Method for synthesizing itaconic acid compound

Abstract

The invention discloses a method for synthesizing an itaconic acid compound, which comprises the following steps of: directly using an allyl ester compound as a raw material, selecting an oxalic acid compound or an amine oxalate compound as an acylation reagent, using triphenylphosphine as an additive, and synthesizing the itaconic acid compound by using metal-free 3, 6, 7, 8-trimethyl-1, 3-pentanediol. The preparation method comprises the following steps: by taking 2, 3-di-tert-butyl-9-mesityl-10-phenyacridine-10-tetrafluoroborate as a photooxidation reduction catalyst, respectively generating corresponding acyl free radicals and allyl free radicals under the catalysis of an organic photooxidation reduction agent, and finally obtaining the itaconic acid compound through a free radical cross-coupling way. The method disclosed by the invention is wide in applicable substrate range, low in preparation cost and simple in steps, and has the characteristics of convenience in operation, environment friendliness, excellent stereoselectivity and broad-spectrum functional group tolerance.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and in particular relates to a method for synthesizing itaconic acid compounds. Background Art

[0002] With the progress of immunometabolism research, more and more evidence shows that metabolic changes can profoundly affect the immune function of macrophages. The tricarboxylic acid cycle is the core metabolic pathway of cells. Itaconic acid, a byproduct of the tricarboxylic acid cycle, is an emerging metabolic small molecule that can regulate the inflammatory response of macrophages and has attracted much attention in recent years due to its powerful anti-inflammatory effect. Itaconic acid regulates the function of macrophages through multiple mechanisms and shows good therapeutic potential in a variety of immune and inflammatory diseases.

[0003] Therefore, from both environmental and economic perspectives, developing green synthetic methods for itaconic acid analogs using nontoxic, inexpensive, readily available, and relatively environmentally benign raw materials, especially synthetic methods compatible with bioactive molecules, to access these specific groups has important appeal in contemporary chemical biology. Summary of the invention

[0004] In order to overcome the shortcomings and deficiencies of the prior art, the primary purpose of the present invention is to provide a method for synthesizing itaconic acid compounds.

[0005] The present invention is achieved by providing a method for synthesizing itaconic acid compounds, the method comprising the following steps:

[0006] (1) adding an allyl ester compound, an acylating agent, a photoredox catalyst, and an additive to a reaction solvent in sequence, stirring and reacting for 30 minutes under an inert gas atmosphere, blue light irradiation, and room temperature to obtain a reaction solution; wherein the chemical structure of the allyl ester compound is shown in the following formula:

[0007]

[0008] The chemical structural formula of the acylating agent is shown below:

[0009]

[0010] (2) removing the reaction solvent from the reaction solution, and then purifying by thin layer chromatography to obtain an itaconic acid compound;

[0011] The chemical structural formula of the itaconic acid compound is shown in the following formula (I):

[0012]

[0013] Among them, R 1Any one selected from hydrogen, alkoxy, alkyl, trifluoromethyl, fused aryl, heteroaryl, aliphatic amine, and aromatic amine;

[0014] R 2 Any one selected from hydrogen, methoxy, cyano, nitro, tert-butyl, fluoro, bromo, chloro, ferrocenyl, trimethylsilylethynyl, fused aryl, heteroaryl, cycloalkyl, and linear alkyl.

