Electrolytic synthesis of a pyrazolone compound intermediate

Abstract

The application discloses an electrolytic synthesis method of a pyrazolone compound intermediate, and the method uses a nitroso acid ester compound as raw material to obtain an electrolyte containing a hydrazine compound through electrochemical reduction; the electrolyte containing the hydrazine compound is subjected to a cyclization reaction to obtain a pyrazolone compound; the application uses a mild and efficient electrochemical reduction mode to replace a high-risk diazotization reaction to synthesize the pyrazolone compound; the electrolyte can be recycled for multiple times, and a large amount of sulfite, acid and other reagents needed in the synthesis process are avoided, and a large amount of 'three wastes' is reduced. The method has better product purity (> 95%) and yield (> 80%), the method is more green and environmental protection, no three wastes are generated, and is suitable for industrial production.

Description

(I) TECHNICAL FIELD

[0001] The present application relates to an electrolytic synthesis method of a pyrazolone compound intermediate, in particular to an electrochemical reduction synthesis method. (II) BACKGROUND

[0002] Pyrazolone compounds are important organic fine chemical raw materials and pharmaceutical synthesis intermediates, and are widely used in the fields of medicine, dyes, color film dyes, pesticides and organic synthesis. In the field of medicine, they have anti-inflammatory, antibacterial, antiviral and antitumor biological activities, and are often used as drug scaffolds or groups for improving drug efficacy. In the field of pesticides, pesticides containing this structural skeleton have become popular varieties due to their high efficiency, low toxicity, broad spectrum, safety and friendliness, among which pyraclostrobin has topped the list of the world's top ten varieties and is widely used.

[0003] However, the traditional synthesis method of pyrazolone compounds has many problems. At present, the most common synthesis method is to use hydrazine or hydrazine substitutes and ketone compounds as raw materials, and to obtain pyrazolone by treating with hydrazine hydrate catalyst. The hydrazine hydrate catalyst is often prepared from urea, sodium hypochlorite and sodium hydroxide as raw materials under high temperature and high pressure. During the reaction, urea is hydrolyzed to generate ammonia and carbon dioxide under alkaline conditions, ammonia reacts with sodium hypochlorite to generate chloramine, and chloramine reacts with excess ammonia to generate hydrazine hydrate. The reaction conditions are relatively harsh, and the method has serious environmental pollution and safety hazards. Other methods such as hydrogen peroxide oxidation method and ketone azine method also have their own shortcomings. Among them, the hydrogen peroxide oxidation method has safety hazards and is not mature in China; the ketone azine method adds acetone, which affects the purity of the product and increases the post-treatment cost of acetone vapor. In addition, if the substituent group of the substituted hydrazine is an aryl substituent group, the synthesis of the raw material needs to go through diazotization and sodium sulfite steps, which has high safety risks and a large amount of three wastes, and is not conducive to industrial production.

[0004] Organic electro-synthesis is a branch of organic synthesis. Compared with general organic synthesis, organic electro-synthesis process occurs on two electrodes for oxidation and reduction reactions, respectively, and exchanges matter and electrons at the electrode-solution interface. Generally, no oxidation or reduction reagent is needed, and the reaction can be carried out at normal temperature and pressure. By adjusting parameters such as electric potential and current density, the reaction can be controlled automatically. In essence, organic electro-synthesis reaction uses clean "electron" reagent with electrode as electron acceptor, reduces the generation of chemical waste, and improves the safety of production, fully meeting the requirements of "atom economy". The product has high yield, less side reactions and less three wastes pollution. Organic electro-synthesis eliminates as much as possible the environmental pollution caused by traditional organic synthesis, and meets the requirements of green chemistry, so it is called a high-tech for producing "green products" in the 21st century.

[0005] Therefore, it is necessary to find a green and efficient synthesis method of hydrazine compounds, which are intermediates of pyrazolone compounds. (III) SUMMARY

[0006] The present application aims to provide an electrolytic synthesis method of intermediates of pyrazolone compounds, which overcomes the problems of high safety risk, large amount of waste and difficulty in industrial production in the prior art.

