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Research progress of phloroglucinol synthesis Phloroglucinol is an important organic synthesis intermediate, which is mainly used in the preparation of anti-cancer and anti-cardiovascular disease drugs such as phloroglucinol and isoxanthan. As an important pharmaceutical intermediate, it can be used to synthesize a variety of pharmaceutical products. For example, in 1996, Medichem Research in the United States synthesized a new drug (±)-Calanolide A against immunodeficiency virus (HIV) from phloroglucinol. The drug is a second-generation non-nucleoside reverse transcriptase inhibitor (one of the important components of the "cocktail therapy" two-in-one). Euglobals analogues synthesized from phloroglucinol can effectively inhibit Epstein-Barr virus and have significant anti-cancer effects. It can also synthesize the antibiotic 2,4-diacylphloroglucinol, the anti-allergic agent oxyindane, chromene, and hexokinase inhibitor phloretin analogs, etc. In addition, phloroglucinol itself is also an excellent pharmaceutical product. It is an antioxidant with superior performance and has been widely used for antibacterial, inhibiting spleen tyrosine activating enzyme, apple preservative, etc. It is also an excellent dye coupling agent and can be used in the synthesis of new phthaleous dyes. Phloroglucinol can also be used as a stabilizer for various systems such as glutaraldehyde solution, synthetic rubber, and composite modified binary fuel rocket propellant (CMDB). It is also widely used in tires, plastic tackifiers, steel resists, dispersants, photographic photosensitive materials, etc. According to research and analysis, in recent years, the annual domestic production of phloroglucinol has been less than 100t, and the technology is relatively backward. The domestic and foreign demand is about 500t/a, and is rising year by year, with a potentially broad market. As a high value-added product, phloroglucinol has high investment value. The product cost of the current process is about 350,000 yuan/t, but the selling price is as high as 700,000 yuan/t. 1 Synthesis process progress Since the 1960s, many methods have appeared in the development of phloroglucinol synthesis process. Such as m-isopropyl-resorcinol method, diethyl malonate method, 1-nitro-3,5-diaminobenzene method, and resorcinol method. However, so far, there are only 4 processes that can be truly used for industrial-scale production, namely: (cumyl) benzene method, trinitrotoluene method, chlorobenzene method and aniline method. 1.1 The (cumene) method uses mesitylene (1) as raw material, and after secondary oxidation and primary decomposition, the target product phloroglucinol (4) can be obtained. In the mid-1950s, the Spanish Hoocker Electrochemical Company took the lead in applying it to industrial production. However, the disadvantage was that the purity was not high, and the mass fraction of phloroglucinol was only 72%. Japan's Sum-itomo Chemical Company and Mitsui Petrochemical Industry Company (Mitsui Petrochem.Ind.) have made technical improvements to this part and obtained phloroglucinol with a purity greater than 99%. Since the 1980s, as product purity requirements have increased, improvements have been made. By adding a certain non-polar solvent or using sodium bicarbonate (sodium bisulfite) for carboxylation (sulfonation) and acidolysis, phloroglucinol with a purity of 99.8% was obtained, with a yield of 60%. However, raw material (1) is relatively rare, which limits the promotion and application of this method. The Dutch company Battaafsche Petroleum and the American company Allied Chemical have conducted research on the reaction of benzene (or cumene) with propylene to synthesize (1) with higher yield and purity. As a result, a new process from (cumyl)benzene to phloroglucinol was formed as shown in the following formula, with a product yield of 57%. The yield of the new process is ideal. The raw materials benzene and propylene used are rich in sources and low in price. Although the process route is long, the reaction conditions are mild, the cost is low, the technology is mature, the purity and yield are ideal, and it is currently a relatively complete phloroglucinol synthesis method. 1.2 Trinitrotoluene method In the 1960s and 1970s, both Whiffen & Sons and Fisons Industrial Chemicals successively carried out trinitrotoluene process. * * * (5) Research and production of synthetic phloroglucinol (4), with a yield of 75%. Merck & Co. also used 2,4,6-three * * * Formic acid (6) was used as raw material, and after reduction with iron and hydrochloric acid and hydrolysis with hydrochloric acid, higher purity phloroglucinol was obtained, with a product yield of 53%. The method has simple reaction and high yield, but the disadvantage is the lack of raw materials, which makes it difficult to meet the needs of industrial production. Gerard Des- * * gne, MLKastens, etc. used trinitrotoluene (8) as raw material and oxidized it with sodium dichromate to prepare the above two raw materials (5) and (6) respectively. The yield of the product (6) prepared from (8) reached 82%. The trinitrotoluene method became the main method for the industrial production of phloroglucinol at that time. Chen Yangying and others improved this and proposed to use potassium chlorate to replace the seriously polluted sodium dichromate, and changed the reduction step to Pb/C hydrogenation reduction. The product yield was 60%-75%. After improvement, this method not only absorbs the advantages of low raw materials, simple and reliable process, and low cost in traditional methods, but also * * Reduces environmental pollution. This method is still a cheap method for industrial production of phloroglucinol. 