WO2020248278A1 - Method for continuous synthesis of substituted benzoic-acid organic substance - Google Patents

Method for continuous synthesis of substituted benzoic-acid organic substance Download PDF

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WO2020248278A1
WO2020248278A1 PCT/CN2019/091400 CN2019091400W WO2020248278A1 WO 2020248278 A1 WO2020248278 A1 WO 2020248278A1 CN 2019091400 W CN2019091400 W CN 2019091400W WO 2020248278 A1 WO2020248278 A1 WO 2020248278A1
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continuous
reaction
synthesis method
oxygen
continuous synthesis
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PCT/CN2019/091400
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French (fr)
Chinese (zh)
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洪浩
张恩选
卢江平
刘志清
李超
谭阳
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吉林凯莱英医药化学有限公司
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Priority to PCT/CN2019/091400 priority Critical patent/WO2020248278A1/en
Publication of WO2020248278A1 publication Critical patent/WO2020248278A1/en

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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
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/58—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/21—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen
    • C07C51/23—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups
    • C07C51/245—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups of keto groups or secondary alcohol groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
    • C07C63/70—Monocarboxylic acids

Definitions

  • the present invention relates to the field of medicine and chemical industry, in particular to a continuous synthesis method of substituted benzoic acid organic compounds.
  • the preparation of substituted benzoic acid is generally based on readily available substituted alkylbenzenes as raw materials.
  • the main synthesis methods are chemical reagent oxidation, photochlorination hydrolysis, gas phase oxidation and liquid oxygen oxidation.
  • the chemical reagent oxidation method uses potassium permanganate, potassium dichromate, sodium hypochlorite or nitric acid as the oxidant, and oxidizes the substituted alkylbenzene in an aqueous solution to obtain substituted benzoic acid.
  • the photochlorination hydrolysis method uses chlorine to chlorinate toluene under light, and then hydrolyze under acidic or alkaline conditions to obtain substituted benzoic acid.
  • the above method has the problems of high production cost, serious corrosion of equipment, generation of a large amount of waste liquid and waste gas, and environmental pollution. Therefore, it has gradually been resisted by people and restricted by governments of various countries.
  • the gas-phase oxidation method vaporizes substituted toluene at high temperature, and when the vapor passes through the catalyst layer, oxygen is oxidized to substituted benzoic acid.
  • This method has the problems of high reaction temperature, high energy consumption, not easy to control, easy to produce a large amount of tar, and low yield. Liquid-phase oxygen oxidation is a method that emerged in the 1980s.
  • the gas phase oxidation method vaporizes substituted toluene at high temperature, and when the vapor passes through the catalyst layer, it is oxidized to substituted benzoic acid by oxygen.
  • This method has high reaction temperature, high energy consumption, is not easy to control, is easy to produce a large amount of tar, and the yield is low.
  • the main purpose of the present invention is to provide a continuous synthesis method of substituted benzoic acid organics, so as to solve the problems of high cost, unenvironmental protection and low yield of substituted benzoic acid organics in the existing batch synthesis method.
  • a continuous synthesis method of substituted benzoic acid organic compounds includes: in the presence of a catalyst and an organic solvent, the organic compound represented by formula (I) is combined with oxygen Continuously input to the continuous reaction device for continuous oxidation reaction to obtain substituted benzoic acid organic matter, which is continuously discharged, and the substituted benzoic acid organic matter has the structure shown in formula (II);
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, alkyl, alkoxy, halogen, nitro, aryl, substituted aryl, heteroaryl, substituted heteroaryl , Ester group or amide, and at least one of R 1 , R 2 , R 3 , R 4 and R 5 is not H, R 6 is an acetyl group, and M 1 , M 2 and M 3 are each independently selected from C and N Or S.
  • R 1 and R 2 are H
  • R 3 is F, Cl, Br or NO 2
  • R 4 and R 5 are H, or one of the following groups: F, methoxy, and R 4 and R 5 is not the same.
  • the aforementioned continuous synthesis method further includes: adding metal halide MX during the continuous oxidation reaction; preferably, the amount of metal halide MX is calculated based on the weight percentage of the organic matter represented by formula (I) 0.5 ⁇ 3%.
  • M is selected from Li, K, Na, Mg or Ca
  • X is selected from Cl or Br.
  • the continuous reaction device is selected from reaction coils.
  • reaction temperature of the continuous oxidation reaction is 130-180°C
  • reaction pressure is 1.0-2.5 MPa.
  • the retention time of the continuous oxidation reaction is 90-240 min.
  • the catalyst is selected from the group consisting of cobalt acetate, cobalt acetylacetonate, cobalt nitrate, manganese acetate, manganese acetylacetonate, manganese nitrate, copper acetate, copper nitrate, copper iodide, iron nitrate, iron chloride and iron acetylacetonate
  • the amount of the catalyst is 0.1-20%, more preferably, the amount of the catalyst is 2-10%.
  • the organic solvent is one or more selected from the group consisting of formic acid, glacial acetic acid, propionic acid, butyric acid, acetonitrile, 1,4-dioxane and water.
  • the above-mentioned continuous synthesis method further includes adding an initiator during the continuous oxidation reaction, and the initiator is a free radical initiator; preferably, the free radical initiator is selected from the group consisting of azobisisobutyronitrile and N-hydroxyphthalic acid.
  • the free radical initiator is selected from the group consisting of azobisisobutyronitrile and N-hydroxyphthalic acid.
  • the dosage is 1.0-30%.
  • the oxidant oxygen used is a green reagent, and it is cheap and easy to obtain. After the reaction is completed, a large amount of three wastes will not be generated, and the system is easy to handle.
  • the use of continuous reaction operation can reduce the risk of solvent flash explosion due to high concentration of oxygen in batch reactions.
  • the continuous preparation process can reduce the escape of oxygen, greatly increase the utilization rate of oxygen, simplify the operation, and improve the safety of the reaction and the yield of substituted benzoic acid organics.
  • the existing batch synthesis method for substituted benzoic acid organics has the problems of high cost, environmental protection and low yield of substituted benzoic acid organics.
  • the present application provides a continuous synthesis method of substituted benzoic acid organic compounds.
  • the continuous synthesis method includes: in the presence of a catalyst and an organic solvent, the organic compound represented by formula (I) is combined with oxygen Continuously input to the continuous reaction device for continuous oxidation reaction to obtain substituted benzoic acid organic matter, which is continuously discharged, and the substituted benzoic acid organic matter has the structure shown in formula (II);
  • R 1 , R 2 , R 3 , R 4 and R 5 each independently include but are not limited to H, alkyl, alkoxy, halogen, nitro, aryl, substituted aryl, heteroaryl, substituted hetero Aryl, ester or amide, and at least one of R 1 , R 2 , R 3 , R 4 and R 5 is not H, R 6 is an acetyl group, and M 1 , M 2 and M 3 each independently include but not Limited to C, N or S.
  • the oxidant oxygen used is a green reagent, and it is cheap and easy to obtain. After the reaction is completed, a large amount of three wastes will not be generated, and the system is easy to handle.
  • the use of continuous reaction operation can reduce the risk of solvent flash explosion due to high concentration of oxygen in batch reactions.
  • the continuous preparation process can reduce the escape of oxygen, greatly increase the utilization rate of oxygen, simplify the operation, and improve the safety of the reaction and the yield of substituted benzoic acid organics.
  • R 1 and R 2 are H
  • R 3 is F, Cl, Br or NO 2
  • R 4 and R 5 are H, or one of the following groups: F, methoxy And R 4 and R 5 are not the same.
  • the aforementioned continuous synthesis method further includes: adding a metal halide MX during the continuous oxidation reaction.
  • the addition of metal halide is beneficial to increase the reaction rate of the continuous oxidation reaction and the conversion rate of the product.
  • M includes but not limited to Li, K, Na, Mg or Ca
  • X includes but not limited to Cl or Br.
  • the amount of metal halide is 0.5-3% based on the weight percentage of the organic matter represented by formula (I).
  • the continuous reaction device can be of the type commonly used in this field.
  • the continuous reaction device includes but is not limited to a reaction coil.
  • reaction coils as a continuous reaction device can reduce the escape of oxygen, which enables the pressure during the continuous oxidation reaction to be controlled by the amount of oxygen, thereby helping to increase the yield of substituted benzoic acid organics.
  • the reaction temperature of the continuous oxidation reaction is 130-180°C, and the reaction pressure is 2.0-2.5 MPa.
  • the reaction temperature and reaction pressure of the continuous oxidation reaction include but are not limited to the above range, and limiting them to the above range is beneficial to further increase the yield of substituted benzoic acid organics.
  • the retention time of the continuous oxidation reaction is 90-240 min.
