WO2013026391A1 - Synthesis method of azoxystrobin and exclusive intermediate in the synthesis thereof - Google Patents

Synthesis method of azoxystrobin and exclusive intermediate in the synthesis thereof Download PDF

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WO2013026391A1
WO2013026391A1 PCT/CN2012/080434 CN2012080434W WO2013026391A1 WO 2013026391 A1 WO2013026391 A1 WO 2013026391A1 CN 2012080434 W CN2012080434 W CN 2012080434W WO 2013026391 A1 WO2013026391 A1 WO 2013026391A1
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reaction
hours
toluene
azoxystrobin
catalyst
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PCT/CN2012/080434
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French (fr)
Chinese (zh)
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丁永良
代小妮
蔡宗杨
邓术清
韩丹
杨莹
曹超
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重庆紫光化工股份有限公司
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    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • 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

Definitions

  • the invention relates to a process for synthesizing chemical substances, in particular to synthesis
  • (E)-2-[2-(6-Chloropyridin-4-yloxy)phenyl]-3-decyloxydecyl acrylate is an important intermediate for the synthesis of azoxystrobin.
  • the existing synthesis process of (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenyl acrylate is mainly as follows:
  • Step-by-step method The main reaction formula is:
  • sodium decoxide 1: 4
  • poor atomic economy excessive sodium sterol needs to be neutralized with acetic acid, not only consume a large amount of organic acid, but also produce solid waste sodium acetate;
  • the main object of the present invention is to provide a method for synthesizing (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-indolyl decyl acrylate. Single can significantly increase the yield of the product and shorten the synthesis time.
  • the technical solution adopted by the present invention is: a synthetic (E) -2- [2-(6-chloropyrimidine-4- The method for the base oxy)phenyl] _ 3-decyloxy decyl acrylate, the steps comprising: a: the raw material 3_( ⁇ -decyloxy) fluorenylenebenzofuran-2_(3H)-one with a carbonic acid clock The mixture is stirred in a solvent of 0. 4 - 0. 6 hours;
  • reaction system is dissolved in toluene, washed with water to remove a water-soluble substance such as an inorganic salt, and then distilled to recover a solvent of toluene, and then the crude product is dissolved in butyl acetate to filter impurities, followed by liquid phase cooling and recrystallization to obtain a target product.
  • the sodium algoxide may be added to the sodium alginate solution in step a, or a solid sodium sterol and a sterol may be added.
  • the weak base added in step a (such as 4A) ensures that the ring opening reaction is always in an alkaline atmosphere, avoiding the opening of the ring-opening product to produce by-products.
  • the addition of the catalyst DABC0 allows the coupling reaction to be completed quickly, greatly reducing the reaction time. In this way, the production time can be controlled within 10 hours, and the production efficiency is greatly improved.
  • step c it is detected that the content of the coupling product in the reaction system is less than 1% as the reaction end point. At this time, the target product content can reach more than 80%, and the final product yield is above 70%. And it also saves production time to the greatest extent.
  • the reaction time was 0. 5 hours.
  • the cooling temperature is the cooling temperature of the commonly used industrial cooling equipment, which is convenient for the equipment; the preferred time is the time value that can guarantee the process index and the most economical. 5 ⁇
  • the reaction time was 1. 5 hours.
  • the heating temperature was 140 °C. The rate of reaction and conversion at this temperature have outstanding effects.
  • the main chemical reaction formula for production is:
  • Another object of the present invention is to provide a process for producing the above-mentioned synthetic (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-indolyl decyl acrylate.
  • the azoxystrobin method allows the synthesis process of azoxystrobin to be simple, which can significantly improve the yield of the product and shorten the synthesis time.
  • the technical solution adopted is: a method for synthesizing azoxystrobin, the steps comprising: a: mixing the raw material 3_( ⁇ -mercaptooxy)-fluorenylenebenzofuran-2-(3H)-one with a carbonic acid clock in the crucible In a benzene solvent, it is cooled to 0-10 ° C, sodium decoxide is added, and the reaction is carried out for 0.4-0.6 hours;
  • step C it is detected that the content of the coupling product in the reaction system is less than 1% as the reaction end point, and then the operation of the step d is performed.
  • the amount of (E) -2- [2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy decyl acrylate can be more than 80%, and the synthesis of azoxystrobin The product yield is also the largest, while at the same time maximizing production time.
  • the cooling temperature is the cooling temperature of the commonly used industrial cooling equipment, which is convenient for the equipment; the preferred time is the time value that can guarantee both the process index and the most economical.
  • the reaction time is 1.5 hours.
  • the heating temperature was 140 °C. The rate of reaction and conversion at this temperature have outstanding effects.
  • the improvement of the invention lies in the improvement of the process and the control index.
  • the ratio of the raw materials, the amount of the catalyst, etc. it can be determined according to the theoretical calculation or referring to the prior art, and is not the technical improvement of the present invention, and the space is no longer saved. A detailed description.
  • the steps are:
  • the steps are:
  • the steps are:
  • the steps are:
  • step a sodium decoxide and decyl alcohol are successively added, and other preferred process conditions are combined, and the yield and product purity are unexpectedly significantly improved.
  • the steps are:
  • the steps are:
  • the steps are:
  • azoxystrobin was directly added to the system, and the azoxystrobin product was isolated and purified to obtain 52.6 g of azoxystrobin product, and the yield of azoxystrobin was 65.2%.
  • the purity of azoxystrobin was 96.9 °/ by HPLC. .
  • the steps are:
  • azoxystrobin was directly added to the system, and 59.4 g of azoxystrobin product was isolated and purified, and the yield of azoxystrobin was 67.5%. The purity of azoxystrobin was 97.9% by HPLC.

