WO2022061918A1 - 一种3,5-二卤三氟甲苯及3'-氯-5'-(三氟甲基)苯基三氟乙酮的制备方法 - Google Patents

一种3,5-二卤三氟甲苯及3'-氯-5'-(三氟甲基)苯基三氟乙酮的制备方法 Download PDF

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WO2022061918A1
WO2022061918A1 PCT/CN2020/118509 CN2020118509W WO2022061918A1 WO 2022061918 A1 WO2022061918 A1 WO 2022061918A1 CN 2020118509 W CN2020118509 W CN 2020118509W WO 2022061918 A1 WO2022061918 A1 WO 2022061918A1
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compound
preparation
reaction
reaction solution
dihalotrifluorotoluene
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PCT/CN2020/118509
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French (fr)
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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 WO2022061918A1 publication Critical patent/WO2022061918A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/20—Diazonium compounds
    • 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
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
    • C07F3/02—Magnesium compounds

Definitions

  • the application relates to the technical field of chemical pharmacy, in particular to a method for preparing 3,5-dihalotrifluorotoluene; the application also relates to a 3'-chloro-5'-(trifluoromethyl)phenyl trifluorotoluene The preparation method of fluoroethyl ketone.
  • 3-Halo-5-(trifluoromethyl)phenyltrifluoroethanone is an important intermediate for synthesizing pesticides or veterinary drugs, and has broad market prospects.
  • 3,5-Dihalotrifluorotoluene is one of the raw materials for the preparation of 3'-chloro-5'-(trifluoromethyl)phenyltrifluoroethanone.
  • the production process of 3,5-dihalotrifluorotoluene is complicated and difficult to produce on a large scale, thereby increasing the production cost of the enterprise and seriously affecting the economic effect of the enterprise.
  • the present application provides a method for preparing 3,5-dihalotrifluorotoluene, which is prepared from cheap and readily available raw materials, and has relatively low cost. good economic effect.
  • the present application provides a method for preparing 3'-chloro-5'-(trifluoromethyl)phenyltrifluoroethanone from the above-mentioned raw materials, which has the advantages of good economic effect and low production cost.
  • the present application provides a method for preparing 3,5-dihalogenotrifluorotoluene, using compound I as a raw material, through diazotization deamination reaction to prepare compound II;
  • R 1 and R 2 can be any one of F, Cl, Br, and I, respectively;
  • reaction solution I dissolving compound 1 in solvent I, and cooling to -10 ⁇ 0°C to obtain reaction solution I;
  • reaction solution II add acid to reaction solution I, and mix evenly, so that reaction solution I is acidified to obtain reaction solution II;
  • reaction solution III S3, adding a nitrous acid reagent solution to the reaction solution II, keeping the temperature of the system below 0 °C, and fully reacting to diazotize the amino group of compound I to obtain compound III to obtain reaction solution III;
  • step S5 separating and purifying the crude product of compound II obtained in step S4 to obtain compound II;
  • solvent I is selected from one in toluene, ethanol, isopropanol or the homogeneous mixed solvent formed by any two or more thereof; in step S3, nitrous acid reagent is selected from sodium nitrite, potassium nitrite, calcium nitrite, Any one of barium nitrite, silver nitrite and C1-C6 alkyl nitrite, and the catalyst is cuprous salt
  • 3,5-dihalotrifluorotoluene is obtained after deamination of the dihalotrifluoromethylbenzene substituted with the para-amino group.
  • the price of the above-mentioned raw materials is relatively low and the supply is relatively sufficient. Taking compound I where both R 1 and R 2 are chlorine as an example, the price is only about 150 yuan/kg, which is relatively cheap.
  • the solvents that need to be used in the deamination reaction process are all conventional solvents, and do not need to go through anhydrous and oxygen-free reaction conditions, and do not need to use complex catalysts, which further reduces the production cost.
  • the treatment of the wastewater finally obtained in the above reaction process is also convenient. The above factors collectively reflect the advantages of the low-cost, high-efficiency, low-cost, and good economic effects of the synthetic method in the technical solution of the present application.
  • step S1 compound I is first dissolved, and then acid I is added to react with compound I.
  • compound I can dissolve and disperse better, is not easy to agglomerate and agglomerate, and can be better acidified with acid I. Dilution of acid I with solvent I helps to suppress the heating process of the system. Carrying out the above reaction at low temperature can suppress the occurrence of side reactions and greatly improve the final yield.
  • the above reaction can be completed in one step, which reduces the additional risk and cost caused by material flow.
  • the generated waste liquids are all acidic waste liquids, which can be centrally and uniformly treated, further reducing the production cost.
  • the present application may be further configured as: in step S1, toluene is selected as the solvent.
  • toluene as a solvent has the following advantages: 1. Toluene is low in toxicity and price, which helps to improve safety and reduce production costs during use. 2. Toluene has a low polarity, and it is not easy to form a solvation effect around the molecule during the reaction, so it is beneficial to increase the reaction rate and make the reaction proceed faster.
  • step S4 cuprous chloride is selected as the catalyst, and the reaction temperature is 20°C.
  • cuprous chloride When cuprous chloride is used as the catalyst, the solubility of cuprous chloride is good, and it can be quickly dispersed in the system at a lower temperature, thereby helping to further improve the reaction rate.
  • the reaction In the above process, the reaction can be completed directly at room temperature, and the conditions are mild and not harsh, which helps to further reduce the production cost of the enterprise.
  • the present application can be further configured as: the nitrous acid reagent is sodium nitrite.
  • sodium nitrite dissolves better in the water phase, and can be directly extracted by adding water in the subsequent process, thereby helping to optimize the process and thereby reducing production costs.
  • sodium nitrite is cheaper and more convenient to store, which further reduces the production cost of the enterprise and improves the economic effect of the enterprise.
  • the present application can be further configured as: in step S2, sulfuric acid is selected to acidify the reaction solution I, and the total amount of sulfuric acid added is 3 to 5 times that of compound I.
  • sulfuric acid is selected for the reaction, and the sulfuric acid is not easy to bring in other impurity ions in the reaction process, so it is helpful to improve the purity of the reaction.
  • the dissociation constant of sulfuric acid is moderate, which can not only keep enough hydrogen ions in the system to make the amino group salt, but also can form a certain hydrogen ion concentration balance in the system during the reaction process, so the hydrogen ion concentration in the reaction process can be reduced. It is not easy to produce large fluctuations.
