Dimethomorph is a derivative of a cinnamic acid compound and belongs to the morpholine fungicide . First reported in France in 1988, it is used to control grape downy mildew and potato and tomato late blight. It is a new high-efficiency systemic fungicide for controlling downy mildew pathogenic fungi and resistant to phenylamide fungicides. Both sexual and sensitive strains have higher activity. In practical applications, enoylmorpholine is another ideal fungicide for the control of Oomycetes after metalaxyl. It is especially suitable for the resistance control of Benzamide fungicide-resistant pathogens in the field. Pharmacy.

It is a morpholine-based fungicide product developed by Shell (now BASF). It was introduced to the market in 1992 and is mainly used in crops such as potatoes and grapes. This product has been applied to Shell, Cyanamide and BASF with the transfer and acquisition of the company. It has been widely used in various regions of the world. In recent years, its global sales have been located in morpholine fungicides (mainly including The first place of dimethomorph, flumorph, butylmorpholine, tridemorpholine and dodecamorpholine.

I. Dimethomorph market

The main dosage form of enoylmorpholine registration: the trade name Forum, used to control grape downy mildew; Acrobat is used to control potato blight. Further registration in the United States in 2002 was also re-registered in the European Union. Since the successful registration of dimethomorph in 2007, its main market is in Europe, followed by Asia.

Since enoylmorpholine is a product against oomycetes, it is widely used in various regions of the world, especially in Europe, the United States, Australia, and Asia. It is mainly used to control diseases caused by the fungi of the flagellate, such as potato, grape, gourd and vegetable downy mildew, blight, seedling disease, tobacco black shank, etc., and is also used for tomatoes and other crops. Disease. The increase in the use of enoyl has also led to the growth of fungicides. In 2005, the sales of dimethomorph was US$65 million, and the sales in 2008 reached US$95 million. Subsequently, an important reason for the decline in sales of dimethomorph was due to the potato market, which dominated the fungicide market. In 2008-2009, the planting area decreased by 7.5% (124,000 hm2) and the fungicide market decreased by 3%. Another reason is that France is the main market for grape fungicides. The products used to control grape downy mildew generally occupy 60% market share. In 2009, affected by the long winter, the inventory is large, causing the price of dimethomorph products to drop. Lead to a decline in sales of dimethomorph. The third reason is that global sales of dimethomorph have declined as more products for Oomycetes have entered the market.

Sales of dimethomorph began to decline steadily, with sales of $85 million in 2009 and sales in 2010 falling to $0.8 billion. Sales of dimethomorphs were almost maintained at a certain level, and BASF's 2013 sales of dimethomorphs were $75 million. In 2013, the global sales of dimethomorph was ranked 7th among grape germicides and 10th among potato fungicides.

Second, the action mechanism of dimethomorph

Dimethomorph has preventive and therapeutic activity and has residual activity on crop leaves, providing excellent preventive action. When the enoylmorpholine is sprayed on the crop, the agent can penetrate into the leaf tissue through the surface of the leaf, and can be used for controlling various important crop diseases by diffusion and local conduction in the leaf. These include cucumber downy mildew, grape downy mildew, potato late blight, tomato late blight, tobacco black shank and the like. Dienomorpholine has no cross-resistance with the most widely used phenylamide fungicides (such as metalaxyl), and has good affinity. It can be mixed with other different types of fungicides, such as mancozeb. Expand the spectrum and use range.

Most of the morpholine fungicides are for controlling powdery mildew, and the bactericidal action of dimethomorph is to directly destroy the formation of fungal cells, causing the decomposition of cell walls, leading to the death of fungal cells, and does not have the effect of preventing powdery mildew. Although enoylmorpholine contains a morpholine ring group, it does not act as a morpholine ring active group, but actually belongs to the acrylamide fungicide; its mechanism of action and characteristics are to inhibit the formation of oocyst cell wall, with internal Soluble, usually used to control potatoes, grapes, cucurbits, mildew, disease, and also for diseases of tomatoes and other crops. Regardless of the resistance of the pathogenic fungi, the use of dimethomorph is more effective than the currently widely used agents such as metalaxyl, cymoxanil, vesculine, and aluminum triethylphosphonate.

