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Diclazuril powder, CAS 101831-37-2, The molecular formula C17H9Cl3N4O2 is a nucleoside analogue with high efficiency, low toxicity, and broad-spectrum anti coccidiosis efficacy, which is present against all Eimeria species infected in chickens. It belongs to the triazine class of broad-spectrum anticoccidial drugs, which have a killing effect on coccidiosis and have effects on various stages of coccidiosis development.
The peak period of action occurs in the early stages of sporozoites and schizonts. It is a white or light yellow powder; Almost odorless. This product is slightly soluble in dimethylformamide, slightly soluble in tetrahydrofuran, and almost insoluble in water and ethanol. It has a preventive effect on various types of coccidiosis and is used to prevent coccidiosis in chickens, ducks, quails, turkeys, geese, and rabbits. It has good effects on the tenderness, clumpiness, toxicity, brucellosis, giant and other Eimeria species in chickens, as well as on the coccidiosis in ducks and rabbits.
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Diclazuril powder, as a representative drug of triazine phenylacetonitrile compounds, has become a core drug for anti parasitic infections in livestock, poultry, and aquaculture worldwide due to its high efficiency, low toxicity, and broad-spectrum characteristics. Its mechanism of action includes inhibiting the mitochondrial respiratory chain of nematodes, interfering with energy metabolism and nucleic acid synthesis, and has a potent killing effect on multiple stages of the lifecycle of nematodes, such as spores, schizonts, and gametophytes. Below is a systematic review of the clinical use of Diclofenac from four dimensions: animal species, disease types, combination therapy, and special application scenarios.
The preferred solution for duck coccidiosis
Duck source coccidiosis spectrum:
Effective against Taize coccidiosis (causing duck cecal coccidiosis) and Fila's Wenyang coccidiosis (causing duck small intestinal coccidiosis), a feed concentration of 1mg/kg can control infection, and the therapeutic effect is superior to polyether antibiotics.
Clinical medication plan:
Prevention: Add 0.1ml of Dikezhuli per 1L of water to ducklings aged 1-7 days for 3 consecutive days.
Treatment: During acute infection, take 0.05ml orally per 1kg body weight once a day for 3 consecutive days, combined with vitamin K for hemostasis.
Extended application of turkeys and specialty poultry
Turkey coccidiosis:
Effective against Eimeria adenophora and Eimeria turkey infections, using a feed concentration of 1mg/kg for 5 consecutive days can reduce mortality and improve feed conversion rate.
Observing poultry:
For the infection of peacock Eimeria and dispersed Eimeria, adding 50g of Dikezhuli per 100kg of feed for 7 consecutive days can achieve a cure rate of over 90%.
Prevention and control of livestock coccidiosis: precise intervention from piglets to lambs
Breakthrough treatment of piglet coccidiosis
Pathogen characteristics:
Isospora suis is the main pathogen causing diarrhea in piglets aged 7-21 days, and traditional drugs such as sulfonamides can easily induce drug resistance.
Dikezhuli Plan:
Prevention: Taking 1ml/head (0.5% solution) orally 3-7 days after birth for 2 consecutive days can reduce the incidence of diarrhea by 60%.
Treatment: During the acute infection period, take 0.1ml orally per 1kg body weight once a day for 3 consecutive days, and correct dehydration with rehydration salts.
Innovative applications in aquaculture: from fish to crustaceans
(1) Breakthrough in Myxosporidiosis of Cyprinidae Fish
Pathogen characteristics:
Myxosporidium (such as iodothyromonas) can parasitize the gills, skin, and internal organs of fish, and traditional medicines (such as dichlorvos) are prone to residue and recurrence.
Dikezhuli Plan:
Prevention: Adding 50g of Dikezhuli premix (0.5%) per 100kg of feed for 7 consecutive days, once a month, can reduce the infection rate by 80%.
Treatment: During the acute infection period, 10ml of Dikezhuli solution (0.1%) should be sprinkled every 1m ³ of water for 3 consecutive days, combined with salt (3% concentration) medicated bath, achieving a cure rate of 75%.
