Process for the preparation of pyridinedicarboximide compounds

Abstract

The present application relates to a kind of preparation method of pyridine dioxime compound, the preparation method utilizes the ring addition reaction of amine group in first compound with two ends of unsaturated double bond in second compound, and pyridine dioxime compound is constructed to obtain.The preparation method described in the present application has (1) raw material is cheap and easy to obtain, reaction yield is high;(2) reaction condition is simple and mild, operation is simple, process is easy to realize;(3) green, environmental protection, economic and other advantages, it is conducive to industrialization large-scale production and the preparation of downstream product, can meet the huge demand of terminal drug production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical technology, and in particular to a method for preparing pyridine dicarboximide compounds. Background Technology

[0002] Moxifloxacin hydrochloride is a fourth-generation quinolone antibiotic developed by Bayer AG in Germany. It is a new generation of broad-spectrum antibiotics. This product is mainly used to treat adult patients with upper and lower respiratory tract infections. It has advantages such as broad spectrum, strong antibacterial activity, low likelihood of developing drug resistance, and few adverse reactions. It has a large market demand and promising prospects.

[0003] The current process for synthesizing moxifloxacin hydrochloride is as follows:

[0004]

[0005] The difficulty in synthesizing moxifloxacin hydrochloride lies in the complexity of its side-chain synthesis process, high cost of raw materials and auxiliary materials, and low reaction yield, which leads to a high production cost of moxifloxacin hydrochloride.

[0006] Pyridine dicarboximide compounds are key intermediates in the synthesis of moxifloxacin hydrochloride side chains, but they are expensive and difficult to obtain. Traditional methods for synthesizing pyridine dicarboximide compounds use quinoline as a starting material, first oxidizing it to pyridine diacid with oxidants such as potassium permanganate, then performing a condensation reaction to synthesize pyridine diacid anhydride, and finally obtaining the pyridine dicarboximide compound through a lactamation reaction. The synthetic route is shown below:

[0007]

[0008] However, the current synthetic route causes severe environmental pollution, and the raw material quinoline is expensive and difficult to obtain due to rising raw material prices. Therefore, developing a method for preparing pyridine dicarboximide compounds that features readily available raw materials, reduced production costs, high reaction yield, and environmental friendliness is of great significance and value to this technical field. Summary of the Invention

[0009] Therefore, it is necessary to provide a method for preparing pyridine dicarboximide compounds to address the above problems. This method has high yield, low cost, readily available raw materials, mild reaction conditions, simple operation, and is easy to implement, which is beneficial for industrial production.

[0010] A method for preparing a pyridinedicarboximide compound, comprising the following steps:

[0011] The first compound shown in formula (2) is reacted with the second compound shown in formula (3) to obtain the pyridine dicarboximide compound shown in formula (4), wherein R1, R2, R3, and R4 are independently selected from hydrogen, C1-C6 straight-chain aliphatic alkyl, C1-C6 branched aliphatic alkyl, C1-C6 alkoxy, or C6-C 10 Aromatic groups;

[0012]

[0013] In one embodiment, the molar ratio of the first compound to the second compound is 1:1.2 to 1:3.0;

[0014] And / or, R1, R2, R3, and R4 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, phenyl, m-methylphenyl, p-methylphenyl, or benzyl.

[0015] In one embodiment, the first compound and the second compound react in the presence of an oxidant, wherein the molar ratio of the first compound to the oxidant is 1:1.2 to 1:2.0.

[0016] In one embodiment, in the step of reacting the first compound with the second compound in the presence of an oxidant, the temperature is 60°C-160°C and the time is 1h-10h.

[0017] And / or, the oxidant is selected from transition metal oxides, peroxides or quinone compounds.

[0018] In one embodiment, the method for preparing the first compound includes the following steps:

[0019] Maleic anhydride is reacted with a third compound having the structural formula R1-NH2 to give a first intermediate product as shown in formula (1), wherein R1 is selected from hydrogen, a C1-C6 straight-chain aliphatic alkyl group, a C1-C6 branched aliphatic alkyl group, a C1-C6 alkoxy group, or a C6-C6 compound. 10 Aromatic groups;

[0020] The first intermediate product was reacted to obtain the first compound;

[0021]

[0022] In one embodiment, the molar ratio of the third compound to the maleic anhydride is 1.2:1 to 2.0:1.

[0023] In one embodiment, the step of reacting maleic anhydride with a third compound includes: reacting the maleic anhydride with the third compound to obtain a first preproduct as shown in formula (5), and then reacting the first preproduct in the presence of an alkylating agent, an alkaline aqueous solution, and a phase transfer catalyst to obtain a first intermediate product as shown in formula (1).

[0024]

[0025] In one embodiment, the molar ratio of the alkylating agent, the solute in the alkaline aqueous solution, the phase transfer catalyst, and the maleic anhydride is (1.2-2.0):(1.2-2.0):(0.01-0.08):1;

[0026] And / or, the phase transfer catalyst is selected from quaternary ammonium salt phase transfer catalysts or quaternary phosphate salt phase transfer catalysts, the solute in the alkaline aqueous solution is selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide, and the alkylating agent is selected from at least one of dialkyl sulfate, alkyl arylsulfonic acid, or trialkyl phosphate.

[0027] In one embodiment, the reaction of the maleic anhydride with the third compound takes place at a temperature of 0°C-10°C for 0.5h-2h.

[0028] And / or, in the step of reacting the first preproduct in the presence of an alkylating agent, an alkaline aqueous solution, and a phase transfer catalyst, the temperature is 25°C-55°C and the time is 10h-16h.

[0029] In one embodiment, the step of reacting the first intermediate product includes: reacting the first intermediate product with a hydroxylamine reagent under alkaline conditions, wherein the molar ratio of the first intermediate product to the hydroxylamine reagent is 1:1.0-1:2.0, and the molar ratio of the first intermediate product to the alkaline reagent is 1:2.0-1:3.0.

[0030] In one embodiment, in the step of reacting the first intermediate with the hydroxylamine reagent under alkaline conditions, the temperature is 45°C-70°C and the time is 6h-12h.

[0031] And / or, the hydroxylamine reagent is selected from NH2-OR·HCl, wherein R is selected from H, a C1-C6 straight-chain aliphatic alkyl group, or a C1-C6 branched aliphatic alkyl group;

[0032] And / or, the alkaline reagent is selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, and potassium methoxide.

[0033] In one embodiment, the step of reacting the first intermediate product includes:

[0034] The first intermediate product was reacted with a halogen element to obtain the second preproduct shown in formula (6);

[0035] The second preproduct was reacted to obtain the third preproduct shown in formula (7);

[0036] The third preproduct is reacted with an amination agent to obtain the first compound;

[0037]

[0038] Where X is selected from halogen elements.