  • the catalyst includes, but is not limited to, cobalt acetate, cobalt acetylacetonate, cobalt nitrate, manganese acetate, manganese acetylacetonate, manganese nitrate, copper acetate, copper nitrate, copper iodide, ferric nitrate, and ferric chloride And one or more of the group consisting of iron acetylacetonate.
  • the above-mentioned catalysts are relatively inexpensive, which helps to reduce the cost of the reaction.
  • the above-mentioned catalyst is a mixture of cobalt acetate and manganese acetate, iron nitrate or copper nitrate.
  • the amount of the catalyst is 0.1-20%, and more preferably, the amount of the catalyst is 2-10%.
  • the organic solvent used in the above continuous oxidation reaction can be selected in a preferred embodiment.
  • the organic solvent includes but not limited to formic acid, glacial acetic acid, propionic acid, butyric acid, acetonitrile, 1,4-dioxane and water. One or more of the group.
  • the above-mentioned continuous synthesis method also includes adding an initiator in the continuous oxidation reaction, wherein the initiator used is a free radical initiator; preferably, the above-mentioned free radical initiator includes but not limited to azobisisobutyronitrile, N-hydroxy ortho One or more of the group consisting of phthalimide, 2,3-butanedione dioxime and acetaldehyde.
  • the use of the above-mentioned free radical initiators is beneficial to increase the rate of free radical generation in the continuous oxidation reaction process, and in turn, is beneficial to increase the reactivity of the continuous oxidation reaction.
  • the amount of the initiator is 1.0-30% based on the weight percentage of the organic matter represented by formula (I).
  • the above-mentioned continuous synthesis method further includes post-treatment of the product system of the continuous oxidation reaction.
  • the post-treatment process includes mixing the above-mentioned product system with water, and using the first pH adjustment Adjust the pH of the above-mentioned aqueous phase to 12-14, and then extract with the extractant to obtain the aqueous phase and the organic phase; use the second pH adjuster to adjust the pH of the above-mentioned aqueous phase to 1, after solid-liquid separation, obtain the desired substitution Benzoic acid organic matter.
  • 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), copper nitrate 10.1g (32.0mmol, 0.2eq), acetonitrile 250mL (10V), increase the temperature of the outer bath of the reaction coil to 180°C, use oxygen Adjust the coil pressure to 2.5MPa, and then start feeding, the system residence time is 1.5h, and the oxygen is 3 ⁇ 5eq.
  • Pump the system directly into 375mL purified water adjust the pH of the system to 12-14 with NaOH solids, extract the water phase twice with 125mL MTBE, and then adjust the pH to 1 with concentrated HCl. A large amount of solids precipitate out and filter to obtain the target product 19.5g, yield 78%.
  • 2,4-difluorophenyl ethanone 25g (160.1mmol, 1.0eq), AIBN 631mg (3.8mmol, 0.024eq), Co (OAc) 2 ⁇ 4H 2 O2.0g (7.8mmol, 0.049eq), NaBr 544mg ( 5.3mmol, 0.033eq), dissolved in HOAc 250mL (10V), stirred to fully dissolve until use, the temperature of the outer bath of the reaction coil was raised to 180°C, the pressure of the coil was adjusted with oxygen to 2.5MPa, and then the feeding was started, the system stayed Time 1.5h, oxygen 3 ⁇ 5eq.
  • 2,4-difluorophenyl ethanone 25g (160.1mmol, 1.0eq), AIBN 631mg (3.8mmol, 0.024eq), Co (OAc) 2 ⁇ 4H 2 O2.0g (7.8mmol, 0.049eq), NaBr 544mg ( 5.3mmol, 0.033eq), dissolved in 250mL of propionic acid (10V), stirred to fully dissolve and set aside, the temperature of the outer bath of the reaction coil was raised to 180°C, the pressure of the coil was adjusted to 2.5MPa with oxygen, and then the feed was started. The residence time is 1.5h, and the oxygen is 3 ⁇ 5eq.
  • 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), Co(OAc) 2 ⁇ 4H 2 O 2.0g (8.0mmol, 0.05eq), Mn(OAc) 2 ⁇ 4H 2 O 2.0g(8.0 mmol, 0.05eq), NHPI 2.6g (16.0mmol, 0.1eq), DMG 1.9g (16.0mmol, 0.1eq) dissolved in HOAc 250mL (10V), stir the whole solution for use, increase the temperature of the outer bath of the reaction coil When the temperature reaches 180°C, the coil pressure is adjusted to 2.5MPa with oxygen, and then the feed is started. The system residence time is 1.5h and the oxygen is 3 ⁇ 5eq.
  • 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), Co(OAc) 2 ⁇ 4H 2 O 1.2g(4.8mmol, 0.03eq), Mn(OAc) 2 ⁇ 4H 2 O 1.2g(4.8 mmol, 0.03eq), NHPI 2.6g (16.0mmol, 0.1eq), LiCl 207mg (4.8mmol, 0.03eq) dissolved in acetonitrile 250mL (10V), stir the whole solution for later use, increase the temperature of the outer bath of the reaction coil to At 180°C, use oxygen to adjust the coil pressure to 2.5 MPa, and then start feeding, the system residence time is 1.5 h, and the oxygen is 3 to 5 eq.
  • 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), Co(OAc) 2 ⁇ 4H 2 O 1.2g(4.8mmol, 0.03eq), Mn(OAc) 2 ⁇ 4H 2 O 1.2g(4.8 mmol, 0.03eq), NHPI 2.6g (16.0mmol, 0.1eq), 7.0g (160.1mmol, 1.0eq) of acetaldehyde dissolved in 250mL (10V) of acetonitrile, stir the whole solution for use, set the temperature of the outer bath of the reaction coil Raise the temperature to 180°C, adjust the coil pressure with oxygen to 2.5MPa, and then start feeding, the system residence time is 1.5h, and the oxygen is 3 ⁇ 5eq.
  • 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), copper acetate 5.8g (32.0mmol, 0.2eq), acetonitrile 250mL (10V), increase the temperature of the outer bath of the reaction coil to 180°C, use oxygen Adjust the coil pressure to 2.5MPa, and then start feeding, the system residence time is 1.5h, and the oxygen is 3 ⁇ 5eq.
  • Pump the system directly into 375mL purified water adjust the pH of the system to 12-14 with NaOH solids, extract the water phase twice with 125mL MTBE, and then adjust the pH to 1 with concentrated HCl. A large amount of solids precipitate out and filter to obtain the target product 17.8g, the yield was 71%.
  • 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), copper acetylacetonate 8.4g (32.0mmol, 0.2eq), acetonitrile 250mL (10V), increase the temperature of the outer bath of the reaction coil to 180°C, Use oxygen to adjust the coil pressure to 2.5MPa, and then start feeding, the system residence time is 1.5h, and the oxygen is 3 ⁇ 5eq.
  • Pump the system directly into 375mL purified water adjust the pH of the system to 12-14 with NaOH solids, extract the water phase twice with 125mL MTBE, and then adjust the pH to 1 with concentrated HCl. A large amount of solids precipitate out and filter to obtain the target product 17.0g, yield 68%.
  • 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), Fe(NO 3 ) 3 ⁇ 9H 2 O 10.1g (32.0mmol, 0.2eq), acetonitrile 250mL (10V), put the reaction coil outside the bath
  • the temperature was raised to 180°C, the coil pressure was adjusted to 2.5MPa with oxygen, and then the feed was started.
  • the system residence time was 1.5h and the oxygen was 3 ⁇ 5eq.
  • Pump the system directly into 375mL purified water adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 20.0g, yield 80%.
  • 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), Co(OAc) 2 ⁇ 4H 2 O 4.0g(16.0mmol, 0.1eq), Mn(OAc) 2 ⁇ 4H 2 O 4.0g(16.0 mmol, 0.1eq), dissolve in 250mL (10V) of acetic acid, stir and fully dissolve until use, increase the temperature of the outer bath of the reaction coil to 180°C, adjust the pressure of the coil to 2.5MPa with oxygen, and then start the feeding, the system residence time 1.5h, oxygen 3 ⁇ 5eq.
  • 2,4-difluorophenyl ethanone 25g (160.1mmol, 1.0eq), AIBN 631mg (3.8mmol, 0.024eq), Co (OAc) 2 ⁇ 4H 2 O2.0g (7.8mmol, 0.049eq), was dissolved in HOAc In 250mL (10V), stir the total solution for use, raise the temperature of the outer bath of the reaction coil to 180°C, adjust the pressure of the coil to 2.5MPa with oxygen, and then start feeding, the system residence time is 1.5h, and the oxygen is 3 ⁇ 5eq.