Abstract

Disclosed are a synthesis method of Azoxystrobin and an intermediate in the synthesis thereof, comprising the steps of: mixing the starting materials 3-(α-methoxyl) methylene benzofuran-2-(3H)-ketone and potassium carbonate in methylbenzene solvent, cooling to 0-10℃, adding sodium methoxide, reacting for 0.4-0.6 hours; adding 4, 6-dichloropyrimide and a catalyst DABCO, reacting for 1-2 hours, filtrating and removing the inorganic salt, washing the filtrate, distilling and recovering the methylbenzene; adding a catalyst potassium hydrosulphate to the distilled residue of the previous step, under reduced pressure, heating to 132-145℃for reaction; afterward, directly adding 2-hydroxy-benzonitril to synthesize the Azoxystrobin, or, after dissolving with methylbenzene, washing, and recovering the solvent, then recrystallizing and filtrating to give the intermediate (E)-2-[2-(6-chloropyrimide-4-yl-oxy) phenyl]-3-methoxyl methyl acrylate.

Description

嘧菌酯及其合成中专用中间体的合成方法 技术领域  Synthesis method of azoxystrobin and special intermediates in its synthesis
本发明涉及一种化学物质的合成工艺， 具体涉及合成 The invention relates to a process for synthesizing chemical substances, in particular to synthesis
(E) -2- [2- (6-氯嘧啶 -4-基氧基）苯基] -3-曱氧基丙烯酸曱酯的方法； 以及利用该物质最终合成嘧菌酯的方法。 (E) -2- [2-(6-chloropyrimidin-4-yloxy)phenyl]-3-indolyl decyl acrylate; and a method for finally synthesizing azoxystrobin using the same.
背景技术 Background technique
(E) -2- [2- (6-氯嘧啶 -4-基氧基）苯基] -3-曱氧基丙烯酸曱酯是 合成嘧菌酯的一个重要的中间体。 现有的（E) -2- [2- (6-氯嘧啶 -4-基 氧基)苯基] - 3-曱氧基丙烯酸曱酯的方法合成工艺主要是：  (E)-2-[2-(6-Chloropyridin-4-yloxy)phenyl]-3-decyloxydecyl acrylate is an important intermediate for the synthesis of azoxystrobin. The existing synthesis process of (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenyl acrylate is mainly as follows:
1、 一锅法： 以 3_ ( α -曱氧基）亚曱基苯并呋喃 _2_ (3H) _酮为起 始原料，与曱醇钠和 4， 6-2二氯嘧啶（DCP)采用一锅法合成，该法耗时 比较长（约 50h)。 化学反应式为：  1. One-pot method: starting with 3_(α-decyloxy)-fluorenylenebenzofuran_2_(3H)-ketone, with sodium decoxide and 4,6-2 dichloropyrimidine (DCP) One-pot synthesis, this method takes a long time (about 50h). The chemical reaction formula is:
Figure imgf000002_0001
Figure imgf000002_0001
副反应主要是:
Figure imgf000002_0002
The main side effects are:
Figure imgf000002_0002
该合成方法的缺点是： 1 )反应时间太长， 并且收率低； 2 ) ¾- 产物  The disadvantages of this synthetic method are: 1) the reaction time is too long and the yield is low; 2) 3⁄4-product
2、 分步法： 主要反应式为:  2. Step-by-step method: The main reaction formula is:
N^N
Figure imgf000002_0003
Figure imgf000003_0001
N^N
Figure imgf000002_0003
Figure imgf000003_0001
其缺点是：  The disadvantages are:
1、 步骤多， 操作繁瑣；  1. There are many steps and the operation is cumbersome;
2、 曱醇钠大量过量， 原料： 曱醇钠 =1 : 4 , 原子经济性差； 过 量的曱醇钠需用醋酸中和， 不但消耗大量的有机酸， 还会产生固体废 弃物乙酸钠；  2, a large excess of sodium sterol, raw materials: sodium decoxide = 1: 4, poor atomic economy; excessive sodium sterol needs to be neutralized with acetic acid, not only consume a large amount of organic acid, but also produce solid waste sodium acetate;
3、 中和过量的曱醇钠需在低温下进行（_20°C ), 能耗高； 3. Neutralization of excess sodium sterol needs to be carried out at low temperature (_20 ° C), high energy consumption;
4、 中和所得开环产物需要有机溶剂萃取、 洗涤、 干燥、 回收溶 剂多个操作步骤； 4. Neutralization of the obtained ring-opening product requires multiple steps of organic solvent extraction, washing, drying, and recovery of the solvent;
5、 需要消耗碳酸 4甲和 DMF, 产生固废， 产物需要有机溶剂萃取、 洗涤、 干燥、 回收溶剂多个操作步骤；  5. It is necessary to consume carbonic acid 4 and DMF to produce solid waste. The product needs multiple steps of organic solvent extraction, washing, drying and solvent recovery;
6、 开环产物在酸性条件下易闭环得副产物， 相应的副反应为：  6. The ring-opening product is easily closed to the by-product under acidic conditions, and the corresponding side reaction is:
Figure imgf000003_0002
Figure imgf000003_0002
不仅降低产品的收率， 而且增大了产品的纯化难度， 降低了生产 效率。  It not only reduces the yield of the product, but also increases the difficulty of purification of the product and reduces the production efficiency.
