WO2021022761A1 - 卤素取代化合物及其制备方法和应用 - Google Patents

卤素取代化合物及其制备方法和应用 Download PDF

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WO2021022761A1
WO2021022761A1 PCT/CN2019/126839 CN2019126839W WO2021022761A1 WO 2021022761 A1 WO2021022761 A1 WO 2021022761A1 CN 2019126839 W CN2019126839 W CN 2019126839W WO 2021022761 A1 WO2021022761 A1 WO 2021022761A1
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formula
substituted
halogen
pyrazole
reaction
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PCT/CN2019/126839
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French (fr)
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王明春
李庆毅
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王明春
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Priority to EP19940643.0A priority Critical patent/EP4008715B1/en
Priority to US17/429,640 priority patent/US11472775B2/en
Priority to JP2021541708A priority patent/JP7080407B2/ja
Publication of WO2021022761A1 publication Critical patent/WO2021022761A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings

Definitions

  • the invention relates to an industrial synthesis method of halogen substituted compounds, belonging to the technical field of chemical synthesis.
  • Halogen-substituted pyrazole derivatives are intermediates for many medicines or pesticides.
  • fluorine-containing pyrazole derivatives 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid is an important pesticide intermediate, which plays a very important role in many new pesticide varieties.
  • the Claisen condensation method is mainly reported by BASF and Syngenta patents. Starting from ethyl difluoroacetate by Claisen condensation reaction to obtain ethyl difluoroacetoacetate, and then condensing with triethyl orthoformate to obtain 4,4-difluoro-2-(ethoxymethylene)-3-oxo Ethyl butyrate, after ring closure with methylhydrazine to produce ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFMMP), which is hydrolyzed by sodium hydroxide and hydrochloric acid After acidification, 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (DFPA) is obtained. Due to the high cost of this route, this method is generally no longer used in the research of new synthetic methods except for the product lines already in production.
  • dimethylamino ethyl acrylate method Bayer patent WO2009043444, similarly, WO2009133178 BASF company replaced dimethylamino with piperidinyl.
  • difluoroacetyl fluoride gas is passed into ethyl dimethylamino acrylate, and the obtained intermediate is directly closed with methylhydrazine to generate 3-(difluoromethyl)-1-methyl-1H-pyrazole
  • Ethyl-4-carboxylate (DFMMP) is hydrolyzed by sodium hydroxide and acidified with hydrochloric acid to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (DFPA).
  • difluoroacetyl fluoride gas is obtained by the high-temperature cracking of tetrafluoroethyl ether.
  • the route is ingeniously designed, has the characteristics of short steps and high yield, and is currently a low cost method.
  • the disadvantage is that the requirements for equipment are relatively high.
  • the reaction will produce a large amount of volatile dimethylamine, which affects the environment, and it does not solve the selectivity problem of methylhydrazine ring-closure synthesis of pyrazole ring.
  • EP 2008996 reported the synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid in a 5-step reaction using dichloroacetyl chloride, vinyl ether compounds, methylhydrazine and other raw materials . Although there are certain advantages in cost control, the reaction conditions are relatively harsh.
  • the technical problem to be solved by the present invention is to provide a halogen-substituted compound suitable for industrial production of pyrazole derivatives, as well as a preparation method of the halogen-substituted compound, and preparation of the halogen-substituted compound as an intermediate for preparing the pyrazole derivative Methods and uses.
  • the present invention proposes a technical solution: a method for preparing halogen-substituted compounds, the piperazine derivative shown in formula I reacts with the halogenated acetyl halide derivative shown in formula VI to produce
  • the reaction solvent is preferably chloroform
  • the catalyst is preferably triethylamine.
  • R 1 is OR A or R A , wherein R A is a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a substituted C3-8 cycloalkyl group, an aryl group, and a substituted aryl group , Heteroaryl or substituted heteroaryl,
  • R 4 is hydrogen, chlorine, fluorine or C1-C8 alkyl group
  • X 1 , X 2 and X 3 are each independently chlorine or fluorine
  • X 1 , X 2 and X 3 are fluorine, R 4 is hydrogen, and R 1 is OC 2 H 5 or CH 3 .
