CN103030598B - The preparation method of methoxy acrylic bactericide - Google Patents
The preparation method of methoxy acrylic bactericide Download PDFInfo
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Abstract
The present invention relates to the preparation method of methoxy acrylic bactericide, comprise step: 1) general formula (II) compound is mixed with general formula (III), react under 90-120 DEG C of condition and within 5-10 hour, obtain general formula (IV) compound; General formula (III) compound is the acetal of Carbox amide, R
1, R
2, R
3for substituted alkyl or aryl; 2) by general formula (IV) compound after hydrolyzed under acidic conditions, under alkalescence, methylating reagent and phase-transfer catalyst condition, within stirring at room temperature 2-4 hour, obtain product; X is 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base or 6-5-flumethiazine-2-oxygen ylmethyl; 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base or 6-5-flumethiazine-2-oxygen ylmethyl; [2-[[[[4-(4-chloro-phenyl-)-Ding-3-alkene-2-base] imido grpup] oxygen base] methyl] phenyl]; 2-(2-((3-butyl-4-methyl-coumarin-7-base oxygen base) methyl) phenyl), the method total recovery reaches more than 85%.
Description
Technical field
The present invention relates to the preparation method of methoxy acrylic bactericide.
Background technology
The discovery of methoxy acrylic (strobilurins) sterilant is the inspiration by the natural compounds 'beta '-methoxy acrylic acid derivatives with fungicidal activity.Become the important sterilant of a class through the research and apply of nearly 20 years, be a class low toxicity, high reactivity, broad spectrum, systemic fungicide, there is protection, treatment, eradicant action.They all have good activity for Ascomycetes, Basidiomycetes, deuteromycetes and Oomycete etc., can prevent and treat the diseases such as the Powdery Mildew of various crop, rust, oidium and rice blast.And effectively can prevent and treat the pathogenic bacteria other sterilant being produced to resistance, the bacterial strain as resisted 14 1 demethylation enzyme inhibitorss, benzamides, dicarboxylic dihydrazides amine and benzimidazole germicide is effective.Its mechanism of action is mitochondrial respiratory inhibitor.By pinning the electron transmission between cytochrome b and c1, stoping the synthesis of cellular energy, thus suppressing its mitochondrial respiratory to reach bacteriostatic action.
From the Azoxystrobin of Syngenta Co., Ltd in 1996 and the kresoxim-methyl of BASF AG since Germany's registration listing, strobilurins series bactericidal agent reaches 10 years by market test, in these 10 years, though this series products also meets with resistance puzzlement, but still with the incomparable annual growth one road paean more than 10%, within 2009, to surmount the leading enterprise-triazole bactericidal agent (20.7%) in sterilant product with sales quota 23.5%, reach 26.28 hundred million dollars.Strobilurins series bactericidal agent with the mechanism of action of its uniqueness, the attitude extremely friendly to environment, the global major antibacterial agent market of nearly cover.Do not have 10 strobilurins series bactericidal agents at present active in the international market, some of them kind has become star's product very important in corporate profit's ranking list.
The main products of having gone on the market at present and be about to go on the market is divided into two large classes according to structure: (1) has 2-substituted-phenyl-3-methoxy-methyl acrylate structure, as Azoxystrobin (azoxystrobin), ZEN 90160 (picoxystrobin), enostroburin (enestroburin), SYP-3375 (coumoxystrobin), ZJ0712 (ZJ0712) and UBF-307; (2) methoxy imino replaces substituted phenylacetic acid methyl esters or the acid amides of methoxy methene formation, as kresoxim-methyl (kresoxim-methyl), SSF 126 (metominostrobin), fluoxastrobin (Fluoxastrobin), oxime bacterium ester (trifloxystrobin), dimoxystrobin (dimoxystrobin), orysastrobin (orysastrobin), pyraclostrobin (pyraclostrobin) and alkene oxime amine (SYP-1260).