(2) Exploratory Study on Parasitic Diseases of Shrimp and Crab
Shrimp Microsporidiosis:
Laboratory studies have shown that Dictuzumab has an inhibitory effect on the spore formation stage of Enterocytozoon hepatopancreas in shrimp, but further clinical safety verification is needed.
Crab fixed ciliate disease:
Combined with copper sulfate (0.5mg/L), it can reduce the attachment of crab surface aggregation insects and improve the appearance quality of commercial crabs.
Diclazuril powder, as an efficient and broad-spectrum triazine phenylacetonitrile based anti coccidial drug, has a direct impact on drug quality, production cost, and environmental friendliness due to its synthesis process. The current mainstream synthesis methods can be divided into two categories: traditional stepwise synthesis and one pot synthesis processes. The following analysis will focus on reaction pathways, key steps, advantages and disadvantages, and optimization directions.
Traditional stepwise synthesis method: refined control of classical pathways
The traditional method starts with 2,6-dichloro-4-nitroaniline and gradually constructs the target molecule through steps such as diazotization, substitution, reduction, and cyclization. The core pathway is as follows:
Preparation of intermediate 3,4,5-trichloronitrobenzene
Reaction conditions: In concentrated sulfuric acid, 2,6-dichloro-4-nitroaniline reacts with sodium nitrite to form diazonium salts, which are then coupled with cuprous chloride and hydrochloric acid. After low-temperature stirring and phosphoric acid treatment, trichloronitrobenzene is obtained.
The temperature should be strictly controlled below 50 ℃ to avoid the decomposition of diazonium salts;
When adding phosphoric acid dropwise, the internal temperature should not exceed 10 ℃ to prevent side reactions from occurring.
Yield: Approximately 86%, the product is a light yellow crystal with a melting point of 49-50 ℃.
Synthesis of 2,6-dichloro - α - (4-chlorophenyl) -4-nitrophenylacetonitrile
Reaction conditions: Tetra-n-butylammonium bromide is used as a phase transfer catalyst, and trichloronitrobenzene reacts with p-chlorocyanobenzyl in sodium hydroxide solution. After dissolution in tetrahydrofuran and acidification with glacial acetic acid, extraction is carried out.
Preparation of Reduction Intermediate 4-amino-2,6-dichloro - α - (4-chlorophenyl) phenylacetonitrile
Reaction conditions: In methanol solvent, 5% platinum carbon is used as a catalyst, and hydrogen is used to reduce nitro to amino.
The hydrogen pressure should be maintained at 1-2 MPa to avoid incomplete reaction;
The catalyst needs to be activated, otherwise the activity will decrease and affect the yield.
Yield: Not explicitly mentioned, but the overall yield of subsequent steps is about 30%.
The cyclization and decarboxylation reactions generate dicyclozolid
Reaction conditions: The reduced product is refluxed with ethyl malonyl carbamate in glacial acetic acid, hydrolyzed and decarboxylated to obtain the crude product, and then purified by DMF recrystallization.
The reflux temperature needs to be precisely controlled at 120-130 ℃, as excessive temperature can lead to product decomposition;
The solvent ratio needs to be optimized during recrystallization to avoid product loss.
Yield: about 70%, final product content ≥ 98% (HPLC), melting point 291 ℃.
Clear reaction steps facilitate intermediate quality control;
Suitable for small-scale synthesis in the laboratory, with high product purity.
Multiple purification steps are required, resulting in high solvent consumption;
The overall yield is low (about 30%) and the cost is high;
Part of the raw materials (such as ethyl malonyldiaminocarbamate) need to be self-made, which increases the complexity of the process.
One pot synthesis process: dual optimization of efficiency and cost
To overcome the shortcomings of traditional methods, researchers have developed a one pot method that shortens steps through continuous reactions. The core pathway is as follows:
Starting from 2,6-dichloro-4-nitroaniline, it reacts with sodium nitrite in concentrated sulfuric acid to form diazonium salts, which are then coupled with cuprous chloride to directly obtain 3,4,5-trichloronitrobenzene.
Optimization point: Omitting the intermediate separation step and reducing solvent usage.
