A nitrification inhibitor for stability fertilizer

Abstract

The application discloses a nitrification inhibitor for stable fertilizer, and belongs to the field of agricultural chemistry.The nitrification inhibitor has a general formula of and is relatively simple to prepare, and is prepared by reacting diketone and substituted hydrazine or by reacting pyrazole compound with different electrophilic reagents.The nitrification inhibitor has good nitrification inhibition activity in agriculture, and has more benefits in reducing nitrogen oxides, improving nitrogen utilization rate, improving crop yield and quality and the like.

Description

Technical Field

[0001] This invention belongs to the field of agricultural chemistry technology, and more specifically to nitrification inhibitors, compositions, and their applications in agriculture.

[0002] Research Background

[0003] Nitrogen is an essential mineral nutrient element for crop growth, and the application of nitrogen fertilizer is of great significance for ensuring stable grain yields. Nitrification in the soil can rapidly convert ammonium nitrogen (NH4+) into nitrogen. + (Obtained directly from nitrogen fertilizer or indirectly) is converted into nitrite ions (NO2). - Furthermore, it is oxidized into nitrate ions (NO3), which are highly susceptible to leaching and pose a risk of groundwater pollution. - The entire oxidation process is also accompanied by nitrogen oxides (N...). eq Nitrous oxide (N2O), a potent greenhouse gas, not only accelerates climate change but also damages the ozone layer, and has become one of the important sources of agricultural non-point source pollution.

[0004] Using nitrification inhibitors can effectively improve fertilizer utilization. Their main principle is to inhibit soil nitrification microorganisms and delay the production of ammonium nitrogen (NH4+). + Nitrification inhibitors improve crop nutrient absorption and utilization efficiency, particularly nitrogen use efficiency, while also helping to reduce nitrogen oxide emissions and nitrate leaching, thus mitigating the environmental impact of agricultural production. The Intergovernmental Panel on Climate Change (IPCC) also recommends the use of nitrification inhibitors in agricultural production to mitigate nitrous oxide (N2O) emissions. Currently, major commercially available nitrification inhibitors include 3,4-dimethylpyrazole phosphate (DMPP), dicyandiamide (DCD), and 2-chloro-6-trichloromethylpyridine (CP). Among these, DMPP is considered the most promising nitrification inhibitor due to its good safety, agronomic effects, and environmental benefits. However, the design and development of novel nitrification inhibitors is relatively lagging behind. It is noteworthy that the University of Melbourne in Australia recently reported a series of triazole nitrification inhibitors, exhibiting good nitrification inhibition activity. However, the synthesis methods of these products require raw materials such as easily burstable pipes or special process conditions such as microwave reactions, which limits their commercialization prospects (Nature, 2021, 11, 14980; ACSAgric.Sci.Technol. 2023, 3, 867; ACSAgric.Sci.Technol. 2024, 4, 255). However, current nitrification inhibitors still face challenges related to activity, half-life, stability, differences in actual efficacy, and ecotoxicology. Furthermore, agricultural production is influenced by a combination of factors, including region, soil, climate, fertilization methods, timing, and crop type. Therefore, designing and developing novel inhibitors remains of practical value and research significance. Summary of the Invention

[0005] This invention addresses the shortcomings of existing nitrification inhibitors by designing and developing a series of novel nitrification inhibitors for reducing nitrification in soil, and provides their synthesis methods.

[0006] The nitration inhibitor of this invention comprises: compound A, compound B, and a salt of compound A or a salt of compound B. Compound A is a mixture of a single compound and isomers at positions 3, 4, and 4, 5 of the pyrazole ring; compound B is a mixture of a single compound and isomers at positions 3, 4, and 4, 5 of the pyrazole ring. The general formula of the nitration inhibitor is:

[0007]

[0008] Where: R 1 and R 2 Each group is independently selected from hydrogen or C1-C6 alkyl; R is selected from C2-C6 alkylyl, benzoyl, succinic acid-2-yl, aminothiocarbonyl, aminocarbonyl, substituted benzenesulfonyl, substituted phenyl, pyridyl, succinimide-2-yl, substituted phenylacetic acid-1-(C1-C4)alkyl, succinic acid-2-(C1-C4)alkyl, 2-ureaacetic acid-1-yl, succinic acid (C1-C4)alkyl ester-2-(C1-C4)alkyl, carboxyl-substituted (C1- C4) Straight-chain or branched alkyl, acyl-substituted C1-C4 alkyl; wherein the substituents in substituted benzenesulfonyl, substituted phenyl, and substituted phenylacetic acid-1-(C1-C4)alkyl are all selected from hydrogen, C1-C4 alkoxycarbonyl, halogen or C1-C4 alkyl, and the acyl substitution is selected from acetyl or benzoyl; X is selected from phthaloyl, oxaloyl, urea N,N'-di(C1-C4)alkyl, diphenylmethane diaminodiacyl, C1-C6 alkyl diaminodiacyl.

[0009] Furthermore, in the above technical solution, R 1 and R 2 Each is independently selected from hydrogen or methyl; R is selected from acetyl, benzoyl, succinic acid-2-yl, aminothiocarbonyl, aminocarbonyl, p-toluenesulfonyl, phenyl, 2-methoxycarbonylphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-ylsuccinimide-2-yl, phenylacetic acid-1-methyl, succinic acid-2-methyl, 2-ureaacetic acid-1-yl, methyl succinate-2-methyl, propionic acid-1-yl, 1-acetylethyl, 1-benzoylethyl; X is selected from phthaloyl, oxaloyl, urea N,N'-dimethyl, diphenylmethane diaminodiacyl, hexamethylenediaminediacyl.

[0010] Furthermore, in the most preferred embodiment of the above technical solution, the nitration inhibitor is selected from... One or more of them.

[0011] Furthermore, the corresponding salt is selected from sodium salts, potassium salts, lithium salts, and quaternary ammonium salts (such as NH4, tetramethylamine, tetra-n-butylamine, etc.).

[0012] The present invention also provides a method for preparing the above-mentioned nitration inhibitor, comprising the following steps: reacting a diketone with a substituted hydrazine, or reacting a pyrazole compound with different electrophilic reagents.

[0013] This invention also provides the application of the above-mentioned nitrification inhibitor in agricultural soils.

