CN116987075A - Process for preparing pyridine dicarboximide compound - Google Patents

Abstract

The invention relates to a preparation method of a pyridine dicarboximide compound, which utilizes an amino group in a first compound and unsaturated double bonds at two ends in a second compound to carry out cycloaddition reaction, so as to construct the pyridine dicarboximide compound. The preparation method provided by the invention has the advantages that (1) raw materials are low in price and easy to obtain, and the reaction yield is high; (2) The reaction condition is simple and mild, the operation is simple, and the process is easy to realize; (3) Green, environmental protection, economy and the like, is beneficial to industrialized mass production and downstream product preparation, and can meet the huge demands of terminal drug production.

Description

Process for preparing pyridine dicarboximide compound

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of a pyridine dicarboximide compound.

Background

Moxifloxacin hydrochloride is a fourth-generation quinolone antibacterial agent developed by Bayer company in Germany, and is a new-generation antibiotic with broad antibacterial spectrum. The product is mainly used for treating adult patients suffering from upper and lower respiratory tract infection, and has the advantages of broad spectrum, strong antibacterial property, difficult generation of drug resistance, less adverse reaction, large market dosage, and wide prospect.

The current process for synthesizing moxifloxacin hydrochloride is as follows:

the difficulty of the process for synthesizing moxifloxacin hydrochloride is that the side chain synthesis process is complex, the raw and auxiliary materials are high in cost, the reaction yield is low, and the like, so that the production cost of moxifloxacin hydrochloride is high.

The pyridine dicarboximide compound is used as a key intermediate in the process of synthesizing the moxifloxacin hydrochloride side chain, and is high in price and not easy to obtain. In the traditional pyridine dicarboximide compound synthesis method, quinoline is taken as a raw material, pyridine diacid is firstly oxidized by oxidizing agents such as potassium permanganate and the like, then condensation reaction is carried out to synthesize pyridine dianhydride, and finally the pyridine dicarboximide compound is obtained through lactamization reaction, wherein the synthesis route is as follows:

however, the current synthetic route has serious environmental pollution, and the raw material quinoline is expensive and not easily available due to the rising price of the raw material. Therefore, the preparation method of the pyridine dicarboximide compound with the characteristics of easily available raw materials, reduced production cost, high reaction yield, environment friendliness and the like is developed, and has important significance and value in the technical field.

Disclosure of Invention

Based on this, it is necessary to provide a preparation method of a pyridine dicarboximide compound, which has high yield, low cost, easily available raw materials, mild reaction conditions, simple operation, easy realization, and is favorable for industrial production, in view of the above problems.

A method for preparing a pyridine dicarboximide compound, comprising the steps of:

reacting a first compound represented by the formula (2) with a second compound represented by the formula (3) to obtain a dipicolinate compound represented by the formula (4), wherein R ₁ 、R ₂ 、R ₃ 、R ₄ Are independently selected from hydrogen, C ₁ -C ₆ Straight-chain fatty alkyl, C ₁ -C ₆ Branched fatty alkyl, C ₁ -C ₆ Alkoxy or C of (C) ₆ -C ₁₀ An aromatic group of (a);

in one embodiment, the molar ratio of the first compound to the second compound is from 1:1.2 to 1:3.0;

and/or R ₁ 、R ₂ 、R ₃ 、R ₄ 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.

In one embodiment, the first compound and the second compound are reacted in the presence of an oxidizing agent, the molar ratio of the first compound to the oxidizing agent being from 1:1.2 to 1:2.0.

In one embodiment, the first compound and the second compound are reacted in the presence of an oxidizing agent at a temperature of 60 ℃ to 160 ℃ for a time of 1h to 10h;

And/or the oxidizing agent is selected from transition metal oxides, peroxides or quinone compounds.

In one embodiment, the method of preparing the first compound comprises the steps of:

maleic anhydride and the structural formula is R ₁ -NH ₂ The third compound of formula (1) is reacted to obtain a first intermediate product represented by formula (1), wherein R ₁ Selected from hydrogen, C ₁ -C ₆ Straight-chain fatty alkyl, C ₁ -C ₆ Branched fatty alkyl, C ₁ -C ₆ Alkoxy or C of (C) ₆ -C ₁₀ An aromatic group of (a);

reacting the first intermediate product to obtain a first compound;

in one embodiment, the molar ratio of the third compound to the maleic anhydride is from 1.2:1 to 2.0:1.

In one embodiment, the step of reacting maleic anhydride with the third compound comprises: reacting the maleic anhydride with the third compound to obtain a first pre-product shown in a formula (5), then reacting the first pre-product in the presence of an alkylating agent, an alkaline aqueous solution and a phase transfer catalyst to obtain a first intermediate product shown in a formula (1),

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

And/or the phase transfer catalyst is selected from quaternary ammonium salt phase transfer catalyst or quaternary phosphonium salt phase transfer catalyst, 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 arylsulfonate and trialkyl phosphate.

In one embodiment, the step of reacting the maleic anhydride with the third compound is performed at a temperature of 0 ℃ to 10 ℃ for a time of 0.5h to 2h;

and/or, in the step of reacting the first pre-product in the presence of an alkylating agent, an alkaline aqueous solution and a phase transfer catalyst, the temperature is 25-55 ℃ and the time is 10-16 h.

In one embodiment, the step of reacting the first intermediate product comprises: 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.

In one embodiment, in the step of reacting the first intermediate product with a hydroxylamine reagent under alkaline conditions, the temperature is 45 ℃ to 70 ℃ for a period of time of 6h to 12h;

And/or the hydroxylamine reagent is selected from NH ₂ -O-r.hcl, wherein R is selected from H, C ₁ -C ₆ Straight-chain fatty alkyl or C ₁ -C ₆ Branched fatty alkyl groups of (a);

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

In one embodiment, the step of reacting the first intermediate product comprises:

reacting the first intermediate product with a halogen simple substance to obtain a second pre-product shown in a formula (6);

reacting the second pre-product to obtain a third pre-product shown in a formula (7);

reacting the third pre-product with an amination agent to obtain the first compound;

wherein X is selected from halogen elements.

