CN110629246A - Vantanib and analogue intermediate electro-reduction preparation method thereof - Google Patents
Vantanib and analogue intermediate electro-reduction preparation method thereof Download PDFInfo
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Abstract
The invention relates to an electroreduction preparation method of a 2-amino-5-methoxybenzoic acid derivative shown in a formula I, which comprises the following preparation reactions:wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl; y is selected from: c6H5HO, Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy orM is selected from: CH or N; w is selected from: CH (CH)2，O，S，NH，HOCH，BocN，MeN，EtN，C6H5N，4‑ClC6H4N or 4-HOC6H4And N is added. The invention relates to an electroreduction preparation method of a 2-amino-5-methoxybenzoic acid derivative I, which is characterized in that in a diaphragm electrolytic cell, an acid solution of a 5-methoxy-2-nitrobenzoic acid derivative is used as a cathode electrolyte; relative to each otherThe voltage of the cathode working electrode on the reference electrode is 1.00V-2.50V; the anolyte is acidic solution, and is electrolyzed at constant current or constant voltage, and the current density of the constant current is 25.0mA/cm2～250.0mA/cm2The temperature of electrolysis is 15-80 ℃.
Description
Technical Field
The invention relates to an electroreduction preparation method of an intermediate of an anticancer drug vandetanib and an analogue thereof, in particular to a method for preparing a 2-amino-5-methoxybenzoic acid derivative by electroreduction of a 5-methoxy-2-nitrobenzoic acid derivative (A).
Background
Vandetanib (Vandetanib, 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- [ (1-methylpiperidin-4-yl) methoxy ] quinazoline), a kinase inhibitor, is indicated for the treatment of unresectable, locally advanced or metastatic symptomatic or progressive medullary thyroid cancer.
Vandetanib (Vandetanib) is prepared by taking vanillic acid as a raw material through a protection and deprotection process [ Chemical process. WO.2007/036713A2.2005 ]: wherein, sodium hydrosulfite [ US20100075916A1] is selected for reduction reaction of the 5-methoxy-4-benzyloxy-2-benzyl nitrobenzoate, and the yield is 71%; tin dichloride reduction [ J Med Chem,2002,45(17):3772-3793] was selected in ethyl acetate solvent in 95% yield.
Zhao Ling et al (Vandini's synthetic process research. Wuhan academy of industry, 2012, 31(2): 35-38).]Also describes that the vandetanib is prepared by adopting the vanillic acid methyl ester as the raw material through a similar process; wherein the reduction of the methyl 5-methoxy-4-benzyloxy-2-nitrobenzoate is catalyzed by potassium carbonate, and sodium hydrosulfite (Na)2S2O4) As a reducing agent, the yield is 93% [ CN102603718A,2012-07-25]](ii) a Selecting iron powder-ammonium chloride [ med.chem.commun.,2017, 8: 1069-1092]Reduction; selecting ethanol solvent, and reducing by iron powder [ CN101835375A,2010-09-15 ]]The yield is 85%; selecting ethanol, glacial acetic acid and water as a mixed solvent, and reducing by iron powder [ ChemMedChem,2016,11(20): 2327-2338)](ii) a Selecting iron powder-ammonium formate (Hangzhou university journal (Nature science edition), 2010,9(4):248-]Reduction, yield 93.12%; selectively armorAlcohol solvent, zinc powder-glacial acetic acid [ Eur Med Chem,2017,125:245-]Reducing and refluxing for 3h, wherein the yield is 84.7%.
Liuyu et al [ Synthesis of anticancer drug vandetanib, J. China antibiotic 2011, 36(12):917-920] describe the synthetic route of vandetanib: selecting 4-hydroxymethyl piperidine tert-butyl formate, and carrying out mesylation, etherification with vanillic acid methyl ester, N-methylation, nitration, reduction, cyclization, acyl chlorination and amination reaction to obtain vandetanib. Wherein, the reduction selective catalytic hydrogenation of 5-methoxy-4- [ (1-methylpiperidin-4-yl) methoxy-2-nitrobenzoic acid methyl ester:
scholars of Beijing university of teachers [ Euro J Med Chem 2017, 138: 669-688 ] describes a preparation method of 2-amino-5-methoxy-4- (3-chloropropoxy) methyl benzoate as an intermediate of anticancer active compound: iron powder is adopted to reduce 5-methoxy-4- (3-chloropropoxy) -2-nitrobenzoic acid methyl ester in acetic acid at 80 ℃ to obtain 2-amino-5-methoxy-4- (3-chloropropoxy) benzoic acid methyl ester with the yield of 82 percent.
