Enoylmorph (dimethomorph) is a derivative of cinnamic acid compound, belongs to the morpholine class of fungicides. 1988 was first reported in France for the control of downy mildew of grapes and potatoes, tomato late blight, is a new control of downy mildew genus pathogenic fungal diseases of highly effective systemic fungicide, and the benzamide fungicide resistant and sensitive strains have high activity. In practical applications, enoylmorph is another ideal fungicide after mefenoxam for the control of oomycete diseases and is particularly suitable for resistance management in fields where benzamide fungicide-resistant pathogen individuals are dominant.
It is a morpholine-ring based fungicide product developed by Shell (now BASF) and entered the market in 1992, mainly for potatoes, grapes and other crops. With the transfer and acquisition of the company, the product has belonged to Shell, Cyanamid and BASF, and has been widely used in various regions of the world. In recent years, its global sales have been in the first place of morpholine-based fungicides (mainly including enoylmorpholine, fluomorpholine, butylmorpholine, tridecamorpholine and dodecamorpholine).
I. Allylmorpholine Market
Allylmorpholine registered major dosage form products: the trade name Forum, for the control of downy mildew of grapes; Acrobat for the control of potato blight. 2002 in the United States to obtain further registration, but also in the EU re-registration, since 2007 allylmorpholine successfully re-registered, its main market in Europe, followed by Asia.
Since enoylmorpholine is a product for oomycete diseases, it is widely used in various regions of the world, especially in Europe, USA, Australia and Asia. It is mainly used for the control of diseases caused by oomycete fungi of the subphylum Flagellomycetes, such as downy mildew, blight, seedling blight, and tobacco black tibia in potatoes, grapes, cucurbits, and vegetables, and is also used for diseases of tomatoes and other crops. Growth in the use of enoylmorph also led to growth in disease fungicides, with sales of $65 million in 2005 and $95 million in 2008. An important reason for the subsequent decline in sales of enoylmorph is the 3% decline in the fungicide market due to the dominance of the potato fungicide market, which declined by 7.5% (to 124,000 hm2) in 2008?2009. Another reason is that France is a major market for grapevine fungicides, and products used to control downy mildew on grapes, which generally account for 60% of the market, were affected by a long winter in 2009, with high inventory levels, resulting in lower prices for enoylmorpholine products and resulting in lower sales of enoylmorpholine. The third reason is that global sales of enoylmorpholine also declined as more products targeting oomycete diseases entered the market.
Sales of enoylmorpholine began to decline steadily from $85 million in 2009 to $80 million in 2010. Then enoylmorpholine sales remained almost at a certain level, and BASF’s 2013 enoylmorpholine sales were $75 million. 2013 enoylmorpholine global sales ranked 7th among grape fungicide varieties and 10th among potato fungicide varieties.
Second, enoylmorpholine mechanism of action
Allylmorpholine has preventive and therapeutic activity and has residual activity on crop leaves, providing excellent preventive action. When enoylmorpholine is sprayed on the crop, the agent can penetrate into the leaf tissue through the leaf surface, and through diffusion, it can be used to control diseases of many important crops by local conduction within the leaves. These include cucumber downy mildew, grape downy mildew, potato late blight, tomato late blight, tobacco black tibia, etc. Allylmorpholine and the most widely used phenyl amide fungicides (such as methomyl) no cross-resistance, and good affinity, can be used with other different types of fungicides, such as daidzein manganese? etc., so as to expand the fungicidal spectrum and use range.
Most morpholine-type fungicides are used to control powdery mildew, while the fungicidal effect of enoylmorpholine is through the direct destruction of fungal cell formation, causing the decomposition of the cell wall, which leads to the death of fungal cells, and does not have the effect of preventing powdery mildew. Although enoylmorpholine contains morpholine ring group, but the role of the morpholine ring is not the active group, but actually belongs to the acrylamide fungicide; its mechanism of action and characteristics of the inhibition of oomycete cell wall formation, with endosmosis, usually used to control potatoes, grapes, cucurbits downy mildew, epidemics, and also used in tomato and other crop diseases. Without considering the resistance of the pathogenic fungus, the use of allylmorpholine with the currently widely used mefenoxam, fenoxycarb, ? The efficacy is still higher when compared with mefenoxam, fenoxycarb, aluminum triethionate and other agents.
Three, enoylmorpholine physical and chemical properties
There are two isomers of enoylmorpholine (Z) and (E), only the (Z)-isomer is active, while the (E)-isomer is not active. However, the isomers are capable of rapid interconversion under light, and the presence of the (E)-isomer is not detrimental in practice, so it is not necessary to mind or separate them.
The original drug of enoylmorpholine consists of (E) and (Z) isomers in the ratio of 1:1. Appearance is colorless crystal, melting point 127～148℃; (E) isomer melting point 135.7～137.5.2℃; (Z) isomer melting point 169.2～170.2℃. Density 1.318 g/cm3(20℃). Solubility: <50 mg/L in water (20～23℃); 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, 20～23℃). Stability: not hydrolyzed and heat stable under normal conditions; stable under dark conditions for >5 years, two isomers of (Z) and (E) mutually change in daylight. The agent should be stored in a cool, dry storehouse under sealed conditions.