[0039] In one embodiment, the molar ratio of the first intermediate product to the halogen element is 1:1.0 to 1:2.0;

[0040] And / or, the halogen element is selected from Cl2, Br2, I2.

[0041] In one embodiment, the second preproduct is reacted in the presence of an organic base, wherein the molar ratio of the second preproduct to the organic base is 1:0.8 to 1:1.5, and wherein the organic base is selected from amines or pyridines.

[0042] In one embodiment, the amination agent is selected from ammonia gas or ammonia water.

[0043] In one embodiment, the amination agent is selected from ammonia gas at a pressure of 0.1 MPa to 1.0 MPa;

[0044] Alternatively, the amination agent is selected from ammonia water, the concentration of which is 18wt%-25wt%, and the molar ratio of the third preproduct to ammonia in the ammonia water is 1:3-1:15.

[0045] In one embodiment, the step of reacting the first intermediate product with a halogen element is carried out at a temperature of 20°C-100°C for 2-5 hours.

[0046] And / or, in the step of reacting the second preproduct, the temperature is 0℃-80℃ and the time is 3h-12h;

[0047] And / or, in the step of reacting the third preproduct with the amination agent, the temperature is 0℃-120℃ and the time is 1h-4h.

[0048] The preparation method of this invention utilizes the cycloaddition reaction between the amino group in the first compound and the unsaturated double bonds at both ends of the second compound to construct a pyridine dicarboximide compound. Compared with traditional processes, the preparation method of this invention has the following advantages: (1) the raw materials are inexpensive and readily available, and the reaction yield is high; (2) the reaction conditions are simple and mild, the operation is simple, and the process is easy to implement; (3) it has many advantages such as being green, environmentally friendly, and economical, which is conducive to large-scale industrial production and the preparation of downstream products, and can meet the huge demand of end-product manufacturing. Detailed Implementation

[0049] To facilitate understanding of the present invention, it will be described in more detail below. However, it should be understood that the present invention can be implemented in many different forms and is not limited to the embodiments or examples described herein. Rather, these embodiments or examples are provided to make the disclosure of the present invention more thorough and complete.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments or examples only and is not intended to be limiting of the invention.

[0051] This invention provides a method for preparing a pyridine dicarboximide compound, comprising the following steps:

[0052] The first compound shown in formula (2) is reacted with the second compound shown in formula (3) to obtain the pyridine dicarboximide compound shown in formula (4), wherein R1, R2, R3, and R4 are independently selected from hydrogen, C1-C6 straight-chain aliphatic alkyl, C1-C6 branched aliphatic alkyl, C1-C6 alkoxy, or C6-C 10 Aromatic groups.

[0053] The specific reaction process is as follows:

[0054]

[0055] The pyridine dicarboximide compound was constructed by cycloaddition reaction of the amino group in the first compound with the unsaturated double bonds at both ends of the second compound.

[0056] Preferably, R1 in the first compound is hydrogen, a C1-C6 straight-chain aliphatic alkyl group, a C1-C6 branched aliphatic alkyl group, a C1-C6 alkoxy group, or a C6-C6 compound. 10The aromatic group is further preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, phenyl, m-methylphenyl, p-methylphenyl, or benzyl.

[0057] In the second compound, R2, R3, and R4 are each independently selected from hydrogen, C1-C6 straight-chain aliphatic alkyl, C1-C6 branched aliphatic alkyl, C1-C6 alkoxy, or C6-C 10 The aromatic group is further preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, phenyl, m-methylphenyl, p-methylphenyl, or benzyl.

[0058] Preferably, the molar ratio of the first compound to the second compound is 1:1.2-1:3.0, more preferably 1:1.5-1:3.0.

[0059] Preferably, the first compound and the second compound are reacted in the presence of an oxidant, which promotes the oxidation of single bonds into double bonds after cyclization. The molar ratio of the first compound to the oxidant is 1:1.2-1:2.0, preferably 1:1.2-1:1.5.

[0060] Specifically, the oxidant is selected from transition metal oxides, peroxides, or quinone compounds, and more preferably at least one of manganese oxide, silver oxide, iron oxide, copper oxide, zinc oxide, chromium oxide, hydrogen peroxide, peracetic acid, perpropionic acid, perbenzoic acid, m-chloroperbenzoic acid, p-benzoquinone, o-benzoquinone, methylbenzoquinone, trimethylbenzoquinone, and naphthoquinone.

[0061] In the step of reacting the first compound with the second compound, the reaction solvent is selected from at least one of toluene, acetonitrile, acetone, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dipropylene glycol dimethyl ether, acetic anhydride, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), more preferably at least one of toluene, acetonitrile, acetone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, DMF, and DMSO. The mass (g) ratio of the first compound to the volume (mL) of the reaction solvent is 1:5 to 1:15, more preferably 1:8 to 1:12.

[0062] Preferably, in the step of reacting the first compound with the second compound, the reaction temperature is 60℃-160℃, more preferably 100℃-140℃; and the time is 1h-10h, more preferably 3h-5h.

[0063] It should be noted that those skilled in the art can obtain the first compound through various existing preparation methods, and the present invention does not limit this.

[0064] The first compound is preferably prepared by the following method:

[0065] S1, maleic anhydride is reacted with a third compound having the structural formula R1-NH2 to give the first intermediate shown in formula (1), wherein R1 is selected from hydrogen, a C1-C6 straight-chain aliphatic alkyl group, a C1-C6 branched aliphatic alkyl group, a C1-C6 alkoxy group, or a C6-C6 compound. 10 Aromatic groups;

[0066] S2, react the first intermediate product to obtain the first compound;

[0067]

[0068] In step S1, maleic anhydride is used as the starting material. The amino functional group in the third compound reacts with the anhydride group in the maleic anhydride to remove water molecules, yielding the first intermediate product. Preferably, R1 in the structural formula of the third compound is hydrogen, a C1-C6 straight-chain aliphatic alkyl group, a C1-C6 branched aliphatic alkyl group, a C1-C6 alkoxy group, or a C6-C6 compound. 10 The aromatic group is further preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, phenyl, m-methylphenyl, p-methylphenyl, or benzyl.

[0069] Preferably, the molar ratio of the third compound to the maleic anhydride is 1.2:1-2.0:1, more preferably 1.2:1-1.5:1.

[0070] It should be noted that in the reaction of maleic anhydride with the third compound, the first preproduct shown in formula (5) is usually generated first, and then the first intermediate product is obtained from the reaction of the first preproduct. The specific reaction process is as follows:

[0071]

[0072] The above reaction process can be obtained by various preparation methods, and the present invention does not limit the method.

