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WO2022061920A1 - 一种3'，5'-二氯-2，2，2-三氟苯乙酮的制备方法 - Google Patents

一种3'，5'-二氯-2，2，2-三氟苯乙酮的制备方法 Download PDF

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Publication number
WO2022061920A1
WO2022061920A1 PCT/CN2020/118513 CN2020118513W WO2022061920A1 WO 2022061920 A1 WO2022061920 A1 WO 2022061920A1 CN 2020118513 W CN2020118513 W CN 2020118513W WO 2022061920 A1 WO2022061920 A1 WO 2022061920A1
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acid
compound
trifluoroacetophenone
dichloro
reaction solution
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PCT/CN2020/118513
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English (en)
French (fr)
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蔡刚华
张凌霄
唐宏渊
程锦涛
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台州臻挚生物科技有限公司
浙江江北南海药业有限公司
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Priority to PCT/CN2020/118513 priority Critical patent/WO2022061920A1/zh
Publication of WO2022061920A1 publication Critical patent/WO2022061920A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • 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
    • 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
    • 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

Definitions

  • the application relates to the technical field of chemical pharmacy, in particular to a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone.
  • 3',5'-dichloro-2,2,2-trifluoroacetophenone is an important intermediate for the synthesis of pesticides and veterinary drugs.
  • the synthetic method of 3',5'-dichloro-2,2,2-trifluoroacetophenone mainly includes the following:
  • the PCT patent of the application number WO2018009751 discloses a preparation method using 3,5-dichlorobromobenzene and methyl trifluoroacetate as starting materials, using tetrahydrofuran as a solvent, by mixing 3,5-dichlorobromobenzene React with isopropyl magnesium chloride-lithium chloride to prepare Grignard reagent and then react with methyl trifluoroacetate.
  • isopropyl magnesium chloride and tetrahydrofuran are relatively expensive and explosive, and the production cost in industrial production is higher and less economical.
  • Chinese invention patent with publication number CN107353189A discloses a kind of taking 3,5-dichlorobromobenzene as raw material, reacting with trifluoroacetyl compound under the effect of butyllithium to obtain 3,5-dichlorobromobenzene and The preparation method of methyl trifluoroacetate, in the same way, in this method, the price of tert-butyl lithium is high, the danger is high, and the whole reaction process needs to be carried out under the condition of -78 ° C, the industrial production cost is high, and the economic effect is poor.
  • the purpose of this application is to provide a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, using inexpensive raw materials and a relatively mild reaction conditions, to achieve the preparation of 3',5'-dichloro-2,2,2-trifluoroacetophenone, which has a good economic effect.
  • the present application provides a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, comprising the following steps:
  • step S2 The composition of compound II and compound III obtained in step S1 is subjected to a nitro reduction reaction to obtain a composition of compound IV and compound V;
  • step S3 The composition of compound IV and compound V obtained in step S2 is subjected to a chlorination reaction with a chlorinating reagent to obtain a composition of compound VI and compound VII;
  • step S4 carrying out a diazotization elimination reaction on the composition of compound VI and compound VII obtained in step S3 to obtain 3',5'-dichloro-2,2,2-trifluoroacetophenone;
  • the acid I is phosphoric acid, polyphosphoric acid, methanesulfonic acid, chlorosulfonic acid, trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, acetic acid, acetic anhydride, boron trifluoride ether, perchloric acid, phosphorus One of molybdic acid, strong acid resin, fuming sulfuric acid and 80%-98% sulfuric acid, or a stable mixed system formed by any two or more of the above-mentioned acids; the nitrating reagent is nitric acid, fuming nitric acid, sodium nitrate, Any one or more of potassium nitrate, ammonium nitrate, lead nitrate, aluminum nitrate, barium nitrate, dinitrogen pentoxide and nitrogen dioxide; the reaction temperature during nitrification is 0 to 80°C;
  • step S3 select any one or more of chlorine, sulfonyl chloride, trichloroisocyanuric acid, and NCS for chlorination.
  • Compound I is a common chemical raw material, which is simple and easy to obtain, can be directly purchased, and is inexpensive. After the nitration of compound I, under the action of chloride ion substitution, two compounds, compound II and compound III, are produced, and compound II and compound III are directly put into the next reaction without separation.
  • step S2 after reducing the nitro group to an amino group, a mixture of compound IV and compound V is obtained, which can also be used in the next step without separation.
  • the amino group is a strong electron-donating group and has a good ortho-para-positioning effect, so both compound IV and compound V will only undergo halogenation reaction at the 5' position of the benzene ring during the chlorination process, And the reaction is easy to occur without harsh reaction conditions.
  • 3',5'-dichloro-2,2,2-trifluoroacetophenone can be obtained by removing the amino group through the diazotization reaction.
  • the whole reaction has no complicated process, and the raw materials are also simple and easy-to-obtain common chemical raw materials, so the production cost in the whole production process is low, and the economic effect is good.
  • Step S1 is as follows:
  • step S1-3 washing the organic phase I obtained in step S1-2 and removing the solvent to obtain a composition of compound II and compound III;
  • acid I is one of 80%-98% sulfuric acid or oleum
  • the nitrifying reagent is fuming nitric acid
  • Sulfuric acid is selected as the catalyst for nitration, and fuming nitric acid is selected.
  • sulfuric acid as an industrial raw material has a large supply and low price, and the degree of dissociation of sulfuric acid in the system has the characteristics of gradient, which can provide more stable in the reaction process.
  • the concentration of hydrogen ions makes the reaction process more controllable and helps save costs.
  • sulfuric acid is not easy to introduce other groups on the benzene ring, which helps to improve the purity of the target product.
  • the fuming nitric acid exists in a liquid state and has good reactivity, and no other solvent needs to be introduced during the reaction, which reduces the difficulty of post-processing and separation.
  • step S1-1 after compound I and acid I are mixed, the temperature is raised to 40-60° C., and then a nitration reagent is added dropwise for the reaction; in step S1-2, First, the intermediate reaction solution I was cooled to 0-10° C., the intermediate reaction solution I was added dropwise to ice water, and then the extractant I was added.
  • the temperature is first heated, and the reaction can be carried out quickly after the temperature is increased, and the site on the benzene ring is activated by the concentrated sulfuric acid by means of pre-heating, and the nitrated
  • the reagent is added dropwise to the above system, so that there is sufficient material in the system for nitrification.
  • the present application can be further configured as: in step S2, the nitro group is reduced by hydrogenation reduction under the action of catalyst I, and catalyst I is any one of platinum carbon, palladium carbon or Raney nickel. kind.