[0014] Furthermore, in the above technical solution, when the nitrification inhibitor is applied in agricultural soil, it is added to nitrogen-containing fertilizer and then added to the soil.

[0015] Furthermore, in the above technical solution, the nitrogen-containing fertilizer is selected from nitrogen-phosphorus-potassium compound fertilizer, ammonium sulfate, ammonium chloride, urea, ammonium phosphate, monoammonium phosphate, diammonium phosphate, ammonium nitrate, etc.

[0016] Furthermore, in the above technical solution, the nitrification inhibitor accounts for 0.1-2.0% of the nitrogen content of the stabilized fertilizer, preferably 0.1-0.5%.

[0017] Furthermore, in the most preferred embodiment of the above technical solution, the nitration inhibitor is selected from... One or more of them.

[0018] The present invention also provides a stabilized fertilizer containing the above-mentioned nitrification inhibitor.

[0019] Furthermore, in the above technical solution, the nitrification inhibitor accounts for 0.1-2.0% of the nitrogen content of the stabilized fertilizer, preferably 0.1-0.5%.

[0020] Furthermore, in the most preferred embodiment of the above technical solution, the inhibitor is selected from...

[0021] One or more of them.

[0022] Beneficial effects of the invention

[0023] The compound of this invention has a novel structure that can effectively inhibit soil nitrification and has many benefits such as reducing nitrogen oxide emissions, nitrate leaching, improving nitrogen fertilizer utilization, and increasing crop yield and quality. Detailed Implementation

[0024] Example 1 Synthesis of a Novel Nitrification Inhibitor

[0025] 1-Acetyl-3,5-dimethylpyrazole (1): 340 mL of water and 170 g (2.3 mol) of acetylhydrazine were added to a round-bottom flask. 241.29 g (2.4 mol, 1.05 eq) of acetylacetone was slowly added dropwise at 0-10 °C, followed by 41.34 g (0.69 mol, 0.3 eq) of acetic acid. After the addition was complete, the system was heated to 50 °C and maintained at this temperature for 3 hours. After the reaction was completed, the mixture was allowed to stand and separate into layers. The organic layer was distilled under reduced pressure to obtain 296 g of colorless liquid product 1, with a yield of 93%.

[0026] 1 H NMR (400MHz, DMSO-d6): δ6.18 (s, 1H), 2.57 (s, 1H), 2.45 (s, 3H), 2.17 (s, 3H). LC-MS: 139.1 (M+H). HPLC99.9%.

[0027] 1-Acetyl-3,4-dimethylpyrazole / 1-Acetyl-4,5-dimethylpyrazole (2): 106.7 g of 3,4-dimethylpyrazole, 554.8 g of dichloromethane, and 131.05 g (1.23 eq) of sodium bicarbonate solid powder were added to a three-necked flask. 102.05 g (0.96 eq) of acetyl chloride was added dropwise while maintaining the temperature (0–15 °C), and the reaction continued for 2–3 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain an oily substance. Further distillation under reduced pressure yielded 147 g of colorless liquid product 2 (a mixture of 2A and 2B), with a yield of 96%.

[0028] 1 H NMR (400MHz, DMSO-d6): δ8.06(s,3H),2.57(s,1H),7.60(s,0.07H),2.59(s,0.3H),2.54 (s,3H),2.40(s,0.3H),2.17(s,0.3H),1.98(s,3H),1.95(s,0.3H).LC-MS:139.1(M+H).

[0029] 2-(3,5-Dimethylpyrazol-1-yl)succinic acid (3): 20 g of 3,5-dimethylpyrazol, 94.32 g of acetonitrile, and 20.04 g (1.002 eq) of maleic anhydride were added to a single-necked flask. The mixture was heated to 60 °C and maintained at this temperature for 20 h. 100 mL (5V) of water was added, and the mixture was concentrated by rotary evaporation at 50 °C. Another 100 mL (5V) of water was added, and the mixture was stirred at 60 °C for 2 h. The mixture was then slowly cooled to 0-10 °C and stirred for 1-2 h. The filter cake was washed 2-3 times with 60-80 mL (3-4V) of MTBE. The filter cake was dried at 45 °C for 20 h to obtain 41 g of grayish-white solid product 3, with a yield of 92%.

[0030] 1 H NMR (400MHz, DMSO-d6): δ12.76(brs,2H),5.79(s,1H),5.04-5.07(q,1H),3.02-3.04(q,1H),2.94-2.97(q,1H),2.14(s,3H),2.01(s,3H).

[0031] 2-(3 / 5-methylpyrazol-1-yl)succinic acid (4): 20 g of 3-methylpyrazole, 78.6 g of acetonitrile, and 28.6 g (1.43 eq) of maleic anhydride were added to a single-necked flask, heated to 40 °C, and maintained at this temperature for 20 h. The mixture was concentrated by rotary evaporation at 50 °C, and 20 mL (1 V) of water was added. The mixture was then slowly cooled to 0-10 °C and stirred for 1-2 h. The mixture was filtered, and the filter cake was washed with ice water. The filter cake was dried in a forced-air dryer at 45 °C for 20 h to obtain 43 g of white solid product 4 (a mixture of 4A and 4B), with a yield of 89%.

[0032] 1 H NMR (400MHz, DMSO-d6): δ12.72(brs,2.6H),7.67(s,1H),7.32(s,0.3H),6.00(s,1.3H),5. 20-5.24(q,1.3H),3.06-3.18(q,1.6H),2.93-2.99(q,1H),2.28(s,1H),2.13(s,3H).HPLC 99.9%.

[0033] 2-(pyrazol-1-yl)succinic acid (5): Add 400 mL of acetonitrile to a three-necked flask, add 50 g of pyrazole while stirring, then add 50.4 g (1.008 eq) of maleic anhydride. After the addition is complete, heat to 60 °C and react for 18 h. Slowly add 54 g (1.1 eq) of 43% KOH solution at 10-20 °C to produce a large amount of solid. Filter by suction, wash the filter cake with 100-150 mL of acetonitrile, and dry the filter cake in a forced-air dryer at 40 °C for 12 h to obtain 91.18 g of white (yellowish) solid product 5.