Have following general formula with the first kind product that Azoxystrobin and ZEN 90160 are representative, wherein X is substituted radical:
Azoxystrobin (Azoxystrobin) is the exploitation of prompt sharp Kanggong department and first commercial methoxy acrylic bactericide, the chemical name of Azoxystrobin is (E)-2-(2-(6-(2-cyano-benzene oxygen) pyrimidine-4-oxygen base) phenyl)-3-methoxy-methyl acrylate (I), structural formula:
Efficient and the wide spectrum of this sterilant, almost can prevent and treat all fungies, Oomycete, Phycomycetes, Ascomycetes and deuteromycetes disease, and be used on cereal, paddy rice, grape, potato, vegetables, fruit tree, beans and other crop by cauline leaf process, seed treatment.
The preparation method of current bibliographical information synthesis Azoxystrobin mainly contains:
(1) from o-methyl hydroxyphenylacetate be starting raw material; protection hydroxyl; then methyl-formiate formylation is used; etherificate; go protection to obtain (E)-(2-hydroxy phenyl)-3-methoxy-methyl acrylate, then obtain Azoxystrobin with 4,6-dichloro pyrimidine and adjacent cyanophenol condensation successively; this is the early stage patented method of Jie Likang, is also the main method of other methyl acrylate series bactericidal agent synthesis.US5395837，EP-A-0242081，PCT/GB97/02015。
(2) from o-hydroxy phenylacetic acid be starting raw material, be benzofuranone through cyclization, (2-hydroxy phenyl)-3 is obtained with sodium methylate/methyl alcohol open loop addition, 3-dimethoxy methyl propionate, with 4, obtain (E) 2-(2-(the chloro-pyrimidine of 6--4-oxygen base) phenyl)-3-methoxy-methyl acrylate with sal enixum separating methanol after the condensation of 6-dichloro pyrimidine, then obtain Azoxystrobin with adjacent cyanophenol condensation.GB2291874，WO1998007707，AustralianJournalofChemistry,26(5),1079,1973;JournalofOrganicChemistry,40(24),3474,1975。
(3) 4; 6-dichloro pyrimidine obtains 2-(2-(6-(2-cyano-benzene oxygen) pyrimidine-4-oxygen base) phenyl)-methyl acetate successively with adjacent cyanophenol and o-methyl hydroxyphenylacetate condensation; Azoxystrobin is prepared again with highly basic alkylations such as organolithiums; it is higher that the method prepares general alkylation products yield; but preparation Azoxystrobin yield is lower; and organolithium danger in large-scale production is higher, the low temperature that reaction needed-78 DEG C is such.WO02100837，US20060229450，US20040242607，US7244737，US7084272，EP1399427，CN02810368。
(4) 2-(2-(6-(2-cyano-benzene oxygen) pyrimidine-4-oxygen base) phenyl)-methyl acetate Lewis acid and trimethyl orthoformate or methyl-formiate formylation, then etherificate is introduced methoxy thiazolinyl and is obtained Azoxystrobin.
CN200710163386, WO2009052719 method (2) and (4) are the main method adopted in current actual production, and method (2) calculates total recovery about 60% with benzofuranone; Method (4), although there is certain amplitude to improve (69%) in total recovery, will use titanium tetrachloride as catalyzer in production process.The unstable chemcial property of titanium tetrachloride, wet gas emits white cigarette immediately, uses inconvenience, and obtain much insoluble substance titanium dioxide in addition in post-reaction treatment and form pasty state colloid, product separation bothers.
ZEN 90160 is methoxy acrylate (Strobilurins) series bactericidal agent, and the mechanism of action and feature are mitochondrial respiratory inhibitor, namely suppress mitochondrial breathing by transfer transport between cytochrome b and C1.Prevent and treat the bacterial strain of 14-demethylation enzyme inhibitors, benzamides, tri carboxylic acid amide class and benzimidazoles generation resistance effective.Due to systemic activity and the fumigation activity of ZEN 90160, thus after dispenser, effective constituent can effectively be reallocated and fully transmit, and therefore ZEN 90160 extremely has better therapeutic activity than Azoxystrobin and oxime bacterium.