  • Step S2 is as follows:
  • step S2-1 The composition of compound II and compound III obtained in step S1 is dissolved in solvent I, a catalyst is added, and air is removed, then the temperature is raised to 40°C to 60°C and hydrogen is introduced, and the intermediate reaction is obtained after sufficient reaction.
  • solvent I a catalyst is added, and air is removed, then the temperature is raised to 40°C to 60°C and hydrogen is introduced, and the intermediate reaction is obtained after sufficient reaction.
  • step S2-2 cooling, filtering, and concentrating the intermediate reaction solution II obtained in step S2-1, and further purifying and drying by recrystallization to obtain the composition of compound IV and compound V;
  • solvent I is any one of the following substances, or a homogeneous mixed system formed by any of the following substances: methanol, ethanol, ethyl acetate, n-butyl acetate, isopropyl acetate, isopropanol and toluene.
  • the material after the reaction is purified and dried by the method of recrystallization, the operation is relatively simple, and the equipment maintenance components are low.
  • the solution obtained after recrystallization can be reused after treatment, which reduces the waste of materials, thereby helping to further reduce the production cost and improve the economic effect.
  • step S2-2 the details are as follows: the intermediate reaction solution II obtained in step S2-1 is cooled and filtered, then toluene is added and the temperature is raised to 40-50°C to fully dissolve After that, the temperature is lowered to -30 ⁇ -20°C, and the solid is precipitated by standing, and then filtered and dried to obtain the composition of compound IV and compound V.
  • step S2-1 Select toluene as a solvent to recrystallize the intermediate reaction solution II obtained in step S2-1, and make the solid material in the intermediate reaction solution II fully dissolve in the toluene by heating first, so that impurities are not easily adsorbed on the residual solid In the process, it is helpful to more fully remove the impurities in the intermediate reaction solution II and improve the purity of the final target product.
  • Step S3 is as follows:
  • step S3-2 cooling the intermediate reaction solution obtained in step S3-1 and adding water for extraction, and retaining the organic phase to obtain organic phase II;
  • step S4 the diazotization deamination reaction is directly carried out in the organic phase II;
  • the chlorination reagent is any one of chlorine, sulfonyl chloride, trichloroisocyanuric acid, and NCS, or a composition formed by any number of chlorine, sulfonyl chloride, trichloroisocyanuric acid, and NCS.
  • the solvent II is any one of toluene, dichloromethane, chloroform, acetonitrile, isopropanol, and ethanol, or a homogeneous system formed by mixing any of the above-mentioned solvents.
  • the organic phase II is directly put into the next step to carry out the reaction, which reduces the post-processing steps between the reactions, thereby reducing the technological steps of the reaction, and improving the reaction efficiency, thereby helping to further improve the economic effect.
  • Step S4 is as follows:
  • step S4-1 cooling the organic phase II obtained in step S3-2 to -10 ⁇ 0°C, and adding acid II dropwise to make it acidified, and fully reacted to obtain intermediate reaction solution IV;
  • acid II is any one in hydrochloric acid, hydrobromic acid, hydrofluoric acid, phosphoric acid, acetic acid or sulfuric acid;
  • nitrous acid reagent is sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite, Any of the C1-C6 alkyl nitrites.
  • step S3-2 the lead organic phase II in step S3-2 is directly introduced into step S4 for reaction, which reduces the separation process, thereby further reducing the process step flow and reducing the production cost.
  • a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone comprising the following steps:
  • step S2 The composition of compound II and compound III obtained in step S1 is subjected to a nitro reduction reaction to obtain a composition of compound IV and compound V;
  • step S3 The composition of compound IV and compound V obtained in step S2 is subjected to a chlorination reaction with a chlorinating reagent to obtain a composition of compound VI and compound VII;
  • step S4 carrying out a diazotization elimination reaction on the composition of compound VI and compound VII obtained in step S3 to obtain 3',5'-dichloro-2,2,2-trifluoroacetophenone;
  • Step S1 specifically includes the following sub-steps:
  • Step S2 specifically includes the following sub-steps:
  • step S2-1 Take 122.8 g (0.484 mol) of the composition of compound II and compound III obtained in step S1-3, add 300 mL of absolute ethanol as solvent I, and add 5.0 g of 5% platinum-carbon catalyst as catalyst I, Replace the air with nitrogen three times to remove the air, and then replace it with hydrogen three times to remove the nitrogen, introduce hydrogen to start stirring and react.
  • the hydrogen pressure is between 0.1 MPa, and the temperature is controlled at 50 ⁇ 10 ° C, and the intermediate reaction solution is obtained after the reaction for 1.5 hours. II;
  • Step S3 specifically includes the following sub-steps:
  • step S3-1 Take 44.7 g of the composition of compound IV and compound V obtained in step S2-2, add 200 mL of toluene (solvent II) and raise the temperature to 50°C. After fully dissolving, 33.7 g (0.25 g (0.25 g) mol) sulfonyl chloride as the chlorination reagent, followed by incubation for 8h to obtain intermediate reaction solution III;
  • Step S4 specifically includes the following sub-steps:
  • the intermediate reaction solution VI is statically layered, the organic layer is washed with 5% sodium bicarbonate solution, dried with sewage magnesium sulfate, and the solvent is distilled under reduced pressure to obtain a clear and transparent liquid that is 3',5'-dicarbonate Chloro-2,2,2-trifluoroacetophenone 41.2g, purity 99.3%, yield 89.1%.
  • step S1-1 A preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is: in step S1-1, acid I selects oleum (200g, 0.4mol).
  • a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that: in step S1-1, acid I selects 80% sulfuric acid, and the reaction is kept warm The time is 2h and 1h respectively.
  • a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that: in step S1-1, acid I selects the same amount of trifluoroacetophenone. Fluoromethanesulfonic acid.
  • step S1-1 A preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is: in step S1-1, acid I selects acetic anhydride, and adds 100 mL Dichloromethane was used as solvent.
  • a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is: in step S1-1, the nitration reagent is selected from saturated aqueous sodium nitrate and The amount of nitrogen dioxide, the nitrifying agent, remains the same.
  • step S1-2 and step S1-3 are replaced by step S1-2' :
  • the intermediate reaction solution I after the reaction was naturally cooled to -5 ⁇ 5°C, and 500 mL of toluene was added and stirred for 30 min. After standing for stratification, the organic layer was retained, and 500 mL of 10% sodium carbonate aqueous solution was added to wash, and then washed with 500 mL of water. Toluene was distilled off under reduced pressure to obtain a composition of compound II and compound III.
  • step S1-1 A preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that in step S1-1, compound I is mixed with 98% sulfuric acid After homogenization, 35.3 g of fuming nitric acid was added dropwise as a nitrifying reagent (0.55 mol) within 10 min, and then the temperature was raised to 60 °C, and the reaction was maintained for 1.5 h to obtain intermediate reaction solution I.