[0034] 1 H NMR (400MHz, D2O): δ7.58(d,J=2.27Hz,1H),7.45(d,J=1.7Hz,1H),6.25(t,J=2.1Hz,1H),5 .17(dd,J=9.5,5.4Hz,1H),3.14(dd,J=16.7,5.4Hz,1H),3.02(dd,J=16.7,9.5Hz,1H).HPLC 99.5%.

[0035] 3-(3,4 / 4,5-dimethyl-1H-pyrazol-1-yl)propionic acid (6): DMP (9.6 g), acrylic acid (7.56 g, 0.788 eq), and 20 mL of water were added sequentially to a 100 mL three-necked flask. The system separated into two layers. The temperature was raised to 50-60 °C and reacted for 16-18 h until the system remained two-layered. Then the temperature was raised to 95-100 °C and reacted for 1-2 h until the system became homogeneous. All volatile substances in the system were evaporated under reduced pressure at 60 °C. After cooling, 10.2 g of a white waxy solid product 6 (a mixture of 6A and 6B) was obtained.

[0036] 1 H NMR (DMSO-d6, 400MHz): δ1.89-1.92(m,3H), 2.04-2.15(m,3H), 2.69-2.79(m,2H), 4.13-4.20(m,2H), 7.15-7.31(m,1H). LC-MS: 169.1(M+H).

[0037] 3,5-Dimethylpyrazole-1-carbosulfan (7): 400 g of water and 49.9 g of thioaminourea were added to a 1 L three-necked flask. 54.8 g (1.096 eq) of acetylacetone was added dropwise at 0-5 °C, and 5.55 g (0.111 eq) of 36% hydrochloric acid was added dropwise at 10-15 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 30-60 min. TLC was used to confirm complete reaction. The temperature was then slowly lowered to 0-10 °C and stirred for 30 min while maintaining this temperature. The mixture was filtered, the filter cake was washed with ice water, and dried at 40 °C for 12 hours to obtain 82.77 g of white solid product 7, with a yield of 97.5%.

[0038] 1 H NMR (400MHz, DMSO-d6): δ9.57(s,1H),9.16(s,1H),6.19(s,1H),2.65(s,3H),2.17(s,3H).

[0039] 3-Methylpyrazole-1 / 2-carbosulfan (8): Add 480 mL of methanol to a three-necked flask, add 41.38 g (0.69 eq) of thioaminourea while stirring at 0-15 °C, then add 60 g of 4,4-dimethoxy-2-butanone at 0-15 °C, and add 23.02 g (0.383 eq) of 36% HCl dropwise at 0-15 °C. After the addition is complete, react at room temperature for 5-6 h, and monitor the reaction completion by TLC. Heat to 60 °C and reflux for 2 h, then concentrate to dryness under vacuum at 40 °C, add 300 mL of water and stir at 0-10 °C for 0.5 h. Filter and wash with ice water at 0-5 °C. Dry the filter cake at 40 °C, yielding a total of 30.75 g of solid product 8 (8A+8B mixture).

[0040] 1 H NMR (400MHz, DMSO-d6): δ9.78 (s, 1H), 9.30 (s, 1H), 8.53 (d, J = 2.7Hz, 1H), 6.38 (d, J = 2.7Hz, 1H), 2.26 (s, 3H). LC-MS: 142.0 (M + H). HPLC 99.9%.

[0041] 3,4-Dimethylpyrazole-1-carbamide (9): 20.5g of 3,4-dimethylpyrazole, 160g of water and 19.7g (1.18eq) of potassium cyanate were added to a three-necked flask. The temperature was controlled at 0-10℃. 24.3g (1.26eq) of 36% hydrochloric acid was slowly added dropwise through a constant pressure dropping funnel. The mixture was stirred at 0-10℃ for 4-5 hours. The raw materials were monitored in the central control. The mixture was filtered, and the filtered solid was dried in a forced-air drying oven at 50℃ for 12 hours to obtain 25.3g of white solid product 9, with a yield of 91.0%.

[0042] 1 H NMR (400MHz, DMSO-d6): δ 7.92 (s, 1H), 7.54 (s, 2H), 2.15 (s, 3H), 1.97 (s, 3H). HPLC 99.5%.

[0043] 3,4 / 4,5-Dimethylpyrazole-1-p-toluenesulfonamide (10): 20.5 g of 3,4-dimethylpyrazole, 160 g of water and 19.7 g (1.18 eq) of potassium cyanate were added to a three-necked flask. The temperature was controlled at 0-10 °C. 24.3 g (1.26 eq) of 36% hydrochloric acid was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred at 0-10 °C for 4-5 hours. The raw materials were monitored in the middle. The mixture was filtered. The filtered solid was dried in a forced-air drying oven at 50 °C for 12 hours to obtain 25.3 g of white solid product 10 (a mixture of 10A and 10B), with a yield of 91.0%. 1 H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.79(d,J=8.4Hz,2H),7.63(s,0.1H),7.44(d,J=8.1Hz,2H),2 .40(s,0.46H),2.38(s,3.46H),2.08(s,3H),1.93(s,3H),1.89(s,0.46H).LC-MS:251.1(M+H).HPLC 99.6%.

[0044] 3,5-Dimethylpyrazole-1-p-toluenesulfonamide (11): 300 mL of ethanol, 100 g (1.00 eq) of p-toluenesulfonyl hydrazine, and 53.8 g (0.538 eq) of acetylacetone were added to a three-necked flask. After addition, the mixture was heated to 85 °C and refluxed for 5 h. The mixture was cooled and concentrated to a minimum volume of liquid. Water was added to form a slurry, which was then filtered. The filter cake was washed with water, and the solid was dried at 40 °C with a forced air drying process to obtain 125.8 g of white solid product 11, with a yield of 93.6%.

[0045] 1 H NMR (400MHz, DMSO-d6): δ 7.80 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 6.14 (s, 1H), 2.47 (s, 3H), 2.39 (s, 3H), 2.09 (s, 3H). HPLC 99.9%.