  • the total amount of sulfuric acid is set to be 3 to 5 times the amount of compound I, which not only ensures that compound I can be acidified quickly and sufficiently, has a faster reaction rate, but also helps to reduce the amount of sulfuric acid used.
  • the present application can be further configured as: in step S2, the sulfuric acid is prepared into a sulfuric acid solution with a mass fraction of 70-95%.
  • sulfuric acid with a concentration of 85-92.5% is selected to acidify the amino group to form a salt.
  • the sulfuric acid of the above concentration is first of all less corrosive and less costly to equipment. Secondly, it has a large hydrogen ion concentration, which can efficiently achieve the effect of acidification, improve the reaction rate and save production time.
  • the sulfuric acid of the above-mentioned concentration has a small volume, so it is not easy to introduce too many other solvents during the reaction process, which reduces the overall volume of the reaction solution and the cost of post-treatment. The above two factors work together to improve the economic effect of the above production process.
  • reaction solution I can be further configured as: slowly dropwise added to the reaction solution I within 20-30 min, and continue to keep the reaction for 0.8-1.5 h.
  • the sulfuric acid is added to the system by dropwise addition, so that it is not easy to cause the sulfuric acid to cause excessive local acidity in the reaction system during the addition process, and it is also difficult to make the system silver sulfuric acid exothermic and generate excessively high temperature, reducing the The occurrence of side reactions, thereby further improving the utilization rate of raw materials.
  • the reaction is continued for a period of time, so that the amino group can be more fully formed into a salt, and the utilization rate of the raw material can be further improved.
  • step S5 specifically includes the following steps:
  • step S5-1 adding inorganic salt solution to the crude product of compound II obtained in step S4, extracting, and retaining the organic phase;
  • step S5-2 adding a desiccant to the organic phase in step S1 for drying, and then distilling under reduced pressure to obtain compound II;
  • Described inorganic salt is selected from any one in sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, or the composition formed by any number of above-mentioned substances, so
  • the desiccant is selected from one of anhydrous sodium sulfate, anhydrous magnesium sulfate, and anhydrous calcium chloride.
  • step S5 the extraction is performed by adding an inorganic salt solution, and the pH value of the system can be adjusted by selecting the above-mentioned inorganic salt, so that the system changes from the previous strong acidity to neutral or weakly alkaline, so as to facilitate the conversion of the acid in the organic phase.
  • It is a salt, so that it can be fully dissolved in water, reduce the impurities in the organic phase after extraction, and then improve the purity of the final product.
  • the application also provides a preparation method of 3'-chloro-5'-(trifluoromethyl)phenyl trifluoroethanone, comprising the following steps:
  • step P3 the Grignard reagent intermediate obtained in step P2 is reacted with reagent B to obtain 3'-chloro-5'-(trifluoromethyl) phenyl trifluoroethanone crude product;
  • reagent A is R 3 is one of Cl, Br, F, dimethylamino, diethylamino, piperidinyl, morpholinyl or tetrahydropyrrole, and R 4 is Na + , Zn2 + , Mg 2+ , Cu 2+ , Li + , K + , Ca 2+ , Ni + , n is the number of positive charges carried by R 4 ;
  • R 1 is Cl
  • R 2 is one of Cl and Br.
  • the present application includes at least one of the following beneficial technical effects:
  • reaction solution I dissolve 0.2 mol of compound 1 in 200 mL of solvent I, and cool it to 0 °C to obtain reaction solution I;
  • reaction solution II Add a nitrous acid reagent solution containing 0.44 mol of nitrous acid reagent to the reaction solution II, keep the temperature of the system below 0 °C, and keep the reaction for 2 hours to obtain reaction solution III;
  • reaction solution III is heated to 20°C, 87 g of 50% hypophosphorous acid is uniformly added within 60 min, and 0.5 g of cuprous chloride is added, and the reaction is fully stirred and reacted for 2 h to obtain a crude product of compound II;
  • step S5 separating and purifying the crude product of compound II obtained in step S4 to obtain compound II.
  • R 1 and R 2 are both -Cl, and the nitrous acid reagent solution is a sodium nitrite solution with a mass fraction of 33%.
  • Step S5 specifically includes the following sub-steps:
  • step S5-1 the compound II crude product obtained in step S4 is left to stand for stratification, and a saturated sodium bicarbonate solution is added as an inorganic salt solution, fully mixed and left to stand for liquid separation and retain the organic phase;
  • a preparation method of 3,5-dihalotrifluorotoluene the difference from Example 1 is that R 1 and R 2 are different.
  • R 1 and R 2 in Examples 2 to 6 are shown in Table 1.
  • step S1 A preparation method of 3,5-dihalotrifluorotoluene, the difference from Example 1 is that in step S1, solvent I selects ethanol and isopropanol respectively.
  • step S2 A preparation method of 3,5-dihalogenotrifluorotoluene, the difference from Example 1 is that in step S2, the added acid is 66.0 g of glacial acetic acid.
  • a preparation method of 3,5-dihalotrifluorotoluene is different from Example 1 in that, in step S2, sulfuric acid with a mass fraction of 45% is selected, and the amount of sulfuric acid added is 193.2 g.
  • a preparation method of 3,5-dihalotrifluorotoluene is different from Example 1 in that in step S2, sulfuric acid with a mass fraction of 98% is selected.
  • a method for preparing 3,5-dihalotrifluorotoluene differs from Example 1 in that in step S2, the dropwise addition process is completed within 20 minutes, and the reaction is continued for 1.5h after the dropwise addition is completed.
  • a method for preparing 3,5-dihalotrifluorotoluene differs from Example 1 in that in step S2, the dropwise addition process is completed within 25 minutes, and the reaction is continued for 0.8h after the dropwise addition is completed.
  • a method for preparing 3,5-dihalogenotrifluorotoluene differs from Example 1 in that, in step S2, the dropwise addition process is completed within 5 min.
  • a preparation method of 3,5-dihalogenotrifluorotoluene is different from Example 1 in that in step S2, the dropwise addition process is completed within 60 min.
  • a method for preparing 3,5-dihalogenotrifluorotoluene differs from Example 1 in that in step S2, after the dropwise addition is completed, the reaction is continued for 30 min.
  • a preparation method of 3,5-dihalotrifluorotoluene is different from Example 1 in that in step S2, after the dropwise addition is completed, the reaction is continued for 3h.