Third, the physicochemical properties of enoylmorpholine

The enoylmorpholine is present in both (Z) and (E) isomers, only the (Z)-isomer is active, while the (E)-isomer is not active. However, the isomers can rapidly interconvert under light, and in fact, the presence of the (E)-isomer is not detrimental, so that it is not necessary to mind or separate.

The dimethomorph drug consists of the (E) and (Z) isomers in a ratio of 1:1. The appearance is colorless crystal, melting point 127 ~ 148 ° C; (E) isomer melting point is 135.7 ~ 137.5.2 ° C; (Z) isomer melting point is 169.2 ~ 170.2 ° C. The density is 1.318 g/cm3 (20 ° C). Solubility: <50 mg/L (20-23 °C) in water; acetone 88 (E), 15 (Z); cyclohexanone 27 (Z); dichloromethane 315 (Z); dimethylformamide 272 ( Z); hexane 0.04 (E), 0.02 (Z); methanol 7 (Z); toluene 7 (Z) (all in g/L, 20 to 23 ° C). Stability: Not hydrolyzed under normal conditions and stable to heat; stable under dark conditions >5 years, interconversion between (Z) and (E) two isomers in daylight. The pharmacy should be sealed and stored in a cool, dry warehouse.

Qi Jiangjie et al. studied the toxicity of fungicide enoylmorpholine. The results showed that enoylmorpholine was low toxicity level by oral toxicity and transdermal toxicity. The agent is sensitive to male rats, is non-irritating to rabbit skin and eyes, has no sensitizing effect on skin, and has no genotoxic effect, and is similar to domestic and foreign reports. The subchronic oral maximum no-effect dose of dimethomorph is 30 mg/(kg•d). Combined with existing data at home and abroad, it can be considered that dimethomorph is safer as a pesticide application.

Shi Jie et al. studied the volatility of dimethomorph in air, water and soil. The samples were tested by HPLC-UV. The results showed that the volatility of dimethomorph in all three media was <1%, indicating that It is difficult to volatilize in air, water and soil.

4. Dimethomorphs and dosage forms

The first registration of dimethomorph in China was in 2002 Shandong Shandong Synthetic Chemical Co., Ltd., which was mainly used as a new agent for controlling downy mildew and epidemic diseases. At that time, the market volume of dimethomorph was very small. Subsequently, the domestic production of dimethomorph was developed to nearly 10 companies, such as Shandong Xianda, Jiangsu Changlong, Jiangsu Gengsheng and other total annual production capacity of more than 1,000 tons, the original drug content is between 95% and 97%.

The domestic market capacity is about 500 tons / year, and the export is between 200 and 300 tons / year, mainly exported to Southeast Asia and South America. The main markets of dimethomorph in foreign countries are Brazil, Europe, the United States, Australia and other countries, mainly used in potatoes, grapes and other crops.

The foreign market enoylmorpholine is mainly based on BASF products, but its production plant in Brazil has a production capacity of less than 500 tons. Due to the low cost of domestic methionine morphogens, the enoylmorpholine products have A certain degree of competitiveness, with the domestic dimethomorph original drug products entering the foreign market, its market prospects are also relatively broad.

There are many types of enoylmorpholine processing agents, such as EC, WP, WG, SC, EW, and ME.

The dosage form of the foreign company Alistida registered in China is 80% dimethomorph water dispersible granules, the trade name is "Love Harmony".

At present, domestically registered dosage forms: WP (50% mostly), WG (40%, 50%, 80%, currently 80%, dozens), SC (10%, 20%, 25%) 40%), EW (10%, 20%), 80% EC (Tianx Sputol Pesticide Company only), 25% ME (Hainan Zhengye Company only).

Because the use of enoylmorpholine has a higher risk of resistance, it is often associated with other such as mancozeb, cymoxanil, metalaxyl, propidium zinc, chlorothalonil, aluminum triethylphosphonate, pyrazole. Protective fungicides such as ether fungus ester and rosin acid ketone are used in combination to delay the generation of resistance and also expand the sterilization spectrum.

Domestic compounding agents include WP (50% enoyl•fumeishuang, 69% enoyl•manganese zinc), etc.; WG (69% enoyl•manganese zinc, 57% enoyl•propenyl zinc), etc.; SC(35 % enoyl • chlorpheniramine cyanide; EW (25% enoyl • pine copper).

