Method for directly synthesizing beta-acyloxy alkenyl amide compound from three components and application of beta-acyloxy alkenyl amide compound

Abstract

The invention discloses a method for directly synthesizing a beta-acyloxy alkenyl amide compound from three components and application of the beta-acyloxy alkenyl amide compound. According to the method, carboxylic acid or amino acid, alpha-trifluoromethyl ketone and secondary amine are taken as raw materials, DMSO is taken as a reaction medium, cesium carbonate or other alkali accelerators are added for stirring reaction, and the beta-acyloxy alkenyl amide compound is synthesized. The beta-acyloxy alkenyl amide compound can be used for synthesizing amides or peptides. The method for one-step synthesis of beta-acyloxy alkenyl amide based on simple commercial raw materials does not need any intermediate synthesis and separation operation, is mild in condition, is excellent in compatibility of secondary structures of the raw materials, and has the internal characteristic of easiness in industrialization. The beta-acyloxy alkenyl amide can react with amine or amino acid, and a large number of different amides and peptides can be synthesized under mild conditions with the characteristics of high universality and compatibility. Analysis of the synthesized peptide product proves that no racemization occurs in the reaction process, which indicates that the synthesized beta-acyloxy alkenyl amide and its important application prospect in peptide synthesis.

Description

Technical Field The invention belongs to the technical field of artificial synthesis of compounds, and specifically relates to a three-component direct synthesis method of a beta-acyloxy enamide compound and its application. Background Art Compounds containing amide structures, including molecules such as amides and peptides, are widely present in nature, especially in living organisms, and play a key role in life activities. In addition, amide structures are also common structural fragments of many drug molecules, functional materials, bioactive lead compounds, etc. For example, important clinical drugs such as peptide drugs such as insulin, vancomycin, and semaglutide are all peptide drugs. Therefore, effective peptide bond construction is crucial to the development of chemistry, medicine, and many related fields. At present, the key to synthesizing amides or peptides from carboxylic acids or amino acids through amide bonds is the addition of condensing agents. In the development history of amide peptide synthesis, people have successively developed a variety of different types of condensing agents to achieve the condensation of amides and peptides. For example, carbodiimide condensing agents DCC, DIC, EDC; carbonyl diimidazole; organophosphorus condensing agents T3P, DPPCI; phosphonium cation / linium salt condensing agents such as BOP, PyBOP, etc.; nitrogen onium salt condensing agents HATU, TBTU, HBTU, etc. Since classical condensing agents often have various limitations and challenges such as difficulty in preparation, poor stability, harmful by-products, high prices, or easy racemization during peptide bond construction, the development of new condensing agents that can overcome the above defects is still of great strategic significance for the synthesis of amides and peptides, as well as related drug development and other industries. β-Acyloxy enamides were first synthesized and reported by Hanfner and Neuenschwander in 1968 (Neuenschwander, M.; Hafner, K. Angew. Chem. Int. Ed. 1968, 7, 459). The method starts from the commercial reagent methyl ketone and undergoes five steps of amine methylation, preparation of bromine enamine salt by bromide, neutralization and deacidification, strong base-promoted elimination, and addition rearrangement of carboxylic acid aminoalkyne. Four of the steps require separation, the process is lengthy, and the chemical consumption and emission are large. The preparation process is as follows: Based on the above work on the synthesis of β-acyloxy enamide, Neuenschwander's own research group (Lienhard, U.; Fahrni, H.