The preparation method of ZEN 90160 sees patent EP-0278595 the earliest, 2-(2 '-aminomethyl phenyl)-3-methoxy-methyl acrylate bromine/AIBN(Diisopropyl azodicarboxylate) or NBS/AIBN bromination obtain (E)-2-(2 '-2-bromomethylphenyl)-3-methoxy-methyl acrylate, then under Different Alkali effect, obtain product with hydroxy pyrimidine condensation.
Later stage document mainly concentrates on key intermediate (E)-2-(2 '-2-bromomethylphenyl) preparation method's research of-3-methoxy-methyl acrylate.
(1) US4822908 describes and under sodium hydride effect, obtains 2-(2 '-aminomethyl phenyl with o-methyl benzoic acid methyl ester and methyl-formiate)-acrolactic acid methyl esters, methyl-sulfate/salt of wormwood etherificate obtains 2-(2 '-aminomethyl phenyl)-3-methoxy-methyl acrylate, then obtain (E)-2-(2 '-2-bromomethylphenyl by NBS/AIBN bromination)-3-methoxy-methyl acrylate.
(2) US6162945 describes one and prepares (E)-2-(2 '-aminomethyl phenyl) method of-3-methoxy-methyl acrylate, solvent is made with N-Methyl pyrrolidone, o-Tolylacetic acid methyl esters and methyl-formiate react under 30% sodium methylate effect, then reclaim under reduced pressure methyl alcohol, excessive methyl-formiate and partial solvent, continuation methyl chloride etherificate obtains product.
(3) WO20100256367 and Bull.KoreanChem.Soc.2006, Vol.27, No.2191 describe with Suzuki reaction, and the iodo-3-methoxy-methyl acrylate of 2-and aryl-boric acid ester coupling obtain the method for 2-aryl-3-methoxy-methyl acrylate structure.
(4) Chinese invention patent 93117232 describes with polymerization alkali and bromine under light illumination (E)-2-(2 '-aminomethyl phenyl)-3-methoxy-methyl acrylate bromo obtains key intermediate (E)-2-(2 '-2-bromomethylphenyl)-3-methoxy-methyl acrylate
(5) Chinese invention patent 200810155355 describes key intermediate (E)-2-(2 '-2-bromomethylphenyl) preparation of-3-methoxy-methyl acrylate, comprising: (1) o-Tolylacetic acid and methanol esterification obtain o-Tolylacetic acid methyl esters; (2) 2-(2 '-aminomethyl phenyl is obtained by reacting with sodium hydride as alkali and methyl-formiate)-acrolactic acid methyl esters; (3) (E)-2-(2 '-aminomethyl phenyl is obtained by methyl-sulfate/sodium hydroxide etherificate)-3-methoxy-methyl acrylate; (4) (E)-2-(2 '-2-bromomethylphenyl is obtained by bromine/AIBN bromination)-3-methoxy-methyl acrylate.
Be specifically ZEN 90160 in scale operation wherein bromo-reaction one step be free radical reaction, reaction preference is bad, has many bromination products, in addition the poor controllability of free radical reaction aborning, and repeatability is bad.
In addition, the difficulty in enostroburin enestroburin and the actual synthetic reaction process of SYP-3375 coumoxystrobin is larger, not easily produces.
Enostroburin enestroburin
Name: α-[2-[[[[4-(4-chloro-phenyl-)-Ding-3-alkene-2-base] imido grpup] oxygen base] methyl] phenyl]-'beta '-methoxy acrylic acid methyl esters
methyl2-{2-[({[3-(4-chlorophenyl)-1-methylprop-2-enylidene]amino}oxy)methyl]phenyl}-3-methoxyacrylate
Chemical formula: C
22h
22clNO
4
Structural formula:
SYP-3375 coumoxystrobin
Name: (E)-2-(2-((3-butyl-4-methyl-coumarin-7-base oxygen base) methyl) phenyl)-3-methoxy-methyl acrylate methyl (2E)-2-{2-[(3-butyl-4-methyl-2-oxo-2H-chromen-7-yl) oxymethyl] phenyl}-3-methoxyacrylate
Chemical formula: C
26h
28o
6
Structural formula:
Summary of the invention
The object of the present invention is to provide a kind of preparation method of methoxy acrylic bactericide, the method synthesis technique environmental friendliness safety, total recovery reaches more than 85%.