  • 2,4-difluorophenyl ethanone 25g (160.1mmol, 1.0eq), AIBN 631mg (3.8mmol, 0.024eq), Co (OAc) 2 ⁇ 4H 2 O2.0g (7.8mmol, 0.049eq), LiBr 460mg ( 5.3mmol, 0.033eq), dissolved in HOAc 250mL (10V), stirred to fully dissolve until use, the temperature of the outer bath of the reaction coil was raised to 180°C, the pressure of the coil was adjusted with oxygen to 2.5MPa, and then the feeding was started, the system stayed Time 1.5h, oxygen 3 ⁇ 5eq.
  • Comparative example 1 (batch reaction): AIBN-Co-NaBr-acetic acid system
  • 2,4-difluorophenyl ethanone 25g (160.1mmol, 1.0eq), AIBN 631mg (3.8mmol, 0.024eq), Co (OAc) 2 ⁇ 4H 2 O2.0g (7.8mmol, 0.049eq), NaBr 544mg ( 5.3mmol, 0.033eq), HOAc 250mL (10V), put in a reaction flask and stir to dissolve completely.
  • the temperature of the outer bath is raised to 100°C, the flow rate is adjusted to 60-100mL/min with oxygen, and oxygen is continuously supplied for 7.5h.
  • TLC still has raw materials
  • For the rest add 375mL purified water to the system, adjust the pH of the system to 12-14 with NaOH solids, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl. A large amount of solids precipitate out and filter to obtain the target product. 3.0g, yield 12%.
  • the above-mentioned embodiments of the present invention achieve the following technical effects: the use of the above-mentioned continuous synthesis method to prepare substituted benzoic acid organics can improve the environmental protection of the process, and the above-mentioned process is also convenient to operate and replace Advantages of high yield of benzoic acid organics.

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Abstract

The present invention provides a method for the continuous synthesis of a substituted benzoic-acid organic substance. The continuous synthesis method comprises: in the presence of catalyst and organic solvent, the organic matter represented by formula (I) and oxygen are continuously inputted to a continuous reaction apparatus for continuous oxidation reaction to obtain a substituted benzoic-acid organic substance, which is discharged continuously, the substituted benzoic-acid organic substance having the structure represented by formula (II). Oxygen is a green reagent and is inexpensive and readily available; a large amount of wastewater, waste gas, and solid waste is not generated after the reaction, and the system is easy to handle. The use of a continuous reaction operation can reduce the risk of flash distillation and explosion of solvent due to a high concentration of oxygen in a batch reaction. Under the same oxidation conditions, the continuous preparation process can reduce the escape of oxygen, greatly increasing the oxygen utilization rate and also simplifying the operation, improving the safety of the reaction and the yield of the substituted benzoic-acid organic substance.

Description

取代苯甲酸类有机物的连续化合成方法Continuous synthesis method of substituted benzoic acid organics 技术领域Technical field
本发明涉及医药化工领域，具体而言，涉及一种取代苯甲酸类有机物的连续化合成方法。The present invention relates to the field of medicine and chemical industry, in particular to a continuous synthesis method of substituted benzoic acid organic compounds.
背景技术Background technique
取代苯甲酸的制备一般是以容易获得的取代的烷基苯为原料。主要合成方法有化学试剂氧化法、光氯化水解法、气相氧化法和液相氧气氧化法。化学试剂氧化法是用高锰酸钾、重铬酸钾、次氯酸钠或硝酸做氧化剂，在水溶液中氧化取代的烷基苯得到取代苯甲酸。光氯化水解法是用氯气在光照下氯化取代甲苯，然后在酸性或碱性条件下水解，得到取代苯甲酸。上述方法具有生产成本高，腐蚀设备严重，产生大量废液、废气，污染环境的问题，因而逐渐受到人们的抵制和各国政府的限制。气相氧化法是在高温下使取代的甲苯汽化，其蒸汽通过催化剂层时由氧气氧化成取代苯甲酸。这种方法存在反应温度高，能耗大，不容易控制，且容易产生大量焦油，以及收率低的问题。液相氧气氧化法是80年代兴起的方法，它以低级脂肪酸为溶剂，过渡金属化合物和溴化物为催化剂，由空气或氧气氧化烷基芳香烃制取芳香族羧酸。由于这种方法生产成本低，不产生废气、废液，利于环境保护。产品以晶体析出，纯度高，后处理工艺简单。国内外不少厂家用此法进行了规模生产。其缺点是溶剂严重腐蚀设备，另外，由于催化剂活性等原因，反应需要在较高的压力下进行。The preparation of substituted benzoic acid is generally based on readily available substituted alkylbenzenes as raw materials. The main synthesis methods are chemical reagent oxidation, photochlorination hydrolysis, gas phase oxidation and liquid oxygen oxidation. The chemical reagent oxidation method uses potassium permanganate, potassium dichromate, sodium hypochlorite or nitric acid as the oxidant, and oxidizes the substituted alkylbenzene in an aqueous solution to obtain substituted benzoic acid. The photochlorination hydrolysis method uses chlorine to chlorinate toluene under light, and then hydrolyze under acidic or alkaline conditions to obtain substituted benzoic acid. The above method has the problems of high production cost, serious corrosion of equipment, generation of a large amount of waste liquid and waste gas, and environmental pollution. Therefore, it has gradually been resisted by people and restricted by governments of various countries. The gas-phase oxidation method vaporizes substituted toluene at high temperature, and when the vapor passes through the catalyst layer, oxygen is oxidized to substituted benzoic acid. This method has the problems of high reaction temperature, high energy consumption, not easy to control, easy to produce a large amount of tar, and low yield. Liquid-phase oxygen oxidation is a method that emerged in the 1980s. It uses lower fatty acids as solvents, transition metal compounds and bromides as catalysts, and oxidizes alkyl aromatic hydrocarbons with air or oxygen to prepare aromatic carboxylic acids. Due to the low production cost of this method, no waste gas or waste liquid is generated, which is beneficial to environmental protection. The product is precipitated as crystals with high purity and simple post-treatment process. Many domestic and foreign manufacturers have used this method for mass production. The disadvantage is that the solvent severely corrodes the equipment. In addition, due to catalyst activity and other reasons, the reaction needs to be carried out under higher pressure.
现有的合成取代苯甲酸的制备方法均在以下问题：The existing preparation methods of synthetic substituted benzoic acid all have the following problems:
(1)以上方法生产成本高，腐蚀设备严重，产生大量废液、废气，污染环境，逐渐受到人们的抵制和各国政府的限制。(1) The above methods have high production costs, severely corroded equipment, and generate a large amount of waste liquid and waste gas, which pollute the environment. They are gradually being resisted by people and restricted by governments of various countries.
(2)气相氧化法是在高温下使取代的甲苯汽化，其蒸汽通过催化剂层时由氧气氧化成取代苯甲酸。这种方法反应温度高，能耗大，不容易控制，容易产生大量焦油，收率低。(2) The gas phase oxidation method vaporizes substituted toluene at high temperature, and when the vapor passes through the catalyst layer, it is oxidized to substituted benzoic acid by oxygen. This method has high reaction temperature, high energy consumption, is not easy to control, is easy to produce a large amount of tar, and the yield is low.
(3)催化剂价格高，生产成本大。(3) The catalyst price is high and the production cost is high.
(4)批次生产，产量低，风险大。(4) Batch production, low output and high risk.
发明内容Summary of the invention
本发明的主要目的在于提供一种取代苯甲酸类有机物的连续化合成方法，以解决现有批次化合成方法存在的成本高、不环保及取代苯甲酸类有机物收率低的问题。The main purpose of the present invention is to provide a continuous synthesis method of substituted benzoic acid organics, so as to solve the problems of high cost, unenvironmental protection and low yield of substituted benzoic acid organics in the existing batch synthesis method.
为了实现上述目的，根据本发明提供了一种取代苯甲酸类有机物的连续化合成方法，该连续化合成方法包括：在催化剂和有机溶剂的存在下，将式(Ⅰ)所示的有机物与氧气连续 地输入连续化反应装置进行连续氧化反应，得到取代苯甲酸类有机物，并连续排出，取代苯甲酸类有机物具有式(Ⅱ)所示结构；In order to achieve the above objective, according to the present invention, a continuous synthesis method of substituted benzoic acid organic compounds is provided. The continuous synthesis method includes: in the presence of a catalyst and an organic solvent, the organic compound represented by formula (I) is combined with oxygen Continuously input to the continuous reaction device for continuous oxidation reaction to obtain substituted benzoic acid organic matter, which is continuously discharged, and the substituted benzoic acid organic matter has the structure shown in formula (II);
Figure PCTCN2019091400-appb-000001
Figure PCTCN2019091400-appb-000001
其中，R 1、R 2、R 3、R 4和R 5分别独立地选自H、烷基、烷氧基、卤素、硝基、芳基、取代芳基、杂芳基、取代杂芳基、酯基或酰胺，且R 1、R 2、R 3、R 4和R 5中至少一个不为H，R 6为乙酰基，M 1、M 2和M 3分别独立地选自C、N或S。 Wherein, R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, alkyl, alkoxy, halogen, nitro, aryl, substituted aryl, heteroaryl, substituted heteroaryl , Ester group or amide, and at least one of R 1 , R 2 , R 3 , R 4 and R 5 is not H, R 6 is an acetyl group, and M 1 , M 2 and M 3 are each independently selected from C and N Or S.