-P.; Neuenschwander, M. Helv. Chem. Acta 1978, 61, 1609-1621) and Gais' research group (Gais, H.-J. Angew. Chem. Int. Ed. Engl. 1978, 17, 597-598) respectively studied and reported a method of synthesizing a peptide by reacting an amino group with the fourth-step intermediate amino alkynone to obtain the corresponding β-acyloxy enamide, and then reacting with another amino acid molecule, and obtained excellent results. Based on the characteristics of the alkynyl groups in amino alkynone containing electron-pushing and electron-pulling groups at both ends, this type of molecule that can be used for peptide bond construction is named "push-pull alkynyl" condensing agent. In addition to the lengthy synthesis process, another problem with the above-mentioned method for synthesizing acetoxypropyleneamine amine compounds through push-pull alkynes is the stability of the intermediates. The bromoenamine ketone in the synthesis route is unstable in itself, and the aminoalkyne intermediate obtained through the elimination reaction under strong alkaline conditions is even more unstable, and it needs to be kept at a low temperature of minus 50 to minus 20 degrees Celsius to have a certain stability. Therefore, it is almost impossible to commercialize and industrialize the synthesis of polar amides, peptides and other related molecules by push-pull alkynes as condensing agents. This also led to the fact that this type of push-pull alkyne condensing agent has not received any attention in the next nearly 50 years, so that the development of related technologies of this type of condensing agent has actually been interrupted. Summary of the invention The purpose of the present invention is to solve the problem that the synthesis method of β-acyloxy enamide compounds, which are condensation precursors of amide and peptide synthesis, is lengthy and the intermediates are unstable and cannot be commercialized and industrialized. We adopt two main methods, multi-component reaction and carbon-fluorine bond cascade functionalization, and through systematic experimental research, realize the first method of synthesizing β-acyloxy enamide in one step using simple and inexpensive commercial reagents, namely α-trifluoromethyl, secondary amine and carboxylic acid. Based on the results of our research, we describe here a method for synthesizing β-acyloxy enamide in one step by three-component reaction. The raw materials of this method are easy to obtain, the operation is recommended, and the β-acyloxy enamide compounds can be obtained in one step without any intermediate separation. β-Acyloxy enamide compounds are excellent precursors for constructing amides and peptides, and can be efficiently used in the synthesis of amides and peptides, and no racemization occurs during the synthesis of peptides. As a simple and efficient strategy for the synthesis of amides and peptides, this method is expected to promote important progress in the field of amide and peptide synthesis. The first part of the present invention is a three-component method for directly synthesizing a β-acyloxy enamide compound, comprising the following steps: (1) Add 0.2-6.0 mmol α-trifluoromethyl ketone, 1.0-30.0 mmol carboxylic acid and 0.3-9.0 mmol secondary amine to a clean reaction bottle or reaction tube, then add 0.3-9.0 mmol cesium carbonate, and use 2.0-30.0 mL DMSO as a medium. Stir at 40° C. for 5 hours under air atmosphere or monitor the reaction by TLC until the reaction is completed. After the reaction is completed, the reaction solution is extracted, separated, dried and concentrated, and then purified by silica gel column chromatography to obtain the target product β-acyloxy enamide of the first step reaction. The reaction equation is: In the formula, 1 represents α-trifluoromethyl ketone, 2 represents carboxylic acid or amino acid, 3 represents secondary amine, and 4 represents β-acyloxy enamide. 