  • a technical solution proposed by the present invention to solve the above technical problems is: a halogen substituted compound having a structure as shown in formula II,
  • R 1 is OR A or R A , wherein R A is a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a substituted C3-8 cycloalkyl group, an aryl group, and a substituted aryl group , Heteroaryl or substituted heteroaryl,
  • R 4 is hydrogen, chlorine, fluorine or C1-C8 alkyl group
  • X 1 and X 2 are each independently chlorine or fluorine
  • X 1 and X 2 are fluorine, R 4 is hydrogen, and R 1 is OC 2 H 5 or CH 3 .
  • a technical solution proposed by the present invention to solve the above technical problems is: a method for preparing a pyrazole derivative from a halogen-substituted compound, such as the reaction of the halogen-substituted compound shown in formula II with methylhydrazine, the pyrazole ring is formed as
  • the halogen-substituted alkyl-1-methylpyrazole derivative represented by formula IV has the following reaction formula:
  • R 1 is OR A or R A , wherein R A is a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a substituted C3-8 cycloalkyl group, an aryl group, and a substituted aryl group , Heteroaryl or substituted heteroaryl,
  • R 4 is hydrogen, chlorine, fluorine or C1-C8 alkyl group
  • X 1 and X 2 are each independently chlorine or fluorine
  • X 1 and X 2 are fluorine, R 4 is hydrogen, and R 1 is OC 2 H 5 or CH 3 ;
  • the halogen-substituted alkyl-1-methylpyrazole derivative represented by formula IV undergoes a hydrolysis reaction with an alkaline solution, and the alkaline solution is preferably sodium hydroxide solution, and the reaction is as follows: halogen-substituted alkyl group shown v -1-methyl -1H- pyrazole-4-carboxylic acid, when R 1 is R a, shown in the formula halogen-substituted alkyl group iv 1-methylpyrazole
  • the azole derivative reacts with an oxidizing agent.
  • the oxidizing agent is preferably sodium hypochlorite solution, sodium hypobromite solution or oxygen to generate halogen-substituted alkyl-1-methyl-1H-pyrazole-4-carboxylic acid as shown in formula V.
  • the reaction formula is as follows:
  • the present invention proposes a technical solution: a method for preparing pyrazole derivatives from halogen-substituted compounds.
  • the halogen-substituted compound shown in formula II is reacted with methylhydrazine benzaldehyde hydrazone to produce the formula
  • the hydrazone compound shown in III the reaction formula is as follows:
  • R 1 is OR A or R A , wherein R A is a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a substituted C3-8 cycloalkyl group, an aryl group, and a substituted aryl group , Heteroaryl or substituted heteroaryl,
  • R 4 is hydrogen, chlorine, fluorine or C1-C8 alkyl group
  • X 1 and X 2 are each independently chlorine or fluorine
  • X 1 and X 2 are fluorine, R 4 is hydrogen, and R 1 is OC 2 H 5 or CH 3 ;
  • the hydrazone compound shown in formula III is under the action of an acid, preferably sulfuric acid, and the pyrazole ring is turned off to generate a halogen-substituted alkyl-1-methylpyrazole derivative shown in formula IV.
  • the reaction formula is as follows:
  • the halogen-substituted alkyl-1-methylpyrazole derivative represented by formula IV undergoes a hydrolysis reaction with an alkaline solution, and the alkaline solution is preferably sodium hydroxide solution, and the reaction is as follows: halogen-substituted alkyl group shown v -1-methyl -1H- pyrazole-4-carboxylic acid, when R 1 is R a, shown in the formula halogen-substituted alkyl group iv 1-methylpyrazole
  • the azole derivative reacts with an oxidizing agent.
  • the oxidizing agent is preferably sodium hypochlorite solution, sodium hypobromite solution or oxygen to generate halogen-substituted alkyl-1-methyl-1H-pyrazole-4-carboxylic acid as shown in formula V.
  • the reaction formula is as follows:
  • a technical solution proposed by the present invention to solve the above technical problems is: a method for preparing pesticides, and the above method for preparing halogen substituted compounds or pyrazole derivatives.
  • the pesticide is an amide fungicide, preferably bixafen, pyraclostrobin, pyraclostrobin or pyraclostrobin.