[0073] For example, Method 1: react the maleic anhydride with the third compound to obtain a first preproduct, and then react the first preproduct in the presence of an alkylating agent, an alkaline aqueous solution, and a phase transfer catalyst to obtain a first intermediate product; Method 2: mix the maleic anhydride and the third compound in a solvent, stir and react to obtain a first preproduct, then mix the first preproduct with acetic acid and reflux, and then successively pass through saturated sodium bicarbonate aqueous solution for neutralization, ethyl acetate extraction, organic layer vacuum concentration, and crystallization steps to obtain a first intermediate product, preferably Method 1.

[0074] In Method 1, the alkylating agent can convert the carboxyl group in the first preproduct into an ester group, and the alkoxy group is easier to leave than the hydroxyl group, thus being more conducive to improving the cyclization yield of the first preproduct. Preferably, the molar ratio of the alkylating agent to the maleic anhydride is (1.2-2.0):1, more preferably (1.2-1.5):1.

[0075] Specifically, the alkylating agent is selected from at least one of dialkyl sulfate, alkyl aryl sulfonate, and trialkyl phosphate, and more preferably from at least one of dimethyl sulfate, diethyl sulfate, dipropyl sulfate, dibutyl sulfate, p-toluenesulfonic acid, and trimethyl phosphate.

[0076] In Method 1, alkaline conditions are beneficial for promoting the de-alcoholization cyclization of the ester group and amide bond in the first preproduct, thereby increasing the yield. Preferably, the molar ratio of the solute in the alkaline aqueous solution to the maleic anhydride is (1.2-2.0):1, more preferably (1.2-1.5):1.

[0077] Specifically, the solute in the alkaline aqueous solution is selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium carbonate.

[0078] In Method 1, since the reaction system contains both an organic phase and an aqueous phase, and the cyclization and hydrolysis of the ester group in the first preproduct are competing reactions, using a phase transfer catalyst is beneficial for promoting the cyclization of the ester group in the first preproduct into the first intermediate product. Preferably, the molar ratio of the phase transfer catalyst to the maleic anhydride is (0.01-0.08):1, more preferably (0.01-0.04):1.

[0079] Specifically, the phase transfer catalyst is selected from quaternary ammonium salt phase transfer catalysts or quaternary phosphorus salt phase transfer catalysts, and is more preferably at least one of benzyltriethylammonium chloride, trioctylmethylammonium chloride, tetramethylammonium bromide, tetrapropylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylbenzylammonium bromide, triethylhexylammonium bromide, triethyloctylammonium bromide, ethyltriphenylphosphine bromide, butyltriphenylphosphine bromide, and tetraphenylphosphine bromide.

[0080] In the step of reacting maleic anhydride with the third compound, the reaction solvent is selected from at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, acetic acid, toluene, xylene, dichloromethane, trichloromethane, and carbon tetrachloride, preferably dichloromethane. The mass (g) ratio of the third compound to the volume (mL) of the reaction solvent is 1:8 to 1:20, more preferably 1:10 to 1:15.

[0081] Preferably, in the step of reacting the maleic anhydride with the third compound, the temperature is 0℃-10℃ and the time is 0.5h-2h.

[0082] Preferably, in the step of reacting the first preproduct in the presence of an alkylating agent, an alkaline aqueous solution, and a phase transfer catalyst, the temperature is 25°C-55°C, more preferably 35°C-45°C, and the time is 10h-16h, more preferably 12h-14h.

[0083] In step S2, by reacting the first intermediate product, the first compound is endowed with an amino functional group, which is beneficial for subsequent transformation to obtain a specific functional group.

[0084] In one embodiment, the first intermediate product is reacted directly with a hydroxylamine reagent under alkaline conditions to obtain a first compound, wherein the molar ratio of the first intermediate product to the hydroxylamine reagent is 1:1.0-1:2.0, preferably 1:1.0-1:1.5; and the molar ratio of the first intermediate product to the alkaline reagent is 1:2.0-1:3.0.

[0085] Specifically, the hydroxylamine reagent is selected from NH2-OR·HCl, wherein R is selected from hydrogen, a C1-C6 straight-chain aliphatic alkyl group or a C1-C6 branched aliphatic alkyl group, and more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or sec-butyl.

[0086] In the step of reacting the first intermediate product with the hydroxylamine reagent, the reaction solvent is selected from at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, acetic acid, toluene, xylene, dichloromethane, trichloromethane, and carbon tetrachloride, preferably tetrahydrofuran. The mass (g) ratio of the first intermediate product to the volume (mL) of the reaction solvent is 1:8-1:20, more preferably 1:10-1:15.

[0087] Preferably, the reaction temperature of the first intermediate product with the hydroxylamine reagent is 45℃-70℃, more preferably 60℃-70℃; and the reaction time is 6h-12h, more preferably 8h-10h.

[0088] In another embodiment, the step of reacting the first intermediate product includes:

[0089] S21, the first intermediate product is reacted with a halogen element to obtain the second preproduct shown in formula (6);

[0090] S22, the second preproduct is reacted to obtain the third preproduct shown in formula (7);

[0091] S23, the third preproduct is reacted with an amination agent to obtain the first compound.

[0092] The specific reaction process is as follows:

[0093]

[0094] X2 is a halogen element.

[0095] In step S21, the molar ratio of the first intermediate product to the halogen element is preferably 1:1.0-1:2.0, more preferably 1:1.2-1:1.5.

[0096] The halogen element is selected from Cl2, Br2, and I2.

[0097] In the step of reacting the first intermediate product with the halogen element, the reaction solvent is selected from at least one of dichloromethane, trichloromethane, carbon tetrachloride, and 1,2-dichloroethane, more preferably dichloromethane. The mass (g) ratio of the first intermediate product to the volume (mL) of the reaction solvent is 1:8-1:20, more preferably 1:10-1:12.

[0098] Preferably, in the step of reacting the first intermediate product with the halogen element, the reaction temperature is 20℃-100℃, more preferably 40℃-60℃, and the reaction time is 2h-5h, more preferably 3h-4h.

[0099] Specifically, the mixture of halogen element and reaction solvent is added in batches to the mixture of first intermediate product and reaction solvent at 40℃-60℃ and reacted for 3h-4h. After the reaction is complete, the mixture is concentrated, washed, and dried to obtain the second preproduct.

[0100] In step S22, the second preproduct is preferably reacted in the presence of an organic base, and the molar ratio of the second preproduct to the organic base is 1:0.8-1:1.5, more preferably 1:1.0-1:1.2.

[0101] The organic base is selected from amines or pyridines, and more preferably at least one of dimethylamine, diethylamine, triethylamine, diisopropylethylamine, isopropylamine, cyclohexylamine, pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine.

[0102] In the step of reacting the second preproduct in the presence of an organic base, the reaction solvent is selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, and 1,2-dichloroethane, more preferably tetrahydrofuran. The mass (g) ratio of the second preproduct to the volume (mL) of the reaction solvent is 1:3 to 1:10, more preferably 1:4 to 1:6.