进一步地，R 1和R 2为H，R 3为F、Cl、Br或NO 2，R 4和R 5为H，或以下基团中的一种：F、甲氧基，且R 4和R 5不相同。 Further, R 1 and R 2 are H, R 3 is F, Cl, Br or NO 2 , R 4 and R 5 are H, or one of the following groups: F, methoxy, and R 4 and R 5 is not the same.
进一步地，上述连续化合成方法还包括：在连续氧化反应的过程中加入金属卤化物MX；优选地，以式(Ⅰ)所示的有机物的重量百分含量计，金属卤化物MX的用量为0.5～3％。Further, the aforementioned continuous synthesis method further includes: adding metal halide MX during the continuous oxidation reaction; preferably, the amount of metal halide MX is calculated based on the weight percentage of the organic matter represented by formula (I) 0.5～3%.
进一步地，M选自Li、K、Na、Mg或Ca，X选自Cl或Br。Further, M is selected from Li, K, Na, Mg or Ca, and X is selected from Cl or Br.
进一步地，连续化反应装置选自反应盘管。Further, the continuous reaction device is selected from reaction coils.
进一步地，连续氧化反应的反应温度为130～180℃，反应压力为1.0～2.5MPa。Further, the reaction temperature of the continuous oxidation reaction is 130-180°C, and the reaction pressure is 1.0-2.5 MPa.
进一步地，连续氧化反应的保留时间为90～240min。Further, the retention time of the continuous oxidation reaction is 90-240 min.
进一步地，催化剂选自醋酸钴、乙酰丙酮钴、硝酸钴、醋酸锰、乙酰丙酮锰、硝酸锰、醋酸铜、硝酸铜、碘化铜、硝酸铁、氯化铁和乙酰丙酮铁组成的组中的一种或多种；优选地，以式(Ⅰ)所示的有机物的重量百分含量计，催化剂的用量为0.1～20％，更优选地，催化剂的用量为2～10％。Further, the catalyst is selected from the group consisting of cobalt acetate, cobalt acetylacetonate, cobalt nitrate, manganese acetate, manganese acetylacetonate, manganese nitrate, copper acetate, copper nitrate, copper iodide, iron nitrate, iron chloride and iron acetylacetonate Preferably, based on the weight percentage of the organic matter represented by formula (I), the amount of the catalyst is 0.1-20%, more preferably, the amount of the catalyst is 2-10%.
进一步地，有机溶剂选自甲酸、冰乙酸、丙酸、丁酸、乙腈、1,4-二氧六环和水组成的组中的一种或多种。Further, the organic solvent is one or more selected from the group consisting of formic acid, glacial acetic acid, propionic acid, butyric acid, acetonitrile, 1,4-dioxane and water.
进一步地，上述连续化合成方法还包括在连续氧化反应过程中加入引发剂，引发剂为自由基引发剂；优选地，自由基引发剂选自偶氮二异丁腈、N-羟基邻苯二甲酰亚胺、2，3-丁二 酮二肟和乙醛组成的组中的一种或多种；优选地，以式(Ⅰ)所示的有机物的重量百分含量计，引发剂的用量为1.0～30％。Further, the above-mentioned continuous synthesis method further includes adding an initiator during the continuous oxidation reaction, and the initiator is a free radical initiator; preferably, the free radical initiator is selected from the group consisting of azobisisobutyronitrile and N-hydroxyphthalic acid. One or more of the group consisting of formimide, 2,3-butanedione dioxime and acetaldehyde; preferably, based on the weight percentage of the organic matter represented by formula (I), the initiator The dosage is 1.0-30%.
应用本发明的技术方案，上述连续化氧化反应中，使用的氧化剂氧气为绿色试剂，且廉价易得，反应结束后不会产生大量的三废，体系易处理。使用连续化反应操作能够降低高浓度氧在批次反应中使溶剂闪蒸爆炸的风险。同时在同等氧化条件中，采用连续化制备工艺能够减少了氧气的逃逸，使氧气利用率大大增加，也简化了操作，提高了反应的安全性和取代苯甲酸类有机物的收率。在此基础上，采用上述连续化合成法制备取代苯甲酸类有机物能够提高工艺的环保性，同时上述工艺还具有便于操作和取代苯甲酸类有机物收率高等优点。By applying the technical scheme of the present invention, in the above continuous oxidation reaction, the oxidant oxygen used is a green reagent, and it is cheap and easy to obtain. After the reaction is completed, a large amount of three wastes will not be generated, and the system is easy to handle. The use of continuous reaction operation can reduce the risk of solvent flash explosion due to high concentration of oxygen in batch reactions. At the same time, under the same oxidation conditions, the continuous preparation process can reduce the escape of oxygen, greatly increase the utilization rate of oxygen, simplify the operation, and improve the safety of the reaction and the yield of substituted benzoic acid organics. On this basis, the use of the above-mentioned continuous synthesis method to prepare substituted benzoic acid organics can improve the environmental protection of the process, and the above-mentioned process also has the advantages of easy operation and high yield of substituted benzoic acid organics.
具体实施方式Detailed ways
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。It should be noted that the embodiments in this application and the features in the embodiments can be combined with each other if there is no conflict. Hereinafter, the present invention will be described in detail in conjunction with embodiments.
正如背景技术所描述的，现有的批次化合成取代苯甲酸类有机物的方法存在的成本高、不环保及取代苯甲酸类有机物收率低的问题。为了解决上述技术问题，本申请提供了一种取代苯甲酸类有机物的连续化合成方法，该连续化合成方法包括：在催化剂和有机溶剂的存在下，将式(Ⅰ)所示的有机物与氧气连续地输入连续化反应装置进行连续氧化反应，得到取代苯甲酸类有机物，并连续排出，取代苯甲酸类有机物具有式(Ⅱ)所示结构；As described in the background art, the existing batch synthesis method for substituted benzoic acid organics has the problems of high cost, environmental protection and low yield of substituted benzoic acid organics. In order to solve the above technical problems, the present application provides a continuous synthesis method of substituted benzoic acid organic compounds. The continuous synthesis method includes: in the presence of a catalyst and an organic solvent, the organic compound represented by formula (I) is combined with oxygen Continuously input to the continuous reaction device for continuous oxidation reaction to obtain substituted benzoic acid organic matter, which is continuously discharged, and the substituted benzoic acid organic matter has the structure shown in formula (II);
Figure PCTCN2019091400-appb-000002
Figure PCTCN2019091400-appb-000002
其中，R 1、R 2、R 3、R 4和R 5分别独立地包括但不限于H、烷基、烷氧基、卤素、硝基、芳基、取代芳基、杂芳基、取代杂芳基、酯基或酰胺，且R 1、R 2、R 3、R 4和R 5中至少一个不为H，R 6为乙酰基，M 1、M 2和M 3分别独立地包括但不限于C、N或S。 Wherein, R 1 , R 2 , R 3 , R 4 and R 5 each independently include but are not limited to H, alkyl, alkoxy, halogen, nitro, aryl, substituted aryl, heteroaryl, substituted hetero Aryl, ester or amide, and at least one of R 1 , R 2 , R 3 , R 4 and R 5 is not H, R 6 is an acetyl group, and M 1 , M 2 and M 3 each independently include but not Limited to C, N or S.
上述连续化氧化反应中，使用的氧化剂氧气为绿色试剂，且廉价易得，反应结束后不会产生大量的三废，体系易处理。使用连续化反应操作能够降低高浓度氧在批次反应中使溶剂闪蒸爆炸的风险。同时在同等氧化条件中，采用连续化制备工艺能够减少了氧气的逃逸，使氧气利用率大大增加，也简化了操作，提高了反应的安全性和取代苯甲酸类有机物的收率。 在此基础上，采用上述连续化合成法制备取代苯甲酸类有机物能够提高工艺的环保性，同时上述工艺还具有便于操作和取代苯甲酸类有机物收率高等优点。In the above continuous oxidation reaction, the oxidant oxygen used is a green reagent, and it is cheap and easy to obtain. After the reaction is completed, a large amount of three wastes will not be generated, and the system is easy to handle. The use of continuous reaction operation can reduce the risk of solvent flash explosion due to high concentration of oxygen in batch reactions. At the same time, under the same oxidation conditions, the continuous preparation process can reduce the escape of oxygen, greatly increase the utilization rate of oxygen, simplify the operation, and improve the safety of the reaction and the yield of substituted benzoic acid organics. On this basis, the use of the above-mentioned continuous synthesis method to prepare substituted benzoic acid organics can improve the environmental protection of the process, and the above-mentioned process also has the advantages of easy operation and high yield of substituted benzoic acid organics.
