WO2017054112A1 - 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法 - Google Patents

3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法 Download PDF

Info

Publication number
WO2017054112A1
WO2017054112A1 PCT/CN2015/090970 CN2015090970W WO2017054112A1 WO 2017054112 A1 WO2017054112 A1 WO 2017054112A1 CN 2015090970 W CN2015090970 W CN 2015090970W WO 2017054112 A1 WO2017054112 A1 WO 2017054112A1
Authority
WO
WIPO (PCT)
Prior art keywords
fluoroalkyl
carboxylic acid
methylpyrazole
formula
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2015/090970
Other languages
English (en)
French (fr)
Inventor
王明春
李庆毅
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Changzhou Keylab Biochemical Co Ltd
Solvay Fluor GmbH
Original Assignee
Changzhou Keylab Biochemical Co Ltd
Solvay Fluor GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Changzhou Keylab Biochemical Co Ltd, Solvay Fluor GmbH filed Critical Changzhou Keylab Biochemical Co Ltd
Priority to PCT/CN2015/090970 priority Critical patent/WO2017054112A1/zh
Priority to JP2018535265A priority patent/JP2018531285A/ja
Priority to KR1020187010626A priority patent/KR20180059471A/ko
Priority to PCT/IB2016/001462 priority patent/WO2017064550A1/zh
Priority to DE112016000140.1T priority patent/DE112016000140B4/de
Priority to IT102016000097392A priority patent/IT201600097392A1/it
Priority to CH00617/17A priority patent/CH711995B1/de
Priority to EP16794724.1A priority patent/EP3357913A1/en
Priority to FR1659165A priority patent/FR3041637B1/fr
Priority to US15/763,472 priority patent/US10457645B2/en
Priority to CN201680056250.4A priority patent/CN108368055B/zh
Publication of WO2017054112A1 publication Critical patent/WO2017054112A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • 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
    • A01N45/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds having three or more carbocyclic rings condensed among themselves, at least one ring not being a six-membered ring
    • A01N45/02—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds having three or more carbocyclic rings condensed among themselves, at least one ring not being a six-membered ring having three carbocyclic rings