[0103] Preferably, in the step of reacting the second preproduct, the reaction temperature is 0℃-80℃, more preferably 0℃-50℃; and the time is 3h-12h, more preferably 4h-8h.

[0104] Specifically, the mixture of organic base and reaction solvent is added in batches to the mixture of second preproduct and reaction solvent, and reacted at 0℃-50℃ for 3-4 hours. After the reaction is complete, the mixture is concentrated, crystallized, and dried to obtain the third preproduct.

[0105] In step S23, the amination agent is selected from ammonia gas or ammonia water.

[0106] Specifically, when the amination agent is ammonia, the ammonia pressure is 0.1 MPa-1.0 MPa, more preferably 0.2 MPa-0.4 MPa; when the amination agent is ammonia water, the concentration of the ammonia water is 18 wt%-25 wt%, and the molar ratio of the third preproduct to ammonia in the ammonia water is 1:3-1:15, more preferably 1:5-1:8.

[0107] In the step of reacting the third preproduct with the amination agent, the reaction solvent is selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, 1,2-dichloroethane, and toluene, more preferably tetrahydrofuran. The mass (g) ratio of the third preproduct to the volume (mL) of the reaction solvent is 1:8 to 1:15, more preferably 1:8 to 1:12.

[0108] Preferably, in the step of reacting the third preproduct with the amination agent, the reaction temperature is 0℃-120℃, more preferably 0℃-50℃; and the time is 1h-4h, more preferably 2h-3h.

[0109] It should be noted that the first intermediate product can be reacted to obtain the first compound through various preparation methods. This invention does not limit the method, and those skilled in the art can also use other existing preparation methods.

[0110] Therefore, the preparation method described in this invention has the following advantages: (1) the raw materials are cheap and readily available, and the reaction yield is high; (2) the reaction conditions are simple and mild, the operation is simple, and the process is easy to implement; (3) it has many advantages such as being green, environmentally friendly, and economical, which is conducive to large-scale industrial production and the preparation of downstream products, and can meet the huge demand for end-product production.

[0111] The preparation method of the pyridine dicarboximide compound will be further described below through specific examples.

[0112] Example 1

[0113] The synthetic route for this embodiment is shown below:

[0114]

[0115] This embodiment is carried out in the following steps:

[0116] Step S1, Preparation of N-benzylmaleimide: Add 49.03 g (0.5 mol) of maleic anhydride to a reaction vessel and dissolve it in 588.34 mL of dichloromethane. Add 64.29 g (0.6 mol) of benzylamine, stir the reaction, control the reaction temperature at 5 °C, and after reacting for 0.5 h, add 94.60 g (0.75 mol) of dimethyl sulfate, 250 mL of water, 63.59 g (0.6 mol) of sodium carbonate, and 3.22 g (0.010 mol) of tetrabutylammonium bromide in sequence. Raise the temperature to 40 °C and stir under reflux for 10 h. After the reaction was completed, the liquid was separated, and the organic phase was retained. The organic phase was washed twice with 75 mL of water and separated again. The organic phase was concentrated by rotary evaporation to obtain crude product. 135 g of ethanol was added, and the product was dissolved by heating at 60 °C. The product was placed at 0 °C, cooled to crystallize, filtered, and dried at 45 °C for 6 h to obtain 91.81 g of N-benzylmaleimide, with a yield of 98.13%.

[0117] Step S2, Preparation of N-benzyl-4-aminomaleimide: 33.36 g (0.48 mol, M = 69.49) of hydroxylamine hydrochloride was added to a reaction vessel and dissolved in 95.3 g of water. After cooling to 5°C, a sodium hydroxide solution prepared by dissolving 35.20 g (0.88 mol) of sodium hydroxide in 140.8 g of water was added, and the mixture was stirred at this temperature for 0.5 h. Then, a solution prepared by dissolving 74.84 g (0.4 mol) of N-benzylmaleimide in 898.14 mL of tetrahydrofuran was added, and the mixture was stirred at this temperature for 2 h. The temperature was then raised to 55°C, and the reaction was maintained at this temperature for 8 h. After the reaction was completed, the aqueous layer was separated, the organic phase was concentrated under reduced pressure, 420 g of toluene was added, and the mixture was washed twice with 140 g of water. The organic phase was separated and concentrated by rotary evaporation to obtain the crude product. 210 g of toluene was added, and the mixture was heated to 60 °C to dissolve it. The solution was placed at 0 °C, cooled to crystallize, filtered, and dried at 45 °C for 6 h to obtain 76.97 g of N-benzyl-4-aminomaleimide, with a yield of 95.23%.

[0118] Step S3, Preparation of N-benzyl-2,3-pyridinedicarboximide: 40.41 g (0.2 mol) of N-benzyl-4-aminomaleimide, 43.25 g (0.29 mol) of trimethylbenzoquinone, 13.46 g (0.24 mol) of acrolein, and 484.97 mL of toluene were added to a reaction vessel and stirred. The reaction was carried out at 110 °C for 6 h. After the reaction was complete, the mixture was concentrated under reduced pressure, cooled with ethanol to crystallize, and dried to obtain 45.94 g of N-benzyl-2,3-pyridinedicarboximide, with a yield of 96.45%.

[0119] Example 2

[0120] The synthetic route for this embodiment is shown below:

[0121]

[0122] The difference between Example 2 and Example 1 is as follows:

[0123] Step S1: Add 68.12 g of 25 wt% ammonia water (containing 1 mol of NH3) as the third compound. The volume of dichloromethane is 490.30 mL. After reacting for 2 h, add 115.64 g (0.75 mol) of diethyl sulfate, 82.92 g (0.6 mol) of potassium carbonate, and 3.33 g (0.015 mol) of tetrapropylammonium chloride. Heat to 30 °C and stir for 16 h. 47.80 g of [the compound] is obtained. The yield was 98.51%.

[0124] Step S2: 55.59 g (0.8 mol, M = 69.49) of hydroxylamine hydrochloride was added, along with 38.82 g (0.4 mol) of [unspecified ingredient]. A solution prepared with 465.80 mL of tetrahydrofuran yielded 43.05 g of [amount missing]. The yield was 96.05%.

[0125] Step S3: Add 22.41g (0.2mol) of 35.15 g (0.29 mol) of methylbenzoquinone, 16.81 g (0.24 mol) of butenone, and 179.27 mL of diethylene glycol dimethyl ether were stirred and reacted at 130 °C for 3 h to obtain 30.65 g of [the product / product / etc.]. The yield was 94.58%.

[0126] Example 3

[0127] The synthetic route for this embodiment is shown below:

[0128]

[0129] The difference between Example 3 and Example 1 is as follows:

[0130] Step S1: Using 72.17 g (0.78 mol) of aniline as the third compound, and 735.45 mL of dichloromethane, after reacting for 2 h, 136.68 g (0.75 mol) of dipropyl sulfate and 3.69 g (0.010 mol) of tetrapropylammonium iodide were added, and the mixture was heated to 35 °C and stirred for 12 h. 84.34 g of [the compound] was obtained. The yield was 97.48%.