1. Suspending agent

For example, Li Gang et al. developed a high concentration of enoylmorpholine suspension, and used a flow point method and a viscosity method to screen 50% dimethomorph suspension suspending agent and anti-precipitant. The optimal formula finally obtained is: dimethomorph (50%) 50% (100%), T2020 (Hensman) 1.34%, WPJ 2.66%, xanthan gum 0.05%, magnesium silicate 0.5 %, ethylene glycol 3.0%, water to 100%. The obtained product has a floating liquid which is easy to flow and easy to measure, and has no agglomeration during storage. After 14 days of heat storage, the content decreased by 0.3%, the decomposition rate was less than 0.6%, the suspension rate decreased by 1.6%, but it was still above 90%, and the pourability was still acceptable, indicating that the product has good thermal stability. After the preparation was stored at (0±2) °C for 7 days, the sieve precipitation decreased by 0.4%, the suspension rate decreased by 1.3%, but still exceeded 91%, and the pourability was still acceptable, indicating that the product has good cold storage stability. Other measured indicators are in line with the requirements of the suspending agent.

2, water dispersion granule formulation research and development

Water-dispersible granules are environmentally safe dosage forms that combine the advantages of both wettable powders and suspending agents while overcoming their shortcomings. The dosage forms are dust-free, do not use organic solvents, have good fluidity, are easy to measure, and are easy to package. It is safe and convenient to store and transport; it has high preparation content, good disintegration and dispersibility in water, high suspension rate, good stability and convenient use. Compared with other dosage forms, enoylmorpholine is more suitable for processing into water-dispersible granules. Therefore, it is preferred to process enoylmorpholine into water-dispersible granules at home and abroad.

4.2.1 Development of single-agent formulation of water-dispersible granules

(1) Liu Qindong carried out the formulation study of 40% dimethomorph water dispersible granules, and determined the optimum formula by screening the additives such as wetting and dispersing agent, disintegrating agent, binder, filler and the like. : dimethomorph original drug (content ≥ 95%) 40% (100%), naphthalene sulfonate dispersant SF 6%, wetting agent BX (open powder) 2%, help disintegrant urea 5%, The binder fructose was 0.3% and the kaolin was made up to 100%. The sample was tested and the appearance was light yellow columnar particles, enoylmorpholine content 40.3%, wetting time 13 s, disintegration time 48 s, suspension rate 92.2%, moisture content 1.2%, pH value 6.8, heat storage stability Qualified, all indicators meet the requirements of water-dispersible granules.

(2) Cheng Xiaohu et al. studied the formulation of 50% dimethomorph water dispersible granules (extrusion granulation method). Wetting agents K12 and FLA-1 (bamboo oil products) are used in combination with the selection of wetting agents, dispersing agents, disintegrating agents and fillers which have a great influence on the performance of the preparation, and the use of wetting agents Plays a good moisturizing effect. When the dosage of the excellent dispersant FLB-1 (bamboo oil product) reaches 4%, the suspension rate reaches 90%. By selecting a disintegrant, urea has better disintegration properties than ammonium sulfate and FLB-3 (a bamboo oil product). Since the filler in the 50% dimethomorph water dispersible granule formulation accounts for 40%, it has a great influence on the performance of the water dispersible granule product. Generally, the filler which is easy to disintegrate in water is selected, and the anhydrous sodium sulfate is used as the filler through the experiment, and the preparation obtained by using diatomaceous earth and bentonite has better disintegration property, the suspension rate is high, and the redispersibility is good. The best formula for obtaining 50% dimethomorph water-dispersible granules is: dimethomorph (97%) 50% (100%), wetting agent K12 1% and FLA-1 6%, dispersant FLB -1 4%, 5% urea, and anhydrous sodium sulfate to 100%. Test results of the sample: appearance of columnar particles, enoylmorpholine content ≥ 50%, suspension rate ≥ 90%, wetting time ≤ 60 s, disintegration ≤ 60 s, pH range 5 ~ 8, wet The sieve test (through the 75 μm test sieve) is ≥98% and the stability is acceptable.