Definitions

  • the present invention relates to an industrial synthesis method of 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid.
  • the global fluorine chemical products total about 2.5 million tons, with sales of more than 21 billion US dollars.
  • the annual average growth rate of global fluorine chemical products has reached 3.5%.
  • the development of fluorine-containing pesticides is very rapid. Through the study of activity, structure and mechanism of action, several heavyweight fluorine-containing nitrogen heterocyclic sterilization products have been developed.
  • 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid is an important intermediate.
  • 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (CAS: 176969-34-9) is an important pesticide intermediate. It plays a very important intermediate role in many new pesticide varieties, such as: Bayer Crop Science's cereal fungicide Bixafen, BASF's new fungicide Fluxapyroxad, first Isopyrazam, sedaxane, etc., which are launched by Masahiro.
  • a method of Claisen condensation of ethyl difluoroacetate is a method currently employed in mass production in the industry and is disclosed in the patent document WO2009106619 of BASF.
  • the process comprises: starting from ethyl difluoroacetate, obtaining a difluoroacetic acid ethyl ester by a Claisen condensation reaction, and then condensing with triethyl orthoformate to obtain 4,4-difluoro-2-(ethoxy bromide) Ethyl 3-oxobutanoate, which is combined with methylhydrazine to form 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (DFMMP).
  • DFPA 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
  • DFPA 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
  • the source of ethyl difluoroacetate has different patent reports, some from the tetrafluoroethylene monomer, through the tetrafluoroethyl ether intermediate, two steps to synthesize ethyl difluoroacetate.
  • ethyl chloride is used as a raw material, and a chlorine atom is converted into a fluorine atom by potassium fluoride.
  • the route adopts the classical synthetic methodology, which has the characteristics of high yield and stable production. The disadvantage is that the route is long, and the exhaust gas, waste water and solid waste are generated.
  • ethyl dimethylamino acrylate method A similar method of substituting a dimethylamino group with a cyclohexylamino group is disclosed in the patent document WO2009133178 of BASF, which is disclosed in the patent document WO2009043444.
  • the process of such a method is: introducing a difluoroacetyl fluoride gas into ethyl dimethylaminoacrylate, and the obtained intermediate directly forms a 3-(difluoromethyl)-1-methyl group with a methylhydrazine ring.
  • DFMMP -1H-pyrazole-4-carboxylic acid ethyl ester
  • DFPA 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
  • difluoroacetyl fluoride gas is obtained by pyrolysis of tetrafluoroethyl ether.
  • the route is ingeniously designed with short steps and high yield.
  • the synthesis cost of ethyl dimethylaminoacrylate is relatively high.
  • Tris difluorochloroacetyl chloride method. It is disclosed in the patent document WO2012025469 by SOLVAY. The process is as follows: using difluorochloroacetyl chloride (CDFAC) as a starting material, reacting with ketene and quenching with ethanol to obtain ethyl difluorochloroacetoacetate, and obtaining 3-(3) by a similar method to Claisen condensation.
  • CDFAC difluorochloroacetyl chloride
  • Ethyl difluorochloromethyl)-1-methyl-1H-pyrazole-4-carboxylate zinc powder reduction or palladium hydrocarbonation to give 3-(difluoromethyl)-1-methyl-1H-pyrazole Ethyl 4-carboxylate (DFMMP), hydrolyzed with sodium hydroxide, acidified with hydrochloric acid to give 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (DFPA).
  • the route has the characteristics of high yield, good atomic economy, low cost, less waste gas, waste water and solid waste.
  • the disadvantage is that the route is long, and the difluorochloroacetyl chloride is obtained by photooxidation, and the equipment investment is high, and To increase the reaction of reducing dechlorination in one step.
  • the technical problem to be solved by the present invention is to provide a 3-difluoromethyl-1-methylpyrazole-4- which is short in reaction route, low in raw material cost, high in reaction yield in each step, and suitable for industrial production.
  • a process for the preparation of a carboxylic acid, and 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid prepared by the process.
  • Step 1 The condensation reaction of the fluoroacetyl halide derivative represented by the formula I with the dimethylamino vinyl methyl ketone to form 3-dimethylaminomethylene-1,1-difluoro group represented by the formula II a derivative of-2,4-pentanedione,
  • R 1 is a hydrogen, fluorine or chlorine atom
  • R 2 is a fluorine or chlorine atom
  • Step 2 reacting the 3-dimethylaminomethylene-1,1-difluoro-2,4-pentanedione derivative represented by the formula II with a methylhydrazine ring to form a formula III 3-fluoroalkyl-1-methyl-4-acetylpyrazole derivatives,
  • Step 3 The 3-fluoroalkyl-1-methyl-4-acetylpyrazole derivative represented by the formula III is oxidized under basic conditions and then acidified to form 3-fluoro group represented by the formula IV. Alkenyl-1-methylpyrazole-4-carboxylic acid,
  • the fluoroacetyl halide derivative gas represented by the formula I is directly introduced into a dichloromethane solution of dimethylamino vinyl methyl ketone at a reaction temperature. It is -5 ° C ⁇ 0 ° C.
  • reaction temperature is -40 ° C to 0 ° C
  • reaction time is 1 h to 8 h
  • the methyl hydrazine and the 3-dimethylamino group represented by the formula II are The molar ratio of the methylene-1,1-difluoro-2,4-pentanedione derivative is from 1.1:1 to 1.5:1.
  • a further preferred embodiment of the above technical solution is that in the second step, the reaction temperature is -25 ° C to -20 ° C, and the reaction time is 1 h to 2 h.
  • the sodium hypochlorite solution or the sodium hypobromite solution is used for oxidation under alkaline conditions, and the sodium hypochlorite solution is prepared by passing chlorine gas into an aqueous sodium hydroxide solution.
  • the sodium hypobromite solution is prepared by passing liquid bromine into an aqueous solution of sodium hydroxide.
  • reaction temperature is from 0 ° C to 50 ° C
  • reaction time is from 1 h to 5 h.
  • a further preferred embodiment of the above technical solution is that in the above step three, the reaction temperature is 10 ° C - At 20 ° C, the reaction time is 2 h to 3 h.
  • One of the above technical solutions is preferably: in the above step 3, the acidification is carried out using a hydrochloric acid solution, and finally adjusted to a pH of 1-2.
  • fluoroacetyl halide derivative represented by the above formula I is difluoroacetyl fluoride, and the 3-fluoroalkyl-1-methylpyrazole-4- represented by the formula IV
  • the carboxylic acid is 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid.
  • Another technical solution proposed by the present invention to solve the above technical problems is a 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid obtained by the above preparation method.
  • the invention has a positive effect: the preparation method of the 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid of the invention has short reaction route, low raw material cost, safety and reliability, high reaction yield in each step, atom High economy and high product quality.
  • the method has the advantages of simple operation, less exhaust gas, waste water and solid waste, and is suitable for industrial production, and the dimethylamino vinyl methyl ketone used in the reaction is convenient to prepare.
