CN116003253A - Preparation method of trifluoro-phenylpyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate - Google Patents
Preparation method of trifluoro-phenylpyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate Download PDFInfo
- Publication number
- CN116003253A CN116003253A CN202211737170.9A CN202211737170A CN116003253A CN 116003253 A CN116003253 A CN 116003253A CN 202211737170 A CN202211737170 A CN 202211737170A CN 116003253 A CN116003253 A CN 116003253A
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- phenyl
- temperature
- reaction
- dimethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title claims abstract description 11
- JPQMWVUHLNFHSH-UHFFFAOYSA-N 4,5,6-trifluoro-2-phenylpyrimidine Chemical compound FC1=C(C(=NC(=N1)C1=CC=CC=C1)F)F JPQMWVUHLNFHSH-UHFFFAOYSA-N 0.000 title claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 64
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 48
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- JOIYKSLWXLFGGR-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]acetonitrile Chemical compound FC(F)(F)C1=CC=CC(CC#N)=C1 JOIYKSLWXLFGGR-UHFFFAOYSA-N 0.000 claims abstract description 26
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 26
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000009833 condensation Methods 0.000 claims abstract description 10
- 230000005494 condensation Effects 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 135
- 239000000243 solution Substances 0.000 claims description 31
- XQRPCXSCASOJDW-UHFFFAOYSA-N dimethyl 2-[3-(trifluoromethyl)phenyl]propanedioate Chemical compound COC(=O)C(C(=O)OC)C1=CC=CC(C(F)(F)F)=C1 XQRPCXSCASOJDW-UHFFFAOYSA-N 0.000 claims description 24
- 239000002994 raw material Substances 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 16
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 12
- 239000012071 phase Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- 239000008096 xylene Substances 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000006482 condensation reaction Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- -1 dimethyl trifluorobenzene pyrimidine Chemical compound 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 2
- OGOBINRVCUWLGN-UHFFFAOYSA-N 3-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC=CC(C#N)=C1 OGOBINRVCUWLGN-UHFFFAOYSA-N 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000011259 mixed solution Substances 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- JWXJRRHHNXLANU-UHFFFAOYSA-N pyrimidine 1,2,3-trifluorobenzene Chemical compound N1=CN=CC=C1.FC=1C(=C(C=CC1)F)F JWXJRRHHNXLANU-UHFFFAOYSA-N 0.000 abstract description 5
- 238000006136 alcoholysis reaction Methods 0.000 abstract description 4
- BLXXCCIBGGBDHI-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC(C(F)(F)F)=C1 BLXXCCIBGGBDHI-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract 2
- 239000000203 mixture Substances 0.000 description 11
- 239000000575 pesticide Substances 0.000 description 8
- 238000005070 sampling Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 4
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 4
- 230000032798 delamination Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 240000007594 Oryza sativa Species 0.000 description 3
- 235000007164 Oryza sativa Nutrition 0.000 description 3
- 241000607479 Yersinia pestis Species 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 235000009566 rice Nutrition 0.000 description 3
- 239000005558 Fluroxypyr Substances 0.000 description 2
- 239000005934 Sulfoxaflor Substances 0.000 description 2
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000003659 bee venom Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- MEFQWPUMEMWTJP-UHFFFAOYSA-N fluroxypyr Chemical compound NC1=C(Cl)C(F)=NC(OCC(O)=O)=C1Cl MEFQWPUMEMWTJP-UHFFFAOYSA-N 0.000 description 2
- 239000002917 insecticide Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- IGISPMBUGPHLBY-UHFFFAOYSA-N 1-iodo-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(I)=C1 IGISPMBUGPHLBY-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 1
- 241001414720 Cicadellidae Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 241001466042 Fulgoromorpha Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 241000219146 Gossypium Species 0.000 description 1
- 241000258937 Hemiptera Species 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 241000255777 Lepidoptera Species 0.000 description 1
- CRZQGDNQQAALAY-UHFFFAOYSA-N Methyl benzeneacetate Chemical compound COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 description 1
- 241001556089 Nilaparvata lugens Species 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of trifluoro-benzene pyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate, which comprises the following steps of firstly, catalyzing condensation of m-trifluoro-benzene acetonitrile and dimethyl carbonate by sodium methoxide to obtain 2-cyano-2- [3- (trifluoromethyl) phenyl ] methyl acetate; then the 2-cyano-2- [3- (trifluoromethyl) phenyl ] methyl acetate, the dry hydrogen chloride and the dry methanol are subjected to alcoholysis reaction to obtain iminoester hydrochloride, and water is directly added for hydrolysis reaction to generate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate. Compared with the prior art, the method omits the process of hydrolyzing the m-trifluoromethyl benzyl cyanide into the m-trifluoromethyl phenylacetic acid, shortens the reaction flow, has mild conditions, is simple to operate, and is easy to realize industrialization.