  • a preparation method of 3,5-dihalogenotrifluorotoluene is different from Example 1 in that in step S3, the nitrous acid reagent is potassium nitrite.
  • a method for preparing 3,5-dihalogenotrifluorotoluene is different from Example 1 in that in step S3, the nitrous acid reagent is methyl nitrite.
  • a method for preparing 3,5-dihalogenotrifluorotoluene is different from Example 1 in that in step S3, the nitrous acid reagent is calcium nitrite, and the amount of the nitrous acid reagent added is 0.22 mol.
  • step S5 the inorganic salt solution is a sodium carbonate solution with a mass fraction of 5% and a hydrogen with a mass fraction of 5%, respectively.
  • step S5 A preparation method of 3,5-dihalotrifluorotoluene, the difference from Example 1 is that in step S5, the desiccant is anhydrous sodium sulfate.
  • a preparation method of 3,5-dihalotrifluorotoluene, the difference from Example 1 is that the reaction is processed in a large amount with the method in Example 1, and the specific steps are as follows:
  • reaction solution I dissolve 2mol of compound 1 in 1.5L of solvent I, and cool to 0°C to obtain reaction solution I;
  • reaction solution III S3, adding a nitrous acid reagent solution containing 4.4 mol of nitrous acid reagent to the reaction solution II, keeping the temperature of the system below 0 °C, and keeping the reaction temperature for 2 hours to obtain reaction solution III;
  • reaction solution III is heated to 20° C., 87 g of 50% hypophosphorous acid and 0.5 g of cuprous chloride are added, fully stirred and reacted for 2 h to obtain a crude product of compound II;
  • step S5 separating and purifying the crude product of compound II obtained in step S4 to obtain compound II.
  • R 1 and R 2 are both -Cl, and the nitrous acid reagent solution is a sodium nitrite solution with a mass fraction of 33%.
  • Step S5 specifically includes the following sub-steps:
  • step S5-1 the compound II crude product obtained in step S4 is left to stand for stratification, and a saturated sodium bicarbonate solution is added as an inorganic salt solution, fully mixed and left to stand for liquid separation and retain the organic phase;
  • a preparation method of 3,5-dihalotrifluorotoluene, the difference from Example 1 is that in step S5-1, the inorganic salt solution is replaced with an equal amount of water.
  • a preparation method of 3,5-dihalotrifluorotoluene is different from Example 1 in that, in step S5-1, an equal amount of sodium chloride solution with a mass fraction of 5% is used as the inorganic salt solution.
  • a preparation method of 3'-chloro-5'-(trifluoromethyl)phenyl trifluoroethanone, the difference from Example 38 is that in step P1, 3 prepared according to the method in Example 2 -Chloro-5-bromotrifluorotoluene, in step P2, replace 3,5-dichlorotrifluorotoluene with an equivalent amount of 3-chloro-5-bromotrifluorotoluene.
  • a kind of preparation method of 3'-chloro-5'-(trifluoromethyl) phenyl trifluoroethanone the difference with embodiment 38 is, in step P3, use the trifluoroacetyl diethyl of equal material amount Amine replaces trifluoroacetyldimethylamine.
  • a kind of preparation method of 3'-chloro-5'-(trifluoromethyl) phenyl trifluoroethanone is, in step P3, with the trifluoroacetyl piperidine of the amount of substance Substitute trifluoroacetyldimethylamine.
  • a kind of preparation method of 3'-chloro-5'-(trifluoromethyl) phenyl trifluoroethanone is, in step P3, with the trifluoroacetyl chloride of the amount of the same substance to replace Trifluoroacetyldimethylamine.
  • a kind of preparation method of 3'-chloro-5'-(trifluoromethyl) phenyl trifluoroethanone is, in step P3, is replaced with the sodium trifluoroacetate of equivalent material amount Trifluoroacetyldimethylamine.
  • a kind of preparation method of 3'-chloro-5'-(trifluoromethyl) phenyl trifluoroethanone the difference with embodiment 39 is, in step P3, with the amount of trifluoroacetyl diethyl Amine replaces trifluoroacetyldimethylamine.
  • a kind of preparation method of 3'-chloro-5'-(trifluoromethyl) phenyl trifluoroethyl ketone is, in step P3, with the trifluoroacetyl piperidine of equal material amount Substitute trifluoroacetyldimethylamine.
  • a kind of preparation method of 3'-chloro-5'-(trifluoromethyl) phenyl trifluoroethanone the difference with embodiment 39 is, in step P3, with the trifluoroacetyl chloride of the amount of the substance is replaced Trifluoroacetyldimethylamine.
  • a kind of preparation method of 3'-chloro-5'-(trifluoromethyl) phenyl trifluoroethyl ketone is, in step P3, replace with the sodium trifluoroacetate of equivalent material amount Trifluoroacetyldimethylamine.
  • Example 9-12 Compared with Example 1, in Examples 9-12, the concentration of sulfuric acid added in step S2 was adjusted, and in Examples 13-14, glacial acetic acid and phosphoric acid were respectively selected to replace sulfuric acid. In Examples 15-18, the amount of sulfuric acid added was adjusted, while in Example 19, the sulfuric acid added was 45% sulfuric acid with a lower concentration. In Example 20, what was selected was concentrated sulfuric acid.
  • the concentration of sulfuric acid should be at least 70% to achieve better reaction effect. Due to the higher price of other organic strong acids, although they can achieve similar effects, they also increase the production cost. In addition, when the concentrated sulfuric acid with a concentration of 98% is selected, other side reactions will be caused, and when the concentration of sulfuric acid exceeds 95%, the corrosion of the equipment will be stronger, so the maintenance cost of the equipment will be additionally increased. Experiments show that the reaction effect is the best when the concentration of sulfuric acid is 92.5%.
  • Example 21-26 the dropping time of sulfuric acid and the reaction time after dropping were adjusted. From the data, it can be seen that the dropping time is within 20-30 min, and the reaction is continued for 0.8-1.5 h after the dropping is completed. The amino group is completely salt-formed, and no other side reactions will occur. If the dropwise addition is too fast, it is easy to cause local overheating, resulting in a series of side reactions, thereby causing both yield and purity to decrease.
  • Example 27 compared with Example 1, the nitrous acid reagent was adjusted. It can be seen from the data that compared with other potassium nitrite and calcium nitrite reagents, the selection of sodium nitrite helps to improve the yield of the reaction, and the price of sodium nitrite is relatively cheap and has a better economic effect. Selecting methyl nitrite can slightly improve the yield of compound II, but methyl nitrite has strong solubility in the organic phase, and it is difficult to directly separate by extraction during the separation process, resulting in a decrease in the purity of compound II.