  • the method for preparing pesticides is to convert halogen-substituted alkyl-1-methyl-1H-pyrazole-4-carboxylic acid, preferably with carboxylic acid halide, into activated halogen-substituted alkyl-1-methyl-1H-pyrazole -4-carboxylic acid, and then react the activated halogen-substituted alkyl-1-methyl-1H-pyrazole-4-carboxylic acid with an amine, preferably aniline, to obtain an amide fungicide.
  • the specific preparation method refers to the international patent WO1992/12970.
  • a technical solution proposed by the present invention to solve the above technical problems is the application of the halogen-substituted alkyl-1-methyl-1H-pyrazole-4-carboxylic acid prepared by the above preparation method as an intermediate for the preparation of pesticides.
  • the pesticide is an amide fungicide, preferably bixafen, pyraclostrobin, pyraclostrobin or pyraclostrobin.
  • the present invention optimizes the structure of the halogen-substituted compound.
  • the two Ns of the halogen-substituted compound constitute piperazine, so that the halogen-substituted compound obtains a centrosymmetric structure.
  • the reaction route of the present invention is relatively short, the reaction conditions are common, only 40% aqueous solution of alkylhydrazine compounds are used, the reaction yield of each step is high, the intermediate is easy to purify, and the product quality is high.
  • the structure of the symmetric diamine has higher atom economy, and the symmetric diamine has a higher boiling point and is easier to recycle.
  • the halogen-substituted compound prepared by the present invention is easy to prepare with raw material compounds and halogenated acetyl halide derivatives, can be directly purchased out, and the raw material cost is low.
  • the halogen-substituted compound can be firstly reacted with methylhydrazine benzaldehyde hydrazone, and then the pyrazole ring is closed under the action of acid.
  • the advantage lies in the formation of methylhydrazine benzaldehyde hydrazone to protect the hydrazone
  • the base can be reacted in a reaction vessel, which further guarantees that the ring-closure product without isomers can be obtained.
  • FIG. 1 is a high performance liquid chromatogram of N,N'-ethyl diacrylate piperazine in Example 1.
  • FIG. 2 is a high performance liquid chromatogram of the halogen-substituted compound in Example 1.
  • FIG. 3 is a gas chromatogram of ethyl 3-fluoroalkyl-1-methylpyrazole-4-carboxylate in Example 1.
  • FIG. 4 is a high performance liquid chromatogram of 3-fluoroalkyl-1-methyl-1H-pyrazole-4-carboxylic acid in Example 1.
  • FIG. 4 is a high performance liquid chromatogram of 3-fluoroalkyl-1-methyl-1H-pyrazole-4-carboxylic acid in Example 1.
  • C1 ⁇ C8 alkyl refers to alkyl with carbon chain length of 1-8, such as: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , Pentyl, hexyl, heptyl, octyl, etc.
  • the C3-C8 cycloalkyl group refers to a cycloalkyl group with a carbon chain length of 3-8, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like.
  • C3-C8 cycloalkyl groups with substituents such as: 2-methylcyclopropyl, 1-methylcyclopentyl, 4-methylcyclohexyl, etc.
  • An aryl group refers to a monovalent group of aromatic hydrocarbons with a carbon chain length of 6-18, such as phenyl, naphthyl, anthracenyl and the like.
  • Substituent aryl groups such as 3-methylphenyl (m-tolyl), 2,4-di-tert-butylphenyl, 4-chlorophenyl, etc.
  • Heteroaryl groups such as furyl, pyrrolyl, indolyl, carbazolyl, imidazolyl, etc.
  • the substituted heteroaryl group refers to a group in which one or more hydrogen atoms of the heteroaryl group are substituted with a substituent.
  • the halogenated acetyl halide derivative represented by formula VI is difluoroacetyl fluoride as an example
  • Difluoroacetyl fluoride gas can be formed by pyrolysis of tetrafluoroethyl ether at high temperature.
  • the cracking reaction temperature is 200°C to 400°C, and the catalyst is aluminum oxide.