在一种优选的实施方式中，R 1和R 2为H，R 3为F、Cl、Br或NO 2，R 4和R 5为H，或以下基团中的一种：F、甲氧基，且R 4和R 5不相同。 In a preferred embodiment, R 1 and R 2 are H, R 3 is F, Cl, Br or NO 2 , R 4 and R 5 are H, or one of the following groups: F, methoxy And R 4 and R 5 are not the same.
在一种优选的实施例中，上述连续化合成方法还包括：在连续氧化反应的过程中加入金属卤化物MX。金属卤化物的加入有利于提高连续化氧化反应的反应速率和产物的转化率。更优选地，M包括但不限于Li、K、Na、Mg或Ca，X包括但不限于Cl或Br。In a preferred embodiment, the aforementioned continuous synthesis method further includes: adding a metal halide MX during the continuous oxidation reaction. The addition of metal halide is beneficial to increase the reaction rate of the continuous oxidation reaction and the conversion rate of the product. More preferably, M includes but not limited to Li, K, Na, Mg or Ca, and X includes but not limited to Cl or Br.
更优选地，以式(Ⅰ)所示的有机物的重量百分含量计，金属卤化物的用量为0.5～3％。More preferably, the amount of metal halide is 0.5-3% based on the weight percentage of the organic matter represented by formula (I).
上述连续化氧化反应中，连续化反应装置可以选用本领域常用的种类。在一种优选的实施例中，连续化反应装置包括但不限于反应盘管。采用反应盘管作为连续化反应装置能够降低氧气的逸出，这使得通过氧气的用量能够调控连续氧化反应过程中的压力，从而有利于提高取代苯甲酸类有机物的收率。In the above-mentioned continuous oxidation reaction, the continuous reaction device can be of the type commonly used in this field. In a preferred embodiment, the continuous reaction device includes but is not limited to a reaction coil. The use of reaction coils as a continuous reaction device can reduce the escape of oxygen, which enables the pressure during the continuous oxidation reaction to be controlled by the amount of oxygen, thereby helping to increase the yield of substituted benzoic acid organics.
在一种优选的实施例中，连续氧化反应的反应温度为130～180℃，反应压力为2.0～2.5MPa。连续氧化反应的反应温度和反应压力包括但不限于上述范围，而将其限定在上述范围内有利于进一步提高取代苯甲酸类有机物的收率。In a preferred embodiment, the reaction temperature of the continuous oxidation reaction is 130-180°C, and the reaction pressure is 2.0-2.5 MPa. The reaction temperature and reaction pressure of the continuous oxidation reaction include but are not limited to the above range, and limiting them to the above range is beneficial to further increase the yield of substituted benzoic acid organics.
为了提高反应原料的充分反应程度，优选地，连续氧化反应的保留时间为90～240min。In order to increase the full reaction degree of the reaction raw materials, preferably, the retention time of the continuous oxidation reaction is 90-240 min.
上述连续化氧化反应中，可以选用本领域常用的催化剂。在一种优选的实施例中，催化剂包括但不限于醋酸钴、乙酰丙酮钴、硝酸钴、醋酸锰、乙酰丙酮锰、硝酸锰、醋酸铜、硝酸铜、碘化铜、硝酸铁、氯化铁和乙酰丙酮铁组成的组中的一种或多种。相比于其它催化剂，上述几种催化剂价格较为低廉，有利于降低反应的成本。为了进一步提高更优选地，上述催化剂为醋酸钴和醋酸锰的混合物、硝酸铁或硝酸铜。In the above continuous oxidation reaction, a catalyst commonly used in the art can be selected. In a preferred embodiment, the catalyst includes, but is not limited to, cobalt acetate, cobalt acetylacetonate, cobalt nitrate, manganese acetate, manganese acetylacetonate, manganese nitrate, copper acetate, copper nitrate, copper iodide, ferric nitrate, and ferric chloride And one or more of the group consisting of iron acetylacetonate. Compared with other catalysts, the above-mentioned catalysts are relatively inexpensive, which helps to reduce the cost of the reaction. In order to further improve it more preferably, the above-mentioned catalyst is a mixture of cobalt acetate and manganese acetate, iron nitrate or copper nitrate.
在一种优选的实施例中，以式(Ⅰ)所示的有机物的重量百分含量计，催化剂的用量为0.1～20％，进一步地优选地，催化剂的用量为2～10％。In a preferred embodiment, based on the weight percentage of the organic matter represented by formula (I), the amount of the catalyst is 0.1-20%, and more preferably, the amount of the catalyst is 2-10%.
上述连续氧化反应中采用的有机溶剂可以选用在一种优选的实施例中，有机溶剂包括但不限于甲酸、冰乙酸、丙酸、丁酸、乙腈、1,4-二氧六环和水组成的组中的一种或多种。The organic solvent used in the above continuous oxidation reaction can be selected in a preferred embodiment. The organic solvent includes but not limited to formic acid, glacial acetic acid, propionic acid, butyric acid, acetonitrile, 1,4-dioxane and water. One or more of the group.
上述连续化合成方法还包括在连续氧化反应中加入引发剂，其中采用的引发剂为自由基引发剂；优选地，上述自由基引发剂包括但不限于偶氮二异丁腈、N-羟基邻苯二甲酰亚胺、2，3-丁二酮二肟和乙醛组成的组中的一种或多种。相比于其它的自由基引发剂，采用上述几种自由基引发剂有利于提高连续氧化反应过程中的自由基产生率，进而有利于提高连续化氧化反应的反应活性。优选地，以式(Ⅰ)所示的有机物的重量百分含量计，引发剂的用量为1.0～30％。The above-mentioned continuous synthesis method also includes adding an initiator in the continuous oxidation reaction, wherein the initiator used is a free radical initiator; preferably, the above-mentioned free radical initiator includes but not limited to azobisisobutyronitrile, N-hydroxy ortho One or more of the group consisting of phthalimide, 2,3-butanedione dioxime and acetaldehyde. Compared with other free radical initiators, the use of the above-mentioned free radical initiators is beneficial to increase the rate of free radical generation in the continuous oxidation reaction process, and in turn, is beneficial to increase the reactivity of the continuous oxidation reaction. Preferably, the amount of the initiator is 1.0-30% based on the weight percentage of the organic matter represented by formula (I).
为了提高取代苯甲酸类有机物的纯度，优选地，上述连续化合成方法还包括对连续化氧化反应的产物体系进行后处理，该后处理过程包括将上述产物体系与水混合，使用第一pH调节剂将其pH调至12-14，然后采用萃取剂进行萃取，得到水相和有机相；使用第二pH调节剂将上述水相的pH调至1，固液分离后，得到所需的取代苯甲酸类有机物。In order to improve the purity of the substituted benzoic acid-based organics, preferably, the above-mentioned continuous synthesis method further includes post-treatment of the product system of the continuous oxidation reaction. The post-treatment process includes mixing the above-mentioned product system with water, and using the first pH adjustment Adjust the pH of the above-mentioned aqueous phase to 12-14, and then extract with the extractant to obtain the aqueous phase and the organic phase; use the second pH adjuster to adjust the pH of the above-mentioned aqueous phase to 1, after solid-liquid separation, obtain the desired substitution Benzoic acid organic matter.
以下结合具体实施例对本申请作进一步详细描述，这些实施例不能理解为限制本申请所要求保护的范围。The application will be further described in detail below in conjunction with specific embodiments, and these embodiments should not be construed as limiting the scope of protection claimed by the application.
典型实施例的合成路线如下：
Figure PCTCN2019091400-appb-000003
The synthetic route of a typical embodiment is as follows:
Figure PCTCN2019091400-appb-000003
实施例1：Example 1:
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，硝酸铜10.1g(32.0mmol,0.2eq)，乙腈250mL(10V)，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品19.5g，收率78％。1H-NMR(500MHz,氯仿)δ:7.05(t,J＝9.3Hz,2H),8.01(dd,J＝15.5,8.2Hz,1H)。2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), copper nitrate 10.1g (32.0mmol, 0.2eq), acetonitrile 250mL (10V), increase the temperature of the outer bath of the reaction coil to 180℃, use oxygen Adjust the coil pressure to 2.5MPa, and then start feeding, the system residence time is 1.5h, and the oxygen is 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solids, extract the water phase twice with 125mL MTBE, and then adjust the pH to 1 with concentrated HCl. A large amount of solids precipitate out and filter to obtain the target product 19.5g, yield 78%. 1H-NMR (500MHz, chloroform) δ: 7.05 (t, J=9.3 Hz, 2H), 8.01 (dd, J=15.5, 8.2 Hz, 1H).