  • Example 30 to 33 the selection of inorganic salts was adjusted.
  • Inorganic salts were mainly used to adjust the pH value of the system, so that the acidic system during the reaction was converted into neutral or weakly alkaline, and the residual acid in the system was salified, thereby Increase the solubility of acid ions in water.
  • the above process helps to simplify the post-treatment process and the process of wastewater treatment on the one hand, and also helps to improve the purity of the product on the other hand.
  • water and sodium chloride solution were selected as the treatment for the crude product of compound II, both of which would lead to a decrease in the purity of compound II.
  • anhydrous sodium sulfate was selected to replace anhydrous magnesium chloride to dry the organic phase, which had no obvious effect on the yield and purity of compound II.
  • step S2 the temperature after the acid is added dropwise is 50°C, and the reaction time is 25 minutes.
  • the yield of Comparative Example 3 was 74.7%, and the final product purity was 99.3%.
  • step S2 the temperature after the acid is added dropwise is 50°C.
  • the yield of Comparative Example 1 was 72.8%, and the final product purity was 99.5%.
  • step S1 the method of first dissolving with a solvent and then acidifying can greatly improve the yield obtained in the production process. And in step S1, compared with performing the reaction after heating, performing the reaction at a low temperature can obtain a higher yield, and at the same time reduce the production cost.
  • the above embodiments provide a preparation method of 3,5-dihalotrifluorotoluene, which has lower production cost, better economic effect, and has the ability to further enlarge production.
  • the above embodiment also provides a production process of 3,5-dihalotrifluorotoluene as a raw material to produce 3'-chloro-5'-(trifluoromethyl)phenyl trifluoroethanone, which also has good economical efficiency. effect.

Abstract

涉及化工制药的技术领域，尤其是涉及一种3,5-二卤三氟甲苯的制备方法；以3,5-二卤-4-氨基三氟甲苯为原料，经重氮化脱氨基反应，得到3,5-二卤三氟甲苯，生产成本较小，就有较好的经济效应。还涉及一种3'-氯-5'-(三氟甲基)苯基三氟乙酮的制备方法，以3,5-二卤三氟甲苯为原料，经格氏试剂化反应，再与三氟甲基化试剂发生亲核加成反应，同样具有较好的经济效应。

Description

一种3,5-二卤三氟甲苯及3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法 技术领域
本申请涉及化工制药的技术领域，尤其是涉及一种3,5-二卤三氟甲苯的制备方法；本申请还涉及一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法。
背景技术
3-卤代-5-(三氟甲基)苯基三氟乙酮是用于合成农药或兽药的重要中间体，具有广阔的市场前景。
3,5-二卤三氟甲苯是制备3’-氯-5’-(三氟甲基)苯基三氟乙酮的原料之一。目前，对3,5-二卤三氟甲苯生产工艺较为复杂且难以大规模生产，从而增大了企业的生产成本，严重影响了企业的经济效应。
发明内容
针对现有技术存在的不足，首先，本申请提供了一种3,5-二卤三氟甲苯的制备方法，通过便宜易得的原料对3,5-二卤三氟甲苯进行制备，具有较好的经济效应。
其次，本申请提供了一种通过上述原料制备3’-氯-5’-(三氟甲基)苯基三氟乙酮的方法，具有经济效应好、生产成本低的优点。
在一个实施方案中，本申请提供了一种3,5-二卤三氟甲苯的制备方法，以化合物I为原料，经重氮化脱氨基反应制得化合物Ⅱ；
Figure PCTCN2020118509-appb-000001
其中，R 1、R 2可分别为F、Cl、Br、I中的任意一种；
具体包括如下步骤：
S1、将化合物1溶解于溶剂I中，并降温至-10～0℃，得到反应液I；
S2、向反应液I中加入酸，并混合均匀，使反应液I酸化，得到反应液Ⅱ；
S3、向反应液Ⅱ中加入亚硝酸试剂溶液，保持体系温度低于0℃，并充分反应，使化合物I的氨基重氮化并得到化合物Ⅲ，得到反应液Ⅲ；
S4、向反应液Ⅲ中加入次磷酸和催化剂，通过次磷酸还原反应液Ⅲ中的化合物Ⅲ上的重氮基团离去，得到化合物Ⅱ粗产品；
S5、对步骤S4中得到的化合物Ⅱ粗产品进行分离提纯，得到化合物Ⅱ；
Figure PCTCN2020118509-appb-000002