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Abstract

本发明涉及一种卤素取代化合物的制备方法，如式Ⅰ所示的哌嗪衍生物与如式Ⅵ所示的卤代乙酰卤衍生物反应生成如式Ⅱ所示的卤素取代化合物。本发明还涉及一种卤素取代化合物制备吡唑衍生物的制备方法，如式Ⅱ所示的卤素取代化合物与甲基肼反应，关吡唑环生成如式Ⅳ所示的卤素取代烷基‑1‑甲基吡唑衍生物；或与甲基肼苯甲醛腙反应，生成如式Ⅲ所示的腙化合物，在酸的作用下，关吡唑环生成如式Ⅳ所示的卤素取代烷基‑1‑甲基吡唑衍生物。本发明还涉及中间体化合物的结构。本发明的卤素取代化合物和吡唑衍生物的制备方法适于产业化生产。

Description

卤素取代化合物及其制备方法和应用 技术领域
本发明涉及一种卤素取代化合物的产业化合成方法，属于化学合成技术领域。
 背景技术
卤素取代的吡唑衍生物，尤其是含氟吡唑衍生物是很多医药或者农药的中间体。在这些含氟吡唑衍生物中，3-二氟甲基-1-甲基吡唑-4-羧酸是一个重要的农药中间体，在很多农药新品种中扮演了非常重要的中间体角色，比如拜耳作物科学公司推出的谷类杀菌剂联苯吡菌胺（Bixafen），巴斯夫推出的新品杀菌剂氟唑菌酰胺（Fluxapyroxad），先正达推出的吡唑萘菌胺（Isopyrazam），氟唑环菌胺（Sedaxane）等。
 
Figure 268072dest_path_image001
国际专利WO1992/12970公开了3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸及其作为杀真菌剂的用途。该方法将3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸转化成对应的酰氯，然后使用合适的胺转化成对应的酰胺，从而制成酰胺类杀菌剂。
由于3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸是合成上述酰胺类新型杀菌剂的关键中间体，其合成工艺的研究激起了化学家们的广泛研究，现有的制备方法可以归结为以下几类：
一，克莱森缩合的方法，主要是BASF和Syngenta专利报道的。从二氟乙酸乙酯出发经克莱森缩合反应得到二氟乙酰乙酸乙酯，再与原甲酸三乙酯缩合得到4,4-二氟-2-(乙氧亚甲基)-3-氧代丁酸乙酯，跟甲基肼关环后生成3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸乙酯（DFMMP），经氢氧化钠水解，盐酸酸化后得到3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸（DFPA）。此路线由于成本较高，除了已经在生产的产品线以外，新的合成方法研究一般不再采用此法。
二，二甲氨基丙烯酸乙酯法，Bayer专利WO2009043444，类似地，WO2009133178 BASF公司将二甲氨基用哌啶基替代。该类方法将二氟乙酰氟气体通入到二甲氨基丙烯酸乙酯中，得到的中间体直接跟甲基肼关环生成3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸乙酯（DFMMP），经氢氧化钠水解，盐酸酸化后得到3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸（DFPA）。其中二氟乙酰氟气体通过四氟乙醚的高温裂解得到。该路线设计巧妙，具有步骤短，收率高的特点，是目前成本较低的方法。缺点在于对设备的要求较高，同时，反应会产生大量挥发性的二甲胺，影响环境，也没有解决甲基肼关环合成吡唑环的选择性问题。
三，二氟氯乙酰氯法，Solvay的专利WO2012025469。该路线由Solvay开发，利用二氟氯乙酰氯（CDFAC）为起始原料，与乙烯酮反应后用乙醇淬灭得到二氟氯乙酰乙酸乙酯，跟克莱森缩合类似的方法得到3-（二氟氯甲基）-1-甲基-1H-吡唑-4-羧酸乙酯，锌粉还原或者钯碳氢化得到3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸乙酯（DFMMP），经氢氧化钠水解，盐酸酸化后得到3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸（DFPA）。该路线的缺点在于路线较长，原材料的来源问题，以及最后脱氯的问题，不但增加了成本，也增加了三废。