1 is an aryl or alkyl group, R 2 is alkyl, aryl, alkenyl or alkynyl; R 3 and R 4 The aryl group includes an aryl structure containing a functional group structure such as an alkyl group, an alkoxy group, a halogen atom substituent, etc. Preferably, the carboxylic acid may be a conventional aryl or alkyl carboxylic acid, sorbic acid, ursolic acid, ibuprofen, or veratric acid, and the amino acid may be an N-protected amino acid. Preferably, any conventional organic solvent that can dissolve or mostly dissolve the reaction raw materials is applicable to the present method, and the organic solvent is preferably ethanol, ethyl acetate, acetone, or DMSO. Preferably, the base promoter is tetra-tert-butylammonium hydroxide, sodium tert-butoxide, sodium carbonate, sodium hydroxide, lithium hydroxide, or cesium carbonate. Preferably, the amine is a secondary amine, and the molar ratio of the α-trifluoromethyl ketone, carboxylic acid and secondary amine is 1:5:1.5; the base promoter is cesium carbonate, and the molar ratio of cesium carbonate to α-trifluoromethyl ketone is 1.5:1; the organic solvent is DMSO, and the amount is 2 to 10 mL; the reaction temperature is 40 to 45° C., and the stirring is 5 to 6 hours. Preferably, the β-acyloxy enamide 4 further contains an aryl or alkyl structure at the β position. In the first step of technical research, we explored and optimized the conditions for the direct synthesis of β-acyloxy enamides through the three-component reaction of α-trifluoromethyl, secondary amine and carboxylic acid. Taking the reaction of α-trifluoromethyl, diethylamine and benzoic acid as a model, we optimized different reaction parameters. First, when DMSO was used as the medium, at 40°C, different alkaline additives such as tetra-tert-butylammonium hydroxide, sodium tert-butoxide, sodium carbonate, sodium hydroxide, lithium hydroxide and cesium carbonate were used to promote the synthesis of the corresponding β-acyloxy enamides. The product yield was 41-63% after 18 hours of reaction, and the highest yield came from the reaction with the addition of cesium carbonate. Subsequently, by fixing cesium carbonate as the base and replacing the reaction medium with ethanol, ethyl acetate and acetone, the target product can also be obtained with a yield of 46-56%, which is not better than DMSO. Subsequently, by adjusting the equivalent of diethylamine, we found that when the substrate was increased to 5 molar equivalents, the optimal product yield of 81% under parallel conditions could be obtained. The reaction temperature was optimized, and the yields were 56% and 77% at 60°C and room temperature, respectively. Finally, by controlling the reaction time, we found that the reaction time also had a significant effect on the results. When the time was shortened to 5 hours, the yield was further increased to 86%. Comparative experiments showed that the reaction could proceed without adding any base or other additives, and the yield of the target product was 51%. Based on the experimental results in this section, we selected a feed ratio of 1:5:1.5 for trifluoromethyl ketone, carboxylic acid and secondary amine, DMSO as the medium, 1 molar equivalent of cesium carbonate as the base, and 40°C for 5 hours as the optimal reaction conditions for the synthesis of β-acyloxy enamide. The obtained product β-acyloxy enamide 4, as an activated form of carboxylic acid, can directly react with amines to achieve the construction of amide bonds to synthesize amides; the product β-acyloxy enamide 4 synthesized using amino acids as substrates and reacting accordingly with another amino acid can achieve the construction of peptide bonds to synthesize peptide molecules. The second part of the present invention is the use of β-acyloxy enamide in the synthesis of amides and peptides. The method for synthesizing amides comprises the following steps: (1) Add 0.2 mmol of β-acyloxy enamide, 0.24 mmol of amine and 1 mL of ethyl acetate to a clean reaction bottle or reaction tube, and stir at 30°C under air atmosphere. Depending on the specific structure of the raw materials, individual reactions are heated and stirred at 80°C in a sealed tube. (2) The reaction was monitored by TLC. For different reactions, the stirring time was 5 to 24 hours. After the reaction was completed, the product was directly