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4,6-dichloropyrimidine is a raw material for the synthesis of azoxystrobin. The chemical name of azoxystrobin is (E) 2- [2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy] phenyl] -3-methoxyacrylate methyl ester. Abbreviated as DCP, with a chemical formula of C4H2Cl2N2, it is usually a white crystal that turns yellow brown when stored. It is insoluble in water but soluble in solvents such as toluene.
This product is a methoxyacrylate (Strobilurin) fungicide, which is highly efficient and broad-spectrum. It has good activity against almost all fungal diseases (Ascomycota, Basidiomycota, Flagella, and Hemimycota) such as powdery mildew, rust, Fusarium wilt, net spot disease, downy mildew, rice blast disease, etc. It can be used for stem and leaf spray, seed treatment, and soil treatment, mainly for grains, rice, peanuts, grapes, potatoes, fruit trees, vegetables, coffee, lawns, etc. It is an important intermediate for the synthesis of pyrimidine compounds, widely used in the synthesis of pharmaceutical and pesticide pyrimidine products, mainly for the synthesis of methoxyacrylate fungicides such as azoxystrobin.
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4,6-dichloropyrimidine, with the chemical formula C4H2Cl2N2, has a molecular weight of 148.9781 and a CAS accession number of 1193-21-1. It is an important chemical substance. Its melting point is not high, with a melting point of 65-67 ° C, a boiling point of 176 ° C, a density of 1.493g/cm ³, and a flash point of 105.12 ° C.
The following is a detailed explanation of the uses of 4,6-dichloropyriidine.
Synthetic sulfonamide drugs
One of the important applications in the pharmaceutical field is as an intermediate for the synthesis of sulfonamide drugs. Sulfonamide drugs are a class of drugs with antibacterial activity, widely used in clinical treatment. It can be converted into sulfonamide drugs such as sulfonamide 6-methoxypyrimidine through specific chemical reactions, which have significant therapeutic effects in treating bacterial infections.
Synthesis of other pharmaceutical intermediates
In addition to sulfonamide drugs, it can also be used as a raw material for synthesizing other pharmaceutical intermediates. Starting materials for the synthesis of disubstituted pyrimidines can be obtained through tandem amination and Suzuki Miyaura cross coupling reactions. These disubstituted pyrimidine compounds have potential application value in the pharmaceutical field and can be used to develop new drugs to address the constantly emerging issue of drug resistance.
Participate in the development of new drugs
With the continuous development of pharmaceutical technology, the research and development of new drugs has become an important issue in the pharmaceutical field. Due to its unique chemical structure and biological activity, it has become one of the important raw materials for new drug development. Through in-depth research on its chemical properties, scientists can develop new drugs with higher efficacy and lower side effects, contributing to human health.
Synthetic fungicide
One of the main applications in the field of pesticides is as an intermediate for synthesizing fungicides. Among them, the methoxy acrylate fungicide azoxystrobin is synthesized from it. Azoxystrobin is a broad-spectrum and highly effective fungicide that has significant control effects on various crop diseases. By using azoxystrobin, farmers can effectively increase crop yield and quality, ensuring food security and sustainable agricultural development.
Developing new pesticides
In addition to azoxystrobin, it can also be used to develop other new pesticides. Through in-depth research on its chemical properties, scientists can develop new pesticides with higher selectivity and lower environmental pollution to address the increasingly serious problem of agricultural pests and diseases. These new pesticides can not only increase crop yield and quality, but also reduce the use of pesticides and lower environmental pollution.
Synthesis of diaryl pyrimidine
It can also be used for synthesizing diarylpyrimidines. Diarylpyrimidines are a class of compounds with special chemical properties and biological activity, which have potential applications in materials science, electronic science, and other fields. By utilizing their chemical reaction properties, scientists can synthesize diaryl pyrimidine compounds with specific structures and properties, providing new materials and technological support for the development of these fields.
Used for organic synthesis reactions
It can also be used as a raw material or catalyst in organic synthesis reactions. Organic compounds with specific structures and functions can be generated through chemical reactions with other compounds. These organic compounds have wide application value in fields such as chemical industry and materials science, and can be used to produce various chemicals and materials.
