WO2022099439A1 - Preparation method for 2,4,5-trifluorophenylacetic acid - Google Patents

Preparation method for 2,4,5-trifluorophenylacetic acid Download PDF

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WO2022099439A1
WO2022099439A1 PCT/CN2020/127713 CN2020127713W WO2022099439A1 WO 2022099439 A1 WO2022099439 A1 WO 2022099439A1 CN 2020127713 W CN2020127713 W CN 2020127713W WO 2022099439 A1 WO2022099439 A1 WO 2022099439A1
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reaction
acid
nitrotoluene
preparation
difluoro
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PCT/CN2020/127713
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French (fr)
Chinese (zh)
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张凌霄
蔡刚华
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杭州臻挚生物科技有限公司
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Publication of WO2022099439A1 publication Critical patent/WO2022099439A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/02—Monocyclic aromatic halogenated hydrocarbons
    • C07C25/13—Monocyclic aromatic halogenated hydrocarbons containing fluorine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings

Definitions

  • the present application relates to the technical field of preparation of pharmaceutical intermediates, and more particularly, to a preparation method of 2,4,5-trifluorophenylacetic acid.
  • 2,4,5-Trifluorophenylacetic acid is a key intermediate in the novel antidiabetic drug dipeptidyl peptidase-4 (DPP-4) inhibitor Sitagliptin phosphate.
  • DPP-4 novel antidiabetic drug dipeptidyl peptidase-4
  • Sitagliptin phosphate At present, a lot of preparation processes of 2,4,5-trifluorophenylethyl have been disclosed.
  • 2,5-difluoro-4-nitrophenylmalonic acid is obtained by condensation of 2,4,5-trifluoronitrobenzene and diethyl malonate as raw materials first. Diethyl ester is then subjected to hydrolysis, acidification, decarboxylation, nitro reduction, and finally to diazotization and fluorination of amino groups.
  • the price of the initial raw material 2,4,5-trifluoronitrobenzene used is relatively high, which may easily lead to a relatively high preparation cost of 2,4,5-trifluorophenylacetic acid.
  • 1,2,4-trifluorobenzene is usually reacted with paraformaldehyde and chlorinating agent as raw materials to obtain 2,4,5-trifluorobenzyl chloride, which is then mixed with a solvent and a phase transfer catalyst.
  • the cyanation reaction is carried out under the following conditions to obtain 2,4,5-trifluorobenzyl cyanide, which is then hydrolyzed under acidic or basic conditions to obtain 2,4,5-trifluorophenylacetic acid.
  • the yields of 2,4,5-trifluorobenzyl chloride and 2,4,5-trifluorobenzyl cyanide obtained in the first two steps are all relatively low, not higher than 66%.
  • the cost of the initial raw materials used is too high; on the other hand, the yield of the corresponding product obtained in each preparation step is relatively low, resulting in obtaining an equivalent amount of 2,4,5-tris Fluorophenylacetic acid needs to consume more raw materials, that is, the preparation cost of 2,4,5-trifluorophenylacetic acid is increased, which in turn affects its industrialized large-scale production and promotion and application in the market.
  • the present application provides a kind of 2,4,5-trifluorophenylacetic acid. Preparation.
  • a preparation method of 2,4,5-trifluorophenylacetic acid provided by the present application adopts the following technical scheme: a preparation method of 2,4,5-trifluorophenylacetic acid, comprising the following steps:
  • Step 1 with raw material, quaternary ammonium salt catalyst, sulfolane, potassium fluoride, under the condition that reaction temperature is 150-230 °C, form sufficient reaction, obtain the first intermediate;
  • step 2 the first intermediate obtained in step 1 is subjected to hydrogenation catalytic reaction to obtain the second intermediate;
  • step 3 the second intermediate obtained in step 2 and the fluorinating reagent are subjected to a salt-forming reaction at a temperature of 25 ⁇ 5 °C, quenched, and then diazotized with an aqueous sodium nitrite solution to obtain diazonium. Salt;
  • step 4 the diazonium salt in step 3 is subjected to high temperature cracking reaction to obtain 2,4,5-trifluorotoluene;
  • step 5 the 2,4,5-trifluorotoluene obtained in step 4 is subjected to halogenation reaction to obtain 2,4,5-trifluorobenzyl chloride;
  • step 6 the 2,4,5-trifluorobenzyl chloride obtained in step 5 is subjected to a cyanation reaction to obtain 2,4,5-trifluorobenzeneacetonitrile;
  • step seven the 2,4,5-trifluorophenylacetonitrile obtained in step six is subjected to a hydrolysis reaction to obtain 2,4,5-trifluorophenylacetic acid;
  • the raw material in step 1 is any one of 3,4-dichloro-6-nitrotoluene, 2,4-dichloro-5-nitrotoluene and 2,5-dichloro-4-nitrotoluene;
  • the first intermediate in step 1 is one of 4,5-difluoro-2-nitrotoluene, 2,4-difluoro-5-nitrotoluene and 2,5-difluoro-4-nitrotoluene. kind;
  • the second intermediate is one of 4,5-difluoro-2-methylaniline, 2,4-difluoro-5-methylaniline and 2,5-difluoro-4-methylaniline. kind;
  • the fluorination reagent includes any one of fluoroboric acid aqueous solution and hydrogen fluoride pyridine solution.
  • 3,4-dichloro-6-nitrotoluene, 2,4-dichloro-5-nitrotoluene, 2,5-dichloro-4-nitrotoluene are used in Any one of the three raw materials is used as a raw material, and the price of the three raw materials is low and easy to obtain, which reduces the cost of the raw materials to a certain extent, and is convenient for industrialized large-scale production.
  • the raw materials are sequentially prepared to obtain the corresponding first intermediate, which is not easy to generate other impurities, which is conducive to the full reaction and improves the purity and yield of the first intermediate.
  • step 2 a hydrogenation catalytic reaction is carried out to form a corresponding second intermediate corresponding to the first intermediate, which is not easy to generate other impurities, and is beneficial to improve the yield and purity of the second intermediate.
  • Fluoroboric acid diazonium salt can be obtained by reacting with fluoroboric acid aqueous solution.
  • 2,4,5-trifluorotoluene, boron trifluoride gas and nitrogen gas can be obtained.
  • Organic solvents such as diethyl ether can be used
  • tetrahydrofuran 1,4-dioxane
  • methanol 1,4-dioxane
  • methanol 1,4-dioxane
  • acetic acid etc.
  • the boron trifluoride organic solution can also be used as a cationic polymerization catalyst for commonly used drug synthesis, providing additional income for the recycling of by-products for enterprises, and further reducing the cost of producing 2,4,5-trifluorophenylacetic acid.
  • step 3 usually add ice brine with a mass concentration of 20-30% for quenching, until the temperature of the reaction system at this time is kept below 0 ° C, in order to control the reaction, safety accidents are not easy to occur, and it can also make the salt-forming reaction relatively. proceed fully. If the quenching treatment is not carried out, it is easy to cause the phenomenon of incomplete salt formation, which is not conducive to the subsequent treatment.
  • Step 4 is carried out under solvent-free conditions, and the high-temperature cracking reaction treatment reduces the use of solvents, which is beneficial to reduce the possibility of generating wastes in the cracking reaction. And through the treatment in step 4, 2,4,5-trifluorotoluene is finally obtained, and through the reaction in steps 5 to 7, 2,4,5-trifluorophenylacetic acid is finally formed.
  • step 1 the weight ratio to sulfolane is 1:(2 ⁇ 5);
  • the raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene;
  • the first intermediate is 4,5-difluoro-2-nitrotoluene or 2,5-difluoro-4-nitrotoluene.
  • step 1 when the raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene, the temperature is 120-180°C and 220°C successively.
  • the reaction is carried out under the temperature condition of -230°C, which is favorable for the meta-position in the first intermediate to be fully fluorinated. If the latter reaction temperature is too low, other impurities are likely to be produced; if the latter reaction temperature is too high, the energy consumption is too large and the preparation cost is increased.
  • step 1 the weight ratio of raw material to sulfolane is 1:(2 ⁇ 5), the molar ratio of potassium fluoride to raw material is (2.1 ⁇ 3.5):1, the reaction temperature is 180°C, and the heat preservation reaction is performed for 10h, obtain the first intermediate;
  • the raw material is 2,4-dichloro-5-nitrotoluene
  • the first intermediate is 2,4-difluoro-5-nitrotoluene.
  • the yield of the obtained first intermediate (2,4-difluoro-5-nitrotoluene) is relatively high by adopting the above technical scheme.
  • step 1 the weight ratio of raw material to sulfolane is 1:(2 ⁇ 5);
  • the raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene;
  • the first intermediate is 4,5-difluoro-2-nitrotoluene or 2,5-difluoro-4-nitrotoluene.
  • step 1 when the raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene, the above operation method is adopted, and the temperature is 120-180°C and 220- The reaction at 230°C is favorable for the meta-position in the first intermediate to be fully fluorinated, and the yield of the first intermediate is improved.
  • step 2 the temperature of the hydrogenation catalytic reaction is 50-75 °C, the pressure of hydrogen is 0.1-1.0 MPa, and the time of the hydrogenation catalytic reaction is 2-5h;
  • the catalyst used in the hydrogenation catalytic reaction is Raney Nickel catalyst or palladium carbon catalyst.
  • Raney nickel catalyst or palladium carbon catalyst can be used but not limited to.
  • step 3 the molar ratio of the second intermediate, the fluorinating reagent and the sodium nitrite is 1:(2.5 ⁇ 4):(1.05 ⁇ 1.1); the second intermediate and the fluorinating reagent undergo a salt-forming reaction After being quenched to -40 ⁇ 0°C, the diazotization reaction is carried out; the mass concentration of the fluorination reagent is 25-40%.
  • the fluorinating reagent concentration is 25-40% and the excess is used, so that the reversible salt-forming reaction can be fully carried out.
  • the diazotization reaction is a rapid exothermic process, that is, when the sodium nitrite aqueous solution is added dropwise, the system heats up, and after the salt-forming reaction, it is quenched to -40 ⁇ 0 ° C, and the drop rate of the sodium nitrite aqueous solution is controlled, which is beneficial to control the reaction. Vigorous intensity for increased safety.
  • step 4 the temperature of the high-temperature cracking reaction is 90-300° C., and the time is 2-4 h.
  • step 5 during the halogenation reaction, 2,4,5-trifluorotoluene and the catalyst are reacted in a weight ratio of 1:(0.005-0.02), the temperature is raised to 110-130 ° C, and the drying is continued. After 3-5 hours of chlorine gas, the chlorine gas is stopped, cooled, washed with water until neutral, dried, and distilled under reduced pressure to obtain 2,4,5-trifluorobenzyl chloride; the catalyst is azobisisobutyronitrile.
  • the halogenation reaction of 2,4,5-trifluorotoluene can be fully carried out, and the yield of 2,4,5-trifluorobenzyl chloride can be improved.
  • the halogenating agent can be any one of chlorine, phosphorus pentachloride, sulfonyl chloride, trichloroisocyanate, hydantoin, bromine, NBS, hydrogen bromide, and hydantoin.
  • step 6 during the cyanation reaction, the molar ratio of 2,4,5-trifluorobenzyl chloride: sodium cyanide in the aqueous sodium cyanide solution is 1:(1-1.1), the phase transfer catalyst, 2 ,
  • the weight ratio of 4,5-trifluorobenzyl chloride and dimethyl sulfoxide is (0.01-0.02): 1: (1-3) for mixing, and the temperature is 60-80 °C under the condition of keeping the cyanidation reaction 2 -5h, then extracted with ethanol, dried, distilled and then rectified to obtain 2,4,5-trifluorophenylacetonitrile
  • the phase transfer catalyst is azobisisobutyronitrile.
  • step 7 during the hydrolysis reaction, the acid is heated to a stable range of 100-110 °C, and 2,4,5-trifluorophenylacetonitrile is added dropwise, the temperature is kept at 120 °C for 6 hours, and then cooled to room temperature, 100 mL of water was added dropwise, cooled and suction filtered, the solid was recrystallized with methanol, purified and dried to obtain 2,4,5-trifluorophenylacetic acid;
  • the acid includes at least one of sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, and acetic acid.