1.3 Chlorinated benzene method 1.3.1 Trichlorobenzene method Tsutomu Kamiyama et al. used 1,3,5-trichlorobenzene (9) as raw material, catalyzed by Et3N or Pr3N, and treated with ammonia water to prepare 3,5-diaminochlorobenzene (10). Based on this, Japan's Ishihara Mining & Chemical Co., Ltd. has carried out a series of research on a new process for synthesizing phloroglucinol from (10). Using copper series as a catalyst, at 170-175°C, ammonia water is used to replace the chlorine atom on the benzene ring to obtain triaminobenzene (7). Add acid hydrolysis to synthesize phloroglucinol with higher yield. 1.3.2 Hexachlorobenzene method The German Akzona Company sequentially performed esterification, dechlorination and catalytic cracking of hexachlorobenzene (11) to synthesize 85.2% crude phloroglucinol, with a purified purity greater than 99%. The raw materials and catalysts of the trichlorobenzene method are economical and cheap, with low cost, simple reaction, mild conditions, high yield and few side reactions. Hexachlorobenzene (hexachlorobenzene) can be obtained by chlorination of dichlorotoluene at higher temperatures and pressures, thus reducing the raw material cost of the hexachlorobenzene method. * * reduce. At the same time, under the current situation where 666 pesticides are completely banned, this has also become a better way for relevant pesticide factories to switch production. The chlorobenzene method undoubtedly has extremely high industrial application value. 1.3.3 Tetrachlorobenzene method The Dutch company Morton International used 1,2,3,5-tetrachlorobenzene to synthesize phloroglucinol through only two steps of ammonia-catalyzed substitution and hydrolysis. The raw material is a by-product of the benzene chlorination process, so the cost advantage is obvious. This method can be used for waste utilization in the process of making raw materials for the hexachlorine method. 1.4 The aniline method is used to synthesize mesostribromobenzene (20) from aniline (16). It is an important method for the preparation of mesostribromobenzene and is divided into three steps.: Benzene ring bromination, amino diazotization, and amino removal. Zhu Haishi et al. proposed an aniline synthesis method on this basis. On the basis of the above three steps, this method adds two additional steps of methoxy-substituted bromine and hydrolysis. The purity of the crude product was 86.7%, and the product yield was 60.5%. This method has high yield, low cost, wide source of raw materials and relatively low price. It is a new method for synthesizing phloroglucinol. The disadvantage is that the route is long, there are many influencing factors, and the production stability is not enough. ； At the same time, the bromine water used has certain corrosion on the equipment. Experiments show that the fourth step, methoxy-substituted bromine, is a key step in this method. After a lot of practical research, they chose oxonium iodide as the catalyst and achieved good results. This method has been used in pilot production and is expected to be further applied in large-scale industrialization. 2 Conclusion Phloroglucinol has wide uses and high added value, but its synthesis method is complicated and the technical requirements are high. At present, there are only a few companies in China that are engaged in the production of phloroglucinol. Most of them use backward trinitrotoluene technology, which causes serious environmental pollution and has no obvious cost advantages. The main manufacturers include Hebei Binyang Group, Sichuan Hongguang Chemical Co., Ltd., etc. The main foreign companies include American Chempacific Company, Japanese Ishihara Industrial Co., Ltd., etc. In the future, the country should adopt the more advanced (cumyl) benzene method and the chlorobenzene method, which have a wide range of raw materials, large output, high quality and low cost. At the same time, they also avoid the high pollution and high danger shortcomings of the trinitrotoluene method. With the improvement of people's living standards, the development of anti-AIDS, anti-tumor, health care and other drugs is in the ascendant, which makes the contradiction between supply and demand of the intermediate phloroglucinol increasingly prominent. Especially the rise of similar drugs in recent years has highlighted the bottleneck effect of phloroglucinol. To this end, Chinese enterprises should seize this opportunity, boldly adopt advanced methods and processes, improve output and quality, and while ensuring the domestic market, actively expand exports and enhance international competitiveness. This post was last edited by tyn565 on 2009-4-16 12:01 ]