Teliez et al [ ChemMedChem 2007, 2: 318-332 describes a preparation method of 2-amino-5-methoxy-4- (3-morpholinylpropoxy) methyl benzoate as an intermediate of an anticancer active compound: the 5-methoxy-4- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester is reduced by tin dichloride to obtain the 2-amino-5-methoxy-4- (3-morpholinylpropoxy) benzoic acid methyl ester with the yield of 40 percent.
By the use of nitro compoundsThe hydrogenation method comprises the following steps: the catalyst palladium is relatively expensive; the palladium catalyst and the reduction product amino compound intermediate form a complex which is difficult to separate, and the purity of the intermediate and the standard exceeding of heavy metals in anticancer drug products are influenced. Inorganic reducing agent sodium hydrosulfite, iron powder/ammonium chloride, iron powder/ethanol, iron powder/ammonium formate, Fe/HOAc, Fe/HCl, zinc powder/glacial acetic acid and tin dichloride have great environmental pollution; FeCl3The reduction of/C-hydrazine hydrate, hydrazine hydrate and the like seriously pollutes the environment.
Disclosure of Invention
The technical problem to be solved by the invention is to provide an electroreduction preparation method of an intermediate 2-amino-5-methoxybenzoic acid derivative of vandetanib and an analogue thereof as an anticancer drug; to overcome the problems of the classical reduction reaction.
In order to solve the technical problem, the invention provides the following technical scheme:
the technical scheme of the invention provides an electroreduction preparation method of a 2-amino-5-methoxybenzoic acid derivative (I) as an intermediate of vandetanib and an analogue thereof, which is characterized in that the 2-amino-5-methoxybenzoic acid derivative (I) is prepared from a 5-methoxy-2-nitrobenzoic acid derivative (A) through an electroreduction method; the preparation reaction is as follows:
wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl;
y is selected from: c6H5HO, Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy orM is selected from: CH or N; w is selected from: CH (CH)2，O，S，NH，HOCH，BocN，MeN，EtN，C6H5N，4-ClC6H4N or 4-HOC6H4N。
Further, a process for producing a 2-amino-5-methoxybenzoic acid derivative (I) by electroreduction, wherein the 2-amino-5-methoxybenzoic acid derivative (I) is selected from the group consisting of compounds represented by the formula II:
wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl; y is selected from: c6H5HO, Cl, Br, methanesulfonyloxy or p-toluenesulfonyloxy.
Further, a process for producing a 2-amino-5-methoxybenzoic acid derivative (I) by electroreduction, wherein the 2-amino-5-methoxybenzoic acid derivative (I) is selected from the group consisting of compounds represented by the following formula III:
wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl; m is selected from: CH or N; w is selected from: CH (CH)2，O，S，NH，HOCH，BocN，MeN，EtN，C6H5N，4-ClC6H4N or 4-HOC6H4N。
Further, a process for producing a 2-amino-5-methoxybenzoic acid derivative (I) by electroreduction, wherein the 2-amino-5-methoxybenzoic acid derivative (I) is selected from the group consisting of the following compounds:
further, a process for producing a 2-amino-5-methoxybenzoic acid derivative (I) by electroreduction, wherein the 2-amino-5-methoxybenzoic acid derivative (I) is selected from the group consisting of the following compounds:
in order to achieve the above object, the electro-reduction preparation method of the 2-amino-5-methoxybenzoic acid derivative of the present invention comprises:
in a diaphragm electrolytic cell, an acid solution of the 5-methoxy-2-nitrobenzoic acid derivative (A) is taken as a cathode electrolyte, or the acid solution of the 5-methoxy-2-nitrobenzoic acid derivative (A) and an organic solvent form the cathode electrolyte; the acid aqueous solution is an anolyte; obtaining a cathode electrolysis product containing the 2-amino-5-methoxybenzoic acid derivative through an electro-reduction reaction.