[0131] Step S2: 41.69 g (0.6 mol, M = 69.49) of hydroxylamine hydrochloride was added, along with 69.22 g (0.4 mol) of [unspecified ingredient]. A solution prepared with 830.64 mL of tetrahydrofuran yielded 70.88 g of [a specific product / product]. The yield was 94.22%.

[0132] Step S3: Add 37.61g (0.2mol) of 71.17 g (0.45 mol) of naphthoquinone, 16.82 g (0.3 mol) of acrolein, and 376.12 mL of diethylene glycol diethyl ether were stirred and reacted at 130 °C for 5 h to obtain 42.27 g of [the desired product]. The yield was 94.32%.

[0133] Example 4

[0134] The synthetic route for this embodiment is shown below:

[0135]

[0136] The difference between Example 4 and Example 1 is as follows:

[0137] Step S1: Add 157.72 g (0.75 mol) of dibutyl sulfate, 82.92 g (0.6 mol) of potassium carbonate, and 3.71 g (0.01 mol) of ethyltriphenylphosphine bromide. 91.68 g of N-benzylmaleimide is obtained, with a yield of 98%.

[0138] Step S2: Add 53.05 g (0.48 mol, R is isopropyl, M = 110.531) of NH2-OR·HCl, cool to 5 °C, then add potassium bicarbonate aqueous solution (containing 104.12 g, 1.04 mol of potassium bicarbonate), 74.84 g (0.4 mol) of N-benzylmaleimide and 748.45 mL of 1,4-dioxane solution, and react at 65 °C for 7 h to obtain 75.83 g of N-benzyl-4-aminomaleimide, with a yield of 93.82%.

[0139] Step S3: Add 23.83 g (0.34 mol) of manganese oxide, 16.81 g (0.24 mol) of 2-methylpropenal, and 404.14 mL of toluene to obtain 47.12 g of [the product / material]. The yield was 93.45%.

[0140] Example 5

[0141] The synthetic route for this embodiment is shown below:

[0142]

[0143] The difference between Example 5 and Example 1 is:

[0144] Step S1: Add 24 g (0.6 mol) of sodium hydroxide. 88.20 g of N-benzylmaleimide was obtained, with a yield of 94.27%.

[0145] Step S2: Add 46.33 g (0.48 mol, R is ethyl, M = 96.515) of NH2-OR·HCl, cool to 5 °C, and then add sodium methoxide aqueous solution (containing 43.22 g, 0.8 mol of sodium methoxide). Add 748.45 mL of tetrahydrofuran, and keep the reaction at 45 °C for 12 h to obtain 76.08 g of N-benzyl-4-aminomaleimide, with a yield of 94.13%.

[0146] Step S3: Add 16.32 g (0.48 mol) of hydrogen peroxide, 20.17 g (0.24 mol) of 2-ethylpropenal, and 404.14 mL of toluene to obtain 49.51 g of [the product / material]. The yield was 93.02%.

[0147] Example 6

[0148] The synthetic route for this embodiment is shown below:

[0149]

[0150] The difference between Example 6 and Example 1 is:

[0151] Step S1: Using 47.29 g (0.8 mol) of propylamine as the third compound, and with a volume of 392.24 mL of dichloromethane, after reacting at 6°C for 1 h, 105.05 g (0.75 mol) of trimethyl phosphate was added. 66.88 g of [the compound] was obtained. The yield was 96.23%.

[0152] Step S2: 50.03 g (0.72 mol, M = 69.49) of hydroxylamine hydrochloride was added, cooled to 5°C, and then an aqueous solution of sodium tert-butoxide (containing 84.57 g, 0.88 mol of sodium tert-butoxide) was added, followed by 55.60 g (0.4 mol) of... A solution prepared with 444.82 mL of tetrahydrofuran was reacted at 50 °C for 10 h to obtain 58.84 g of [the product / product]. The yield was 95.46%.

[0153] Step S3: Add 30.82g (0.2mol) of 54.76 g (0.72 mol) of peracetic acid, 40.02 g (0.4 mol) of 2-(methoxymethyl)propenal, and 308.2 mL of toluene were stirred and reacted at 100 °C for 8 h to obtain 43.48 g of [the desired product]. The yield was 93.25%.

[0154] Example 7

[0155] The synthetic route for this embodiment is shown below:

[0156]

[0157] The difference between Example 7 and Example 1 is as follows:

[0158] Step S1: 52.55 g (0.7 mol) of 2-(aminooxy)propane (CAS: 4427-29-6) was used as the third compound. The volume of dichloromethane was 490.3 mL. After reacting at 8°C for 1.5 h, 129.15 g (0.75 mol) of p-toluenesulfonic acid, 82.92 g (0.60 mol) of potassium carbonate, and 2.78 g (0.01 mol) of tetrabutylammonium chloride were added. 74.31 g of [the compound] was obtained. The yield was 95.84%.

[0159] Step S2: 44.47 g (0.64 mol, M = 69.49) of hydroxylamine hydrochloride was added, cooled to 5°C, and then an aqueous solution of potassium carbonate (containing 121.62 g (0.88 mol)) was added. 62.03 g (0.4 mol) of [unspecified ingredient] was then added. A solution prepared with 992.49 mL of toluene was reacted at 70 °C for 6 h to obtain 64.07 g of [the product / product]. The yield was 94.17%.

[0160] Step S3: Add 34.02 g (0.2 mol) of 222.47 g (0.96 mol) of silver oxide, 58.88 g (0.6 mol) of 4-methyl-2-pentenal, and 408.22 mL of dipropylene glycol dimethyl ether were stirred and reacted at 160 °C for 10 h to obtain 39.76 g of [the desired product]. The yield was 93.72%.

[0161] Example 8

[0162] The difference between this embodiment and step S2 in Embodiment 1 is that:

[0163]

[0164] Step S2, Preparation of 1-benzyl-3,4-dibromo-pyrrolidine-2,5-dione: 74.84 g (0.4 mol) of N-benzylmaleimide was added to a reaction vessel and dissolved in 898.14 mL of dichloromethane. A mixture of 75.76 g (0.48 mol) of bromine and 100 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature. After the addition was complete, the mixture was heated to 40 °C and refluxed for 2.5 h. After the reaction was complete, the pressure was reduced, the mixture was washed with dichloromethane, concentrated under reduced pressure, and dried to obtain the crude product containing 134 g of 1-benzyl-3,4-dibromo-pyrrolidine-2,5-dione, with a yield of 97.13%.