The toxicity study of the fungicide enoylmorpholine by Cen Jiangjie et al. showed that the oral toxicity and transdermal toxicity of enoylmorpholine were of low toxicity level. The agent is more sensitive to female rats than male rats, no irritation to the skin and eyes of rabbits, no sensitization to the skin, and no genotoxic effect was shown, which is similar to domestic and foreign reports. The maximum subchronic oral no-effect dose of enoylmorpholine was 30 mg/(kg?d). Combined with the information available at home and abroad, it can be concluded that enoylmorpholine is relatively safe to be applied as a pesticide.
Shi Jie et al. studied the volatility of enoylmorpholine in air, water and soil, and the samples were detected by HPLC-UV, and the test results showed that the volatility of enoylmorpholine in three media were <1%, which means that it is difficult to volatilize in air, water and soil.
IV. Allylmorpholine original drug and dosage form
Allylmorpholine original drug in the domestic first registered in 2002, Shandong Xianda Chemical Company, mainly as a new agent for the control of downy mildew, epidemic disease, when the allylmorpholine market volume is very small. Subsequently, the domestic production of enoylmorpholine developed to nearly 10 enterprises, such as Shandong Xianda, Jiangsu Changlong, Jiangsu Cultivation and other total annual production capacity of more than a thousand tons, the original drug content between 95% to 97%.
The domestic market capacity is about 500 tons/year, and the export is 200-300 tons/year, mainly sold to Southeast Asia and South America and other regions. The main markets of enoylmorpholine in foreign countries are Brazil, Europe, the United States, Australia and other countries, mainly for potatoes, grapes and other crops.
The foreign market of enoylmorpholine is mainly based on BASF products, but its production plant in Brazil, the production capacity of less than 500 tons; due to the lower cost of domestic enoylmorpholine API prices, enoylmorpholine API products have a certain degree of competitiveness, with the domestic enoylmorpholine API products into foreign markets, its market prospects are also relatively broad.
There are more processed dosage forms of enoylmorpholine, mainly: EC, WP, WG, SC, EW, ME, etc.
The dosage form registered in China by foreign company Alisda is 80% of allylmorpholine water dispersible granules, with the trade name of “Aixun”.
At present, the domestic registered dosage form products: single agent WP (50% mostly), WG (40%, 50%, 80%, currently 80% mostly, dozens of), SC (10%, 20%, 25%, 40%), EW (10%, 20%), 80% EC (only Tianjin Spurrer Pesticide Company), 25% ME (only Hainan Zhengye Company).
Because of the high risk of resistance to the use of enoylmorpholine alone, it is often used in combination with other protective fungicides such as difenoconazole, fenoxycarb, methomyl, propamocarb, chlorothalonil, aluminum triethionate, pyraclofosfomycin, turpentine, etc. to delay the emergence of resistance and also expand the fungicidal spectrum.
The domestic compounding mixes are WP (50% enoyl? Fomesan, 69% enoyl? Manganese zinc), etc.; WG (69% enoyl? Manganese zinc, 57% enoyl? Probenecid), etc.; SC (35% enoyl? Cyanuric acid); EW (25% enoyl? Pine copper).
1、Suspension agent
For example, Li Gang et al. developed a high concentration of enoylmorpholine suspension, and used the flow point method and viscosity method to screen the wetting and dispersing agent and anti-sedimentation agent of 50% enoylmorpholine suspension. The final optimal formulation was obtained as follows: 50% of the original enoylmorpholine (96%) (folded hundred), 1.34% of T2020 (Huntsman), 2.66% of WPJ, 0.05% of xanthan gum, 0.5% of magnesium aluminum silicate, 3.0% of ethylene glycol, and water replenishment to 100%. The product obtained had the appearance of an easily flowable and volume-measured suspended liquid with no agglomeration during storage. After 14 d of hot 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 decantability was still qualified, which indicated that the product was thermally stable. After the preparation was stored at (0±2)℃ for 7 d, the sieve analysis decreased by 0.4%, the suspension rate decreased by 1.3%, but it was still above 91%, and the pouring property was still qualified, which indicated that the product had good cold storage stability. Other measured indexes are in line with the requirements of suspension agent.
2、Formulation development of water dispersible granules
Water dispersible granule is a kind of both wettable powder and suspension agent, while overcoming their shortcomings of environmental protection and safety formulations, the formulations have no dust, do not use organic solvents, good fluidity, easy to measure, easy to pack, safe and convenient storage and transportation; high formulation content, good disintegration and dispersion in water, high suspension rate, good stability, easy to use and other characteristics. It is more suitable for processing into water dispersible granules than processing other dosage forms, so it is preferred to be processed into water dispersible granules at home and abroad.