The voltage of the cathode working electrode is 1.00V-2.50V relative to the reference electrode; the current density of the cathode working electrode is 25.0mA/cm2～250.0mA/cm2To (c) to (d); the electrolysis temperature is between 15 and 80 ℃.
The principle of the electro-reduction reaction of the 5-methoxy-2-nitrobenzoic acid derivative (A) is that the reaction formula of a cathode under an acidic condition is as follows:
the stepwise reaction formula is as follows:
in the step reaction formula, the structural formula (1) is taken as a raw material, and the structural formulas (2) to (5) are intermediate products or byproducts; the structural formula I is a main product, namely a 2-amino-5-methoxybenzoic acid derivative.
The reaction formula of the anode under the acidic condition is as follows:
6H2O→12H++3O2+12e-
the overall reaction formula is:
after the electrolysis is completed, a cathode electrolysis product containing the 2-amino-5-methoxybenzoic acid derivative shown as I is obtained.
Preferably, the reference electrode of the diaphragm electrolyzer is: a saturated potassium chloride calomel electrode.
The cathode of the diaphragm electrolytic cell is as follows: brass electrodes, red copper electrodes, titanium mesh electrodes, nickel, lead, platinum or graphite electrodes.
The anode of the diaphragm electrolytic cell is: DSA electrode, platinum mesh electrode or titanium-based platinum electrode; the DSA electrode and the metal oxide anode are mainly oxides of titanium, manganese, cobalt, noble metals such as ruthenium and iridium, and the matrix is titanium.
The diaphragm of the diaphragm electrolytic cell is as follows: HF-101 strong acid cation exchange membrane.
The organic solvent in the catholyte is any one or more of ethyl acetate, C1-C5 straight-chain alcohol, C2-C5 branched-chain alcohol or acetonitrile.
Preferably, the concentration of the 5-methoxy-2-nitrobenzoic acid derivative (A) in the catholyte is between 3.0g/L and 15.0 g/L.
The acidic aqueous solution serves as an electrolyte for the electro-reduction reaction, and the catholyte has suitable conductivity in this concentration range.
Preferably, the acid solution in the catholyte is selected from: phosphoric acid solution, sulfuric acid solution or hydrochloric acid solution; the acidic solution facilitates the supply and migration of protons.
Preferably, the anolyte is selected from the group consisting of: phosphoric acid solution, sulfuric acid solution or hydrochloric acid solution, the acid solution being favorable for the supply and migration of protons.
Preferably, the liquid levels of the catholyte and the anolyte are at the same level.
The beneficial technical effects are as follows:
the invention relates to an electroreduction preparation method of an intermediate I of vandetanib and an analogue thereof serving as an anticancer drug, and the electroreduction preparation method of the 2-amino-5-methoxybenzoic acid derivative has the following advantages:
(1) no toxic or dangerous reducing agent is needed in the reduction reaction, and the 'electron' is a clean reaction reagent and is an important component for developing the 'green pharmaceutical industry'.
(2) During the electroreduction process, the conversion rate and selectivity can be controlled by changing the electrode potential; thereby obtaining the intermediate with high purity and high yield.
(3) In industrial production, the process flow is simplified, the production cost is reduced, and the method is safe and environment-friendly and is suitable for large-scale popularization and application.
(4) The electro-reduction of the 5-methoxy-2-nitrobenzoic acid derivative (A) may not require the use of an organic solvent.
Toxic or dangerous reducing agents are not needed in the electro-reduction reaction, and the method is an important component for developing the green pharmaceutical industry; by varying the electrode potential, the conversion and selectivity can be controlled, thereby obtaining high purity and high yield intermediates.