For realizing above object, the present invention is achieved through the following technical solutions:
The preparation method of methoxy acrylic bactericide, described methoxy acrylic bactericide comprises Azoxystrobin, ZEN 90160, enostroburin and SYP-3375, is prepared by following steps:
1) by general formula (II) compound and general formula (III) compound, within reacting by heating 5-10 hour under 90-120 DEG C of condition, general formula (IV) compound is obtained:
Wherein, general formula (III) compound is the acetal of Carbox amide, R
1, R
2, R
3for substituted alkyl or aryl;
2) by general formula (IV) compound after hydrolyzed under acidic conditions obtains logical formula V compound, then under alkalescence, methylating reagent and phase-transfer catalyst condition, within stirring at room temperature 2-4 hour, obtain product (I):
Wherein, X is 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base or 6-5-flumethiazine-2-oxygen ylmethyl; 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base or 6-5-flumethiazine-2-oxygen ylmethyl; [2-[[[[4-(4-chloro-phenyl-)-Ding-3-alkene-2-base] imido grpup] oxygen base] methyl] phenyl]; 2-(2-((3-butyl-4-methyl-coumarin-7-base oxygen base) methyl) phenyl).
Preferably, the acetal of described Carbox amide is be selected from the one in dimethylformamide dimethyl acetal, dimethylformamide diethyl acetal, dimethyl formamide dibutyl acetal, dimethyl formamide dibenzyl acetal and diethylformamide diethyl acetal.
Preferably, step 1) reaction is carried out in inert solvent.
Preferably, described inert solvent is be selected from one or more mixed solvent of normal hexane, sherwood oil, toluene, dimethylbenzene, chlorobenzene, ether, isopropyl ether, methyl tertiary butyl ether, acetone, butanone, methyl iso-butyl ketone (MIBK), ethyl acetate, butylacetate, acetonitrile, DMF, methyl-sulphoxide, tetramethylene sulfone and hexamethylphosphoramide.
Preferably, step 2) described methylating reagent is methyl-sulfate or methyl iodide.
Preferably, step 2) described alkali is be selected from arbitrarily solid in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium methylate, sodium ethylate or sodium tert-butoxide or its solution.
Preferably, step 2) general formula (IV) compound and methyl alcohol reacted in acid condition within 10-14 hour, obtain general formula compound (VI) product after, general formula compound (VI) and sal enixum or sodium pyrosulfate are obtained by reacting compound (I):
Wherein, X is 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base or 6-5-flumethiazine-2-oxygen ylmethyl; 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base or 6-5-flumethiazine-2-oxygen ylmethyl; [2-[[[[4-(4-chloro-phenyl-)-Ding-3-alkene-2-base] imido grpup] oxygen base] methyl] phenyl]; 2-(2-((3-butyl-4-methyl-coumarin-7-base oxygen base) methyl) phenyl).
Preferably, general formula (IV) compound room temperature reaction 10-14 hour in hydrogenchloride and methanol mixed solution, methyl alcohol and sulfuric acid mixed solution, methyl alcohol and tosic acid mixing solutions obtains general formula compound (VI), and general formula compound (VI) and sal enixum are obtained by reacting compound (I).
Preferably, step 2) reaction terminate after by extraction solvent purification by liquid extraction.
Preferably, described extraction solvent is be selected from one or more reagent in toluene, 2-butanols, propyl carbinol, normal hexane, Skellysolve A, normal heptane, methylene dichloride, ethyl acetate, diethyl ether, diisopropyl ether, benzene, chloroform and hexanaphthene.