四，其他合成方法。1)EP 2008996报道了以二氯乙酰氯、乙烯基醚类化合物、甲基肼等原料5 步反应合成3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸。虽然在成本的控制上有一定优势，但反应条件比较苛刻，其中二氯乙酰氯和乙烯基醚类化合物需要在-40～-20℃的条件下反应；催化加压上羧基的反应中，反应温度150℃，过程中要不断改变釜内压强，操作不便，且异构体不易分离；2）WO2009000442报道了以二氟乙酸乙酯为原料，跟水合肼反应生成酰肼，甲基化后再跟丙炔酸乙酯关环得到3-（二氟甲基）-1-甲基-1H-吡唑-4-羧酸乙酯（DFMMP），该方法收率不高，且丙炔酸乙酯价格较贵，不适合工业化生产。
 技术问题
本发明要解决的技术问题是，提供一种适于产业化生产吡唑衍生物的卤素取代化合物，以及该卤素取代化合物的制备方法，以及该卤素取代化合物作为中间体制备吡唑衍生物的制备方法和用途。
 技术解决方案
本发明为解决上述技术问题提出的一种技术方案是：一种卤素取代化合物的制备方法，如式Ⅰ所示的哌嗪衍生物与如式Ⅵ所示的卤代乙酰卤衍生物反应生成如式Ⅱ所示的卤素取代化合物，反应溶剂优选为氯仿，催化剂优选为三乙胺，反应式如下：
Figure 115199dest_path_image002
，
其中，
R 1为OR A或R A，其中，R A为C1～C8的烷基、C3～C8的环烷基、具有取代基的C3～8的环烷基、芳基、具有取代基的芳基、杂芳基或具有取代基的杂芳基，
R 4为氢、氯、氟或C1～C8的烷基，
X 1、X 2和X 3各自独立为氯或氟，
优选X 1、X 2和X 3为氟，R 4为氢，R 1为OC 2H 5或CH 3。
本发明为解决上述技术问题提出的一种技术方案是：一种卤素取代化合物，具有如式Ⅱ所示的结构，
Figure 517361dest_path_image003
，
其中，
R 1为OR A或R A，其中，R A为C1～C8的烷基、C3～C8的环烷基、具有取代基的C3～8的环烷基、芳基、具有取代基的芳基、杂芳基或具有取代基的杂芳基，
R 4为氢、氯、氟或C1～C8的烷基，
X 1和X 2各自独立为氯或氟，
优选X 1、X 2为氟，R 4为氢，R 1为OC 2H 5或CH 3。
本发明为解决上述技术问题提出的一种技术方案是：一种卤素取代化合物制备吡唑衍生物的制备方法，如式Ⅱ所示的卤素取代化合物与甲基肼反应，关吡唑环生成如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物，反应式如下：
Figure 389502dest_path_image004
，
其中，
R 1为OR A或R A，其中，R A为C1～C8的烷基、C3～C8的环烷基、具有取代基的C3～8的环烷基、芳基、具有取代基的芳基、杂芳基或具有取代基的杂芳基，
R 4为氢、氯、氟或C1～C8的烷基，
X 1和X 2各自独立为氯或氟，
优选X 1、X 2为氟，R 4为氢，R 1为OC 2H 5或CH 3；
当R 1为OR A时，所述如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物与碱性溶液进行水解反应，碱性溶液优选为氢氧化钠溶液，生成如式Ⅴ所示的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸，当R 1为R A时，所述如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物与氧化剂进行氧化反应，氧化剂优选为次氯酸钠溶液、次溴酸钠溶液或氧气，生成如式Ⅴ所示的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸，反应式如下：
Figure 225609dest_path_image005
。
本发明为解决上述技术问题提出的一种技术方案是：一种卤素取代化合物制备吡唑衍生物的制备方法，如式Ⅱ所示的卤素取代化合物与甲基肼苯甲醛腙反应，生成如式Ⅲ所示的腙化合物，反应式如下：
Figure 448780dest_path_image006
，
其中，
R 1为OR A或R A，其中，R A为C1～C8的烷基、C3～C8的环烷基、具有取代基的C3～8的环烷基、芳基、具有取代基的芳基、杂芳基或具有取代基的杂芳基，
R 4为氢、氯、氟或C1～C8的烷基，
X 1和X 2各自独立为氯或氟，
优选X 1、X 2为氟，R 4为氢，R 1为OC 2H 5或CH 3；
所述如式Ⅲ所示的腙化合物在酸的作用下，酸优选为硫酸，关吡唑环生成如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物，反应式如下：
Figure 389054dest_path_image007
，