  • Example 1 is a reaction scheme for preparing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid according to Example 1 of the present invention
  • Figure 2 is a gas chromatogram of 3-difluoromethyl-1-methyl-4-acetylpyrazole synthesized in Example 1 of the present invention
  • Figure 3 is a liquid chromatogram of 3-difluoromethyl-1-methyl-4-acetylpyrazole synthesized in Example 1 of the present invention
  • Figure 4 is a nuclear magnetic resonance spectrum of 3-difluoromethyl-1-methyl-4-acetylpyrazole synthesized in Example 1 of the present invention
  • Figure 5 is a liquid chromatogram of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid synthesized in Example 1 of the present invention
  • Figure 6 is a nuclear magnetic resonance spectrum of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid synthesized in Example 1 of the present invention.
  • the preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid of the present embodiment comprises the following steps:
  • reaction liquid is concentrated under reduced pressure on a rotary evaporator to remove the solvent, and the residue is a crude product of 3-dimethylaminomethylene-1,1-difluoro-2,4-pentanedione, and the gas phase purity is more than 95%. , used directly in the next step according to the quantitative yield.
  • the difluoroacetyl fluoride gas used is pyrolyzed by tetrafluoroethyl ether at a temperature of 300 ° C, and an aluminum phosphate inorganic salt is used as a catalyst during the reaction.
  • the dimethylamino vinyl methyl ketone used is obtained by subjecting acetone, ethyl formate and sodium methoxide to a condensation reaction and then treating with dimethylamine hydrochloride.
  • the reaction formula is as follows:
  • the dimethylamino vinyl methyl ketone has a simple preparation method and low cost, and has a positive effect on the cost control of the preparation method of the present invention.
  • a 40% strength aqueous solution of methylhydrazine was added to a three-neck round bottom flask, and the methyl hydrazine in the solution was 126 g (1.1 mol).
  • the temperature was lowered to -20 ° C, and then the prepared dichloromethane solution of 3-dimethylaminomethylene-1,1-difluoro-2,4-pentanedione was added dropwise to the flask, and the temperature was controlled at - Add dropwise at 25 ° C ⁇ -20 ° C, and keep warm for 1 h after the addition.
  • dichloromethane was added to extract an aqueous layer, and the organic layer was used to recover dichloromethane as a waste liquid.
  • the extracted aqueous layer was added with a concentration of 31% hydrochloric acid to adjust the pH to 1-2, and then cooled to about 10 ° C, kept for 0.5 h, suction filtered, and dried to obtain 95 g of the final product, yield 95%.
  • the preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid of the present embodiment comprises the following steps:
  • reaction liquid is concentrated under reduced pressure on a rotary evaporator to remove the solvent, and the residue is a crude product of 3-dimethylaminomethylene-1,1-difluoro-2,4-pentanedione, and the gas phase purity is more than 95%. , used directly in the next step according to the quantitative yield.
  • a 40% strength aqueous solution of methylhydrazine was added to a three-neck round bottom flask, and the methyl hydrazine in the solution was 126 g (1.1 mol).
  • the temperature was lowered to -20 ° C, and then the prepared dichloromethane solution of 3-dimethylaminomethylene-1,1-difluoro-2,4-pentanedione was added dropwise to the flask, and the temperature was controlled at - Add dropwise at 25 ° C ⁇ -20 ° C, and keep warm for 1 h after the addition.
  • the reaction of the starting material was completely determined by gas chromatography, and the mixture was allowed to warm to room temperature, and the aqueous layer was separated. The organic layer was concentrated and recrystallized to give a white solid product 150 g, yield 86%.
  • dichloromethane was added to extract an aqueous layer, and the organic layer was used to recover dichloromethane as a waste liquid.
  • the extracted aqueous layer was added with a concentration of 31% hydrochloric acid to adjust the pH to 1-2, and then cooled to about 10 ° C, kept for 0.5 h, suction filtered, and dried to obtain 95 g of the final product, yield 95%.
  • the preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid of the present embodiment comprises the following steps:
  • reaction liquid is concentrated under reduced pressure on a rotary evaporator to remove the solvent, and the residue is a crude product of 3-dimethylaminomethylene-1,1-difluoro-2,4-pentanedione, and the gas phase purity is more than 95%. , used directly in the next step according to the quantitative yield.
  • dichloromethane was added to extract an aqueous layer, and the organic layer was used to recover dichloromethane as a waste liquid.
  • the extracted aqueous layer was added with a concentration of 31% hydrochloric acid to adjust the pH to 1-2, and then cooled to about 10 ° C, kept for 0.5 h, suction filtered, and dried to obtain 84 g of the final product, yield 96%.
  • the preparation method of 3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (CAS: 113100-53-1) of the present embodiment comprises the following steps:
  • reaction liquid is concentrated under reduced pressure on a rotary evaporator to remove the solvent, and the residue is a crude product of 3-dimethylaminomethylene-1,1,1-trifluoro-2,4-pentanedione. At 95%, it was directly used in the next reaction according to the quantitative yield.
  • dichloromethane was added to extract an aqueous layer, and the organic layer was used to recover dichloromethane as a waste liquid.
  • the extracted aqueous layer was added with a concentration of 31% hydrochloric acid to adjust the pH to 1-2, and then cooled to about 10 ° C, kept for 0.5 h, suction filtered, and dried to obtain 92 g of the final product in a yield of 95%.
  • the preparation method of 3-(difluorochloromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid of the present embodiment comprises the following steps:
  • reaction liquid is concentrated under reduced pressure on a rotary evaporator to remove the solvent, and the residue is a crude product of 3-dimethylaminomethylene-1,1,1-trifluoro-2,4-pentanedione, and the gas phase purity is greater than 95%, directly used in the next reaction according to the quantitative yield.
  • a 40% strength aqueous solution of methylhydrazine was added to a three-neck round bottom flask, and the methyl hydrazine in the solution was 126 g (1.1 mol).
  • the temperature was lowered to -20 ° C, and then the above-prepared dichloromethane solution of 3-dimethylaminomethylene-1-chloro-1,1-difluoro-2,4-pentanedione was added dropwise to the flask at a temperature.
  • the control was carried out at -25 ° C to -20 ° C for dropwise addition, and the temperature was kept for 1 h after the completion of the dropwise addition.
  • dichloromethane was added to extract an aqueous layer, and the organic layer was used to recover dichloromethane as a waste liquid.
  • the extracted aqueous layer is added with a concentration of 31% hydrochloric acid to adjust the pH to 1-2, and then cooled to about 10 ° C, kept for 0.5 h, suction filtered, and dried to give 3-(difluorochloromethyl)-1-methyl -1H-pyrazole-4-carboxylic acid 100 g, yield 95%.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Plant Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明涉及一种3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，包括以下步骤：步骤一、以式I所示的氟代乙酰卤衍生物与二甲胺基乙烯基甲基酮缩合反应，生成式II所示的3-二甲胺基亚甲基-1,1-二氟代-2,4-戊二酮衍生物；步骤二、以所述式II所示的3-二甲胺基亚甲基-1,1-二氟代-2,4-戊二酮衍生物与甲基肼关环反应，生成式III所示的3-氟代烷基-1-甲基-4-乙酰基吡唑衍生物；步骤三、以所述式III所示的3-氟代烷基-1-甲基-4-乙酰基吡唑衍生物在碱性条件下氧化，再酸化，生成式IV所示的3-氟代烷基-1-甲基吡唑-4-羧酸。本发明的制备方法反应路线较短，原料成本较低，各步骤反应收率高，适于工业化生产。

Description

3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法 技术领域
本发明涉及一种3-氟代烷基-1-甲基吡唑-4-羧酸的产业化合成方法。
背景技术
目前，全球氟化工产品(包括无机氟)总量约为250万吨，销售额逾210亿美元。近五年来，全球氟化工产品的年平均增长率达3.5％。无机氟化物产品有近百种，总量约100万吨，销售额约20亿美元，一半以上用于电子化学品、光学材料、催化剂等；含氟精细化学品有数千种，销售额约150亿美元，约占氟化工产品的70％。其中，含氟农药的发展更是非常迅速，通过对活性，结构和作用机制的研究，多个重量级的含氟氮杂环类杀菌产品被开发出来。
在这些含氟氮杂环化合物中，3-氟代烷基-1-甲基吡唑-4-羧酸是重要的中间体。例如：3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸(CAS：176969-34-9)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 PCTCN2015090970-appb-000001
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、二氟乙酸乙酯克莱森缩合的方法。是目前工业上大规模生产所采用的方法，在巴斯夫公司(BASF)的专利文献WO2009106619中被公开。其工艺流程为：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，与甲基肼关环后生成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)。其中，二氟乙酸乙酯的来源有不同的专利报道，有的是从四氟乙烯单体出发，经过四氟乙醚中间体，两步合成二氟乙酸乙酯。还有的以二氯乙酸乙酯为原料，用氟化钾将氯原子转化成氟原子。该路线采用的是经典的合成方法学，具有收率较高，生产稳定的特点，缺点是路线较长，产生的废气、废水、固体废弃物较多。
二，二甲氨基丙烯酸乙酯法。在拜耳公司(Bayer)的专利文献WO2009043444中被公开，另外，将二甲氨基用环己基氨基代替的类似方法在巴斯夫公司(BASF)的专利文献WO2009133178中被公开。此类方法的工艺流程为：将二氟乙酰氟气体通入到二甲氨基丙烯酸乙酯中，得到的中间体直接与甲基肼关环生成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。但是，二甲氨基丙烯酸乙酯的合成成本偏高。
三，二氟氯乙酰氯法。在苏威公司(SOLVAY)的专利文献WO2012025469中被公开。其工艺流程为：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，用与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)。该路线具有收率高，原子经济性较好，成本较低，废气、废水、固体废弃物少的特点，缺点是路线较长，二氟氯乙酰氯要通过光氧化得到，设备投资高，而且要增加一步还原脱氯的反应。
四，其他合成方法。1)专利文献EP2008996中公开的以二氯乙酰氯、乙烯基 醚类化合物、甲基肼等原料五步反应合成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；催化加压导入羧基的反应中，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)专利文献WO2009000442中公开的以二氟乙酸乙酯为原料，与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。
发明内容
本发明要解决的技术问题是，提供一种反应路线较短，原料成本较低，各步骤反应收率高，适于工业化生产的3-二氟甲基-1-甲基吡唑-4-羧酸的制备方法，以及通过该方法制备的3-氟代烷基-1-甲基吡唑-4-羧酸。
本发明为解决上述技术问题提出的一种技术方案是：一种3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，包括以下步骤：
步骤一、以式I所示的氟代乙酰卤衍生物与二甲胺基乙烯基甲基酮缩合反应，生成式II所示的3-二甲胺基亚甲基-1,1-二氟代-2,4-戊二酮衍生物，
Figure PCTCN2015090970-appb-000002
其中，R1是氢、氟或氯原子，R2是氟或氯原子；
步骤二、以所述式II所示的3-二甲胺基亚甲基-1,1-二氟代-2,4-戊二酮衍生物与甲基肼关环反应，生成式III所示的3-氟代烷基-1-甲基-4-乙酰基吡唑衍生物，
Figure PCTCN2015090970-appb-000003
步骤三、以所述式III所示的3-氟代烷基-1-甲基-4-乙酰基吡唑衍生物在碱性条件下氧化，再酸化，生成式IV所示的3-氟代烷基-1-甲基吡唑-4-羧酸，
Figure PCTCN2015090970-appb-000004
上述技术方案的一种优选是：上述步骤一中，将所述式I所示的氟代乙酰卤衍生物气体直接通入二甲胺基乙烯基甲基酮的二氯甲烷溶液中，反应温度为-5℃～0℃。
上述技术方案的一种优选是：上述步骤二中，反应温度为-40℃～0℃，反应时间为1h～8h，所述甲基肼与所述式II所示的3-二甲胺基亚甲基-1,1-二氟代-2,4-戊二酮衍生物的摩尔比为1.1∶1～1.5∶1。
上述技术方案的一种进一步的优选是：上述步骤二中，反应温度为-25℃～-20℃，反应时间为1h～2h。
上述技术方案的一种优选是：上述步骤三中，在碱性条件下氧化所采用的是次氯酸钠溶液或者次溴酸钠溶液，所述次氯酸钠溶液是通过将氯气通入氢氧化钠水溶液中制备的，所述次溴酸钠溶液是通过将液溴通入氢氧化钠水溶液中制备的。
上述技术方案的一种优选是：上述步骤三中，反应温度为0℃～50℃，反应时间为1h～5h。
上述技术方案的一种进一步的优选是：上述步骤三中，反应温度为10℃～ 20℃，反应时间为2h～3h。
上述技术方案的一种优选是：上述步骤三中，酸化所采用的是盐酸溶液，最终调节至PH值为1～2。
上述技术方案的一种优选是：上述式I所示的氟代乙酰卤衍生物是二氟乙酰氟，所述式IV所示的3-氟代烷基-1-甲基吡唑-4-羧酸是3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸。
本发明为解决上述技术问题提出的另一种技术方案是：一种如上述的制备方法制得的3-氟代烷基-1-甲基吡唑-4-羧酸。
本发明具有积极的效果：本发明的3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法反应路线短，原料成本低，安全可靠，各步反应收率高，原子经济性高，产品质量高。该方法操作简便，废气、废水、固体废弃物排放少，适宜于工业化生产，反应中所采用的二甲胺基乙烯基甲基酮制备方便。
附图说明
图1是本发明实施例1的制备3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的反应流程图；
图2是本发明实施例1中合成的3-二氟甲基-1-甲基-4-乙酰基吡唑的气相色谱图；
图3是本发明实施例1中合成的3-二氟甲基-1-甲基-4-乙酰基吡唑的液相色谱图；
图4是本发明实施例1中合成的3-二氟甲基-1-甲基-4-乙酰基吡唑的核磁共振氢谱图；
图5是本发明实施例1中合成的3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的液相色谱图；
图6是本发明实施例1中合成的3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的核磁共振氢谱图。
具体实施方式
实施例1
见图1，本实施例的3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的制备方法，包括以下步骤：
3-二甲胺基亚甲基-1,1-二氟-2,4-戊二酮的合成。