In one embodiment, the molar ratio of the first intermediate product to the elemental halogen is from 1:1.0 to 1:2.0;

and/or the halogen simple substance is selected from Cl ₂ 、Br ₂ 、I ₂ 。

In one embodiment, the second pre-product is reacted in the presence of an organic base in a molar ratio of the second pre-product to the organic base of from 1:0.8 to 1:1.5, wherein the organic base is selected from amines or pyridines.

In one embodiment, the amination agent is selected from ammonia or aqueous ammonia.

In one embodiment, the amination agent is selected from ammonia gas, the ammonia gas pressure being 0.1MPa to 1.0MPa;

or the amination agent is selected from ammonia water, the concentration of the ammonia water is 18-25 wt%, and the molar ratio of the third pre-product to the ammonia in the ammonia water is 1:3-1:15.

In one embodiment, in the step of reacting the first intermediate product with elemental halogen, the temperature is 20 ℃ to 100 ℃ and the time is 2 hours to 5 hours;

and/or, in the step of reacting the second pre-product, the temperature is 0-80 ℃ and the time is 3-12 h;

and/or, in the step of reacting the third pre-product with an amination agent, the temperature is 0-120 ℃ and the time is 1-4 h.

According to the preparation method, cycloaddition reaction is carried out on the amino group in the first compound and unsaturated double bonds at two ends in the second compound, so that the pyridine dicarboximide compound is obtained. Compared with the traditional process, the preparation method has the advantages that (1) the raw materials are low in price and easy to obtain, and the reaction yield is high; (2) The reaction condition is simple and mild, the operation is simple, and the process is easy to realize; (3) Green, environmental protection, economy and the like, is beneficial to industrialized mass production and downstream product preparation, and can meet the huge demands of terminal drug production.

Detailed Description

The present invention will be described in more detail below in order to facilitate understanding of the present invention. It should be understood, however, that the invention may be embodied in many different forms and is not limited to the implementations or embodiments described herein. Rather, these embodiments or examples are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, 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 belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments or examples only and is not intended to be limiting of the invention.

The invention provides a preparation method of a pyridine dicarboximide compound, which comprises the following steps:

reacting a first compound represented by the formula (2) with a second compound represented by the formula (3) to obtain a dipicolinate compound represented by the formula (4), wherein R ₁ 、R ₂ 、R ₃ 、R ₄ Are independently selected from hydrogen, C ₁ -C ₆ Straight-chain fatty alkyl, C ₁ -C ₆ Branched fatty alkyl, C ₁ -C ₆ Alkoxy or C of (C) ₆ -C ₁₀ Aromatic groups of (a).

The specific reaction process is as follows:

And performing cycloaddition reaction on the amino group in the first compound and unsaturated double bonds at two ends in the second compound to construct the pyridine dicarboximide compound.

Preferably, R in the first compound ₁ Preferably hydrogen, C ₁ -C ₆ Straight-chain fatty alkyl, C ₁ -C ₆ Branched fatty alkyl, C ₁ -C ₆ Alkoxy or C of (C) ₆ -C ₁₀ Further preferred is 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.

R in the second compound ₂ 、R ₃ 、R ₄ Are independently selected from hydrogen, C ₁ -C ₆ Straight-chain fatty alkyl, C ₁ -C ₆ Branched fatty alkyl, C ₁ -C ₆ Alkoxy or C of (C) ₆ -C ₁₀ Further preferred is 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.

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.

Preferably, the first compound is reacted with the second compound in the presence of an oxidizing agent which facilitates oxidation of the single bond to a double bond after ring formation, wherein the molar ratio of the first compound to the oxidizing agent is from 1:1.2 to 1:2.0, preferably from 1:1.2 to 1:1.5.

Specifically, the oxidizing agent is selected from transition metal oxides, peroxides or quinone compounds, and further preferably at least one of manganese oxide, silver oxide, iron oxide, copper oxide, zinc oxide, chromium oxide, hydrogen peroxide, peracetic acid, peroxypropionic acid, peroxybenzoic acid, m-chloroperoxybenzoic acid, p-benzoquinone, o-benzoquinone, methyl benzoquinone, trimethyl benzoquinone, and naphthoquinone.

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

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

It should be noted that, the person skilled in the art may obtain the first compound by various existing preparation methods, which is not limited in the present invention.

The present invention preferably provides a first compound prepared by the following method:

s1, maleic anhydride and a structural formula of R ₁ -NH ₂ The third compound of formula (1) is reacted to obtain a first intermediate product represented by formula (1), wherein R ₁ Selected from hydrogen, C ₁ -C ₆ Straight-chain fatty alkyl, C ₁ -C ₆ Branched fatty alkyl, C ₁ -C ₆ Alkoxy or C of (C) ₆ -C ₁₀ An aromatic group of (a);

s2, reacting the first intermediate product to obtain a first compound;

in step S1, maleic anhydride is used as a starting material, and an amino functional group in the third compound is utilized to react with an anhydride group in the maleic anhydride, so that a water molecule is removed to obtain a first intermediate product. Wherein the third compound has the structural formulaR of (2) ₁ Preferably hydrogen, C ₁ -C ₆ Straight-chain fatty alkyl, C ₁ -C ₆ Branched fatty alkyl, C ₁ -C ₆ Alkoxy or C of (C) ₆ -C ₁₀ Further preferred is 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. .

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

In the reaction process of maleic anhydride and the third compound, a first pre-product shown in formula (5) is usually produced, and then the first pre-product is reacted to obtain a first intermediate product, wherein the specific reaction process is as follows:

the reaction process can be prepared in various preparation modes, and the invention is not limited thereto.