  • the acid is formed by mixing sulfuric acid and acetic acid, the weight ratio of 2,4,5-trifluorophenylacetonitrile, sulfuric acid and acetic acid is 1:(1.5-3):0.1, and the mass concentration of sulfuric acid is 70%.
  • step 1 to step 4 can be used to obtain 2,4,5-trifluorotoluene, and then halogenation, cyanation, and hydrolysis are carried out in turn, and 2,4,5-trifluorophenylacetic acid is finally obtained.
  • the yields of the corresponding products obtained after each step are all high, and the by-products produced in the preparation process are less, which is beneficial to improve the purity and yield of the final product 2,4,5-trifluorophenylacetic acid formed, and the use of etc.
  • a higher yield of the final product, 2,4,5-trifluorophenylacetic acid can be obtained with a higher amount of starting material.
  • the cost of the initial raw materials involved in the reaction process is relatively low, and the preparation cost in the present application is reduced from the source, which is conducive to industrialized large-scale production.
  • the 2,4,5-trifluorotoluene prepared in this application has a purity higher than 98%, stable quality, and meets the requirements for the use of pharmaceutical intermediates. It can be directly subjected to subsequent halogenation reactions without further purification operations. , cyanation reaction, hydrolysis reaction, easy to operate.
  • the preparation method in the present application has low operational difficulty, which is beneficial to the industrialized large-scale production of 2,4,5-trifluorophenylacetic acid.
  • Embodiment 1 a preparation method of 2,4,5-trifluorophenylacetic acid, comprising the steps:
  • Step 1 the preparation of the first intermediate 4,5-difluoro-2-nitrotoluene:
  • Step 2 the preparation of the second intermediate 4,5-difluoro-2-methylaniline, the reaction formula is as follows:
  • Step 3 the preparation of 4,5-difluoro-2-methylaniline fluoroborate diazonium salt, the reaction formula is as follows:
  • the filter cake is washed with 20 ml of frozen 40% fluoroboric acid aqueous solution, and then washed with 20 ml of alcohol aqueous solution with a freezing point temperature of -15 °C and a mass concentration of 30%. The operation was repeated twice, and the filter cake was subjected to vacuum distillation to remove the solvent to obtain 4,5-difluoro-2-methylaniline fluoroborate diazonium salt.
  • the 4,5-difluoro-2-methylaniline fluoroborate diazonium salt in step 3 is subjected to a high temperature cracking reaction, that is, the temperature is slowly raised to 100 ° C, and kept for 1 h, and then slowly raised to 180 ° C and kept for 1 h to obtain 2,4,5-Trifluorotoluene.
  • the reflux condenser is connected to an HCl absorption system, and a light source is installed near the flask.
  • Embodiment 2 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 1, 2,5-dichloro-4-nitrotoluene is used as a raw material for the reaction , the reaction operation is the same as that in Example 1, and the first intermediate finally obtained is 2,5-difluoro-4-nitrotoluene which is a light red oily substance.
  • the reaction formula is as follows:
  • Embodiment 3 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 1, 2,4-dichloro-5-nitrotoluene is used as a raw material for the reaction , potassium fluoride is 62.0g, tetrabutylammonium bromide catalyst is 1g, tracked by GC, the content of raw materials is ⁇ 0.2% after 10h of reaction, cooled to 75 ⁇ 80°C, filtered, and the filtrate is rectified to separate sulfolane and light yellow oily substance the first intermediate.
  • the reaction formula is as follows:
  • Embodiment 4 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in the process of preparing the second intermediate in step 2, the first intermediate obtained in embodiment 3 is used 2,4-difluoro-5-nitrotoluene was reacted, and the reaction operation was the same as that of step 2 in Example 1, and finally the second intermediate 2,4-difluoro-5 with pale yellow oily texture was obtained -methylaniline, and the mass of the second intermediate is 81.2 g, the GC purity is 99.6%, and the yield is 98.2%.
  • the reaction formula is as follows:
  • Embodiment 5 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in the process of preparing the second intermediate in step 2, the first intermediate obtained in embodiment 2 is used 2,5-difluoro-4-nitrotoluene was reacted, and the reaction operation was the same as that of step 2 in Example 1, and finally the second intermediate 2,5-difluoro-4 with pale yellow oily texture was obtained -methylaniline, and the mass of the second intermediate 2,5-difluoro-4-methylaniline was 79.2 g, the GC purity was 99.5%, and the yield was 95.8%.
  • the reaction formula is as follows:
  • Example 6 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 4 is that in the process of preparing the third intermediate in step 3, the second intermediate prepared in Example 4 is used. 2,4-difluoro-5-methylaniline is reacted, and the reaction operation is the same as that in step 3 in Example 1, and finally the third intermediate 2,4-difluoro-5-methyl is obtained Aniline fluoroborate diazonium salt, and the mass is 63.2g.
  • the reaction formula is as follows:
  • Example 7 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 5 is that in the process of preparing the third intermediate in step 3, the second intermediate prepared in Example 5 is used. 2,5-difluoro-4-methylaniline is reacted, and the reaction operation is the same as that in step 3 in Example 1, and finally the third intermediate 2,5-difluoro-4-methyl is obtained Aniline fluoroborate diazonium salt, and the mass is 64.3g.
  • the reaction formula is as follows:
  • Embodiment 8 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that during the high temperature cracking in step 4, the temperature is slowly raised to 100 ° C, and kept for 1 h to obtain 2,4, 5-Trifluorotoluene.
  • Embodiment 9 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Embodiment 1 is that during the high temperature cracking in step 4, the temperature is slowly raised to 100 ° C, and kept for 2 h to obtain 2,4, 5-Trifluorotoluene.
  • Example 10 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 1 is that during the high-temperature cracking in step 4, the temperature is slowly raised to 100° C., kept for 1 hour, and then slowly raised to 150° C. °C, and kept for 1 h to obtain 2,4,5-trifluorotoluene.
  • Example 11 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 9 is that during the high-temperature cracking in step 4, the temperature is slowly raised to 100° C., and kept for 4 hours to obtain 2,4, 5-Trifluorotoluene.
  • Example 12 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 9 is that during the high-temperature cracking in step 4, the temperature is slowly raised to 90° C., kept for 1 hour, and then slowly raised to 300° C. °C, and kept for 1 h to obtain 2,4,5-trifluorotoluene.
  • Embodiment 13 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 3, the molar ratio of the second intermediate, fluoroboric acid, and sodium nitrite is 1:2.5 : 15, and finally 2,4,5-trifluorotoluene was obtained.
  • Embodiment 14 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 3, the molar ratio of the second intermediate, fluoroboric acid, and sodium nitrite is 1:4 : 1.1, and finally obtain 2,4,5-trifluorotoluene.
  • Embodiment 15 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 3, the molar ratio of the second intermediate, fluoroboric acid, and sodium nitrite is 1:2.8 : 15, and finally 2,4,5-trifluorotoluene was obtained.
  • Embodiment 16 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Embodiment 1 is that the fluorination reagent in step 3 is a hydrogen fluoride pyridine solution.
  • Embodiment 17 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Embodiment 1 is that in step five,
  • Embodiment 18 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step six, 2,4,5-trifluorobenzyl chloride: cyanide in sodium cyanide aqueous solution
  • the molar ratio of sodium chloride is 1:1, and the weight ratio of tetrabutylammonium bromide, 2,4,5-trifluorobenzyl chloride and dimethyl sulfoxide is 0.01:1:3.
  • Embodiment 19 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 1 is that in step seven, the weight ratio of 2,4,5-trifluorophenylacetonitrile, sulfuric acid, and acetic acid is: 1:3:0.1 to obtain 2,4,5-trifluorophenylacetic acid.
  • Comparative Example 1 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 1 is that it is a Chinese application with an authorization announcement number of CN100347142C and an authorization announcement date of November 7, 2007. Preparation:
  • Test sample the corresponding product obtained in each step in Example 1; the corresponding product obtained in each step in Comparative Example 1.
  • Test method The corresponding products obtained in each step in Example 1 are collected and the yield is calculated, recorded and analyzed; the corresponding products obtained in each step in Example 1 are collected and the yield is calculated. Calculate, record and analyze.
  • Test results the specific conditions of the corresponding products obtained in each step in Example 1 are shown in Table 1; the specific conditions of the corresponding products obtained in each step in Comparative Example 1 are shown in Table 2.
  • Step 2 4,5-Difluoro-2-methylaniline 96.8 99.4
  • Step 3 4,5-Difluoro-2-methylaniline fluoroborate diazonium salt 76.2 / Step 4
  • 2,4,5-Trifluorotoluene 73 99.3
  • Step 6 2,4,5-Trifluorophenylacetonitrile 88.10 99.20 Step seven 2,4,5-Trifluorophenylacetic acid 99.00 99.50
  • the yield and purity of the corresponding products obtained in each step are relatively high, especially the yields in steps 1 and 2, and the yield and purity of the final product obtained are also relatively high.
  • Test object select the preparation method in Examples 2-19.
  • Test method Calculate the yield of the 2,4,5-trifluorophenylacetic acid prepared in Examples 2-19, record and analyze.
  • Table 3 adopts the yields of corresponding products obtained in different steps in the preparation methods in Examples 2-19
  • Example 3 As can be seen from Table 1 and Table 3, compared with Example 1-3, the yield of the obtained first intermediate is different, the main reason is that the raw materials used in Example 2-3 are different, resulting in the obtained first intermediate. different and their yields are also different. But relatively speaking, it is easier to prepare the first intermediate 2,4-difluoro-5-nitrotoluene by using 2,4-dichloro-5-nitrotoluene as a raw material.
  • Example 4-5 and Example 1 Compared with Example 4-5 and Example 1, the yields of the obtained second intermediates are different, the main reason is that the first intermediates obtained in Examples 3 and 4 are respectively used in Examples 4-5 as product, resulting in different obtained second intermediates and different yields.
  • the 2,5-difluoro-4-nitrotoluene prepared by the method in Example 2 as the first intermediate it is easier to obtain a higher yield of the second intermediate 2,5-dinitrotoluene Fluoro-4-methylaniline.
  • Example 6-7 Compared with Example 6-7 and Example 1, the yield of the obtained third intermediate is different, the main reason is that in Example 6-7, the second intermediate obtained in Examples 4 and 5 was used as product, resulting in different obtained third intermediates and different yields.
  • Example 6-7 the second intermediate obtained in Examples 4 and 5 was used as product, resulting in different obtained third intermediates and different yields.
  • using 4,5-difluoro-2-methylaniline as the second intermediate for thermal cracking is beneficial to improve the yield of the third intermediate obtained, which is also related to the purity of the second intermediate. close connection.
  • Embodiments 17-19 are relative to embodiment 1, although steps five to seven are different respectively, but the product yield obtained in the corresponding steps is not much different from that in embodiment 1, indicating that the operations in steps five to seven are not easy to correspond to the steps. impact on the product yield.

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Abstract

A preparation method for 2,4,5-trifluorophenylacetic acid, comprising: step one, reacting raw materials, a quaternary ammonium salt catalyst, sulfolane and potassium fluoride to obtain a first intermediate; step two, subjecting the first intermediate to a hydrogenation catalytic reaction to obtain a second intermediate; step three, reacting the second intermediate with a fluorinating reagent to form a salt, quenching, and then performing a diazotization reaction with an aqueous solution of sodium nitrite to obtain a diazonium salt; step four, cracking the diazonium salt at a high temperature to obtain 2,4,5-trifluorotoluene; and steps five to seven, successively subjecting the 2,4,5-trifluorotoluene to halogenation, cyanation and hydrolysis reactions so as to obtain 2,4,5-trifluorophenylacetic acid. The raw materials of the method are easy to obtain and costs are relatively low; in addition, the yield of each step is relatively high, which is beneficial to the large-scale production of 2,4,5-trifluorophenylacetic acid.

Description

一种2,4,5-三氟苯乙酸的制备方法A kind of preparation method of 2,4,5-trifluorophenylacetic acid 技术领域technical field
本申请涉及药物中间体制备技术领域，更具体地说，它涉及一种2,4,5-三氟苯乙酸的制备方法。The present application relates to the technical field of preparation of pharmaceutical intermediates, and more particularly, to a preparation method of 2,4,5-trifluorophenylacetic acid.