在三口圆底烧瓶中加入二甲胺基乙烯基甲基酮的二氯甲烷溶液565mL，溶液中的二甲胺基乙烯基甲基酮为113g(1.0mol)。在氮气保护下降温至-5℃。接着通入二氟乙酰氟气体108g(1.1mol)。通入气体的过程中，保持体系温度在0℃以下，通入气体完毕后保温搅拌2h。然后反应液在旋转蒸发仪上减压浓缩除去溶剂，残余物即为3-二甲胺基亚甲基-1,1-二氟-2,4-戊二酮的粗品，气相纯度大于95％，按照定量收率直接用于下一步反应。
所采用的二氟乙酰氟气体由四氟乙醚高温裂解而成，反应温度为300℃，反应过程中使用磷酸铝类无机盐作为催化剂。
所采用的二甲胺基乙烯基甲基酮是丙酮、甲酸乙酯和甲醇钠进行缩合反应后，再用二甲胺盐酸盐进行处理，从而制得的。反应式如下：
Figure PCTCN2015090970-appb-000005
二甲胺基乙烯基甲基酮制备方法简单，成本较低，对本发明的制备方法的成本控制有积极效果。
3-二氟甲基-1-甲基-4-乙酰基吡唑的合成。
在三口圆底烧瓶中加入浓度为40％的甲基肼水溶液，溶液中的甲基肼为126g(1.1mol)。降温至-20℃，接着向烧瓶中滴加上述制备好的3-二甲胺基亚甲基-1,1-二氟-2,4-戊二酮的二氯甲烷溶液，温度控制在-25℃～-20℃进行滴加，滴加完毕后保温1h。采用气相色谱检测原料反应完全，升至室温，分去水层，浓缩干有机层，重结晶烘干得白色固体产物148g，收率85％。
如图2所示，白色固体产物通过气相色谱分析，验证其纯度，气相色谱分析结果如表1所示。
表1 3-二氟甲基-1-甲基-4-乙酰基吡唑的气相色谱分析结果
峰号 保留时间(min) 峰高 峰面积 含量(％)
1 7.998 302654.188 1048392.313 100.0000
总计 7.998 302654.188 1048392.313 100.0000
如图3所示，白色固体产物通过液相色谱分析，验证其纯度，液相色谱分析结果如表2所示。
表2 3-二氟甲基-1-甲基-4-乙酰基吡唑的液相色谱分析结果
峰号 保留时间(min) 峰高 峰面积 含量(％)
1 3.350 1483.95544 8274.68066 100.0000
总计 3.350 1483.95544 8274.68066 100.0000
如图4所示，分别采用气相色谱和液相色谱对合成得到的白色固体产物进行了纯度的双重验证后，再采用Bruker 400M核磁共振波谱仪对白色固体产物进行核磁共振氢谱分析，溶剂为CDCl3，核磁共振氢谱分析结果如下：
HNMR(CDCl3,400M):
Figure PCTCN2015090970-appb-000006
＝7.85(s,1H),7.24(d,J＝12Hz,1H),7.10(s,1H),6.96(s,1H),3.96(s,3H),2.45(s,3H).
从而确定白色固体产物确为3-二氟甲基-1-甲基-4-乙酰基吡唑，用于下一步反应。
3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸6的合成。
在三口圆底烧瓶中加入浓度为10％的NaClO水溶液887.5g。冷却反应液至10℃。将100g的3-二氟甲基-1-甲基-4-乙酰基吡唑，溶解在100ml的甲醇中配制成有机溶液。接着向烧瓶中缓慢滴加该有机溶液。滴加过程中保持反应温度10℃～15℃。滴加完毕后，保温继续反应3h。采用TLC薄层色谱法检测原料反应完全。然后加入二氯甲烷萃取水层，有机层作为废液回收二氯甲烷。萃取的水层加入浓度为31％的盐酸调节PH值至1～2，再冷却至10℃左右，保温0.5h，抽滤，烘干得到最终产物95g，收率95％。
如图5所示，最终产物通过液相色谱分析，验证其纯度，液相色谱分析结果如表3所示。
表3 3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的液相色谱分析结果
峰号 保留时间(min) 峰高 峰面积 含量(％)
1 2.172 417.05890 3670.01538 100.0000
总计 2.172 417.05890 3670.01538 100.0000
如图6所示，采用液相色谱对合成得到的最终产物进行了纯度验证后，再采用Bruker 400M核磁共振波谱仪对最终产物进行核磁共振氢谱分析，溶剂为DMSO-d6，核磁共振氢谱分析结果如下：
HNMR(DMSO-d6,400M):
Figure PCTCN2015090970-appb-000007
＝12.78(s,1H),8.31(s,1H),7.18(t,J1＝56Hz,J2＝52Hz,1H),3.89(s,3H).
从而确定最终产物确为3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸。
实施例2
本实施例的3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的制备方法，包括以下步骤：
3-二甲胺基亚甲基-1,1-二氟-2,4-戊二酮的合成。
在三口圆底烧瓶中加入二甲胺基乙烯基甲基酮的二氯甲烷溶液565mL，溶液中的二甲胺基乙烯基甲基酮为113g(1.0mol)。在氮气保护下降温至-5℃。接着通入二氟乙酰氟气体119g(1.2mol)。通入气体的过程中，保持体系温度在0℃以下，通入气体完毕后保温搅拌2h。然后反应液在旋转蒸发仪上减压浓缩除去溶剂，残余物即为3-二甲胺基亚甲基-1,1-二氟-2,4-戊二酮的粗品，气相纯度大于95％，按照定量收率直接用于下一步反应。
3-二氟甲基-1-甲基-4-乙酰基吡唑的合成。
在三口圆底烧瓶中加入浓度为40％的甲基肼水溶液，溶液中的甲基肼为126g(1.1mol)。降温至-20℃，接着向烧瓶中滴加上述制备好的3-二甲胺基亚甲基-1,1-二氟-2,4-戊二酮的二氯甲烷溶液，温度控制在-25℃～-20℃进行滴加，滴加完毕后保温1h。采用气相色谱检测原料反应完全，升至室温，分去水层，浓缩干有机层，重结晶烘干得白色固体产物150g，收率86％。
3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的合成。
在三口圆底烧瓶中加入浓度为10％的NaClO水溶液887.5g。冷却反应液至10℃。将100g的3-二氟甲基-1-甲基-4-乙酰基吡唑，溶解在100ml的甲醇中配制成有机溶液。接着向烧瓶中缓慢滴加该有机溶液。滴加过程中保持反应温度10℃～15℃。滴加完毕后，保温继续反应3h。采用TLC薄层色谱法检测原料反应完全。然后加入二氯甲烷萃取水层，有机层作为废液回收二氯甲烷。萃取的水层加入浓度为31％的盐酸调节PH值至1～2，再冷却至10℃左右，保温0.5h，抽滤，烘干得到最终产物95g，收率95％。
实施例3
本实施例的3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的制备方法，包括以下步骤：
3-二甲胺基亚甲基-1,1-二氟-2,4-戊二酮的合成。
在三口圆底烧瓶中加入二甲胺基乙烯基甲基酮的二氯甲烷溶液565mL，溶液中的二甲胺基乙烯基甲基酮为113g(1.0mol)。在氮气保护下降温至-5℃。接着通入二氟乙酰氟气体108g(1.1mol)。通入气体的过程中，保持体系温度在0℃以下，通入气体完毕后保温搅拌2h。然后反应液在旋转蒸发仪上减压浓缩除去溶剂，残余物即为3-二甲胺基亚甲基-1,1-二氟-2,4-戊二酮的粗品，气相纯度大于95％，按照定量收率直接用于下一步反应。
3-二氟甲基-1-甲基-4-乙酰基吡唑的合成。
在三口圆底烧瓶中加入浓度为40％的甲基肼水溶液，溶液中的甲基肼为137g(1.2mol)。降温至-20℃，接着向烧瓶中滴加上述制备好的3-二甲胺基亚甲基-1,1-二氟-2,4-戊二酮的二氯甲烷溶液，温度控制在-25℃～-20℃进行滴加，滴加完毕后保温1h。采用气相色谱检测原料反应完全，升至室温，分去水层，浓缩干有机层，重结晶烘干得白色固体产物147g，收率85％。
3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的合成。
在三口圆底烧瓶中加入浓度为20％的NaOH水溶液500克，冰浴下滴加160克溴素，滴加完后保持温度在10度以下将87g的3-二氟甲基-1-甲基-4-乙酰基吡唑，溶解在90ml的甲醇中配制成有机溶液。接着向烧瓶中缓慢滴加该有机溶液。滴加过程中保持反应温度10℃～15℃。滴加完毕后，保温继续反应3h。采用TLC薄层色谱法检测原料反应完全。然后加入二氯甲烷萃取水层，有机层作为废液回收二氯甲烷。萃取的水层加入浓度为31％的盐酸调节PH值至1～2，再冷却至10℃左右，保温0.5h，抽滤，烘干得到最终产物84g，收率96％。
实施例4
本实施例的3-(三氟甲基)-1-甲基-1H-吡唑-4-羧酸(CAS：113100-53-1)的制备方法，包括以下步骤：
3-二甲胺基亚甲基-1,1,1-三氟-2,4-戊二酮的合成。
在三口圆底烧瓶中加入二甲胺基乙烯基甲基酮的二氯甲烷溶液250mL，溶液中的二甲胺基乙烯基甲基酮为57g(0.5mol)。在氮气保护下降温至-5℃。接着通入三氟乙酰氯气体73g(0.55mol)。通入气体的过程中，保持体系温度在0℃以下，通入气体完毕后保温搅拌2h。然后反应液在旋转蒸发仪上减压浓缩除去溶剂，残余物即为3-二甲胺基亚甲基-1,1,1-三氟-2,4-戊二酮的粗品，气相纯度大 于95％，按照定量收率直接用于下一步反应。
3-三氟甲基-1-甲基-4-乙酰基吡唑的合成。
在三口圆底烧瓶中加入浓度为40％的甲基肼水溶液，溶液中的甲基肼为63g(0.55mol)。降温至-20℃，接着向烧瓶中滴加上述制备的3-二甲胺基亚甲基-1,1,1-三氟-2,4-戊二酮的二氯甲烷溶液，温度控制在-25℃～-20℃进行滴加，滴加完毕后保温1h。采用气相色谱检测原料反应完全，升至室温，分去水层，浓缩干有机层，重结晶烘干得到3-三氟甲基-1-甲基-4-乙酰基吡唑86.4g，收率90％。
3-(三氟甲基)-1-甲基-1H-吡唑-4-羧酸的合成。
在三口圆底烧瓶中加入浓度为20％的NaOH水溶液500克，冰浴下滴加160克溴素，滴加完后保持温度在10度以下将96g的3-三氟甲基-1-甲基-4-乙酰基吡唑，溶解在100ml的甲醇中配制成有机溶液。接着向烧瓶中缓慢滴加该有机溶液。滴加过程中保持反应温度10℃～15℃。滴加完毕后，保温继续反应3h。采用TLC薄层色谱法检测原料反应完全。然后加入二氯甲烷萃取水层，有机层作为废液回收二氯甲烷。萃取的水层加入浓度为31％的盐酸调节PH值至1～2，再冷却至10℃左右，保温0.5h，抽滤，烘干得到最终产物92g，收率95％。
实施例5
本实施例的3-(二氟氯甲基)-1-甲基-1H-吡唑-4-羧酸的制备方法，包括以下步骤：
3-二甲胺基亚甲基-1-氯-1,1-二氟-2,4-戊二酮的合成。
在三口圆底烧瓶中加入二甲胺基乙烯基甲基酮的二氯甲烷溶液560mL，溶液中的二甲胺基乙烯基甲基酮为113g(1.0mol)。在氮气保护下降温至-5℃。接着通入二氟氯乙酰氯气体164g(1.1mol)。通入气体的过程中，保持体系温度在0℃以下，通入气体完毕后保温搅拌2h。然后反应液在旋转蒸发仪上减压浓缩除去溶剂，残余物即为3-二甲胺基亚甲基-1,1,1-三氟-2,4-戊二酮的粗品，气相纯度大于95％，按照定量收率直接用于下一步反应。
3-二氟氯甲基-1-甲基-4-乙酰基吡唑的合成。
在三口圆底烧瓶中加入浓度为40％的甲基肼水溶液，溶液中的甲基肼为126g(1.1mol)。降温至-20℃，接着向烧瓶中滴加上述制备的3-二甲胺基亚甲基-1-氯-1,1-二氟-2,4-戊二酮的二氯甲烷溶液，温度控制在-25℃～-20℃进行滴加，滴加完毕后保温1h。采用气相色谱检测原料反应完全，升至室温，分去水层，浓 缩干有机层，重结晶烘干得到3-二氟氯甲基-1-甲基-4-乙酰基吡唑184g，收率88％。
3-(二氟氯甲基)-1-甲基-1H-吡唑-4-羧酸的合成。
在三口圆底烧瓶中加入浓度为10％的NaClO水溶液887.5g。冷却反应液至10℃。将105g的3-二氟氯甲基-1-甲基-4-乙酰基吡唑，溶解在100ml的甲醇中配制成有机溶液。接着向烧瓶中缓慢滴加该有机溶液。滴加过程中保持反应温度10℃～15℃。滴加完毕后，保温继续反应3h。采用TLC薄层色谱法检测原料反应完全。然后加入二氯甲烷萃取水层，有机层作为废液回收二氯甲烷。萃取的水层加入浓度为31％的盐酸调节PH值至1～2，再冷却至10℃左右，保温0.5h，抽滤，烘干得到3-(二氟氯甲基)-1-甲基-1H-吡唑-4-羧酸100g，收率95％。
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3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，其特征在于，包括以下步骤：
    步骤一、以式I所示的氟代乙酰卤衍生物与二甲胺基乙烯基甲基酮缩合反应，生成式II所示的3-二甲胺基亚甲基-1,1-二氟代-2,4-戊二酮衍生物，
    Figure PCTCN2015090970-appb-100001
    其中，R1是氢、氟或氯原子，R2是氟或氯原子；
    步骤二、以所述式II所示的3-二甲胺基亚甲基-1,1-二氟代-2,4-戊二酮衍生物与甲基肼关环反应，生成式III所示的3-氟代烷基-1-甲基-4-乙酰基吡唑衍生物，
    Figure PCTCN2015090970-appb-100002
    步骤三、以所述式III所示的3-氟代烷基-1-甲基-4-乙酰基吡唑衍生物在碱性条件下氧化，再酸化，生成式IV所示的3-氟代烷基-1-甲基吡唑-4-羧酸，
    Figure PCTCN2015090970-appb-100003
  2. 根据权利要求1所述的3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，其 特征在于：所述步骤一中，将所述式I所示的氟代乙酰卤衍生物气体直接通入二甲胺基乙烯基甲基酮的二氯甲烷溶液中，反应温度为-5℃～0℃。
  3. 根据权利要求1所述的3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，其特征在于：所述步骤二中，反应温度为-40℃～0℃，反应时间为1h～8h，所述甲基肼与所述式II所示的3-二甲胺基亚甲基-1,1-二氟代-2,4-戊二酮衍生物的摩尔比为1.1∶1～1.5∶1。
  4. 根据权利要求3所述的3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，其特征在于：所述步骤二中，反应温度为-25℃～20℃，反应时间为1h～2h。
  5. 根据权利要求1所述的3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，其特征在于：所述步骤三中，在碱性条件下氧化所采用的是次氯酸钠溶液或者次溴酸钠溶液，所述次氯酸钠溶液是通过将氯气通入氢氧化钠水溶液中制备的，所述次溴酸钠溶液是通过将液溴通入氢氧化钠水溶液中制备的。
  6. 根据权利要求1所述的3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，其特征在于：所述步骤三中，反应温度为0℃～50℃，反应时间为1h～5h。
  7. 根据权利要求6所述的3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，其特征在于：所述步骤三中，反应温度为10℃～20℃，反应时间为2h～3h。
  8. 根据权利要求6所述的3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，其特征在于：所述步骤三中，酸化所采用的是盐酸溶液，最终调节至PH值为1～2。
  9. 根据权利要求1所述的3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法，其特征在于：所述式I所示的氟代乙酰卤衍生物是二氟乙酰氟，所述式IV所示的3-氟代烷基-1-甲基吡唑-4-羧酸是3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸。
  10. 一种如权利要求1所述的制备方法制得的3-氟代烷基-1-甲基吡唑-4-羧酸。
PCT/CN2015/090970 2015-09-28 2015-09-28 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法 Ceased WO2017054112A1 (zh)