当R 1为OR A时，所述如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物与碱性溶液进行水解反应，碱性溶液优选为氢氧化钠溶液，生成如式Ⅴ所示的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸，当R 1为R A时，所述如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物与氧化剂进行氧化反应，氧化剂优选为次氯酸钠溶液、次溴酸钠溶液或氧气，生成如式Ⅴ所示的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸，反应式如下：
Figure 480814dest_path_image008
。
本发明为解决上述技术问题提出的一种技术方案是：一种制备农药的方法，上述制备卤素取代化合物或吡唑衍生物的方法。所述农药是酰胺类杀菌剂，优选为联苯吡菌胺、氟唑菌酰胺、吡唑萘菌胺或氟唑环菌胺。制备农药的方法是将卤素取代烷基-1-甲基-1H-吡唑-4-羧酸，优选用羧酸卤化物转化为活化的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸，再将所述活化的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸与胺，优选是苯胺，反应以获得酰胺类杀菌剂。具体制备方法参考国际专利WO1992/12970。
本发明为解决上述技术问题提出的一种技术方案是：上述制备方法制得的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸作为制备农药的中间体的应用。所述农药是酰胺类杀菌剂，优选为联苯吡菌胺、氟唑菌酰胺、吡唑萘菌胺或氟唑环菌胺。
 有益效果
（1）本发明对卤素取代化合物的结构进行了优化，卤素取代化合物的两个N构成哌嗪，使得卤素取代化合物获得了中心对称的结构，采用该结构的卤素取代化合物合成吡唑衍生物时，反应副产物少。本发明的反应的路线较短，反应条件普通，只需用到40%的烷基肼类化合物水溶液，各步反应收率高，中间体易纯化，产品质量高。与3-哌啶环丙烯酸酯结构相比，此对称二胺的结构，原子经济性更高，同时对称二胺的沸点较高，更易回收利用。
（2）本发明制备卤素取代化合物采用与原料化合物和卤代乙酰卤衍生物易于制备，可直接外购，原料成本低。
（3）本发明制备吡唑衍生物时，可以先用卤素取代化合物与甲基肼苯甲醛腙反应，再在酸的作用下关吡唑环，优点在于甲基肼苯甲醛腙的形成腙保护基，在一个反应容器中即可反应，进一步地保障了得到无异构体的关环产物。
 附图说明
图1是实施例1中的N,N’-双丙烯酸乙酯哌嗪的高效液相色谱图。
图2是实施例1中的卤素取代化合物的高效液相色谱图。
图3是实施例1中的3-氟代烷基-1-甲基吡唑-4-羧酸乙酯的气相色谱图。
图4是实施例1中的3-氟代烷基-1-甲基-1H-吡唑-4-羧酸的高效液相色谱图。
 本发明的实施方式
下面通过实施例对本发明进行具体的描述，有必要在此指出的是以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，该领域的技术人员可以根据上述本发明内容对本发明作出一些非本质的改进和调整。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。例如：C1～C8的烷基是指碳链长度为1～8的烷基，如：甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基等。C3～C8的环烷基是指碳链长度为3～8的环烷基，如：环丙基、环丁基、环戊基、环己基、环辛基等。具有取代基的C3～C8的环烷基，如:2-甲基环丙基、1-甲基环戊基、4-甲基环己基等。芳基是指碳链长度为6～18的芳香族烃的一价基团，如：苯基、萘基、蒽基等。具有取代基的芳基，如：3-甲基苯基(间甲苯基)、2 ,4-二叔丁基苯基、4-氯苯基等。杂芳基，如：呋喃基、吡咯基、吲哚基、咔唑基、咪唑基等。具有取代基的杂芳基是指杂芳基的氢原子的1个以上被取代基取代而成的基团。
本发明的实施例以式Ⅵ所示的卤代乙酰卤衍生物为二氟乙酰氟为例，
Figure 441817dest_path_image009
，
如式Ⅵ所示的卤代乙酰卤衍生物，当X 1、X 2和X 3为氟，R 4为氢时，即为二氟乙酰氟。
二氟乙酰氟气体可由四氟乙醚高温裂解而成，裂解反应温度为200℃～400℃，催化剂是三氧化铝。
实施例 1
本实施例的吡唑衍生物的制备方法，包括以下步骤：
