CN114195723A - Preparation method of azoxystrobin - Google Patents
Preparation method of azoxystrobin Download PDFInfo
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- CN114195723A CN114195723A CN202111442859.4A CN202111442859A CN114195723A CN 114195723 A CN114195723 A CN 114195723A CN 202111442859 A CN202111442859 A CN 202111442859A CN 114195723 A CN114195723 A CN 114195723A
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- 239000005730 Azoxystrobin Substances 0.000 title claims abstract description 67
- WFDXOXNFNRHQEC-GHRIWEEISA-N azoxystrobin Chemical compound CO\C=C(\C(=O)OC)C1=CC=CC=C1OC1=CC(OC=2C(=CC=CC=2)C#N)=NC=N1 WFDXOXNFNRHQEC-GHRIWEEISA-N 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 58
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000011230 binding agent Substances 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 14
- 239000012442 inert solvent Substances 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000004064 recycling Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- ZIXOZNNAUYNERI-UHFFFAOYSA-N [K].OC1=C(C=CC=C1)O Chemical compound [K].OC1=C(C=CC=C1)O ZIXOZNNAUYNERI-UHFFFAOYSA-N 0.000 claims description 2
- OQMUXQPCUBYTEB-UHFFFAOYSA-N benzene-1,2-diol;sodium Chemical compound [Na].OC1=CC=CC=C1O OQMUXQPCUBYTEB-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract 1
- YRYZZSRRDCTETP-DHZHZOJOSA-N methyl (e)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3-methoxyprop-2-enoate Chemical compound CO\C=C(\C(=O)OC)C1=CC=CC=C1OC1=CC(Cl)=NC=N1 YRYZZSRRDCTETP-DHZHZOJOSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 14
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 11
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000005703 Trimethylamine hydrochloride Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 6
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000012973 diazabicyclooctane Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000004821 distillation Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- ONQBOTKLCMXPOF-UHFFFAOYSA-N 1-ethylpyrrolidine Chemical compound CCN1CCCC1 ONQBOTKLCMXPOF-UHFFFAOYSA-N 0.000 description 2
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of azoxystrobin, which utilizes 2-cyanophenol or salt thereof and a compound shown in formula I
Description
Technical Field
The invention relates to the field of pesticide bactericides, and in particular relates to a preparation method of azoxystrobin.
Background
Azoxystrobin is a novel efficient, broad-spectrum and systemic bactericide. Can be used for stem and leaf spraying, seed treatment or soil treatment. The conventional azoxystrobin synthesis process generally has the problems of low yield, difficult aftertreatment, difficult catalyst recovery, low yield in amplified production and the like, so that the azoxystrobin is high in cost and is not beneficial to popularization and utilization of the azoxystrobin.
CN101163682 discloses a compound prepared from 2-cyanophenol and a compound shown in formula (I) under the catalytic action of triethylene Diamine (DABCO)
In the method for preparing azoxystrobin, the dosage of DABCO is 0.1-2% mol relative to the compound shown in formula (I), the reaction solvent is a high-boiling polar aprotic solvent N, N-Dimethylformamide (DMF), the reaction yield can reach 98.7%, but the subsequent treatment is complicated, the DMF needs to be removed by vacuum distillation, and then toluene and water are added to be stirred and layered to obtain a toluene solution containing azoxystrobin. Because the DABCO catalyst has good water solubility, most of the catalyst enters the wastewater, and the DABCO catalyst has high boiling point and is difficult to recover, so that the cost is increased, the total nitrogen and COD (chemical oxygen demand) in the wastewater are high, and the treatment is difficult. In addition, in the post-treatment process of the method, high vacuum distillation is needed to remove DMF, the difficulty of workshop operation is increased, about 10% of DMF can be actually remained, and finally the DMF enters the wastewater.
Patent CN109721548 reports that azoxystrobin is synthesized by using trimethylamine hydrochloride catalyst, which solves the problem of catalyst recycling, and although the reported pilot plant yield can reach more than 96%, we carry out amplification experiments, and find that when the method is expanded to kilogram level, the actual yield is obviously lower than the reported pilot plant yield.