The currently reported preparation methods, considering yield and manufacturing costs, mainly use dimethyl malonate and sodium methoxide as raw materials for the cyclization part of 4,6-dichloropyrimidine synthesis in existing technology. However, methanol is very harmful to human health; There are many methods for synthesizing the chlorinated portion of 4,6-dichloropyriidine, which can be summarized into two main approaches: one is obtained by the diphosgene or triphosgene method, and the other is obtained by the phosphoryl chloride method.
However, in the actual production process, it was found that phosgene poses a high risk, has high technical requirements, and the yield and product quality are not very high; The production of phosphoryl chloride method requires the use of phosphorus oxychloride, which is a highly toxic chemical and prone to production accidents during the production process. It is also highly hazardous, with a large amount of waste, difficult separation, and high energy consumption.
The technical problem to be solved by the present invention is to provide a new low-cost and high-yield method for preparing 4,6-dichloropyriidine, which is simple in process and environmentally friendly, in response to the shortcomings of existing technology.
Optimization of Preparation Methods
(1) Preparation of 4,6-dihydroxypyrimidine
Take formamide and anhydrous ethanol in a weight ratio of 1:3-5 and put them into a container; Add sodium ethoxide again, with a molar ratio of 1:1-3.5 between formamide and sodium ethoxide. Stir for 10-40 minutes and gradually raise the temperature to 70-90 ℃. Add diethyl malonate dropwise at a constant speed; The molar ratio of formamide to diethyl malonate is 2-3.5:1, added dropwise for 2-5 hours, and then kept at reflux for 4-8 hours after the addition is complete; After the insulation is completed, slowly recover anhydrous ethanol for use in the next reaction; When the recovery amount of anhydrous ethanol reaches 75% of the input amount, open the valve of the aqueous ethanol receiving tank and close the valve of the anhydrous ethanol receiving tank; Slowly add hydrochloric acid aqueous solution with a mass concentration of 0.5-3% while recovering ethanol with water; When the temperature rises to 85 ℃, close the valve of the water ethanol receiving tank and the steam heating valve, and neutralize, dehydrate, and distill the water ethanol to anhydrous ethanol before using it; Continue to add the above hydrochloric acid aqueous solution dropwise to the container until the pH of the reaction solution is 2-6. After cooling to -5-5 ℃, centrifuge and dry to obtain 4,6-dihydroxypyridine.
(2) Preparation of 4,6-dichloropyriidine
4,6-dihydroxypyrimidine, dichloroethane, and a chlorination catalyst are added to a container in a weight ratio of 1:3-6:0.005-0.05. The chlorination catalyst is anhydrous boric acid or activated alumina; Start stirring and slowly raise the temperature to reflux. Open the drip valve of the thionyl chloride storage tank and the tail gas absorption system, and add thionyl chloride evenly; The molar ratio of 4,6-dihydroxypyrimidine to sulfonyl chloride is 1:2-4, and the dropwise addition time is 2-6 hours. After the dropwise addition is completed, the mixture is kept at room temperature for 3-8 hours and then cooled to room temperature; Open the vacuum system on the dichloroethane receiving tank, finished product crystallization kettle, and container. When the vacuum stabilizes at -0.095Mpa, slowly raise the temperature and open the valve of the dichloroethane receiving tank to recover dichloroethane; When the recovery amount of dichloroethane reaches 60% of the input amount, open the valve on the finished crystallization kettle and stir, and close the valve of the dichloroethane receiving tank to collect dichloroethane and finished products; When the temperature of the container kettle reaches 115-130 ℃, close the valve of the finished crystallization kettle, end the distillation and cool down the container. When the temperature of the container cools down to 30-40 ℃, drain the distillation residue; When the finished crystallization kettle is cooled to -8~8 ℃, the 4,6-dichloropyriidine product is obtained by centrifugation and drying. It is used for the next distillation of the mother liquor.