背景技术Background technique
2,4,5-三氟苯乙酸是新型降糖药二肽基肽酶-4(DPP-4)抑制剂磷酸西他列汀(Sitagliptin phosphate)中的关键中间体。目前，已有较多关于2,4,5-三氟苯乙的制备工艺被公开。2,4,5-Trifluorophenylacetic acid is a key intermediate in the novel antidiabetic drug dipeptidyl peptidase-4 (DPP-4) inhibitor Sitagliptin phosphate. At present, a lot of preparation processes of 2,4,5-trifluorophenylethyl have been disclosed.
然而，在一些相关技术中，先以2,4,5-三氟硝基苯与丙二酸二乙酯为原料，缩合制备获得2,5-二氟-4-硝基苯基丙二酸二乙酯，再进行水解、酸化、脱羧、硝基还原反应，最后进行氨基的重氮化氟化反应。However, in some related technologies, 2,5-difluoro-4-nitrophenylmalonic acid is obtained by condensation of 2,4,5-trifluoronitrobenzene and diethyl malonate as raw materials first. Diethyl ester is then subjected to hydrolysis, acidification, decarboxylation, nitro reduction, and finally to diazotization and fluorination of amino groups.
然而，上述相关技术中，采用的初始原料2,4,5-三氟硝基苯价格较高，易导致2,4,5-三氟苯乙酸的制备成本偏高。However, in the above-mentioned related art, the price of the initial raw material 2,4,5-trifluoronitrobenzene used is relatively high, which may easily lead to a relatively high preparation cost of 2,4,5-trifluorophenylacetic acid.
在另一些相关技术中，通常以1,2,4-三氟苯和多聚甲醛及氯化剂作为原料进行反应，得到2,4,5-三氟苄氯，再在溶剂和相转移催化剂下进行氰化反应，得到2,4,5-三氟苄氰，再在酸性或碱性下水解得2,4,5-三氟苯乙酸。In other related technologies, 1,2,4-trifluorobenzene is usually reacted with paraformaldehyde and chlorinating agent as raw materials to obtain 2,4,5-trifluorobenzyl chloride, which is then mixed with a solvent and a phase transfer catalyst. The cyanation reaction is carried out under the following conditions to obtain 2,4,5-trifluorobenzyl cyanide, which is then hydrolyzed under acidic or basic conditions to obtain 2,4,5-trifluorophenylacetic acid.
上述相关技术中，前两个步骤得到的2,4,5-三氟苄氯、2,4,5-三氟苄氰的收率均较低，均不高于66％。In the above-mentioned related art, the yields of 2,4,5-trifluorobenzyl chloride and 2,4,5-trifluorobenzyl cyanide obtained in the first two steps are all relatively low, not higher than 66%.
因此，相关技术中，一方面，采用的初始原料的成本过高；另一方面，每个制备步骤中所获得的对应产物的收率较低，导致获得等量的2,4,5-三氟苯乙酸需要耗费更多原料，即提高了2,4,5-三氟苯乙酸的制备成本，进而影响其工业化大规模生产及在市场上的推广应用。Therefore, in the related art, on the one hand, the cost of the initial raw materials used is too high; on the other hand, the yield of the corresponding product obtained in each preparation step is relatively low, resulting in obtaining an equivalent amount of 2,4,5-tris Fluorophenylacetic acid needs to consume more raw materials, that is, the preparation cost of 2,4,5-trifluorophenylacetic acid is increased, which in turn affects its industrialized large-scale production and promotion and application in the market.
申请内容Application content
为了降低2,4,5-三氟苯乙酸在制备过程中的成本并提高2,4,5-三氟苯乙酸的收率，本申请提供一种2,4,5-三氟苯乙酸的制备方法。In order to reduce the cost of 2,4,5-trifluorophenylacetic acid in the preparation process and improve the yield of 2,4,5-trifluorophenylacetic acid, the present application provides a kind of 2,4,5-trifluorophenylacetic acid. Preparation.
本申请提供的一种2,4,5-三氟苯乙酸的制备方法，采用如下的技术方案：一种2,4,5-三氟苯乙酸的制备方法，包括如下步骤：A preparation method of 2,4,5-trifluorophenylacetic acid provided by the present application adopts the following technical scheme: a preparation method of 2,4,5-trifluorophenylacetic acid, comprising the following steps:
步骤一，将原料、季铵盐催化剂、环丁砜、氟化钾，在反应温度为150-230℃的 条件下，形成充分反应，获得第一中间体；Step 1, with raw material, quaternary ammonium salt catalyst, sulfolane, potassium fluoride, under the condition that reaction temperature is 150-230 ℃, form sufficient reaction, obtain the first intermediate;
步骤二，将步骤一中获得的第一中间体通过加氢催化反应获得第二中间体；In step 2, the first intermediate obtained in step 1 is subjected to hydrogenation catalytic reaction to obtain the second intermediate;
步骤三，将步骤二中获得的第二中间体与氟化试剂，在25±5℃的温度下，发生成盐反应，骤冷，再与亚硝酸钠水溶液形成重氮化反应，获得重氮盐；In step 3, the second intermediate obtained in step 2 and the fluorinating reagent are subjected to a salt-forming reaction at a temperature of 25±5 °C, quenched, and then diazotized with an aqueous sodium nitrite solution to obtain diazonium. Salt;
步骤四，将步骤三中的重氮盐经高温裂解反应，获得2,4,5-三氟甲苯；In step 4, the diazonium salt in step 3 is subjected to high temperature cracking reaction to obtain 2,4,5-trifluorotoluene;
步骤五，将步骤四中获得的2,4,5-三氟甲苯经过卤代反应，获得2,4,5-三氟苄氯；In step 5, the 2,4,5-trifluorotoluene obtained in step 4 is subjected to halogenation reaction to obtain 2,4,5-trifluorobenzyl chloride;
步骤六，将步骤五中获得的2,4,5-三氟苄氯经过氰化反应，获得2,4,5-三氟苯乙腈；In step 6, the 2,4,5-trifluorobenzyl chloride obtained in step 5 is subjected to a cyanation reaction to obtain 2,4,5-trifluorobenzeneacetonitrile;
步骤七，将步骤六中获得的2,4,5-三氟苯乙腈经过水解反应，获得2,4,5-三氟苯乙酸；In step seven, the 2,4,5-trifluorophenylacetonitrile obtained in step six is subjected to a hydrolysis reaction to obtain 2,4,5-trifluorophenylacetic acid;
步骤一中的原料为3,4-二氯-6-硝基甲苯、2,4-二氯-5-硝基甲苯、2,5-二氯-4-硝基甲苯中的任意一种；The raw material in step 1 is any one of 3,4-dichloro-6-nitrotoluene, 2,4-dichloro-5-nitrotoluene and 2,5-dichloro-4-nitrotoluene;
步骤一中的第一中间体为4,5-二氟-2-硝基甲苯、2,4-二氟-5-硝基甲苯、2,5-二氟-4-硝基甲苯中的一种；The first intermediate in step 1 is one of 4,5-difluoro-2-nitrotoluene, 2,4-difluoro-5-nitrotoluene and 2,5-difluoro-4-nitrotoluene. kind;
步骤二中，第二中间体为4,5-二氟-2-甲基苯胺、2,4-二氟-5-甲基苯胺、2,5-二氟-4-甲基苯胺中的一种；In step 2, the second intermediate is one of 4,5-difluoro-2-methylaniline, 2,4-difluoro-5-methylaniline and 2,5-difluoro-4-methylaniline. kind;
步骤三中，氟化试剂包括氟硼酸水溶液、氟化氢吡啶溶液中的任意一种。In step 3, the fluorination reagent includes any one of fluoroboric acid aqueous solution and hydrogen fluoride pyridine solution.
通过采用上述技术方案，本申请中，采用3,4-二氯-6-硝基甲苯、2,4-二氯-5-硝基甲苯、2,5-二氯-4-硝基甲苯中的任意一种作为原料，三种原料的价格较低且易得，在一定程度上降低原料的成本，且便于进行工业化大规模生产。By adopting the above technical solutions, in this application, 3,4-dichloro-6-nitrotoluene, 2,4-dichloro-5-nitrotoluene, 2,5-dichloro-4-nitrotoluene are used in Any one of the three raw materials is used as a raw material, and the price of the three raw materials is low and easy to obtain, which reduces the cost of the raw materials to a certain extent, and is convenient for industrialized large-scale production.
步骤一中的制备工艺，将原料依次制备获得对应的第一中间体，不易产生其他杂质，有利于反应充分进行并提高第一中间体的纯度和收率。In the preparation process in step 1, the raw materials are sequentially prepared to obtain the corresponding first intermediate, which is not easy to generate other impurities, which is conducive to the full reaction and improves the purity and yield of the first intermediate.
在步骤二中进行加氢催化反应，对应第一中间体形成对应第二中间体，不易产生其他杂质，并且利于提高第二中间体的收率和纯度。In step 2, a hydrogenation catalytic reaction is carried out to form a corresponding second intermediate corresponding to the first intermediate, which is not easy to generate other impurities, and is beneficial to improve the yield and purity of the second intermediate.
步骤三中采用的氟化试剂均能较好进行过重氮化反应。采用氟硼酸水溶液可反应获得氟硼酸重氮盐，在步骤四中，经高温裂解反应后，获得2,4,5-三氟甲苯、三氟化硼气体、氮气，可采用有机溶剂(如乙醚、四氢呋喃、1,4-二氧六环、甲醇、乙醇、醋酸等中的任意一种)处理三氟化硼气体，获得三氟化硼有机溶液，不易对操作环境和操作人员造成威胁；同时，三氟化硼有机溶液还可作为 常用的药物合成的阳离子聚合催化剂，为企业提供副产物回收利用的额外收入，进一步降低生产2,4,5-三氟苯乙酸的成本。All the fluorinated reagents used in step 3 can preferably undergo diazotization reaction. Fluoroboric acid diazonium salt can be obtained by reacting with fluoroboric acid aqueous solution. In step 4, after high temperature cracking reaction, 2,4,5-trifluorotoluene, boron trifluoride gas and nitrogen gas can be obtained. Organic solvents (such as diethyl ether can be used) , tetrahydrofuran, 1,4-dioxane, methanol, ethanol, acetic acid, etc.) to process boron trifluoride gas to obtain boron trifluoride organic solution, which is not easy to pose a threat to the operating environment and operators; , The boron trifluoride organic solution can also be used as a cationic polymerization catalyst for commonly used drug synthesis, providing additional income for the recycling of by-products for enterprises, and further reducing the cost of producing 2,4,5-trifluorophenylacetic acid.
且步骤三，通常添加质量浓度为20-30％的冰盐水进行骤冷，直至此时的反应体系温度保持在0℃以下，以控制反应，不易发生安全事故，并且还能使成盐反应较为充分地进行。若不进行骤冷处理，较易造成成盐不彻底的现象，不利于后续处理。And step 3, usually add ice brine with a mass concentration of 20-30% for quenching, until the temperature of the reaction system at this time is kept below 0 ° C, in order to control the reaction, safety accidents are not easy to occur, and it can also make the salt-forming reaction relatively. proceed fully. If the quenching treatment is not carried out, it is easy to cause the phenomenon of incomplete salt formation, which is not conducive to the subsequent treatment.
步骤四在无溶剂条件下进行，高温裂解反应处理减少溶剂的使用，利于减少裂解反应中产生废弃物的可能性。且经步骤四的处理，最终获得2,4,5-三氟甲苯，再经步骤五至步骤七中的反应，最终形成2,4,5-三氟苯乙酸。Step 4 is carried out under solvent-free conditions, and the high-temperature cracking reaction treatment reduces the use of solvents, which is beneficial to reduce the possibility of generating wastes in the cracking reaction. And through the treatment in step 4, 2,4,5-trifluorotoluene is finally obtained, and through the reaction in steps 5 to 7, 2,4,5-trifluorophenylacetic acid is finally formed.