In the present invention, methoxy acrylic bactericide includes but not limited to Azoxystrobin, ZEN 90160, enostroburin and SYP-3375; In addition, step 2) alkali be more preferably sodium hydroxide and potassium hydroxide solid or its solution.
General formula compound (II):
When X is 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base, it is azoxystrobin intermediate, and synthetic route is as follows:
When X is 6 '-5-flumethiazine-2-oxygen ylmethyl, it is ZEN 90160 intermediate, and synthetic route is as follows:
General formula (III) compound is:
Compound (III) is the acetal of Carbox amide, includes but not limited to dimethylformamide dimethyl acetal (being called for short DMFDMA), dimethylformamide diethyl acetal, dimethyl formamide dibutyl acetal, dimethyl formamide dibenzyl acetal and diethylformamide diethyl acetal; It is for the reaction such as alkylation and formylation, and reaction mechanism is as follows:
Me: methyl;
Inert solvent is for including but not limited to hydro carbons, ethers, ketone and ester class and associated class solvent, such as normal hexane, sherwood oil, toluene, dimethylbenzene, chlorobenzene, ether, isopropyl ether, methyl tertiary butyl ether, acetone, butanone, methyl iso-butyl ketone (MIBK), ethyl acetate, butylacetate, acetonitrile, DMF, methyl-sulphoxide, tetramethylene sulfone and hexamethylphosphoramide.
One of step 1) compound (II) and general formula (III) compound mix, and be heated to 90 DEG C of-120 reaction 5-10 hour, reaction can obtain almost quantitative yield, product directly or steam except after low boil-off dose for next step reaction.
General formula (IV) the compound acid hydrolysis obtained obtains 2-(2-substituted-phenyl)-acrolactic acid methyl esters (V), more namely obtains product by etherification method etherificate.
General formula (IV) compound is added 10% acid (example hydrochloric acid), stirring at room temperature 3 hours, enamine is hydrolyzed to the enol form of aldehyde, and reaction solution obtains almost quantitative yield, and reaction terminates the common solvent such as rear toluene and extracts, and extraction liquid directly applies to next step etherificate.With methyl-sulfate and sodium hydroxide, methylate and obtain product (I) under phase-transfer catalyst effect, calculating total recovery from compound (II) can reach more than 85%.
Ar: aromatic ring group
x is 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base or 6-5-flumethiazine-2-oxygen ylmethyl; 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base or 6-5-flumethiazine-2-oxygen ylmethyl; [2-[[[[4-(4-chloro-phenyl-)-Ding-3-alkene-2-base] imido grpup] oxygen base] methyl] phenyl]; 2-(2-((3-butyl-4-methyl-coumarin-7-base oxygen base) methyl) phenyl);
Methyl alcohol/the acid treatment of general formula (IV) compound obtains 2-(2-substituted-phenyl)-3,3-dimethoxy methyl propionate (VI), then sloughs a part methyl alcohol with the material of sal enixum or sodium pyrosulfate or the similar sal enixum of character or sodium pyrosulfate and obtains (I).
Step 2) general formula (IV) compound hydrogenchloride/methanol solution room temperature treatment 12 hours, obtain compound (VI), compound (VI) sloughs a part methyl alcohol with the material of sal enixum or the similar sal enixum of character can obtain compound (I), calculates total recovery more than 80% from compound (II).
Wherein, step 2) namely general formula (IV) compound hydrogenchloride/methanol solution, methyl alcohol/sulfuric acid adopt methyl alcohol and acid catalyst, as sulfuric acid, tosic acid etc. except hydrogen bromide, hydrogen iodide and nitric acid, room temperature reaction 10-14 hour obtains general formula compound (VI), and general formula compound (VI) and sal enixum are obtained by reacting compound (I).
Synthetic method of the present invention has following characteristics: (1) raw material is cheaply easy to get; (2) feature such as process environments close friend, mild condition, yield be high and easy and simple to handle.
Accompanying drawing explanation
Fig. 1 is the Azoxystrobin nuclear magnetic spectrogram synthesized in embodiment.