  • step S1-2 A preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that in step S1-2, the intermediate reaction solution I after the reaction is added 1000 mL of dichloromethane was used as extractant I, and after fully stirring for 30 min, it was kept still and separated to obtain organic phase I.
  • step S2-1 Raney nickel is selected as catalyst I, solvent I
  • step S2-1 Raney nickel is selected as catalyst I
  • step S2-1 Raney nickel is selected as catalyst I
  • solvent I A homogeneous mixed system obtained by mixing ethanol and isopropanol at a volume of 1:1 was selected.
  • a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that in step S2-1, the pressure of hydrogen is 1.0 MPa.
  • step S2-2 A preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that in step S2-2, the amount of toluene added is 200 mL, and toluene is added Then, the temperature was raised to 50°C, fully dissolved and then cooled to -30°C, left standing overnight, filtered and dried to obtain the composition of compound IV and compound V.
  • step S3 A preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 18 is that in step S3, chlorine is selected as the chlorination reagent, and the specific steps are as follows:
  • step S3-1' take 44.7 g of the composition of compound IV and compound V obtained in step S2-2, add 500 mL of glacial acetic acid (solvent II) and heat up to 40°C, after fully dissolving, slowly pass chlorine gas 17.04 g in 3 h g (0.24mol), at the same time point plate tracking detection raw material, after the completion of the reaction, pass nitrogen gas to blow the hydrogen chloride and excess chlorine generated into the tail gas absorption device to obtain the intermediate reaction solution III';
  • step S4 the above-obtained composition of compound IV and compound V is added to toluene again to prepare organic phase II for reaction.
  • a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that in step S4, acid II selects hydrochloric acid with a mass fraction of 30%, and hydrochloric acid is The add-on amount is 240g, and the nitrous acid reagent is selected as a saturated solution of potassium nitrite in the amount of the substance.
  • a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that in step S4, 150g glacial acetic acid is selected for acid II, and nitrous acid reagent is selected, etc.
  • the amount of substance is a saturated solution of calcium nitrite.
  • a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that in step S4, the nitrous acid reagent selects nitrous acid in an equivalent amount methyl ester.
  • step S1 A preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that in step S1, it further comprises the following steps:
  • step S1-4 Add the composition of compound II and compound III obtained in step S1-3 into 330 mL of toluene, heat up to 40°C and dissolve it completely, then cool down to -20°C, stand overnight and filter to obtain a solid , which is compound compound III, and the remaining liquid is distilled under reduced pressure to remove toluene to obtain compound II.
  • step S2, S3 and S4 are carried out separately for compound II and compound III, and the finally obtained products are combined, namely 3',5'-dichloro-2,2,2-trifluoroacetophenone .
  • a preparation method of 3',5'-dichloro-2,2,2-trifluoroacetophenone, the difference from Example 1 is that the experimental conditions in Example 1 are amplified, wherein each material The addition amount of 10 times in Example 1, the reaction time and other reaction conditions remain unchanged.
  • Step 1 Under nitrogen protection, n-butyllithium (23.2 mmol was dissolved in 14.5 mL of n-hexane to prepare a 1.6 M solution) was uniformly added dropwise to compound VIII (5 g, 22.1 mmol) at -78°C within 30 min.
  • compound VIII 5 g, 22.1 mmol
  • the reaction was kept stirring for 1 h, and then trifluoroacetic anhydride (2.56 g, 23.2 mmol) was added dropwise to the above mixed solution, and the reaction was kept at -78 °C for 2 h. It was then warmed to room temperature and the reaction was continued at room temperature for 2.5 h.
  • Compound VIII was the same as that of Comparative Example 1 to obtain 2.28 g of 3',5'-dichloro-2,2,2-trifluoroacetophenone with a yield of 42.5% and a purity of 98.8%.
  • Example 3 sulfuric acid with a concentration of 80% was used for the reaction, and the yield still decreased under the conditions of prolonging the reaction time. Compared with Example 3, Example 4 shortens the reaction time, which further leads to the reduction of the yield in step S1.
  • Embodiment 5 and embodiment 6 select trifluoromethanesulfonic acid and acetic anhydride to replace 98% sulfuric acid respectively, all cause the reduction of yield, prove that 98% sulfuric acid and oleum have better reaction characteristics in many acid reagents .
  • Example 8 the nitration reagent was selected from saturated aqueous sodium nitrate solution, and in Example 9, the method of feeding nitrogen dioxide was selected to react. Wherein the purchase cost of the aqueous sodium nitrate solution is lower, but its reaction performance is less effective than the technical scheme of using fuming nitric acid in Example 1. The introduction of nitrogen dioxide requires additional equipment support.
  • the above solutions can be selected according to the conditions of the actual production line, and all have good industrial application value.
  • Example 11 the specific process steps in step S1 were adjusted, all of which resulted in a decrease in yield.
  • the intermediate reaction solution I was cooled by a natural cooling method, which took a long time, and the temperature of the system was still relatively high during the cooling process, which was easy to produce some side reactions, which reduced the yield of step S1.
  • Example 12 fuming nitric acid was added dropwise and then the system was heated up, which also had a certain adverse effect on the yield of step S1.
  • Example 13 the reacted material did not undergo ice-water quenching reaction, resulting in difficulties in the separation process, and impurities could not be fully separated from the organic phase during liquid separation, thereby causing the yield of step S1 to decrease, and finally The purity of the obtained product is somewhat reduced.
  • Example 14 to 17 adjusted the process parameters in step S2. It can be seen that the increase of hydrogen pressure helps to improve the yield of step S2, and the selection of Raney nickel and palladium carbon instead of platinum carbon both helps to improve the yield in S2. In Examples 18 and 19, some parameters in step S3 were adjusted, which had little effect on the final yield. In Examples 20 to 22, step S4 was adjusted to some extent. From the above data, it can be seen that the use of methyl nitrite has a higher yield in the production process than other nitrous acid reagents.
  • Example 23 after the completion of step S1, compound II and compound III were separated and the subsequent reaction was carried out. It can be seen that no matter whether compound II and compound III are separated or not, there is basically no obvious effect on the subsequent reaction. Therefore, in the actual production process, the process of separating compound II and compound III can be completely omitted, thereby reducing the production cost. The purpose of improving economic efficiency.
  • Example 24 is an experiment in which the solution in Example 1 is amplified. It can be seen that the technical solution in Example 1 can still achieve 3',5'-dichloro-2 , The production of 2,2-trifluoroacetophenone, and the yield and purity have no obvious change, which proves that the technical scheme in this application has the prospect of amplifying the reaction and applying it to large-scale production.