进一步优选为：步骤一中，与环丁砜的重量比为1:(2～5)；Further preferably: in step 1, the weight ratio to sulfolane is 1:(2～5);
在120-180℃的条件下，先加入与原料的摩尔比为(2～2.5):1的氟化钾，反应10h后升温至220-230℃；Under the condition of 120-180 ℃, firstly add potassium fluoride with a molar ratio of (2-2.5):1 to the raw material, and then heat up to 220-230 ℃ after reacting for 10 hours;
再补加与原料的摩尔比＝(1～1.5):1的氟化钾，保温，反应2h，获得第一中间体；Then add potassium fluoride with a molar ratio to the raw material=(1～1.5):1, keep the temperature, and react for 2h to obtain the first intermediate;
原料为3,4-二氯-6-硝基甲苯或2,5-二氯-4-硝基甲苯；The raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene;
第一中间体为4,5-二氟-2-硝基甲苯或2,5-二氟-4-硝基甲苯。The first intermediate is 4,5-difluoro-2-nitrotoluene or 2,5-difluoro-4-nitrotoluene.
通过采用上述技术方案，在步骤一中，当原料为3,4-二氯-6-硝基甲苯或2,5-二氯-4-硝基甲苯时，先后依次在120-180℃和220-230℃的温度条件下反应，利于第一中间体中的间位被充分上氟。若后面反应温度过低，易产生其他杂质；后面反应温度过高，则能耗过大，增加制备成本。By adopting the above technical solution, in step 1, when the raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene, the temperature is 120-180°C and 220°C successively. The reaction is carried out under the temperature condition of -230°C, which is favorable for the meta-position in the first intermediate to be fully fluorinated. If the latter reaction temperature is too low, other impurities are likely to be produced; if the latter reaction temperature is too high, the energy consumption is too large and the preparation cost is increased.
进一步优选为：步骤一中，原料与环丁砜的重量比为1:(2～5)，氟化钾与原料的摩尔比为(2.1～3.5):1，反应温度为180℃，保温反应10h，获得第一中间体；It is further preferred as follows: in step 1, the weight ratio of raw material to sulfolane is 1:(2～5), the molar ratio of potassium fluoride to raw material is (2.1～3.5):1, the reaction temperature is 180°C, and the heat preservation reaction is performed for 10h, obtain the first intermediate;
原料为2,4-二氯-5-硝基甲苯；The raw material is 2,4-dichloro-5-nitrotoluene;
第一中间体为2,4-二氟-5-硝基甲苯。The first intermediate is 2,4-difluoro-5-nitrotoluene.
当原料为2,4-二氯-5-硝基甲苯时，通过采用上述技术方案，获得的第一中间体(2,4-二氟-5-硝基甲苯)收率较高。When the raw material is 2,4-dichloro-5-nitrotoluene, the yield of the obtained first intermediate (2,4-difluoro-5-nitrotoluene) is relatively high by adopting the above technical scheme.
进一步优选为：步骤一中，原料与环丁砜的重量比为1:(2～5)；Further preferably: in step 1, the weight ratio of raw material to sulfolane is 1:(2～5);
在120-180℃的条件下，先加入与原料的摩尔比为(2～2.5):1的氟化钾，反应10h后升温至220-230℃；Under the condition of 120-180 ℃, firstly add potassium fluoride with a molar ratio of (2-2.5):1 to the raw material, and then heat up to 220-230 ℃ after reacting for 10 hours;
再补加与原料的摩尔比＝(1～1.5):1的氟化钾，保温，反应2h，获得第一中间体；Then add potassium fluoride with a molar ratio to the raw material=(1～1.5):1, keep the temperature, and react for 2h to obtain the first intermediate;
原料为3,4-二氯-6-硝基甲苯或2,5-二氯-4-硝基甲苯；The raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene;
第一中间体为4,5-二氟-2-硝基甲苯或2,5-二氟-4-硝基甲苯。The first intermediate is 4,5-difluoro-2-nitrotoluene or 2,5-difluoro-4-nitrotoluene.
在步骤一中，当原料为3,4-二氯-6-硝基甲苯或2,5-二氯-4-硝基甲苯时，采用上述操作方式，先后依次在120-180℃和220-230℃中反应，利于第一中间体中的间位被充分上氟，提高第一中间体的收率。In step 1, when the raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene, the above operation method is adopted, and the temperature is 120-180°C and 220- The reaction at 230°C is favorable for the meta-position in the first intermediate to be fully fluorinated, and the yield of the first intermediate is improved.
进一步优选为：步骤二中，加氢催化反应的温度为50-75℃，氢气的压力为0.1-1.0MPa，加氢催化反应的时间为2-5h；加氢催化反应采用的催化剂为雷尼镍催化剂或钯碳催化剂。It is further preferred that: in step 2, the temperature of the hydrogenation catalytic reaction is 50-75 °C, the pressure of hydrogen is 0.1-1.0 MPa, and the time of the hydrogenation catalytic reaction is 2-5h; the catalyst used in the hydrogenation catalytic reaction is Raney Nickel catalyst or palladium carbon catalyst.
通过采用上述技术方案，利于加氢催化反应充分进行，从而提高第二中间体的收率。本申请中可以采用但不限于采用雷尼镍催化剂或钯碳催化剂这两种催化剂。By adopting the above technical scheme, the hydrogenation catalytic reaction can be fully carried out, thereby improving the yield of the second intermediate. In the present application, Raney nickel catalyst or palladium carbon catalyst can be used but not limited to.
进一步优选为：步骤三中，第二中间体、氟化试剂、亚硝酸钠的摩尔比为1:(2.5～4):(1.05～1.1)；第二中间体与氟化试剂发生成盐反应后骤冷至-40～0℃，进行重氮化反应；氟化试剂的质量浓度为25-40％。It is further preferred that: in step 3, the molar ratio of the second intermediate, the fluorinating reagent and the sodium nitrite is 1:(2.5～4):(1.05～1.1); the second intermediate and the fluorinating reagent undergo a salt-forming reaction After being quenched to -40～0℃, the diazotization reaction is carried out; the mass concentration of the fluorination reagent is 25-40%.
通过采用上述技术方案，氟化试剂量浓度为25-40％且使用过量，可使可逆的成盐反应充分进行。重氮化反应是一个急速放热的过程，即滴加亚硝酸钠水溶液时导致体系升温，成盐反应后骤冷至-40～0℃，控制亚硝酸钠水溶液的滴加速度，利于控制反应的剧烈程度，提高安全性。By adopting the above-mentioned technical scheme, the fluorinating reagent concentration is 25-40% and the excess is used, so that the reversible salt-forming reaction can be fully carried out. The diazotization reaction is a rapid exothermic process, that is, when the sodium nitrite aqueous solution is added dropwise, the system heats up, and after the salt-forming reaction, it is quenched to -40 ~ 0 ° C, and the drop rate of the sodium nitrite aqueous solution is controlled, which is beneficial to control the reaction. Vigorous intensity for increased safety.
进一步优选为：步骤四中，高温裂解反应的温度为90-300℃，时间为2-4h。It is further preferred that: in step 4, the temperature of the high-temperature cracking reaction is 90-300° C., and the time is 2-4 h.
通过采用上述技术方案，利于减少副产物的形成，提高最终获得的2,4,5-三氟甲苯的纯度和收率。By adopting the above technical scheme, the formation of by-products can be reduced, and the purity and yield of the finally obtained 2,4,5-trifluorotoluene can be improved.
进一步优选为：步骤五中，卤代反应时，将2,4,5-三氟甲苯、催化剂以重量比为1：(0.005-0.02)进行反应，升温至110-130℃，持续通入干燥的氯气3-5h，后停止通氯气，冷却，水洗至中性，干燥，减压蒸馏，获得2,4,5-三氟苄氯；催化剂为偶氮二异丁腈。It is further preferred that: in step 5, during the halogenation reaction, 2,4,5-trifluorotoluene and the catalyst are reacted in a weight ratio of 1:(0.005-0.02), the temperature is raised to 110-130 ° C, and the drying is continued. After 3-5 hours of chlorine gas, the chlorine gas is stopped, cooled, washed with water until neutral, dried, and distilled under reduced pressure to obtain 2,4,5-trifluorobenzyl chloride; the catalyst is azobisisobutyronitrile.
通过采用上述技术方案，能使2,4,5-三氟甲苯充分进行卤代反应，提高2,4,5-三氟苄氯的收率。且卤化剂可为氯气、五氯化磷、磺酰氯、三氯异氰酸酯、二氯海因、溴素、NBS、氢溴酸双氧水、二溴海因中的任意一种。By adopting the above technical scheme, the halogenation reaction of 2,4,5-trifluorotoluene can be fully carried out, and the yield of 2,4,5-trifluorobenzyl chloride can be improved. And the halogenating agent can be any one of chlorine, phosphorus pentachloride, sulfonyl chloride, trichloroisocyanate, hydantoin, bromine, NBS, hydrogen bromide, and hydantoin.
进一步优选为：步骤六中，氰化反应时，2,4,5-三氟苄氯：氰化钠水溶液中的氰化钠的摩尔比为1:(1～1.1)，相转移催化剂、2,4,5-三氟苄氯、二甲基亚砜的重量比为(0.01-0.02)：1:(1-3)进行混合，在温度为60-80℃的条件下保温氰化反应2-5h，再采用乙醇萃取，干燥，蒸馏再精馏，获得2,4,5-三氟苯乙腈；相转移催化剂为偶氮二异丁腈。It is further preferred that: in step 6, during the cyanation reaction, the molar ratio of 2,4,5-trifluorobenzyl chloride: sodium cyanide in the aqueous sodium cyanide solution is 1:(1-1.1), the phase transfer catalyst, 2 , The weight ratio of 4,5-trifluorobenzyl chloride and dimethyl sulfoxide is (0.01-0.02): 1: (1-3) for mixing, and the temperature is 60-80 ℃ under the condition of keeping the cyanidation reaction 2 -5h, then extracted with ethanol, dried, distilled and then rectified to obtain 2,4,5-trifluorophenylacetonitrile; the phase transfer catalyst is azobisisobutyronitrile.
通过采用上述技术方案，利于提高氰化反应的充分性，进而使获得的2,4,5-三氟苯乙腈的收率较高。By adopting the above technical scheme, the sufficiency of the cyanation reaction is improved, and the yield of the obtained 2,4,5-trifluorophenylacetonitrile is higher.
进一步优选为：步骤七中，水解反应时，将酸升温至100-110℃的稳定范围内滴加2,4,5-三氟苯乙腈，在120℃的温度下保温6h，冷却至室温，滴加100mL水，冷却、抽滤，将固体用甲醇重结晶后精制烘干后得到2,4,5-三氟苯乙酸；It is further preferred that: in step 7, during the hydrolysis reaction, the acid is heated to a stable range of 100-110 °C, and 2,4,5-trifluorophenylacetonitrile is added dropwise, the temperature is kept at 120 °C for 6 hours, and then cooled to room temperature, 100 mL of water was added dropwise, cooled and suction filtered, the solid was recrystallized with methanol, purified and dried to obtain 2,4,5-trifluorophenylacetic acid;
酸包括硫酸、盐酸、磷酸、多聚磷酸、醋酸中的至少一种。The acid includes at least one of sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, and acetic acid.
通过采用上述技术方案，利于水解反应的充分进行，提高终产物2,4,5-三氟苯乙酸的纯度和收率。By adopting the above technical scheme, the hydrolysis reaction can be fully carried out, and the purity and yield of the final product 2,4,5-trifluorophenylacetic acid are improved.
进一步优选为：酸为硫酸与醋酸混合形成，2,4,5-三氟苯乙腈、硫酸、醋酸的重量比为1:(1.5～3):0.1，硫酸的质量浓度为70％。More preferably, the acid is formed by mixing sulfuric acid and acetic acid, the weight ratio of 2,4,5-trifluorophenylacetonitrile, sulfuric acid and acetic acid is 1:(1.5-3):0.1, and the mass concentration of sulfuric acid is 70%.