发明内容 Summary of the invention
本发明的主要目的是提供一种合成（E) -2- [2- (6-氯嘧啶 -4-基氧 基）苯基] -3-曱氧基丙烯酸曱酯的方法， 该方法操作筒单， 可显著提 高产品的收率并且缩短合成时间。  The main object of the present invention is to provide a method for synthesizing (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-indolyl decyl acrylate. Single can significantly increase the yield of the product and shorten the synthesis time.
本发明所采取的技术方案是： 一种合成（E) -2- [2- (6-氯嘧啶 -4- 基氧基)苯基] _ 3-曱氧基丙烯酸曱酯的方法， 步骤包括： a: 将原料 3_ ( α -曱氧基）亚曱基苯并呋喃- 2_ (3H) -酮与碳酸钟 混合于曱苯溶剂中， 冷却至 0-10 °C , 加入曱醇钠， 反应 0. 4 - 0. 6小 时； The technical solution adopted by the present invention is: a synthetic (E) -2- [2-(6-chloropyrimidine-4- The method for the base oxy)phenyl] _ 3-decyloxy decyl acrylate, the steps comprising: a: the raw material 3_(α-decyloxy) fluorenylenebenzofuran-2_(3H)-one with a carbonic acid clock The mixture is stirred in a solvent of 0. 4 - 0. 6 hours;
b: 向上步反应液中加入 4 , 6-二氯嘧啶和催化剂 DABC0，反应 l-2h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯；  b: adding 4,6-dichloropyrimidine and catalyst DABC0 to the reaction solution, reacting for l-2h, filtering and removing inorganic salts, washing the filtrate with water, and distilling and recovering toluene;
c: 向上步反应蒸馏残余物中加入催化剂硫酸氢钾， 减压状态下 加热至 1 32 ~ 145 °C反应；  c: adding a catalyst potassium hydrogen sulfate to the reaction residue of the upward step reaction, and heating to a pressure of 1 32 to 145 ° C under reduced pressure;
d: 将反应体系用曱苯溶解、 水洗除掉无机盐等水溶物、 然后蒸 馏回收曱苯溶剂，然后用乙酸丁酯溶解粗产品过滤杂质后液相冷却重 结晶过滤得到目标产品。  d: The reaction system is dissolved in toluene, washed with water to remove a water-soluble substance such as an inorganic salt, and then distilled to recover a solvent of toluene, and then the crude product is dissolved in butyl acetate to filter impurities, followed by liquid phase cooling and recrystallization to obtain a target product.
利用本发明的生产工艺生产合成 (E) -2- [2- (6-氯嘧啶 -4-基氧基) 苯基] - 3-曱氧基丙烯酸曱酯的收率高，并且操作筒单，所使用的原料、 工艺都是常规试剂和方法。  Production of synthetic (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenyl acrylate by the production process of the present invention has high yield and operation The raw materials and processes used are conventional reagents and methods.
步骤 a中加入曱醇钠可以是加入曱醇钠曱醇溶液，也可以是加入 固体曱醇钠和曱醇。 并且步骤 a中所加入的弱碱（如碳酸 4甲 )保证开 环反应始终处于碱性氛围，避免开环产物在闭合产生副产物。加入催 化剂 DABC0使耦合反应快速完成， 大大缩短了反应时间。 这样生产时 间可以控制在 10小时以内， 生产效率大幅提高。  The sodium algoxide may be added to the sodium alginate solution in step a, or a solid sodium sterol and a sterol may be added. And the weak base added in step a (such as 4A) ensures that the ring opening reaction is always in an alkaline atmosphere, avoiding the opening of the ring-opening product to produce by-products. The addition of the catalyst DABC0 allows the coupling reaction to be completed quickly, greatly reducing the reaction time. In this way, the production time can be controlled within 10 hours, and the production efficiency is greatly improved.
进一步的， 所述的步骤 c中，检测到反应体系中偶联产物含量小 于 1%为反应终点。 此时目标产物含量可达 80%以上， 最终产品收率在 70%以上。 而且又最大程度地节省了生产时间。  Further, in the step c, it is detected that the content of the coupling product in the reaction system is less than 1% as the reaction end point. At this time, the target product content can reach more than 80%, and the final product yield is above 70%. And it also saves production time to the greatest extent.
进一步的， 所述的步骤 a中， 冷却温度为 8 °C , 反应时间为 0. 5 小时。 冷却温度为常用的工业冷却设备的冷却温度， 便于设备配套； 所优选的时间是既能保证工艺指标同时又最经济的时间值。 同理， 所 述的步骤 b中， 反应时间为 1. 5小时。 所述的步骤 c中， 加热温度为 140°C。 在此温度条件下反应的速度和转化率具有突出的效果。 生产的主要化学反应式为: 5小时。 The reaction time was 0. 5 hours. The cooling temperature is the cooling temperature of the commonly used industrial cooling equipment, which is convenient for the equipment; the preferred time is the time value that can guarantee the process index and the most economical. 5小时。 The reaction time was 1. 5 hours. In the step c described, the heating temperature was 140 °C. The rate of reaction and conversion at this temperature have outstanding effects. The main chemical reaction formula for production is:
Figure imgf000005_0001
Figure imgf000005_0001
本发明的另一个目的是提供一种配套上述的合成（E) -2- [2- (6- 氯嘧啶 -4-基氧基）苯基] -3-曱氧基丙烯酸曱酯的方法生产嘧菌酯的 方法，使得嘧菌酯的合成工艺筒单， 可显著提高产品的收率和缩短合 成时间。  Another object of the present invention is to provide a process for producing the above-mentioned synthetic (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-indolyl decyl acrylate. The azoxystrobin method allows the synthesis process of azoxystrobin to be simple, which can significantly improve the yield of the product and shorten the synthesis time.
