WO2020248278A1 - Procédé de synthèse continue d'une substance organique d'acide benzoïque substitué - Google Patents

Procédé de synthèse continue d'une substance organique d'acide benzoïque substitué 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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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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Publication of WO2020248278A1 publication Critical patent/WO2020248278A1/fr

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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

La présente invention concerne un procédé de synthèse continue d'une substance organique d'acide benzoïque substitué. Le procédé de synthèse continue comprend : l'introduction de manière continue, en présence d'un catalyseur et d'un solvant organique, de la matière organique représentée par la formule (I) et d'oxygène dans un appareil de réaction continue pour une réaction d'oxydation continue afin d'obtenir une substance organique d'acide benzoïque substitué, qui est déchargée de manière continue, la substance organique d'acide benzoïque substitué ayant la structure représentée par la formule (II). L'oxygène est un réactif écologique et est peu coûteux et facilement disponible ; la réaction ne génère pas de grandes quantités d'eaux usées, de gaz effluents et de déchets solides après la réaction, et le système est facile à manipuler. L'utilisation d'un fonctionnement continu de la réaction peut réduire le risque de distillation éclair et d'explosion de solvant due à une concentration élevée en oxygène dans une réaction discontinue. Dans les mêmes conditions d'oxydation, le procédé de préparation en continu peut réduire les fuites d'oxygène, augmentant fortement le taux d'utilisation d'oxygène et simplifiant également le fonctionnement, améliorant la sécurité de la réaction et le rendement de la substance organique d'acide benzoïque substitué.
PCT/CN2019/091400 2019-06-14 2019-06-14 Procédé de synthèse continue d'une substance organique d'acide benzoïque substitué WO2020248278A1 (fr)

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JPH04159247A (ja) * 1990-10-19 1992-06-02 New Japan Chem Co Ltd カルボキシビフェニル類の製造方法
CN103304422A (zh) * 2013-07-15 2013-09-18 江苏德峰药业有限公司 一种2,4-二氯-3-硝基-5-氟苯甲酸一锅法合成方法
CN108002968A (zh) * 2016-10-31 2018-05-08 中国科学院大连化学物理研究所 一种酮类化合物氧化断裂碳碳键制备羧酸类化合物的方法
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CN109053347A (zh) * 2018-08-08 2018-12-21 浙江工业大学 一种以芳基烷基酮为原料制备芳基甲酸的方法
CN109503540A (zh) * 2017-09-14 2019-03-22 黎明化工研究设计院有限责任公司 一种制备ε-己内酯的方法及其连续化生产装置

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4423245A (en) * 1982-01-18 1983-12-27 Union Carbide Corporation Process for preparing 2,5-dichloro-3-nitrobenzoic acid from 2,5-dichloro-3-nitro-p-xylene
JPH04159247A (ja) * 1990-10-19 1992-06-02 New Japan Chem Co Ltd カルボキシビフェニル類の製造方法
CN103304422A (zh) * 2013-07-15 2013-09-18 江苏德峰药业有限公司 一种2,4-二氯-3-硝基-5-氟苯甲酸一锅法合成方法
CN108002968A (zh) * 2016-10-31 2018-05-08 中国科学院大连化学物理研究所 一种酮类化合物氧化断裂碳碳键制备羧酸类化合物的方法
CN109503540A (zh) * 2017-09-14 2019-03-22 黎明化工研究设计院有限责任公司 一种制备ε-己内酯的方法及其连续化生产装置
CN108911944A (zh) * 2018-07-09 2018-11-30 浙江工业大学上虞研究院有限公司 2,4-二氯氟苯的制备方法
CN109053347A (zh) * 2018-08-08 2018-12-21 浙江工业大学 一种以芳基烷基酮为原料制备芳基甲酸的方法

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