[0165] Preparation of N-benzyl-4-bromomaleimide: 68.98 g (0.2 mol) of 1-benzyl-3,4-dibromo-pyrrolidine-2,5-dione was added to a reaction vessel and dissolved in 413.88 mL of tetrahydrofuran. A mixed solution of 20.24 g (0.2 mol) of triethylamine and 100 mL of tetrahydrofuran was added dropwise. The reaction was stirred and the temperature was controlled at 20 °C. After the addition was complete, the mixture was transferred to room temperature and reacted for 4 h. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and crystallized by cooling with ethanol. After drying, 50.67 g of N-benzyl-4-bromomaleimide was obtained, with a yield of 95.61%.

[0166] Preparation of N-benzyl-4-aminomaleimide: 39.75 g (0.15 mol) of N-benzyl-4-bromomaleimide was added to a reaction vessel and dissolved in 476.95 mL of tetrahydrofuran. Ammonia gas was introduced, and the reactor pressure was controlled at 0.25 MPa. The reaction was stirred at 20 °C for 1.5 h. After the reaction was complete, the pressure was released, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then cooled with dichloromethane to crystallize, and dried to obtain 28.58 g of N-benzyl-4-aminomaleimide, with a yield of 94.28%.

[0167] Example 9

[0168] The difference between this embodiment and step S2 in Embodiment 2 is that:

[0169]

[0170] Step S2: Add 38.82 g (0.4 mol) of [agent / material] to the reaction vessel. Dissolved in 310.53 mL of dichloromethane, a mixed solution of 75.76 g (0.48 mol) of bromine and 100 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature. After the addition was complete, the mixture was heated to 40 °C and refluxed for 5 h. After the reaction was complete, the solution was reduced under reduced pressure, washed with dichloromethane, concentrated under reduced pressure, and dried to obtain the crude product, containing 96.57 g of bromine. The yield was 94%.

[0171] Add 51.37 g (0.2 mol) of [agent] to the reaction vessel. Dissolved in 154.10 mL of tetrahydrofuran, 18.98 g (0.24 mol) of a mixed solution of pyridine and 100 mL of tetrahydrofuran was added dropwise. The reaction was stirred and the temperature was controlled at 20 °C. After the addition was complete, the mixture was transferred to room temperature and the reaction was allowed to proceed for 8 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and crystallized by cooling with ethanol. After drying, 57.06 g of the solution was obtained. The yield was 94.74%.

[0172] 37.64 g (0.15 mol) of [agent name] was added to the reaction vessel. Dissolved in 301.15 mL of tetrahydrofuran, ammonia gas was introduced, the reactor pressure was controlled at 0.25 MPa, the reaction was stirred, the reaction temperature was 20 °C, and the reaction was carried out for 1.5 h. After the reaction was complete, the pressure was released, the mixture was filtered, the filtrate was concentrated under reduced pressure, cooled with dichloromethane to crystallize, and dried to obtain 15.75 g of [the product / solution / product]. The yield was 93.71%.

[0173] Example 10

[0174] The difference between this embodiment and step S2 in Embodiment 3 is that:

[0175]

[0176] Step S2: Add 69.22 g (0.4 mol) of [unspecified ingredient] to the reaction vessel. Dissolved in 692.20 mL of carbon tetrachloride, a mixed solution of 75.76 g (0.48 mol) of bromine and 100 mL of carbon tetrachloride was added dropwise. The mixture was stirred at room temperature. After the addition was complete, the temperature was raised to 60 °C and the reaction was allowed to proceed for 2.5 h. After the reaction was complete, the solution was reduced under reduced pressure, washed with carbon tetrachloride, concentrated under reduced pressure, and dried to obtain the crude product, containing 128.18 g of bromine. The yield was 96.27%.

[0177] Add 66.57 g (0.2 mol) of [agent / material] to the reaction vessel. Dissolved in 266.30 mL of 1,4-dioxane, 9.46 g (0.16 mol) of isopropylamine and 50 mL of 1,4-dioxane were added dropwise. The mixture was stirred and the reaction temperature was controlled at 40 °C. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 4 h. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and crystallized by cooling with ethanol. After drying, 38.41 g of [the product] was obtained. The yield was 95.28%.

[0178] 37.79 g (0.15 mol) of [agent name] was added to the reaction vessel. Dissolved in 377.94 mL of 1,4-dioxane, ammonia gas was introduced, the reactor pressure was controlled at 0.25 MPa, the reaction was stirred, the reaction temperature was 35 °C, and the reaction was carried out for 1.5 h. After the reaction was complete, the pressure was released, the mixture was filtered, the filtrate was concentrated under reduced pressure, cooled with dichloromethane to crystallize, and dried to obtain 26.61 g of [the product / solution / product]. The yield was 94.32%.

[0179] Example 11

[0180] The difference between this embodiment and step S2 in Embodiment 4 is that:

[0181]

[0182] Step S2: 74.84 g (0.4 mol) of N-benzylmaleimide was added to a reaction vessel and dissolved in 898.14 mL of dichloromethane. A mixture of 45.38 g (0.64 mol) of chlorine and 100 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature. After the addition was complete, the temperature was raised to 40 °C and refluxed for 2.5 h. After the reaction was complete, the pressure was reduced, the mixture was washed with dichloromethane, concentrated under reduced pressure, and dried to obtain the crude product, which contained 98.48 g of 1-benzyl-3,4-dichloro-pyrrolidine-2,5-dione, with a yield of 95.43%.

[0183] 51.60 g (0.2 mol) of 1-benzyl-3,4-dichloropyrrolidine-2,5-dione was added to a reaction vessel and dissolved in 309.58 mL of tetrahydrofuran. A mixed solution of 20.24 g (0.2 mol) of triethylamine and 100 mL of tetrahydrofuran was added dropwise, and the reaction was stirred while maintaining the temperature at 20 °C. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 4 h. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the solution was cooled and crystallized with ethanol. The crystals were then dried to obtain 42.59 g of N-benzyl-4-chloromaleimide, with a yield of 96.14%.

[0184] 33.23 g (0.15 mol) of N-benzyl-4-chloromaleimide was added to a reaction vessel and dissolved in 398.74 mL of tetrahydrofuran. Ammonia gas was introduced, and the reactor pressure was controlled at 0.35 MPa. The reaction was stirred at 20 °C for 1 h. After the reaction was complete, the pressure was released, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then cooled with dichloromethane to crystallize, and dried to obtain 28.91 g of N-benzyl-4-aminomaleimide, with a yield of 95.38%.

[0185] Example 12

[0186] The difference between this embodiment and step S2 in Embodiment 5 is that:

[0187]

[0188] Step S2: 74.84 g (0.4 mol) of N-benzylmaleimide was added to a reaction vessel and dissolved in 898.14 mL of dichloromethane. A mixture of 75.76 g (0.48 mol) of bromine and 100 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature. After the addition was complete, the mixture was heated to 40 °C and refluxed for 2 h. After the reaction was complete, the pressure was reduced, the mixture was washed with dichloromethane, concentrated under reduced pressure, and dried to obtain the crude product, which contained 135.49 g of 1-benzyl-3,4-dibromo-pyrrolidine-2,5-dione, with a yield of 97.65%.