(3) Zhou Zeyi developed 60% dimethomorph water dispersible granules, and used the flow point method to screen the wetting and dispersing agent, and optimized the dosage of dispersing agent, binder and disintegrant by orthogonal design. It indicates that the choice of wetting and dispersing agent has a great influence on the levitation rate of the processed preparation. The dispersing agent NNO is worse than the dispersing agents GY-D900 and GY-D10, but the effect of dispersing agent GY-D900 and GY-D10 is not the same. Big. The best formula for obtaining 60% dimethomorph water dispersible granules is: dimethomorph original drug 60% (100%), SP-2836 5%, GY-D900 5%, L-HPC 1.0%, carrier supplement To 100%. The formulation has a disintegration time of 42 s and a suspension rate of 94% by testing the quality control standard of the water-dispersible granules.

(4) Shang Jibing et al. developed an 80% dimethomorph WG formula. The modified lignosulfonate sodium GCL4-1 was used as a dispersing agent to determine the excellent properties of the two preferred formulations by screening the wetting agent, the disintegrant and the dispersing agent and the amount. Formulation A: enoylmorpholine (content ≥ 95%) 80% (100%), dispersant GCL4-1 8%, dispersant naphthalene NMS-90 (naphthalene sulfonic acid formaldehyde condensate sodium salt) 3%, pull Open powder (sodium butyl naphthalene sulfonate) 5%, ammonium sulfate 4%, bentonite to 100%. Formulation B: enoylmorpholine (content ≥95%) 80% (100%), dispersant GCL4-1 10%, pulverized powder (sodium butylnaphthalene sulfonate) 5%, ammonium sulfate 4%, bentonite complement To 100%.

The two formulations of enoylmorpholine were compared with the performance of commercially available control products, see Table 1.

It can be seen that it is preferred that Formulation A and Formulation B are similar in performance to the control product (in particular, Formula A is superior to the control product), but the cost used in the water-dispersible granules, Formula A and Formula B are much lower than Compare product costs.

Formulation A and Formulation B were determined. The suspension rates before heat storage were 96.67% and 95.47%, respectively. The suspension rates after heat storage were basically the same as those of the commercially available control products (95.03% and 89.60%, respectively, before and after heat storage).

The above three kinds of 80% enoylmorpholine water-dispersible granule products were measured for stability of the water-dispersible granule suspension by a Turbiscan LabExpert dispersion stabilizer (Formulaction, France), and it was found that the stability of the suspension of the three formulations was deteriorated. However, the water-dispersible granule suspensions of the A and B formulations are relatively stable. The initial particle size of the suspension after the heat storage of Formulation A and Formula B is about 4 μm, and the thickness and particle size of the precipitate layer of 2 h are 0.4 mm and 5 μm, respectively. They are better than the commercially available control products (0.54 mm and 8.73 μm), especially the cost of the additive is only 900 yuan / ton, far lower than the cost of the control product 2000 yuan / ton, and higher cost performance.

4.2.2 Development of water-dispersible granules

(1) Li Jianhui carried out the 69% enoyl-manganese-zinc (9+60) WG formula by extrusion granulation method, and the optimal formula was determined: enoylmorpholine (content 95%) 9% (100%) ), mancozeb (content 90%) 60% (100%), RNF066 (complex dispersant) 3.5%, lignosulfonate 3.0%, BNY088 (combined wetting agent) 1.5%, fructose to 100 %. The obtained product has a pale yellow cylindrical particle shape; the thermal decomposition rate of dimethomorph and mancozeb is less than 5%, and the suspension rates of dimethomorph and mancozeb are 89.0, respectively. % and 83.0%, wetting time 6 s, pH 7.3, moisture 1.8%, disintegration (stationary time) 33 s, storage stability.

(2) The compound preparation developed by BASF is 18.7% pyraclostrobin•enoylmorpholine (6.7+12.0) WG product, trade name Kate.

Domestic Wang Tiewei and other fluidized bed granulation methods also developed 18.7% pyraclostrobin enoylmorpholine WG. The final optimal composition is: 6.7% pyridostigmine, enoylmorpholine (content 98%) 12%, wetting agent TERWET 1004 4%, dispersant D-425+T /36 9%, 8% ammonium sulfate, and bentonite to 100%.

The obtained product performance index was 93.68%, the wetting time was 11.23 s, the disintegration time was 35.36 s, and the heat storage stability was qualified. The effect of 18.7% pyraclostrobin enoylmorpholine WG on potato late blight was tested. The results showed that the product had obvious control effect on potato late blight, which was 82.3%～90.6%, and it has obvious therapeutic effect. .

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