[0015] Specifically, the allyl ester compound is selected from 2-acetoxy(phenyl)methyl methacrylate, 2-acetoxy(4-fluorobenzene)methyl methacrylate, 2-acetoxy(3-fluorobenzene)methyl methacrylate, 2-acetoxy(2-fluorobenzene)methyl methacrylate, 2-acetoxy(4-chlorobenzene)methyl methacrylate, 2-acetoxy(3-chlorobenzene)methyl methacrylate, 2-acetoxy(2-chlorobenzene)methyl methacrylate, 2-acetoxy(4-bromobenzene)methyl methacrylate, 2-acetoxy(3-bromobenzene)methyl methacrylate, 2-acetoxy(4-nitrobenzene)methyl methacrylate, 2-acetoxy any one of methyl (4-cyanobenzene) methacrylate, methyl 2-acetoxy (4-methoxybenzene) methacrylate, methyl 2-acetoxy (4-tert-butylbenzene) methacrylate, methyl 2-acetoxy (4-formylphenyl) methacrylate, methyl 2-acetoxy (naphthalen-1-yl) methacrylate, methyl 2-acetoxy (furan-2-yl) methacrylate, ethyl 2-acetoxy (phenyl) methacrylate, 2-cyano-1-phenyl allyl acetate, 2-acetoxy-(2,4-dichlorophenyl) methacrylate menthyl ester, and cholesteryl 2-acetoxy-(2,4-dichlorophenyl) methacrylate;

[0016] The acylating agent is an oxalic acid compound and an oxalic acid amine compound, selected from 2-oxo-2-phenylacetic acid, 2-(4-fluorophenyl)-2-oxoacetic acid, 2-(4-chlorophenyl)-2-oxoacetic acid, 2-(4-bromophenyl)-2-oxoacetic acid, 2-(4-iodophenyl)-2-oxoacetic acid, 2-(2,4,6-trimethylphenyl)-2-oxoacetic acid, 2-oxobutyric acid, 2-oxopentanoic acid, 2-oxo-2-(thiophen-2-yl)acetic acid, 2-oxo-2-(furan-2-yl)acetic acid, 2-oxo-2-(phenylamino)acetic acid, 2-(cyclopentylamino)-2-oxoacetic acid, 2-(cyclohexylamino)-2-oxoacetic acid, 2-(tert-butylamino)-2-oxoacetic acid, 2-(benzylamino)-2-oxoacetic acid, 2-((2,2-difluoroethyl)amino)-2-oxoacetic acid acetic acid, 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetic acid, 2-(adamantylamino)-2-oxoacetic acid, 2-(dehydroabietinamino)-2-oxoacetic acid, 2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoacetic acid, (S)-2-((1-methoxy-1-oxopropane-2-yl)amino)-2-oxoethyl acid, (S)-4-isobutyl-3,6,9,12-tetraoxo-2-oxa-5,8,11-triazatridecane-13-oleic acid, (4S,7S,16S)-7-benzyl-4-isobutyl-16-(4-methoxybenzyl)-3,6,9,12,15,18-hexaoxo-2-oxa-5,8,11,14,17-pentaazanonadeca-19-oleic acid.

[0017] Preferably, the heteroaryl group is, for example, furyl or thienyl; and the cycloalkyl group is cyclohexyl.

[0018] Preferably, in step (1), the molar volume ratio of the allyl ester, the acylating agent, 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, the additive and the reaction solvent is (0.2-0.) mmol: (0.24-0.48) mmol: (0.01-0.02) mmol: (0.04-0.08) mmol: (2-4) mL.

[0019] Preferably, in step (1), the inert gas is argon; in step (2), the purified developing agent system is petroleum ether / ethyl acetate = 5:1.

[0020] Preferably, in step (1), the reaction solvent is selected from any one of toluene, xylene, dichloromethane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane and isopropanol.

[0021] Preferably, in step (1), the additive is selected from any one of triphenylphosphine, tri(4-methoxyphenyl)phosphine, 4-dimethylaminopyridine, triethylamine and triethylenediamine.

[0022] Preferably, in step (1), the photoredox catalyst is 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate.