其中溶剂I选自甲苯、乙醇、异丙醇中的一种或其中任意两种或以上形成的均相混合溶剂；步骤S3中亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的任意一种，所述催化剂为亚铜盐
以对位氨基取代的二卤三氟甲基苯脱氨基处理后得到3,5-二卤三氟甲苯，首先，上述原料价格较为低廉，供应量也较为充足。以R 1、R 2均为氯的化合物I为例，其价格仅为150元/公斤左右，价格较为低廉。此外，脱氨基反应过程中需要使用到的溶剂均为常规溶剂，且无需经过无水无氧的反应条件，也无需使用复杂的催化剂，进一步减少了生产的成本。此外，上述反应过程中最终得到的废水处理也较为方便。上述因素共同体现了本申请技术方案中合成方法低价高效、成本较低，经济效应较好的优势。
在上述技术方案中，反正整体处于低于0℃的状态进行，较为安全，且没有需要涉及到-78℃温度范畴的反应，因此控温成本较低。在步骤S1中，先将化合物I溶解后，再加入酸I与化合物I进行反应，一方面化合物I可以更好地溶解分散，不易团聚结块，可以更好的与酸I进行酸化反应，同时通过溶剂I稀释酸I，有助于抑制体系的升温过程。在低温下进行上述反应，可以抑制副反应的发生，大大提高最终产率。另外，上述反应一步即可完成，减少了物料流动带来的额外风险和成本。此外，在上述反应过程中，产生的废液均为酸性废液，可以集中统一处理、进一步降低了生产成本。
本申请在一较佳示例中可以进一步配置为：在步骤S1中，溶剂选用甲苯。
选用甲苯作为溶剂具有如下优势：1.甲苯毒性和价格均较低，在使用过程中有助于提高安全性，降低生产成本。2.甲苯极性较低，在反应过程中不易在分子周围形成溶剂化效应，因此有利于提高反应速率，使反应更快进行。
本申请在一较佳示例中可以进一步配置为：在步骤S4中，所述催化剂选用氯化亚铜，反应温度为20℃。
选用氯化亚铜作为催化剂时，氯化亚铜的溶解性较好，在较低的温度下也能够快速分散于体系中，从而有助于进一步提高反应速率。且上述过程中直接在室温下即可完成反应，条件温和不苛刻，有助于进一步降低企业的生产成本。
本申请在一较佳示例中可以进一步配置为：所述亚硝酸试剂为亚硝酸钠。
在上述技术方案中，亚硝酸钠相较于其他亚硝酸试剂，其在水相中溶解较好，后续过程中可以直接通过加水萃取出去，从而有助于优化工艺，进而降低生产成本。另外，相较于其他亚硝酸盐，亚硝酸钠价格更为低廉，储存较为方便，进一步降低了企业的生产成本，提高了企业的经济效应。
本申请在一较佳示例中可以进一步配置为：在步骤S2中，选用硫酸对反应液I进行酸化，加入的硫酸的总物质的量为化合物I的3～5倍。
在上述技术方案中，选用硫酸进行反应，硫酸在反应过程中不易带入其他杂质离子，因此有助于提高反应的纯度。且硫酸的解离常数适中，既能苟保持体系内有足够的氢离子使氨基成盐，在反应过程中，也可以在体系内形成一定的氢离子浓度平衡，因此使反应过程中氢离子浓度不易产生较大的波动。另外，硫酸的总物质的量设置为化合物I物质的量的3～5倍，既保证了化合物I能够快速充分地酸化，具有较快的反应速率，也有助于减少硫酸的使用量。
本申请在一较佳示例中可以进一步配置为：在步骤S2中，将硫酸配制成质量分数为70～95％的硫酸溶液。
在上述技术方案中，选用浓度为85～92.5％的硫酸对氨基进行酸化成盐，上述浓度的硫酸首先腐蚀性较小，对设备的损耗程度较小。其次，具有较大的氢离子浓度，可以高效地实现酸化的效果，提高反应的速率，节约生产时间。另外，上述浓度的硫酸具有较小的体积，因此在反应过程中不易因引入过多的其他溶剂，减小了反应液整体体积和后处理的成本。上述两个因素共同作用，共同提高了上述生产过程的经济效应。
本申请在一较佳示例中可以进一步配置为：在20～30min时间内缓慢滴加至反应液I中，并继续保温反应0.8～1.5h。
在上述技术方案中，通过滴加的方式将硫酸加入到体系中，不易使硫酸在加入过程中造成反应体系内局部酸性过大，也不易使体系银硫酸放热而产生过高的温度，减少副反应的发生，从而进一步提高原料的利用率。将酸滴加完毕后，继续保温反应一段时间，可以使氨 基更加充分地成盐，进一步提高原料的利用率。
本申请在一较佳示例中可以进一步配置为：步骤S5具体包括如下步骤：
S5-1、向步骤S4中得到的化合物Ⅱ粗产品中加入无机盐溶液，进行萃取，保留有机相；
S5-2、向步骤S1中的有机相中加入干燥剂进行干燥后，减压蒸馏，得到化合物Ⅱ；
所述无机盐选自碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化钙中的任意一种，或上述物质中任意数种形成的组合物，所述干燥剂选自无水硫酸钠、无水硫酸镁、无水氯化钙中的一种。
在步骤S5中，先通过加入无机盐溶液进行萃取，选用上述无机盐可以调节体系的pH值，使体系由之前的强酸性变为中性或弱碱性，以方便将有机相中的酸转化为盐，使之可以充分溶解于水中，减少经萃取后有机相中的杂质，进而提高最终产物的纯度。
另外，在萃取完毕后通过干燥剂进行干燥，有机相中残留的微量水及溶解于水中给的杂质会被干燥剂一同吸附，进一步提高处理得到的化合物Ⅱ的纯度。
本申请还提供了一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，包括如下步骤：
P1、通过前述方法制备化合物Ⅳ；
P2、将化合物Ⅳ与试剂A反应，制备得到格氏试剂中间体；
P3、将步骤P2中得到的格氏试剂中间体与试剂B反应，得到3’-氯-5’-(三氟甲基)苯基三氟乙酮粗产物；
P4、对3’-氯-5’-(三氟甲基)苯基三氟乙酮粗产物进行酸化并分液，保留有机相，进一步提纯得到3’-氯-5’-(三氟甲基)苯基三氟乙酮；
其中，试剂A为
Figure PCTCN2020118509-appb-000003
R 3为Cl、Br、F、二甲氨基、二乙氨基、哌啶基、吗啉基或四氢吡咯基中的一种，R 4为Na +、Zn2 +、Mg 2+、Cu 2+、Li +、K +、Ca 2+、Ni +中的一种，n为R 4所带正电荷的数量；R 1为Cl，R 2为Cl、Br中的一种。
在上述技术方案中，以化合物Ⅳ为原料，对3’-氯-5’-(三氟甲基)苯基三氟乙酮进行合成。其中，选取R 1和R 2均为氯取代基的化合物Ⅳ，可以进一步降低反应的生产成本，从而有助于进一步提高经济效应。
综上所述，本申请包括以下至少一种有益技术效果：
1.在本申请中，提供了一种3,5-二卤代三氟甲苯的合成方法，通过可直接购买得到的化工原料经脱氨基化一步得到目标产物，条件温和，原料简单易得，后处理流程也较为简单，节约了生产成本，提高了企业的经济效应。
2.在本申请中，通过3,5-二卤代三氟甲苯对3’-氯-5’-(三氟甲基)苯基三氟乙酮进行合成，原料较为便宜，且工艺较为简单，进一步降低了企业的生产成本，提高了企业的经济效应。
具体实施方式
以下对本申请作进一步详细说明。
实施例1
一种3,5-二卤三氟甲苯的制备方法，以3，5-二氯三氟甲苯(化合物I)为原料，经如下步骤制备得到化合物Ⅱ。
S1、将0.2mol化合物1溶解于200mL溶剂I中，并降温至0℃，得到反应液I；
S2、以滴加的方式向反应液I中84g质量分数为92.5％的硫酸，滴加过程在30min内完成，滴加完毕后继续保温反应1h，得到反应液Ⅱ；