实施例2：AIBN-Co-NaBr-乙酸体系Example 2: AIBN-Co-NaBr-acetic acid system
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，AIBN 631mg(3.8mmol,0.024eq)，Co(OAc) 2·4H 2O2.0g(7.8mmol,0.049eq)，NaBr 544mg(5.3mmol,0.033eq)，溶于HOAc 250mL(10V)中，搅拌全溶待用，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品12.3g，收率49％。 2,4-difluorophenyl ethanone 25g (160.1mmol, 1.0eq), AIBN 631mg (3.8mmol, 0.024eq), Co (OAc) 2 · 4H 2 O2.0g (7.8mmol, 0.049eq), NaBr 544mg ( 5.3mmol, 0.033eq), dissolved in HOAc 250mL (10V), stirred to fully dissolve until use, the temperature of the outer bath of the reaction coil was raised to 180℃, the pressure of the coil was adjusted with oxygen to 2.5MPa, and then the feeding was started, the system stayed Time 1.5h, oxygen 3～5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 12.3g, yield 49%.
实施例3：AIBN-Co-NaBr-丙酸体系Example 3: AIBN-Co-NaBr-propionic acid system
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，AIBN 631mg(3.8mmol,0.024eq)，Co(OAc) 2·4H 2O2.0g(7.8mmol,0.049eq)，NaBr 544mg(5.3mmol,0.033eq)，溶于丙酸250mL(10V)中，搅拌全溶待用，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品11.3g，收率45％。 2,4-difluorophenyl ethanone 25g (160.1mmol, 1.0eq), AIBN 631mg (3.8mmol, 0.024eq), Co (OAc) 2 · 4H 2 O2.0g (7.8mmol, 0.049eq), NaBr 544mg ( 5.3mmol, 0.033eq), dissolved in 250mL of propionic acid (10V), stirred to fully dissolve and set aside, the temperature of the outer bath of the reaction coil was raised to 180℃, the pressure of the coil was adjusted to 2.5MPa with oxygen, and then the feed was started. The residence time is 1.5h, and the oxygen is 3～5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 11.3g, the yield is 45%.
实施例4：Co-Mn-NHPI-DMG体系Example 4: Co-Mn-NHPI-DMG system
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，Co(OAc) 2·4H 2O 2.0g(8.0mmol,0.05eq)，Mn(OAc) 2·4H 2O 2.0g(8.0mmol,0.05eq)，NHPI 2.6g(16.0mmol，0.1eq)，DMG 1.9g(16.0mmol，0.1eq)溶于HOAc 250mL(10V)中，搅拌全溶待用，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品11.5g，收率46％。 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), Co(OAc) 2 ·4H 2 O 2.0g (8.0mmol, 0.05eq), Mn(OAc) 2 ·4H 2 O 2.0g(8.0 mmol, 0.05eq), NHPI 2.6g (16.0mmol, 0.1eq), DMG 1.9g (16.0mmol, 0.1eq) dissolved in HOAc 250mL (10V), stir the whole solution for use, increase the temperature of the outer bath of the reaction coil When the temperature reaches 180°C, the coil pressure is adjusted to 2.5MPa with oxygen, and then the feed is started. The system residence time is 1.5h and the oxygen is 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 11.5g, yield 46%.
实施例5：Co-Mn-NHPI-LiCl体系Example 5: Co-Mn-NHPI-LiCl system
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，Co(OAc) 2·4H 2O 1.2g(4.8mmol,0.03eq)，Mn(OAc) 2·4H 2O 1.2g(4.8mmol,0.03eq)，NHPI 2.6g(16.0mmol，0.1eq)，LiCl 207mg(4.8mmol，0.03eq)溶于乙腈250mL(10V)中，搅拌全溶待用，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品10.1g，收率40％。 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), Co(OAc) 2 ·4H 2 O 1.2g(4.8mmol, 0.03eq), Mn(OAc) 2 ·4H 2 O 1.2g(4.8 mmol, 0.03eq), NHPI 2.6g (16.0mmol, 0.1eq), LiCl 207mg (4.8mmol, 0.03eq) dissolved in acetonitrile 250mL (10V), stir the whole solution for later use, increase the temperature of the outer bath of the reaction coil to At 180°C, use oxygen to adjust the coil pressure to 2.5 MPa, and then start feeding, the system residence time is 1.5 h, and the oxygen is 3 to 5 eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 10.1g, the yield is 40%.
实施例6：Co-Mn-NHPI-乙醛体系Example 6: Co-Mn-NHPI-acetaldehyde system
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，Co(OAc) 2·4H 2O 1.2g(4.8mmol,0.03eq)，Mn(OAc) 2·4H 2O 1.2g(4.8mmol,0.03eq)，NHPI 2.6g(16.0mmol，0.1eq)，乙醛7.0g(160.1mmol，1.0eq)溶于乙腈250mL(10V)中，搅拌全溶待用，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品9.5g，收率38％。 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), Co(OAc) 2 ·4H 2 O 1.2g(4.8mmol, 0.03eq), Mn(OAc) 2 ·4H 2 O 1.2g(4.8 mmol, 0.03eq), NHPI 2.6g (16.0mmol, 0.1eq), 7.0g (160.1mmol, 1.0eq) of acetaldehyde dissolved in 250mL (10V) of acetonitrile, stir the whole solution for use, set the temperature of the outer bath of the reaction coil Raise the temperature to 180°C, adjust the coil pressure with oxygen to 2.5MPa, and then start feeding, the system residence time is 1.5h, and the oxygen is 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 9.5g, the yield is 38%.
实施例7：醋酸铜Example 7: Copper acetate
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，醋酸铜5.8g(32.0mmol,0.2eq)，乙腈250mL(10V)，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品17.8g，收率71％。2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), copper acetate 5.8g (32.0mmol, 0.2eq), acetonitrile 250mL (10V), increase the temperature of the outer bath of the reaction coil to 180℃, use oxygen Adjust the coil pressure to 2.5MPa, and then start feeding, the system residence time is 1.5h, and the oxygen is 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solids, extract the water phase twice with 125mL MTBE, and then adjust the pH to 1 with concentrated HCl. A large amount of solids precipitate out and filter to obtain the target product 17.8g, the yield was 71%.
实施例8：乙酰丙酮酸铜Example 8: Copper acetylacetonate
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，乙酰丙酮酸铜8.4g(32.0mmol,0.2eq)，乙腈250mL(10V)，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品17.0g，收率68％。2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), copper acetylacetonate 8.4g (32.0mmol, 0.2eq), acetonitrile 250mL (10V), increase the temperature of the outer bath of the reaction coil to 180℃, Use oxygen to adjust the coil pressure to 2.5MPa, and then start feeding, the system residence time is 1.5h, and the oxygen is 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solids, extract the water phase twice with 125mL MTBE, and then adjust the pH to 1 with concentrated HCl. A large amount of solids precipitate out and filter to obtain the target product 17.0g, yield 68%.
实施例9：硝酸铁Example 9: Ferric Nitrate
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，Fe(NO 3) 3·9H 2O 10.1g(32.0mmol,0.2eq)，乙腈250mL(10V)，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品20.0g，收率80％。 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), Fe(NO 3 ) 3 ·9H 2 O 10.1g (32.0mmol, 0.2eq), acetonitrile 250mL (10V), put the reaction coil outside the bath The temperature was raised to 180°C, the coil pressure was adjusted to 2.5MPa with oxygen, and then the feed was started. The system residence time was 1.5h and the oxygen was 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 20.0g, yield 80%.
实施例10：Co-Mn体系Example 10: Co-Mn system
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，Co(OAc) 2·4H 2O 4.0g(16.0mmol,0.1eq)，Mn(OAc) 2·4H 2O 4.0g(16.0mmol,0.1eq)，溶于醋酸250mL(10V)中，搅拌全溶待用，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品21.3g，收率85％。 2,4-Difluoroacetophenone 25g (160.1mmol, 1.0eq), Co(OAc) 2 ·4H 2 O 4.0g(16.0mmol, 0.1eq), Mn(OAc) 2 ·4H 2 O 4.0g(16.0 mmol, 0.1eq), dissolve in 250mL (10V) of acetic acid, stir and fully dissolve until use, increase the temperature of the outer bath of the reaction coil to 180℃, adjust the pressure of the coil to 2.5MPa with oxygen, and then start the feeding, the system residence time 1.5h, oxygen 3～5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 21.3g, yield 85%.