[0007] The technical scheme adopted by the present application is as follows:

[0008] The present application provides an electrolytic synthesis method of intermediates of pyrazolone compounds, which uses nitroso acid ester compounds as raw materials to obtain an electrolyte containing hydrazine compounds (intermediates of pyrazolone compounds) through electrochemical reduction; the electrolyte can be directly used for pyrazolone compounds.

[0009] Further, the electrochemical reduction uses a solution containing nitroso acid ester compounds, electrolytes and / or reduction media as the electrolyte; the reduction media are used for indirect electrochemical reduction, including anthracene, phenanthrene, zinc salt, tetramethylpiperidine oxide (TEMPO), ferrocene, 9-azabicyclo[3.3.1]nonane-N-oxide (ABNO), N-hydroxyphthalimide (NHPI), and preferably ZnCl2.

[0010] Further, the solvent of the electrolyte is water or an organic solvent, which includes one or more of alcohols, ketones, ethers, nitriles, esters and halogenated hydrocarbons, preferably methanol, acetonitrile (ACN), ethyl acetate, 1,4-dioxane (1,4-Dioxane) and methyl isobutyl ketone (MIBK); the electrolyte includes quaternary ammonium salt (PhSO3Na, NaHBF4, TEABF4), metal hydroxide, chloride (NH4Cl, KCl, IBr) and carbonate, preferably tetraethylammonium tetrafluoroborate (TEABF4) among the quaternary ammonium salts.

[0011] Further, the concentration of nitroso acid ester compounds in the electrolyte is 0.05-1.2 mol / L (preferably 0.3 mol / L), the concentration of electrolytes is 0.1-2 mol / L (preferably 0.5 mol / L), and the concentration of reduction media is 0-1.5 mol / L (preferably 0.5 mol / L, no reduction media is needed when direct electrochemical reduction is used), and the solvent is methanol.

[0012] Further, the electrochemical reduction reaction uses one or a composite of metal electrode, graphite electrode or metal oxide coated material as cathode; the metal electrode includes mercury, silver, tin, iron, zinc, copper, titanium, nickel, lead, platinum; the noble metal oxide coated material includes titanium coated with ruthenium oxide, preferably the cathode material is titanium; the electrode shape can be plate, rod, wire, net, mesh, wool, sheet, arc or porous, preferably mesh.

[0013] Further, the anode reaction is hydrogen evolution, sacrificial anode reaction, sacrificial ammonium salt reaction, hydroxide oxidation reaction, preferably the anode is made of chemically inert material.

[0014] Further, the chemically inert material includes platinum, iridium graphite, carbon, nickel based alloy (such as Hastelloy C) or metal oxide coated material (such as silver material coated with silver oxide), preferably platinum.

[0015] Further, the electrochemical reduction reaction is carried out in a diaphragm electrolytic cell or a diaphragm-free electrolytic cell. The diaphragm of the diaphragm electrolytic cell includes ion membrane Nafion 417, and the anode liquid is aqueous sulfuric acid, preferably 2 mol / L aqueous sulfuric acid.

[0016] Further, the electrochemical reduction reaction temperature is -40℃ to 75℃.

[0017] Further, the cathode potential of the electrochemical reduction reaction is -0.2 to -2.5 volts relative to Ag / Ag+ reference electrode, preferably the electrode potential is -1.95V.