S3、向反应液Ⅱ中加入含有0.44mol亚硝酸试剂的亚硝酸试剂溶液，保持体系温度低于0℃，保温反应2h，得到反应液Ⅲ；
S4、反应液Ⅲ升温至20℃，在60min内均匀加入50％的次磷酸87g，并加入氯化亚铜0.5g，充分搅拌并反应2h，得到化合物Ⅱ粗产品；
S5、对步骤S4中得到的化合物Ⅱ粗产品进行分离提纯，得到化合物Ⅱ。
其中，化合物I和化合物Ⅱ中，R 1和R 2均为-Cl，亚硝酸试剂溶液选用质量分数为33％的亚硝酸钠溶液。
步骤S5具体包括如下分步骤：
S5-1、向步骤S4中得到的化合物Ⅱ粗产品静置分层，并加入饱和碳酸氢钠溶液作为无机盐溶液，充分混合后静置分液并保留有机相；
S5-2、使用无水硫酸镁作为干燥剂对有机相进行干燥，过滤后对滤液进行减压蒸馏，即得到最终产物。
实施例2～6
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，R 1和R 2不同。实施例2～6中的R 1和R 2如表1所示。
Figure PCTCN2020118509-appb-000004
实施例7～8
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S1中，溶剂I分别选用乙醇和异丙醇。
实施例9～12
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，加入的硫酸的浓度依次为70％，80％，85％，95％，实施例1级实施例9～12在步骤S2中加入的硫酸的物质的量保持不变。
实施例13
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，加入的酸为66.0g冰醋酸。
实施例14
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，加入的酸为74.0g磷酸。
实施例15
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，硫酸的加入量为62.3g。
实施例16
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，硫酸的加入量为45g。
实施例17
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，硫酸的加入量为105.9g。
实施例18
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，硫酸的加入量为150g。
实施例19
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，选用质量分数为45％的硫酸，硫酸的加入量为193.2g。
实施例20
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，选用质量分数为 98％的硫酸。
实施例21
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，滴加过程在20min内完成，滴加完毕后继续保温反应1.5h。
实施例22
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，滴加过程在25min内完成，滴加完毕后继续保温反应0.8h。
实施例23
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，滴加过程在5min内完成。
实施例24
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，滴加过程在60min内完成。
实施例25
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，滴加完毕后，继续反应30min。
实施例26
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，滴加完毕后，继续反应3h。
实施例27
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S3中，亚硝酸试剂为亚硝酸钾。
实施例28
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S3中，亚硝酸试剂为亚硝酸甲酯。
实施例29
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S3中，亚硝酸试剂为亚硝酸钙，亚硝酸试剂加入的物质的量为0.22mol。
实施例30～33
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S5中，无机盐溶液分别 为质量分数为5％的碳酸钠溶液、质量分数为5％的氢氧化钠溶液、质量分数为10％的碳酸钾溶液和质量分数为3％的氢氧化钙溶液。
实施例34
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S5中，干燥剂为无水硫酸钠。
实施例35
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，以实施例1中的方法对反应进行放大量处理，具体步骤如下：
S1、将2mol化合物1溶解于1.5L溶剂I中，并降温至0℃，得到反应液I；
S2、以滴加的方式向反应液I中840g质量分数为92.5％的硫酸，滴加过程在30min内完成，滴加完毕后继续保温反应1h，得到反应液Ⅱ；
S3、向反应液Ⅱ中加入含有4.4mol亚硝酸试剂的亚硝酸试剂溶液，保持体系温度低于0℃，保温反应2h，得到反应液Ⅲ；
S4、反应液Ⅲ升温至20℃，加入50％的次磷酸87g和和氯化亚铜0.5g，充分搅拌并反应2h，得到化合物Ⅱ粗产品；
S5、对步骤S4中得到的化合物Ⅱ粗产品进行分离提纯，得到化合物Ⅱ。
其中，化合物I和化合物Ⅱ中，R 1和R 2均为-Cl，亚硝酸试剂溶液选用质量分数为33％的亚硝酸钠溶液。
步骤S5具体包括如下分步骤：
S5-1、向步骤S4中得到的化合物Ⅱ粗产品静置分层，并加入饱和碳酸氢钠溶液作为无机盐溶液，充分混合后静置分液并保留有机相；
S5-2、使用无水硫酸镁作为干燥剂对有机相进行干燥，过滤后对滤液进行减压蒸馏，即得到最终产物。
实施例36
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S5-1中，用等量水替代无机盐溶液。
实施例37
一种3,5-二卤三氟甲苯的制备方法，与实施例1的区别在于，在步骤S5-1中，用等量质量分数为5％的氯化钠溶液作为无机盐溶液。
实施例38
一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，具体步骤如下，
P1、通过如实施例1中的制备方法制备3,5-二氯三氟甲苯；
P2、取7.2g(0.3mol)镁屑投入60mL四氢呋喃中，室温下搅拌混合均匀，再称取3,5-二氯三氟甲苯64.5g(0.3mol)溶解于90mL四氢呋喃并加入到滴液漏斗中。将镁屑和四氢呋喃混合体系升温至40℃并加入1.0mL1,2-二溴乙烷引发反应，然后在此温度下缓慢滴加3,5-二氯三氟甲苯的四氢呋喃溶液，滴加完毕后保温反应2h，再冷却到20℃，得到反应液Ⅳ；