For example, method one: reacting the maleic anhydride with the third compound to obtain a first pre-product, and then reacting the first pre-product in the presence of an alkylating agent, an alkaline aqueous solution and a phase transfer catalyst to obtain a first intermediate product; the second method is as follows: mixing maleic anhydride and a third compound in a solvent, stirring and reacting to obtain a first pre-product, mixing the first pre-product with acetic acid for reflux reaction, neutralizing by saturated sodium bicarbonate aqueous solution, extracting by ethyl acetate, concentrating an organic layer under reduced pressure and crystallizing to obtain a first intermediate product, wherein the first intermediate product is preferably selected as a method I.

In the first method, the alkylating reagent can convert carboxyl in the first pre-product into ester group, and alkoxy is easier to leave relative to hydroxyl, so that the cyclization yield of the first pre-product is more beneficial to improvement. 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.

Specifically, the alkylating agent is at least one selected from dialkyl sulfate, alkyl arylsulfonate and trialkyl phosphate, and further preferably at least one selected from dimethyl sulfate, diethyl sulfate, dipropyl sulfate, dibutyl sulfate, p-toluenesulfonic acid and trimethyl phosphate.

In the first method, the dealcoholization and cyclization of the ester groups and the amide bonds in the first pre-product are promoted under alkaline conditions, and the yield is preferably improved, and the molar ratio of the solute in the alkaline aqueous solution to the maleic anhydride is preferably (1.2-2.0): 1, more preferably (1.2-1.5): 1.

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

In the first method, the organic phase and the aqueous phase are two phases in the reaction system, and the cyclization and the hydrolysis of the ester groups in the first pre-product are competing reactions, so that the phase transfer catalyst is beneficial to promoting the cyclization and the conversion of the ester groups in the first pre-product 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.

Specifically, the phase transfer catalyst is selected from quaternary ammonium salt phase transfer catalysts or quaternary phosphonium salt phase transfer catalysts, and more preferably at least one of benzyl triethyl ammonium chloride, trioctylmethyl ammonium chloride, tetramethyl ammonium bromide, tetrapropyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium iodide, triethyl benzyl ammonium bromide, triethyl hexyl ammonium bromide, triethyl octyl ammonium bromide, ethyl triphenyl phosphonium bromide, butyl triphenyl phosphonium bromide, and tetraphenyl phosphonium bromide.

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

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

Preferably, the first pre-product is reacted in the presence of an alkylating agent, an aqueous alkaline solution and a phase transfer catalyst at a temperature of from 25 ℃ to 55 ℃, more preferably from 35 ℃ to 45 ℃; the time is 10h-16h, more preferably 12h-14h.

In step S2, the first intermediate is reacted to make the first compound have an amino functional group, which is beneficial to the subsequent conversion to obtain a specific functional group.

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

In particular, the hydroxylamine reagent is selected from the group consisting of NH ₂ -O-R.HCl, wherein R is selected from hydrogen, C ₁ -C ₆ Straight-chain fatty alkyl or C ₁ -C ₆ Further preferred are hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl.

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

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

In another embodiment, the step of reacting the first intermediate product comprises:

s21, reacting the first intermediate product with a halogen simple substance to obtain a second pre-product shown in a formula (6);

s22, reacting the second pre-product to obtain a third pre-product shown in a formula (7);

s23, reacting the third pre-product with an amination agent to obtain the first compound.

The specific reaction process is as follows:

wherein X is ₂ Is a halogen simple substance.

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

Wherein the halogen element is selected from Cl ₂ 、Br ₂ 、I ₂ 。

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

Preferably, in the step of reacting the first intermediate product with the elemental halogen, the reaction temperature is 20 ℃ to 100 ℃, more preferably 40 ℃ to 60 ℃; the time is 2h-5h, more preferably 3h-4h.

Specifically, the mixed solution of the halogen simple substance and the reaction solvent is added into the mixed solution of the first intermediate product and the reaction solvent in batches at the temperature of 40-60 ℃ for reaction for 3-4 hours, and the second pre-product is obtained after the reaction is completed and concentrated, washed and dried.

In step S22, the second pre-product is preferably reacted in the presence of an organic base, the molar ratio of the second pre-product to the organic base being from 1:0.8 to 1:1.5, more preferably from 1:1.0 to 1:1.2.

Wherein 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.

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

Preferably, in the step of reacting the second pre-product, the reaction temperature is from 0 ℃ to 80 ℃, more preferably from 0 ℃ to 50 ℃; the time is 3h-12h, more preferably 4h-8h.

Specifically, the mixed solution of the organic base and the reaction solvent is added into the mixed solution of the second pre-product and the reaction solvent in batches, the reaction is carried out for 3 to 4 hours at the temperature of between 0 and 50 ℃, and the third pre-product is obtained after the reaction is completed, concentrated, crystallized and dried.

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

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

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

Preferably, in the step of reacting the third pre-product with the amination agent, the reaction temperature is from 0 ℃ to 120 ℃, more preferably from 0 ℃ to 50 ℃; the time is 1h-4h, more preferably 2h-3h.

It should be noted that, the first intermediate product may be reacted in various preparation manners to obtain the first compound, which is not limited in the present invention, and those skilled in the art may also use other existing preparation manners.

Therefore, the preparation method of the invention has the advantages that (1) the raw materials are cheap and easy to obtain, and the reaction yield is high; (2) The reaction condition is simple and mild, the operation is simple, and the process is easy to realize; (3) Green, environmental protection, economy and the like, is beneficial to industrialized mass production and downstream product preparation, and can meet the huge demands of terminal drug production.

Hereinafter, the preparation method of the pyridine dicarboximide compound will be further described by the following specific examples.