通过采用上述技术方案，将醋酸、硫酸相互混合后，可起到更好的水解作用。且三者重量比在上述范围内，更利于水解反应的充分进行。By adopting the above technical scheme, after acetic acid and sulfuric acid are mixed with each other, better hydrolysis can be achieved. And the weight ratio of the three is within the above range, which is more conducive to the sufficient progress of the hydrolysis reaction.
综上，本申请具有以下有益效果：To sum up, this application has the following beneficial effects:
1、本申请中采用步骤一至步骤四的操作，均能获得2,4,5-三氟甲苯，再依次进行卤代、氰化、水解反应，最终获得2,4,5-三氟苯乙酸。每一步骤后获得的对应产物的收率均较高，且制备过程产生的副产物较少，利于提高形成的终产物2,4,5-三氟苯乙酸的纯度和收率，且采用等量的原料能制备获得的更高收率的终产物2,4,5-三氟苯乙酸。且反应过程中所涉及到的初始原料的成本较低，从源头上降低本申请中的制备成本，利于进行工业化大规模生产。1. In this application, the operations from step 1 to step 4 can be used to obtain 2,4,5-trifluorotoluene, and then halogenation, cyanation, and hydrolysis are carried out in turn, and 2,4,5-trifluorophenylacetic acid is finally obtained. . The yields of the corresponding products obtained after each step are all high, and the by-products produced in the preparation process are less, which is beneficial to improve the purity and yield of the final product 2,4,5-trifluorophenylacetic acid formed, and the use of etc. A higher yield of the final product, 2,4,5-trifluorophenylacetic acid, can be obtained with a higher amount of starting material. In addition, the cost of the initial raw materials involved in the reaction process is relatively low, and the preparation cost in the present application is reduced from the source, which is conducive to industrialized large-scale production.
2、本申请中制得的2,4,5-三氟甲苯，纯度高于98％，质量稳定，且符合药物中间体的使用要求，无需再经过提纯操作，可以直接进行后续的卤代反应、氰化反应、水解反应，方便操作。2. The 2,4,5-trifluorotoluene prepared in this application has a purity higher than 98%, stable quality, and meets the requirements for the use of pharmaceutical intermediates. It can be directly subjected to subsequent halogenation reactions without further purification operations. , cyanation reaction, hydrolysis reaction, easy to operate.
3、本申请中的制备方法操作难度较低，利于2,4,5-三氟苯乙酸的工业化大规模生产。3. The preparation method in the present application has low operational difficulty, which is beneficial to the industrialized large-scale production of 2,4,5-trifluorophenylacetic acid.
具体实施方式Detailed ways
以下结合实施例对本申请作进一步详细说明。The present application will be further described in detail below with reference to the examples.
实施例1：一种2,4,5-三氟苯乙酸的制备方法，包括如下步骤：Embodiment 1: a preparation method of 2,4,5-trifluorophenylacetic acid, comprising the steps:
步骤一，第一中间体4,5-二氟-2-硝基甲苯的制备：Step 1, the preparation of the first intermediate 4,5-difluoro-2-nitrotoluene:
在无水反应瓶1中将原料3,4-二氯-6-硝基甲苯100g于220g环丁砜中混合，并在减压下升温至75～80℃(在实际操作过程中，无法控制升温的温度在一个定值)，搅拌2h后，加入58.1g氟化钾和12g四丁基溴化铵催化剂，减压75～80℃搅拌脱水2h，至蒸馏头无水珠(去除水的过程，只有去除水之后，再进行反应)；将反应体系升温至180℃，通过GC跟踪，反应10h后原料含量≤0.2％，得一次氟化后的产物(化学式Ⅰ)；In anhydrous reaction flask 1, 100 g of raw material 3,4-dichloro-6-nitrotoluene was mixed with 220 g of sulfolane, and the temperature was raised to 75-80° C. The temperature is at a fixed value), after stirring for 2h, add 58.1g potassium fluoride and 12g tetrabutylammonium bromide catalyst, depressurize at 75 ~ 80 ℃, stir and dehydrate for 2h, until the distillation head has no water beads (the process of removing water, only After the water is removed, the reaction is carried out again); the reaction system is heated to 180 ° C, followed by GC, the content of raw materials after the reaction for 10h is ≤ 0.2%, and the product after primary fluorination (chemical formula I) is obtained;
Figure PCTCN2020127713-appb-000001
Figure PCTCN2020127713-appb-000001
在无水反应瓶2中加入100g环丁砜、30.0g氟化钾和10g四丁基溴化铵催化剂，减压75～80℃搅拌脱水2h，至蒸馏头无水珠，得二次氟化需补加的混合反应液；将无水反应瓶2中的二次氟化需补加的混合反应液加入到无水反应瓶1中，与一次氟化后的产物形成混合，升温至220℃，通过GC跟踪，2h后反应到达终点，降温到75～80℃，过滤后滤液精馏分离环丁砜与浅黄色油状物的第一中间体4,5-二氟-2-硝基甲苯。反应式如下：Add 100g sulfolane, 30.0g potassium fluoride and 10g tetrabutylammonium bromide catalyst to the anhydrous reaction flask 2, stir and dehydrate under reduced pressure at 75-80 °C for 2 hours, until there are no water beads in the distillation head, and the secondary fluorination needs to be supplemented. The mixed reaction solution added; the mixed reaction solution that needs to be added for the secondary fluorination in the anhydrous reaction flask 2 is added into the anhydrous reaction flask 1 to form a mixture with the product after the primary fluorination, and the temperature is raised to 220° C. GC tracking, the reaction reached the end point after 2 hours, and the temperature was lowered to 75-80 °C. After filtration, the filtrate was rectified to separate the first intermediate 4,5-difluoro-2-nitrotoluene of sulfolane and light yellow oil. The reaction formula is as follows:
Figure PCTCN2020127713-appb-000002
Figure PCTCN2020127713-appb-000002
核磁共振氢谱数据：H NMR data:
1HNMR(CDCl 3):7.91(1H,dd,J＝8,10),7.14(1H,dd,J＝8,10),2.57(3H,s)。 1 H NMR (CDCl 3 ): 7.91 (1H, dd, J=8,10), 7.14 (1H, dd, J=8,10), 2.57 (3H, s).
步骤二，第二中间体4,5-二氟-2-甲基苯胺的制备，反应式如下：Step 2, the preparation of the second intermediate 4,5-difluoro-2-methylaniline, the reaction formula is as follows:
Figure PCTCN2020127713-appb-000003
Figure PCTCN2020127713-appb-000003
在高压釜中加入100.0g第一中间体4,5-二氟-2-硝基甲苯、100.0g甲醇、3.0g雷尼镍催化剂，密闭反应釜，先用氮气置换三次，再用氢气置换三次，充氢至压强为0.8MPa，升温至55℃，后维持压强在0.8MPa，并继续升温至60℃反应，反应3h，反应结束后过滤雷尼镍催化剂，滤液先常压蒸馏，再精馏收集浅黄色油状质地的第二中间体4,5-二氟-2-甲基苯胺。Add 100.0g of the first intermediate 4,5-difluoro-2-nitrotoluene, 100.0g of methanol, and 3.0g of Raney nickel catalyst to the autoclave, seal the autoclave, and replace it with nitrogen three times and then with hydrogen three times. , charged with hydrogen to a pressure of 0.8 MPa, heated to 55 °C, maintained at a pressure of 0.8 MPa, and continued to heat up to 60 °C to react for 3 hours. After the reaction, the Raney nickel catalyst was filtered. The filtrate was first distilled at atmospheric pressure, and then rectified. The second intermediate, 4,5-difluoro-2-methylaniline, was collected as a pale yellow oily texture.
步骤三，4,5-二氟-2-甲基苯胺氟硼酸重氮盐的制备，反应式如下：Step 3, the preparation of 4,5-difluoro-2-methylaniline fluoroborate diazonium salt, the reaction formula is as follows:
Figure PCTCN2020127713-appb-000004
Figure PCTCN2020127713-appb-000004
在反应瓶中加入50g 4,5-二氟-2-甲基苯胺，在25±5℃的条件下滴加为质量浓度为40％的氟硼酸230g，滴加完后直接用冰盐水骤冷到-40～0℃，维持该温度并滴加亚硝酸钠水溶液(由25.88g亚硝酸钠和40g水配制而成)，同时使滴加亚硝酸钠水溶液后的体系的温度在0℃以下，滴加完亚硝酸钠水溶液后保温1～2h，抽滤，滤饼先用冰冻的40％氟硼酸水溶液20ml洗涤，再用20ml冰点温度为-15℃且质量浓度为30％的酒精水溶液洗涤，重复操作2次，滤饼进行减压蒸馏脱干溶剂，得到4,5-二氟-2-甲基苯胺氟硼酸重氮盐。50g of 4,5-difluoro-2-methylaniline was added to the reaction flask, and 230g of fluoroboric acid with a mass concentration of 40% was added dropwise at 25±5°C. After the dropwise addition, it was directly quenched with ice brine. To -40 ~ 0 ℃, maintain the temperature and dropwise add sodium nitrite aqueous solution (prepared by 25.88g sodium nitrite and 40g water), while making the temperature of the system after the dropwise addition of sodium nitrite aqueous solution below 0 ℃, After adding the sodium nitrite aqueous solution dropwise, keep it for 1 to 2 hours, and filter it with suction. The filter cake is washed with 20 ml of frozen 40% fluoroboric acid aqueous solution, and then washed with 20 ml of alcohol aqueous solution with a freezing point temperature of -15 °C and a mass concentration of 30%. The operation was repeated twice, and the filter cake was subjected to vacuum distillation to remove the solvent to obtain 4,5-difluoro-2-methylaniline fluoroborate diazonium salt.
步骤四，2,4,5-三氟甲苯的制备：Step 4, the preparation of 2,4,5-trifluorotoluene:
将步骤三中的4,5-二氟-2-甲基苯胺氟硼酸重氮盐经高温裂解反应，即缓慢升温至100℃，并保温1h，在缓慢升温至180℃，并保温1h，获得2,4,5-三氟甲苯。The 4,5-difluoro-2-methylaniline fluoroborate diazonium salt in step 3 is subjected to a high temperature cracking reaction, that is, the temperature is slowly raised to 100 ° C, and kept for 1 h, and then slowly raised to 180 ° C and kept for 1 h to obtain 2,4,5-Trifluorotoluene.
步骤五，2,4,5-三氟苄氯(X＝Cl)的制备：Step 5, preparation of 2,4,5-trifluorobenzyl chloride (X=Cl):
在四口烧瓶上，安装搅拌器、温度计、通氯气管和回流冷凝管，回流冷凝管上连接HCl吸收系统，靠近烧瓶处安装光源。On the four-necked flask, install a stirrer, a thermometer, a chlorine gas pipe and a reflux condenser. The reflux condenser is connected to an HCl absorption system, and a light source is installed near the flask.
在反应瓶中加入146.0g 2,4,5-三氟甲苯(由步骤四制备获得)、3.0g偶氮二异丁腈，搅拌加热，当温度升至110℃时，通入干燥的氯气，并采用GC跟踪，通氯气约3h后，停止通卤化剂氯气，冷却反应物，并将其水洗至中性，干燥后减压蒸馏得到2,4,5-三氟苄氯。Add 146.0g 2,4,5-trifluorotoluene (prepared from step 4) and 3.0g azobisisobutyronitrile into the reaction flask, stir and heat, when the temperature rises to 110°C, pass dry chlorine gas, And adopt GC tracking, after about 3 hours of chlorine gas, stop the halogenating agent chlorine gas, cool the reactant, wash it with water until neutral, dry it and distill under reduced pressure to obtain 2,4,5-trifluorobenzyl chloride.
步骤六，2,4,5-三氟苯乙腈的制备：Step 6, the preparation of 2,4,5-trifluorophenylacetonitrile:
向反应瓶中加入质量浓度为30％、质量为91.0g的氰化钠水溶液，再加入93.0g的2,4,5-三氟苄氯(由步骤五制备获得)、150ml二甲基亚砜和1.5g相转移催化剂偶氮二异丁腈，升温至70℃，并保温反应5h。待反应完毕，用100ml乙醇萃取2次，干燥后蒸馏再精馏得到2,4,5-三氟苯乙腈。Add sodium cyanide aqueous solution with a mass concentration of 30% and a mass of 91.0 g into the reaction flask, and then add 93.0 g of 2,4,5-trifluorobenzyl chloride (prepared from step 5), 150 ml of dimethyl sulfoxide and 1.5g of phase transfer catalyst azobisisobutyronitrile, the temperature was raised to 70°C, and the reaction was kept for 5h. After the reaction is completed, extract twice with 100 ml of ethanol, dry, and then distill and then rectify to obtain 2,4,5-trifluorophenylacetonitrile.