Under the catalysis of TEBA (benzyl triethylammonium chloride), trichloronitrobenzene directly condenses with p-chlorocyanobenzyl to form nitroacetonitrile;
Subsequently, sodium hydrosulfite was added to reduce the nitro group to an amino group, resulting in the intermediate 4-amino-2,6-dichloro - α - (4-chlorophenyl) phenylacetonitrile.
Optimization point:
Catalysts can be recycled to reduce raw material costs;
The reduction reaction is carried out under alkaline conditions to avoid corrosion of equipment in acidic environments.
The intermediate and ethyl malonyldiaminocarbamate are boiled in one pot in glacial acetic acid, and then undergo diazotization, coupling, cyclization, hydrolysis, and decarboxylation reactions to directly generate dicyclozolid.
Optimization point:
Control the reaction temperature at 5-10 ℃ to avoid side reactions;
Optimize the cyclization efficiency by adjusting the dosage of potassium acetate.
Yield: about 37.6%, an increase of 7.6 percentage points compared to traditional methods.
advantage:
The reaction steps were shortened from 5 to 3, reducing the total reaction time by 40%;
The solvent recovery rate has been increased to 85%, reducing the cost of waste disposal;
The raw materials are readily available and suitable for industrial production.
Disadvantages:
The reaction conditions require precise control and high equipment requirements;
Some intermediates, such as ethyl malonyl carbamate, still rely on imports.
Optimization direction and industry trend of synthesis methods
Green chemistry orientation
Developing aqueous reaction systems to reduce the use of organic solvents;
Explore enzyme catalysis, photocatalytic isothermal and reaction conditions to reduce energy consumption.
Application of Continuous Flow Process
Using microchannel reactors to achieve continuous production of dangerous steps such as diazotization and cyclization, improving safety;
Real time control of reaction parameters through online monitoring technology to ensure product consistency.
Raw material substitution and localization
Develop a domestically produced synthetic route for key raw materials such as ethyl malonyl carbamate;
Using biomass resources (such as glucose) as starting materials to reduce dependence on petrochemicals.
Standardization of Quality Control
Establish HPLC, IR and other detection method standards for diclazuril powder and its intermediates;
Establish impurity control limits to ensure drug safety.
FAQ
Dikezhuli did not complete the complete crystal structure analysis through synchrotron X-ray powder diffraction data until 2022, and its unit cell contains dimer units connected by strong hydrogen bonds.
Its crystal structure was not fully deciphered until 2022. It belongs to the P21/a space group, and its most unique structure is that molecules are connected to each other through strong N-H ⋯ O hydrogen bonds to form dimers, forming layered stacking on a two-dimensional plane. An extremely obscure knowledge point is that its powder diffraction pattern and crystallographic data were only recently officially submitted to the International Center for Diffraction Data (ICDD) for inclusion. This means that for a long time, scientists did not fully see its "true face" in the solid state.
Dikezhuli is a rare "high margin of safety" molecule in veterinary medicine. In sheep, even with a single dose of 60 times the therapeutic dose, no adverse reactions were observed.
Toxicity studies have shown that the safety window of Dikezhuli is extremely broad. In the registered study, sheep were given a single oral treatment dose up to 60 times the recommended dose (i.e. 60 times the recommended dose), and no clinical adverse reactions were reported; Even if administered four times in a row, five times the dose each time, with a 7-day interval, it is still tolerated. At this dose, it still exhibits highly tolerated characteristics, which is very rare among all veterinary antigen insecticides.
Forced degradation experiments have shown that Dikezhuli is unstable to light and heat in aqueous solutions, and is particularly prone to degradation under alkaline conditions. But under oxidative conditions such as hydrogen peroxide, it exhibits unexpected chemical stability.
Dikezhuli raw materials and formulations were subjected to extreme conditions testing in forced degradation experiments (stability indicator method). The results are very 'abnormal': many drugs are easily oxidized and destroyed, but they exhibit antioxidant properties; On the contrary, light and heat can cause degradation, and the solution is extremely unstable in an alkaline state. Therefore, the Dikezhuli solution formulation must strictly follow the "cool, dark" rule in laboratory and industrial storage. This is a key but easily overlooked trap in formulation development.
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