Drawings
FIG. 1 is a schematic view of a diaphragm electrolyzer
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of 2-amino-5-methoxy-4- (3-chloropropoxy) methyl benzoate by electroreduction
A diaphragm type electrolytic cell (figure 1) is installed and separated by a HF-101 strong acid type cation exchange membrane. Adding 0.61g of 5-methoxy-4- (3-chloropropoxy) -2-nitrobenzoic acid methyl ester into a cathode (Cu) electrolytic cell of a diaphragm type electrolytic cell, adding 30ml of acetonitrile, and then adding 30ml of 1mol/L hydrochloric acid aqueous solution; adding 60ml of 0.25mol/L sulfuric acid aqueous solution into an anode (DSA) electrolytic bath, and stirring in a constant temperature water bath kettle at 40 ℃; electrifying for reduction: the voltage of a reference electrode relative to a working electrode is 2.0V, the power supply voltage is 25V, the current is 0.65A, a cathode electrode (brass is 2cm multiplied by 2cm), and an anode electrode (platinum net is 1cm multiplied by 1cm) are subjected to electrolytic reduction for 3.0 h. After the reaction is finished, neutralizing potassium carbonate, extracting dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, recovering the solvent by rotary evaporation, recrystallizing and drying to obtain 0.52g of 2-amino-5-methoxy-4- (3-chloropropoxy) methyl benzoate (light yellow solid), wherein the yield is 94.6%, the melting point is 96-98 ℃,1H NMR(400MHz，DMSO)δ：7.15(s，1H，C6H2 6-H)，6.46(s，2H，NH2)，6.41(s，1H，C6H2 3-H)，4.06(t，J＝6.1Hz，2H，OCH2)，3.80(t，J＝6.4Hz，2H，CH2Cl)，3.76(s，3H，OCH3)，3.67(s，3H，COOCH3)，2.24～2.18(m，2H，CH2)。
example 2 (control experiment)
Preparation of methyl 2-amino-5-methoxy-4- (3-chloropropoxy) benzoate
According to [ Euro J Med Chem 2017, 138: 669-688 ] reducing 5-methoxy-4- (3-chloropropoxy) -2-nitrobenzoic acid methyl ester in acetic acid at 80 ℃ by using iron powder to obtain 2-amino-5-methoxy-4- (3-chloropropoxy) methyl benzoate, wherein the yield is 82% and the melting point is 97-99 ℃.
Example 3
Preparation of 2-amino-5-methoxy-4- (3-morpholinylpropoxy) methyl benzoate by electroreduction
A diaphragm type electrolytic cell (figure 1) is installed and separated by a HF-101 strong acid type cation exchange membrane. Adding a magnetic stirrer, 0.36g of 5-methoxy-4- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester and 60mL0.5mol/L hydrochloric acid solution into a cathode (Cu) electrolytic tank, stirring for dissolving, and adding 60mL of 0.25mol/L sulfuric acid solution into an anode (DSA) electrolytic tank; the cathode uses saturated calomel electrode as reference electrode, and is electrolyzed at constant current with current density of 200mA/cm2The voltage between the cathode and the reference is 1.2-1.6V; stirring for 4.0h at 40 ℃, after the reaction is finished, adjusting the catholyte to alkalescence by using a 10% NaOH solution, extracting with dichloromethane for 2 times, drying with anhydrous sodium sulfate, filtering, desolventizing the solvent, recrystallizing and drying to obtain 0.31g of 2-amino-5-methoxy-4- (3-morpholinylpropoxy) methyl benzoate (light brown solid), wherein the yield is 94.2%, the melting point is 94-96 ℃,1H NMR(400MHz，CDCl3)δ:7.30(s，1H，C6H2 6-H)，6.17(s，1H，C6H2 3-H)，5.55(s，2H，NH2)，4.06(t，J＝6.6Hz，2H，OCH2)，3.85(s，3H，OCH3)，3.81(s，3H，COOCH3)，3.72(t，J＝4.8Hz，4H，CH2OCH2)，2.52(t，J＝7.1Hz，2H，NCH2)，2.46(br，4H，CH2NCH2)，2.01～2.08(m，2H，CH2)。
example 4 (control experiment)
Preparation of methyl 2-amino-5-methoxy-4- (3-morpholinylpropoxy) benzoate
Prepared according to the method of the document [ ChemMedChem 2007, 2, 318-332 ], and 1g of methyl 5-methoxy-4- (3-morpholinopropoxy) -2-nitrobenzoate is reduced by tin dichloride to obtain 0.37g of methyl 2-amino-5-methoxy-4- (3-morpholinopropoxy) benzoate with the melting point of 147-151 ℃ and the yield of 40%.