Description
Technical Field
The invention belongs to the field of pesticide synthesis, relates to a preparation method of a pesticide intermediate, and in particular relates to a preparation method of a trifluoro-phenylpyrimidine intermediate.
Background
Nicotinic acetylcholine receptors are one of the important targets for pesticide action, and pesticides acting on nicotinic acetylcholine receptors occupy an important market place in agricultural pest control. However, as a dominant product for controlling piercing-sucking mouthpart pests, the neonicotinoid insecticides look like a scene limitless, and in recent years, the product is much forbidden due to the occurrence of 'high bee venom'. Aiming at the important target of the nicotinic acetylcholine receptor, the development of products with low bee venom becomes a new subject of great need for research of the transnational pesticides. The sulfoxaflor, the Bayer fluroxypyr and the DuPont trifluoro-phenylpyrimidine of the Dow Yinong are marketed in sequence, and the toxicity of the sulfoxaflor, the Bayer fluroxypyr and the DuPont trifluoro-phenylpyrimidine to bees is obviously lower than that of tap products in the neonicotinoid insecticide. Wherein the trifluoro-phenylpyrimidine is a novel mesoionic or zwitterionic pesticide and also is a novel pyrimidinone compound. Trifluoro-phenylpyrimidine is the only compound that inhibits but does not activate nicotinic acetylcholine receptors, has no cross-resistance to other pesticides both in-group (including neonicotinoid pesticides) and out-of-group, has no adverse effects on powdery insects, and is environmentally friendly. The trifluoro-benzene pyrimidine has broad spectrum, internal absorption, high efficiency, lasting effect and slight toxicity, has good prevention effect on various pests such as lepidoptera, homoptera and the like, and can be used for crops such as cotton, rice, corn, soybean and the like. Tao Shidu the product is developed for rice to prevent and treat rice planthoppers, leafhoppers and the like, especially brown planthoppers. The DuPont of the United states has been approved for formal registration in China in 2017, month 8, and the preparation Bai Liang Long is formally marketed in China in 2018, month 11. According to the statistics of AgrAlspire, the global sales of trifluorophenylpyrimidine was $ 100 tens of thousands of dollars in 2016, all for non-crop applications. At present, the market expansion stage is still in Tao Shidu bang, and the annual peak sales of the future trifluoro-phenylpyrimidine can break through the dollar of 1.50 hundred million, so that the market growth potential is large.
The chemical name of the trifluorobenzene pyrimidine is 3, 4-dihydro-2, 4-dihydro-1- (pyrimidin-5-ylmethyl) -3- (alpha, alpha-trifluoro-m-methylphenyl) -2H-pyridine [1, 2-alpha ] pyrimidine-1-onium-3-salt, and the structural formula of the 2- [3- (trifluoromethyl) phenyl ] malonic acid dimethyl ester are respectively shown as (I) and (II).
The existing preparation method of the trifluorobenzene pyrimidine generally comprises the steps of preparing a dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate intermediate, and then synthesizing the trifluorobenzene pyrimidine by utilizing the intermediate, but the existing preparation method of the dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate intermediate is harsh in preparation conditions and low in yield, cannot meet market demands, for example, pahutski T F takes m-trifluoromethyl iodobenzene, diethyl malonate and cesium carbonate as raw materials, and the dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate is obtained through coupling, so that the yield is 58%, and the method is harsh in reaction conditions, difficult to control and more in byproducts. In Shenyang, metatrifluoromethyl phenylacetic acid is taken as raw material, firstly, the raw material is chloridized with thionyl chloride to obtain acyl chloride, the acyl chloride is esterified into metatrifluoromethyl phenylacetic acid methyl ester, then, the methyl chloride is condensed with dimethyl carbonate and sodium methoxide to obtain 2- [3- (trifluoromethyl) phenyl ] malonic acid dimethyl ester, the yield of the raw material from the esterification step is 96.3%, and the yield of the condensation step is 57.5%.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the preparation method of the trifluoro-phenylpyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate, which has the advantages of short preparation flow, small wastewater amount and wide industrialization prospect.