Therefore, a more efficient and simple catalyst is needed to be found for the synthesis of azoxystrobin, so that the yield of azoxystrobin is further improved, especially the yield in large-scale production, and the synthesis of azoxystrobin is more convenient for industrial operation and has environmental protection advantages.
Disclosure of Invention
The invention aims to provide a preparation method of azoxystrobin, which has simple process, recyclable catalyst and higher yield in scale-up production.
In order to achieve the purpose, the invention adopts the technical scheme that:
in the preparation method of the azoxystrobin, 2-cyanophenol or salt thereof reacts with a compound shown as a formula I in the presence of an N-alkyl cyclic amine catalyst and a nonpolar inert solvent to obtain the azoxystrobin shown as a formula II,
the structural formula of the N-alkyl cyclic amine catalyst is shown in the specification
Wherein n is1Is 1, 2 or 3, n2Is 4 or 5.
In the invention, the chemical name of the compound shown in the formula I can be (E) -2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxy methyl acrylate.
Preferably, the N-alkyl cyclic amine catalyst is one or more of N-alkyl pyrrole and salts thereof or N-alkyl piperidine and salts thereof.
Further, the N-alkyl is any one of N-methyl, N-ethyl, N-propyl or N-isopropyl.
Preferably, the reaction is carried out in the presence of an acid-binding agent, wherein the molar ratio of the acid-binding agent to the compound represented by formula I is (0.5-2):1, for example, 0.5:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1 or 2:1, and the like, preferably (0.6-1): 1.
Further preferably, the non-polar inert solvent is toluene and/or xylene.
Still more preferably, the non-polar inert solvent is toluene.
Further preferably, the acid-binding agent is potassium carbonate and/or sodium carbonate.
Preferably, the salt of the 2-cyanophenol is sodium 2-hydroxyphenol and/or potassium 2-hydroxyphenol.
Preferably, the charge amount of the N-alkylcycloamine catalyst is 1-10 mol%, such as 1 mol%, 3 mol%, 5 mol%, 7 mol%, 9 mol% or 10 mol% of the charge amount of the compound of formula I.
Preferably, the molar ratio of the 2-cyanophenol or salt thereof to the compound of formula I is (1-1.5):1, e.g. 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1, preferably (1-1.2): 1.
Preferably, the reaction temperature is 60-120 ℃, such as 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃ or 120 ℃.
Preferably, the reaction is carried out for a reaction time of 5 to 15h, such as 5h, 8h, 10h, 12h, 14 h.
Preferably, the preparation method further comprises a post-treatment step, wherein the post-treatment step comprises the following steps: after the reaction is finished, mixing the obtained reaction liquid with water, removing a water phase after layering, removing the nonpolar inert solvent and the N-alkyl cyclic amine catalyst by reduced pressure rotary evaporation, collecting the solid, adding methanol, keeping the temperature at 60-70 ℃ for 0.5-2h, cooling to 0-5 ℃ and keeping the temperature for 1-3h, filtering, washing with cold methanol, and drying to obtain the azoxystrobin.
Further preferably, the preparation method further comprises the steps of recycling the N-alkyl cyclic amine catalyst, collecting a mixed solution formed by the nonpolar inert solvent evaporated under reduced pressure and the N-alkyl cyclic amine catalyst, introducing hydrogen chloride for reaction, filtering to obtain hydrochloride of the N-alkyl cyclic amine catalyst, alkalifying with liquid alkali, layering, and recycling the recovered N-alkyl cyclic amine catalyst to the preparation method, wherein an organic phase is the N-alkyl cyclic amine catalyst.
The reaction equation of the invention is as follows:
the invention uses some cheap and little toxic catalysts on the premise of not using transition metal catalysts, obtains better yield which can reach more than 99 percent and is more suitable for industrial production.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
according to the azoxystrobin preparation method, 2-cyanophenol or salt thereof is catalyzed by an N-alkyl cyclic amine catalyst to react with the compound shown in the formula I, so that the reaction yield of the azoxystrobin product can reach more than 98% in a small test (gram level) and a scale-up test (kilogram level), the aftertreatment is simple, the loss is low, and the yield after the aftertreatment is still more than 96%; the N-alkyl cyclic amine catalyst can be recovered and reused for synthesizing the target product azoxystrobin, so that the cost is reduced, and the method has the advantage of environmental protection.