[0018] Further, the nitroso acid ester compound has the structure shown in Formula II, and the hydrazine compound has the structure shown in Formula III:

[0019]

[0020] In Formula II, X1, X2 each independently represents H, C 1- C6alkyl, C 1- C6substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, polycyclic ring, substituted polycyclic ring, heterocyclic ring, substituted heterocyclic ring, carboxyl, ester, halogen, amide, substituted amide, one or more of them; the substituents include aryl, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, carboxyl, ester, halogen, hydrogen deuterium, cyano;

[0021] Y independently represents H, C 1- C6alkyl, C 1-C6 substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, polycyclic ring, substituted polycyclic ring, heterocyclic ring, substituted heterocyclic ring, amido, nitroso, amino, keto, carboxyl, ester; the groups used for the substitution include alkyl, cycloalkyl, halogen, aryl, carboxyl, ester, hydrogen deuterium, cyano;

[0022] R represents C1-C6 alkyl, C1-C6 substituted alkyl, amino, substituted amino, aryl, substituted aryl, keto, acyl, hydroxyl; the groups used for the substitution include alkyl, halogen, aryl, carboxyl, cyano;

[0023] In formula III, X1, X2, Y, R are the same as those in formula II.

[0024] Further, in formula II, X1 is preferably hydrogen, methyl; X2 is preferably hydrogen, methyl, carboxyl; Y is preferably methyl, deuteromethyl (CD3), nitroso, propionyl, phenyl, p-chlorophenyl, arylhetero, o-methoxyphenyl, benzamido; R is preferably methyl, hydroxyl, ethoxyl, methoxyl, amino, phenyl, p-methoxyphenyl; X2 and Y form dihydroindole, piperidine; X1 and X2 form benzene ring, aryl cyanide.

[0025] The electrolyte containing the hydrazine compound shown in formula III is directly subjected to a cyclization reaction to prepare the pyrazolone compound shown in formula I, and the cyclization reaction method is as follows: the electrolyte containing the hydrazine compound shown in formula III is heated to 65-85°C, the cyclization reaction is completed, the reaction solution is separated and purified, and the pyrazolone compound is obtained.

[0026] Further, the method is as follows: the electrolyte containing the hydrazine compound shown in formula III is heated to 65-85°C, the cyclization reaction is completed, the reaction solution is cooled to room temperature, rotary evaporation is performed to remove the solvent, the concentrated solution obtained is dissolved in diethylene glycol dimethyl ether, and then filtered to remove the filter cake containing the electrolyte and zinc salt, the filtrate is subjected to rotary evaporation until no liquid flows out, and then vacuum dried at 60°C to obtain the pyrazolone compound shown in formula I.

[0027]

[0028] In formula I, X1, X2, Y are the same as those in formula II.

[0029] The reaction involved in the electrolytic synthesis method of the pyrazolone compound is as follows:

[0030] Cathode reaction:

[0031]

[0032] Anode reaction:

[0033] 2H2O-4e - →O2↑+4H +

[0034] Cyclization reaction:

[0035]

[0036] The person skilled in the art can appreciate that the reduction sequence of functional groups is not fixed, but is determined according to the reaction conditions and the activity of the functional groups. Therefore, in practical applications, the system and conditions should be determined according to the specific type of functional group to be reduced.

[0037] Compared with the prior art, the present application has the following beneficial effects:

[0038] (1) The present application uses electrochemical reduction method to synthesize hydrazine compounds from nitroso acid ester compounds, the reaction conditions are mild, and the yield of hydrazine compounds is as high as 80% or more, reducing the risk of diazotization reaction.

[0039] (2) The electrolyte of the present application can be directly used for cyclization reaction to synthesize pyrazolone compounds, and the electrolyte can be recycled for multiple times, avoiding the need for a large amount of addition of sulfite, acid and other reagents in the synthesis process, and reducing the generation of a large amount of "three wastes".

[0040] (3) The method of the present application has better purity (>95%) and yield (>80%) of pyrazolone compounds, and the method is more green and environmentally friendly, without the generation of three wastes, and is suitable for industrial production. (Four) Description of Drawings

[0041] Figure 1 , NMR spectrum of cathode liquid after electrolysis of Example 6.