The aim of the invention can be achieved by the following technical scheme: a preparation method of 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate, which relates to the following equation:
the process comprises the following steps:
1) Preparation of intermediate methyl 2-cyano-2- [3- (trifluoromethyl) phenyl ] acetate
Weighing a certain amount of m-trifluoromethyl benzyl cyanide, dimethyl carbonate and a condensation solvent, adding the mixture into a reactor (the condensation solvent is selected from one or more of dimethyl carbonate, toluene and xylene, the dimethyl carbonate can be only used as a reactant to participate in condensation reaction, and toluene or xylene is used as a solvent, or excessive dimethyl carbonate is added, and the dimethyl carbonate is used as both a solvent and a reactant), after a reflux reaction device is connected, stirring is started, and sodium methoxide methanol solution is slowly dripped or sodium methoxide solid is added in batches; starting heating after finishing, raising the temperature to the reaction temperature and preserving the heat; after sampling analysis, no raw material residue is generated, the temperature is controlled in a water bath, dimethyl carbonate and methanol are distilled out under reduced pressure, and a certain amount of toluene or xylene is added after the distillation is finished (the dimethyl carbonate is only used as a reactant, and toluene or xylene is used as a condensation solvent without the operation); after cooling, slowly dripping a pre-prepared hydrochloric acid solution, keeping the temperature for a period of time after dripping, standing to separate a water phase, adding a certain amount of water to wash an organic phase, and layering again to obtain a toluene solution of 2-cyano-2- [3- (trifluoromethyl) phenyl ] methyl acetate; and (3) controlling the temperature in a water bath, and decompressing to evaporate part of toluene and a small amount of water.
2) Preparation of intermediate iminoester hydrochloride
Adding part of toluene into the methyl 2-cyano-2- [3- (trifluoromethyl) phenyl ] acetate toluene reaction liquid from which water is distilled, adding methanol, stirring, and cooling in a low-temperature constant-temperature tank; the hydrogen chloride gas inlet device is connected, hydrogen chloride is slowly introduced, the ventilation is finished, water bath control is changed, and the temperature is raised to the reaction temperature for heat preservation; and after the alcoholysis heat preservation is finished, sampling and analyzing to obtain a solution of the intermediate iminoester hydrochloride, wherein no raw material remains, and stopping the reaction.
3) Preparation of intermediate dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate
The intermediate imino ester hydrochloride solution is not treated, a certain amount of water is added dropwise after being cooled to the reaction temperature, and the stirring is continued for a period of time after the dripping is finished, and the water phase is separated and removed; washing the organic phase with water, layering again, controlling the temperature in water bath, and evaporating toluene under reduced pressure to obtain 2- [3- (trifluoromethyl) phenyl ] malonic acid dimethyl ester with the purity of more than 97%.
In one embodiment of the invention, in the step 1), a sodium methoxide methanol solution with the mass fraction of 25-28% is slowly dripped or 99% sodium methoxide solid is added in batches, and the temperature of adding sodium methoxide is controlled to be between-5 ℃ and 25 ℃.
In one embodiment of the invention, in step 1), the reaction temperature is 70-80℃and the reaction time is 3-6 hours.
In one embodiment of the present invention, in step 1), after no raw material residue is analyzed, dimethyl carbonate and methanol are distilled off under reduced pressure by controlling the water bath temperature to be less than 45 ℃.
In one embodiment of the invention, in the step 1), the temperature of the reaction solution is controlled to be 0-10 ℃, hydrochloric acid with the mass concentration of 10-20% is dripped, the pH value at the end of dripping is less than 2, and the heat preservation is continued for 0.5-1h.
In one embodiment of the invention, in step 1), the temperature of the water bath is controlled to not exceed 50 ℃ and reduced pressure is used to distill about 1/3 of the toluene and water, requiring less than 0.2% water in the product.
In one embodiment of the present invention, in step 1), m-trifluoromethyl benzyl cyanide, dimethyl carbonate and sodium methoxide are used as reaction raw materials, toluene or xylene is used as a reaction solvent, wherein the molar ratio of each reaction raw material is n (m-trifluoromethyl benzyl cyanide): n (dimethyl carbonate): n (sodium methoxide) =1: 1-8:1-2, m (m-trifluoromethyl benzyl cyanide): m (toluene or xylene) =1: 3-6.
In one embodiment of the invention, in the step 2), the temperature of the reaction liquid is controlled to be 0-20 ℃, and hydrogen chloride gas is slowly introduced for 0.5-1.5 hours.
In one embodiment of the invention, in step 2), after the introduction of hydrogen chloride is completed, the temperature is raised to 25-45 ℃ and the reaction time is 3-20h.
In one embodiment of the present invention, in step 2), the molar ratio of the addition of hydrogen chloride and methanol to m-trifluoromethylphenyl acetonitrile is n (hydrogen chloride): n (methanol): n (m-trifluoromethyl benzyl cyanide) =1-2: 1-2:1.
in one embodiment of the invention, in step 3), the temperature of the hydrolysis reaction is between 0 and 10 ℃.
In one embodiment of the present invention, in step 3), the amount of water added dropwise is 1 to 3 times the weight of m-trifluoromethylphenyl acetonitrile.
In one embodiment of the invention, in step 3), water is added dropwise, stirring is continued for 0.5-1h after water is added dropwise, the aqueous phase is separated, the organic phase is washed for 0.25-1h by adding water which is 1-2 times the weight of m-trifluoromethyl benzyl cyanide, layering is carried out again, and the temperature of the whole process is kept at 0-10 ℃.