In step (1) of the preparation method technical scheme described in the present invention, the preferred weight ratio of formamide to anhydrous ethanol is 1:3.5 to 4.5; The molar ratio of formamide to sodium ethoxide is preferably 1:1.2 to 2.5; The molar ratio of formamide to diethyl malonate is preferably between 2.2 and 3:1. The preferred mass percentage concentration of hydrochloric acid aqueous solution is 1-2%. It is preferred to add hydrochloric acid aqueous solution dropwise until the pH of the reaction solution is 4-5, and then cool it down. In step (2), the weight ratio of 4,6-dihydroxypyrimidine, dichloroethane, and chlorination catalyst is preferably 1:3.5 to 5:0.01 to 0.03, and the molar ratio of 4,6-dihydroxypyrimidine to thionyl chloride is preferably 1:2.2 to 3.5.
Compared with existing technologies, the present invention uses diethyl malonate and sodium ethoxide as raw materials for the cyclization part in the preparation of 4,6-dichloropyriidine, with ethanol as the solvent, resulting in less harm to employees during production; The chlorination part of synthesizing 4,6-dichloropyriidine uses sulfonyl chloride as raw material, and key technologies such as self-made catalysts and unique separation crystallization equipment are used to obtain high-quality 4,6-dichloropyriidine through four steps of chlorination, distillation, crystallization, and drying. The raw materials are based in China, and the process technology is mature and reliable. The by-products and solvents can be recycled and reused, reducing the risks in the production process of the workshop and achieving international standards for product quality. The preparation method of the present invention has a more reasonable and simple process, low cost, high quality, environmental friendliness, and is more suitable for industrial production.
I. Foundation and Early Exploration of Pyrimidine Chemistry (1900–1940s)
The discovery of 4,6-dichloropyrimidine is rooted in systematic studies of the pyrimidine ring system. In 1900, Gabriel first synthesized the parent pyrimidine and established chlorination methods, laying the foundation for research on halogenated pyrimidines. In the 1940s, driven by growing demand in heterocyclic chemistry and pharmaceutical intermediates, researchers began to focus on the synthetic potential of 4,6-disubstituted pyrimidines. Early preparations relied on the cyclization of malonic esters with amidines to yield 4,6-dihydroxypyrimidine. However, direct chlorination to form the dichloro derivative remained underdeveloped, with unsatisfactory yields and purity, restricting progress to the laboratory research stage.
II. First Synthesis and Establishment of the Classic Route (1943–1950s)
In 1943, the synthesis of 4,6-dichloropyrimidine was first reported in the Journal of the Chemical Society. Starting from 4,6-dihydroxypyrimidine, the product was obtained by refluxing with excess phosphorus oxychloride (POCl₃) and dimethylaniline, followed by extraction and distillation, affording a yield of approximately 75%. This route became the classic method, solving the key challenge of chlorinating hydroxypyrimidines. In 1951, researchers optimized the work-up procedure, reducing hydrolytic byproducts and improving purity, enabling scalable production and paving the way for subsequent applications.
III. Industrialization and Emerging Application Value (1960–1980s)
In the 1960s, with the development of sulfonamide drugs and heterocyclic pesticides, 4,6-dichloropyrimidine emerged as a key intermediate due to its high reactivity, where chlorine atoms are readily displaced by nucleophiles. Industry adopted a two-step scalable process starting from dibutyl malonate via cyclization and chlorination, significantly lowering production costs. During the 1970s–80s, its applications in Suzuki–Miyaura coupling and amination reactions were systematically validated, leading to widespread use in pharmaceuticals and agrochemicals and establishing its status as an important building block.
IV. Modern Process Optimization and Sustained Applications (1990s to Present)
From the 1990s onward, new processes such as phosgenation and phosphorus trichloride/chlorine methods were developed to address environmental and byproduct issues associated with the traditional POCl₃ route. After 2000, driven by advances in targeted therapies and fine chemicals, research focused on high-purity preparation and stereoselective transformations of 4,6-dichloropyrimidine. To this day, it remains a critical starting material for the synthesis of disubstituted pyrimidines, sulfonamide drugs, and heterocyclic functional molecules.
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