[0189] 69.38 g (0.2 mol) of 1-benzyl-3,4-dibromopyrrolidine-2,5-dione was added to a reaction vessel and dissolved in 416.26 mL of tetrahydrofuran. A mixed solution of 18.63 g (0.2 mol) of 2-methylpyridine and 100 mL of tetrahydrofuran was added dropwise. The reaction was stirred and the temperature was maintained at 20 °C. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 3 h. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the solution was cooled and crystallized with ethanol. The crystals were dried to obtain 48.85 g of N-benzyl-4-bromomaleimide, with a yield of 92.18%.

[0190] 39.75 g (0.15 mol) of N-benzyl-4-bromomaleimide was added to a reaction vessel and dissolved in 476.95 mL of tetrahydrofuran. 81.75 g of 25 wt% ammonia solution (containing 1.2 mol of NH3) was added, and the mixture was stirred at 20 °C for 3 h. After the reaction was complete, the pressure was released, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then cooled with dichloromethane to crystallize, and dried to obtain 28.03 g of N-benzyl-4-aminomaleimide, with a yield of 92.46%.

[0191] Example 13

[0192] The difference between this embodiment and step S2 in Embodiment 6 is that:

[0193]

[0194] Step S2: Add 55.6 g (0.4 mol) of [agent / material] to the reaction vessel. Dissolved in 889.64 mL of carbon tetrachloride, a mixed solution of 101.52 g (0.4 mol) of iodine and 100 mL of carbon tetrachloride was added dropwise. The mixture was stirred at room temperature. After the addition was complete, the temperature was raised to 55 °C and the reaction was carried out for 3 hours. After the reaction was complete, the solution was reduced under reduced pressure, washed with carbon tetrachloride, concentrated under reduced pressure, and dried to obtain the crude product, containing 244.78 g of iodine. The yield was 94.63%.

[0195] 129.34 g (0.2 mol) of [agent name] was added to the reaction vessel. The cyclohexylamine was dissolved in 776.01 mL of 1,4-dioxane, and 25.78 g (0.26 mol) of a mixed solution of cyclohexylamine and 125 mL of 1,4-dioxane was added dropwise. The mixture was stirred and the reaction temperature was controlled at 35 °C. After the addition was complete, the mixture was transferred to room temperature and the reaction was allowed to proceed for 6 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the solution was crystallized by cooling with ethanol. After drying, 93.8 g of the cyclohexylamine was obtained. The yield was 92.06%.

[0196] Add 58.78 g (0.15 mol) of [agent / material] to the reaction vessel. Dissolved in 587.8 mL of 1,4-dioxane, 94.62 g of 18 wt% ammonia solution (containing 0.75 mol NH3) was added, and the mixture was stirred at 35 °C for 3 h. After the reaction was complete, the pressure was released, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the solution was cooled and crystallized with dichloromethane. The crystals were then dried to obtain 21.2 g of the product. The yield was 91.71%.

[0197] Example 14

[0198] The difference between this embodiment and step S2 in Embodiment 7 is that:

[0199]

[0200] Step S2: Add 62.03 g (0.4 mol) of [unspecified ingredient] to the reaction vessel. Dissolved in 992.49 mL of 1,2-dichloroethane, a mixed solution of 51.05 g (0.72 mol) of chlorine and 100 mL of 1,2-dichloroethane was added dropwise. The mixture was stirred at room temperature. After the addition was complete, the temperature was raised to 80 °C and the reaction proceeded for 2 hours. After the reaction was complete, the solution was reduced under reduced pressure, washed with 1,2-dichloroethane, concentrated under reduced pressure, and dried to obtain the crude product, containing 84.41 g of chlorine. The yield was 93.38%.

[0201] Add 45.2 g (0.2 mol) of [agent / material] to the reaction vessel. Dissolved in 361.57 mL of 1,2-dichloroethane, a mixed solution of 23.73 g (0.3 mol) of pyridine and 125 mL of 1,2-dichloroethane was added dropwise. The mixture was stirred and the reaction temperature was controlled at 50 °C. After the addition was complete, the mixture was transferred to room temperature and the reaction was allowed to proceed for 3 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and crystallized by cooling with ethanol. After drying, 54.7 g of the solution was obtained. The yield was 96.21%.

[0202] 28.43 g (0.15 mol) of [agent name] was added to the reaction vessel. Dissolved in 454.85 mL of 1,2-dichloroethane, ammonia gas was introduced, the reactor pressure was controlled at 0.4 MPa, the reaction was stirred, the reaction temperature was 50 °C, and the reaction was carried out for 1.5 h. After the reaction was complete, the pressure was released, the mixture was filtered, the filtrate was concentrated under reduced pressure, cooled with dichloromethane to crystallize, and dried to obtain 23.87 g of [the product / solution]. The yield was 93.56%.

[0203] Example 15

[0204] The difference between this embodiment and the synthesis route in steps S1-S2 of Embodiment 2 is as follows:

[0205]

[0206] 20 g (0.206 mol) of maleimide was added to a reaction vessel and dissolved in 200 mL of dichloromethane. A mixture of 40.65 g (0.256 mol) of bromine and 100 mL of dichloromethane was added dropwise. The reaction mixture was heated under reflux for 2.5 h, allowed to cool to room temperature for 1 h, and the solvent was removed by vacuum distillation to obtain crude 2,3-dibromomaleimide. This crude product was dissolved in 200 mL of tetrahydrofuran, and a mixture of 20.85 g (0.206 mol) of triethylamine and 100 mL of tetrahydrofuran was added over 15 min at 0 °C. The reaction mixture was then heated to room temperature and stirred for 18 h. The solid was removed by filtration, and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography to obtain 30.72 g of 3-bromo-1H-pyrrole-2,5-dione, with a yield of 84.73%.

[0207] 20 g (0.114 mol) of 3-bromo-1H-pyrrole-2,5-dione and 44.33 g (0.682 mol) of sodium azide were added to 100 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 3 h. Then, 400 mL of water was added to the reaction mixture and thoroughly mixed. The mixture was then extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed under vacuum to obtain 10.09 g of azide, with a yield of 64.31%.

[0208] In a reaction vessel, 9.6 g (0.07 mol) of azide, 200 mL of ethanol, and 2.24 g (10 wt%) of Pd / C catalyst were added. After purging with nitrogen and then hydrogen, the reaction was carried out at 2 MPa pressure and room temperature for 4 h. After the reaction was complete, the Pd / C catalyst was removed by filtration, and the solvent was removed under reduced pressure to obtain 7.2 g of [the desired product]. The yield was 92.43%.