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Abstract

一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，以3'-氯-2,2,2-三氟苯乙酮为原料，经硝化、还原、氯代、脱氨基四个步骤，制备得到3',5'-二氯-2,2,2-三氟苯乙酮，其原料成本较低，反应条件温和，反应工艺简单，有助于降低生产成本，提高经济效应。

Description

一种3′，5′-二氯-2，2，2-三氟苯乙酮的制备方法 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'-二氯-2,2,2-三氟苯乙酮的制备方法。
背景技术
3',5'-二氯-2,2,2-三氟苯乙酮是一种用于合成农药以及兽药的重要中间体。
现有技术中，3',5'-二氯-2,2,2-三氟苯乙酮的合成方法主要有以下几种：
1.申请号WO2018009751的PCT专利公开了一种以3,5-二氯溴苯和三氟乙酸甲酯为起始物料的制备方法，以四氢呋喃为溶剂，通过将3,5-二氯溴苯与异丙基氯化镁-氯化锂反应制备成格氏试剂再与三氟乙酸甲酯进行反应，上述现有技术中，异丙基氯化镁和四氢呋喃较为昂贵，且易爆，在工业生产中生产成本较高，经济效应较差。
2.公开号为CN107353189A的中国发明专利公开了一种以3,5-二氯溴苯为原料，在丁基锂的作用下与三氟乙酰基化合物反应得到3,5-二氯溴苯和三氟乙酸甲酯的制备方法，同样的，该方法中叔丁基锂的价格昂贵，危险性大，且反应全程需要在-78℃条件下进行，工业生产成本较高，经济效应较差。
上述两种现有技术中，原料成本较高，且反应条件较为苛刻，在反应过程中使用了部分易燃易爆且价格昂贵的原料，增加了工业生产的成本，在大规模生产中经济效应较差。
发明内容
针对现有技术存在的不足，本申请的目的是提供一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，选用价格低廉的原料和较为温和的反应条件，实现对3',5'-二氯-2,2,2-三氟苯乙酮的制备，具有较好的经济效应。
在一个实施方案中，本申请提供了一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，包括如下步骤：
S1、将化合物Ⅰ在酸Ⅰ的催化下与硝化试剂进行硝化反应，得到化合物Ⅱ和化合物Ⅲ的组合物；
S2、将步骤S1中得到的化合物Ⅱ和化合物Ⅲ的组合物进行硝基还原反应，得到化合物Ⅳ和化合物Ⅴ的组合物；
S3、通过氯化试剂对步骤S2中得到的化合物Ⅳ和化合物Ⅴ的组合物进行氯化反应，得到化合物Ⅵ和化合物Ⅶ的组合物；
S4、对步骤S3中得到的化合物Ⅵ和化合物Ⅶ的组合物进行重氮化消除反应，得到3',5'-二氯-2,2,2-三氟苯乙酮；
Figure PCTCN2020118513-appb-000001
在步骤S1中，酸Ⅰ为磷酸，多聚磷酸、甲烷磺酸，氯磺酸、三氟甲磺酸、三氟甲磺酸酐、醋 酸、醋酸酐、三氟化硼乙醚、高氯酸、磷钼酸、强酸树脂、发烟硫酸和80％-98％的硫酸中的一种，或上述酸中任意两种及以上物料形成的稳定混合体系；硝化试剂为硝酸、发烟硝酸、硝酸钠、硝酸钾、硝酸铵、硝酸铅、硝酸铝、硝酸钡、五氧化二氮和二氧化氮中的任意一种或多种；硝化时的反应温度为0～80℃；
在步骤S3中，选用氯气，磺酰氯，三氯异氰尿酸，NCS中的任意一种或多种进行氯化。
化合物Ⅰ是一种常用的化工原料，其简单易得，可以直接购买得到，价格低廉。将化合物Ⅰ硝化后，在氯离子取代效应的作用下，会产生化合物Ⅱ和化合物Ⅲ两种化合物，化合物Ⅱ和化合物Ⅲ无需分离直接投入下一步反应中。在步骤S2中，将硝基还原为氨基后，得到化合物Ⅳ和化合物Ⅴ的混合物，同样无需进行分离，即可投入下一步。步骤S3中，氨基为强给电子基团，且具有较好的邻对位定位效应，因此化合物Ⅳ和化合物Ⅴ在氯化过程中均只会在苯环的5'位上发生卤代反应，且反应较为容易发生，无需苛刻的反应条件。反应完成后，通过重氮化反应将氨基脱去即可得到3',5'-二氯-2,2,2-三氟苯乙酮。
在上述过程中，整个反应无复杂的工艺，原料也均为简单易得的普通化工原料，因此整个生产过程中生产成本较低，具有较好的经济效应。
本申请在一较佳示例中可以进一步配置为：步骤S1具体如下：
S1-1、将化合物Ⅰ与酸Ⅰ混合，随后滴加硝化试剂，并充分反应，得到中间反应液Ⅰ；
S1-2、向反应完毕的中间反应液Ⅰ中加入水和萃取剂Ⅰ，保留有机相Ⅰ；
S1-3、对步骤S1-2中得到的有机相Ⅰ进行洗涤并脱除溶剂，得到化合物Ⅱ和化合物Ⅲ的组合物；
其中，酸Ⅰ为80％-98％硫酸或发烟硫酸中的一种，硝化试剂为发烟硝酸。
选用硫酸作为硝基化的催化剂，并选用发烟硝酸首先，硫酸作为工业原料供应量大，价格低廉，且硫酸在体系中解离程度具有梯度化的特性，可以在反应过程中提供更加稳定的氢离子浓度，使反应过程更加可控，且有助于节约成本。另外，硫酸不易在苯环上引入其他基团，有助于提高目标产物的纯度。
发烟硝酸以液体的状态存在，且具有较好的反应活性，在反应时不需要引入其他溶剂，降低了后处理和分离的难度。
本申请在一较佳示例中可以进一步配置为：在步骤S1-1中，化合物Ⅰ和酸Ⅰ混合后，升温至40～60℃，再滴加硝化试剂进行反应；在步骤S1-2中，先将中间反应液Ⅰ降温至0～10℃，将中间反应液Ⅰ滴加到冰水中，再加入萃取剂Ⅰ。
在上述技术方案中，将化合物Ⅰ与酸Ⅰ混合后，先进行升温，升温后可以使反应快速 进行，且通过预先升温的方式使浓硫酸先对苯环上的位点进行活化，并将硝化试剂以滴加的方式加入到上述体系中，使体系中有充足的物料发生硝化。
本申请在一较佳示例中可以进一步配置为：在步骤S2中，在催化剂Ⅰ作用下通过加氢还原的方式对硝基进行还原，催化剂Ⅰ为铂炭、钯炭或Raney镍中的任意一种。
本申请在一较佳示例中可以进一步配置为：步骤S2具体如下：
S2-1、将步骤S1中得到的化合物Ⅱ和化合物Ⅲ的组合物溶解于溶剂Ⅰ中，加入催化剂，并除去空气，随后升温至40℃～60℃并通入氢气，充分反应后得到中间反应液Ⅱ；
S2-2、将步骤S2-1中得到的中间反应液Ⅱ降温、过滤、浓缩，通过重结晶的方法进一步提纯并干燥，得到化合物Ⅳ和化合物Ⅴ的组合物；