Detailed Description
The present invention will be further described with reference to the following examples. However, the present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions not mentioned are conventional conditions in the industry. The technical features of the embodiments of the present invention may be combined with each other as long as they do not conflict with each other.
Although the pilot experiment in the example of patent CN109721548 shows that the reaction yield is more than 96%, the amplification experiment shows that when the method of patent CN109721548 is amplified to kilogram level, the actual yield is obviously reduced. Therefore, in order to improve the yield of the azoxystrobin in large-scale production, the invention utilizes the N-alkyl cyclic amine catalyst to catalyze the reaction of the 2-cyanophenol or the salt thereof and the compound shown in the formula I, and selects the nonpolar inert solvent which is the same as or similar to the post-treatment as the reaction solvent, so that the reaction yield of the azoxystrobin is up to more than 98 percent, and the post-treatment operation is simplified, wherein the N-alkyl cyclic amine catalyst can be recovered and reused for the synthesis of the target product azoxystrobin.
As a preferred technical scheme, the preparation method of the azoxystrobin specifically comprises the following steps:
under the catalysis of an N-alkyl cyclic amine catalyst, 2-cyanophenol and a compound shown in a formula I react in a nonpolar inert solvent at 60-120 ℃ to obtain azoxystrobin shown in a formula II, wherein the molar ratio of the 2-cyanophenol to the compound shown in the formula I is (1-1.5):1, the molar ratio of an acid acceptor to the compound shown in the formula I is (0.5-2):1, and the N-alkyl cyclic amine catalyst is 1-10 mol% of the compound shown in the formula I. After the reaction is finished, water is directly added, layering is carried out, an organic phase containing azoxystrobin is reserved, the reaction yield can reach more than 98% by determination, a crude azoxystrobin product is obtained by desolventizing, then methanol is added for crystallization, the product is obtained, the yield reaches more than 95%, the product content is more than 98%, the equipment and the operation time are saved, the production implementation is convenient, the production efficiency is improved, the N-alkylcycloamine catalyst can be recycled, the total nitrogen and COD in water are greatly reduced, and the method has the advantage of environmental protection.
The technical scheme and the effect of the invention are further illustrated by combining the specific embodiment.
The raw materials, reagents and the like used in the following examples and comparative examples are all commercially available.
Example 1
In this example, N-methylpyrrolidine, which is 2 mol% of the amount of methyl (E) -2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxypropenoate used, was used as a catalyst to synthesize azoxystrobin, and the specific preparation method was:
60g of toluene, (E) -2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxy acrylic acid methyl ester 20.1g (0.062mol, 99%), 2-cyanophenol 8.6g (0.068mol, 95%), potassium carbonate 13.0g (0.093mol, 99%), and N-methylpyrrolidine 0.11g (1.25mmol, 98%) were added into a reaction flask in sequence, the mixture was stirred and heated to 100 ℃, the temperature was kept for 5 hours, after the reaction was completed, water 40g was added, a toluene solution of azoxystrobin was obtained by layering, toluene was removed by reduced pressure distillation, methanol 40g was added, the temperature was kept at 60-70 ℃, after 1 hour, the temperature was slowly reduced to 0-5 ℃, the reaction solution was kept for 2 hours, the reaction solution was filtered, washed twice with cold methanol (5g × 2), and dried to obtain azoxystrobin 24.6g, a white solid, the content was 98.2%, and the yield was 96.5%.
Example 2
In this example, N-methylpyrrolidine, which is 4 mol% of the amount of methyl (E) -2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxypropenoate used, was used as a catalyst to synthesize azoxystrobin, and the specific preparation method was:
60g of toluene, (E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate 20.1g (0.062mol, 99%), 2-cyanophenol 8.6g (0.068mol, 95%), potassium carbonate 13.0g (0.093mol, 99%), and N-methylpyrrolidine 0.22g (2.48mmol, 98%) were sequentially added to a reaction flask, and after the reaction was completed, water 40g was added and the mixture was layered to obtain a toluic solution of azoxystrobin.
The same aftertreatment method as in example 1 was used to obtain azoxystrobin 24.6g, with a content of 98.4% and a yield of 96.7%.