In one embodiment of the present invention, in step 3), all toluene is distilled off under reduced pressure at a temperature below 60℃and an absolute pressure of not more than 300Pa to obtain dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate.
In carrying out the technical scheme of the invention, the preparation process of the 2-cyano-2- [3- (trifluoromethyl) phenyl ] methyl acetate is preferable, wherein n (m-trifluoromethyl benzyl cyanide): n (dimethyl carbonate): n (sodium methoxide) =1: 1-2:1.15-1.8, m (m-trifluoromethyl benzyl cyanide): m (toluene) =1: 5-6, adding 99% sodium methoxide solid in batches, controlling the temperature of adding sodium methoxide at 0-10 ℃, the condensation reaction temperature at 70-75 ℃ and the reaction time at 3-4h, and controlling the water bath temperature at less than 45 ℃ and decompressing to distill dimethyl carbonate and methanol. Cooling to 0-10deg.C after distillation, dropwise adding 18-20% hydrochloric acid, keeping the pH at the end of dropwise adding less than 2, keeping the temperature for 0.5-0.6 hr, layering, and steaming out toluene and water at a temperature of no more than 50deg.C under reduced pressure to obtain water content of about 1/3, wherein the water content is required to be lower than 0.2%.
In carrying out the technical scheme of the invention, the preparation process of 2- [3- (trifluoromethyl) phenyl ] malonic acid dimethyl ester is preferable, and n is hydrogen chloride: n (methanol): n (m-trifluoromethyl benzyl cyanide) =1.3-1.6: 1.2-1.5:1, controlling the temperature of the reaction liquid to be 0-15 ℃, the ventilation time to be 0.5-1.5h, and heating to be 35-45 ℃ after the hydrogen chloride is introduced, wherein the reaction time is 3-5h. The alcoholysis reaction is completed and the reaction is completed,
in the implementation of the technical scheme of the invention, as the preferential hydrolysis reaction is cooled to 0-10 ℃, water which is 1-3 times of the weight of the m-trifluoromethyl benzyl cyanide is dripped, the stirring is carried out for 0.9-1h, the water phase is separated and removed, the water which is 1-2 times of the weight of the m-trifluoromethyl benzyl cyanide is added for washing the organic phase for 0.25-1h, the delamination is carried out again, the temperature in the whole process is kept at 0-10 ℃, the temperature is lower than 60 ℃, and all toluene is distilled out under reduced pressure, and the absolute pressure is not more than 300Pa.
Compared with the prior art, the technical scheme of the invention uses m-trifluoromethyl benzyl cyanide, dimethyl carbonate and sodium methoxide as reaction raw materials, toluene is used as a reaction solvent, and 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate is directly obtained through condensation, alcoholysis and hydrolysis, the process of hydrolyzing m-trifluoromethyl benzyl cyanide into m-trifluoromethyl phenylacetic acid is omitted, the reaction flow is shortened, the yield is high, the operation is simple, and industrialization is easy to realize.
Detailed Description
The invention will be further described with reference to specific embodiments in order to make the technical solutions and advantages of the invention more clear. The following examples illustrate in detail the preparation of dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate as an intermediate of trifluorophenylpyrimidine, comprising methyl 2-cyano-2- [3- (trifluoromethyl) phenyl ] acetate and the corresponding imido ester hydrochloride, but are not intended to limit the scope of the invention.
Example 1
1) Preparation of intermediate methyl 2-cyano-2- [3- (trifluoromethyl) phenyl ] acetate
30g (0.162 mol) of m-trifluoromethyl benzyl cyanide and 116.8g (1.2968 mmol,8 eq) of dimethyl carbonate are weighed and placed in a 500ml four-necked flask, a reaction device is connected, the materials are cooled to 5 ℃, 39.06g (10.94 g for fixation and 1.25 eq) of 28% sodium methoxide methanol solution is slowly dripped into the flask, heating is started after the completion, the temperature is raised to 72 ℃ for condensation reaction, and the temperature is kept for 3 hours. After no raw material residue is detected by sampling and analysis, the temperature of the water bath is controlled to be less than 45 ℃ and reduced pressure is controlled to evaporate dimethyl carbonate and methanol, and then 180g of toluene is rapidly added. Cooling to 0deg.C, adding water into 21.06g (1.3 eq) of 36.5% hydrochloric acid to obtain 20% hydrochloric acid aqueous solution, slowly dripping, controlling reaction solution temperature to 5deg.C, maintaining the temperature for 0.5h, keeping pH less than 2, standing to remove water phase, adding 50g water to wash organic phase for 0.25h, and layering again. The temperature of the organic phase is controlled to be not more than 50 ℃, about 50g of toluene and a small amount of water are distilled out under reduced pressure, the water content is 0.1%, and then 50g of anhydrous toluene is added to obtain a toluene solution of 2-cyano-2- [3- (trifluoromethyl) phenyl ] methyl acetate.