Fig. 2 is the ZEN 90160 nuclear magnetic spectrogram synthesized in embodiment.
Embodiment
Below in conjunction with accompanying drawing, the present invention is described in detail:
The following example is just in order to set forth the present invention, and the present invention institute applies for protecting content and scope not to be subject to the restriction of following embodiment, and Azoxystrobin and ZEN 90160 all contrast with standard model.
Embodiment 1
36.1 grams of (0.1mol) (I) are dissolved in 100 milliliters of toluene, add 15 grams of (0.126mol) DMF-DMA, load onto the water distilling apparatus with segment rectifying column, be slowly warmed up to 90 DEG C, have lowly to boil cut slowly out; It is moderate that control distillates speed, continues to be warmed up to 120 DEG C, and TLC follows the tracks of until feedstock conversion is complete.It is azoxystrobin intermediate that decompression steams remaining low-boiling-point substance, cooling, for subsequent use.
Embodiment 2
Product in embodiment (1) is dissolved in 50 milliliter of 10% hydrochloric acid, stirred at ambient temperature 3 hours; Divide three extractions with 150 milliliters of toluene, combining methylbenzene phase, add 1 gram of benzyltriethylammoinium chloride, 30 gram of 20% sodium hydroxide solution and 20 grams of methyl-sulfates, stirring at room temperature 3 hours, be warmed up to 50 DEG C of reactions 2 hours; Separate toluene phase, with 20 milliliter of 5% salt acid elution once, concentrating under reduced pressure toluene, resistates 20 ml methanol recrystallizations obtain Azoxystrobin product 35 grams, content 98.5%(external standard method detect), yield 85.1%.
1HNMR（CDCl
3），δ3.64（s，3H），3.75(s，3H)，6.42（s，1H），7.22（d，1H），7.26-7.43（m，5H），7.49（s，1H），7.66（t，1H），7.71（d，1H），8.4（s，1H）
Embodiment 3
Product in embodiment (1) is dissolved in 80 milliliters of 20% hydrogenchloride/methanol solutions, stirred at ambient temperature 12 hours; Excessive hydrogenchloride/the methanol solution of major part is reclaimed in air distillation, and then remove low-boiling-point substance under reduced pressure, resistates adds 1 gram of sal enixum, and water pump heated under reduced pressure was to 140-150 DEG C of reaction 6 hours; Cool to room temperature, adds toluene 150 milliliters, filters, and wash once with 5% sodium bicarbonate 25 milliliters, concentrating under reduced pressure toluene, resistates 20 ml methanol recrystallizations obtain product 32.9 grams, and content 98.8%(external standard method detects HPLC), yield 80.6%.
Embodiment 4
32.5 grams of (0.1mol) (I) are dissolved in 100 milliliters of toluene, add 15 grams of (0.126mol) DMFDMA, load onto the water distilling apparatus with segment rectifying column, be slowly warmed up to 90 DEG C, have lowly to boil cut slowly out; It is moderate that control distillates speed, continues to be warmed up to 120 DEG C, and TLC follows the tracks of until feedstock conversion is complete.It is ZEN 90160 intermediate that decompression steams remaining low-boiling-point substance, cooling, for subsequent use.
Embodiment 5
Product in embodiment (4) is dissolved in 50 milliliter of 10% hydrochloric acid, stirred at ambient temperature 3 hours; Divide three extractions with 150 milliliters of toluene, combining methylbenzene phase, add 1 gram of benzyltriethylammoinium chloride, 30 gram of 20% sodium hydroxide solution and 20 grams of methyl-sulfates, stirring at room temperature 3 hours, be warmed up to 50 DEG C of reactions 2 hours; Separate toluene phase, with 20 milliliter of 5% salt acid elution once, concentrating under reduced pressure toluene, resistates 15 ml methanol recrystallizations obtain product ZEN 90160 30.5 grams, content 98.2%(external standard method detect), yield 81.5%.