[0023] The present invention overcomes the deficiencies of the prior art and provides a method for synthesizing itaconic acid compounds. The present invention directly uses an allyl ester compound as a raw material, selects an oxalic acid compound as an acylating agent, uses triphenylphosphine as an additive, and metal-free 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate as a photoredox catalyst. Under the catalysis of the organic photoredox agent, corresponding acyl radicals and allyl radicals are generated respectively, so that the reaction occurs in an environmentally friendly manner under mild conditions. The reaction process is as follows:

[0024]

[0025] Compared with the shortcomings and deficiencies of the prior art, the present invention has the following beneficial effects:

[0026] (1) The allyl ester used in the preparation method of the present invention is a simple esterification raw material of MoritA-Baylis-Hillman alcohol allyl alcohol, which is simple to synthesize and has a high conversion rate. It has a wide range of applicable substrates, such as various substituted phenyl groups and alkyl groups on the allyl ester, and has the characteristics of low preparation cost. In addition, the preparation method of the present invention has simple steps, is easy to operate, is green and environmentally friendly, has excellent stereoselectivity, and can tolerate a wide spectrum of functional groups.

[0027] (2) The itaconic acid compounds synthesized by the method of the present invention are universal precursors for preparing related carbonyl molecules, have potential pharmaceutical activity and biological activity, and can provide a new approach for the synthesis and application of biologically and pharmaceutically active molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the compound (E)-2-benzylidene-4-oxo-4-phenylbutyrate in Example 1 of the present invention;

[0029] Figure 2 is the carbon nuclear magnetic resonance spectrum of the compound (E)-2-benzylidene-4-oxo-4-phenylbutyric acid methyl ester in Example 1 of the present invention; DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0031] Example 1

[0032] (1) In a 10 mL Shrek tube, under argon atmosphere, 0.4 mmol 2-acetoxy(phenyl)methyl methacrylate, 0.48 mmol 2-oxo-2-phenylacetic acid, 0.02 mmol 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, and 0.08 mmol triphenylphosphine were added to 4 mL acetonitrile, and stirred under argon atmosphere, room temperature, and 54 W blue light to react. The reaction equation is:

[0033]

[0034] (2) After the reaction was completed as monitored by TLC, the solvent was removed by vacuum rotary evaporator and the product was separated by thin layer chromatography. The developing solvent was petroleum ether / ethyl acetate system (5:1). The product was a colorless transparent liquid compound (E)-2-benzylidene-4-oxo-4-phenylbutyric acid methyl ester (Compound 1) with a yield of 94%.

[0035] The compound (E)-2-benzylidene-4-oxo-4-phenylbutyric acid methyl ester was characterized. Figures 1-2 As shown, Figure 1 is the H NMR spectrum of methyl (E)-2-benzylidene-4-oxo-4-phenylbutyrate; Figure 2 This is the carbon NMR spectrum of methyl (E)-2-benzylidene-4-oxo-4-phenylbutyrate.

[0036] Example 2

[0037] (1) In a 10 mL Shrek tube, under argon atmosphere, 0.4 mmol 2-acetoxy (4-formylphenyl) methyl methacrylate, 0.48 mmol 2-oxo-2-phenylacetic acid, 0.02 mmol 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, and 0.08 mmol triphenylphosphine were added to 4 mL acetonitrile, and stirred under argon atmosphere, room temperature, and 54 W blue light to react. The reaction equation is:

[0038]

[0039] (2) After the reaction was completed as monitored by TLC, the solvent was removed by vacuum rotary evaporator and the product was separated by thin layer chromatography. The developing solvent was petroleum ether / ethyl acetate system (5:1). The product was a yellow solid (E)-2-(4-formylbenzylidene)-4-oxo-4-phenylbutyric acid methyl ester with a yield of 92%.

[0040] Example 3

[0041] (1) At room temperature, menthol is added to a dichloromethane solution, triethylamine is added at 0°C, and the mixture is stirred for 0.5 h. Then, a dichloromethane solution of acryloyl chloride is dropped into the above reaction solution at 0°C, and the mixture is stirred at room temperature for 12 h to obtain a reaction mixture; wherein the molar ratio of menthol, triethylamine, and acryloyl chloride is 1:2:1; and the reaction equation is:

[0042]

[0043] (2) The reaction mixture was quenched by adding saturated ammonium chloride solution, extracted with ether three times, the organic phases were combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the product was separated by column silica gel chromatography. The developing solvent was a petroleum ether / ethyl acetate system (80:1). The product was a colorless liquid menthyl acrylate with a yield of 93%.