2) Preparation of intermediate iminoester hydrochloride
The toluene reaction solution of 2-cyano-2- [3- (trifluoromethyl) phenyl ] acetate treated in step 1) was cooled to 0℃in a low-temperature constant-temperature bath, and 7.775g (1.5 eq) of methanol was added. The hydrogen chloride inlet device was connected, the temperature was controlled to be 2℃and the supply of hydrogen chloride was stopped when the amount of hydrogen chloride was about 7.687g (1.3 eq). Changing into water bath control, heating to 45 ℃ and preserving heat, precipitating a large amount of white iminoester hydrochloride after a period of time, sampling and analyzing after preserving heat for 3 hours without raw material residues, and stopping the reaction to obtain iminoester hydrochloride solution.
3) Preparation of intermediate dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate
Cooling the imino ester hydrochloride solution obtained in the step 2) to 0 ℃, keeping the temperature of 0 ℃ and dripping 70g of water, continuously stirring for 0.5h, and then separating out the water phase. 50g of water is added to wash the organic phase for 0.25h, delamination is carried out again, toluene is distilled off under reduced pressure at the temperature of lower than 60 ℃, 42g of tan liquid which is 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate is obtained, the main content is more than 97%, and the total yield is 91.03%.
Example 2
1) Preparation of intermediate methyl 2-cyano-2- [3- (trifluoromethyl) phenyl ] acetate
30g (0.162 mol) of m-trifluoromethyl benzyl cyanide, 26.26g (1.8 eq) of dimethyl carbonate and 180g of toluene are taken as solvents, the mixture is placed in a 500ml four-necked flask, a reaction device is connected, the materials are cooled to 8 ℃, 10.94g (1.25 eq) of solid sodium methoxide is added in 6 times under controlled temperature, heating is started after the completion, the temperature is raised to 70 ℃ for condensation reaction, and the temperature is kept for 3 hours. After sampling analysis, no raw material residue is left, the mixture is directly cooled to 0 ℃, 21.06g (1.3 eq) of 36.5% hydrochloric acid is additionally weighed and added with water to prepare 20% hydrochloric acid aqueous solution, the mixture is slowly dripped, the temperature of the reaction solution is controlled to be 5 ℃, the dripping is finished, the temperature is kept for 0.5h, the pH is less than 2, the mixture is kept stand for separating the water phase, 50g of water is added for washing the organic phase for 0.25h, and the mixture is layered again. The temperature of the organic phase is controlled to be not more than 50 ℃, about 55g of toluene and a small amount of water are distilled off under reduced pressure, the water content is 0.06%, and then 55g of anhydrous toluene is added to obtain a toluene solution of 2-cyano-2- [3- (trifluoromethyl) phenyl ] methyl acetate.
2) Preparation of intermediate dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate
The toluene reaction solution of 2-cyano-2- [3- (trifluoromethyl) phenyl ] acetate treated in step 1) was cooled to 0℃in a low-temperature constant-temperature bath, and 7.775g (1.5 eq) of methanol was added. Cooling to 0 ℃ in a low-temperature constant-temperature tank. The hydrogen chloride inlet device was connected, and hydrogen chloride was introduced at 0℃and stopped when the amount of hydrogen chloride introduced was about 7.687g (1.3 eq). Changing into water bath control, heating to 45 ℃ and preserving heat, precipitating a large amount of white iminoester hydrochloride after a period of time, sampling and analyzing after preserving heat for 3 hours without raw material residues, and stopping stirring to obtain iminoester hydrochloride solution.
3) Preparation of intermediate dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate
Cooling the imino ester hydrochloride solution obtained in the step 2) to 0 ℃, keeping the temperature of 0 ℃ and dripping 70g of water, continuously stirring for 0.5h, and then separating out the water phase. 50g of water is added to wash the organic phase for 0.25h, delamination is carried out again, toluene is distilled off under reduced pressure at the temperature lower than 60 ℃, 43.2g of tan liquid is obtained, namely, the main content of 2- [3- (trifluoromethyl) phenyl ] malonic acid dimethyl ester is more than 97%, and the total yield is 93.6%.