所采取的技术方案是： 一种嘧菌酯的合成方法， 步骤包括： a: 将原料 3_(α -曱氧基）亚曱基苯并呋喃- 2_(3H) -酮与碳酸钟 混合于曱苯溶剂中， 冷却至 0-10°C, 加入曱醇钠， 反应 0.4-0.6小 时；  The technical solution adopted is: a method for synthesizing azoxystrobin, the steps comprising: a: mixing the raw material 3_(α-mercaptooxy)-fluorenylenebenzofuran-2-(3H)-one with a carbonic acid clock in the crucible In a benzene solvent, it is cooled to 0-10 ° C, sodium decoxide is added, and the reaction is carried out for 0.4-0.6 hours;
b: 向上步反应液中加入 4, 6-二氯嘧啶和催化剂 DABC0，反应 l-2h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯；  b: adding 4,6-dichloropyrimidine and catalyst DABC0 to the reaction solution, reacting for l-2h, filtering and removing inorganic salts, washing the filtrate with water, and distilling and recovering toluene;
c: 向上步反应蒸馏残余物中加入催化剂 酸氢钾， 减压状态下 加热至 132 ~ 145°C反应；  c: adding a catalyst potassium hydrogen hydride to the residue of the reaction distillation step, and heating to 132 ~ 145 ° C under reduced pressure;
d: 然后向体系中直接加水杨腈合成嘧菌酯。  d: Then add azoxystrobin to the system to synthesize azoxystrobin.
由上述技术方案可见，步骤 c中已经得到了大量的（E) -2- [2- (6- 氯嘧啶 -4-基氧基)苯基] -3-曱氧基丙烯酸曱酯中间体。然后加入水杨 腈即可获得嘧菌酯。再进行分离和提纯即可获得嘧菌酯终产物。 这样 省去了中间体的重结晶和分离操作， 实现了集约效应， 节省了生产时 间和原料、 能耗成本。 至于中间体与水杨腈的合成和嘧菌酯的分离纯 化是可以参考现有技术确定的 ,并且其技术内容本身并不是本发明的 发明点， 故不再赘述。 As can be seen from the above technical scheme, a large amount of (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-indolyl decyl acrylate intermediate has been obtained in the step c. Azoxystrobin can then be obtained by adding salicylonitrile. The azoxystrobin end product can be obtained by further separation and purification. This eliminates the recrystallization and separation of the intermediates, achieves an intensive effect, and saves production time, raw materials, and energy costs. As for the synthesis of the intermediate with salicylonitrile and the separation and purification of azoxystrobin, it can be determined with reference to the prior art, and the technical content itself is not the present invention. The invention is not described here.
进一步的， 所述的步骤 C中，检测到反应体系中偶联产物含量小 于 1%为反应终点，然后进行步骤 d的操作。此时体系中（E) -2- [2- (6- 氯嘧啶 -4-基氧基)苯基] -3-曱氧基丙烯酸曱酯的量可达 80%以上， 合 成嘧菌酯的产品收率也相应最大， 同时又最大程度地节省了生产时 间。  Further, in the step C, it is detected that the content of the coupling product in the reaction system is less than 1% as the reaction end point, and then the operation of the step d is performed. At this time, the amount of (E) -2- [2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxy decyl acrylate can be more than 80%, and the synthesis of azoxystrobin The product yield is also the largest, while at the same time maximizing production time.
同理的， 与中间体的合成类似， 所述的步骤 a中， 冷却温度为 8 °C ,反应时间为 0. 5小时。 冷却温度为常用的工业冷却设备的冷却温 度，便于设备配套； 所优选的时间是既能保证工艺指标同时又最经济 的时间值。 同理， 所述的步骤 b中， 反应时间为 1. 5小时。 所述的步 骤 c中， 加热温度为 140°C。 在此温度条件下反应的速度和转化率具 有突出的效果。  5小时。 The same as the reaction time was 0. 5 hours. The cooling temperature is the cooling temperature of the commonly used industrial cooling equipment, which is convenient for the equipment; the preferred time is the time value that can guarantee both the process index and the most economical. Similarly, in the step b, the reaction time is 1.5 hours. In the step c, the heating temperature was 140 °C. The rate of reaction and conversion at this temperature have outstanding effects.
本发明的改进在于工艺过程和控制指标的改进， 至于原料配比、 催化剂的投料量等则是根据理论计算或者参考现有技术可以确定的， 不是本发明的技术改进所在， 为节约篇幅不再详细描述。  The improvement of the invention lies in the improvement of the process and the control index. As for the ratio of the raw materials, the amount of the catalyst, etc., it can be determined according to the theoretical calculation or referring to the prior art, and is not the technical improvement of the present invention, and the space is no longer saved. A detailed description.
具体实施方式 detailed description
为使本领域技术人员详细了解本发明的生产工艺和技术效果， 下面以具体的生产实例来进一步介绍本发明的应用和技术效果。  In order to enable those skilled in the art to understand the production process and technical effects of the present invention in detail, the application and technical effects of the present invention will be further described below with specific production examples.