[0042] Figure 2 , NMR spectrum of cathode liquid after cyclization reaction of Example 6. (Five) Specific Embodiments

[0043] The present application will be further described below in conjunction with specific embodiments, but the scope of protection of the present application is not limited to this:

[0044] Example 1: Preparation of pyrazolone compounds by indirect electro-reduction method

[0045] (1) Electro-reduction reaction

[0046] A diaphragm electrolytic cell was used, Nafion 417 was used as an ion membrane, platinum pieces with an area of 1 cm 2 were used as anodes, and platinum pieces with an area of 8.75 cm 2The titanium mesh is cathode. The 2 mol / L sulfuric acid aqueous solution is used as anolyte (40 mL), the methanol solution containing 0.5 mol / L tetraethylammonium tetrafluoroborate, 0.3 mol / L raw material II-1 in Table 1 and 0.5 mol / L ZnCl2 is used as catholyte (40 mL), and the Ag / AgNO3 reference electrode is inserted into the catholyte. The reaction temperature is 0℃, the current of 300 mA is applied (the cathode current density is 3.4 A / dm 2 , the anode current density is 20.8 A / dm 2 , the reduction potential is -1.5 V vs Ag / Ag + ), the raw material concentration is detected by HPLC sampling of the catholyte, the electrolysis is carried out for 3 hours, and the catholyte containing the intermediate III-1 is obtained, and the yield of the intermediate is 97.8%.

[0047] (2) cyclization reaction

[0048] The catholyte of step (1) is divided into three parts, which are respectively heated to 65, 75 and 85℃ for cyclization reaction for 10 hours. After the reaction is completed by TLC detection, the reaction liquid is cooled to room temperature, concentrated by rotary evaporation until no liquid flows out, and the solvent is removed. The concentrated liquid is dissolved in 20 mL of diethylene glycol dimethyl ether, filtered to remove the filter cake containing electrolyte and zinc salt, and then the filtrate is rotary evaporated until no liquid flows out, and vacuum dried at 60℃. 0.906 g, 0.983 g and 0.945 g of product I-1 are respectively obtained, and the mass yields are 87.7%, 95.1% and 91.5% respectively. The purities are 95.3%, 98.8% and 96.5% respectively by HPLC detection.

[0049] The HPLC detection conditions are as follows: Acclaim C18 (4.5 μm*250 nm), T=25℃, λ=254 nm, and the elution method is as follows: 0 min: v=0.8 ml / min, water: acetonitrile=50%; 20 min: v=1.0 ml / min, water: acetonitrile=30%.

[0050] The TLC detection developing agent is ethyl acetate / n-hexane=1:3.

[0051] Example 2-17, preparation of pyrazolone compounds by indirect electro-reduction method

[0052] The raw material II in Example 1 is replaced according to Table 1, the cyclization temperature is 75℃, and other operations are the same as those in Example 1. The detection is carried out by the method of Example 1, and the results are shown in Table 1.

[0053] Table 1 yield and purity of pyrazolone compounds

[0054]

[0055]

[0056] Example 18: Direct electro-reduction method for preparing 1-(4-chlorophenyl)-3- pyrazolone (I-6)

[0057] (1) Electro-reduction reaction

[0058] A diaphragm electrolytic cell was used, Nafion 417 was used as the ion membrane, the area of the platinum plate used as the anode was 1 cm 2 , and the area of the foam copper used as the cathode was 8.75 cm 2 . A 2 mol / L aqueous sulfuric acid solution was used as the anode liquid (40 mL), and a methanol solution containing 0.5 mol / L tetraethylammonium tetrafluoroborate and 0.3 mol / L of the raw material II-6 was used as the cathode liquid (40 mL). The reaction temperature was 0°C, a current of 300 mA was applied (the cathode current density was 3.4 A / dm 2 , and the anode current density was 20.8 A / dm 2 ), the reduction potential was -1.1 V vs Ag / Ag + ), and the cathode liquid was sampled to detect the raw material concentration by HPLC. The electrolysis was completed after 3 hours, and the cathode liquid containing the intermediate III-6 was obtained, with a yield of 52.2%.