Example 3
1) Preparation of intermediate methyl 2-cyano-2- [3- (trifluoromethyl) phenyl ] acetate
30g (0.162 mol) of m-trifluoromethyl benzyl cyanide, 26.26g (1.8 eq) of dimethyl carbonate and 180g of toluene are taken as solvents, the mixture is placed in a 500ml four-necked flask, a reaction device is connected, the materials are cooled to 5 ℃, 10.94g (1.25 eq) of solid sodium methoxide is added in 6 times under controlled temperature, heating is started after the completion, the temperature is raised to 75 ℃ for condensation reaction, and the temperature is kept for 3 hours. After sampling analysis, no raw material residue is left, the mixture is directly cooled to 0 ℃, 21.06g (1.3 eq) of 36.5% hydrochloric acid is additionally weighed and added with water to prepare 20% hydrochloric acid aqueous solution, the mixture is slowly dripped, the temperature of the reaction solution is controlled to be 0 ℃, the dripping is finished, the temperature is kept for 0.5h, the pH is less than 2, the mixture is kept stand for separating the water phase, 50g of water is added for washing the organic phase for 0.25h, and the mixture is layered again. The organic phase is controlled to be at a temperature not exceeding 50 ℃, about 55g of toluene and a small amount of water are distilled off under reduced pressure, the water content is 0.06 percent, and then 55g of anhydrous toluene is added to obtain a toluene solution of 2-cyano-2- [3- (trifluoromethyl) phenyl ] methyl acetate
2) Preparation of intermediate dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate
The toluene reaction solution of 2-cyano-2- [3- (trifluoromethyl) phenyl ] acetate treated in step 1) was cooled to 0℃in a low-temperature constant-temperature bath, and 6.739g (1.3 eq) of methanol was added. Cooling to 0 ℃ in a low-temperature constant-temperature tank. The hydrogen chloride inlet device was connected, and hydrogen chloride was introduced at 0℃and stopped when the amount of hydrogen chloride introduced was about 9.461g (1.6 eq). Changing into water bath control, heating to 45 ℃ and preserving heat, precipitating a large amount of white iminoester hydrochloride after a period of time, sampling and analyzing after preserving heat for 3 hours without raw material residues, and stopping stirring to obtain iminoester hydrochloride solution.
3) Preparation of intermediate dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate
Cooling the imino ester hydrochloride solution obtained in the step 2) to 0 ℃, keeping the temperature of 0 ℃ and dripping 70g of water, continuously stirring for 0.5h, and then separating out the water phase. 50g of water is added to wash the organic phase for 0.25h, delamination is carried out again, toluene is distilled off under reduced pressure at the temperature lower than 60 ℃, 43.3g of tan liquid is obtained, namely, the main content of 2- [3- (trifluoromethyl) phenyl ] malonic acid dimethyl ester is more than 97.5%, and the total yield is 94.3%.
Claims (10)
1. A method for preparing a trifluoro-phenylpyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate, which is characterized by comprising the following steps:
1) Preparation of intermediate methyl 2-cyano-2- [3- (trifluoromethyl) phenyl ] acetate
Mixing m-trifluoromethyl benzyl cyanide, dimethyl carbonate and a condensation solvent, slowly dripping sodium methoxide methanol solution or adding sodium methoxide solid in batches, starting heating after the completion of the reaction, performing condensation reaction, and performing post-treatment to obtain a 2-cyano-2- [3- (trifluoromethyl) phenyl ] methyl acetate solution;
2) Preparation of intermediate iminoester hydrochloride
Adding methanol into the 2-cyano-2- [3- (trifluoromethyl) phenyl ] methyl acetate solution obtained in the step 1), cooling in a low-temperature constant-temperature tank, introducing enough hydrogen chloride, controlling in a water bath, heating to the reaction temperature, and reacting to obtain an intermediate iminoester hydrochloride solution;
3) Preparation of intermediate dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate
And 2) dripping the iminoester hydrochloride solution obtained in the step 2) into water for hydrolysis reaction, separating out a water phase after the reaction, adding water to wash an organic phase, layering again, and evaporating toluene under reduced pressure to obtain a tan liquid which is the dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate product.
2. The preparation method of the trifluoro-phenylpyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate according to claim 1, wherein in the reaction process of step 1), m-trifluoro-methylbenzonitrile, dimethyl carbonate and sodium methoxide are used as reaction raw materials, one or more of dimethyl carbonate, toluene and xylene are used as condensation solvents, wherein the molar ratio of the reaction raw materials is n (m-trifluoro-methylbenzonitrile): n (dimethyl carbonate): n (sodium methoxide) =1: 1-8:1-2, the molar ratio of toluene or xylene to m-trifluoromethylphenyl acetonitrile is m (m-trifluoromethylphenyl acetonitrile): m (toluene or xylene) =1: 0-6.
3. The process for preparing a trifluopyrimidyl intermediate 2- [3- (trifluoromethyl) phenyl ] malonic acid dimethyl ester according to claim 1, wherein the temperature of adding sodium methoxide is controlled to be-5-25 ℃ in step 1) and the adding time is controlled to be 0-1h.
4. The process for preparing dimethyl trifluorobenzene pyrimidine as claimed in claim 1, wherein the condensation reaction temperature is 70-80 ℃ and the reaction time is 3-6h.