P3、在20℃下向反应液Ⅳ中滴加三氟乙酰二甲胺46.6g(0.033mol)(化合物)，滴加完毕后继续搅拌1h，得到反应液Ⅴ；
P4、向反应液Ⅴ中加入100mL质量分数为35％的盐酸，保温静置分层，保留有机相并蒸出四氢呋喃，经精馏后得到澄清透明的油状液体，即为3’-氯-5’-(三氟甲基)苯基三氟乙酮。
实施例39
一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，与实施例38的区别在于，在步骤P1中，依照实施例2中的方法制备得到的3-氯-5-溴三氟甲苯，在步骤P2中，将3,5-二氯三氟甲苯替换为等物质的量的3-氯-5-溴三氟甲苯。
实施例40
一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，与实施例38的区别在于，在步骤P3中，用等物质的量的三氟乙酰二乙胺替换三氟乙酰二甲胺。
实施例41
一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，与实施例38的区别在于，在步骤P3中，用等物质的量的三氟乙酰哌啶替换三氟乙酰二甲胺。
实施例42
一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，与实施例38的区别在于，在步骤P3中，用等物质的量的三氟乙酰氯替换三氟乙酰二甲胺。
实施例43
一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，与实施例38的区别在于，在步骤P3中，用等物质的量的三氟乙酸钠替换三氟乙酰二甲胺。
实施例44
一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，与实施例39的区别在于，在步骤P3中，用等物质的量的三氟乙酰二乙胺替换三氟乙酰二甲胺。
实施例45
一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，与实施例39的区别在于，在步骤P3中，用等物质的量的三氟乙酰哌啶替换三氟乙酰二甲胺。
实施例46
一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，与实施例39的区别在于，在步骤P3中，用等物质的量的三氟乙酰氯替换三氟乙酰二甲胺。
实施例47
一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，与实施例39的区别在于，在步骤P3中，用等物质的量的三氟乙酸钠替换三氟乙酰二甲胺。
通过称重计算上述实施例中最终产物的收率，并通过液相色谱法测定实施例1～37中化合物Ⅱ的纯度，测定结果分别如表2所示。
Figure PCTCN2020118509-appb-000005
通过上述数据可知，通过实施例1～37中的制备方法制备得到的3,5-二卤三氟甲苯，具有较好的纯度和收率，且通过实施例35证明，上述工艺在放大后依旧具有较高的产率和纯度，具备扩大生产的工业运用价值。且上述过程中，采用的原料成本较低，过程工艺也较为简单，无需苛刻的反应条件，具有较低的生产成本和较好的经济效应，且具备工业化大规模生产的能力。
在实施例内进行比对，可以得出如下结论：首先，通过对比实施例1～6可知，对于化合物I，可以选取不同的R 1和R 2基团，且一般情况下，R 1和R 2基团的吸电子能力越弱，其脱氨基的产率越高，反应越容易进行。但是实际生产中，当R 1和R 2中为F或I时，原料的价格较高，因此一般在后续反应中，会使用实施例1～2中制得的化合物Ⅱ作为制备3’-氯-5’-(三氟甲基)苯基三氟乙酮的原料，当需要制备的物质为1-[3-溴-5-(三氟甲基)苯基]-2,2,2-三氟乙酮时，则会使用实施例3中制备得到的原料，如此会具有更好的经济效应。
实施例7～8相对于实施例1，对步骤S1中给的溶剂进行了调整。甲苯相较于乙醇和异丙醇，其极性较小，溶剂化效应不明显，有助于提高化合物Ⅱ的收率。
实施例9～12相较于实施例1，调整了在步骤步骤S2中加入的硫酸的浓度，实施例13～14则分别选用了冰醋酸和磷酸对硫酸进行替代。实施例15～18调整了硫酸的加入量，而实施例19中，加入的硫酸为质量分数为45％的硫酸，浓度较低。实施例20中，选用的则是浓硫酸。通过上述实施例的数据比对可知，选用浓度为92.5％的硫酸，且硫酸的物质的量为化合物I的四倍时，该工艺具有最好的收率。当选用磷酸或冰醋酸时，体系内的氢离子浓度不足，会造成反应速率降低，转化率降低，从而影响收率。硫酸的浓度过低同样也具有这个缺点。经测试，硫酸浓度至少在70％以上，方能取得较好的反应效果。其他有机强酸因价格较高，虽能达到接近的效果，但是同样增加了生产成本。另外，当选用浓度为98％的浓硫酸时，会引发其他副反应，且当硫酸的浓度超过95％之后，对设备的腐蚀较强，因此会额外增加设备的维护成本。实验证明，当硫酸的浓度为92.5％时，反应效果最佳。
实施例21～26中，对硫酸的滴加时间和滴加后的反应时间进行了调整，通过数据可知，滴加时间在20～30min内，滴加完毕后继续反应0.8～1.5h，可以使氨基完全成盐，也不会产生其他副反应。滴加过快的话，容易造成局部过热，产生一系列副反应，进而造成产率和纯度均下降。
实施例27～29相较于实施例1，对亚硝酸试剂进行了调整。通过数据可知，选用亚硝酸钠相较于其他亚硝酸钾和亚硝酸钙试剂，有助于提高反应的收率，且亚硝酸钠的价格较为较为便宜，具有更优的经济效应。选用亚硝酸甲酯可以略微提高化合物Ⅱ的收率，但亚硝酸甲酯在有机相中溶解性较强，分离过程中难以直接通过萃取分离，造成化合物Ⅱ纯度降低。
实施例30～33中调整了无机盐的选择，无机盐主要用于调节体系的pH值，使反应时的酸性体系转变为中性或弱碱性，并使体系中残留的酸成盐，从而增大酸根离子在水中的溶解性。上述过程一方面有助于简化后处理过程，并简化废水处理的工艺，另一方面也有助于提高产物的纯度。实施例36和37中分别选用水和氯化钠溶液作对化合物Ⅱ粗产品进行处理，均会导致化合物Ⅱ的纯度降低。实施例34中，选用无水硫酸钠替代无水氯化镁对有机相进行干燥，对化合物Ⅱ的收率和纯度没有十分明显的影响。
进一步地，设置如下对比例，与上述实施例进行比对。
对比例1
3',5'-二氯三氟甲苯的制备方法，与实施例1的区别在于，在步骤S1和S2中，直接将化合物I加入到酸I中，并保温反应1h，得到第一第二反应液。对比例1的产率为69.6％，最终产物 纯度为99.3％。
对比例2
3',5'-二氯三氟甲苯的制备方法，与对比例1的区别在于，酸I替换为200mL盐酸。对比例2的产率为72.9％，最终产物纯度为99.4％。
对比例3
3',5'-二氯三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，酸滴加后温度为50℃，反应时间为25min。对比例3的产率为74.7％，最终产物纯度为99.3％。
对比例4
3',5'-二氯三氟甲苯的制备方法，与实施例1的区别在于，在步骤S2中，酸滴加后温度为50℃。对比例1的产率为72.8％，最终产物纯度为99.5％。