其中，溶剂Ⅰ为以下物质中的任意一种，或以下物质中任意多种形成的均相混合体系：甲醇、乙醇、乙酸乙酯、乙酸正丁酯、乙酸异丙酯、异丙醇和甲苯。
通过重结晶的方法对反应完成的物料进行提纯和干燥，操作比较简单，设备维护成分较低。重结晶后得到的溶液经处理后可以回用，减少了物料的浪费，从而有助于进一步降低生产成本，提高经济效应。
本申请在一较佳示例中可以进一步配置为：在步骤S2-2具体如下：将步骤S2-1中得到的中间反应液Ⅱ降温并过滤，随后加入甲苯并升温至40～50℃，充分溶解后，降温至-30～-20℃，静置析出固体，随后过滤、干燥，即得到化合物Ⅳ和化合物Ⅴ的组合物。
选用甲苯作为溶剂对步骤S2-1中得到的中间反应液Ⅱ进行重结晶处理，通过先升温的方式使中间反应液Ⅱ中的固体物料充分溶解于甲苯中，进而使杂质不易吸附在残留的固体中，有助于更加充分地除去中间反应液Ⅱ中的杂质，提高最终得到的目标产物的纯度。
本申请在一较佳示例中可以进一步配置为：步骤S3具体如下：
S3-1、将化合物Ⅳ和化合物Ⅴ溶解于溶剂Ⅱ中，升温至50～60℃，充分溶解后在90min内均匀加入氯化试剂，随后保温并充分反应，得到中间反应液Ⅲ；
S3-2、将步骤S3-1中得到的中间反应液降温并加水萃取，保留有机相得到有机相Ⅱ；
步骤S4中，直接在有机相Ⅱ中进行重氮化脱氨基反应；
所述氯化试剂为氯气，磺酰氯，三氯异氰尿酸，NCS中的任意一种，或氯气，磺酰氯，三氯异氰尿酸，NCS中任意数种形成的组合物。
所述溶剂Ⅱ为甲苯、二氯甲烷、氯仿、乙腈、异丙醇、乙醇中的任意一种，或上述溶剂中任意数种混合形成的均相体系。
在上述技术方案中，直接将有机相Ⅱ投入下一步进行反应，减少了反应间的后处理工 序，从而减少了反应的工艺步骤，提高了反应效率，从而有助于进一步提高经济效应。
本申请在一较佳示例中可以进一步配置为：步骤S4具体如下：
S4-1、将步骤S3-2中得到的有机相Ⅱ降温至-10～0℃，并滴加酸Ⅱ使之酸化，充分反应后得到中间反应液Ⅳ；
S4-2、向中间反应液Ⅳ中加入亚硝酸试剂溶液，并保持温度低于0℃，充分反应后得到中间反应液Ⅴ；
S4-3、将中间反应液Ⅴ升温至20℃以上，并加入次磷酸和催化剂Ⅱ，得到中间反应液Ⅵ；
S4-4、对中间反应液Ⅴ进行进一步提纯和分离，得到3',5'-二氯-2,2,2-三氟苯乙酮；
其中，酸Ⅱ为盐酸、氢溴酸、氢氟酸、磷酸、醋酸或硫酸中的任意一种；亚硝酸试剂为亚硝酸钠、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。
在上述技术方案中，直接将步骤S3-2中的导的有机相Ⅱ引入到步骤S4中进行反应，减少了分离的工序，从而进一步减少了工艺的步骤流程，降低了生产成本。
具体实施方式
通过以下实施例对本申请作进一步详细说明。
实施例1
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，包括如下步骤：
S1、将化合物Ⅰ在酸Ⅰ的催化下与硝化试剂进行硝化反应，得到化合物Ⅱ和化合物Ⅲ的组合物；
S2、将步骤S1中得到的化合物Ⅱ和化合物Ⅲ的组合物进行硝基还原反应，得到化合物Ⅳ和化合物Ⅴ的组合物；
S3、通过氯化试剂对步骤S2中得到的化合物Ⅳ和化合物Ⅴ的组合物进行氯化反应，得到化合物Ⅵ和化合物Ⅶ的组合物；
S4、对步骤S3中得到的化合物Ⅵ和化合物Ⅶ的组合物进行重氮化消除反应，得到3',5'-二氯-2,2,2-三氟苯乙酮；
Figure PCTCN2020118513-appb-000002
Figure PCTCN2020118513-appb-000003
步骤S1具体包括如下分步骤：
S1-1、取化合物Ⅰ104.5g(0.5mol)，与200g质量分数为98％的浓硫酸(酸Ⅰ)搅拌混合均匀，升温至60℃，升温完毕后，在10min内均匀滴加35.3g发烟硝酸作为硝化试剂(0.55mol)，保温反应1.5h，得到中间反应液Ⅰ；
S1-2、将反应完毕的中间反应液Ⅰ降温至0℃，并将反应液滴加于0℃的冰水混合液中，再加入1000mL二氯甲烷作为萃取剂Ⅰ，充分搅拌30min后，静止并分液得到有机相Ⅰ；
S1-3、向有机相Ⅰ中加入500mL10％碳酸氢钠溶液进行洗涤，再次分液后减压蒸馏脱除萃取剂Ⅰ，得到化合物Ⅱ和化合物Ⅲ的组合物。
步骤S2具体包括如下分步骤：
S2-1、取步骤S1-3中得到的化合物Ⅱ和化合物Ⅲ的组合物122.8g，(0.484mol)，并加入无水乙醇300mL作为溶剂Ⅰ，加入5％铂碳催化剂5.0g作为催化剂Ⅰ，用氮气置换三次除去空气，再用氢气置换三次除去氮气，通入氢气开启搅拌并反应，反应过程中氢气压力为0.1MPa之间，温度控制于50±10℃，反应1.5h后得到中间反应液Ⅱ；
S2-2、将中间反应液Ⅱ降温至室温，并过滤除去铂碳催化剂，并将乙醇蒸出，蒸出后加入150mL甲苯，升温至40℃并搅拌溶解澄清后，在降温至-20℃，静置过夜，过滤，干燥，得到化合物Ⅳ和化合物Ⅴ的组合物。
步骤S3具体包括如下分步骤：
S3-1、取步骤S2-2中得到的化合物Ⅳ和化合物Ⅴ的组合物44.7g，加入200mL甲苯(溶剂Ⅱ)并升温至50℃，充分溶解后，在90min内均匀滴加33.7g(0.25mol)磺酰氯作为氯化试剂，随后保温反应8h，得到中间反应液Ⅲ；
S3-2、将中间反应液Ⅲ降至室温，加水200mL漂洗，漂洗完毕后静置分层，得到有机相Ⅱ。
步骤S4具体包括如下分步骤：
S4-1、将S3-2中得到的有机相Ⅱ(含有化合物Ⅵ和化合物Ⅶ共49.3g，总摩尔数0.191mol)降温至-10℃，并在30min内滴加80g质量分数为92.5％的硫酸(酸Ⅱ)，滴加完毕后保温搅拌1h，得到中间反应液Ⅳ；
S4-2、在1h内向中间反应液Ⅳ中均匀滴加质量分数为33％的亚硝酸钠溶液(含有亚硝酸钠0.41mol)作为亚硝酸试剂溶液，并保持温度低于0℃，滴加完毕后继续保温反应2h，得到中间反应液Ⅴ；
S4-3、将中间反应液Ⅴ升温至20℃，并加入50％次磷酸溶液83g，加入氧化亚铜0.5g作为催化剂Ⅱ，保温搅拌反应2h，得到中间反应液Ⅵ；
S4-4、将中间反应液Ⅵ静止分层，用5％碳酸氢钠溶液清洗有机层，用污水硫酸镁干燥后，减压蒸馏溶剂，得到的澄清透明液体即为3',5'-二氯-2,2,2-三氟苯乙酮41.2g，纯度99.3％，收率89.1％。