[0044] (3) Dissolving 2,4-dichlorobenzaldehyde, menthyl acrylate, and triethylenediamine in tetrahydrofuran at room temperature, and stirring at room temperature for 1 week to obtain a reaction mixture; wherein the molar ratio of 2,4-dichlorobenzaldehyde, menthyl acrylate, and triethylenediamine is 1:1.2:0.5; and the reaction equation is:

[0045]

[0046] (4) The reaction mixture was purified by column silica gel chromatography using petroleum ether and ethyl acetate (PE / EA=30 / 1) to obtain colorless liquid 2-hydroxy-(2,4-dichlorophenyl) methacrylate with a yield of 89%.

[0047] (5) At room temperature, 2-hydroxy-(2,4-dichlorophenyl) methacrylate, acetic anhydride, and 4-dimethylaminopyridine are mixed and stirred at room temperature for 1 hour to obtain a reaction mixture; wherein the molar ratio of 2-hydroxy-(2,4-dichlorophenyl) methacrylate, acetic anhydride, and 4-dimethylaminopyridine is 1:2:0.2

[0048]

[0049] (6) The reaction mixture was purified by column silica gel chromatography using petroleum ether and ethyl acetate (PE / EA=1 / 1) to obtain white solid 2-acetoxy-(2,4-dichlorophenyl) methacrylate menthyl ester in a yield of 85%.

[0050] (7) Synthesis of itaconic acid compounds

[0051] In a 10 mL Shrek tube, under argon atmosphere, 0.4 mmol 2-acetoxy (2,4-dichlorophenyl) methacrylate, 0.48 mmol 2-oxo-2-phenylacetic acid, 0.02 mmol 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, and 0.08 mmol triphenylphosphine were added to 4 mL acetonitrile, and stirred under argon atmosphere, room temperature, and 54 W blue light irradiation to react. The reaction equation is:

[0052]

[0053] (8) After the reaction was completed as monitored by TLC, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography. The developing solvent was a petroleum ether / ethyl acetate system (5:1). The product was a colorless transparent liquid compound (E)-2-benzylidene-4-oxo-4-phenylbutyric acid diacetone menthol ester with a yield of 90%.

[0054] Example 4

[0055] (1) At room temperature, diacetone galactose is added to a dichloromethane solution, triethylamine is added at 0°C, and the mixture is stirred for 0.5 h. Then, a dichloromethane solution of acryloyl chloride is dropped into the above reaction solution at 0°C, and the mixture is stirred at room temperature for 12 h to obtain a reaction mixture; wherein the molar ratio of diacetone galactose, triethylamine, and acryloyl chloride is 1:2:1; and the reaction equation is:

[0056]

[0057] (2) The reaction mixture was quenched by adding a saturated ammonium chloride solution, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the product was separated by column silica gel chromatography using a petroleum ether / ethyl acetate system (80:1) as the developing solvent to obtain white solid diacetone galactose acrylate with a yield of 87%.

[0058] (3) dissolving 2,4-dichlorobenzaldehyde, diacetone galactose acrylate, and triethylenediamine in tetrahydrofuran at room temperature, and stirring at room temperature for 1 week to obtain a reaction mixture; wherein the molar ratio of the 2,4-dichlorobenzaldehyde, diacetone galactose acrylate, and triethylenediamine is 1:1.2:0.5;

[0059]

[0060] (4) The reaction mixture was decompressed to remove the solvent, and the residue was purified by column silica gel chromatography using petroleum ether and ethyl acetate (PE / EA=30 / 1) to obtain white solid 2-hydroxy-(2,4-dichlorophenyl) methacrylate diacetone galactose ester in a yield of 94%.