[0059] (2) Cyclization reaction

[0060] The cathode liquid was warmed to 75°C for cyclization reaction for 10 hours, and other operations were the same as in Example 1. The product I-6 was obtained, with a yield of 47.0% and a purity of 87.5%.

[0061] Example 19: Electro-preparation of 1-(4-chlorophenyl)-3-pyrazolone by a sacrificial anode method

[0062] (1) Electro-reduction reaction

[0063] A diaphragm electrolytic cell was used, Nafion 417 was used as the ion membrane, the area of the platinum plate used as the anode was 1 cm 2 , and the area of the foam copper used as the cathode was 8.75 cm 2 . A 2 mol / L aqueous sulfuric acid solution was used as the anode liquid (40 mL), and a methanol solution containing 0.5 mol / L tetraethylammonium tetrafluoroborate and 0.3 mol / L of the raw material II-6 was used as the cathode liquid (40 mL). The reaction temperature was 0°C, a current of 300 mA was applied (the cathode current density was 3.4 A / dm 2 , and the anode current density was 20.8 A / dm 2 ), the reduction potential was -1.1 V vs Ag / Ag + ), and the cathode liquid was sampled to detect the raw material concentration by HPLC. The electrolysis was completed after 3 hours, and the cathode liquid containing the intermediate III-6 was obtained, with a yield of 52.2%.

[0064] (2) Cyclization reaction

[0065] The cathode liquid was heated to 75° C. and subjected to cyclization reaction for 10 hours. Other operations were the same as in Example 1 to obtain product I-6 with a yield of 87.3% and a purity of 95.3%.

[0066] Example 20: Electropreparation of 1-(4-chlorophenyl)-3-pyrazolone by sacrificial ammonium salt method

[0067] (1) Electroreduction reaction

[0068] A diaphragm electrolyzer was used with Nafion 417 as the ion membrane and an area of ​​17.5 cm 2 The graphite plate is the anode, with an area of ​​8.75cm 2 The titanium mesh was used as cathode. A methanol solution containing 0.5 mol / L tetraethylammonium tetrafluoroborate, 0.3 mol / L raw material II-6, and 0.5 mol / L ZnCl2 was used as cathode solution (40 mL), and an ammonia solution containing 0.01 mol / L ammonium chloride was used as anode solution. The reaction temperature was 0°C, and a current of 300 mA was applied (cathode current density was 3.4 A / dm 2 , anode current density: 1.7A / dm 2 , the reduction potential is -0.98V vs Ag / Ag + ), the cathode liquid was sampled and the raw material concentration was detected by HPLC, 0.1 ml of 98% hydrochloric acid was added dropwise to the cathode liquid every half hour of electrolysis, and the electrolysis reaction was completed after 3 hours to obtain the cathode liquid containing intermediate III-6 with a yield of 94.7%.

[0069] (2) Cyclization reaction

[0070] The cathode liquid was heated to 75° C. and subjected to cyclization reaction for 10 hours. Other operations were the same as in Example 1 to obtain product I-6 with a yield of 84.3% and a purity of 90.7%.

[0071] Example 21: Electrochemical preparation of 1-(4-chlorophenyl)-3-pyrazolone by hydrogenation reaction

[0072] (1) Electroreduction reaction

[0073] The electrolytic cell is 6.25cm2 without diaphragm. 2 The platinum-plated gas diffusion electrode is used as the anode. The area is 8.75 cm 2 The titanium mesh was used as cathode, and a methanol solution containing 0.5 mol / L tetraethylammonium tetrafluoroborate, 0.3 mol / L raw material II-6, and 0.5 mol / L ZnCl2 was used as cathode solution (40 mL). Hydrogen was introduced at a flow rate of 20 ml / min. The reaction temperature was 0 ° C, and a current of 300 mA was applied (cathode current density was 3.4 A / dm 2 , anode current density: 4.8A / dm 2Reduction potential is -0.88 V vs Ag / Ag + The catholyte was sampled for HPLC analysis of the raw material concentration. The electrolysis was completed after 3 hours of reaction, and the catholyte containing intermediate III-6 was obtained with a yield of 68.6%.