Example 1

The synthetic route for this example is shown below:

this example is carried out in the following steps:

step S1, preparation of N-benzyl maleimide: 49.03g (0.5 mol) of maleic anhydride was added to a reaction vessel, dissolved in 588.34mL of methylene chloride, 64.29g (0.6 mol) of benzylamine was added, stirred and reacted at a reaction temperature of 5℃for 0.5 hour, followed by 94.60g (0.75 mol) of dimethyl sulfate, 250mL of water, 63.59g (0.6 mol) of sodium carbonate and 3.22g (0.010 mol) of tetrabutylammonium bromide, and stirred and refluxed at a temperature of 40℃for 10 hours. After the reaction is finished, separating liquid, reserving an organic phase, washing twice with 75mL of water, separating the liquid to obtain the organic phase, concentrating the organic phase by rotary evaporation to obtain a crude product, adding 135g of ethanol, heating and dissolving at 60 ℃, placing at 0 ℃, cooling and crystallizing, carrying out suction filtration, and drying at 45 ℃ for 6 hours to obtain 91.81g of N-benzyl maleimide, wherein the yield is 98.13%.

Step S2, preparation of N-benzyl-4-aminomaleimide: into the reaction vessel, 33.36g (0.48 mol, m= 69.49) of hydroxylamine hydrochloride was added, dissolved in 95.3g of water, cooled to 5 ℃, and then 35.20g (0.88 mol) of sodium hydroxide and 140.8g of a sodium hydroxide solution prepared from water were added, followed by stirring at a constant temperature for 0.5 hours. A solution of 74.84g (0.4 mol) of N-benzyl maleimide and 898.14mL of tetrahydrofuran was added thereto, followed by stirring at a constant temperature for 2 hours, heating to 55℃and reacting at a constant temperature for 8 hours. After the reaction, separating the water layer, concentrating the organic phase under reduced pressure, adding 420g of toluene, washing twice with 140g of water, separating the liquid to obtain the organic phase, concentrating the organic phase by rotary evaporation to obtain a crude product, adding 210g of toluene, heating at 60 ℃ for dissolution, placing at 0 ℃, cooling for crystallization, filtering, and drying at 45 ℃ for 6 hours to obtain 76.97g of N-benzyl-4-aminomaleimide, wherein the yield is 95.23%.

Step S3, preparation of N-benzyl-2, 3-pyridine dicarboximide: into the reaction vessel, 40.41g (0.2 mol) of N-benzyl-4-aminomaleimide, 43.25g (0.29 mol) of trimethylbenzoquinone, 13.46g (0.24 mol) of acrolein and 484.97mL of toluene were charged and reacted at 110℃for 6 hours with stirring. After the reaction is completed, the mixture is concentrated under reduced pressure, cooled by ethanol for crystallization, and dried to obtain 45.94g of N-benzyl-2, 3-pyridine dicarboximide, wherein the yield is 96.45%.

Example 2

The synthetic route for this example is shown below:

example 2 differs from example 1 in that:

step S1, 68.12g of 25wt% ammonia (containing 1mol of NH) ₃ ) As a third compound, methylene chloride was added in a volume of 490.30mL, followed by reaction for 2 hours by 115.64g (0.75 mol) of diethyl sulfate, 82.92g (0.6 mol) of potassium carbonate and 3.33g (0.015 mol) of tetrapropylammonium chloride, and then heated to 30℃and stirred for 16 hours. 47.80g of a mixture was obtainedThe yield thereof was found to be 98.51%.

Step S2, hydroxylamine hydrochloride 55.59g (0.8 mol, m= 69.49), add 38.82g (0.4 mol)And 465.80mL of tetrahydrofuran to give 43.05g of +.>The yield thereof was found to be 96.05%.

Step S3, adding 22.41g (0.2 mol)35.15g (0.29 mol) of methylbenzquinone, 16.81g (0.24 mol) of butenone and 179.27mL of diethylene glycol dimethyl ether are reacted under stirring at 130 ℃ for 3h to obtain 30.65g ∈>The yield thereof was found to be 94.58%.

Example 3

The synthetic route for this example is shown below:

example 3 differs from example 1 in that:

step S1, using 72.17g (0.78 mol) aniline as the third compound, wherein the volume of dichloromethane is 735.45mL, adding 136.68g (0.75 mol) dipropyl sulfate and 3.69g (0.010 mol) tetrapropyl ammonium iodide after 2h of reaction, heating to 35 ℃ and stirring for reaction for 12h. 84.34g of a mixture is obtained The yield thereof was found to be 97.48%.

Step S2, hydroxylamine hydrochloride 41.69g (0.6 mol, M= 69.49), 69.22g (0.4 mol) was addedAnd 830.64mL of tetrahydrofuran to give 70.88g of +.>The yield thereof was found to be 94.22%. />

Step S3, adding 37.61g (0.2 mol)71.17g (0.45 mol) of naphthoquinone, 16.82g (0.3 mol) of acrolein and 376.12mL of diethylene glycol diethyl ether are reacted with stirring at 130℃for 5h to give 42.27g of +.>The yield thereof was found to be 94.32%.

Example 4

The synthetic route for this example is shown below:

example 4 differs from example 1 in that:

step S1, 157.72g (0.75 mol) of dibutyl sulfate, 82.92g (0.6 mol) of potassium carbonate and 3.71g (0.01 mol) of ethyl triphenyl phosphorus bromide were added. 91.68g of N-benzylmaleimide are obtained in 98% yield.

Step S2, adding 53.05g (0.48 mol, r is isopropyl, m= 110.531) of NH ₂ O-R.HCl, cooling to 5 ℃, adding aqueous solution of potassium bicarbonate (containing 104.12g and 1.04mol of potassium bicarbonate), and carrying out thermal insulation reaction on 74.84g (0.4 mol) of N-benzyl maleimide and 748.45mL of 1, 4-dioxane configured solution at 65 ℃ for 7 hours to obtain 75.83g of N-benzyl-4-amino maleimide, wherein the yield is 93.82%.

Step S3, adding 23.83g (0.34 mol) of manganese oxide, 16.81g (0.24 mol) of 2-methacrolein, 404.14mL of toluene, obtaining 47.12g The yield thereof was found to be 93.45%.