步骤七，2,4,5-三氟苯乙酸的制备：Step seven, the preparation of 2,4,5-trifluorophenylacetic acid:
在反应瓶中加入质量浓度为70％的硫酸98g、醋酸3g，升温，并在100～110℃的温度范围内滴加60g的2,4,5-三氟苯乙腈(由步骤六制备获得)，滴加完毕后在120℃的温度下保温6h。结束后冷却至室温，滴加100ml的水，冷却、抽滤，并收集固体，用甲醇重结晶后精制烘干后得到2,4,5-三氟苯乙酸。Add 98 g of sulfuric acid and 3 g of acetic acid with a mass concentration of 70% into the reaction flask, heat up, and dropwise add 60 g of 2,4,5-trifluorophenylacetonitrile (prepared from step 6) in the temperature range of 100-110 °C , and kept at 120℃ for 6h after the dropwise addition. After completion, it was cooled to room temperature, 100 ml of water was added dropwise, cooled, filtered with suction, and the solid was collected, recrystallized with methanol, purified and dried to obtain 2,4,5-trifluorophenylacetic acid.
注1：实施例1中所采用的反应物由其前一步骤反应制得。Note 1: The reactants used in Example 1 were prepared by the reaction in the previous step.
注2：本实验过程中由于反应较为剧烈，所采用的减压、升温、搅拌等操作，需要根据实际的操作过程出发，通过实际的反应情况进行相应的调节。如减压处理，能够实现脱水，并且使整个反应体系更为稳定，若压力过大，易把溶剂带走，造成反应不够充分和稳定。因此，需要使内部环境保持在较为平衡的状态。Note 2: During this experiment, due to the violent reaction, the operations such as decompression, temperature rise, stirring, etc., need to be adjusted according to the actual operation process and the actual reaction situation. For example, decompression treatment can achieve dehydration and make the whole reaction system more stable. If the pressure is too large, the solvent will be easily taken away, resulting in insufficient and stable reaction. Therefore, it is necessary to keep the internal environment in a relatively balanced state.
实施例2：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，在步骤一中，采用2,5-二氯-4-硝基甲苯作为原料进行反应，反应操作与实施例1中的相同，最终获得的第一中间体为浅红色油状物的2,5-二氟-4-硝基甲苯。反应式如下：Embodiment 2: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 1, 2,5-dichloro-4-nitrotoluene is used as a raw material for the reaction , the reaction operation is the same as that in Example 1, and the first intermediate finally obtained is 2,5-difluoro-4-nitrotoluene which is a light red oily substance. The reaction formula is as follows:
Figure PCTCN2020127713-appb-000005
Figure PCTCN2020127713-appb-000005
核磁共振氢谱数据：H NMR data:
1HNMR(CDCl 3):7.127(1H,dd,J＝8.1,6.0),7.734(1H,dd,J＝8.4,6.3),2.369(3H,d,J＝1.8)。 1 H NMR (CDCl 3 ): 7.127 (1H, dd, J=8.1, 6.0), 7.734 (1H, dd, J=8.4, 6.3), 2.369 (3H, d, J=1.8).
实施例3：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，在步骤一中，采用2,4-二氯-5-硝基甲苯作为原料进行反应，氟化钾为62.0g，四丁基溴化铵催化剂1g，通过GC跟踪，反应10h后原料含量≤0.2％，降温到75～80℃，过滤，滤液精馏分离环丁砜与浅黄色油状物质地的第一中间体。反应式如下：Embodiment 3: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 1, 2,4-dichloro-5-nitrotoluene is used as a raw material for the reaction , potassium fluoride is 62.0g, tetrabutylammonium bromide catalyst is 1g, tracked by GC, the content of raw materials is ≤0.2% after 10h of reaction, cooled to 75～80℃, filtered, and the filtrate is rectified to separate sulfolane and light yellow oily substance the first intermediate. The reaction formula is as follows:
Figure PCTCN2020127713-appb-000006
Figure PCTCN2020127713-appb-000006
实施例4：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，步骤二制备第二中间体的过程中，采用实施例3中获得的第一中间体2,4-二氟-5-硝基甲苯进行反应，且反应操作与实施例1中的步骤二的反应操作相同，最终获得浅黄色油状质地的第二中间体2,4-二氟-5-甲基苯胺，且第二中间体的质量为81.2g，GC纯度99.6％，收率98.2％。反应式如下：Embodiment 4: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in the process of preparing the second intermediate in step 2, the first intermediate obtained in embodiment 3 is used 2,4-difluoro-5-nitrotoluene was reacted, and the reaction operation was the same as that of step 2 in Example 1, and finally the second intermediate 2,4-difluoro-5 with pale yellow oily texture was obtained -methylaniline, and the mass of the second intermediate is 81.2 g, the GC purity is 99.6%, and the yield is 98.2%. The reaction formula is as follows:
Figure PCTCN2020127713-appb-000007
Figure PCTCN2020127713-appb-000007
实施例5：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，步骤二制备第二中间体的过程中，采用实施例2中获得的第一中间体2,5-二氟-4-硝基甲苯进行反应，且反应操作与实施例1中的步骤二的反应操作相同，最终获得浅黄色油状质地的第二中间体2,5-二氟-4-甲基苯胺，且第二中间体2,5-二氟-4-甲基苯胺的质量为79.2g，GC纯度99.5％，收率95.8％。反应式如下：Embodiment 5: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in the process of preparing the second intermediate in step 2, the first intermediate obtained in embodiment 2 is used 2,5-difluoro-4-nitrotoluene was reacted, and the reaction operation was the same as that of step 2 in Example 1, and finally the second intermediate 2,5-difluoro-4 with pale yellow oily texture was obtained -methylaniline, and the mass of the second intermediate 2,5-difluoro-4-methylaniline was 79.2 g, the GC purity was 99.5%, and the yield was 95.8%. The reaction formula is as follows:
Figure PCTCN2020127713-appb-000008
Figure PCTCN2020127713-appb-000008
实施例6：一种2,4,5-三氟苯乙酸的制备方法，与实施例4的区别在于，步骤三制备第三中间体的过程中，采用实施例4中制备获得的第二中间体2,4-二氟-5-甲基苯胺进行反应，且反应操作与实施例1中的步骤三中的反应操作相同，最终获得第三中间体2,4-二氟-5-甲基苯胺氟硼酸重氮盐，且质量为63.2g。反应式如下：Example 6: A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 4 is that in the process of preparing the third intermediate in step 3, the second intermediate prepared in Example 4 is used. 2,4-difluoro-5-methylaniline is reacted, and the reaction operation is the same as that in step 3 in Example 1, and finally the third intermediate 2,4-difluoro-5-methyl is obtained Aniline fluoroborate diazonium salt, and the mass is 63.2g. The reaction formula is as follows:
Figure PCTCN2020127713-appb-000009
Figure PCTCN2020127713-appb-000009
实施例7：一种2,4,5-三氟苯乙酸的制备方法，与实施例5的区别在于，步骤三制备第三中间体的过程中，采用实施例5中制备获得的第二中间体2,5-二氟-4-甲基苯胺进行反应，且反应操作与实施例1中的步骤三中的反应操作相同，最终获得第三中间体2,5-二氟-4-甲基苯胺氟硼酸重氮盐，且质量为64.3g。反应式如下：Example 7: A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 5 is that in the process of preparing the third intermediate in step 3, the second intermediate prepared in Example 5 is used. 2,5-difluoro-4-methylaniline is reacted, and the reaction operation is the same as that in step 3 in Example 1, and finally the third intermediate 2,5-difluoro-4-methyl is obtained Aniline fluoroborate diazonium salt, and the mass is 64.3g. The reaction formula is as follows:
Figure PCTCN2020127713-appb-000010
Figure PCTCN2020127713-appb-000010
实施例8：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，在步骤四高温裂解时，缓慢升温至100℃，并保温1h，获得2,4,5-三氟甲苯。Embodiment 8: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that during the high temperature cracking in step 4, the temperature is slowly raised to 100 ° C, and kept for 1 h to obtain 2,4, 5-Trifluorotoluene.
实施例9：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，在步骤四高温裂解时，缓慢升温至100℃，并保温2h，获得2,4,5-三氟甲苯。Embodiment 9: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Embodiment 1 is that during the high temperature cracking in step 4, the temperature is slowly raised to 100 ° C, and kept for 2 h to obtain 2,4, 5-Trifluorotoluene.
实施例10：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于， 在步骤四高温裂解时，缓慢升温至100℃，并保温1h，再缓慢升温至150℃，并保温1h，获得2,4,5-三氟甲苯。Example 10: A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 1 is that during the high-temperature cracking in step 4, the temperature is slowly raised to 100° C., kept for 1 hour, and then slowly raised to 150° C. ℃, and kept for 1 h to obtain 2,4,5-trifluorotoluene.
实施例11：一种2,4,5-三氟苯乙酸的制备方法，与实施例9的区别在于，在步骤四高温裂解时，缓慢升温至100℃，并保温4h，获得2,4,5-三氟甲苯。Example 11: A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 9 is that during the high-temperature cracking in step 4, the temperature is slowly raised to 100° C., and kept for 4 hours to obtain 2,4, 5-Trifluorotoluene.
实施例12：一种2,4,5-三氟苯乙酸的制备方法，与实施例9的区别在于，在步骤四高温裂解时，缓慢升温至90℃，并保温1h，再缓慢升温至300℃，并保温1h，获得2,4,5-三氟甲苯。Example 12: A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 9 is that during the high-temperature cracking in step 4, the temperature is slowly raised to 90° C., kept for 1 hour, and then slowly raised to 300° C. ℃, and kept for 1 h to obtain 2,4,5-trifluorotoluene.
实施例13：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，步骤三中，第二中间体、氟硼酸、亚硝酸钠的摩尔比为1:2.5:15，最终获得2,4,5-三氟甲苯。Embodiment 13: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 3, the molar ratio of the second intermediate, fluoroboric acid, and sodium nitrite is 1:2.5 : 15, and finally 2,4,5-trifluorotoluene was obtained.
实施例14：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，步骤三中，第二中间体、氟硼酸、亚硝酸钠的摩尔比为1:4:1.1，最终获得2,4,5-三氟甲苯。Embodiment 14: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 3, the molar ratio of the second intermediate, fluoroboric acid, and sodium nitrite is 1:4 : 1.1, and finally obtain 2,4,5-trifluorotoluene.
实施例15：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，步骤三中，第二中间体、氟硼酸、亚硝酸钠的摩尔比为1:2.8:15，最终获得2,4,5-三氟甲苯。Embodiment 15: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 3, the molar ratio of the second intermediate, fluoroboric acid, and sodium nitrite is 1:2.8 : 15, and finally 2,4,5-trifluorotoluene was obtained.
实施例16：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，步骤三中氟化试剂为氟化氢吡啶溶液。Embodiment 16: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Embodiment 1 is that the fluorination reagent in step 3 is a hydrogen fluoride pyridine solution.
实施例17：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，步骤五中，Embodiment 17: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Embodiment 1 is that in step five,
2,4,5-三氟甲苯(实施例1的步骤四获得)、偶氮二异丁腈的重量比为1：0.005，搅拌加热至130℃，通氯气时间为3h，得2,4,5-三氟苄氯。The weight ratio of 2,4,5-trifluorotoluene (obtained in step 4 of Example 1) and azobisisobutyronitrile is 1:0.005, heated to 130°C with stirring, and the time of passing chlorine gas is 3h to obtain 2,4, 5-Trifluorobenzyl chloride.