实施例一  Embodiment 1
步骤为：  The steps are:
a: 将原料 3_ ( α -曱氧基）亚曱基苯并呋喃 _2_ (3H) -酮 0. lmol与 碳酸钟 0. 05mol混合于 80mL 曱苯溶剂中， 冷却温度（TC , 加入 28% 的曱醇钠曱醇溶液 21. 2g (含曱醇钠 0. l lmol )， 反应 0. 4小时；  a: The raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-ketone 0. lmol and carbonic acid clock 0. 05mol mixed in 80mL of toluene solvent, cooling temperature (TC, added 28% 4小时; The reaction of 0. 4 hours;
b: 向上步反应液中加入 4 , 6 -二氯嘧啶 0. l lmol和催化剂 DABC0 1. 7g，反应 lh, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯；  b: 4,6-dichloropyrimidine 0. l lmol and catalyst DABC0 1. 7g are added to the reaction solution, and the reaction is carried out for 1 hour. The inorganic salt is removed by filtration, the filtrate is washed with water, and the benzene is distilled by distillation;
c: 向上步蒸馏残余物中加入催化剂 酸氢钾 1. 5g, 在 -0. 05MPa 下加热至 132 °C反应 1. 5小时， 冷却降温。 d: 将上步反应混合物用曱苯溶解、 水洗、 回收曱苯溶剂， 然后 用乙酸丁酯溶解粗产品重结晶过滤得到（E) -2- [2- (6-氯嘧啶 -4-基氧 基）苯基] -3-曱氧基丙烯酸曱酯 22.8g, 产品收率 71.1%。 经 HPLC检 测， 产品纯度为 98.6%0 5小时,冷冷却冷却。 After the step of distillation to the residue was added to the catalyst potassium hydrogen sulfate 1. 5g, heated to 132 ° C under -0.55MPa reaction 1. 5 hours, cooling and cooling. d: The reaction mixture of the above step is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) 2) g of phenyl] phenyl methoxy acrylate, the product yield was 71.1%. By HPLC, purity 98.6% 0
实施例二  Embodiment 2
步骤为：  The steps are:
a: 将原料 3_(α -曱氧基）亚曱基苯并呋喃 _2_(3H) -酮 0. Imol与 碳酸钟 0. Imol混合于 80mL曱苯溶剂中， 冷却温度 5°C, 加入 28%的 曱醇钠曱醇溶液 21.2g (含曱醇钠 0.11 mol ) ，反应 0.5小时；  a: The raw material 3_(α-decyloxy) fluorenylene benzofuran-2_(3H)-ketone 0. Imol and carbonic acid clock 0. Imol mixed in 80mL of benzene solvent, cooling temperature 5 ° C, added 28 21.2 g of sodium sterol sodium sterol solution (containing 0.11 mol of sodium decyl alcohol), and reacted for 0.5 hour;
b: 向上步反应液中加入 4, 6 -二氯嘧啶 0. llmol和催化剂 DABC0 1.7g，反应 1.2h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯；  b: 4,6-dichloropyrimidine 0. llmol and catalyst DABC0 1.7g were added to the reaction solution, and the reaction was carried out for 1.2 hours. The inorganic salt was removed by filtration, the filtrate was washed with water, and toluene was recovered by distillation;
c: 向上步反应蒸馏残余物中加入催化剂 酸氢钾 1.5g, 在 - 0.04MPa下加热至 138°C反应， 直至用 HPLC检测到反应体系中偶联 产物含量为 0.85%为反应终点；  c: a catalyst of 1.5 g of potassium hydrogen hydride was added to the reaction residue of the upward reaction, and the reaction was heated to 138 ° C at -0.04 MPa until the content of the coupling product in the reaction system was 0.85% as the reaction end point by HPLC;
d: 将上步反应混合物用曱苯溶解、 水洗、 回收曱苯溶剂， 然后 用乙酸丁酯溶解粗产品重结晶过滤得到（E) -2- [2- (6-氯嘧啶 -4-基氧 基）苯基 ]_3 -曱氧基丙烯酸曱酯 23.6g, 产品收率 73.6 %。 经 HPLC检 测， 产品纯度为 99.5%0 d: The reaction mixture of the above step is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) The base is phenyl]_3-indenyl decyl acrylate 23.6 g, and the product yield is 73.6 %. By HPLC, purity 99.5% 0
实施例三  Embodiment 3
步骤为：  The steps are:
a: 将原料 3_(α -曱氧基）亚曱基苯并呋喃 _2_(3H) -酮 0. Imol与 碳酸钟 0. Imol混合于 lOOmL曱苯溶剂中， 冷却温度 8°C, 先后加入 曱醇钠 0. llmoK 曱醇 10mL, 反应 0.5小时;  a: The raw material 3_(α-decyloxy) fluorenylene benzofuran-2_(3H)-ketone 0. Imol and carbonic acid clock 0. Imol mixed in lOOmL benzene solvent, cooling temperature 8 ° C, successively added Sodium sterol 0. llmoK sterol 10mL, reaction for 0.5 hours;
b: 向上步反应液中加入 4, 6-二氯嘧啶 0. llmol 和催化剂 DABC02.0g，反应 1.5h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯； c: 向上步反应蒸馏残余物中加入催化剂 酸氢钾 1.5g, 在 - 0.03MPa下加热至 140°C反应， 直至用 HPLC检测到反应体系中偶联 产物含量为 0.9%为反应终点； b: 4,6-dichloropyrimidine 0. llmol and catalyst DABC02.0g were added to the reaction solution, and the reaction was carried out for 1.5 hours. The inorganic salt was removed by filtration, the filtrate was washed with water, and toluene was recovered by distillation; c: the reaction residue was distilled up to the reaction step. 1.5 g of potassium hydrogen hydride catalyst was added, and the reaction was heated to 140 ° C at -0.03 MPa until the coupling in the reaction system was detected by HPLC. The product content is 0.9% as the reaction end point;
d: 将反应体系用曱苯溶解、 水洗、 回收曱苯溶剂， 然后用乙酸 丁酯溶解粗产品重结晶过滤得到（E) -2- [2- (6-氯嘧啶 -4-基氧基）苯 基] -3-曱氧基丙烯酸曱酯 25. Og, 产品收率 78.0%。 经 HPLC检测， 产 品纯度为 99. Ί 。  d: The reaction system is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) Phenyl]-3-indolyl acrylate acrylate 25. Og, product yield 78.0%. The purity of the product was 99. Ί by HPLC.