Example 3
In this example, N-ethylpyrrolidine, which is 2 mol% of the amount of methyl (E) -2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxypropenoate, was used as a catalyst to synthesize azoxystrobin, and the specific preparation method was:
60g of toluene, (E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate 20.1g (0.062mol, 99%), 2-cyanophenol 8.6g (0.068mol, 95%), potassium carbonate 13.0g (0.093mol, 99%), and N-ethylpyrrolidine 0.125g (1.24mmol, 98%) were sequentially added to a reaction flask, stirred and heated to 100 ℃, kept warm for 5 hours, after the reaction was completed, water 40g was added, and a toluene solution of azoxystrobin was obtained by layering.
The same aftertreatment method as in example 1 was used to obtain azoxystrobin 24.5g, with a content of 98.3% and a yield of 96.2%.
Example 4
In this example, N-methylpyrrolidine, which is 2 mol% of the amount of methyl (E) -2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxypropenoate, was used as a catalyst to synthesize azoxystrobin, and the amount of potassium carbonate was reduced, and the specific preparation method was:
60g of toluene, (E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate 20.1g (0.062mol, 99%), 2-cyanophenol 8.6g (0.068mol, 95%), potassium carbonate 5.2g (0.037mol, 99%), N-methylpyrrolidine 0.11g (1.24mmol, 98%) were added into a reaction flask in this order, and after the reaction was completed, water 40g was added and the mixture was layered to obtain a toluic solution of azoxystrobin.
The same aftertreatment method as in example 1 was used to obtain azoxystrobin 24.3g, with a content of 98.2% and a yield of 95.3%.
Example 5
In this example, the azoxystrobin was synthesized using 2 mol% of N-methylpiperidine, which is the amount of methyl (E) -2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxypropenoate used, as a catalyst, and the specific preparation method was:
60g of toluene, (E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate 20.1g (0.062mol, 99%), 2-cyanophenol 8.6g (0.068mol, 95%), potassium carbonate 13.0g (0.093mol, 99%), N-methylpiperidine 0.13g (1.24mmol, 98%) were sequentially added to a reaction flask, and after the reaction was completed, the temperature was raised to 100 ℃ with stirring, the temperature was kept for 5 hours, water 40g was added, and a toluene solution of azoxystrobin was obtained by layering.
The same post-treatment method as in example 1 was used to obtain azoxystrobin 24.2g, content 98.1% and yield 94.9%.
Example 6
In this example, 2 mol% of N-ethylpiperidine, which is the amount of methyl (E) -2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxypropenoate, was used as a catalyst to synthesize azoxystrobin, and the specific preparation method was:
60g of toluene, (E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate 20.1g (0.062mol, 99%), 2-cyanophenol 8.6g (0.068mol, 95%), potassium carbonate 13.0g (0.093mol, 99%), N-ethylpiperidine 0.14g (1.24mmol, 98%) were sequentially added to a reaction flask, and after the reaction was completed, the temperature was raised to 100 ℃ with stirring, the temperature was kept for 5 hours, water 40g was added, and a toluene solution of azoxystrobin was obtained by layering.
The same post-treatment method as in example 1 was used to obtain azoxystrobin 24.1g, content 98.1% and yield 94.5%.
Example 7
In this example, the recovered N-methylpyrrolidine, which is 2 mol% of the amount of methyl (E) -2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxypropenoate used, was used as a catalyst to synthesize azoxystrobin, and the specific preparation method was:
60g of toluene, (E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate 20.1g (0.062mol, 99%), 2-cyanophenol 8.5g (0.068mol, 95%), potassium carbonate 13.0g (0.093mol, 99%), recovered N-methylpyrrolidine 0.11g (1.24mmol, 97%), stirring and heating to 100 ℃, keeping the temperature for 5h, finishing the reaction, adding water 40g, and layering to obtain azoxystrobin toluene liquid.
The same aftertreatment method as in example 1 was used to obtain azoxystrobin 24.5g, with a content of 98.1% and a yield of 96.0%.
The catalyst recovery scheme comprises the following steps: in the embodiment 1, the toluene liquid is evaporated under reduced pressure, hydrogen chloride is introduced, the hydrochloride of the catalyst is obtained by filtering, and the recovered catalyst is obtained by alkalization with liquid alkali and layering.