Example 5
Preparation of 2-amino-5-methoxy-4-benzyloxybenzoic acid methyl ester by electroreduction
A diaphragm type electrolytic cell (figure 1) is installed and separated by a HF-101 strong acid type cation exchange membrane. Adding a magnetic stirrer, 0.32g of 5-methoxy-4-benzyloxy-2-nitrobenzoic acid methyl ester and 30mL of ethanol into a cathode (Cu) electrolytic cell, stirring for dissolving, and then adding 30mL of deionized water and 4mL of hydrochloric acid; adding 60mL of deionized water and 1.25mL of sulfuric acid into an anode (Pt mesh) electrolytic cell, selecting a saturated calomel electrode as a reference electrode, keeping constant current at 0.8A, using a cathode electrode (brass 2cm multiplied by 2cm) and an anode electrode (platinum mesh 1cm multiplied by 1cm), and stirring and electrolyzing for 2.0h at 25 ℃; adjusting the cathode electrolyte to be alkalescent by using a potassium hydroxide solution, extracting by using dichloromethane for four times, drying the combined organic layers by using anhydrous sodium sulfate, recovering the solvent by rotary evaporation, and recrystallizing to obtain 0.28g of 4-benzyloxy-5-methoxy-2-aminobenzoic acid benzyl ester (reddish brown solid) with the yield of 97.6 percent;1H NMR(400MHz，DMSO)δ：7.35～7.46(m，5H，C6H5)，7.35(s，1H，C6H2 6-H)，6.47(s，1H，C6H2 3-H)，7.45(s，2H，NH2)，5.05(s，2H，OCH2)，3.75(s，3H，OCH3)，3.65(s，3H，COOCH3)。
example 6 (control experiment)
Preparation of methyl 2-amino-5-methoxy-4-benzyloxybenzoate
Prepared according to the method of the literature [ CN102603718A,2012-07-25 ]: potassium carbonate is selected as an alkaline catalyst, ethanol is selected as a solvent, sodium hydrosulfite is selected as a reducing agent, and 2-amino-5-methoxy-4-benzyloxy methyl benzoate is prepared with the yield of 93%.
The electro-reduction preparation method of the 2-amino-5-methoxybenzoic acid derivative simplifies the process flow and reduces the production cost in industrial production, basically has no pollution to the environment, and is suitable for large-scale popularization and application.
In the present specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.
Claims (10)
1. The electro-reduction preparation method of the 2-amino-5-methoxybenzoic acid derivative shown in the structural formula I is characterized in that the preparation reaction is as follows:
wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl;
y is selected from: c6H5HO, Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy orM is selected from: CH or N; w is selected from: CH (CH)2，O，S，NH，HOCH，BocN，MeN，EtN，C6H5N，4-ClC6H4N or 4-HOC6H4N。
The electroreduction preparation method of the 2-amino-5-methoxybenzoic acid derivative is characterized in that in a diaphragm electrolytic cell, an acidic solution of the 5-methoxy-2-nitrobenzoic acid derivative (A) is used as a catholyte, or the acidic solution of the 5-methoxy-2-nitrobenzoic acid derivative (A) and an organic solvent form the catholyte; the acid aqueous solution is an anolyte; obtaining a cathode electrolysis product containing the 2-amino-5-methoxybenzoic acid derivative through an electro-reduction reaction.