Priority Applications (11)

Application Number Priority Date Filing Date Title
PCT/CN2015/090970 WO2017054112A1 (zh) 2015-09-28 2015-09-28 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法
JP2018535265A JP2018531285A (ja) 2015-09-28 2016-09-28 ３−フルオロアルキル−１−メチルピラゾール−４−カルボン酸の合成方法
KR1020187010626A KR20180059471A (ko) 2015-09-28 2016-09-28 3-플루오로알킬-1-메틸피라졸-4-카르복실산의 제조 방법
PCT/IB2016/001462 WO2017064550A1 (zh) 2015-09-28 2016-09-28 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法
DE112016000140.1T DE112016000140B4 (de) 2015-09-28 2016-09-28 Verfahren zur Herstellung von 3-Fluoralkyl-1-methylpyrazol-4-carbonsäure
IT102016000097392A IT201600097392A1 (it) 2015-09-28 2016-09-28 Metodo per la preparazione di acido 3-fluoroalchil-1-metilpirazol-4-carbossilico
CH00617/17A CH711995B1 (de) 2015-09-28 2016-09-28 Verfahren zur Herstellung von 3-Fluoralkyl-1-methylpyrazol-4-Carbonsäure und eines Pestizids.
EP16794724.1A EP3357913A1 (en) 2015-09-28 2016-09-28 Preparation method for 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid
FR1659165A FR3041637B1 (fr) 2015-09-28 2016-09-28 Methode de preparation de l'acide 3-fluoroalkyl-1-methylpyrazol-4-carboxylique
US15/763,472 US10457645B2 (en) 2015-09-28 2016-09-28 Method for the preparation of 3-fluoroalkyl-1-methylpyrazol-4-carboxylic acid
CN201680056250.4A CN108368055B (zh) 2015-09-28 2016-09-28 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2015/090970 WO2017054112A1 (zh) 2015-09-28 2015-09-28 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法

Publications (1)

Publication Number Publication Date
WO2017054112A1 true WO2017054112A1 (zh) 2017-04-06

Family

ID=57286749

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/CN2015/090970 Ceased WO2017054112A1 (zh) 2015-09-28 2015-09-28 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法
PCT/IB2016/001462 Ceased WO2017064550A1 (zh) 2015-09-28 2016-09-28 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/001462 Ceased WO2017064550A1 (zh) 2015-09-28 2016-09-28 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法

Country Status (10)

Country Link
US (1) US10457645B2 (zh)
EP (1) EP3357913A1 (zh)
JP (1) JP2018531285A (zh)
KR (1) KR20180059471A (zh)
CN (1) CN108368055B (zh)
CH (1) CH711995B1 (zh)
DE (1) DE112016000140B4 (zh)
FR (1) FR3041637B1 (zh)
IT (1) IT201600097392A1 (zh)
WO (2) WO2017054112A1 (zh)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018202677A1 (en) 2017-05-02 2018-11-08 Solvay Sa Process for the manufacture of carboxylic acids or carboxylic acid derivatives
US10239841B2 (en) 2015-03-26 2019-03-26 AGC Inc. Method for producing pyrazole derivative
EP3495351A1 (en) 2017-12-08 2019-06-12 Solvay Sa Oxidation of a pyrazolyl ketone compound to the corresponding carboxylic acid
CN117603069A (zh) * 2023-11-10 2024-02-27 安徽泓泽新材料科技有限公司 一种2-二氟乙酰基-3-二甲胺基丙烯酸乙酯化合物及其制备方法和应用
CN117603070A (zh) * 2023-11-10 2024-02-27 安徽泓泽新材料科技有限公司 一种2-二氟乙酰基-3-二甲胺基丙烯酸乙酯化合物及其制备方法和应用
CN120682149A (zh) * 2025-07-04 2025-09-23 蓝启生科(浙江)新材料有限公司 一种1-甲基-3-二氟甲基-4-吡唑酸酯的合成方法

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020532524A (ja) 2017-09-04 2020-11-12 ソルヴェイ（ソシエテ アノニム） ジフルオロアセチルクロリドの製造方法及び製造中間体
CN113912541A (zh) * 2021-10-29 2022-01-11 南通宝凯药业有限公司 一种3-二氟甲基-1-甲基-1h-吡唑-4-羧酸的制备方法
CN114790173B (zh) * 2022-04-29 2023-08-01 浙江南郊化学有限公司 1-甲基-3-二氟甲基吡唑-4-甲酸绿色合成工艺
CN116947638B (zh) * 2023-07-24 2025-10-10 淄博飞源化工有限公司 一锅法制备西格列汀中间体的方法
CN117447401B (zh) * 2023-12-26 2024-04-19 山东国邦药业有限公司 一种二氟吡唑酸的合成方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101115723A (zh) * 2005-02-16 2008-01-30 巴斯福股份公司 吡唑甲酰苯胺、其制备方法以及用于防治有害真菌的包含它们的试剂
WO2009010871A2 (en) * 2007-07-13 2009-01-22 Addex Pharma S.A. Pyrazole derivatives as antagonists of adenosine a3 receptor
CN101687806A (zh) * 2007-06-27 2010-03-31 先正达参股股份有限公司 制备吡唑的方法
CN101874029A (zh) * 2007-07-13 2010-10-27 艾德克斯药品股份有限公司 作为代谢型谷氨酸受体调节剂的吡唑衍生物
CN105541716A (zh) * 2015-03-26 2016-05-04 旭硝子株式会社 吡唑衍生物的制造方法