实施例18：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，步骤六中，2,4,5-三氟苄氯：氰化钠水溶液中的氰化钠的摩尔比为1:1，四丁基溴化铵、2,4,5-三氟苄氯、二甲基亚砜的重量比为0.01:1:3。Embodiment 18: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step six, 2,4,5-trifluorobenzyl chloride: cyanide in sodium cyanide aqueous solution The molar ratio of sodium chloride is 1:1, and the weight ratio of tetrabutylammonium bromide, 2,4,5-trifluorobenzyl chloride and dimethyl sulfoxide is 0.01:1:3.
实施例19：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于，步骤七中，2,4,5-三氟苯乙腈、硫酸、醋酸的重量比为1:3:0.1，得2,4,5-三氟苯乙酸。Embodiment 19: a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 1 is that in step seven, the weight ratio of 2,4,5-trifluorophenylacetonitrile, sulfuric acid, and acetic acid is: 1:3:0.1 to obtain 2,4,5-trifluorophenylacetic acid.
对比例1：一种2,4,5-三氟苯乙酸的制备方法，与实施例1的区别在于， 为授权公告号为CN100347142C、授权公告日为2007年11月7日的中国申请中的制备方法：Comparative Example 1: A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 1 is that it is a Chinese application with an authorization announcement number of CN100347142C and an authorization announcement date of November 7, 2007. Preparation:
2,4,5-三氟苄氯的制备：Preparation of 2,4,5-trifluorobenzyl chloride:
在250ml的四口反应瓶中加入1,2,4-三氟苯84克，多聚甲醛24克，在室温下滴加氯磺酸52克，滴加完后保温1～2小时，到入冰水中水解，分出有机层，水洗至中性，干燥后进行减压蒸馏，得到2,4,5-三氟苄氯。Add 84 grams of 1,2,4-trifluorobenzene and 24 grams of paraformaldehyde to a 250ml four-neck reaction flask, add 52 grams of chlorosulfonic acid dropwise at room temperature, and keep the temperature for 1 to 2 hours after the dropwise addition. After hydrolysis in ice water, the organic layer was separated, washed with water until neutral, dried and then distilled under reduced pressure to obtain 2,4,5-trifluorobenzyl chloride.
2,4,5-三氟苄氰的制备：Preparation of 2,4,5-trifluorobenzyl cyanide:
在500ml四口反应瓶中加入氰化钠25.5克，水25.5ml，升温至氰化钠基本全溶，加入2.2克四甲基氯化铵和100ml乙醇，在80℃左右滴加2,4,5-三氟苄氯，滴完后保温1～2小时，反应后经抽滤，滤液脱溶后分出有机层，再进行减压精馏，得到2,4,5-三氟苄氰。Add 25.5 grams of sodium cyanide and 25.5 ml of water to a 500ml four-neck reaction flask, heat up until the sodium cyanide is almost completely dissolved, add 2.2 grams of tetramethylammonium chloride and 100ml of ethanol, and dropwise add 2,4, 5-trifluorobenzyl chloride is kept for 1-2 hours after dropping, suction filtration is carried out after the reaction, the filtrate is desolvated and the organic layer is separated, and then rectified under reduced pressure to obtain 2,4,5-trifluorobenzyl cyanide.
2,4,5-三氟苯乙酸的制备：Preparation of 2,4,5-trifluorophenylacetic acid:
在200ml四口反应瓶中加入2,4,5-三氟苄氰47克，120ml盐酸和34ml醋酸，回流反应3小时，到入冰水中水解，抽滤得滤饼，烘干后得2,4,5-三氟苯乙酸。47 grams of 2,4,5-trifluorobenzyl cyanide, 120ml of hydrochloric acid and 34ml of acetic acid were added to a 200ml four-neck reaction flask, refluxed for 3 hours, hydrolyzed in ice water, filtered with suction to obtain a filter cake, and dried to obtain 2, 4,5-Trifluorophenylacetic acid.
收率检测试验Yield detection test
一、试验样品：实施例1中每一步骤所获得的对应产物；对比例1中每一步骤所获得的对应产物。1. Test sample: the corresponding product obtained in each step in Example 1; the corresponding product obtained in each step in Comparative Example 1.
试验方法：将实施例1中每一步骤所获得的对应产物进行收集并且进行收率的计算，记录并进行分析；将对比例1中每一步骤所获得的对应产物进行收集并且进行收率的计算，记录并进行分析。Test method: The corresponding products obtained in each step in Example 1 are collected and the yield is calculated, recorded and analyzed; the corresponding products obtained in each step in Example 1 are collected and the yield is calculated. Calculate, record and analyze.
试验结果：实施例1中每一步骤所获得的对应产物的具体情况如表1所示；对比例1中每一步骤所获得的对应产物的具体情况如表2所示。Test results: the specific conditions of the corresponding products obtained in each step in Example 1 are shown in Table 1; the specific conditions of the corresponding products obtained in each step in Comparative Example 1 are shown in Table 2.
表1实施例1中每一步骤所获得的对应产物的具体情况The specific situation of the corresponding product obtained in each step in Table 1 Example 1
步骤step 对应产物名称corresponding product name 收率/％Yield/% GC纯度/％GC purity/%
步骤一step one 4,5-二氟-2-硝基甲苯4,5-Difluoro-2-nitrotoluene 8282 98.698.6
步骤二Step 2 4,5-二氟-2-甲基苯胺4,5-Difluoro-2-methylaniline 96.896.8 99.499.4
步骤三Step 3 4,5-二氟-2-甲基苯胺氟硼酸重氮盐4,5-Difluoro-2-methylaniline fluoroborate diazonium salt 76.276.2 //
步骤四Step 4 2,4,5-三氟甲苯2,4,5-Trifluorotoluene 7373 99.399.3
步骤五Step 5 2,4,5-三氟苄氯(X＝Cl)2,4,5-Trifluorobenzyl chloride (X=Cl) 79.2079.20 99.3099.30
步骤六Step 6 2,4,5-三氟苯乙腈2,4,5-Trifluorophenylacetonitrile 88.1088.10 99.2099.20
步骤七Step seven 2,4,5-三氟苯乙酸2,4,5-Trifluorophenylacetic acid 99.0099.00 99.5099.50
由表1可知，每一步中得到的对应的产物的收率、纯度均较高，尤其是步骤一和二中的收率，最终获得的终产物的得率和纯度也较高。As can be seen from Table 1, the yield and purity of the corresponding products obtained in each step are relatively high, especially the yields in steps 1 and 2, and the yield and purity of the final product obtained are also relatively high.
表2对比例1中每一步骤所获得的对应产物的收率情况The yield situation of the corresponding product obtained by each step in Table 2 Comparative Example 1
步骤step 对应产物corresponding product 收率/％Yield/%
步骤一step one 2,4,5-三氟苄氯2,4,5-Trifluorobenzyl chloride 65.0065.00
步骤二Step 2 2,4,5-三氟苄氰2,4,5-Trifluorobenzyl cyanide 66.0066.00
步骤三Step 3 2,4,5-三氟苯乙酸2,4,5-Trifluorophenylacetic acid 99.0099.00
由表2可知，对比例1中，步骤一和步骤二对应的产物收率均不高。结合表1可知，采用本申请中的制备方法，可有效提高每一步获得的对应产物的收率，最终，在采用相同量原料的情况下，利于提高最终获得的2,4,5-三氟苯乙酸的收率。As can be seen from Table 2, in Comparative Example 1, the product yields corresponding to step 1 and step 2 are not high. It can be seen from Table 1 that the preparation method in the present application can effectively improve the yield of the corresponding product obtained in each step, and finally, in the case of using the same amount of raw materials, it is beneficial to improve the final obtained 2,4,5-trifluoro Yield of phenylacetic acid.
二、试验对象：选择实施例2-19中的制备方法。2. Test object: select the preparation method in Examples 2-19.
试验方法：将通过实施例2-19分别制备获得的2,4,5-三氟苯乙酸进行收率的计算，记录并进行分析。Test method: Calculate the yield of the 2,4,5-trifluorophenylacetic acid prepared in Examples 2-19, record and analyze.
试验结果：采用实施例2-19中的制备方法，最终所获得的2,4,5-三氟苯乙酸的收率如表3所示。Test results: using the preparation methods in Examples 2-19, the yield of the 2,4,5-trifluorophenylacetic acid finally obtained is shown in Table 3.
表3采用实施例2-19中的制备方法中不同步骤所获得的对应产物的收率Table 3 adopts the yields of corresponding products obtained in different steps in the preparation methods in Examples 2-19
Figure PCTCN2020127713-appb-000011
Figure PCTCN2020127713-appb-000011
由表1和表3可知，相比较实施例1-3，所获得的第一中间体的收率不同，主要原因在于实施例2-3中所采用的原料不同，导致获得的第一中间体不同及其收率也不同。但相对而言，采用2,4-二氯-5-硝基甲苯作为原料更易制备出第一中间体2,4-二氟-5-硝基甲苯。As can be seen from Table 1 and Table 3, compared with Example 1-3, the yield of the obtained first intermediate is different, the main reason is that the raw materials used in Example 2-3 are different, resulting in the obtained first intermediate. different and their yields are also different. But relatively speaking, it is easier to prepare the first intermediate 2,4-difluoro-5-nitrotoluene by using 2,4-dichloro-5-nitrotoluene as a raw material.
相比较实施例4-5和实施例1，所获得的第二中间体的收率不同，主要原因在于，实施例4-5中分别采用实施例3和4中所获得的第一中间体作为产物，导致获得的第二中间体不同及其收率也不同。但相对而言，采用实施例2中的方法制备获得的2,5-二氟-4-硝基甲苯作为第一中间体，较易得到更高收率的第二中间体2,5-二氟-4-甲基苯胺。Compared with Example 4-5 and Example 1, the yields of the obtained second intermediates are different, the main reason is that the first intermediates obtained in Examples 3 and 4 are respectively used in Examples 4-5 as product, resulting in different obtained second intermediates and different yields. However, relatively speaking, using the 2,5-difluoro-4-nitrotoluene prepared by the method in Example 2 as the first intermediate, it is easier to obtain a higher yield of the second intermediate 2,5-dinitrotoluene Fluoro-4-methylaniline.
相比较实施例6-7和实施例1，所获得的第三中间体的收率不同，主要原因在于，实施例6-7中分别采用实施例4和5中所获得的第二中间体作为产物，导致获得的第三中间体不同及其收率也不同。但相对而言，采用4,5-二氟-2-甲基苯胺作为第二中间体进行加热裂解反应，利于提高获得的第三中间体的收率，这也跟第二中间体的纯度有着紧密的联系。Compared with Example 6-7 and Example 1, the yield of the obtained third intermediate is different, the main reason is that in Example 6-7, the second intermediate obtained in Examples 4 and 5 was used as product, resulting in different obtained third intermediates and different yields. However, relatively speaking, using 4,5-difluoro-2-methylaniline as the second intermediate for thermal cracking is beneficial to improve the yield of the third intermediate obtained, which is also related to the purity of the second intermediate. close connection.
相比较实施例8-16和实施例1，步骤三和四中的参数发生变化时，会对 2,4,5-三氟甲苯的收率和纯度产生一定影响，但变化幅度较小。说明在本申请的制备工艺下，2,4,5-三氟甲苯的收率均较高。Compared with Examples 8-16 and Example 1, when the parameters in steps 3 and 4 change, the yield and purity of 2,4,5-trifluorotoluene will have a certain impact, but the change range is small. It is indicated that under the preparation process of the present application, the yields of 2,4,5-trifluorotoluene are all high.
实施例17-19相对于实施例1而言，虽然步骤五至七分别不同，但对应步骤获得的产物得率与实施例1中相差不大，表明步骤五至七中的操作不易对对应步骤的产物收率产生影响。Embodiments 17-19 are relative to embodiment 1, although steps five to seven are different respectively, but the product yield obtained in the corresponding steps is not much different from that in embodiment 1, indicating that the operations in steps five to seven are not easy to correspond to the steps. impact on the product yield.
本具体实施例仅仅是对本申请的解释，其并不是对本申请的限制，本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改，但只要在本申请的权利要求范围内都受到专利法的保护。This specific embodiment is only an explanation of the application, and it does not limit the application. Those skilled in the art can make modifications to the embodiment without creative contribution as needed after reading this specification, but as long as the rights of the application are All claims are protected by patent law.

Claims (10)

  1. 一种2,4,5-三氟苯乙酸的制备方法，其特征在于，包括如下步骤：A kind of preparation method of 2,4,5-trifluorophenylacetic acid, is characterized in that, comprises the steps:
    步骤一，将原料、季铵盐催化剂、环丁砜、氟化钾，在反应温度为150-230℃的条件下，形成充分反应，获得第一中间体；In step 1, the raw materials, quaternary ammonium salt catalyst, sulfolane, and potassium fluoride are fully reacted under the condition that the reaction temperature is 150-230° C. to obtain the first intermediate;
    步骤二，将步骤一中获得的第一中间体通过加氢催化反应获得第二中间体；In step 2, the first intermediate obtained in step 1 is subjected to hydrogenation catalytic reaction to obtain the second intermediate;
    步骤三，将步骤二中获得的第二中间体与氟化试剂，在25±5℃的温度下，发生成盐反应，骤冷，再与亚硝酸钠水溶液形成重氮化反应，获得重氮盐；In step 3, the second intermediate obtained in step 2 and the fluorinating reagent are subjected to a salt-forming reaction at a temperature of 25±5 °C, quenched, and then diazotized with an aqueous sodium nitrite solution to obtain diazonium. Salt;
    步骤四，将步骤三中的重氮盐经高温裂解反应，获得2,4,5-三氟甲苯；In step 4, the diazonium salt in step 3 is subjected to high temperature cracking reaction to obtain 2,4,5-trifluorotoluene;
    步骤五，将步骤四中获得的2,4,5-三氟甲苯经过卤代反应，获得2,4,5-三氟苄氯；In step 5, the 2,4,5-trifluorotoluene obtained in step 4 is subjected to halogenation reaction to obtain 2,4,5-trifluorobenzyl chloride;
    步骤六，将步骤五中获得的2,4,5-三氟苄氯经过氰化反应，获得2,4,5-三氟苯乙腈；In step 6, the 2,4,5-trifluorobenzyl chloride obtained in step 5 is subjected to a cyanation reaction to obtain 2,4,5-trifluorobenzeneacetonitrile;
    步骤七，将步骤六中获得的2,4,5-三氟苯乙腈经过水解反应，获得2,4,5-三氟苯乙酸；In step seven, the 2,4,5-trifluorophenylacetonitrile obtained in step six is subjected to a hydrolysis reaction to obtain 2,4,5-trifluorophenylacetic acid;
    步骤一中的原料为3,4-二氯-6-硝基甲苯、2,4-二氯-5-硝基甲苯、2,5-二氯-4-硝基甲苯中的任意一种；The raw material in step 1 is any one of 3,4-dichloro-6-nitrotoluene, 2,4-dichloro-5-nitrotoluene and 2,5-dichloro-4-nitrotoluene;
    步骤一中的第一中间体为4,5-二氟-2-硝基甲苯、2,4-二氟-5-硝基甲苯、2,5-二氟-4-硝基甲苯中的一种；The first intermediate in step 1 is one of 4,5-difluoro-2-nitrotoluene, 2,4-difluoro-5-nitrotoluene and 2,5-difluoro-4-nitrotoluene. kind;
    步骤二中，第二中间体为4,5-二氟-2-甲基苯胺、2,4-二氟-5-甲基苯胺、2,5-二氟-4-甲基苯胺中的一种；In step 2, the second intermediate is one of 4,5-difluoro-2-methylaniline, 2,4-difluoro-5-methylaniline and 2,5-difluoro-4-methylaniline. kind;
    步骤三中，氟化试剂包括氟硼酸水溶液、氟化氢吡啶溶液中的任意一种。In step 3, the fluorination reagent includes any one of fluoroboric acid aqueous solution and hydrogen fluoride pyridine solution.
    Figure PCTCN2020127713-appb-100001
    Figure PCTCN2020127713-appb-100001
    Figure PCTCN2020127713-appb-100002
    Figure PCTCN2020127713-appb-100002
  2. 根据权利要求1的一种2,4,5-三氟苯乙酸的制备方法，其特征在于，步骤一中，原料与环丁砜的重量比为1:(2～5)，氟化钾与原料的摩尔比为(2.1～3.5):1，反应温度为180℃，保温反应10h，获得第一中间体；The preparation method of a kind of 2,4,5-trifluorophenylacetic acid according to claim 1, is characterized in that, in step 1, the weight ratio of raw material and sulfolane is 1:(2～5), the ratio of potassium fluoride to raw material is 1:(2～5). The molar ratio is (2.1～3.5):1, the reaction temperature is 180°C, and the reaction is kept for 10h to obtain the first intermediate;
    原料为2,4-二氯-5-硝基甲苯；The raw material is 2,4-dichloro-5-nitrotoluene;
    第一中间体为2,4-二氟-5-硝基甲苯。The first intermediate is 2,4-difluoro-5-nitrotoluene.
  3. 根据权利要求1的一种2,4,5-三氟苯乙酸的制备方法，其特征在于，步骤一中，原料与环丁砜的重量比为1:(2～5)；The preparation method of a kind of 2,4,5-trifluorophenylacetic acid according to claim 1, is characterized in that, in step 1, the weight ratio of raw material and sulfolane is 1:(2～5);
    在120-180℃的条件下，先加入与原料的摩尔比为(2～2.5):1的氟化钾，反应10h后升温至220-230℃；Under the condition of 120-180 ℃, firstly add potassium fluoride with a molar ratio of (2-2.5):1 to the raw material, and then heat up to 220-230 ℃ after reacting for 10 hours;
    再补加与原料的摩尔比＝(1～1.5):1的氟化钾，保温，反应2h，获得第一中间体；原料为3,4-二氯-6-硝基甲苯或2,5-二氯-4-硝基甲苯；Then add potassium fluoride with a molar ratio to the raw material=(1～1.5):1, keep the temperature, and react for 2 h to obtain the first intermediate; the raw material is 3,4-dichloro-6-nitrotoluene or 2,5 - Dichloro-4-nitrotoluene;
    第一中间体为4,5-二氟-2-硝基甲苯或2,5-二氟-4-硝基甲苯。The first intermediate is 4,5-difluoro-2-nitrotoluene or 2,5-difluoro-4-nitrotoluene.
  4. 根据权利要求1的一种2,4,5-三氟苯乙酸的制备方法，其特征在于，步骤二中，加氢催化反应的温度为50-75℃，氢气的压力为0.1-1.0MPa，加氢催化反应的时间为2-5h；加氢催化反应采用的催化剂为雷尼镍催化剂或钯碳催化剂。A kind of preparation method of 2,4,5-trifluorophenylacetic acid according to claim 1, is characterized in that, in step 2, the temperature of hydrogenation catalytic reaction is 50-75 ℃, and the pressure of hydrogen is 0.1-1.0MPa, The time of the hydrogenation catalytic reaction is 2-5h; the catalyst used in the hydrogenation catalytic reaction is a Raney nickel catalyst or a palladium carbon catalyst.
  5. 根据权利要求1的一种2,4,5-三氟苯乙酸的制备方法，其特征在于，步骤三中，第二中间体、氟化试剂、亚硝酸钠的摩尔比为1:(2.5～4):(1.05～1.1)；第二中间体与氟化试剂发生成盐反应后骤冷至-40～0℃，进行重氮化反应；氟化试剂的质量浓度为25-40％。The preparation method of a kind of 2,4,5-trifluorophenylacetic acid according to claim 1, is characterized in that, in step 3, the mol ratio of the second intermediate, fluorination reagent, sodium nitrite is 1:(2.5～ 4): (1.05～1.1); the second intermediate and the fluorinated reagent are subjected to a salt-forming reaction and then quenched to -40～0° C. to carry out a diazotization reaction; the mass concentration of the fluorinated reagent is 25-40%.
  6. 根据权利要求1的一种2,4,5-三氟苯乙酸的制备方法，其特征在于，步骤四中，高温裂解反应的温度为90-300℃，时间为2-4h。The method for preparing 2,4,5-trifluorophenylacetic acid according to claim 1, wherein in step 4, the temperature of the high-temperature cracking reaction is 90-300°C, and the time is 2-4h.
  7. 根据权利要求1的一种2,4,5-三氟苯乙酸的制备方法，其特征在于，步骤五中，卤代反应时，将2,4,5-三氟甲苯、催化剂以重量比为1：(0.005-0.02)进行反应，升温至110-130℃，持续通入干燥的氯气3-5h，后停止通氯气，冷却，水洗至中 性，干燥，减压蒸馏，获得2,4,5-三氟苄氯；催化剂为偶氮二异丁腈。The preparation method of a kind of 2,4,5-trifluorophenylacetic acid according to claim 1, is characterized in that, in step 5, during halogenation reaction, 2,4,5-trifluorotoluene and catalyst are in a weight ratio of 1: (0.005-0.02) to react, heat up to 110-130 ° C, continue to feed dry chlorine for 3-5h, then stop the chlorine, cool, wash with water until neutral, dry, and distilled under reduced pressure to obtain 2,4, 5-Trifluorobenzyl chloride; the catalyst is azobisisobutyronitrile.
  8. 根据权利要求1的一种2,4,5-三氟苯乙酸的制备方法，其特征在于，步骤六中，氰化反应时，2,4,5-三氟苄氯：氰化钠水溶液中的氰化钠的摩尔比为1:(1～1.1)，相转移催化剂、2,4,5-三氟苄氯、二甲基亚砜的重量比为(0.01-0.02)：1:(1-3)进行混合，在温度为60-80℃的条件下保温氰化反应2-5h，再采用乙醇萃取，干燥，蒸馏再精馏，获得2,4,5-三氟苯乙腈；相转移催化剂为偶氮二异丁腈。The method for preparing 2,4,5-trifluorophenylacetic acid according to claim 1, wherein in step 6, during the cyanation reaction, 2,4,5-trifluorobenzyl chloride: sodium cyanide aqueous solution The molar ratio of sodium cyanide is 1:(1～1.1), and the weight ratio of phase transfer catalyst, 2,4,5-trifluorobenzyl chloride and dimethyl sulfoxide is (0.01-0.02):1:(1 -3) Mixing, keeping the cyanation reaction at a temperature of 60-80°C for 2-5h, then extracting with ethanol, drying, distilling and then rectifying to obtain 2,4,5-trifluorophenylacetonitrile; phase transfer The catalyst is azobisisobutyronitrile.
  9. 根据权利要求1的一种2,4,5-三氟苯乙酸的制备方法，其特征在于，步骤七中，水解反应时，将酸升温至100-110℃的稳定范围内滴加2,4,5-三氟苯乙腈，在120℃的温度下保温6h，冷却至室温，滴加100mL水，冷却、抽滤，将固体用甲醇重结晶后精制烘干后得到2,4,5-三氟苯乙酸；A method for preparing 2,4,5-trifluorophenylacetic acid according to claim 1, characterized in that, in the seventh step, during the hydrolysis reaction, the acid is heated to a stable range of 100-110° C. and added dropwise to 2,4 ,5-Trifluorophenylacetonitrile was kept at 120°C for 6h, cooled to room temperature, 100mL of water was added dropwise, cooled, filtered with suction, the solid was recrystallized from methanol, purified and dried to obtain 2,4,5-trifluorophenylacetonitrile. Fluorophenylacetic acid;
    酸包括硫酸、盐酸、磷酸、多聚磷酸、醋酸中的至少一种。The acid includes at least one of sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, and acetic acid.
  10. 根据权利要求9的一种2,4,5-三氟苯乙酸的制备方法，其特征在于，酸为硫酸与醋酸混合形成，2,4,5-三氟苯乙腈、硫酸、醋酸的重量比为1:(1.5～3):(0.02～0.1)，硫酸的质量浓度为70％。A kind of preparation method of 2,4,5-trifluorophenylacetic acid according to claim 9, it is characterised in that the acid is formed by mixing sulfuric acid and acetic acid, the weight ratio of 2,4,5-trifluorophenylacetonitrile, sulfuric acid, acetic acid It is 1:(1.5～3):(0.02～0.1), and the mass concentration of sulfuric acid is 70%.
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