Example 5

The synthetic route for this example is shown below:

example 5 differs from example 1 in that:

step S1, adding 24g (0.6 mol) of sodium hydroxide. 88.20g of N-benzylmaleimide was obtained in a yield of 94.27%.

Step S2, adding 46.33g (0.48 mol, r is ethyl, m= 96.515) of NH ₂ After cooling to 5 ℃ with O-R.HCl, adding aqueous solution of sodium methoxide (containing 43.22g and 0.8mol of sodium methoxide), adding 748.45mL of tetrahydrofuran, and reacting at 45 ℃ for 12h under heat preservation to obtain 76.08g of N-benzyl-4-aminomaleimide with a yield of 94.13%.

Step S3, adding 16.32g (0.48 mol) of hydrogen peroxide, 20.17g (0.24 mol) of 2-ethylacrolein and 404.14mL of toluene to obtain 49.51gThe yield thereof was found to be 93.02%.

Example 6

The synthetic route for this example is shown below:

example 6 differs from example 1 in that:

step S1, using 47.29g (0.8 mol) of propylamine as the third compound, the volume of methylene chloride was 392.24mL, and 105.05g (0.75 mol) of trimethyl phosphate was added after 1 hour of reaction at 6 ℃. 66.88g of a catalyst was obtainedThe yield thereof was found to be 96.23%.

Step S2, hydroxylamine hydrochloride 50.03g (0.72 mol, M= 69.49), cooling to 5℃and adding sodium tert-butoxide aqueous solution (containing 84.57g, 0.88mol of sodium tert-butoxide) and 55.60g (0.4 mol) And 444.82mL of tetrahydrofuran, and reacting at 50deg.C for 10h to obtain 58.84g +.>The yield thereof was found to be 95.46%.

Step S3, adding 30.82g (0.2 mol)54.76g (0.72 mol) of peracetic acid, 40.02g (0.4 mol) of 2- (methoxymethyl) acrolein and 308.2mL of toluene are reacted with stirring at 100℃for 8h to give 43.48 g->The yield thereof was found to be 93.25%.

Example 7

The synthetic route for this example is shown below:

example 7 differs from example 1 in that:

step S1, using 52.55g (0.7 mol) of 2- (aminooxy) propane (CAS: 4427-29-6) as the third compound, the volume of methylene chloride was 490.3mL, and 129.15g (0.75 mol) of p-toluenesulfonic acid, 82.92g (0.60 mol) of potassium carbonate and 2.78g (0.01 mol) of tetrabutylammonium chloride were added after 1.5 hours of reaction at 8 ℃. 74.31g of a mixture is obtainedThe yield thereof was found to be 95.84%.

Step S2, hydroxylamine hydrochloride of 44.47g (0.64 mol, M= 69.49), cooling to 5℃and adding an aqueous potassium carbonate solution (containing 121.62g, 0.88mol of potassium carbonate) to 62.03g (0.4 mol)And 992.49mL of toluene, and reacting at 70deg.C for 6h64.07 g->The yield thereof was found to be 94.17%.

Step S3, adding 34.02g (0.2 mol)222.47g (0.96 mol) of silver oxide, 58.88g (0.6 mol) of 4-methyl-2-pentenal, 408.22mL of dipropylene glycol dimethyl ether were reacted with stirring, and reacted at 160℃for 10 hours to obtain 39.76g of- >The yield thereof was found to be 93.72%.

Example 8

This example differs from the synthetic route of step S2 in example 1 in that:

step S2, preparation of 1-benzyl-3, 4-dibromo-pyrrolidine-2, 5-dione: 74.84g (0.4 mol) of N-benzyl maleimide was added to the reaction vessel, dissolved in 898.14mL of methylene chloride, and a mixed solution of 75.76g (0.48 mol) of bromine and 100mL of methylene chloride was added dropwise, followed by stirring at room temperature, and after the completion of the dropwise addition, the temperature was raised to 40℃and the reaction was refluxed for 2.5 hours. After the reaction is completed, the mixture is decompressed, washed by methylene dichloride and then concentrated under reduced pressure, and the crude product is obtained after drying, wherein 134g of 1-benzyl-3, 4-dibromo-pyrrolidine-2, 5-dione is contained, and the yield is 97.13%.

Preparation of N-benzyl-4-bromomaleimide: 68.98g (0.2 mol) of 1-benzyl-3, 4-dibromo-pyrrolidine-2, 5-dione are added into a reaction vessel, dissolved in 413.88mL of tetrahydrobarking, and a mixed solution of 20.24g (0.2 mol) of triethylamine and 100mL of tetrahydrobarking is added dropwise for reaction, the reaction temperature is controlled to be 20 ℃, and after the dropwise addition, the reaction is carried out, the reaction vessel is transferred to room temperature and reacted for 4 hours. After the reaction is completed, suction filtration is carried out, the filtrate is concentrated under reduced pressure, ethanol is used for cooling crystallization, and 50.67g of N-benzyl-4-bromomaleimide is obtained after drying, and the yield is 95.61%.

Preparation of N-benzyl-4-aminomaleimide: 39.75g (0.15 mol) of N-benzyl-4-bromomaleimide was added to the reaction vessel, dissolved in 476.95mL of tetrahydrobarking, and then the reaction vessel was stirred at 20℃under a pressure of 0.25MPa with ammonia gas being introduced, and the reaction was carried out for 1.5 hours. Decompression after the reaction is completed, suction filtration, decompression concentration of filtrate, cooling crystallization by using methylene dichloride, and drying to obtain 28.58g of N-benzyl-4-amino maleimide, wherein the yield is 94.28%.

Example 9

This example differs from the synthetic route of step S2 in example 2 in that:

step S2, 38.82g (0.4 mol) of the mixture was introduced into the reaction vesselA mixed solution of 75.76g (0.48 mol) of bromine and 100mL of dichloromethane was added dropwise to 310.53mL of dichloromethane, and the mixture was stirred at room temperature, and the mixture was heated to 40℃and reacted under reflux for 5 hours. After the reaction is completed, the pressure is reduced, the mixture is washed by methylene dichloride and then concentrated under reduced pressure, and the crude product is obtained after drying, and the crude product contains 96.57g of ∈>The yield thereof was found to be 94%.