[0046] N,N'-(hexane-1,6-diyl)bis(3,5-dimethyl-1H-pyrazole-1-carboxamide) (12): Add 300 mL of acetonitrile to a three-necked flask, then add 34.3 g (1.14 eq) of 3,5-dimethylpyrazole. Cool to 0-15 °C, then slowly add 30 g of 1,6-hexanediisocyanate, and react at 0-15 °C for 3 h. Keep the temperature below 35 °C, concentrate under reduced pressure to dryness, add water, stir at 0-5 °C, filter, and dry the filter cake at 40 °C. A total of 63.5 g of solid product 12 was obtained, with a yield of 98%.

[0047] 1 H NMR (400MHz, DMSO-d6): δ8.14(t,J=5.9Hz,2H),6.05(s,2H),3.18(dd,J=13.6,6.6Hz ,4H),2.44(s,6H),2.16(s,6H),1.60-1.43(m,4H),1.29(m,4H).LC-MS:361.2(M+H).

[0048] N,N'-(hexane-1,6-diyl)bis(3,4-dimethyl-1H-pyrazole-1-carboxamide) (13): Add 300 mL of acetonitrile to a three-necked flask, then add 34.3 g (1.14 eq) of 3,4-dimethylpyrazole. Cool to 0-15 °C, then slowly add 30 g of 1,6-hexanediisocyanate, and react at 0-15 °C for 3 h. Keep the temperature below 35 °C, concentrate under reduced pressure to dryness, add water, stir at 0-5 °C, filter, and dry the filter cake at 40 °C. A total of 62 g of solid product 13 was obtained, with a yield of 97%.

[0049] 1H NMR (400MHz, DMSO-d6): δ8.24(t,J=5.8Hz,1H),8.17(t,J=5.7Hz,1H),7.93(s,1H),7.46(s,1H),3.18(dd,J=12.6,6.2Hz,4H ), 2.40 (s, 3H), 2.15 (s, 3H), 1.96 (s, 3H), 1.94 (s, 3H), 1.47-1.54 (m, 4H), 1.25-1.32 (m, 4H). LC-MS: 361.2 (M+H). HPLC99.9%.

[0050] N,N'-(methylbis(4,1-phenylene))bis(3,4-dimethyl-1H-pyrazole-1-carboxamide) (14): 150 mL of acetonitrile and 30 g of 4,4-diphenylmethane diisocyanate were added to a three-necked flask. The temperature was lowered to 0-15 °C, and a solution of 30 g of 3,4-dimethylpyrazole in acetonitrile (pre-dissolved in 150 mL of acetonitrile) was slowly added dropwise. After addition, the mixture was kept at 0-15 °C for 3 hours. The solution was concentrated to dryness under reduced pressure, water was added, and the mixture was stirred at 0-5 °C. The mixture was filtered, and the solid was dried at 40 °C. A total of 50.5 g of solid product 14 was obtained, with a yield of 95%.

[0051] 1 H NMR (400MHz, DMSO-d6): δ10.15(s,0.2H),10.08(s,2H),8.07(s,2H),7.62(d,J=8.5Hz,4H),7.20(d,J=8.4Hz,4H),3. 88(s,1.8H),3.71(s,0.2H),2.46(s,0.6H),2.22(s,6H),2.01(s,6H),1.99(s,0.6H).LC-MS:443.2(M+H).HPLC99.9%.

[0052] 1-((3,4-Dimethyl-1H-pyrazole-1-yl)methyl)urea (15): 15.0 g of 3,4-dimethylpyrazole, 13.4 g of 35-38 wt% formaldehyde, and 46.85 g of urea were added to a reaction flask, followed by the dropwise addition of 0.5 g of phosphoric acid. The mixture was stirred overnight at 15-20 °C. After filtration, washing with water, and drying the filter cake at 45 °C, 5.0 g of a white solid product 15 was obtained, with a yield of 19%.

[0053] 1H NMR (400MHz, DMSO-d6): δ7.42 (s), 7.18 (s), 6.59 (dt, J = 20.2, 7.4Hz), 5.30 (d, J = 7. 2Hz), 5.20 (d, J=7.4Hz), 3.69 (s), 2.19 (s), 2.07 (s), 1.92 (s). LC-MS: 169.2 (M+H).

[0054] 1,3-Bis((3,4-dimethyl-1H-pyrazol-1-yl)methyl)urine (16): 15.0 g of DMP, 18 g (0.53 eq) of 35-38 wt% formaldehyde and 12.6 g (0.65 eq) of urea were added to a reaction flask, and 2.0 g (0.1 eq) of phosphoric acid was added dropwise. The mixture was stirred overnight at 45 °C, concentrated, dissolved in 100 mL of ethyl acetate, washed with 100 mL of 8.5% phosphoric acid aqueous solution, and the organic phase was separated. The organic phase was concentrated, slurried in 30 mL of petroleum ether for 0.5 h, filtered, and the resulting filter cake was dried at 45 °C to obtain 18 g of white solid product 16.

[0055] 1 H NMR (400MHz, DMSO-d6): δ7.31(s,1H),7.16(s,1H),5.21(d,J=6.5Hz,1H),5.11(dd,J=14 .0,6.6Hz,2H),2.04(s,1H),2.03(s,2H),1.90(s,1H),1.89(s,3H).LC-MS:276.34(M+H).

[0056] 3-(3,4 / 4,5-dimethyl-1H-pyrazol-1-yl)pyrrolidine-2,5-dione (17): DMP (9.6 g), maleimide (10.7 g, 1.11 eq) and 20 mL of water were added to a three-necked flask. The mixture was heated to 100-110 °C and reacted for 16 h. The mixture was then cooled naturally to 10-20 °C with stirring and stirred for 4 h. A solid precipitated out. The mixture was then cooled with ice water and stirred for 2 h. The mixture was filtered, and the filter cake was washed twice with water to obtain the product. The product was dried in a forced-air dryer at 45-50 °C for 20 h. The product was weighed to obtain 12 g of pink powder product 17 (a mixture of 17A and 17B). 1 H NMR(DMSO-d6,400MHz): δ1.90-1.93(m,3H),2.03-2.07(m,3H),2.87-2.92(m,1H),3.10- 3.19(m,1H),5.29-5.47(m,1H),7.25-7.54(m,1H),10.47(brs,1H).LC-MS:194.1(M+H).