实施例四  Embodiment 4
步骤为：  The steps are:
a: 将原料 3_(α -曱氧基）亚曱基苯并呋喃 _2_(3H) -酮 0. Imol与 碳酸钟 0. Imol混合于 lOOmL曱苯溶剂中， 冷却温度 5°C, 先后加入 曱醇钠 0. llmoK 曱醇 10mL, 反应 0.5小时；  a: The raw material 3_(α-decyloxy) fluorenylene benzofuran-2_(3H)-ketone 0. Imol and carbonic acid clock 0. Imol mixed in lOOmL benzene solvent, cooling temperature 5 ° C, successively added Sodium sterol 0. llmoK sterol 10mL, reaction for 0.5 hours;
b: 向上步反应液中加入 4, 6-二氯嘧啶 0. llmol 和催化剂 DABC02.0g，反应 1.5h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯； c: 向上步反应蒸馏残余物中加入催化剂 酸氢钾 1.5g, 在 - 0.03MPa下加热至 140°C反应， 直至用 HPLC检测到反应体系中偶联 产物含量为 0.86%为反应终点；  b: 4,6-dichloropyrimidine 0. llmol and catalyst DABC02.0g were added to the reaction solution, and the reaction was carried out for 1.5 hours. The inorganic salt was removed by filtration, the filtrate was washed with water, and toluene was recovered by distillation; c: the reaction residue was distilled up to the reaction step. 1.5 g of catalyst potassium hydrogen hydride was added, and the reaction was heated to 140 ° C at -0.03 MPa until the content of the coupling product in the reaction system was 0.86% as the reaction end point by HPLC;
d: 将反应体系用曱苯溶解、 水洗、 回收曱苯溶剂， 然后用乙酸 丁酯溶解粗产品重结晶过滤得到（E) -2- [2- (6-氯嘧啶 -4-基氧基）苯 基] -3-曱氧基丙烯酸曱酯 25.42g, 产品收率 79.3%。 经 HPLC检测， 产品纯度为 99. Ί 。  d: The reaction system is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) Phenyl]-3-decyloxy decyl acrylate 25.42 g, product yield 79.3%. The purity of the product was 99. Ί by HPLC.
由实施例三、 四可见， 步骤 a中， 先后加入曱醇钠、 曱醇， 配合 其它优选的工艺条件， 产率和产品纯度有意料不到的显著提高。  It can be seen from Examples 3 and 4 that in step a, sodium decoxide and decyl alcohol are successively added, and other preferred process conditions are combined, and the yield and product purity are unexpectedly significantly improved.
实施例五  Embodiment 5
步骤为：  The steps are:
a: 将原料 3_(α -曱氧基）亚曱基苯并呋喃 _2_(3H) -酮 0. Imol与 碳酸钟 0. Imol混合于 80mL曱苯溶剂中， 冷却温度 8°C, 加入 28%的 曱醇钠曱醇溶液 21.2g (含曱醇钠 0. llmol )， 反应 0.6小时；  a: The raw material 3_(α-decyloxy) fluorenylene benzofuran 2 - (3H)-ketone 0. Imol and carbonic acid 0. Imol mixed in 80mL of benzene solvent, cooling temperature 8 ° C, added 28 % of sodium sterol sodium sterol solution 21.2g (containing sodium decoxide 0. llmol), the reaction is 0.6 hours;
b: 向上步反应液中加入 4, 6 -二氯嘧啶 0. llmol和催化剂 DABC0 1.7g，反应 2h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯； c: 向上步反应蒸馏残余物中加入催化剂 酸氢钾 1.7g, 在 - 0. IMPa下加热至 140°C反应，直至用 HPLC检测到反应体系中偶联产 物含量为 0.83°/。为反应终点； b: 4,6-dichloropyrimidine 0. llmol and catalyst DABC0 were added to the reaction solution. 1.7g, reaction for 2h, the inorganic salt is removed by filtration, the filtrate is washed with water, and the benzene is distilled by distillation; c: 1.7 g of potassium hydrogen hydride catalyst is added to the reaction residue of the upward reaction, and heated to 140 ° C under -0. IMPa until the reaction is completed. The content of the coupling product in the reaction system was determined by HPLC to be 0.83 ° /. The end of the reaction;
d: 将反应体系用曱苯溶解、 水洗、 回收曱苯溶剂， 然后用乙酸 丁酯溶解粗产品重结晶过滤得到（E) -2- [2- (6-氯嘧啶 -4-基氧基）苯 基] -3-曱氧基丙烯酸曱酯 23.2g, 产品收率 72.4%。 经 HPLC检测， 产 品纯度为 98. Ί%。  d: The reaction system is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) Phenyl]-3-decyloxy decyl acrylate was 23.2 g, and the product yield was 72.4%. The purity of the product was 98. Ί% by HPLC.