1HNMR（CDCl
3），δ3.66（s，3H），3.80(s，3H)，5.33（s，2H），6.87（d，1H），7.17-7.19（m，1H），7.22-7.25（m，1H），7.31-7.36（m，2H），7.54-7,57（m，2H），7.67（t，1H）
Embodiment 6
Product in embodiment (4) is dissolved in 80 milliliters of 20% hydrogenchloride/methanol solutions, stirred at ambient temperature 12 hours; Excessive hydrogenchloride/the methanol solution of major part is reclaimed in air distillation, and then remove low-boiling-point substance under reduced pressure, resistates adds 1 gram of sal enixum, and water pump heated under reduced pressure was to 130-140 DEG C of reaction 6 hours; Cool to room temperature, adds toluene 150 milliliters, filters, and wash once with 5% sodium bicarbonate 25 milliliters, concentrating under reduced pressure toluene, resistates 15 ml methanol recrystallizations obtain Azoxystrobin product 31.2 grams, and content 98.5%(external standard method detects HPLC), yield 83.7%.
Embodiment in the present invention, only for the present invention will be described, does not form the restriction to right, other equivalent in fact substituting, all in scope that those skilled in that art can expect.
Claims (7)
1. the preparation method of methoxy acrylic bactericide, described methoxy acrylic bactericide comprises Azoxystrobin, ZEN 90160, enostroburin and SYP-3375, is prepared by following steps:
1) by general formula (II) compound and general formula (III) compound, within reacting by heating 5-10 hour under 90-120 DEG C of condition, general formula (IV) compound is obtained:
Wherein, general formula (III) compound is the acetal of Carbox amide, R
1, R
2, R
3for substituted alkyl or aryl; Step 1) react and carry out in inert solvent; Described inert solvent is be selected from one or more mixed solvent of normal hexane, sherwood oil, toluene, dimethylbenzene, chlorobenzene, ether, isopropyl ether, methyl tertiary butyl ether, acetone, butanone, methyl iso-butyl ketone (MIBK), ethyl acetate, butylacetate, acetonitrile, DMF, methyl-sulphoxide, tetramethylene sulfone and hexamethylphosphoramide;
2) by general formula (IV) compound after hydrolyzed under acidic conditions obtains logical formula V compound, then under alkalescence, methylating reagent and phase-transfer catalyst condition, within stirring at room temperature 2-4 hour, obtain product (I):
Wherein, X is 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base or 6-5-flumethiazine-2-oxygen ylmethyl, 6-(2 '-cyano-benzene oxygen) pyrimidine-4-oxygen base or 6-5-flumethiazine-2-oxygen ylmethyl, [2-[[[[4-(4-chloro-phenyl-)-Ding-3-alkene-2-base] imido grpup] oxygen base] methyl] phenyl] or 2-(2-((3-butyl-4-methyl-coumarin-7-base oxygen base) methyl) phenyl);
Or, general formula (IV) compound and methyl alcohol are reacted in acid condition after within 10-14 hour, obtaining general formula compound (VI) product, general formula compound (VI) and sal enixum or sodium pyrosulfate are obtained by reacting compound (I):
2. the preparation method of methoxy acrylic bactericide according to claim 1, it is characterized in that, the acetal of described Carbox amide is be selected from the one in dimethylformamide dimethyl acetal, dimethylformamide diethyl acetal, dimethyl formamide dibutyl acetal, dimethyl formamide dibenzyl acetal and diethylformamide diethyl acetal.
3. the preparation method of methoxy acrylic bactericide according to claim 1, is characterized in that, step 2) described methylating reagent is methyl-sulfate or methyl iodide.
4. the preparation method of methoxy acrylic bactericide according to claim 1, it is characterized in that, step 2) described alkali is be selected from solid in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium methylate, sodium ethylate or sodium tert-butoxide or its solution.