51.37g (0.2 mol) of the catalyst were introduced into a reaction vesselTo 154.10mL of tetrahydrofuran was added dropwise a mixed solution of 18.98g (0.24 mol) of pyridine and 100mL of tetrahydrofuran, and the mixture was stirred to react at 20℃until the completion of the addition, and then the mixture was transferred to room temperature and reacted for 8 hours. Filtering after the reaction is completed, concentrating the filtrate under reduced pressure, cooling and crystallizing with ethanol, and drying to obtain 57.06g of ∈ >Yield is good94.74%.

Into the reaction vessel was charged 37.64g (0.15 mol)Dissolving in 301.15mL tetrahydrobarking, charging ammonia gas, controlling the pressure of the reactor to be 0.25MPa, stirring for reaction, and reacting at 20 ℃ for 1.5h. Decompression after the reaction is completed, suction filtration, decompression concentration of filtrate, cooling crystallization by using dichloromethane, and drying to obtain 15.75g of ∈>The yield thereof was found to be 93.71%.

Example 10

This example differs from the synthetic route of step S2 in example 3 in that:

/>

step S2, 69.22g (0.4 mol) of the catalyst was charged into the reaction vesselDissolving in 692.20mL of carbon tetrachloride, dropwise adding a mixed solution of 75.76g (0.48 mol) of bromine and 100mL of carbon tetrachloride, stirring at room temperature, and heating to 60 ℃ for reaction for 2.5h after the completion of dropwise adding. After the reaction is completed, the pressure is reduced, the crude product is obtained by washing with carbon tetrachloride, then concentrating under reduced pressure and drying, and 128.18g of the crude product is contained>The yield thereof was found to be 96.27%.

66.57g (0.2 mol) of the catalyst were introduced into the reaction vesselTo 266.30mL of 1, 4-dioxane was added dropwise a mixed solution of 9.46g (0.16 mol) of isopropylamine and 50mL of 1, 4-dioxane, and the mixture was stirred to react at 40℃until the addition was completed, and then the mixture was transferred to room temperature and reacted for 4 hours. Filtering after the reaction is completed, and subtracting filtrate Concentrating under pressure, cooling with ethanol for crystallization, and drying to obtain 38.41g of herba Cistanchis>The yield thereof was found to be 95.28%.

37.79g (0.15 mol) of the catalyst were charged into the reaction vesselDissolving in 377.94mL of 1, 4-dioxane, filling ammonia gas, controlling the pressure of a reactor to be 0.25MPa, stirring for reaction, and reacting at 35 ℃ for 1.5h. Decompression after the reaction is completed, suction filtration, decompression concentration of filtrate, cooling crystallization by using dichloromethane and drying to obtain 26.61gThe yield thereof was found to be 94.32%.

Example 11

This example differs from the synthetic route of step S2 in example 4 in that:

step S2, 74.84g (0.4 mol) of N-benzyl maleimide is added into a reaction vessel, dissolved in 898.14mL of dichloromethane, and a mixed solution of 45.38g (0.64 mol) of chlorine and 100mL of dichloromethane is added dropwise, stirred at room temperature, and after the dropwise addition, the temperature is raised to 40 ℃ for reflux reaction for 2.5h. After the reaction is completed, the mixture is decompressed, washed by methylene dichloride and then concentrated under reduced pressure, and the crude product is obtained after drying, wherein 98.48g of 1-benzyl-3, 4-dichloro-pyrrolidine-2, 5-dione is contained, and the yield is 95.43 percent.

51.60g (0.2 mol) of 1-benzyl-3, 4-dichloro-pyrrolidine-2, 5-dione, dissolved in 309.58mL of tetrahydrobarking, was added dropwise to a mixture of 20.24g (0.2 mol) of triethylamine and 100mL of tetrahydrobarking, and the mixture was stirred to react at 20℃until the addition was completed, and the reaction temperature was allowed to reach room temperature and then allowed to react for 4 hours. After the reaction is completed, suction filtration is carried out, the filtrate is concentrated under reduced pressure, ethanol is used for cooling crystallization, and 42.59g of N-benzyl-4-chloromaleimide is obtained after drying, and the yield is 96.14%.

33.23g (0.15 mol) of N-benzyl-4-chloromaleimide was added to the reaction vessel, dissolved in 398.74mL of tetrahydrobarking, and then the reaction vessel was stirred and reacted at 20℃for 1 hour under a pressure of 0.35MPa by charging ammonia gas. Decompression after the reaction is completed, suction filtration, decompression concentration of filtrate, cooling crystallization by using dichloromethane, and drying to obtain 28.91g of N-benzyl-4-aminomaleimide, wherein the yield is 95.38%.

Example 12

This example differs from the synthetic route of step S2 in example 5 in that:

step S2, 74.84g (0.4 mol) of N-benzyl maleimide is added into a reaction vessel, dissolved in 898.14mL of dichloromethane, and a mixed solution of 75.76g (0.48 mol) of bromine and 100mL of dichloromethane is added dropwise, stirred at room temperature, and after the dropwise addition, the temperature is raised to 40 ℃ for reflux reaction for 2h. After the reaction is completed, the mixture is decompressed, washed by methylene dichloride and then concentrated under reduced pressure, and dried to obtain a crude product, wherein 135.49g of 1-benzyl-3, 4-dibromo-pyrrolidine-2, 5-dione is contained, and the yield is 97.65%.

69.38g (0.2 mol) of 1-benzyl-3, 4-dibromo-pyrrolidine-2, 5-dione, dissolved in 416.26mL of tetrahydrobarking, was added dropwise to a mixture of 18.63g (0.2 mol) of 2-methylpyridine and 100mL of tetrahydrobarking, and the mixture was stirred to react at 20℃until the completion of the dropwise addition, and then transferred to room temperature to react for 3 hours. After the reaction is completed, suction filtration is carried out, the filtrate is concentrated under reduced pressure, cooled and crystallized by ethanol, and 48.85g of N-benzyl-4-bromomaleimide is obtained after drying, and the yield is 92.18 percent.