[0209] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0210] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for preparing a pyridinedicarboximide compound, characterized in that, Includes the following steps: The first compound shown in formula (2) and the second compound shown in formula (3) are reacted in the presence of an oxidant at 60°C-160°C to obtain the pyridine dicarboximide compound shown in formula (4), wherein R1, R2, R3, and R4 are independently selected from hydrogen, C1-C6 straight-chain aliphatic alkyl, C1-C6 branched aliphatic alkyl, C1-C6 alkoxy or phenyl, benzyl; 、 、 ； The oxidant is selected from trimethylbenzoquinone, methylbenzoquinone, naphthoquinone, manganese oxide, hydrogen peroxide, peracetic acid, or silver oxide.

2. The method for preparing the pyridine dicarboximide compound according to claim 1, characterized in that, The molar ratio of the first compound to the second compound is 1:1.2 to 1:3.

0.

3. The method for preparing the pyridinedicarboximide compound according to claim 1, characterized in that, R1, R2, R3, and R4 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, phenyl, or benzyl.

4. The method for preparing the pyridinedicarboximide compound according to any one of claims 1 to 3, characterized in that, The first compound and the second compound react in the presence of an oxidant, wherein the molar ratio of the first compound to the oxidant is 1:1.2 to 1:2.

0.

5. The method for preparing the pyridinedicarboximide compound according to claim 4, characterized in that, In the step of reacting the first compound with the second compound in the presence of an oxidant, the reaction time is 1 h to 10 h.

6. The method for preparing the pyridinedicarboximide compound according to claim 1, characterized in that, The preparation method of the first compound includes the following steps: Maleic anhydride is reacted with a third compound having the structural formula R1-NH2 to give the first intermediate product shown in formula (1), wherein R1 is selected from hydrogen, a straight-chain aliphatic alkyl group of C1-C6, a branched aliphatic alkyl group of C1-C6, an alkoxy group of C1-C6, or a phenyl or benzyl group. The first intermediate product was reacted to obtain the first compound; 。 7. The method for preparing the pyridine dicarboximide compound according to claim 6, characterized in that, The molar ratio of the third compound to the maleic anhydride is 1.2:1 to 2.0:

1.

8. The method for preparing the pyridinedicarboximide compound according to claim 6 or 7, characterized in that, The step of reacting maleic anhydride with a third compound includes: reacting the maleic anhydride with the third compound to obtain a first preproduct as shown in formula (5), and then reacting the first preproduct in the presence of an alkylating agent, an alkaline aqueous solution, and a phase transfer catalyst to obtain a first intermediate product as shown in formula (1). 。 9. The method for preparing the pyridine dicarboximide compound according to claim 8, characterized in that, The molar ratio of the alkylating agent, the solute in the alkaline aqueous solution, the phase transfer catalyst, and the maleic anhydride is (1.2-2.0):(1.2-2.0):(0.01-0.08):

1.

10. The method for preparing the pyridine dicarboximide compound according to claim 8, wherein the phase transfer catalyst is selected from quaternary ammonium salt phase transfer catalysts or quaternary phosphate salt phase transfer catalysts, the solute in the alkaline aqueous solution is selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, and the alkylating agent is selected from at least one of dialkyl sulfate, alkyl arylsulfonic acid, and trialkyl phosphate.

11. The method for preparing the pyridine dicarboximide compound according to claim 8, characterized in that, In the step of reacting the maleic anhydride with the third compound, the temperature is 0℃-10℃ and the time is 0.5h-2h.

12. The method for preparing the pyridine dicarboximide compound according to claim 8, wherein in the step of reacting the first preproduct in the presence of an alkylating agent, an alkaline aqueous solution and a phase transfer catalyst, the temperature is 25°C-55°C and the time is 10h-16h.

13. The method for preparing the pyridinedicarboximide compound according to claim 6, characterized in that, The step of reacting the first intermediate product includes: reacting the first intermediate product with a hydroxylamine reagent under alkaline reagent conditions, wherein the molar ratio of the first intermediate product to the hydroxylamine reagent is 1:1.0-1:2.0, and the molar ratio of the first intermediate product to the alkaline reagent is 1:2.0-1:3.

0.

14. The method for preparing the pyridine dicarboximide compound according to claim 13, characterized in that, In the step of reacting the first intermediate with the hydroxylamine reagent under alkaline conditions, the temperature is 45℃-70℃ and the time is 6h-12h.

15. The method for preparing the pyridine dicarboximide compound according to claim 13, characterized in that, The hydroxylamine reagent is selected from NH2-OR·HCl, wherein R is selected from H, a straight-chain aliphatic alkyl group of C1-C6 or a branched aliphatic alkyl group of C1-C6.

16. The method for preparing the pyridine dicarboximide compound according to claim 13, characterized in that, The alkaline reagent is selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, and potassium methoxide.

17. The method for preparing the pyridinedicarboximide compound according to claim 6, characterized in that, The step of reacting the first intermediate product includes: The first intermediate product was reacted with a halogen element to obtain the second preproduct shown in formula (6); The second preproduct was reacted to obtain the third preproduct shown in formula (7); The third preproduct is reacted with an amination agent to obtain the first compound; 、 ； Where X is selected from halogen elements.

18. The method for preparing the pyridine dicarboximide compound according to claim 17, characterized in that, The molar ratio of the first intermediate product to the halogen element is 1:1.0 to 1:2.

0.

19. The method for preparing the pyridine dicarboximide compound according to claim 17, wherein the halogen element is selected from Cl2, Br2, and I2.

20. The method for preparing the pyridine dicarboximide compound according to claim 17, characterized in that, The second preproduct is reacted in the presence of an organic base, wherein the molar ratio of the second preproduct to the organic base is 1:0.8 to 1:1.5, and the organic base is selected from amines or pyridines.

21. The method for preparing the pyridine dicarboximide compound according to claim 17, characterized in that, The amination agent is selected from ammonia gas or ammonia water.

22. The method for preparing the pyridine dicarboximide compound according to claim 21, characterized in that, The amination agent is selected from ammonia gas, and the ammonia gas pressure is 0.1 MPa-1.0 MPa; Alternatively, the amination agent is selected from ammonia water, the concentration of which is 18wt%-25wt%, and the molar ratio of the third preproduct to ammonia in the ammonia water is 1:3-1:

15.

23. The method for preparing the pyridine dicarboximide compound according to claim 17, characterized in that, In the step of reacting the first intermediate product with a halogen element, the temperature is 20℃-100℃ and the time is 2h-5h.

24. The method for preparing the pyridine dicarboximide compound according to claim 17, characterized in that, In the step of reacting the second preproduct, the temperature is 0℃-80℃ and the time is 3h-12h.

25. The method for preparing the pyridine dicarboximide compound according to claim 17, characterized in that, In the step of reacting the third preproduct with the amination agent, the temperature is 0℃-120℃ and the time is 1h-4h.

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