实施例2
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于：在步骤S1-1中，酸Ⅰ选用发烟硫酸(200g，0.4mol)。
实施例3～4
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于：在步骤S1-1中，酸Ⅰ选用80％硫酸，保温反应时间分别为2h和1h。
实施例5
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于：在步骤S1-1中，酸Ⅰ选用等物质的量的三氟甲磺酸。
实施例6
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于：在步骤S1-1中，酸Ⅰ选用醋酸酐，并加入100mL二氯甲烷作为溶剂。
实施例7
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例6的区别在于：在步骤S1-1中，溶剂选用四氯化碳。
实施例8～9
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于：在步骤S1-1中，硝化试剂分别选用饱和硝酸钠水溶液和二氧化氮，硝化试剂的物质的量保持不变。
实施例10
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例2的区别在于：在步骤S1-2中，选用甲苯作为萃取剂Ⅰ。
实施例11
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例2的区别在于：步骤S1-2和步骤S1-3替换为步骤S1-2'：将反应完毕的中间反应液Ⅰ自然降温至-5±5℃，并加入500mL甲苯搅拌30min，静置分层后保留有机层并加入500mL10％碳酸钠水溶液洗涤，再用500mL水洗，分液后减压蒸馏除去甲苯，得到化合物Ⅱ和化合物Ⅲ的组合物。
实施例12
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S1-1中，向将化合物Ⅰ与98％硫酸混合均匀后，在10min内均匀滴加35.3g发烟硝酸作为硝化试剂(0.55mol)，再升温至60℃，保温反应1.5h，得到中间反应液Ⅰ。
实施例13
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S1-2中，将反应完毕的中间反应液Ⅰ加入1000mL二氯甲烷作为萃取剂Ⅰ，充分搅拌30min后，静止并分 液得到有机相Ⅰ。
实施例14
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S2-1中，选用5％钯碳作为催化剂Ⅰ，溶剂Ⅰ选用甲苯。
实施例15
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S2-1中，选用Raney镍作为催化剂Ⅰ，溶剂Ⅰ选用乙醇和异丙醇以1:1的体积混合得到的均相混合体系。
实施例16
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S2-1中，氢气的压力为1.0MPa。
实施例17
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S2-2中，甲苯的加入量为200mL，加入甲苯后升温至50℃，充分溶解后降温至-30℃，静置过夜，过滤，干燥，得到化合物Ⅳ和化合物Ⅴ的组合物。
实施例18
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S3-1中，溶剂Ⅱ选用乙腈，氯化试剂选用等物质的量的NCS，NCS直接以固体的形式加入体系中。
实施例19
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例18的区别在于，在步骤S3中，选用氯气作为氯化试剂，具体步骤如下：
S3-1'、取步骤S2-2中得到的化合物Ⅳ和化合物Ⅴ的组合物44.7g，加入500mL冰醋酸(溶剂Ⅱ)并升温至40℃，充分溶解后，在3h内缓慢通入氯气17.04g(0.24mol)，同时点板跟踪检测原料，反应完成后通入氮气将产生的氯化氢和多余氯气吹入尾气吸收装置中，得到中间反应液Ⅲ'；
S3-2'、将中间反应液Ⅲ'降至室温，并抽滤，滤饼用200mL冰醋酸洗涤两次，并在60℃下真空干燥，得到化合物Ⅳ和化合物Ⅴ的组合物。
在步骤S4中，重新将上述得到的化合物Ⅳ和化合物Ⅴ的组合物加入甲苯中配制成有机相Ⅱ进行反应。
实施例20
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，步骤S4中，酸Ⅱ选用 质量分数为30％的盐酸，盐酸的加入量为240g，亚硝酸试剂选用等物质的量亚硝酸钾饱和溶液。
实施例21
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，步骤S4中，酸Ⅱ选用150g冰醋酸，亚硝酸试剂选用等物质的量亚硝酸钙饱和溶液。
实施例22
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S4中，亚硝酸试剂选用等物质的量的亚硝酸甲酯。
实施例23
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S1中，还包括如下步骤：
S1-4、将步骤S1-3中得到的化合物Ⅱ和化合物Ⅲ的组合物加入330mL甲苯中，升温至40℃并使其完全溶解，再降温至-20℃，静置过夜后过滤，得到固体，即为化合物化合物Ⅲ，剩余液体通过减压蒸馏的方式除去甲苯，即得到化合物Ⅱ。
在后续反应中，将化合物Ⅱ和化合物Ⅲ单独进行步骤S2、S3和S4，并将最后得到的产物合并，即为3',5'-二氯-2,2,2-三氟苯乙酮。
实施例24
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，与实施例1的区别在于，对实施例1中的实验条件进行了放大处理，其中各物料的加入量均为实施例1中的10倍，反应时间和其他反应条件保持不变。