[0057] 2-(3,4 / 4,5-Dimethyl-1H-pyrazol-1-yl)pyridine (18): 3,4-Dimethylpyrazole (7.03 g, 0.70 eq), cuprous oxide (0.14 g, 0.01 eq), N1,N2-di(furan-2-ylmethyl)oxyaldehyde amide (0.24 g, 0.02 eq), potassium phosphate (20.71 g, 2.07 eq), acetonitrile (50 mL), and 2-iodine were added sequentially to a three-necked flask. Pyridine (10.00 g); after nitrogen purging three times, the temperature was raised to 80-90 °C and reacted for 142 h; TLC showed almost no 2-iodopyridine remaining; heating was stopped, and the mixture was allowed to cool naturally to 20-30 °C with stirring; the mixture was filtered through diatomaceous earth to remove insoluble matter, and the filter cake was washed with acetonitrile; the filtrate was collected and concentrated to obtain a yellow oily substance; the product was concentrated by column chromatography with wet petroleum ether to obtain 4.98 g of off-white crystalline (yellowish) product 18 (a mixture of 18A and 18B), with a yield of 58.9%.

[0058] 1 H NMR (400MHz, DMSO-d6) δ8.48(ddd,J=4.8,3.6,2.4Hz,1H),8.41(ddd,J=4.8,1.7,0.7Hz,1H),8.31(s,1H),8.00-7.88(m,1H),7.83(dd,J= 8.3, 4.0Hz, 1H), 7.53 (s, 1H), 7.37-7.29 (m, 1H), 7.30-7.14 (m, 1H), 2.21 (s, 3H), 2.03 (d, J = 0.7Hz, 3H), 2.02 (s, 3H). LC-MS: 174.1 (M+H).

[0059] 3-(3,4 / 4,5-dimethyl-1H-pyrazol-1-yl)pyridine (19): Under nitrogen protection, acetonitrile (75 mL), DMP (7.0 g, 0.7 eq), Cu2O (0.14 g, 0.01 eq), BMFO (0.24 g, 0.01 eq), K3PO4 (20.7 g, 2.1 eq), and 3-iodopyridine (10 g) were added to a three-necked flask, and the mixture was refluxed for 72 h. The color gradually changed from pink to brownish-yellow. Heating was stopped, and the mixture was allowed to cool naturally to 30–50°C with stirring. The mixture was filtered through diatomaceous earth to remove insoluble matter. The filter cake was washed with ethyl acetate, and the filtrate was collected. 20g of 200–300 mesh silica gel was added, and the mixture was concentrated to dryness under vacuum at 40–45°C. Column chromatography with a PE / EA ratio of 10 / 1 and a PE / EA ratio of 5 / 1 was used to separate 4.5g of yellow oily substance 19 (a mixture of 19A and 19B), with a yield of 53.3%.

[0060] 1H NMR (400MHz, DMSO-d6): δ9.04(d,J=2.6Hz,1H),8.79(d,J=2.5Hz,0.3H),8.61( dd,J=4.7,1.4Hz,0.3H),8.44(dd,J=4.7,1.3Hz,1H),8.25(s,1H),7.96(m,J=8 .2,2.4,1.5Hz,0.3H),7.52(s,0.3H),7.47(dd,J=8.3,4.7Hz,1H),2.27(d,J=4 .7Hz, 1H), 2.20 (d, J = 7.6Hz, 3H), 2.03 (s, 3H), 2.00 (s, 1H). LC-MS: 174.1 (M+H).

[0061] 4-(3,4 / 4,5-dimethyl-1H-pyrazol-1-yl)pyridine (20): 10 g of 4-iodopyridine was added to the reaction flask, 7.0 g (0.73 eq) of DMP was added to the reaction flask, 0.14 g (0.014 eq) of cuprous oxide was added to the reaction flask, 0.24 g (0.024 eq) of BFMO was added to the reaction flask, and 20.7 g (2.0 eq) of potassium phosphate was added to the reaction flask. Nitrogen gas was purged three times, 50 mL of acetonitrile was added, and the reaction was carried out at 85 °C for 72 h. After the DMP reaction was basically completed, the reaction solution was cooled to room temperature naturally, filtered, the filtrate was concentrated to dryness, column chromatography was performed, and the sample was loaded by dry method to obtain 2.3 g of yellow solid 20 (20A+20B mixture).

[0062] 1 H NMR (400MHz, DMSO-d6): δ8.66(dd,J=4.6,1.6Hz,1H),8.62-8.49(m,4H),8.36(s,2H),7.72(dd,J=4.7,1.6Hz,4H),7.61(dd,J=4. 6, 1.6Hz, 1H), 7.56 (d, J = 7.0Hz, 1H), 2.37 (d, J = 7.5Hz, 1H), 2.20 (s, 6H), 2.03 (d, J = 0.6Hz, 6H), 2.02 (s, 2H). LC-MS: 174.1 (M+H).

[0063] 3,4 / 4,5-Dimethyl-1-phenyl-1H-pyrazole (21): Under nitrogen protection, acetonitrile (12 mL), DMP (0.85 g, 0.43 eq), Cu2O (0.04 g, 0.02 eq), BMFO (0.07 g, 0.02 eq), K3PO4 (3.4 g, 1.7 eq), and iodobenzene (2 g) were added to a three-necked flask. The mixture was heated to reflux for 48 h, and the color gradually changed from pink to brownish-yellow. Heating was stopped, and the mixture was allowed to cool naturally to 30–50 °C with stirring. The mixture was filtered through diatomaceous earth to remove insoluble matter, washed with ethyl acetate, and the filtrate was collected. 4 g of 200–300 mesh silica gel was added, and the mixture was concentrated to dryness under vacuum at 40–45 °C. PE / EA=40 / 1 column chromatography and PE / EA=30 / 1 column chromatography were used to separate 0.6 g of yellow oily substance 21 (a mixture of 21A and 21B), with a yield of 35%.

[0064] 1 H NMR (400MHz, DMSO-d6): δ8.14 (s, 1H), 7.73 (d, J = 7.7Hz, 2H), 7.48-7.40 (m, 2H), 7.21 (t, J = 7.4Hz, 1H), 2.19 (s, 3H), 2.02 (s, 3H). LC-MS: 173.1 (M + H).