39.75g (0.15 mol) of N-benzyl-4-bromomaleimide was added to a reaction vessel, dissolved in 476.95mL of tetrahydrobarking, and 81.75g of 25wt% aqueous ammonia (containing 1.2mol of NH) ₃ ) The reaction was stirred at 20℃for 3h. Decompression, suction filtering, decompression concentration of filtrate, cooling with dichloromethane to crystallize, and drying to obtain 28.03g N-benzyl-4-aminomaleimide in a yield of 92.46%.

Example 13

This example differs from the synthetic route of step S2 in example 6 in that:

step S2, 55.6g (0.4 mol) of the catalyst was charged into the reaction vesselIn 889.64mL of carbon tetrachloride, 101.52g (0.4 mol) of a mixed solution of iodine and 100mL of carbon tetrachloride was added dropwise, and the mixture was stirred at room temperature, and the temperature was raised to 55℃after the completion of the addition, and the reaction was carried out for 3 hours. After the reaction is completed, the pressure is reduced, the crude product is obtained by washing with carbon tetrachloride, then concentrating under reduced pressure and drying, and 244.78g of the crude product is contained>The yield thereof was found to be 94.63%.

129.34g (0.2 mol) of the catalyst were charged into the reaction vesselDissolving in 776.01mL of 1, 4-dioxane, dropwise adding 25.78g (0.26 mol) of a mixed solution of cyclohexane and 125mL of 1, 4-dioxane, stirring for reaction, controlling the reaction temperature at 35 ℃, transferring to room temperature after the dropwise adding is completed, and reacting for 6 hours. Filtering after the reaction is completed, concentrating the filtrate under reduced pressure, cooling and crystallizing with ethanol, and drying to obtain 93.8g of ∈ >The yield thereof was found to be 92.06%.

58.78g (0.15 mol) of a catalyst were introduced into the reaction vesselInto 587.8mL of 1, 4-dioxane, 94.62g of 18wt% ammonia (containing 0.75mol of NH) ₃ ) Stirring for reaction at 35 deg.C3h. Decompression after the reaction is completed, suction filtration, decompression concentration of filtrate, cooling crystallization by using dichloromethane, and drying to obtain 21.2gThe yield thereof was found to be 91.71%. />

Example 14

This example differs from the synthetic route of step S2 in example 7 in that:

step S2, 62.03g (0.4 mol) of the catalyst was charged into the reaction vesselA mixed solution of 51.05g (0.72 mol) of chlorohydrin and 100mL of 1, 2-dichloroethane was dissolved in 992.49mL of 1, 2-dichloroethane, and the mixture was stirred at room temperature, and the temperature was raised to 80℃after the completion of the dropwise addition, and the reaction was carried out for 2 hours. After the reaction is completed, the pressure is reduced, the mixture is washed by 1, 2-dichloroethane and then concentrated under reduced pressure, and the crude product is obtained after drying, and 84.41g of the crude product is contained>The yield thereof was found to be 93.38%.

45.2g (0.2 mol) of the catalyst were charged into the reaction vesselA mixed solution of 23.73g (0.3 mol) of pyridine and 125mL of 1, 2-dichloroethane was added dropwise to 361.57mL of 1, 2-dichloroethane, the reaction was stirred and carried out at a reaction temperature of 50℃and the mixture was transferred to room temperature after the completion of the dropwise addition and reacted for 3 hours. Filtering after the reaction is completed, concentrating the filtrate under reduced pressure, cooling and crystallizing with ethanol, and drying to obtain 54.7g of ∈ >The yield thereof was found to be 96.21%.

28.43g (0.15 mol) of the catalyst were charged into the reaction vesselDissolving in 454.85mL of 1, 2-dichloroethane, charging ammonia gas, controlling the pressure of the reactor to be 0.4MPa, stirring for reaction, and reacting at 50 ℃ for 1.5h. Decompression after the reaction is completed, suction filtration, decompression concentration of filtrate, cooling crystallization by using dichloromethane, and drying to obtain 23.87g of ∈>The yield thereof was found to be 93.56%.

Example 15

This example differs from the synthetic route of steps S1-S2 in example 2 in that:

into the reaction vessel, 20g (0.206 mol) of maleimide was added and dissolved in 200mL of methylene chloride, and a mixed solution of 40.65g (0.256 mol) of bromine and 100mL of methylene chloride was added dropwise. Heating and refluxing the reaction mixture for 2.5h, standing and cooling to room temperature for 1h, and removing the solvent by reduced pressure distillation to obtain a crude product of 2, 3-dibromomaleimide; this was dissolved in 200mL of tetrahydrofuran solvent, and a mixed solution of 20.85g (0.206 mol) of triethylamine and 100mL of tetrahydrofuran was added at 0℃for 15 min. Then the reaction mixture was heated to room temperature, stirred and reacted for 18 hours, the solid was removed by filtration, the solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography to obtain 30.72g of 3-bromo-1H-pyrrole-2, 5-dione with a yield of 84.73%.

To 100mL of tetrahydrofuran were added 20g (0.114 mol) of 3-bromo-1H-pyrrole-2, 5-dione and 44.33g (0.682 mol) of sodium azide, and the reaction was stirred at room temperature for 3 hours. Then 400mL of water was added to the reaction mixture and thoroughly mixed, the dichloromethane was used for extraction, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to give 10.09g of azide in 64.31%.

In a reaction vessel, 9.6g (0.07 mol) of azide, 200mL of ethanol and 2.24g of 10wt% Pd/C catalyst were added, and after the successive replacement with nitrogen and hydrogen, the mixture was subjected to a pressure of 2MPa at room temperatureThe reaction was carried out for 4 hours. After the reaction, filtering to remove Pd/C catalyst, and removing solvent under reduced pressure to obtain 7.2gThe yield thereof was found to be 92.43%.