针对上述实施例，设置如下对比例进行比对。
对比例1
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，参照申请号为WO2018009751的PCT发明中的方法进行合成，具体如下：
将化合物Ⅷ(25g，110.6mmol)室温下溶解于400mLTHF中，并将110.6mmol异丙基氯化镁溶解于85mLTHF中，在15min内均匀滴加于上述化合物Ⅷ的THF溶液体系内，保持温度在20～25℃。滴加完毕后，反应在室温下继续保持1.5h。
将上述反应完毕的溶液降温至0℃以下。将三氟甲基乙酸乙酯(12.23mL，121.6mmol)溶解于20mLTHF中，并滴加于上述反应完毕的溶液中，保温继续反应0.5h，之后恢复至室温并继续搅拌1.5h。之后，将上述体系降温至-5～-10℃将73.7mL6M盐酸溶液加水稀释至 150mL，并滴加于降温后的上述体系中。滴加完毕后，继续保温并搅拌0.5h，再重新升温至室温。
将水加入上述体系中并分液，保留有机相，并将水相用二氯甲烷反复洗三次。将二氯甲烷相与之前的有机相合并，并以无水硫酸钠干燥后，减压蒸馏除去溶剂，即得到3',5'-二氯-2,2,2-三氟苯乙酮。
化合物Ⅷ为
Figure PCTCN2020118513-appb-000004
最终得到3',5'-二氯-2,2,2-三氟苯乙酮19.9g，收率74.2％，纯度95.9％。
对比例2
一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，参照公开号为CN107353189A的中国发明中的方法进行，具体如下：
步骤1，在氮气保护下，在30min内均匀将正丁基锂(23.2mmol溶解于14.5mL正己烷中，配制成1.6M溶液)在-78℃下滴加到化合物Ⅷ(5g，22.1mmol)的四氢呋喃溶液(50mL)中，保持搅拌反应1h，再将三氟乙酸酐(2.56g，23.2mmol)滴加于上述混合溶液汇总，保持-78℃反应2h。随后升至室温并在室温下继续反应2.5h。加入饱和氯化铵溶液50mL终止反应，通过减压蒸馏除去四氢呋喃并用乙醚进行萃取，保留有机相，用饱和氯化钠溶液洗涤，在用无水硫酸镁干燥，完成后通过减压蒸馏除去溶剂，得到3',5'-二氯-2,2,2-三氟苯乙酮。
化合物Ⅷ与对比例1相同，得到3',5'-二氯-2,2,2-三氟苯乙酮2.28g，产率42.5％，纯度98.8％。
对于上述实施例和对比例，其各步骤的产率、总收率及最终目标化合物的纯度对比如表1所示。
Figure PCTCN2020118513-appb-000005
化合物Ⅴ在氘代氯仿中的核磁共振氢谱数据为：1HNMR(500MHz,CDCl 3):d＝6.46(brs,2H),6.70(d,1H,J＝9.0Hz),7.32(dd,1H,J＝2.1Hz,9.0Hz),7.71(d,1H,J＝2.1Hz)。
化合物Ⅵ在氘代氯仿中的核磁共振氢谱数据为：1HNMR(400MHz,CDC1 3):7.95(s,2H),5.23(bs,2H)。
最终制得的3',5'-二氯-2,2,2-三氟苯乙酮在氘代氯仿中的核磁共振氢谱数据为：1H-NMR(360MHz,CDCl 3):δ＝7.7(s,1H),7.9(s,2H)。
通过上述实验数据进行对比可以发现，通过本申请中实施例1～24中的方法对3',5'-二氯-2,2,2-三氟苯乙酮进行制备，均可以得到可观的收率和纯度。其中最终产物的纯度均高于对比例1和对比例2，且收率相较对比例2有较为明显的优势，与对比例1比较接近。但是在对比例2中，以四氢呋喃为反应体系，且使用了昂贵且易燃易爆的异丙基氯化镁，相较于上述实施例中的制备方法，大大提高了生产的成本和后处理的成本。因此，本申请中提供的技术方案相较于对比例1中的技术方案，具有良好的经济效应。
实施例1～13中，对步骤S1进行了一定的调整，其对于收率的整体影响不大。其中 实施例3中用了浓度为80％硫酸进行反应，在延长了反应时间的条件下收率依旧有所降低。实施例4相较于实施例3在缩短了反应时间，进一步导致了步骤S1中收率的降低。实施例5和实施例6分别选用三氟甲磺酸和乙酸酐替代98％硫酸，均导致了收率的降低，证明了98％硫酸和发烟硫酸在诸多酸试剂中具有较好的反应特性。
在实施例8中，硝化试剂选用了饱和硝酸钠水溶液，实施例9中则选用通入二氧化氮的方法进行反应。其中硝酸钠水溶液的购买成本较低，但其反应性能相较于实施例1中使用发烟硝酸的技术方案效果较差。通入二氧化氮需要额外的设备支持，上述方案可以依据实际生产线所具备的条件进行选择，均具有较好的工业运用价值。
实施例11～13中对步骤S1中的具体工艺步骤进行了调节，均导致了收率的下降。在实施例11中，采用自然降温的方式对中间反应液Ⅰ进行降温，花费的时间较长，且在降温的过程中体系仍然温度较高，容易产生部分副反应，降低了步骤S1的收率。实施例12中，先滴加发烟硝酸再将体系进行升温处理，同样对步骤S1的收率有一定的不良影响。在实施例13中，反应完毕的物料未经过冰水淬灭反应，导致分离过程中出现困难，分液时无法将杂质充分从有机相中分出，进而导致步骤S1的收率降低，且最终得到的产品纯度有一定的降低。
实施例14～17相较于实施例1，对步骤S2中的工艺参数进行了调整。可以看到，氢气压力的增大有助于提高步骤S2的收率，且选用Raney镍和钯碳替代铂炭均有助于提高S2中的收率。实施例18和19对步骤S3中的部分参数进行了调整，对最终产率的影响较小。实施例20～22中，对步骤S4进行了一定程度的调整。通过上述数据可知，选用亚硝酸甲酯相较于其他亚硝酸试剂，生产过程中具有更高的产率。
实施例23中，在步骤S1完成后，将化合物Ⅱ和化合物Ⅲ进行分离并进行后续的反应。可以看到，不论是否分离化合物Ⅱ和化合物Ⅲ，对于后续的反应基本无明显的影响，因此在实际生产过程中，完全可以省略分离化合物Ⅱ和化合物Ⅲ的工序，从而可以起到减少生产成本，提高经济效应的目的。
实施例24则是对实施例1中的方案进行了放大处理的实验，可以看到在放大十倍当量后，实施例1中的技术方案依旧可以实现对3',5'-二氯-2,2,2-三氟苯乙酮的生产，且收率和纯度均没有明显的变化，证明了本申请中的技术方案具有放大反应并运用于大规模生产的前景。