实施例11：底物拓展1Example 11: Substrate Expansion 1
Figure PCTCN2019091400-appb-000004
Figure PCTCN2019091400-appb-000004
2-氟-4-氯苯乙酮25g(144.9mmol,1.0eq)，Cu(NO 3) 2·4H 2O 7.0g(29.0mmol,0.2eq)，乙腈250mL(10V)，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品19.3g，收率77％。1H NMR(500MHz,氯仿)δ8.08(dd,J＝7.5,5.0Hz,1H),7.90(dd,J＝8.0,1.5Hz,1H),7.43(dd,J＝7.5,1.4Hz,1H)。 2-Fluoro-4-chloroacetophenone 25g (144.9mmol, 1.0eq), Cu(NO 3 ) 2 ·4H 2 O 7.0g (29.0mmol, 0.2eq), acetonitrile 250mL (10V), put the reaction coil outside The bath temperature was raised to 180°C, the coil pressure was adjusted to 2.5MPa with oxygen, and then the feed was started. The system residence time was 1.5h, and the oxygen was 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 19.3g, the yield is 77%. 1H NMR (500MHz, chloroform) δ 8.08 (dd, J = 7.5, 5.0 Hz, 1H), 7.90 (dd, J = 8.0, 1.5 Hz, 1H), 7.43 (dd, J = 7.5, 1.4 Hz, 1H) .
实施例12：底物拓展2Example 12: Substrate Expansion 2
Figure PCTCN2019091400-appb-000005
Figure PCTCN2019091400-appb-000005
2-氟-4-溴苯乙酮25g(115.2mmol,1.0eq)，Cu(NO 3) 2·4H 2O 5.6g(23.0mmol,0.2eq)，乙腈250mL(10V)，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品19.8g，收率79％。 1H-NMR(CDCl 3)δ:7.38–7.42(m,2H),7.89(t,1H,J＝7.88)。 2-Fluoro-4-bromoacetophenone 25g (115.2mmol, 1.0eq), Cu(NO 3 ) 2 ·4H 2 O 5.6g (23.0mmol, 0.2eq), acetonitrile 250mL (10V), put the reaction coil outside The bath temperature was raised to 180°C, the coil pressure was adjusted to 2.5MPa with oxygen, and then the feed was started. The system residence time was 1.5h, and the oxygen was 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 19.8g, the yield was 79%. 1 H-NMR (CDCl 3 ) δ: 7.38-7.42 (m, 2H), 7.89 (t, 1H, J=7.88).
实施例13：底物拓展3Example 13: Substrate Expansion 3
Figure PCTCN2019091400-appb-000006
Figure PCTCN2019091400-appb-000006
3-氟-4-溴苯乙酮25g(115.2mmol,1.0eq)，Cu(NO 3) 2·4H 2O 5.6g(23.0mmol,0.2eq)，乙腈250mL(10V)，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品18.3g，收率73％。 1H NMR(500MHz,氯仿)δ7.76–7.69(m,2H),7.64(dd,J＝7.5,1.4Hz,1H)。 3-Fluoro-4-bromoacetophenone 25g (115.2mmol, 1.0eq), Cu(NO 3 ) 2 ·4H 2 O 5.6g (23.0mmol, 0.2eq), acetonitrile 250mL (10V), put the reaction coil outside The bath temperature was raised to 180°C, the coil pressure was adjusted to 2.5MPa with oxygen, and then the feed was started. The system residence time was 1.5h, and the oxygen was 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 18.3g, yield 73%. 1 H NMR (500MHz, chloroform) δ 7.76-7.69 (m, 2H), 7.64 (dd, J=7.5, 1.4 Hz, 1H).
实施例14：底物拓展4Example 14: Substrate Development 4
Figure PCTCN2019091400-appb-000007
Figure PCTCN2019091400-appb-000007
2-氟-4-硝基苯乙酮25g(136.5mmol,1.0eq)，Cu(NO 3) 2·4H 2O 6.6g(27.3mmol,0.2eq)，乙腈250mL(10V)，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品17.3g，收率69％。 1H NMR(500MHz,氯仿)δ8.39-8.40(dd,J＝7.5,5.0Hz,1H),8.12-8.14(ddd,J＝13.3,7.8,1.4Hz,2H)。 2-Fluoro-4-nitroacetophenone 25g (136.5mmol, 1.0eq), Cu(NO 3 ) 2 ·4H 2 O 6.6g (27.3mmol, 0.2eq), acetonitrile 250mL (10V), the reaction coil The temperature of the outer bath is increased to 180°C, the coil pressure is adjusted to 2.5MPa with oxygen, and then the feeding is started. The residence time of the system is 1.5h, and the oxygen is 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 17.3g, yield 69%. 1 H NMR (500MHz, chloroform) δ 8.39-8.40 (dd, J=7.5, 5.0 Hz, 1H), 8.12-8.14 (ddd, J=13.3, 7.8, 1.4 Hz, 2H).
实施例15：底物拓展5Example 15: Substrate Expansion 5
Figure PCTCN2019091400-appb-000008
Figure PCTCN2019091400-appb-000008
3-甲氧基-4硝基苯乙酮25g(128.1mmol,1.0eq)，Cu(NO 3) 2·4H 2O 6.2g(25.6mmol,0.2eq)，乙腈250mL(10V)，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品19.3g，收率77％。 1H NMR(500MHz,氯仿)δ8.33(d,J＝7.5Hz,1H),8.07(dd,J＝7.5,1.4Hz,1H),7.97(d,J＝1.4Hz,1H),4.07(s,3H)。 3-methoxy-4nitroacetophenone 25g (128.1mmol, 1.0eq), Cu(NO 3 ) 2 ·4H 2 O 6.2g (25.6mmol, 0.2eq), acetonitrile 250mL (10V), put the reaction plate The temperature of the external bath of the tube was increased to 180°C, the pressure of the coil was adjusted to 2.5MPa with oxygen, and the feeding was started. The residence time of the system was 1.5h and the oxygen was 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 19.3g, the yield is 77%. 1 H NMR (500MHz, chloroform) δ8.33 (d, J = 7.5Hz, 1H), 8.07 (dd, J = 7.5, 1.4Hz, 1H), 7.97 (d, J = 1.4Hz, 1H), 4.07 ( s,3H).
实施例16(无NaBr)：AIBN-Co-乙酸体系Example 16 (No NaBr): AIBN-Co-acetic acid system
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，AIBN 631mg(3.8mmol,0.024eq)，Co(OAc) 2·4H 2O2.0g(7.8mmol,0.049eq)，溶于HOAc 250mL(10V)中，搅拌全溶待用，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品5.8g，收率23％。 2,4-difluorophenyl ethanone 25g (160.1mmol, 1.0eq), AIBN 631mg (3.8mmol, 0.024eq), Co (OAc) 2 · 4H 2 O2.0g (7.8mmol, 0.049eq), was dissolved in HOAc In 250mL (10V), stir the total solution for use, raise the temperature of the outer bath of the reaction coil to 180°C, adjust the pressure of the coil to 2.5MPa with oxygen, and then start feeding, the system residence time is 1.5h, and the oxygen is 3~5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 5.8g, yield 23%.
实施例17:AIBN-Co-LiBr-乙酸体系Example 17: AIBN-Co-LiBr-acetic acid system
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，AIBN 631mg(3.8mmol,0.024eq)，Co(OAc) 2·4H 2O2.0g(7.8mmol,0.049eq)，LiBr 460mg(5.3mmol,0.033eq)，溶于HOAc 250mL(10V)中，搅拌全溶待用，将反应盘管外浴温度升至180℃，用氧气调节盘管压力2.5MPa，进而开始打料，体系停留时间1.5h，氧气3～5eq。将体系直接泵入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品13.8g，收率55％。 2,4-difluorophenyl ethanone 25g (160.1mmol, 1.0eq), AIBN 631mg (3.8mmol, 0.024eq), Co (OAc) 2 · 4H 2 O2.0g (7.8mmol, 0.049eq), LiBr 460mg ( 5.3mmol, 0.033eq), dissolved in HOAc 250mL (10V), stirred to fully dissolve until use, the temperature of the outer bath of the reaction coil was raised to 180℃, the pressure of the coil was adjusted with oxygen to 2.5MPa, and then the feeding was started, the system stayed Time 1.5h, oxygen 3～5eq. Pump the system directly into 375mL purified water, adjust the pH of the system to 12-14 with NaOH solid, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl for the water phase. A large amount of solids precipitate out and filter to obtain the target product 13.8g, yield 55%.