4.2.1 Research and development of single agent formulation for water dispersible granules
(1) Liu Qin Dong carried out the formulation research of 40% enoylmorpholine water dispersible granules, through the screening of wetting and dispersing agent, disintegrant, binder, filler and other additives and dosage, to determine the best formula: enoylmorpholine original drug (content ≥ 95%) 40% (fold hundred), naphthalene sulfonate dispersant SF 6%, wetting agent BX (pull off powder) 2%, disintegrant urea 5%, binder fructose 0.3% The formula was tested, and the appearance of the sample was as follows The formula sample was tested, the appearance of 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 6.8, heat storage stability qualified, all indicators are in line with the requirements of water dispersible granules.
(2) Cheng Xiaohu et al. studied the formulation of 50% enoylmorpholine aqueous dispersible granules (extrusion granulation method). Through the screening of wetting agent, dispersant, disintegrant and filler which have a great influence on the performance of the formulation and their dosage selection, the wetting agent K12 and FLA-1 (Takemoto oil product) were selected to be used together, which played a good wetting effect on enoylmorpholine. The suspension rate reached 90% when the amount of excellent dispersant FLB-1 (Takemoto oil product) reached 4%. By the selection of disintegrants, urea had better disintegration performance than ammonium sulfate and FLB-3 (Takemoto grease product). As 50% of enoylmorpholine aqueous dispersible granule formulation accounted for 40% of the filler, it has a great impact on the performance of aqueous dispersible granule products. Generally, the filler which is easy to disintegrate in water is chosen. Through the experiment, anhydrous sodium sulfate is chosen as the filler which has better disintegration, high suspension rate and good redispersibility than the formulation obtained with diatomaceous earth and bentonite. Finally, the best formulation of 50% enoylmorpholine aqueous dispersible granules was obtained as follows: 50% of original enoylmorpholine (97%) (folded hundred), 1% of wetting agent K12 and FLA-1 6%, 4% of dispersant FLB-1, 5% of urea, and anhydrous sodium sulfate filler to 100%. The test results of the formulation samples: the appearance of columnar particles, enoylmorpholine content ≥ 50%, suspension rate ≥ 90%, wetting time ≤ 60 s, disintegration ≤ 60 s, pH range 5 ~ 8, wet sieve test (through 75 μm test sieve) ≥ 98%, stability qualified.
(3) Zhou Zeyi developed 60% enoylmorpholine aqueous dispersible granules. The wetting and dispersing agents were screened by the flow point method, and the amounts of dispersant, binder and disintegrant were optimized by the orthogonal design method. It was shown that the selection of wetting and dispersing agents had a great influence on the high suspension rate of processed formulations, and dispersant NNO was worse than both dispersants GY-D900 and GY-D10, while the effect of using dispersants GY-D900 and GY-D10 was not much different. The best formulation of 60% enoylmorpholine aqueous dispersible granules was obtained as follows: 60% of original enoylmorpholine (folded hundred), 5% of SP-2836, 5% of GY-D900, 1.0% of L-HPC, and the carrier was made up to 100%. The disintegration time of the formulation was 42 s and the suspension rate was 94% by testing the quality control standard of the water dispersible granule.
(4) The formulation of 80% enoylmorpholine WG was developed by Shang Jibing et al. Using modified sodium lignosulfonate GCL4-1 as dispersant, 2 preferred formulations were finally determined to have excellent performance through screening of wetting agent, disintegrant and co-dispersant as well as dosage. Formulation A: enoylmorpholine (content ≥95%) 80% (discounted), dispersant GCL4-1 8%, auxiliary dispersant naphthalene NMS-90 (sodium salt of formaldehyde condensate of naphthalene sulfonic acid) 3%, pulling open powder (sodium butyl naphthalene sulfonate) 5%, ammonium sulfate 4%, soap clay make up to 100%. Formulation B: enoylmorpholine (content ≥ 95%) 80% (fold hundred), dispersant GCL4-1 10%, pull apart powder (butyl naphthalene sulfonic acid sodium salt) 5%, ammonium sulfate 4%, soap soil to make up to 100%.
The application performance of the two formulations of enoylmorpholine was compared with that of the commercially available control product, as shown in Table 1.
Table 1 Application performance and additive cost of three kinds of 80% enoylmorpholine water dispersible granule products
WG product type
Suspension rate(%)
Wettability(s)
Disintegration(s)
Cost of additives
(yuan/ton)
Before hot storage
After hot storage
Before hot storage
After hot storage
Before hot storage
After hot storage
Recipe A
96.67
90.65
17
17
42
48
920
Formulation B
95.47
88.65
18
23
43
46
790
Commercially available products
95.03
89.60
36
38
44
52
2,000
It can be seen that the preferred formulations A and B are similar to the control product in terms of application performance (in particular, all indicators of formulation A are better than the control product), but the cost used in the water dispersible granules, formulation A and formulation B are much lower than the cost of the control product.