Claims (8)

  1. 一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，其特征在于：包括如下步骤：
    S1、将化合物Ⅰ在酸Ⅰ的催化下与硝化试剂进行硝化反应，得到化合物Ⅱ和化合物Ⅲ的组合物；
    S2、将步骤S1中得到的化合物Ⅱ和化合物Ⅲ的组合物进行硝基还原反应，得到化合物Ⅳ和化合物Ⅴ的组合物；
    S3、通过氯化试剂对步骤S2中得到的化合物Ⅳ和化合物Ⅴ的组合物进行氯化反应，得到化合物Ⅵ和化合物Ⅶ的组合物；
    S4、对步骤S3中得到的化合物Ⅵ和化合物Ⅶ的组合物进行重氮化消除反应，得到3',5'-二氯-2,2,2-三氟苯乙酮；
    Figure PCTCN2020118513-appb-100001
    Figure PCTCN2020118513-appb-100002
    在步骤S1中，酸Ⅰ为磷酸，多聚磷酸、甲烷磺酸，氯磺酸、三氟甲磺酸、三氟甲磺酸酐、醋酸、醋酸酐、三氟化硼乙醚、高氯酸、磷钼酸、强酸树脂、发烟硫酸或80％-98％的硫酸中的一种，或上述酸中任意两种及以上物料形成的稳定混合体系；硝化试剂为硝酸、发烟硝酸、硝酸钠、硝酸钾、硝酸铵、硝酸铅、硝酸铝、硝酸钡、五氧化二氮和二氧化氮中的任意一种或多种；
    在步骤S3中，选用氯气，磺酰氯，三氯异氰尿酸，NCS中的任意一种或多种进行氯化。
  2. 根据权利要求1所述的一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，其特征在于：步骤S1具体如下：
    S1-1、将化合物Ⅰ与酸Ⅰ混合，随后滴加硝化试剂，并充分反应，得到中间反应液Ⅰ；
    S1-2、向反应完毕的中间反应液Ⅰ中加入水和萃取剂Ⅰ，保留有机相Ⅰ；
    S1-3、对步骤S1-2中得到的有机相Ⅰ进行洗涤并脱除溶剂，得到化合物Ⅱ和化合物Ⅲ的组合物；
    其中，酸Ⅰ为80％-98％硫酸或发烟硫酸中的一种，硝化试剂为发烟硝酸。
  3. 根据权利要求2所述的一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，其特征在于：在步骤S1-1中，化合物Ⅰ和酸Ⅰ混合后，升温至40～60℃，再滴加 硝化试剂进行反应；在步骤S1-2中，先将中间反应液Ⅰ降温至0～10℃，将中间反应液Ⅰ滴加到冰水中，再加入萃取剂Ⅰ。
  4. 根据权利要求1所述的一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，其特征在于：在步骤S2中，在催化剂Ⅰ作用下通过加氢还原的方式对硝基进行还原，催化剂Ⅰ为铂炭、钯炭或Raney镍中的任意一种。
  5. 根据权利要求4所述的一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，其特征在于：步骤S2具体如下：
    S2-1、将步骤S1中得到的化合物Ⅱ和化合物Ⅲ的组合物溶解于溶剂Ⅰ中，加入催化剂，并除去空气，随后升温至40℃～60℃并通入氢气，充分反应后得到中间反应液Ⅱ；
    S2-2、将步骤S2-1中得到的中间反应液Ⅱ降温、过滤、浓缩，通过重结晶的方法进一步提纯并干燥，得到化合物Ⅳ和化合物Ⅴ的组合物；
    其中，溶剂Ⅰ为以下物质中的任意一种，或以下物质中任意多种形成的均相混合体系：甲醇、乙醇、乙酸乙酯、乙酸正丁酯、乙酸异丙酯、异丙醇和甲苯。
  6. 根据权利要求5所述的一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，其特征在于：在步骤S2-2具体如下：将步骤S2-1中得到的中间反应液Ⅱ降温并过滤，随后加入甲苯并升温至40～50℃，充分溶解后，降温至-30～-20℃，静置析出固体，随后过滤、干燥，即得到化合物Ⅳ和化合物Ⅴ的组合物。
  7. 根据权利要求1所述的一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，其特征在于：步骤S3具体如下：
    S3-1、将化合物Ⅳ和化合物Ⅴ溶解于溶剂Ⅱ中，升温至50～60℃，充分溶解后在90min内均匀加入氯化试剂，随后保温并充分反应，得到中间反应液Ⅲ；
    S3-2、将步骤S3-1中得到的中间反应液降温并加水萃取，保留有机相得到有机相Ⅱ；
    步骤S4中，直接在有机相Ⅱ中进行重氮化脱氨基反应；
    所述氯化试剂为氯气，磺酰氯，三氯异氰尿酸，NCS中的任意一种，或氯气，磺酰氯，三氯异氰尿酸，NCS中任意数种形成的组合物；
    所述溶剂Ⅱ为甲苯、二氯甲烷、氯仿、乙腈、异丙醇、乙醇中的任意一种，或上述溶剂中任意数种混合形成的均相体系。
  8. 根据权利要求7所述的一种3',5'-二氯-2,2,2-三氟苯乙酮的制备方法，其特征在于：步骤S4具体如下：
    S4-1、将步骤S3-2中得到的有机相Ⅱ降温至-10～0℃，并滴加酸Ⅱ使之酸化，充分反应后得到中间反应液Ⅳ；
    S4-2、向中间反应液Ⅳ中加入亚硝酸试剂溶液，并保持温度低于0℃，充分反应后得到中间反应液Ⅴ；
    S4-3、将中间反应液Ⅴ升温至20℃以上，并加入次磷酸和催化剂Ⅱ，得到中间反应液Ⅵ；
    S4-4、对中间反应液Ⅴ进行进一步提纯和分离，得到3',5'-二氯-2,2,2-三氟苯乙酮；
    其中，酸Ⅱ为盐酸、氢溴酸、氢氟酸、磷酸、醋酸或硫酸中的任意一种；亚硝酸试剂为亚硝酸钠、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。
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CN116535298A (zh) * 2023-07-06 2023-08-04 研峰科技(北京)有限公司 一种3'，5'-二氯-2，2，2-三氟苯乙酮的合成方法
CN116535298B (zh) * 2023-07-06 2023-09-22 研峰科技(北京)有限公司 一种3'，5'-二氯-2，2，2-三氟苯乙酮的合成方法

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