2. The process for preparing 2-amino-5-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the reference electrode of the diaphragm electrolyzer is: a saturated potassium chloride calomel electrode; the cathode is: brass electrodes, red copper electrodes, titanium mesh electrodes, nickel, lead, platinum or graphite electrodes; the anode is: DSA electrode, platinum mesh electrode or titanium-based platinum electrode; the diaphragm is: a strong acid type cation exchange membrane.
3. The process for producing 2-amino-5-methoxybenzoic acid derivative by electroreduction according to claim 1 or 2, characterized in that the working voltage of the cathode of the diaphragm electrolyzer is 1.00V to 2.50V relative to a reference electrode; the electrode current density of the cathode is 25.0mA/cm2～250.0mA/cm2To (c) to (d); the working temperature of the diaphragm electrolytic cell is 15-80 ℃.
4. The process for preparing 2-amino-5-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the organic solvent in the catholyte is one or more of ethyl acetate, C1-C5 straight-chain alcohol, C2-C5 branched-chain alcohol, and acetonitrile.
5. The process for preparing 2-amino-5-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the acidic solution in the catholyte is selected from the group consisting of: phosphoric acid solution, sulfuric acid solution or hydrochloric acid solution; the anolyte is selected from: phosphoric acid solution, sulfuric acid solution, or hydrochloric acid solution.
6. The process for producing 2-amino-5-methoxybenzoic acid derivative by electroreduction according to claim 1, wherein the concentration of the 5-methoxy-2-nitrobenzoic acid derivative (a) in the catholyte is 3.0g/L to 15.0 g/L.
7. The process for producing a 2-amino-5-methoxybenzoic acid derivative by electroreduction according to claim 1, wherein the 2-amino-5-methoxybenzoic acid derivative (i) is selected from the group consisting of compounds represented by the formula ii:
wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl; y is selected from: c6H5HO, Cl, Br, methanesulfonyloxy or p-toluenesulfonyloxy.
8. The process for producing a 2-amino-5-methoxybenzoic acid derivative by electroreduction according to claim 1, wherein the 2-amino-5-methoxybenzoic acid derivative (i) is selected from the group consisting of compounds represented by the formula iii:
wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl; m is selected from: CH or N; w is selected from: CH (CH)2，O，S，NH，HOCH，BocN，MeN，EtN，C6H5N，4-ClC6H4N or 4-HOC6H4N。
9. The process for producing 2-amino-5-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the 2-amino-5-methoxybenzoic acid derivative (i) is selected from the group consisting of the following compounds:
10. the process for producing 2-amino-5-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the 2-amino-5-methoxybenzoic acid derivative (i) is selected from the group consisting of the following compounds:
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| CN112079812A (en) * | 2020-09-29 | 2020-12-15 | 浙江大学 | Prazoles antipsychotic key intermediate and electroreduction method thereof |
| CN112125896A (en) * | 2020-09-29 | 2020-12-25 | 浙江大学 | Novel preparation method of novel antipsychotic drug brexpiprazole |
| CN112079812B (en) * | 2020-09-29 | 2021-08-06 | 浙江大学 | Prazoles antipsychotic key intermediate and electroreduction method thereof |
| CN112125896B (en) * | 2020-09-29 | 2021-10-29 | 湖南省湘中制药有限公司 | Electrochemical preparation method of antipsychotic drug brexpiprazole |
| CN112251770A (en) * | 2020-10-14 | 2021-01-22 | 湖南大学 | Novel electrochemical preparation method of antihypertensive drug telmisartan intermediate |
| CN112251770B (en) * | 2020-10-14 | 2021-07-27 | 湖南大学 | Novel electrochemical preparation method of antihypertensive drug telmisartan intermediate |
| CN113308704A (en) * | 2021-05-31 | 2021-08-27 | 湖南大学 | Electrooxidation preparation method of naproxen intermediate |
| CN113308705A (en) * | 2021-05-31 | 2021-08-27 | 湖南大学 | Electrooxidation preparation method of kresoxim-methyl and trifloxystrobin intermediate |
| CN113308705B (en) * | 2021-05-31 | 2022-04-08 | 湖南大学 | Electrooxidation preparation method of kresoxim-methyl and trifloxystrobin intermediate |
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