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223526A (en) * 1991-12-06 1993-06-29 Monsanto Company Pyrazole carboxanilide fungicides and use
EA017900B1 (ru) * 2006-11-03 2013-04-30 Басф Се Способ получения дифторметилпиразолилкарбоксилатов
EP2042482A1 (de) 2007-09-26 2009-04-01 Bayer CropScience AG Verfahren zur Herstellung von 2-Dihalogenacyl-3-amino-acrylsäure-Derivaten
AR072447A1 (es) 2008-02-29 2010-09-01 Basf Se Proceso para preparar 2- alcoximetilen-4,4-difluoro-3-oxobutiratos de alquilo
BRPI0911898A2 (pt) * 2008-05-02 2015-10-13 Basf Se processo para preparar compostos, e, composto.
MX2010011790A (es) * 2008-05-14 2010-11-25 Syngenta Ltd Proceso para la preparacion de amidas.
GB201004299D0 (en) * 2010-03-15 2010-04-28 Syngenta Participations Ag Process
WO2012025469A1 (en) 2010-08-24 2012-03-01 Solvay Sa Improved process for the preparation of esters of 1-h-pyrazole-4-carboxylic acids
CN103360313A (zh) * 2013-07-12 2013-10-23 雅本化学股份有限公司 3-氟代烷基-1-取代吡唑-4-羧酸及其制备方法
CN106554310A (zh) * 2015-09-25 2017-04-05 陈旭 一种3-二氟甲基-1-甲基吡唑-4-甲酸的合成方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101115723A (zh) * 2005-02-16 2008-01-30 巴斯福股份公司 吡唑甲酰苯胺、其制备方法以及用于防治有害真菌的包含它们的试剂
CN101687806A (zh) * 2007-06-27 2010-03-31 先正达参股股份有限公司 制备吡唑的方法
CN101796021A (zh) * 2007-06-27 2010-08-04 先正达参股股份有限公司 制备吡唑的方法
WO2009010871A2 (en) * 2007-07-13 2009-01-22 Addex Pharma S.A. Pyrazole derivatives as antagonists of adenosine a3 receptor
CN101874029A (zh) * 2007-07-13 2010-10-27 艾德克斯药品股份有限公司 作为代谢型谷氨酸受体调节剂的吡唑衍生物
CN105541716A (zh) * 2015-03-26 2016-05-04 旭硝子株式会社 吡唑衍生物的制造方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN, QIAN ET AL.: "Synthesis of 1-Methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonyl Chloride", PESTICIDES, vol. 51, no. 8, 31 August 2012 (2012-08-31), pages 569 - 572 *
LI, LIFENG ET AL.: "Synthesis of 3-difluoromethyl-1-methyl-1H-pyrazol-4-carboxylic acid", FINE CHEMICAL INTERMEDIATES, vol. 43, no. 6, 31 December 2013 (2013-12-31), pages 17 - 19 and 47 *
SINGH, S.P. ET AL.: "A Facile Synthesis of 5-Methyl-1-(phenyl/heterocyctr-4-trifluoroacetylpyrazoles", J. CHEM. RESEARCH (S, 1 January 1997 (1997-01-01), pages 142 and 143 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10239841B2 (en) 2015-03-26 2019-03-26 AGC Inc. Method for producing pyrazole derivative
WO2018202677A1 (en) 2017-05-02 2018-11-08 Solvay Sa Process for the manufacture of carboxylic acids or carboxylic acid derivatives
EP3495351A1 (en) 2017-12-08 2019-06-12 Solvay Sa Oxidation of a pyrazolyl ketone compound to the corresponding carboxylic acid
WO2019110795A1 (en) 2017-12-08 2019-06-13 Solvay Sa Oxidation of a pyrazolyl ketone compound to the corresponding carboxylic acid
CN117603069A (zh) * 2023-11-10 2024-02-27 安徽泓泽新材料科技有限公司 一种2-二氟乙酰基-3-二甲胺基丙烯酸乙酯化合物及其制备方法和应用
CN117603070A (zh) * 2023-11-10 2024-02-27 安徽泓泽新材料科技有限公司 一种2-二氟乙酰基-3-二甲胺基丙烯酸乙酯化合物及其制备方法和应用
CN120682149A (zh) * 2025-07-04 2025-09-23 蓝启生科(浙江)新材料有限公司 一种1-甲基-3-二氟甲基-4-吡唑酸酯的合成方法

Also Published As

Publication number Publication date
EP3357913A1 (en) 2018-08-08
CN108368055A (zh) 2018-08-03
WO2017064550A1 (zh) 2017-04-20
CN108368055B (zh) 2021-04-16
FR3041637B1 (fr) 2019-04-05
US20180273486A1 (en) 2018-09-27
US10457645B2 (en) 2019-10-29
IT201600097392A1 (it) 2018-03-28
FR3041637A1 (fr) 2017-03-31
DE112016000140T5 (de) 2017-07-27
CH711995B1 (de) 2018-01-15
DE112016000140B4 (de) 2021-01-21
KR20180059471A (ko) 2018-06-04
JP2018531285A (ja) 2018-10-25

Similar Documents

Publication Publication Date Title
CN108368055B (zh) 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法
CN107663172B (zh) 一种吡唑衍生物的制备方法
JP2018531285A6 (ja) ３−フルオロアルキル−１−メチルピラゾール−４−カルボン酸の合成方法
US11472775B2 (en) Halogen-substituted compound, preparation method therefor, and use thereof
CN104016920A (zh) 一种含氟甲基吡唑类化合物的联产方法
AU2025279661A1 (en) Preparation of substituted pyrazoles and their use as anthranilamides precursors
CN107365262B (zh) 一种5,5-二甲基-2-氰基环戊酮的制备方法
CN106365966A (zh) 一种苄基芳基醚的制备方法
CN113912541A (zh) 一种3-二氟甲基-1-甲基-1h-吡唑-4-羧酸的制备方法
CN102428072B (zh) 1-甲基吡唑-4-羧酸酯类的纯化方法
CN110577477A (zh) 一种卤素取代中间体化合物及其制备方法和应用
WO2019178947A1 (zh) 一种嘧菌酯及其中间体的制备方法
CN106554311A (zh) 3-氟代烷基-1-甲基吡唑-4-羧酸的制备方法
CN111072566B (zh) 一种吡唑衍生物的制备方法和应用
EP2894150B1 (en) Method for producing 1-substituted-3-fluoroalkylpyrazole-4-carboxylic acid ester
CN119798177B (zh) 一种甲磺草胺中间体的制备方法
CN115894518B (zh) 一种唑啉草酯代谢物m3的合成方法
CN120682149A (zh) 一种1-甲基-3-二氟甲基-4-吡唑酸酯的合成方法
CN109320418B (zh) 1,3,5-苯三甲酸三甲酯的合成方法及其应用
KR101789771B1 (ko) 피라졸 카르보알데히드 화합물의 제조방법
CN119504588A (zh) 一种含氟吡唑衍生物的制备方法
CN117658919A (zh) 碱性离子液体促进高效合成3-二氟甲基-1-甲基-1h-吡唑-4-羧酸的方法
CN119192082A (zh) 一种吡唑类除草剂中间体及其制备方法
CN117903114A (zh) 一种1-(2-(5-甲基-3-(三氟甲基)-1h-吡唑-1-基)乙酰基)哌啶-4-甲腈的合成方法
JPH01168674A (ja) １．３−ジアルキルピラゾール−４−カルボン酸誘導体の製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15905024

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15905024

Country of ref document: EP

Kind code of ref document: A1