On the basis of small trial process research and development, the process is amplified in a kilogram level so as to verify the stability of the process and the practicability of industrialization. In the following examples, we used N-methylpyrrolidine as a catalyst to synthesize azoxystrobin.
Example 8
In this example, N-methylpyrrolidine, which is 2 mol% of the amount of methyl (E) -2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxypropenoate used, was used as a catalyst to synthesize azoxystrobin, and the specific preparation method was:
3000g of toluene, (E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate 1004.3g (3.1mol, 99%), 2-cyanophenol 426.3g (3.4mol, 95%), potassium carbonate 649.1g (4.65mol, 99%), and N-methylpyrrolidine 5.4g (62mmol, 98%) were sequentially added into a 10L reaction flask, the mixture was stirred, the temperature was raised to 100 ℃, the temperature was kept for 5 hours, the reaction was finished, 2000g of water was added, and a toluene solution of azoxystrobin was obtained by layering.
The toluene solution of azoxystrobin is subjected to reduced pressure distillation to remove toluene, 2000g of methanol is added, the temperature is kept at 60-70 ℃, after 1h, the temperature is slowly reduced to 0-5 ℃, the temperature is kept for 2h, the filtrate is filtered, the azoxystrobin is washed twice by using cold methanol (250g multiplied by 2), and the filtrate is dried to obtain 1230g of azoxystrobin, white solid with the content of 98.1 percent and the yield of 96.5 percent.
Comparative example 1
In this example, azoxystrobin was synthesized without adding a catalyst, and the specific preparation method was:
60g of toluene, (E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate 20.1g (0.062mol, 99%), 2-cyanophenol 8.5g (0.068mol, 95%), potassium carbonate 13.0g (0.093mol, 99%), stirring and heating to 100 ℃, and keeping the temperature for 10h, wherein the conversion rate of the raw material ((E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate) is only about 3% and no further crystallization treatment is performed due to low conversion rate.
Comparative example 2
Basically, the difference is that the catalyst is replaced by trimethylamine hydrochloride which is reported in patent CN109721548, and the specific preparation method is as follows:
60g of toluene, (E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate 20.1g (0.062mol, 99%), 2-cyanophenol 8.5g (0.068mol, 95%), potassium carbonate 13.0g (0.093mol, 99%), trimethylamine hydrochloride 0.12g (1.24mmol, 98%), stirring, heating to 100 ℃, keeping the temperature for 5h, adding water 40g after the reaction is finished, and layering to obtain a toluene solution of azoxystrobin.
The same post-treatment method as in example 1 was used to obtain azoxystrobin 23.7g, with a content of 98.3% and a yield of 93.1%.
Comparative example 3
In this example, the catalyst trimethylamine hydrochloride reported in patent CN109721548 is amplified to synthesize azoxystrobin, and the specific preparation method comprises:
3000g of (E) -methyl 2- [2- [ 6-chloropyrimidin-4-yloxy ] phenyl ] -3-methoxyacrylate 1004.3g (3.1mol, 99%), 2-cyanophenol 426.3g (3.4mol, 95%), potassium carbonate 649.1g (4.65mol, 99%), trimethylamine hydrochloride 6.0g (62mol, 98%), stirring and heating to 100 ℃, keeping the temperature for 5 hours, finishing the reaction, adding 2000g of water, and layering to obtain a toluene solution of azoxystrobin.
The toluene solution of azoxystrobin is subjected to reduced pressure distillation to remove toluene, 2000g of methanol is added, the temperature is kept at 60-70 ℃, after 1h, the temperature is slowly reduced to 0-5 ℃, the temperature is kept for 2h, the filtrate is filtered, the filtrate is washed twice by cold methanol (250g multiplied by 2), and the filtrate is dried to obtain 1179g of azoxystrobin, namely white solid with the content of 98.0 percent and the yield of 92.4 percent.
It is obvious from the above examples and comparative examples that the N-alkyl cyclic amine catalyst can obtain better yield, and the catalytic effect is still significant even if the catalyst is amplified to a kilogram level. In comparative example 1, when the reaction was not catalyzed by a catalyst, the product formation was very small and the yield was less than 5% of theoretical. Comparative example 2 and comparative example 3 the reaction was catalyzed using trimethylamine hydrochloride in a yield of about 3-4% lower than that of the N-alkylcycloamine catalyst under otherwise identical conditions.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (10)
1. A preparation method of azoxystrobin is characterized in that 2-cyanophenol or salt thereof reacts with a compound shown as a formula I in the presence of an N-alkyl cyclic amine catalyst and a nonpolar inert solvent to obtain azoxystrobin shown as a formula II,
the structural formula of the N-alkyl cyclic amine catalyst is shown in the specification
Wherein n is1Is 1, 2 or 3, n2Is 4 or 5.
2. The process of claim 1, wherein the N-alkylcycloamine catalyst is one or more of N-alkylpyrroles and salts thereof or N-alkylpiperidines and salts thereof.
3. The method according to claim 2, wherein the N-alkyl group is any one of an N-methyl group, an N-ethyl group, an N-propyl group and an N-isopropyl group.
4. The preparation method according to claim 1, wherein the reaction is carried out in the presence of an acid-binding agent, and the molar ratio of the acid-binding agent to the compound represented by formula I is (0.5-2): 1.
5. The process according to claim 4, wherein the non-polar inert solvent is toluene and/or xylene; the acid-binding agent is potassium carbonate and/or sodium carbonate.
6. The method according to claim 1, wherein the salt of 2-cyanophenol is sodium 2-hydroxyphenol and/or potassium 2-hydroxyphenol.
7. The method according to claim 1, wherein the charge amount of the N-alkylcycloamine catalyst is 1-10 mol% of the charge amount of the compound represented by the formula I;
and/or the feeding molar ratio of the 2-cyanophenol or the salt thereof to the compound shown in the formula I is (1-1.5): 1.
8. The method of claim 1, wherein the reaction temperature is 60-120 ℃; and/or the reaction time is 5-15 h.
9. The method of claim 1, further comprising a post-treatment step, wherein the post-treatment step comprises: after the reaction is finished, mixing the obtained reaction liquid with water, removing a water phase after layering, removing the nonpolar inert solvent and the N-alkyl cyclic amine catalyst by reduced pressure rotary evaporation, collecting the solid, adding methanol, keeping the temperature at 60-70 ℃ for 0.5-2h, cooling to 0-5 ℃ and keeping the temperature for 1-3h, filtering, washing with cold methanol, and drying to obtain the azoxystrobin.
10. The preparation method according to claim 9, further comprising recycling the N-alkylcycloamine catalyst, collecting a mixed solution of the nonpolar inert solvent and the N-alkylcycloamine catalyst evaporated under reduced pressure, introducing hydrogen chloride for reaction, filtering to obtain a hydrochloride of the N-alkylcycloamine catalyst, alkalifying with liquid alkali, and layering, wherein the organic phase is the N-alkylcycloamine catalyst, and the recycled N-alkylcycloamine catalyst can be recycled to the preparation method.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20140085204A (en) * | 2012-12-27 | 2014-07-07 | 동부팜한농 주식회사 | A method for preparing methyl (E)-2-[2-[6-(2-cyanophenoxy)pyrimidine-4-yloxy]phenyl]-3-methoxyacrylate |
| CN109721548A (en) * | 2017-10-31 | 2019-05-07 | 南通泰禾化工股份有限公司 | A kind of preparation method of Fluoxastrobin |
| CN111233775A (en) * | 2018-11-28 | 2020-06-05 | 兴农股份有限公司 | Preparation method of azoxystrobin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20140085204A (en) * | 2012-12-27 | 2014-07-07 | 동부팜한농 주식회사 | A method for preparing methyl (E)-2-[2-[6-(2-cyanophenoxy)pyrimidine-4-yloxy]phenyl]-3-methoxyacrylate |
| CN109721548A (en) * | 2017-10-31 | 2019-05-07 | 南通泰禾化工股份有限公司 | A kind of preparation method of Fluoxastrobin |
| CN111233775A (en) * | 2018-11-28 | 2020-06-05 | 兴农股份有限公司 | Preparation method of azoxystrobin |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023226456A1 (en) * | 2022-05-26 | 2023-11-30 | 安徽广信农化股份有限公司 | Method for preparing azoxystrobin and intermediate thereof |
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