[0065] Methyl 2-(3,4 / 4,5-dimethyl-1H-pyrazole-1-yl)benzoate (22): Under nitrogen protection, acetonitrile (50 mL), DMP (5.5 g, 0.55 eq), Cu2O (0.16 g, 0.01 eq), BFM2O (0.28 g, 0.03 eq), K3PO4 (16.18 g, 1.62 eq) and methyl 2-iodobenzoate (10 g) were added to a three-necked flask; the temperature was raised to 85-95 °C and reacted for 22-24 h. A small amount of methyl 2-iodobenzoate remained in the TLC. Heating was stopped, and the mixture was allowed to cool naturally to 10-30 °C with stirring; the mixture was filtered through diatomaceous earth and washed with acetonitrile; the crude product was obtained after vacuum concentration, and column chromatography yielded 3.42 g of pale yellow oily substance 22 (a mixture of 22A and 22B), with a yield of 38.9%.

[0066] 1 H NMR (400MHz, DMSO-d6): δ7.87(s,1H),7.68-7.49(m,3H),7.43-7.32(m,1H),3 .64(d,J=5.4Hz,3H),2.13(s,3H),2.01(d,J=0.7Hz,3H).LC-MS:231.1(M+H).

[0067] 1,2-Bis(3,4 / 4,5-dimethyl-1H-pyrazol-1-yl)ethane-1,2-one (23): 15.0 g of DMP and 100 mL of THF were added to the reaction flask. The temperature was controlled at 5-15 °C in an ice-salt bath. 8.0 g (0.53 eq) of oxaloyl chloride was added dropwise to the reaction flask. The mixture was stirred for 30 min. The temperature was controlled at 15-25 °C in an ice-salt bath. 15.7 g (1.05 eq) of triethylamine was added to the reaction flask. The mixture was stirred overnight. The filtrate was filtered and concentrated. The filtrate was dissolved in 100 mL of ethyl acetate and washed with 100 mL of 8.5% phosphoric acid aqueous solution. The organic phase was concentrated, pulped with petroleum ether, filtered, and dried at 45 °C to obtain 3.65 g of white solid 23 (a mixture of 23A, 23B, and 23C).

[0068] 1 H NMR (400MHz, DMSO-d6): δ8.30 (s, 2H), 2.12 (s, 6H), 2.03 (s, 6H). LC-MS: 247.1 (M+H).

[0069] (1,4-Terephthaloyl)(3,4 / 4,5-dimethyl-1H-pyrazole (24): In a three-necked reaction flask, add 15.0 g of DMP and 30 mL of THF. Dissolve 15.08 g of terephthaloyl chloride in 150 mL of THF. Add the solution dropwise to the reaction flask while maintaining the temperature in an ice-salt bath at 5–15 °C. Stir for 30 min. Add 18.7 g of triethylamine to the reaction flask while maintaining the temperature in an ice-salt bath at 15–25 °C. Stir overnight. Filter the solution. Concentrate the filtrate. Slurry the resulting solid in water and filter. Wash with petroleum ether. Filter again and dry at 45 °C to obtain 14.9 g of white solid 24 (a mixture of 24A, 24B, and 24C).

[0070] 1 H NMR (400MHz, DMSO-d6): δ8.29 (s, 2H), 8.04 (s, 4H), 2.20 (s, 6H), 2.05 (t, J = 4.5Hz, 6H). LC-MS: 323.2 (M+H).

[0071] 3-(3,4 / 4,5-dimethyl-1H-pyrazol-1-yl)-1-phenylpropanone (25): 10 mL of 50% aqueous ethanol solution, 2.0 g of DMP, and 5.3 g of 3-(dimethylamino)-1-phenylpropanone hydrochloride were added sequentially to a three-necked flask, and the mixture was heated to 85-95℃ and reacted for 6 h. The ethanol was concentrated off, and the mixture was diluted and dispersed with water. The mixture was extracted with ethyl acetate and separated. The organic phase was washed with saturated brine and separated. The mixture was concentrated to obtain a yellow oily substance, which was cooled and crystallized to obtain 4.61 g of pale yellow crystals 25 (a mixture of 25A and 25B), with a yield of 97%.

[0072] 1H NMR (400MHz, DMSO-d6): δ8.01-7.92(m,2H),7.68-7.58(m,1H),7.52(t,J=7.6Hz,2H),7.39(s,1H),7.13(s,1H),4.31( t, J=6.7Hz, 2H), 3.55 (td, J=6.7, 3.2Hz, 2H), 2.20 (s, 3H), 2.03 (s, 3H), 1.90 (s, 3H), 1.89 (s, 3H). LC-MS: 229.1 (M+H).

[0073] 4-(3,4 / 4,5-dimethyl-1H-pyrazol-1-yl)but-2-one (26): 50% aqueous ethanol solution (20 mL), DMP (10.57 g), and 4-dimethylamino-2-butanone hydrochloride (20.01 g, 1.9 eq) were added sequentially to a three-necked flask, and the mixture was heated to 85-95 °C and reacted for 19 h. The ethanol was concentrated off, and the mixture was diluted and dispersed with water. The organic phase was extracted with ethyl acetate and separated. The organic phase was washed with saturated saline solution and separated. The mixture was concentrated to obtain 14.71 g of a yellow oily substance. The product 26 (a mixture of 26A and 26B) was obtained by wet column chromatography with PE / EA ratios of 20:1 to 3:1 (isomer ratio of 2:1) with a yield of 44.1%.

[0074] 1 H NMR (400MHz, DMSO-d6): δ7.31(d,J=7.8Hz,1H),7.12(s,1H),4.11(tt,J=6.8,3.4Hz,2H),2.99-2.83(m ,2H),2.08(d,J=7.4Hz,3H),2.06-2.01(m,2H),1.99(s,1H),1.89(d,J=4.5Hz,3H).LC-MS:167.1(M+H).

[0075] 3-(3,4 / 4,5-dimethyl-1H-pyrazole-1-yl)-2-phenylpropionic acid (27): 3,4-dimethylpyrazole (6.17 g), atropic acid (9.98 g, 1.6 eq), and 18.5 mL of water were added to a three-necked flask; the mixture was heated to 100-110 °C and reacted for 20 h; heating was stopped, and the mixture was allowed to cool naturally to 20-30 °C with stirring; the mixture was filtered; the filter cake was dissolved in ethyl acetate by heating; after concentration, methyl tert-butyl ether was added and the mixture was stirred; the mixture was filtered; the filter cake was dried to obtain 12.5 g of white powder 27 (a mixture of 27A and 27B), with a yield of 79.67%.

[0076] 1H NMR (400MHz, DMSO-d6): δ12.59(s,1H),7.39-7.25(m,5H),7.22(s,1H),7.17(s,1H),4.55(ddd,J=1 1.5, 6.5, 2.7Hz, 1H), 4.22-4.07 (m, 2H), 2.03 (s, 2H), 1.96 (s, 1H), 1.85 (s, 3H). LC-MS: 245.2 (M+H).

[0077] 2-((3,4 / 4,5-dimethyl-1H-pyrazol-1-yl)methyl)succinic acid (28): 20 g DMP, 28.4 g itaconic acid and 40 mL water were added sequentially to a three-necked flask; the temperature was raised to 100-110 °C and the reaction was carried out for 22 h; heating was stopped and TLC showed no residue of the two raw materials; the mixture was allowed to cool naturally to 20-30 °C with stirring; water was added to make a slurry; the mixture was filtered, and the filter cake was washed with water; the filter cake was dried to obtain 26.48 g of white powder 28 (28A+28B mixture), with a yield of 56.2%.

[0078] 1 H NMR (400MHz, DMSO-d6): δ12.39(s,2H),7.31(s,1H),4.25(d,J=5.8Hz,1H),4.21(d,J=5.8Hz,1H),4.15(d,J=7.1Hz,1H),4.12(d,J=7.1Hz,1 H), 2.41 (d, J = 8.7Hz, 1H), 2.37 (d, J = 8.7Hz, 1H), 2.29 (d, J = 4.8Hz, 1H), 2.25 (d, J = 4.7Hz, 1H), 2.04 (s, 3H), 1.90 (s, 3H). LC-MS: 227.1 (M+H).

[0079] 3-(3,4 / 4,5-dimethyl-1H-pyrazol-1-yl)butyric acid (29): DMP (9.6 g), crotonic acid (9 g, 0.94 eq) and 20 mL of water were added sequentially to a three-necked flask. The mixture was heated to 100–110 °C and reacted for 20 h. Heating was stopped, and the mixture was allowed to cool naturally to 20–30 °C with stirring. The mixture was then concentrated under vacuum at 60–65 °C to remove water. 60 mL of ethyl acetate was added to the residue, and the mixture was concentrated under vacuum at 40–45 °C to a small volume. MTBE was added to replace the residue, and the mixture was concentrated under vacuum at 30–35 °C to a small volume where solid precipitates. The mixture was then transferred to an ice-water bath and stirred for 15 min. After filtration and MTBE washing, the mixture was dried under forced air at 45 °C for 8–12 h. 10.26 g of white solid powder 29 (a mixture of 29A and 29B) was obtained, with a yield of 56%.

[0080] 1H NMR (400MHz, DMSO-d6): δ12.24(s,1H),7.36(s,1H),4.62-4.45(m,1H),2.77(dd,J=16.0,7.7Hz,1H) ,2.63(dd,J=16.0,6.4Hz,1H),2.04(s,3H),1.89(s,3H),1.34(d,J=6.7Hz,3H).LC-MS:183.2(M+H).

[0081] Dimethyl 2-((3,4-dimethyl-1H-pyrazol-1-yl)methyl)succinate (30): DMP (11.6 g), dimethyl itaconic acid (20 g, 1.7 eq) and 25 mL of water were added sequentially to a three-necked flask. The mixture was heated to 100-110 °C and reacted for 30 h. The mixture was then cooled naturally to 20-30 °C with stirring. The mixture was concentrated under vacuum at 60-65 °C to remove water. 60 mL of ethyl acetate was added to the residue. The mixture was concentrated under vacuum at 40-45 °C to a small volume. MTBE was added to replace the residue. The mixture was concentrated under vacuum at 40-45 °C until no fraction was clearly distilled off. 28.67 g of a pale yellow oily substance 30 (a mixture of 30A and 30B) was obtained, with a yield of 93%.

[0082] 1 H NMR (400MHz, DMSO-d6): δ7.31(s,1H),7.17(s,1H),4.31-4.22(m,2H),4.21-4.14(m,2H),3.59(d,J=9.7Hz,12H),3.29-3.16(m ,2H),2.61-2.52(m,2H),2.50-2.40(m,2H),2.12(s,3H),2.04(s,3H),1.92(d,J=5.8Hz,3H),1.90(s,3H).LC-MS:255.1(M+H).

[0083] 3-(3,4 / 4,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropionic acid (31): 9.6 g of DMP was added to the reaction flask, 8.6 g (0.9 eq) of methacrylic acid was added to the reaction flask, and water (2 V) was added to the reaction flask. The mixture was heated to 105 °C and reacted for 28 h. After cooling, 30 mL of water was added, 2 g of 85% phosphoric acid was added, and 50 mL of ethyl acetate was added. The mixture was washed three times with acid water, and the organic phase was concentrated to obtain 8.5 g of oily substance 31 (a mixture of 31A and 31B).

[0084] 1H NMR (400MHz, DMSO-d6): δ12.34(s),7.31(s),7.16(s),6.02-5.95(m),5.75(s),5.69-5.46(m),4.20(ddd,J=20.7,13.3,6.9Hz),4.02 -3.84(m),2.86(ddt,J=28.2,14.1,7.1Hz),2.14(s),2.04(s),1.90(s),1.89(s),1.86-1.79(m),1.07-0.91(m).LC-MS:183.2(M+H).

[0085] 2-(3,4-Dimethyl-1H-pyrazole-1-yl)-2-urea-acetic acid (32): Glyoxylic acid (55%) (7.7 g, 1.1 eq), 3,4-dimethylpyrazole (5.0 g, 1.0 eq), urea (3.4 g, 1.1 eq), water (50 mL) and 0.3 g phosphoric acid were added sequentially to a three-necked flask, and the mixture was heated to 45-55 °C and reacted for 24 h. Heating was stopped, and the mixture was allowed to cool naturally to 20-30 °C with stirring. The mixture was filtered, and the filter cake was washed with water. The mixture was dried at 50 °C to obtain 9.11 g of white powder 32, with a yield of 82.5%.