将上述对比例与实施例进行对比可知，在步骤S1中，采用先用溶剂溶解，再进行酸化的方法，可以大大提高该生产过程所得到的产率。且在步骤S1中，在低温下进行反应相较于加热后进行反应，可以获得更高的产率，同时也降低了生产成本。
对实施例38～47中制备得到的3’-氯-5’-(三氟甲基)苯基三氟乙酮的收率和纯度进行测定，结果如表3所示。
Figure PCTCN2020118509-appb-000006
通过上述数据可知，通过3,5-二卤三氟甲苯制备3’-氯-5’-(三氟甲基)苯基三氟乙酮，具有较高的收率和较高的纯度。且上述过程中，使用的试剂均为较为常规的试剂，价格较为便宜，也无苛刻的反应条件，后处理也较为简单，因此有助于降低生产成本。
另外，3,5-二氯三氟甲苯相较于3-氯-5-溴三氟甲苯，制备产率稍低，但是制备成本也较低。在三氟甲基化试剂的选择中，选用三氟乙酰胺类的物质有助于提高3’-氯-5’-(三氟甲基)苯基三氟乙酮的产率，且三氟乙酰二甲胺相较于三氟乙酰二乙胺和三氟乙酰哌啶，其反应性更强，具有更好的收率。
综上所述，上述实施例提供了一种3,5-二卤三氟甲苯的制备方法，生产成本较低，经济效应较好，且具有进一步放大生产的能力。同时，上述实施例也提供了3,5-二卤三氟甲苯作为原料生产3’-氯-5’-(三氟甲基)苯基三氟乙酮的生产工艺，同样具有较好的经济效应。

Claims (9)

  1. 一种3,5-二卤三氟甲苯的制备方法，其特征在于：以化合物I为原料，经重氮化脱氨基反应制得化合物Ⅱ；
    Figure PCTCN2020118509-appb-100001
    其中，R 1、R 2可分别为F、Cl、Br、I中的任意一种；
    具体包括如下步骤：
    S1、将化合物1溶解于溶剂I中，并降温至-10～0℃，得到反应液I；
    S2、向反应液I中加入酸，并混合均匀，使反应液I酸化，得到反应液Ⅱ；
    S3、向反应液Ⅱ中加入亚硝酸试剂溶液，保持体系温度低于0℃，并充分反应，使化合物I的氨基重氮化并得到化合物Ⅲ，得到反应液Ⅲ；
    S4、向反应液Ⅲ中加入次磷酸和催化剂，通过次磷酸还原反应液Ⅲ中的化合物Ⅲ上的重氮基团离去，得到化合物Ⅱ粗产品；
    S5、对步骤S4中得到的化合物Ⅱ粗产品进行分离提纯，得到化合物Ⅱ；
    Figure PCTCN2020118509-appb-100002
    其中溶剂I选自甲苯、乙醇、异丙醇中的一种或其中任意两种或以上形成的均相混合溶剂；步骤S3中亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的任意一种，所述催化剂为亚铜盐。
  2. 根据权利要求1所述的一种3,5-二卤三氟甲苯的制备方法，其特征在于：在步骤S1中，溶剂选用甲苯。
  3. 根据权利要求1所述的一种3,5-二卤三氟甲苯的制备方法，其特征在于：在 步骤S4中，所述催化剂选用氯化亚铜，反应温度为20℃。
  4. 根据权利要求1所述的一种3,5-二卤三氟甲苯的制备方法，其特征在于：所述亚硝酸试剂为亚硝酸钠。
  5. 根据权利要求1所述的一种3,5-二卤三氟甲苯的制备方法，其特征在于：在步骤S2中，选用硫酸对反应液I进行酸化，加入的硫酸的总物质的量为化合物I的3～5倍。
  6. 根据权利要求5所述的一种3,5-二卤三氟甲苯的制备方法，其特征在于：在步骤S2中，将硫酸配制成质量分数为70～95％的硫酸溶液。
  7. 根据权利要求6所述的一种3,5-二卤三氟甲苯的制备方法，其特征在于：在步骤S2中，酸I在20～30min时间内缓慢滴加至反应液I中，并继续保温反应0.8～1.5h。
  8. 根据权利要求2所述的一种3,5-二卤三氟甲苯的制备方法，其特征在于：步骤S5具体包括如下步骤：
    S5-1、向步骤S4中得到的化合物Ⅱ粗产品中加入无机盐溶液，进行萃取，保留有机相；
    S5-2、向步骤S1中的有机相中加入干燥剂进行干燥后，减压蒸馏，得到化合物Ⅱ；
    所述无机盐为碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化钙中的任意一种，或上述物质中任意数种形成的组合物，所述干燥剂为无水硫酸钠、无水硫酸镁、无水氯化钙中的一种。
  9. 一种3’-氯-5’-(三氟甲基)苯基三氟乙酮的制备方法，其特征在于：包括如下步骤：
    P1、通过如权利要求1～8中任意一项所述的方法制备化合物Ⅳ；
    P2、将化合物Ⅳ与试剂A反应，制备得到格氏试剂中间体；
    P3、将步骤P2中得到的格氏试剂中间体与试剂B反应，得到3’-氯-5’-(三氟甲基)苯基三氟乙酮粗产物；
    P4、对3’-氯-5’-(三氟甲基)苯基三氟乙酮粗产物进行酸化并分液，保留有机相，进一步提纯得到3’-氯-5’-(三氟甲基)苯基三氟乙酮；
    其中，试剂A为
    Figure PCTCN2020118509-appb-100003
    R 3为Cl、Br、F、二甲氨基、二乙氨基、哌啶基、吗啉基或四氢吡咯基中的一种，R 4为Na +、Zn2 +、Mg 2+、Cu 2+、Li +、K +、Ca 2+、Ni +中的一种，n为R 4所带正电荷的数量；R 1为Cl，R 2为Cl、Br中的一种。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1367695A (zh) * 1999-03-30 2002-09-04 诺瓦提斯公司 治疗炎性疾病的酞嗪衍生物
CN101990530A (zh) * 2008-04-09 2011-03-23 杜邦公司 用于制备3-三氟甲基查耳酮的方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1367695A (zh) * 1999-03-30 2002-09-04 诺瓦提斯公司 治疗炎性疾病的酞嗪衍生物
CN101990530A (zh) * 2008-04-09 2011-03-23 杜邦公司 用于制备3-三氟甲基查耳酮的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ASMUS SÖREN, STEPHAN BECKENDORF, MERCEDES ZURRO, CHRISTIAN MÜCK-LICHTENFELD, ROLAND FRÖHLICH, OLGA GARCIA MANCHENO: "Influence of the Substitution and Conformation of C-H-Bond-Based Bis-Triazole Acceptors in Anion-Binding Catalysis", CHEMISTRY AN ASIAN JOURNAL, vol. 9, no. 8, 31 December 2014 (2014-12-31), XP055913567, DOI: 0.1002/asia.201402237 *

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