5. the preparation method of methoxy acrylic bactericide according to claim 2, it is characterized in that, general formula (IV) compound room temperature reaction 10-14 hour in hydrogenchloride and methanol mixed solution, methyl alcohol and sulfuric acid mixed solution or methyl alcohol and tosic acid mixing solutions obtains general formula compound (VI), and general formula compound (VI) and sal enixum are obtained by reacting compound (I).
6. the preparation method of methoxy acrylic bactericide according to claim 1, is characterized in that, step 2) reaction terminate after by extraction solvent purification by liquid extraction.
7. the preparation method of methoxy acrylic bactericide according to claim 6, it is characterized in that, described extraction solvent is be selected from one or more reagent in toluene, 2-butanols, propyl carbinol, normal hexane, Skellysolve A, normal heptane, methylene dichloride, ethyl acetate, diethyl ether, diisopropyl ether, benzene, chloroform and hexanaphthene.
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| CN104151233A (en) * | 2014-08-25 | 2014-11-19 | 浙江泰达作物科技有限公司 | Preparation method of agricultural bactericide |
| CN105272906B (en) * | 2015-06-11 | 2018-04-27 | 厦门医学院 | A kind of preparation method of (Z)-ZEN 90160 |
| CN106008367A (en) * | 2015-11-20 | 2016-10-12 | 江苏长青农化股份有限公司 | Synthesis method of azoxystrobin |
| GB2546498B (en) * | 2016-01-19 | 2020-04-08 | Rotam Agrochem Int Co Ltd | Novel crystalline form of picoxystrobin, method of preparing and use of the same |
| CN107973751A (en) * | 2016-10-21 | 2018-05-01 | 四川福思达生物技术开发有限责任公司 | The synthetic method that methylates based on pyraclostrobin intermediate |
| CN110294716B (en) | 2018-03-23 | 2021-05-07 | 帕潘纳(北京)科技有限公司 | Preparation method of azoxystrobin and intermediate thereof |
| CN108558818B (en) * | 2018-04-28 | 2020-08-28 | 帕潘纳(北京)科技有限公司 | Preparation method of methoxymethyl alkenyl compound |
| CN108516962A (en) * | 2018-05-21 | 2018-09-11 | 帕潘纳(北京)科技有限公司 | A kind of preparation method of azoxystrobin intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5264609A (en) * | 1989-11-18 | 1993-11-23 | Schering Agrochemicals Limited | Preparation of propenoic acid derivatives |
| JP2003012416A (en) * | 2001-07-04 | 2003-01-15 | Nissan Chem Ind Ltd | Microbicidal insecticide agent for agriculture and horticulture including phenyl acetic acid derivatives |
| CN101268780A (en) * | 2008-05-08 | 2008-09-24 | 华中师范大学 | Methoxy group acrylic ester fungicide, preparation method and uses thereof |
| CN100509807C (en) * | 1999-04-20 | 2009-07-08 | 辛根塔有限公司 | Indazole derivative for pestide |
| CN102115458A (en) * | 2010-11-25 | 2011-07-06 | 大连凯飞精细化工有限公司 | Synthesis method of 3-methoxy-2-aryl(methyl)acrylate compounds |
-
2012
- 2012-12-17 CN CN201210549373.5A patent/CN103030598B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5264609A (en) * | 1989-11-18 | 1993-11-23 | Schering Agrochemicals Limited | Preparation of propenoic acid derivatives |
| CN100509807C (en) * | 1999-04-20 | 2009-07-08 | 辛根塔有限公司 | Indazole derivative for pestide |
| JP2003012416A (en) * | 2001-07-04 | 2003-01-15 | Nissan Chem Ind Ltd | Microbicidal insecticide agent for agriculture and horticulture including phenyl acetic acid derivatives |
| CN101268780A (en) * | 2008-05-08 | 2008-09-24 | 华中师范大学 | Methoxy group acrylic ester fungicide, preparation method and uses thereof |
| CN102115458A (en) * | 2010-11-25 | 2011-07-06 | 大连凯飞精细化工有限公司 | Synthesis method of 3-methoxy-2-aryl(methyl)acrylate compounds |
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