[0074] (2) Cyclization reaction

[0075] The catholyte was heated to 75°C for cyclization reaction for 10 hours. The other operations were the same as in Example 1, and the product I-6 was obtained with a yield of 62.1% and a purity of 89.3%.

[0076] Examples 22-51: Optimization of conditions for synthesis of 1-(4-chlorophenyl)-3-pyrazolone by indirect electro-reduction method

[0077] According to Table 2, the raw material II-6 was used as the raw material, and the electro-reduction reaction was carried out by the method of Example 1 step (1). The effects of cathode material, catholyte composition, current density, temperature, and reduction potential were investigated. As shown in Table 2, the yield of intermediate III-6 was less affected by temperature, current density, cathode material, and concentration of reduction medium. The type of electrolyte had a certain effect on the yield, and the reaction was preferably carried out at -40-40°C.

[0078] Table 2: Effect of different conditions on electrolysis reaction a

[0079]

[0080]

[0081]

[0082] Note: a Other conditions not specified are the same as in Example 1; S indicates that the conditions are the same as in Example 1.

Claims

1. A method for the electrolytic synthesis of an intermediate of a pyrazolone compound, characterized in that, The method uses nitroso acid ester as raw material, and obtains hydrazine-containing electrolyte by electrochemical reduction; after the hydrazine-containing electrolyte is heated to 65-85℃ and the cyclization reaction is completed, the reaction solution is separated and purified to obtain pyrazolone compound; The electrochemical reduction uses a solution containing nitroso acid ester, electrolyte and reducing medium as electrolyte; The reducing medium is zinc salt; The nitroso acid ester has a structure as shown in formula II, and the hydrazine compound has a structure as shown in formula III: In formula II, X1, X2 each independently represents H, C 1- C6alkyl, C 1- one or more of C6substituted alkyl, aryl; the groups used for the substitution include alkyl, cycloalkyl, halogen; Y independently represents H, C 1- C6alkyl, C 1- C6substituted alkyl, aryl; the groups used for substitution include alkyl, cycloalkyl, halogen; R represents C1-C6 alkoxy; In formula III, X1, X2, Y and R are the same as those in formula II.

2. The method of claim 1, wherein, The solvent of the electrolyte is water or organic solvent, and the organic solvent includes one or more of alcohol, ketone, ether, nitrile, ester and halogenated hydrocarbon; the electrolyte includes quaternary ammonium salt, metal hydroxide, chloride, iodide, bromide, benzene sulfonate, fluoroborate and carbonate.

3. The method of claim 1, wherein, The concentration of nitroso acid ester in the electrolyte is 0.05-1.2 mol / L, the concentration of electrolyte is 0.1-2 mol / L, and the concentration of reducing medium is 0-1.5 mol / L.

4. The method of claim 1, wherein, The anode reaction of the electrochemical reduction is sacrificial anode reaction, sacrificial ammonium salt reaction, hydrogen oxidation reaction or hydrogen evolution reaction.

5. The method of claim 1, wherein, The cathode electrode of the electrochemical reduction includes one or a composite electrode of metal electrode, graphite electrode or material containing noble metal oxide coating; the material containing metal oxide coating includes titanium containing ruthenium oxide coating; the metal electrode includes mercury, silver, tin, iron, zinc, copper, titanium, nickel, lead and platinum.

6. The method of claim 1, wherein, The temperature of the electrochemical reduction is-40℃-75℃.

7. The method of claim 1, wherein, The cathode potential of the electrochemical reduction is-0.2--2.5 volts relative to Ag / Ag+reference electrode.

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