5. The process for the preparation of the intermediate dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate according to claim 1, characterized in that the mode of working up is chosen according to the condensation solvent:
when the condensing solvent is selected from dimethyl carbonate or the mixed solution of toluene, dimethylbenzene and dimethyl carbonate, controlling the temperature to be less than 45 ℃ and decompressing to evaporate excessive dimethyl carbonate and methanol, adding toluene or dimethylbenzene after distillation, adding 0-6 times of m-trifluoromethyl benzyl cyanide, controlling the temperature of the reaction solution to be 0-10 ℃ and dropwise adding 10-25% hydrochloric acid to adjust the pH to be less than 2; standing for removing water phase, adding a certain amount of water to wash the organic phase for 0.25-1h, and layering again to obtain toluene solution of 2-cyano-2- [3- (trifluoromethyl) phenyl ] methyl acetate; controlling the temperature of the water bath to be not more than 50 ℃, decompressing and distilling 1/3 of toluene and a small amount of water, and adding the same amount of toluene or xylene after the distillation is finished;
when toluene or xylene is selected as the condensation solvent, the reaction is finished and the reaction is directly cooled to 0-10 ℃ for the post-treatment.
6. The method for preparing the trifluoro-phenylpyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] malonic acid dimethyl ester according to claim 1, wherein the temperature of the low-temperature constant-temperature tank is controlled to be 0-20 ℃, and hydrogen chloride gas is slowly introduced for 0.5-1.5h.
7. The process for preparing dimethyl trifluorobenzene pyrimidine as claimed in claim 1, wherein the reaction time is 3-20h after the end of the introduction of hydrogen chloride in the step 2) is raised to 25-45 ℃.
8. The method for preparing the intermediate 2- [3- (trifluoromethyl) phenyl ] malonic acid dimethyl ester of trifluoro-phenylpyrimidine according to claim 1, wherein the molar ratio of the addition amount of hydrogen chloride and methanol to m-trifluoro-methylbenzonitrile in the step 2) is n (hydrogen chloride): n (methanol): n (m-trifluoromethyl benzyl cyanide) =1-3: 1-3:1.
9. the method for preparing the intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate according to claim 1, characterized in that the temperature of the hydrolysis reaction in step 3) is reduced to 0-10 ℃, the amount of dropwise added water is 1-3 times the weight of m-trifluoromethyl benzyl cyanide, stirring is continued for 0.5-1h after the dropwise addition, the aqueous phase is separated, the organic phase is washed for 0.25-1h by adding 1-2 times the weight of m-trifluoromethyl benzyl cyanide, layering is carried out again, and the temperature of the whole process is kept at 0-10 ℃.
10. The process for the preparation of the intermediate dimethyl 2- [3- (trifluoromethyl) phenyl ] malonate according to claim 1, characterized in that step 3) consists in evaporating all the toluene under reduced pressure at a temperature lower than 60 ℃ and in an absolute pressure not higher than 300Pa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211737170.9A CN116003253A (en) | 2022-12-31 | 2022-12-31 | Preparation method of trifluoro-phenylpyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211737170.9A CN116003253A (en) | 2022-12-31 | 2022-12-31 | Preparation method of trifluoro-phenylpyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116003253A true CN116003253A (en) | 2023-04-25 |
Family
ID=86022655
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211737170.9A Pending CN116003253A (en) | 2022-12-31 | 2022-12-31 | Preparation method of trifluoro-phenylpyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116003253A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4909830A (en) * | 1987-11-17 | 1990-03-20 | Bayer Aktiengesellschaft | Herbicidal 3-aminopyrazolin-5-ones, compositions and use |
| US6395921B1 (en) * | 1999-08-16 | 2002-05-28 | Bayer Aktiengesellschaft | Process for preparing [bis-(trifluoromethyl)-phenyl]-acetic acids and alkyl esters thereof and dialkyl [bis-(trifluoromethyl)-phenyl]-malonates |
| CN1764649A (en) * | 2003-03-24 | 2006-04-26 | 弗·哈夫曼-拉罗切有限公司 | Benzyl-pyridazinons as reverse transcriptase inhibitors |
| CN104066713A (en) * | 2011-12-15 | 2014-09-24 | 纳幕尔杜邦公司 | Malonic acid di-salts and a method for preparing malonyl dihalides |
| CN110256280A (en) * | 2018-11-20 | 2019-09-20 | 上海试四化学品有限公司 | A kind of 2,2 '-azos (2- methyl-N-(2- hydroxyethyl) propionamide) preparation method |