实施例六  Embodiment 6
步骤为：  The steps are:
a: 将原料 3_(α -曱氧基）亚曱基苯并呋喃 _2_(3H) -酮 0.2mol与 碳酸钟 0.22mol混合于 150mL 曱苯溶剂中， 冷却温度 10°C, 加 28% 的曱醇钠曱醇溶液 42.4g (含曱醇钠 0.22mol ), 反应 0.5小时;  a: Mixing raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-one 0.2mol with 0.22 mol of carbonic acid clock in 150 mL of toluene solvent, cooling temperature 10 ° C, adding 28% 42.4 g of sodium sterol sterol solution (containing 0.22 mol of sodium decoxide), and reacting for 0.5 hour;
b: 向上步反应液中加入 4, 6-二氯嘧啶和催化剂 DABC03.4g，反 应 1.5h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯；  b: 4,6-dichloropyrimidine and catalyst DABC03.4g were added to the reaction solution, and the reaction was carried out for 1.5 hours. The inorganic salt was removed by filtration, the filtrate was washed with water, and toluene was recovered by distillation;
c: 向上步反应蒸馏残余物中加入催化剂 酸氢钾 3.0g, 在 - 0.02MPa下加热至 145°C反应， 直至用 HPLC方法检测到反应体系中 偶联产物含量为 0.92%为反应终点；  c: adding 3.0 g of potassium hydrogen hydride to the reaction residue of the upward reaction, and heating to 145 ° C at -0.02 MPa until the content of the coupling product in the reaction system was 0.92% by HPLC.
d: 将反应体系用曱苯溶解、 水洗、 回收曱苯溶剂， 然后用乙酸 丁酯溶解粗产品重结晶过滤得到（E) -2- [2- (6-氯嘧啶 -4-基氧基）苯 基] -3-曱氧基丙烯酸曱酯 47.5g, 产品收率 74.1%。 经 HPLC检测， 产 品纯度为 97.6%0 d: The reaction system is dissolved in toluene, washed with water, and the solvent of toluene is recovered, and then the crude product is dissolved in butyl acetate to be recrystallized and filtered to obtain (E)-2-[2-(6-chloropyrimidin-4-yloxy) 47.5 g of phenyl]-3-decyloxy decyl acrylate, the product yield was 74.1%. By HPLC, purity 97.6% 0
实施例七  Example 7
步骤为：  The steps are:
a: 将原料 3_(α -曱氧基）亚曱基苯并呋喃 _2_(3H) -酮 0.2mol与 碳酸钟 0.22mol混合于 150mL曱苯溶剂中， 冷却温度 8°C , 加 28%的 曱醇钠曱醇溶液 42.4g (含曱醇钠 0.22 mol ), 反应 0.5小时; b: 向上步反应液中加入 4, 6-二氯嘧啶 0.22mol 和催化剂 DABC03.4g，反应 1.5h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯； c: 向上步反应蒸馏残余物中加入催化剂 酸氢钾 3. Og, 在 - 0.03MPa下加热至 140°C反应， 直至用 HPLC检测到反应体系中偶联 产物含量为 0.9%为反应终点； a: The raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-one 0.2 mol and 0.22 mol of carbonic acid clock were mixed in 150 mL of toluene solvent, the cooling temperature was 8 ° C, and 28% was added. 42.4 g of sodium sterol sterol solution (containing 0.22 mol of sodium decyl alcohol), and reacting for 0.5 hour; b: adding 0.22 mol of 4,6-dichloropyrimidine and 03.4 g of catalyst DABC to the reaction solution, reacting for 1.5 h, removing inorganic salts by filtration, washing the filtrate with water, and recovering toluene by distillation; c: adding the distillation residue to the upper step reaction Catalyst potassium hydrogen sulfate 3. Og, heated to 140 ° C at - 0.03MPa, until the content of the coupling product in the reaction system was 0.9% as the reaction end point;
d: 然后向体系中直接加水杨腈合成嘧菌酯， 分离纯化得到嘧菌 酯产品 52.6g, 嘧菌酯产品收率 65.2%。 经 HPLC检测， 嘧菌酯产品纯 度为 96.9°/。。  d: Then, azoxystrobin was directly added to the system, and the azoxystrobin product was isolated and purified to obtain 52.6 g of azoxystrobin product, and the yield of azoxystrobin was 65.2%. The purity of azoxystrobin was 96.9 °/ by HPLC. .
实施例八  Example eight
步骤为：  The steps are:
a: 将原料 3_(α -曱氧基）亚曱基苯并呋喃 _2_(3H) -酮 0.2mol与 碳酸钟 0.22mol混合于 150mL曱苯溶剂中， 冷却温度 8°C , 加 28%的 曱醇钠曱醇溶液 42.4g (含曱醇钠 0.22mol ), 反应 0.5小时;  a: The raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-one 0.2 mol and 0.22 mol of carbonic acid clock were mixed in 150 mL of toluene solvent, the cooling temperature was 8 ° C, and 28% was added. 42.4 g of sodium sterol sterol solution (containing 0.22 mol of sodium decoxide), and reacting for 0.5 hour;
b: 向上步反应液中加入 4, 6-二氯嘧啶 0.22mol 和催化剂 DABC03.4g，反应 1.5h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯； c: 向上步反应蒸馏残余物中加入催化剂 酸氢钾 3. Og, 在 - 0.03MPa下加热至 140°C反应， 直至用 HPLC检测到反应体系中偶联 产物含量为 0.8%为反应终点；  b: adding 0.22 mol of 4,6-dichloropyrimidine and 03.4 g of catalyst DABC to the reaction solution, reacting for 1.5 h, removing inorganic salts by filtration, washing the filtrate with water, and recovering toluene by distillation; c: adding the distillation residue to the upper step reaction Catalyst potassium hydrogen sulfate 3. Og, heated to 140 ° C at - 0.03 MPa, until the content of the coupling product in the reaction system was 0.8% as the reaction end point;
d: 然后向体系中直接加水杨腈合成嘧菌酯， 分离纯化得到嘧菌 酯产品 54.4g, 嘧菌酯产品收率 67.5%。 经 HPLC检测， 嘧菌酯产品纯 度为 97. Ί%。  d: Then, azoxystrobin was directly added to the system, and 59.4 g of azoxystrobin product was isolated and purified, and the yield of azoxystrobin was 67.5%. The purity of azoxystrobin was 97.9% by HPLC.

Claims

权 利 要 求 Rights request
1、 一种合成 (E) -2- [2- (6_氯嘧啶 _4 -基氧基)苯基] _3 -曱氧基丙 烯酸曱酯的方法， 步骤包括： A method for synthesizing (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]_3-decyloxy decanoate, the steps comprising:
a: 将原料 3_(α -曱氧基）亚曱基苯并呋喃- 2_(3H) -酮与碳酸钟 混合于曱苯溶剂中， 冷却至 0-10°C, 加入曱醇钠， 反应 0.4-0.6小 时；  a: The raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-one is mixed with a carbonic acid clock in a solvent of toluene, cooled to 0-10 ° C, and sodium decoxide is added, and the reaction is 0.4. -0.6 hours;
b: 向上步反应液中加入 4, 6-二氯嘧啶和催化剂 DABC0，反应 l-2h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯；  b: adding 4,6-dichloropyrimidine and catalyst DABC0 to the reaction solution, reacting for l-2h, filtering and removing inorganic salts, washing the filtrate with water, and distilling and recovering toluene;
c: 向上步反应蒸馏残余物中加入催化剂 酸氢钾， 减压状态下 加热至 132 ~ 145°C反应；  c: adding a catalyst potassium hydrogen hydride to the residue of the reaction distillation step, and heating to 132 ~ 145 ° C under reduced pressure;
d: 将反应体系用曱苯溶解、 水洗除掉无机盐等水溶物、 然后蒸 馏回收曱苯溶剂，然后用乙酸丁酯溶解粗产品过滤杂质后液相冷却重 结晶过滤得到目标产品。  d: The reaction system is dissolved in toluene, washed with water to remove a water-soluble substance such as an inorganic salt, and then distilled to recover a solvent of toluene, and then the crude product is dissolved in butyl acetate to filter impurities, followed by liquid phase cooling and recrystallization to obtain a target product.
2、 根据权利要求 1所述的方法， 其特征在于： 所述的步骤 c中， 检测到反应体系中偶联产物含量小于 1°/。为反应终点。  2. The method according to claim 1, wherein in the step c, the content of the coupling product in the reaction system is detected to be less than 1°/. For the end of the reaction.
3、 根据权利要求 1或 2所述的方法， 其特征在于： 所述的步骤 a中， 冷却温度为 8°C, 反应时间为 0.5小时。  The method according to claim 1 or 2, wherein in the step a, the cooling temperature is 8 ° C and the reaction time is 0.5 hour.
4、 根据权利要求 1或 2所述的方法， 其特征在于： 所述的步骤 b中， 反应时间为 1.5小时。  4. The method according to claim 1 or 2, wherein in the step b, the reaction time is 1.5 hours.
5、 根据权利要求 1或 2所述的方法， 其特征在于： 所述的步骤 c中， 加热温度为 140°C。  The method according to claim 1 or 2, wherein in the step c, the heating temperature is 140 °C.
6、 一种嘧菌酯的合成方法， 步骤包括：  6. A method for synthesizing azoxystrobin, the steps comprising:
a: 将原料 3_(α -曱氧基）亚曱基苯并呋喃- 2_(3H) -酮与碳酸钟 混合于曱苯溶剂中， 冷却至 0-10°C, 加入曱醇钠， 反应 0.4-0.6小 时；  a: The raw material 3_(α-decyloxy)-fluorenylene benzofuran-2_(3H)-one is mixed with a carbonic acid clock in a solvent of toluene, cooled to 0-10 ° C, and sodium decoxide is added, and the reaction is 0.4. -0.6 hours;
b: 向上步反应液中加入 4, 6-二氯嘧啶和催化剂 DABC0，反应 l-2h, 过滤除去无机盐， 滤液水洗， 蒸馏回收曱苯； c: 向上步反应蒸馏残余物中加入催化剂 酸氢钾， 减压状态下 加热至 1 32 ~ 145 °C反应； b: adding 4,6-dichloropyrimidine and catalyst DABC0 to the reaction solution, reacting L-2h, the inorganic salt is removed by filtration, the filtrate is washed with water, and the benzene is distilled by distillation; c: the catalyst hydrogen chloride is added to the reaction residue of the upward step, and heated to a pressure of 1 32 to 145 ° C under reduced pressure;
d: 然后向体系中直接加水杨腈合成嘧菌酯。  d: Then add azoxystrobin to the system to synthesize azoxystrobin.
7、 根据权利要求 6所述的方法， 其特征在于： 所述的步骤 c中， 检测到反应体系中偶联产物含量小于 1°/。为反应终点。  7. The method according to claim 6, wherein in the step c, the content of the coupling product in the reaction system is detected to be less than 1 ° /. For the end of the reaction.
8、 根据权利要求 6或 7所述的方法， 其特征在于： 所述的步骤 a中， 冷却温度为 8 °C , 反应时间为 0. 5小时。  5小时。 The method of the method of the present invention, wherein the cooling time is 0 ° C, the reaction time is 0.5 hours.
9、 根据权利要求 6或 7所述的方法， 其特征在于： 所述的步骤 b中， 反应时间为 1. 5小时。  9. The method according to claim 6 or 7, wherein in the step b, the reaction time is 1.5 hours.
1 0、 根据权利要求 6或 7所述的方法， 其特征在于： 所述的步骤 c中， 加热温度为 140 °C。  The method according to claim 6 or 7, wherein in the step c, the heating temperature is 140 °C.
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