[0061] (5) At room temperature, 2-hydroxy-(2,4-dichlorophenyl) methacrylate diacetone galactose ester, acetic anhydride, and 4-dimethylaminopyridine are mixed and stirred at room temperature for 1 hour to obtain a reaction mixture; wherein the molar ratio of 2-hydroxy-(2,4-dichlorophenyl) methacrylate diacetone galactose ester, acetic anhydride, and 4-dimethylaminopyridine is 1:2:0.2

[0062]

[0063] (6) The reaction mixture was purified by column silica gel chromatography using petroleum ether and ethyl acetate (PE / EA=30 / 1) to obtain colorless liquid 2-acetoxy-(2,4-dichlorophenyl) methacrylate diacetone galactose ester with a yield of 85%.

[0064] (7) Synthesis of itaconic acid compounds

[0065] In a 10mL Shrek tube, under argon atmosphere, 0.4mmol 2-acetoxy (2,4-dichlorophenyl) methacrylate diacetone galactose ester, 0.48mmol 2-oxo-2-phenylacetic acid, 0.02mmol 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, 0.08mmol triphenylphosphine were added to 4mL acetonitrile, and stirred under argon atmosphere, room temperature and 54w blue light irradiation to react. The reaction equation is:

[0066]

[0067] (8) After the reaction was completed as monitored by TLC, the solvent was removed by vacuum rotary evaporator, and the product was separated by thin layer chromatography. The developing solvent was petroleum ether / ethyl acetate system (9:1). The product was a colorless transparent liquid compound (E)-2-benzylidene-4-oxo-4-phenylbutyric acid diacetone galactose ester with a yield of 85%.

[0068] Example 5

[0069] (1) Cholesterol was added to a dichloromethane solution at room temperature, triethylamine was added at 0°C, and the mixture was stirred for 0.5 h. Then, a dichloromethane solution of acryloyl chloride was added dropwise to the reaction solution at 0°C, and the mixture was stirred at room temperature for 12 h to obtain a reaction mixture; wherein the molar ratio of cholesterol, triethylamine, and acryloyl chloride was 1:2:1; the reaction equation is:

[0070]

[0071] (2) The reaction mixture was quenched by adding saturated ammonium chloride solution, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the product was separated by column silica gel chromatography using a petroleum ether / ethyl acetate system (80:1) as the developing solvent. The product was white solid cholesterol acrylate with a yield of 61%.

[0072] (3) dissolving 2,4-dichlorobenzaldehyde, cholesteryl acrylate and triethylenediamine in tetrahydrofuran at room temperature, and stirring at room temperature for 1 week to obtain a reaction mixture; wherein the molar ratio of 2,4-dichlorobenzaldehyde, cholesteryl acrylate and triethylenediamine is 1:1.2:0.5;

[0073]

[0074] (4) The reaction mixture was decompressed to remove the solvent, and the residue was purified by column silica gel chromatography using petroleum ether and ethyl acetate (PE / EA=30 / 1) to obtain white solid 2-hydroxy-(2,4-dichlorophenyl) methacrylate cholesterol ester with a yield of 58%

[0075] (5) At room temperature, 2-hydroxy-(2,4-dichlorophenyl) methacrylate cholesterol ester, acetic anhydride, and 4-dimethylaminopyridine are mixed, and stirred at room temperature for 1 hour to obtain a reaction mixture; wherein the molar ratio of 2-hydroxy-(2,4-dichlorophenyl) methacrylate cholesterol ester, acetic anhydride, and 4-dimethylaminopyridine is 1:2:0.2

[0076]

[0077] (6) The reaction mixture was purified by column silica gel chromatography using petroleum ether and ethyl acetate (PE / EA=1 / 1) to obtain white solid 2-acetoxy-(2,4-dichlorophenyl) methacrylate cholesterol ester in a yield of 85%.

[0078] (7) Synthesis of itaconic acid compounds

[0079] In a 10 mL Shrek tube, under argon atmosphere, 0.4 mmol 2-(acetoxy-(2,4-dichlorophenyl)methyl)acrylic acid cholesterol ester, 0.48 mmol 2-oxo-2-phenylacetic acid, 0.02 mmol 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, and 0.08 mmol triphenylphosphine were added with 4 mL acetonitrile, and stirred under argon atmosphere, room temperature, and 54 W blue light irradiation to react. The reaction equation is:

[0080]

[0081] (8) After the reaction was completed as monitored by TLC, the solvent was removed by vacuum rotary evaporator, and the product was separated by thin layer chromatography. The developing solvent was petroleum ether / ethyl acetate system (9:1). The product was a colorless transparent liquid compound (E)-2-benzylidene 4-oxo-4-phenylbutyric acid cholesterol ester with a yield of 90%.

[0082] Example 6

[0083] (1) In a 10 mL Shrek tube, under an argon atmosphere, 0.4 mmol of 2-acetoxy(4-formylphenyl)methyl methacrylate, 0.48 mmol of (S)-2-((1-methoxy-1-oxopropyl-2-yl)amino)-2-oxoacetic acid, 0.02 mmol of 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, and 0.08 mmol of triphenylphosphine were added to 4 mL of acetonitrile, and the mixture was stirred under argon atmosphere, room temperature, and irradiation with a 54 W blue light to react. The reaction equation is:

[0084]

[0085] (2) After the reaction was completed as monitored by TLC, the solvent was removed by a vacuum rotary evaporator and the product was separated by thin layer chromatography. The developing solvent was a petroleum ether / ethyl acetate system (1:5). The product was a white solid (S, E)-2-benzylidene-4-((1-methoxy-1-oxopropyl-2-yl)amino)-4-oxobutanoic acid methyl ester with a yield of 60%.

[0086] Example 7

[0087] (1) In a 10 mL Shrek tube, under argon atmosphere, 0.4 mmol 2-acetoxy (4-formylphenyl) methyl methacrylate, 0.48 mmol Leu-Gly-Gly oxalic acid derivative, 0.02 mmol 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, and 0.08 mmol triphenylphosphine were added to 4 mL acetonitrile, and stirred under argon atmosphere, room temperature, and 54 W blue light irradiation to react. The reaction equation is:

[0088]

[0089] (2) After the reaction was completed as monitored by TLC, the solvent was removed by vacuum rotary evaporator and the product was separated by thin layer chromatography. The developing solvent was dichloromethane / methanol system (1:5). The product was colorless oily (E)-(3-(methoxycarbonyl)-4-phenylbut-3-enoyl)glycylglycyl-L-leucine methyl ester with a yield of 57%.

[0090] Example 8

[0091] (1) In a 10 mL Shrek tube, under argon atmosphere, 0.4 mmol 2-acetoxy (4-formylphenyl) methyl methacrylate, 0.48 mmol leucine enkephalin oxamate derivative, 0.02 mmol 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, and 0.08 mmol triphenylphosphine were added to 4 mL acetonitrile and stirred under argon atmosphere, room temperature, and 54 W blue light irradiation to react. The reaction equation is:

[0092]

[0093] (2) After the reaction was completed as monitored by TLC, the solvent was removed by a vacuum rotary evaporator and the product was separated by thin layer chromatography. The developing solvent was a dichloromethane / methanol system (1:5). The product was a colorless oily dimethyl (2S, 5S, 14S)-5-benzyl-19-((E)-benzylidene)-2-isobutyl-14-(4-methoxybenzyl)-4,7,10,13,17-pentaoxo-3,6,9,12,15-pentaazaeicosanedioate with a yield of 44%.

[0094] Example 9

[0095] (1) In a 10 mL Shrek tube, under argon atmosphere, 0.4 mmol of 2-(acetoxymethyl) methyl acrylate, 0.48 mmol of 2-oxo-2-(prop-2-yn-1-ylamino)acetic acid, 0.02 mmol of 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, and 0.08 mmol of triphenylphosphine were added to 4 mL of acetonitrile, and the mixture was stirred under argon atmosphere, room temperature, and irradiation with a 54 W blue light to react. The reaction equation is:

[0096]

[0097] (2) After the reaction was completed as monitored by TLC, the solvent was removed by a vacuum rotary evaporator and the product was separated by thin layer chromatography. The developing solvent was a dichloromethane / methanol system (1:5). The product was a colorless oily 2-methyl-4-oxo-4-(prop-2-yn-1-ylamino)butyric acid methyl ester with a yield of 85%.