| CN114369090A (en) * | 2020-10-15 | 2022-04-19 | 东莞市东阳光农药研发有限公司 | Mesoionic compound and preparation method and application thereof |
-
2022
- 2022-12-31 CN CN202211737170.9A patent/CN116003253A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4909830A (en) * | 1987-11-17 | 1990-03-20 | Bayer Aktiengesellschaft | Herbicidal 3-aminopyrazolin-5-ones, compositions and use |
| US6395921B1 (en) * | 1999-08-16 | 2002-05-28 | Bayer Aktiengesellschaft | Process for preparing [bis-(trifluoromethyl)-phenyl]-acetic acids and alkyl esters thereof and dialkyl [bis-(trifluoromethyl)-phenyl]-malonates |
| CN1764649A (en) * | 2003-03-24 | 2006-04-26 | 弗·哈夫曼-拉罗切有限公司 | Benzyl-pyridazinons as reverse transcriptase inhibitors |
| CN104066713A (en) * | 2011-12-15 | 2014-09-24 | 纳幕尔杜邦公司 | Malonic acid di-salts and a method for preparing malonyl dihalides |
| CN110256280A (en) * | 2018-11-20 | 2019-09-20 | 上海试四化学品有限公司 | A kind of 2,2 '-azos (2- methyl-N-(2- hydroxyethyl) propionamide) preparation method |
| CN114369090A (en) * | 2020-10-15 | 2022-04-19 | 东莞市东阳光农药研发有限公司 | Mesoionic compound and preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| KOHEI YAMADA，等: "Mild Amide-Cleavage Reaction Mediated by Electrophilic Benzylation", 《CHEMISTRY.》, vol. 22, no. 19, 19 September 2016 (2016-09-19), pages 14042 - 14047, XP055479514, DOI: 10.1002/chem.201603120 * |
| TAYLOR, MARK S.，等: "Enantioselective Michael Additions to r, â-Unsaturated Imides Catalyzed by a Salen-Al Complex", 《JOURNAL OF AMERICAN CHEMICAL SOCIETY》, vol. 125, no. 37, 31 December 2002 (2002-12-31), pages 11204 - 11205 * |
| YOGESH KUMAR, ，等: "Metal-Free Catalyst-Controlled Chemoselective Synthesis of Aryl a-Ketoesters and Primary a-Ketoamides from Aryl Acetimidates", 《CHEMISTRY SELECT》, vol. 2, no. 21, 31 December 2017 (2017-12-31), pages 6143 - 6148 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2021147484A1 (en) | 2-(1,2,4-triazolyl)benzoyl arylamine active compound for inhibiting wheat take-all pathogen | |
| DD280097A5 (en) | METHOD FOR PRODUCING NEW CYCLOPROPANCARBOXY ACID ESTERS | |
| CN109232429B (en) | Bisamide compound containing 1, 3-dialkyl substituted pyrazole, and preparation method and application thereof | |
| CN116003253A (en) | Preparation method of trifluoro-phenylpyrimidine intermediate 2- [3- (trifluoromethyl) phenyl ] dimethyl malonate | |
| CN107176929A (en) | A kind of method for efficiently preparing high purity 1 H Tebuconazole | |
| CN103613535A (en) | Synthesis method of 5-(methoxy methyl)-2,3-pyridine dimethyl dicarboxylate | |
| CN105693612A (en) | Bridging type arylpyrazole amide compound as well as solvent heat one-pot synthesis method and application thereof | |
| CN102351740B (en) | Method for synthesizing metaflumizone | |
| CN101429162A (en) | Method for producing 1-phenyl-3,5-di-substituted aryl-2-pyrazoline | |
| CN101445485B (en) | Synthesis method of 4,6-dichloro-5-fluoropyrimidine compound | |
| CN107021966A (en) | The synthetic method of improved penoxsuam | |
| KR102236167B1 (en) | Manufacturing method for 3-(2-chloropropionylamino)propionic acid alkyl ester | |
| US4902337A (en) | Herbicidal hydantoin derivatives | |
| CN1081440A (en) | 2-aryl-5,6-ring-fused pyrimidines and weeding are used | |
| CN106234387A (en) | A kind of 1,2,4 triazole derivatives containing methyl benzopyrazines structure are as the application of antibacterial | |
| CN106243109B (en) | A kind of 1,2,4- triazole derivatives of the structure of benzopyrazines containing methyl and its preparation method and application | |
| CN105753856A (en) | Preparation and application of difluoromethyl pyrazole compound comprising 1,3,4-oxadiazole structure | |
| CN107935948A (en) | A kind of method for synthesizing carfentrazoneethyl | |
| CN108516962A (en) | A kind of preparation method of azoxystrobin intermediate | |
| CN110054609A (en) | A kind of preparation method of Ficam intermediate and raw medicine | |
| CN109320549A (en) | A kind of method of high―temperature nuclei chlopyrifos | |
| CN115974729B (en) | Preparation method of 2- (2, 2-difluoroethoxy) -6-trifluoromethyl benzenesulfonyl chloride | |
| CN1058960C (en) | Trifluoro-indolebutyric acid of new plant growth regulator and its synthesis of derivatives | |
| CN106212487A (en) | A kind of 1,2,4 triazole derivatives containing methoxyl group benzopyrazines structure are as the application of antibacterial | |
| CN87108192A (en) | diazolones derivative, its preparation method, and contain the weedicide of this derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |