution of sodium methoxide is a liquid obtained by dissolving sodium methoxide in methanol. Add the above-mentioned 1.3.5-tribromobenzene to this methanol solution of sodium methoxide. The mass of the methanol solution of sodium methoxide is 8-10 times the mass of 1.3.5-tribromobenzene. After stirring for 0.5-2 hours, it will be equivalent to 1.3.5-Pour 1-5% cuprous chloride by mass of tribromobenzene into the pressure cooker, seal the lid and continue stirring for 0.5-2 hours; then heat the pressure cooker, and stop when the pressure in the pressure cooker reaches 0.1-0.3Mpa. Heating, at this time due to the exothermic reaction in the pressure cooker, the pressure in the pot will continue to rise. Start timing when the pressure in the pot reaches 0.4-0.6Mpa. At the same time, use heating or cooling methods to keep the pressure in the pressure cooker at 0.4-0.9Mpa for 5-10 hours; then cool down to reduce the pressure in the pot to 0.05-0.1Mpa. , hydraulically force the material into the distillation kettle through the pressure in the pot; without stirring, heat the stillization kettle to keep the temperature in the distillation kettle at 60-100°C, steam for 5-10 hours, and put the steamed methanol into Methanol recovery barrel; then close the methanol storage tank drain valve, evacuate the distillation kettle, the vacuum degree is -0.01–0.08Mpa, the temperature is controlled at 60-80°C, the distillation time is about 1-4 hours, and the steamed methanol is Put it into the methanol recovery barrel; release the materials in the distillation kettle to obtain crude product 1.3.5-trimethoxybenzene.

Method 2: Synthesis method of 1,3,5-trimethoxybenzene, including the following steps:

1) Mix methanol and catalyst, add argon gas, control the pressure to 7 atmospheres, control the temperature to 135°C, maintain for 30 minutes, and add dropwise a solution composed of 1,3,5-tribromobenzene and toluene. , control the dropping time of the solution to 45 minutes, start adding triethylamine dropwise after the solution is added, control the dropping time of triethylamine to 10 minutes, after the addition of triethylamine is completed, increase the temperature to 165°C, and increase the pressure to 11 atmospheres, and then continue the reaction for 11 hours. The reaction is completed. The preparation method of the catalyst is as follows: mix sodium oxide and barium oxide, grind them, pass them through a 700-mesh sieve, take the material below the sieve and activate it at 800°C, mix and grind the resulting mixture with dextran gel, and pass it through a 500-mesh sieve to obtain the catalyst; oxidize The weight ratio of sodium to barium oxide is 1:0.32; the weight ratio of the activated mixture to dextran gel is 1:55; the dextran gel model is G-25. 1,3,5-tri The molar ratio of bromobenzene to methanol is 1:95, and the weight ratio of 1,3,5-tribromobenzene to catalyst is 1:0.22, 1, the dosage ratio of 3,5-tribromobenzene to toluene is 1g:6.5ml, and the molar ratio of 1,3,5-tribromobenzene to triethylamine is 1:1.22.

2) After cooling the system, filter to remove the solid. The filtrate is added to 5 times the volume of water, and then extracted with chloroform. The extract is dried with anhydrous sodium sulfate, concentrated and the solvent is evaporated to obtain the product. The molar yield was 99.5%, and the GC purity was 98.9%.

Main reference materials

[1] CN200910210382.X Preparation method of 1.3.5-trimethoxybenzene

[2] CN201811405135.0 Synthesis method of buflodil hydrochloride intermediate 1,3,5-trimethoxybenzene