在反应瓶中加入28.2g(0.1mol)的N,N’-双丙烯酸乙酯哌嗪（如式Ⅰ所示，其中R 1为OC 2H 5，高效液相色谱图如图1所示），200g的氯仿，22.2g(0.22mol)的三乙胺，控温10℃～30℃内，通入21.5g（0.22mol）的二氟乙酰氟（DFAF），通气完毕后，继续保温反应5小时，减压浓缩溶剂，残留物，加入100g的水，搅拌30分钟，过滤，干燥得到相应的卤素取代化合物（如式Ⅱ所示，高效液相色谱图如图2所示）42.9g，收率98%。
将39g（0.0889mol）的卤素取代化合物产品悬浮于200g的氯仿中，搅拌冷却至-25℃，慢慢滴入20.5g（0.178mol）的浓度为40%的甲基肼（MMH）滴加完毕后，继续保温反应30分钟，升温至室温，分去水层，有机层，浓缩至干，残留物加入石油醚重结晶，得到3-氟代烷基-1-甲基吡唑-4-羧酸乙酯（EDFMPA）（如式Ⅳ所示）30.8g，收率85%，气相色谱图如图3所示。
将30.8g（0.151mol）的3-氟代烷基-1-甲基吡唑-4-羧酸乙酯（EDFMPA）投入反应瓶内，加入100g水，6.7g氢氧化钠，70℃搅拌反应2小时，反应完毕后，滴加盐酸中和至pH值为2，冷却至10℃，过滤，少量冷水洗涤，干燥得到3-氟代烷基-1-甲基-1H-吡唑-4-羧酸（DFMPA）（如式Ⅴ所示）25.2g，收率95%，高效液相色谱法检测纯度为99%，高效液相色谱图如图4所示。
实施例 2
本实施例的吡唑衍生物的制备方法，包括以下步骤：
在反应瓶中加入28.2g(0.1mol)的N,N’-双丙烯酸乙酯哌嗪（如式Ⅰ所示，其中R 1为OC 2H 5），200g的氯仿，22.2g(0.22 mol)的三乙胺，控温10℃～30℃内，通入21.5g（0.22mol）的二氟乙酰氟（DFAF），通气完毕后，继续保温反应5小时，反应完毕后，滴加26.8g（0.2mol）的甲基肼苯甲醛腙（BzH）升温至50℃，保温反应3小时，减压蒸去溶剂，残留物，再加入200g的氯仿和5g的硫酸，室温反应8小时，加入50g的水，分取有机层，升温至60℃，滴加浓度为10%的氢氧化钠溶液90g。滴完后继续反应3小时，反应毕，分取水层，滴加盐酸中和至pH值为2，冷却至10℃，过滤，水洗，干燥，得到3-氟代烷基-1-甲基-1H-吡唑-4-羧酸（DFMPA）（如式Ⅴ所示）26g，总收率73.8%，高效液相色谱法检测纯度为99%。
实施例 3
本实施例的吡唑衍生物的制备方法，包括以下步骤：
在反应瓶中，加入22.2g（0.1mol）的N,N’-双乙烯基甲基酮哌嗪（如式Ⅰ所示，其中R 1为CH 3）、200g的氯仿、22.2g（0.22mol）的三乙胺，控温10℃～30℃内，通入21.5g（0.22mol）的二氟乙酰氟（DFAF），通气完毕后，继续保温反应5小时，滴加26.8g（0.2mol）的甲基肼苯甲醛腙（BzH）升温至50℃，保温反应3小时，减压蒸去溶剂，残留物，再加入200g的氯仿和5g的硫酸，室温反应8小时，加入50g的水，分取有机层，有机层浓缩至干，加入石油醚重结晶，过滤、干燥，得到3-三氟甲基-1-甲基-4-乙酰基吡唑衍生物（如式Ⅳ所示）27.2g，收率78%。
在反应瓶中加入25g（0.14mol）的3-三氟甲基-1-甲基-4-乙酰基吡唑衍生物、80g的醋酸、1g的硝酸锰和1g的硝酸铁，升温至80℃，通入氧气反应20小时，减压蒸去醋酸，残留物加入80g的水，搅拌升温至80℃，冷却至10℃，过滤，干燥，得到3-氟代烷基-1-甲基-1H-吡唑-4-羧酸（DFMPA）（如式Ⅴ所示）24g，收率95%，高效液相色谱法检测纯度为99%。
显然，上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而这些属于本发明的精神所引伸出的显而易见的变化或变动仍处于本发明的保护范围之中。

Claims (10)

  1. 一种卤素取代化合物，其特征在于：具有如式Ⅱ所示的结构，
    Figure dest_path_image001
    ，
    其中，
    R 1为OR A或R A，其中，R A为C1～C8的烷基、C3～C8的环烷基、具有取代基的C3～8的环烷基、芳基、具有取代基的芳基、杂芳基或具有取代基的杂芳基，
    R 4为氢、氯、氟或C1～C8的烷基，
    X 1和X 2各自独立为氯或氟。
  2. 一种如权利要求1所述的卤素取代化合物的制备方法，其特征在于：
    如式Ⅰ所示的哌嗪衍生物与如式Ⅵ所示的卤代乙酰卤衍生物反应生成如式Ⅱ所示的卤素取代化合物，反应式如下：
    Figure 291420dest_path_image002
    ，
    其中，
    R 1为OR A或R A，其中，R A为C1～C8的烷基、C3～C8的环烷基、具有取代基的C3～8的环烷基、芳基、具有取代基的芳基、杂芳基或具有取代基的杂芳基，