对比例1(批次化反应)：AIBN-Co-NaBr-乙酸体系Comparative example 1 (batch reaction): AIBN-Co-NaBr-acetic acid system
2，4-二氟苯乙酮25g(160.1mmol,1.0eq)，AIBN 631mg(3.8mmol,0.024eq)，Co(OAc) 2·4H 2O2.0g(7.8mmol,0.049eq)，NaBr 544mg(5.3mmol,0.033eq)，HOAc 250mL(10V)，置于反应瓶中搅拌全溶，外浴温度升至100℃，用氧气调节流速60～100mL/min，连续通氧气7.5h，TLC仍然有原料剩余，体系中加入375mL纯化水中，用NaOH固体将体系pH调至12～14，用125mL MTBE萃取水相两次，水相再用浓HCl调pH至1，有大量固体析出，过滤得到目标产品3.0g，收率12％。 2,4-difluorophenyl ethanone 25g (160.1mmol, 1.0eq), AIBN 631mg (3.8mmol, 0.024eq), Co (OAc) 2 · 4H 2 O2.0g (7.8mmol, 0.049eq), NaBr 544mg ( 5.3mmol, 0.033eq), HOAc 250mL (10V), put in a reaction flask and stir to dissolve completely. The temperature of the outer bath is raised to 100℃, the flow rate is adjusted to 60-100mL/min with oxygen, and oxygen is continuously supplied for 7.5h. TLC still has raw materials For the rest, add 375mL purified water to the system, adjust the pH of the system to 12-14 with NaOH solids, extract the water phase twice with 125mL MTBE, and adjust the pH to 1 with concentrated HCl. A large amount of solids precipitate out and filter to obtain the target product. 3.0g, yield 12%.
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：采用上述连续化合成法制备取代苯甲酸类有机物能够提高工艺的环保性，同时上述工艺还具有便于操作和取代苯甲酸类有机物收率高等优点。From the above description, it can be seen that the above-mentioned embodiments of the present invention achieve the following technical effects: the use of the above-mentioned continuous synthesis method to prepare substituted benzoic acid organics can improve the environmental protection of the process, and the above-mentioned process is also convenient to operate and replace Advantages of high yield of benzoic acid organics.
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The foregoing descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and changes. Any modification, equivalent replacement, improvement, etc., made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

  1. 一种取代苯甲酸类有机物的连续化合成方法，其特征在于，所述连续化合成方法包括：A continuous synthesis method of substituted benzoic acid organic compounds, characterized in that, the continuous synthesis method includes:
    在催化剂和有机溶剂的存在下，将式(Ⅰ)所示的有机物与氧气连续地输入连续化反应装置进行连续氧化反应，得到所述取代苯甲酸类有机物，并连续排出，所述取代苯甲酸类有机物具有式(Ⅱ)所示结构；In the presence of a catalyst and an organic solvent, the organic matter represented by the formula (I) and oxygen are continuously fed into the continuous reaction device for continuous oxidation reaction to obtain the substituted benzoic acid organic matter, which is continuously discharged. The similar organic matter has the structure shown in formula (II);
    Figure PCTCN2019091400-appb-100001
    Figure PCTCN2019091400-appb-100001
    其中，所述R 1、所述R 2、所述R 3、所述R 4和所述R 5分别独立地选自H、烷基、烷氧基、卤素、硝基、芳基、取代芳基、杂芳基、取代杂芳基、酯基或酰胺，且所述R 1、所述R 2、所述R 3、所述R 4和所述R 5中至少一个不为H，所述R 6为乙酰基，所述M 1、所述M 2和所述M 3分别独立地选自C、N或S。 Wherein, the R 1 , the R 2 , the R 3 , the R 4 and the R 5 are each independently selected from H, alkyl, alkoxy, halogen, nitro, aryl, substituted aromatic Group, heteroaryl group, substituted heteroaryl group, ester group or amide, and at least one of said R 1 , said R 2 , said R 3 , said R 4 and said R 5 is not H, said R 6 is an acetyl group, and the M 1 , the M 2 and the M 3 are independently selected from C, N or S.
  2. 根据权利要求1所述的连续化合成方法，其特征在于，所述R 1和所述R 2为H，所述R 3为F、Cl、Br或NO 2，所述R 4和所述R 5为H，或以下基团中的一种：F、甲氧基，且所述R 4和所述R 5不相同。 The continuous synthesis method according to claim 1, wherein said R 1 and said R 2 are H, said R 3 is F, Cl, Br or NO 2 , and said R 4 and said R 5 is H, or one of the following groups: F, methoxy, and the R 4 and the R 5 are not the same.
  3. 根据权利要求1或2所述的连续化合成方法，其特征在于，所述连续化合成方法还包括：在所述连续氧化反应的过程中加入金属卤化物MX；The continuous synthesis method according to claim 1 or 2, wherein the continuous synthesis method further comprises: adding a metal halide MX during the continuous oxidation reaction;
    优选地，以式(Ⅰ)所示的有机物的重量百分含量计，所述金属卤化物MX的用量为0.5～3％。Preferably, the amount of the metal halide MX is 0.5-3% based on the weight percentage of the organic matter represented by formula (I).
  4. 根据权利要求3所述的连续化合成方法，其特征在于，所述M选自Li、K、Na、Mg或Ca，所述X选自Cl或Br。The continuous synthesis method according to claim 3, wherein the M is selected from Li, K, Na, Mg or Ca, and the X is selected from Cl or Br.
  5. 根据权利要求1至4中任一项所述的连续化合成方法，其特征在于，所述连续化反应装置选自反应盘管。The continuous synthesis method according to any one of claims 1 to 4, wherein the continuous reaction device is selected from reaction coils.
  6. 根据权利要求5所述的连续化合成方法，其特征在于，所述连续氧化反应的反应温度为130～180℃，反应压力为1.0～2.5MPa。The continuous synthesis method according to claim 5, wherein the reaction temperature of the continuous oxidation reaction is 130-180°C, and the reaction pressure is 1.0-2.5 MPa.
  7. 根据权利要求5所述的连续化合成方法，其特征在于，所述连续氧化反应的保留时间为90～240min。The continuous synthesis method according to claim 5, wherein the retention time of the continuous oxidation reaction is 90-240 min.
  8. 根据权利要求1至7中任一项所述的连续化合成方法，其特征在于，所述催化剂选自醋酸钴、乙酰丙酮钴、硝酸钴、醋酸锰、乙酰丙酮锰、硝酸锰、醋酸铜、硝酸铜、碘化铜、硝酸铁、氯化铁和乙酰丙酮铁组成的组中的一种或多种；The continuous synthesis method according to any one of claims 1 to 7, wherein the catalyst is selected from cobalt acetate, cobalt acetylacetonate, cobalt nitrate, manganese acetate, manganese acetylacetonate, manganese nitrate, copper acetate, One or more of the group consisting of copper nitrate, copper iodide, iron nitrate, iron chloride and iron acetylacetonate;
    优选地，以式(Ⅰ)所示的有机物的重量百分含量计，所述催化剂的用量为0.1～20％，更优选地，所述催化剂的用量为2～10％。Preferably, the amount of the catalyst is 0.1-20% based on the weight percentage of the organic matter represented by formula (I), more preferably, the amount of the catalyst is 2-10%.
  9. 根据权利要求1至7中任一项所述的连续化合成方法，其特征在于，所述有机溶剂选自甲酸、冰乙酸、丙酸、丁酸、乙腈、1,4-二氧六环和水组成的组中的一种或多种。The continuous synthesis method according to any one of claims 1 to 7, wherein the organic solvent is selected from the group consisting of formic acid, glacial acetic acid, propionic acid, butyric acid, acetonitrile, 1,4-dioxane and One or more of the group consisting of water.
  10. 根据权利要求1至7中任一项所述的连续化合成方法，其特征在于，所述连续化合成方法还包括在所述连续氧化反应过程中加入引发剂，所述引发剂为自由基引发剂；优选地，所述自由基引发剂选自偶氮二异丁腈、N-羟基邻苯二甲酰亚胺、2，3-丁二酮二肟和乙醛组成的组中的一种或多种；The continuous synthesis method according to any one of claims 1 to 7, characterized in that, the continuous synthesis method further comprises adding an initiator during the continuous oxidation reaction, and the initiator is free radical initiation Preferably, the free radical initiator is selected from the group consisting of azobisisobutyronitrile, N-hydroxyphthalimide, 2,3-butanedione dioxime and acetaldehyde Or multiple
    优选地，以式(Ⅰ)所示的有机物的重量百分含量计，所述引发剂的用量为1.0～30％。Preferably, based on the weight percentage of the organic matter represented by formula (I), the amount of the initiator is 1.0-30%.
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