The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.

The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (17)

1. A method for preparing a pyridine dicarboximide compound, comprising the steps of:

reacting a first compound represented by the formula (2) with a second compound represented by the formula (3) to obtain a dipicolinate compound represented by the formula (4), wherein R ₁ 、R ₂ 、R ₃ 、R ₄ Are independently selected from hydrogen, C ₁ -C ₆ Straight-chain fatty alkyl, C ₁ -C ₆ Branched fatty alkyl, C ₁ -C ₆ Alkoxy or C of (C) ₆ -C ₁₀ An aromatic group of (a);

2. the method for producing a pyridine dicarboximide compound according to claim 1, wherein the molar ratio of the first compound to the second compound is 1:1.2 to 1:3.0;

and/or R ₁ 、R ₂ 、R ₃ 、R ₄ 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.

3. The method for producing a pyridine dicarboximide compound according to claim 1 or 2, wherein the first compound and the second compound are reacted in the presence of an oxidizing agent, and the molar ratio of the first compound to the oxidizing agent is 1:1.2 to 1:2.0.

4. A method for producing a pyridine dicarboximide compound according to claim 3, wherein in the step of reacting the first compound with the second compound in the presence of an oxidizing agent, the temperature is 60 ℃ to 160 ℃ for 1h to 10h;

and/or the oxidizing agent is selected from transition metal oxides, peroxides or quinone compounds.

5. The method for producing a dipicolinimide compound according to claim 1, wherein the method for producing the first compound comprises the steps of:

maleic anhydride and the structural formula is R ₁ -NH ₂ The third compound of formula (1) is reacted to obtain a first intermediate product represented by formula (1), wherein R ₁ Selected from hydrogen, C ₁ -C ₆ Straight-chain fatty alkyl, C ₁ -C ₆ Branched fatty alkyl, C ₁ -C ₆ Alkoxy or C of (C) ₆ -C ₁₀ An aromatic group of (a);

reacting the first intermediate product to obtain a first compound;

6. the method for producing a dipicolinate compound according to claim 5, wherein the molar ratio of the third compound to the maleic anhydride is 1.2:1-2.0:1.

7. The method for producing a dipicolinimide compound according to claim 5 or 6, wherein the step of reacting maleic anhydride with the third compound comprises: reacting the maleic anhydride with the third compound to obtain a first pre-product shown in a formula (5), then reacting the first pre-product in the presence of an alkylating agent, an alkaline aqueous solution and a phase transfer catalyst to obtain a first intermediate product shown in a formula (1),

8. The method for producing a pyridine dicarboxylic monoimide compound according to claim 7, wherein the molar ratio of said alkylating agent, said solute in said aqueous alkali solution, said phase transfer catalyst to said maleic anhydride is (1.2-2.0): 0.01-0.08): 1;

and/or the phase transfer catalyst is selected from quaternary ammonium salt phase transfer catalyst or quaternary phosphonium salt phase transfer catalyst, 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 arylsulfonate and trialkyl phosphate.

9. The method for producing a dipicolinate compound according to claim 7, wherein in the step of reacting the maleic anhydride with the third compound, the temperature is 0 ℃ to 10 ℃ for 0.5h to 2h;

and/or, in the step of reacting the first pre-product in the presence of an alkylating agent, an alkaline aqueous solution and a phase transfer catalyst, the temperature is 25-55 ℃ and the time is 10-16 h.

10. The method for producing a dipicolinate compound according to claim 5, wherein the step of reacting the first intermediate product comprises: 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.

11. The method for producing a pyridine dicarboximide compound according to claim 10, wherein in the step of reacting the first intermediate with a hydroxylamine reagent under alkaline conditions, the temperature is 45 to 70 ℃ for 6 to 12 hours;

and/or the hydroxylamine reagent is selected from NH ₂ -O-r.hcl, wherein R is selected from H, C ₁ -C ₆ Straight-chain fatty alkyl or C ₁ -C ₆ Branched fatty alkyl groups of (a);

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

12. The method for producing a dipicolinate compound according to claim 5, wherein the step of reacting the first intermediate product comprises:

reacting the first intermediate product with a halogen simple substance to obtain a second pre-product shown in a formula (6);

reacting the second pre-product to obtain a third pre-product shown in a formula (7);

reacting the third pre-product with an amination agent to obtain the first compound;

wherein X is selected from halogen elements.

13. The method for producing a pyridine dicarboximide compound according to claim 12, wherein the molar ratio of the first intermediate to the elemental halogen is 1:1.0 to 1:2.0;

And/or the halogen simple substance is selected from Cl ₂ 、Br ₂ 、I ₂ 。

14. The method for producing a pyridine dicarboximide compound according to claim 12, wherein the second pre-product is reacted in the presence of an organic base, and the molar ratio of the second pre-product to the organic base is 1:0.8 to 1:1.5, wherein the organic base is selected from amines and pyridines.

15. The method for producing a dipicolinimide compound according to claim 12, wherein the amination agent is selected from ammonia gas or aqueous ammonia.

16. The method for producing a dipicolinimide compound according to claim 15, wherein the amination agent is selected from ammonia gas having a pressure of 0.1MPa to 1.0MPa;

or the amination agent is selected from ammonia water, the concentration of the ammonia water is 18-25 wt%, and the molar ratio of the third pre-product to the ammonia in the ammonia water is 1:3-1:15.

17. The method for producing a dipicolinate compound according to claim 12, wherein in the step of reacting the first intermediate with a halogen element, the temperature is 20 ℃ to 100 ℃ for 2h to 5h;

and/or, in the step of reacting the second pre-product, the temperature is 0-80 ℃ and the time is 3-12 h;

And/or, in the step of reacting the third pre-product with an amination agent, the temperature is 0-120 ℃ and the time is 1-4 h.