[0086] 1 H NMR (400MHz, DMSO-d6): δ7.45 (s, 1H), 7.24 (d, J = 8.9 Hz, 1H), 6.14 (d, J = 8.9 Hz, 1H), 5.91 (s, 2H), 2.04 (s, 3H), 1.91 (s, 3H). LC-MS: 169.1 (M+H).

[0087] Example 2

[0088] The nitrification inhibition rate of soil culture was evaluated according to the methods and requirements of GB / T 35113-2017. The nitrification inhibition rate of 3,4-dimethylpyrazole phosphate (DMPP) and the nitrification inhibitor of this invention were evaluated respectively. The nitrification inhibition rate of DMPP and nitrification inhibitor (both added at an equivalent DMP (3,4-dimethylpyrazole) N 0.25%) was added to compound fertilizer (N15-P15-K15) or ammonium sulfate (N20-P0-K0).

[0089] The soils used in this experiment were collected from two different locations in China: (i) rice-growing soil from Shouxian County, Anhui Province (116°27, N, 31°54, E), and (ii) maize-growing soil from Quzhou County, Hebei Province (114.92, E, 36.78, N).

[0090] Table 1: Basic Soil Properties

[0091]

[0092] Table 2: Nitrification inhibition rate of different nitrification inhibitors added to 15-15-15 compound fertilizer and ammonium sulfate

[0093]

[0094]

[0095] Example 3: Stability of preferred nitration inhibitors on ammonium sulfate (20-0-0) (compared to DMPP)

[0096] 3,4-Dimethylpyrazole phosphate (DMPP) and the nitration inhibitors 3, 7, 8, 17 and 19 of this invention were all sprayed into ammonium sulfate (20-0-0) at an equivalent DMP (3,4-dimethylpyrazole) N of 0.25%.

[0097] Preparation of spraying solution: Weigh 70g of dimethyl sulfoxide (DMSO) solution and add 30g of 3,4-dimethylpyrazole phosphate (DMPP) to prepare an inhibitor solution with a mass fraction of 30%. Other preferred inhibitors are also prepared according to this method.

[0098] Method for coating nitrogen fertilizer synergist on fertilizer: Weigh 1000g of ammonium sulfate (20-0-0) and add it to a small spinning coating machine. Adjust the speed to 20r / min and the temperature to 25-30℃ for preheating. Put the prepared inhibitor solution into a small spray bottle and spray it evenly multiple times. After the coating is even, take it out, air dry it, and repackage it. Store it in a constant temperature and humidity chamber at 25℃ and 45℃. Test the change in inhibitor content every 0, 10, 20 and 30 days.

[0099] Table 3: Changes in ammonium sulfate (20-0-0) content after the addition of different nitration inhibitors

[0100]

[0101] Example 4: Field application of soil ammonium nitrogen and nitrate nitrogen content (preferred compounds and DMPP control).

[0102] 3,4-Dimethylpyrazole phosphate (DMPP) and the nitrification inhibitor compounds 3, 7, 8, 17, 19 and DMPP of this invention were all added to ammonium sulfate (20-0-0) at an equivalent DMP (3,4-dimethylpyrazole) N of 0.25%, and applied during the tillering stage of rice. Soil ammonium nitrogen and nitrate nitrogen content were sampled regularly.

[0103] Table 4: Soil ammonium nitrogen and nitrate nitrogen content at different times after several nitrification inhibitor products were added to ammonium sulfate.

[0104]

[0105]

[0106] Example 5: Field application effects (preferred compound vs. DMPP control)

[0107] A field plot experiment was conducted on irrigated desert soil in Zhangye, Gansu Province, involving the combined application of 3,4-dimethylpyrazole phosphate (DMPP) and the preferred nitrification inhibitor compound of this invention. Both DMPP and the preferred nitrification inhibitor compound were added to ammonium sulfate (20-0-0) at an equivalent DMP (3,4-dimethylpyrazole) N concentration of 0.25%. The application was performed as topdressing at the corn tasseling stage. Fresh samples were taken on days 7, 14, 28, and 49 after topdressing to determine soil ammonium nitrogen and nitrate nitrogen. Finally, yield was measured, and ear length, tip barrenness length, and 100-grain weight were collected.

[0108] Table 5: Soil ammonium nitrogen and nitrate nitrogen content at different times when selected nitrification inhibitor products are applied in combination with ammonium sulfate.

[0109]

[0110] Table 6: Field performance of preferred nitrification inhibitor products combined with ammonium sulfate

[0111]

[0112]

[0113] The above are merely preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be considered as limitations on the present invention, and the scope of protection of the present invention should be determined by the scope defined in the claims. For those skilled in the art, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A nitration inhibitor, characterized in that, The nitrification inhibitor is selected from a mixture. ,mixture One or more of the following; wherein 17 is a mixture of 17A and 17B, and 19 is a mixture of 19A and 19B.

2. The application of the nitrification inhibitor as described in claim 1 in agricultural soils.

3. The application of the nitrification inhibitor according to claim 2 in agricultural soil, characterized in that: Add nitrification inhibitor compounds to nitrogen-containing compounds Add soil to the fertilizer.

4. The application of the nitrification inhibitor according to claim 3 in agricultural soil, characterized in that: The nitrogen-containing fertilizer is selected from nitrogen-phosphorus-potassium compound fertilizer. Ammonium sulfate, ammonium chloride, urea, ammonium phosphate, ammonium nitrate.

5. The application of the nitrification inhibitor according to claim 4 in agricultural soil, characterized in that: The ammonium phosphate is selected from monoammonium phosphate or phosphoric acid. diammonium phosphate.

6. The application of the nitrification inhibitor according to claim 3 in agricultural crops, characterized in that: The nitrification inhibitor accounts for a significant portion of the nitrogen content in nitrogen-containing fertilizers. The proportion is 0.1-2.0%.

7. A stabilized fertilizer containing the nitrification inhibitor as described in claim 1.

8. The stabilized fertilizer with nitrification inhibitor according to claim 7, characterized in that: The nitrification inhibitor accounts for the nitrogen content of the stabilized fertilizer. For example, the range is 0.1-2.0%.

Images