[0098] (3) 2-methyl-4-oxo-4-(prop-2-yn-1-ylamino)butyric acid methyl ester (0.3mmol) was dissolved in THF (0.5mL) and H2O (1mL). NaOH (0.45mmol, 1.5 equivalents) was added and the solution was stirred at room temperature for 5 hours. The mixture was diluted with H2O (4mL) and washed with ether (10mL). The aqueous phase was separated and the pH was adjusted to 2-3 with 1M HCl. The mixture was extracted three times with EtOAc (12 milliliters). After combining the organic phases, they were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to give 2-methyl-4-oxo-4-(prop-2-yn-1-ylamino)butyric acid as a colorless oil in a yield of 84%.

[0099]

[0100] Embodiments 10 to 17

[0101] The Examples 10 to 17 are substantially the same as the above Example 1, and the obtained products are the same, except that they are shown in Table 1 below:

[0102] Table 1 Comparison of implementation differences

[0103] serial number Reaction solvent additive Yield Example 10 Toluene Triphenylphosphine 77％ Embodiment 11 Xylene Tris(4-methoxyphenyl)phosphine 86％ Example 12 Dichloromethane 4-Dimethylaminopyridine 88％ Embodiment 13 Acetonitrile Triethylamine 85％ Embodiment 14 1,2-Dichloroethane Triethylenediamine 84％ Embodiment 15 Tetrahydrofuran Triphenylphosphine 81％ Example 16 1,4-Dioxane Tris(4-methoxyphenyl)phosphine 89％ Embodiment 17 Isopropyl alcohol 4-Dimethylaminopyridine 82％

[0104] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing itaconic acid compounds, characterized in that: The method comprises the following steps: (1) adding an allyl ester compound, an acylating agent, a photoredox catalyst, and an additive to a reaction solvent in sequence, stirring and reacting for 30 minutes under an inert gas atmosphere, blue light irradiation, and room temperature to obtain a reaction solution; wherein the chemical structure of the allyl ester compound is shown in the following formula: The chemical structural formula of the acylating agent is shown below: (2) removing the reaction solvent from the reaction solution, and then purifying by thin layer chromatography to obtain an itaconic acid compound; The chemical structural formula of the itaconic acid compound is shown in the following formula (I): Among them, R 1 Any one selected from hydrogen, alkoxy, alkyl, trifluoromethyl, fused aromatic, heteroaromatic, aliphatic amine, aromatic amine, amino acid, and polypeptide; R 2 Any one selected from hydrogen, methoxy, cyano, nitro, tert-butyl, fluoro, bromo, chloro, ferrocenyl, trimethylsilylethynyl, fused aryl, heteroaryl, cycloalkyl, and linear alkyl.

2. The method according to claim 1, characterized in that The heteroaryl group is, for example, furyl or thienyl; the cycloalkyl group is cyclohexyl.

3. The method according to claim 1, characterized in that In step (1), the molar volume ratio of the allyl ester, the acylating agent, 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, the additive and the reaction solvent is (0.2-0.4) mmol: (0.24-0.48) mmol: (0.01-0.02) mmol: (0.04-0.08) mmol: (2-4) mL.

4. The method according to claim 1, characterized in that In step (1), the inert gas is argon; in step (2), the purified developing agent system is petroleum ether / ethyl acetate = 5:

1.

5. The preparation method according to claim 1, characterized in that: In step (1), the reaction solvent is selected from any one of toluene, xylene, dichloromethane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane and isopropanol.

6. The preparation method according to claim 1, characterized in that: In step (1), the additive is selected from any one of triphenylphosphine, tri(4-methoxyphenyl)phosphine, 4-dimethylaminopyridine, triethylamine and triethylenediamine.

7. The preparation method according to claim 1, characterized in that: In step (1), the photoredox catalyst is 3,6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate.

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