    R 4为氢、氯、氟或C1～C8的烷基，
    X 1、X 2和X 3各自独立为氯或氟。
  3. 一种采用如权利要求1所述的卤素取代化合物制备吡唑衍生物的制备方法，其特征在于：
    如式Ⅱ所示的卤素取代化合物与甲基肼反应，关吡唑环生成如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物，反应式如下：
    Figure 274419dest_path_image003
    ，
    其中，
    R 1为OR A或R A，其中，R A为C1～C8的烷基、C3～C8的环烷基、具有取代基的C3～8的环烷基、芳基、具有取代基的芳基、杂芳基或具有取代基的杂芳基，
    R 4为氢、氯、氟或C1～C8的烷基，
    X 1和X 2各自独立为氯或氟。
  4. 根据权利要求3所述的卤素取代化合物制备吡唑衍生物的制备方法，其特征在于：其中R 1为OR A，所述如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物进行水解反应，生成如式Ⅴ所示的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸，反应式如下：
    Figure dest_path_image004
    。
  5. 根据权利要求3所述的卤素取代化合物制备吡唑衍生物的制备方法，其特征在于：其中R 1为R A，所述如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物进行氧化反应，生成如式Ⅴ所示的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸，反应式如下：
    Figure 136807dest_path_image005
    。
  6. 一种采用如权利要求1所述的卤素取代化合物制备吡唑衍生物的制备方法，其特征在于：
    如式Ⅱ所示的卤素取代化合物与甲基肼苯甲醛腙反应，生成如式Ⅲ所示的腙化合物，反应式如下：
    Figure dest_path_image006
    ，
    其中，
    R 1为OR A或R A，其中，R A为C1～C8的烷基、C3～C8的环烷基、具有取代基的C3～8的环烷基、芳基、具有取代基的芳基、杂芳基或具有取代基的杂芳基，
    R 4为氢、氯、氟或C1～C8的烷基，
    X 1和X 2各自独立为氯或氟；
    所述如式Ⅲ所示的腙化合物在酸的作用下，关吡唑环生成如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物，反应式如下：
    Figure 528343dest_path_image007
    。
  7. 根据权利要求6所述的卤素取代化合物制备吡唑衍生物的制备方法，其特征在于：其中R 1为OR A，所述如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物进行水解反应，生成如式Ⅴ所示的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸，反应式如下：
    Figure 819647dest_path_image008
    。
  8. 根据权利要求6所述的卤素取代化合物制备吡唑衍生物的制备方法，其特征在于：其中R 1为R A，所述如式Ⅳ所示的卤素取代烷基-1-甲基吡唑衍生物进行氧化反应，生成如式Ⅴ所示的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸，反应式如下：
    Figure 24363dest_path_image004
    。
  9. 一种制备农药的方法，其特征在于：包括权利要求2、3、6中任一项所述的制备方法。
  10. 一种如权利要求3和6中任一项所述的制备方法制得的卤素取代烷基-1-甲基-1H-吡唑-4-羧酸作为制备农药的中间体的应用。
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CN111116364B (zh) * 2019-12-30 2022-11-11 浙江本立科技股份有限公司 2-多卤代乙酰基-3-烷氧基丙烯酸酯的制备方法
CN111362874B (zh) * 2020-03-16 2021-06-29 徐州圣元化工有限公司 一种3-(二氟甲基)-1-甲基-1h-吡唑-4-羧酸的制备方法
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