concentrated and the residue was purified by silica gel column chromatography to obtain the amide product. The method for synthesizing a peptide comprises the following steps: (1) In a clean reaction bottle or reaction tube, 0.1 mmol of β-acyloxy enamide synthesized from amino acids as raw materials, 0.12 mmol of amino acid ester and 1 mL of ethyl acetate were added and stirred at 30° C. under air atmosphere. (2) The reaction was monitored by TLC. For different reactions, the stirring time was 5 to 24 hours. After the reaction was completed, the product was directly concentrated and the residue was purified by silica gel column chromatography to obtain the peptide product. The general reaction formula for the synthesis of amides and peptides is: Wherein 4 represents β-acyloxy enamide, 5 represents amine or amino acid, 6 represents amide or peptide product, 7 represents β-ketoamide, R 1 is an aryl group or an alkyl group, R 2 is aryl, alkyl, alkenyl, sorbic acid, ursolic acid, ibuprofen, veratric acid, N-protected amino acid, etc., R 3 and R 4 Alkyl, aryl and carboxyl protected amino acids. After high performance liquid chromatography analysis, the de values ​​of the peptide products during the peptide synthesis process were all greater than 99%, indicating that no racemization occurred during the reaction process. This peptide synthesis strategy has great application prospects. The byproduct 7 obtained in the above reaction is β-ketoamide, which can be recovered together during the product purification process. The product itself is also an important organic synthesis building block and has a wide range of important applications in organic synthetic chemistry, see references (Li, W.; Zheng, Y.; Qu, E.; Bai, J.; Deng, Q. Eur. J. Org. Chem. 2021, 5151-5192). In the method, the molar ratio of β-acyloxy enamide 4 to amine or amino acid 5 is 1:1.2. The beneficial effects of the present invention are: in view of the bottleneck problems such as the difficulty in synthesizing β-acyloxy enamide and the inability to commercialize, the present invention is a method for synthesizing β-acyloxy enamide in one step based on simple commercial raw materials. The method does not require any intermediate synthesis and separation operation, has mild conditions, and has excellent compatibility of the secondary structure of the raw materials, and has the inherent characteristics of easy industrialization. On the basis of synthesizing β-acyloxy enamide compounds with diverse structures, the invention also includes the synthesis of amides and peptides using β-acyloxy enamide. It is confirmed that β-acyloxy enamide can react with amines or amino acids as an activated carboxylic acid species, and a large number of different amides and peptides can be synthesized under mild conditions with high versatility and compatibility. It is particularly worth mentioning that the synthesized peptide product was analyzed and confirmed that no racemization occurred during the reaction, indicating the synthesis of β-acyloxy enamide itself and its great application prospects in peptide synthesis. DETAILED DESCRIPTION The beneficial effects of the present invention are described in detail below in conjunction with Examples 1 to 27, which is intended to help readers better understand the essence of the present invention, but does not constitute any limitation on the implementation and protection scope of the present invention. Part I. Specific examples of one-step synthesis of β-acyloxy enamide compounds, Examples 1 to 16. Example 1 Add 2-trifluoromethylacetophenone (0.2mmol), benzoic acid (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the resulting mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the resulting solution under reduced pressure, and perform column chromatography on the resulting residue to obtain a pure product, (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-ene-1-ylbenzoate, a yellow solid, with a yield of 86%. The following is the structural formula of the product and the nuclear magnetic resonance experimental data and mass spectrometry experimental data: H NMR(400MHz, CDCl3)δ8.18(d,J=7.3Hz,2H),7.63–7.55(m,3H),7.48(t,J=7.7Hz,2H),7.40–7.35(m,3H) ,6.49(s,1H),3.47(q,J=7.2Hz,2H),3.37(q,J=7.1Hz,2H),1.23(t,J=7.2Hz,3H),1.04(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ164.1,164.0,152.6,134.3,133.5,130.3,129.8,129.4,128.7,128.6,125.5,109.2,42.6,39.6,14.4,12.9; HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 22 NO3 324.1594; Found 324.1591. Example 2 Add 1-(3,4-dichlorophenyl)-3,3,3-trifluoropropane-1-one (0.2mmol), benzoic acid (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean 25mL reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the obtained solution under reduced pressure, and perform column chromatography on the obtained residue to obtain a pure product, a yellow liquid, with a yield of 88%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ8.16 (d, J = 7.2Hz, 2H), 7.65–7.60 (m, 2H), 7.52–7.39 (m, 4H), 6.48 (s, 1H) ),3.45(q,J=7.1Hz,2H),3.37(q,J=7.1Hz,2H),1.24(t,J=7.2Hz,3H),1.03(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ163.9,163.4,150.3,134.4,134.0,133.9,133.2,130.8,130.4,128.8,128.7,127.4,124.7,110.7,42.6,39.6,14.5,12.9. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 20 Cl2NO3 392.0815; Found392.0817. Example 3 Add 4,4,4-trifluoro-2-butanone (0.2mmol), benzoic acid (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40℃ for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the obtained solution under reduced pressure, and perform column chromatography on the obtained residue to obtain a pure product, a yellow liquid, with a yield of 61%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ8.11–8.05(m,2H),7.57(t,J=7.4Hz,1H),7.44(t,J=7.8Hz,2H),5. 81(s,1H),3.41–3.30(m,4H),2.13(s,3H),1.16(t,J=7.2Hz,3H),1.00(t,J=7.1Hz,3H). 13 C NMR (150MHz, CDCl3) δ164.1,164.0,152.9,133.4,130.2,129.5,128.5,110.5,42.4,39.3,20.8,14.3,12.9. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 15 H 20 NO3 262.1438; Found 262.1433. Example 4 Add 3,3,3-trifluoro-1-(thiophene-2-yl)-1-propanone (0.2mmol), benzoic acid (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the obtained solution under reduced pressure, and perform column chromatography on the obtained residue to obtain a pure product, a brown solid, with a yield of 50%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ8.22–8.15(m,2H),7.61(t,J=7.5Hz,1H),7.49(t,J=7.8Hz,2H),7.33(d,J=5.0Hz,1H),7.31–7.28(m,1H ),7.04–7.00(m,1H),6.43(s,1H),3.46(q,J=7.2Hz,2H),3.35(q,J=7.1Hz,2H),1.25(t,J=7.2Hz,3H),1.05(t,J=7.1Hz,3H). 13C NMR (100MHz, CDCl3) δ163.7,163.5,148.2,138.3,133.6,130.4,129.2,128.6,127.9,127.3,126.6,106.8,42.6,39.8,14.5,13.0. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 20 NO3S 330.1158; Found 330.1158. Example 5 Add 2-trifluoromethylacetophenone (0.2mmol), benzoic acid (1mmol), cesium carbonate (0.3mmol), dimethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the obtained mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the obtained solution under reduced pressure, and perform column chromatography on the obtained residue to obtain a pure product, a yellow solid, with a yield of 62%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ8.19(d,J=7.6Hz,2H),7.64–7.55(m,3H),7.49(t,J=7.7Hz,2H),7.41–7.34(m,3H),6.51(s,1H),3.14(s,3H),2.93(s,3H). 13 C NMR (100MHz, CDCl3) δ164.9,164.0,152.7,134.2,133.6,130.4,130.0,129.3,128.7,128.6,125.5,108.9,37.8,35.0. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 18 NO3 296.1281; Found 296.1281. Example 6 Add 2-trifluoromethylacetophenone (0.2mmol), benzoic acid (1mmol), cesium carbonate (0.3mmol), diisobutylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the obtained mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the obtained solution under reduced pressure, and perform column chromatography on the obtained residue to obtain a pure product, a yellow liquid, with a yield of 72%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ8.17(d,J=6.5Hz,2H),7.63–7.53(m,3H),7.47(t,J=7.7Hz,2H),7.41–7.35(m,3H),6.51(s, 1H), 3.25 (d, J=7.6Hz, 2H), 3.20 (d, J=7.6Hz, 2H), 2.04–1.89 (m, 2H), 0.96 (d, J=6.7Hz, 6H), 0.78 (d, J=6.7Hz, 6H). 13 C NMR (100MHz, CDCl3) δ165.2,164.0,151.9,134.3,133.5,130.4,129.7,129.3,128.7,128.5,125.4,110.3,56.1,52.4,27.8,26.4,20.2,20.1. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 24 H 30 NO3 380.2220; Found 380.2221. Example 7 Add 2-(trifluoromethyl)acetophenone (0.2mmol), 3-fluorobenzoic acid (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the resulting mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the resulting solution under reduced pressure, and perform column chromatography on the resulting residue to obtain a pure product, a yellow solid, with a yield of 80%. The following is the structural formula of the product and the nuclear magnetic resonance experimental data and mass spectrometry experimental data: 1 H NMR(400MHz, CDCl3)δ7.98(d,J=7.7Hz,1H),7.90–7.81(m,1H),7.61–7.54(m,2H),7.49–7.43(m,1H),7.42–7.35(m,3H),7 .34–7.28(m,1H),6.51(s,1H),3.47(q,J=7.2Hz,2H),3.38(q,J=7.1Hz,2H),1.25(t,J=7.2Hz,3H),1.06(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ163.9, 163.8, 163.0 (d, J = 2.9Hz), 161.4, 152.8, 134.0, 131.5 (d, J = 7.4Hz), 130.3 (d, J = 7.8Hz) ,130.1,128.8,126.1(d,J=2.9Hz),125.5,120.7(d,J=21.3Hz),117.2(d,J=23.2Hz),108.8,42.6,39.8,14.5,13.0. 19 F NMR (376MHz,CDCl3)δ-112.09. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 21 FNO3 342.1500; Found 342.1500. Example 8 Add 2-(trifluoromethyl)acetophenone (0.2mmol), cyclohexanecarboxylic acid (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the resulting mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the resulting solution under reduced pressure, and perform column chromatography on the resulting residue to obtain a pure product, a yellow liquid, with a yield of 92%. The following is the structural formula of the product and the nuclear magnetic resonance experimental data and mass spectrometry experimental data: 1H NMR (400MHz, CDCl3) δ7.55–7.45(m,2H),7.43–7.31(m,3H),6.36(s,1H),3.46–3.35(m,4H),2.69–2.51(m,1H),2.15–2.06(m,2H ),1.85–1.75(m,2H),1.67(d,J=11.5Hz,1H),1.61–1.50(m,2H),1.42–1.25(m,3H),1.21(t,J=7.2Hz,3H),1.14(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ173.2,164.2,152.6,134.5,129.7,128.6,125.4,108.8,43.1,42.5,39.7,28.8,25.7,25.4,14.3,13.1. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 28 NO3 330.2064; Found 330.2058. Example 9 Add 2-trifluoromethylacetophenone (0.2mmol), furoic acid (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40℃ for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the obtained solution under reduced pressure, and perform column chromatography on the obtained residue to obtain a pure product, a white solid, with a yield of 76%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR(400MHz, CDCl3)δ7.65(d,1H),7.60–7.56(m,2H),7.43–7.36(m,4H),6.57(q,1H),6.50(s, 1H), 3.46 (q, J = 7.1Hz, 2H), 3.39 (q, J = 7.1Hz, 2H), 1.24 (t, J = 7.3Hz, 3H), 1.08 (t, J = 7.1Hz, 3H). 13C NMR (100MHz, CDCl3) δ164.4,158.0,152.1,134.3,129.8,128.7,125.5,124.3,121.5,117.3,110.7,109.3,42.6,39.6,14.4,12.8; HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 20 NO4 314.1387; Found 314.1385. Example 10 Add 2-trifluoromethylacetophenone (0.2mmol), sorbic acid (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the obtained solution under reduced pressure, and perform column chromatography on the obtained residue to obtain a pure product, a yellow liquid, with a yield of 68%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.50–7.41(m,2H),7.41–7.32(m,1H),7.32–7.25(m,3H),6.33(s,1H),6.23–6.06(m,2H), 5.91(d,J=15.4Hz,1H),3.38–3.33(m,3H),1.80(d,J=6.0Hz,4H),1.14(t,J=7.2Hz,3H),1.04(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ164.4,164.2,152.5,147.3,140.7,134.4,129.9,129.7,128.6,125.5,117.7,108.8,42.5,39.6,18.7,14.4,13.0. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 19 H 24 NO3 314.1751; Found 314.1748. Example 11 Add 2-trifluoromethylacetophenone (0.2mmol), veratric acid (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the resulting mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the resulting solution under reduced pressure, and perform column chromatography on the resulting residue to obtain a pure product, a white liquid, with a yield of 79%. The following is the structural formula of the product and the nuclear magnetic resonance experimental data and mass spectrometry experimental data: 1 H NMR (400MHz, CDCl3) δ7.89–7.84(m,1H),7.65(d,J=2.0Hz,1H),7.60–7.56(m,2H),7.40–7.36(m,3H),6.94(d,J=8.4Hz,1H),6 .49(s,1H),3.94(d,J=7.5Hz,6H),3.48(q,J=7.2Hz,2H),3.38(q,J=7.1Hz,2H),1.23(t,J=7.1Hz,3H),1.05(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ164.1,163.8,153.6,152.6,148.8,134.4,129.8,128.7, 125.5,124.7,121.7,112.6,110.5,109.1,56.1,56.1,42.6,39.6,14.4,12.9. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 22 H 26 NO5 384.1805; Found 384.1806. Example 12 Add 2-trifluoromethylacetophenone (0.2mmol), ibuprofen (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the resulting mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the resulting solution under reduced pressure, and perform column chromatography on the resulting residue to obtain a pure product, a white solid, with a yield of 61%. The following is the structural formula of the product and the nuclear magnetic resonance experimental data and mass spectrometry experimental data: 1 H NMR (400MHz, CDCl3) δ7.29 (d, J = 8.2Hz, 3H), 7.20–7.12 (m, 6H), 6.35 (s, 1H), 4.00 (q, J = 7.1Hz, 1H), 3.45–3. 32(m,4H),2.48(d,J=7.2Hz,2H),1.91–1.84(m,1H),1.59(d,3H),1.21–1.12(m,6H),0.92(d,J=6.6Hz,6H). 13 C NMR (100MHz, CDCl3) δ171.8,164.1,152.5,140.8,137.2,134.1,129.7,129.4,128.5,127.6, 125.3,108.6,45.2,45.1,42.5,39.8,30.3,22.4,17.9,14.4,13.0.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 26 H 34 NO3 408.2533; Found 408.2529. Example 13 Add 2-trifluoromethylacetophenone (0.2mmol), ursolic acid (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 5 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of water. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the obtained solution under reduced pressure, and perform column chromatography on the obtained residue to obtain a pure product, a colorless liquid, with a yield of 82%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 1H NMR (400 MHz, CDCl3) δ 7.52–7.49 (m, 2H), 7.34–7.31 (m, 3H), 6.18 (s, 1H), 5.32–5.26 (m, 1H), 3.55–3.29 (m, 5H), 3.21–3.15 (m, 1H), 2.55 (q, J = 7.2 Hz, 1H), 2.32 (d, J = 11.2 Hz, 1H), 2.08–2.02 (m, 1H), 1.88–1.77 (m, 5H), 1.64–1.56 (m, 4H), 1.51–1.41 (m, 4H), 1.20 (t, J = 7.2 Hz, 4H), 1.14 (t, J = 7.1 Hz, 4H), 1.08–1.02 (m, 6H), 0.98–0.93 (m, 7H), 0.87–0.83 (m, 6H), 0.75 (s, 3H), 0.68 (d, J = 11.0 Hz, 1H), 0.39 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 174.1, 164.3, 152.0, 138.0, 135.4, 129.3, 128.3, 126.3, 126.1, 111.4, 78.9, 55.2, 52.8, 48.3, 47.6, 46.2, 42.7, 42.1, 39.6, 39.4, 38.7, 38.7, 38.6, 36.9, 35.8, 33.2, 30.7, 28.2, 27.8, 27.2, 24.6, 23.4, 23.3, 21.3, 18.3, 17.1, 17.0, 15.6, 15.4, 14.2, 13.1, 11.4. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 43 H 64 NO4 658.4830; Found 658.4830. Example 14 Add 2-trifluoromethylacetophenone (0.2mmol), Boc-L-tryptophan (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 3 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the obtained mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of saturated sodium bicarbonate solution. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the obtained solution under reduced pressure, and perform column chromatography on the obtained residue to obtain a pure product, a yellow liquid, with a yield of 69%. The following is the structural formula of the product and the nuclear magnetic resonance experimental data and mass spectrometry experimental data: 1 H NMR (400MHz, CDCl3) δ8.36(s,1H),7.66(d,J=7.8Hz,1H),7.45(d,J=6.8Hz,2H),7.37–7.27(m,4H),7.19–7.14(m,1H),7.13–7.07(m,2H),6.39(s,1 H),4.86(q,J=7.6Hz,1H),3.54(q,1H),3.41(q,J=6.9Hz,4H),3.29(q,1H ),1.88(s,1H),1.38(s,9H),1.21(t,J=7.2Hz,3H),1.14(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ169.9,164.1,155.5,153.0,136.2,129.9,128.7,127.9,125.7,123.4 ,121.9,119.5,118.9,111.2,110.5,108.6,79.8,54.6,42.6,39.9,28.3,27.3,14.4,13.1. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 29 H 35 N3NaO5 528.2469; Found528.2464. Embodiment 15 Add 2-trifluoromethylacetophenone (0.2mmol), Boc-L-phenylalanine (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 3 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the mixture with ethyl acetate, collect the organic phase and wash three times with a small amount of saturated sodium bicarbonate solution. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the obtained solution under reduced pressure, and perform column chromatography on the obtained residue to obtain a pure product, a colorless liquid, with a yield of 74%. The following is the structural formula of the product and the nuclear magnetic resonance experimental data and mass spectrometry experimental data: 1 H NMR (400MHz, CDCl3) δ7.50–7.46(m,2H),7.36(d,J=6.9Hz,3H),7.31–7.25(m,5H),6.41(s,1H),5.27(d,J=8.3Hz,1H),4.78(q ,J=7.5Hz,1H),3.44–3.40(m,4H),3.13–3.05(m,1H),1.80(s,1H),1.38(s,9H),1.23(t,J=7.2Hz,3H),1.15(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ169.6,163.9,155.4,153.4,136.9,133.6,130.0,129.5,128.7,128.5,1 26.7,125.7,108.1,79.8,55.0,42.6,40.0,37.5,28.3,14.4,13.1.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 27 H 35 N2O5 467.2541; Found 467.2551. Example 16 Add 2-trifluoromethylacetophenone (0.2mmol), Cbz-L-alanine (1mmol), cesium carbonate (0.3mmol), diethylamine (0.3mmol) to a clean reaction tube, add 5mL dimethyl sulfoxide as solvent, react at 40°C for 2 hours, monitor by TLC, cool to room temperature after the reaction, add a small amount of water, extract the resulting mixture with ethyl acetate, collect the organic phase and wash it three times with a small amount of saturated sodium bicarbonate solution. After drying with anhydrous Na2SO4, filter and remove the solid. Remove the solvent in the resulting solution under reduced pressure, and perform column chromatography on the resulting residue to obtain a pure product, a colorless liquid, with a yield of 69%. The following is the structural formula of the product and the nuclear magnetic resonance experimental data and mass spectrometry experimental data: 1 H NMR (400MHz, CDCl3) δ7.56–7.49(m,2H),7.40–7.28(m,8H),6.39(s,1H),5.78(d,J=7.9Hz,1H),5.16–5.08(m, 2H), 4.72–4.63 (m, 1H), 3.42–3.36 (m, 4H), 1.58 (d, J = 7.1Hz, 3H), 1.21 (t, J = 7.2Hz, 3H), 1.12 (t, J = 7.1Hz, 3H). 13 C NMR (150MHz, CDCl3) δ170.3,163.8,155.9,153.5,136.4,133.7,130.2,128.8 ,128.5,128.1,128.0,125.6,107.7,66.9,50.0,42.6,40.1,17.9,14.4,13.1. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 24 H 29 N2O5 425.2071; Found 425.2068. Part II, Specific implementation methods of the application of β-acyloxy enamide compounds in amide and polypeptide synthesis, Examples 17 to 27 Embodiment 17 In a clean reaction tube, add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-ylbenzoate (0.2 mmol) prepared in Example 1, 4-methylbenzylamine (0.24 mmol), add an appropriate amount of ethyl acetate as solvent, react at 30°C for 3 hours, and monitor by TLC. After the reaction is completed, the organic layer is concentrated and column chromatographed to obtain a pure product as a white solid with a yield of 98%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.72–7.68(m,2H),7.41(t,J=7.4Hz,1H),7.33(t,J=7.4Hz,2H),7.1 6(d,J=8.0Hz,2H),7.08(d,J=7.8Hz,2H),6.39(s,1H),4.51(d,J=5.6Hz,2H),2.26(s,3H). 13 C NMR (100MHz, CDCl3) δ167.4,137.3,135.2,134.5,131.5,129.5,128.6,128.0,127.0,43.9,21.1. Embodiment 18 Add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-ylbenzoate (0.2mmol), tetrahydropyrrole (0.24mmol) to a clean reaction tube, add an appropriate amount of ethyl acetate as solvent, react at 30°C for 12 hours, monitor by TLC, after the reaction, concentrate the organic layer and column chromatography to obtain a pure product, a yellow liquid, with a yield of 99%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.54–7.49(m,2H),7.43–7.36(m,3H),3.65(s,2H),3.43(s,2H),1.95(s,2H),1.88(s,2H). 13 C NMR (100MHz, CDCl3) δ169.7,137.3,129.8,128.2,127.1,49.6,46.2,26.4,24.5. Embodiment 19 Add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-ylbenzoate (0.2mmol), propargylamine (0.24mmol) to a clean reaction tube, add an appropriate amount of ethyl acetate as solvent, react at 30°C for 24 hours, and monitor by TLC. After the reaction is completed, the organic layer is concentrated and column chromatographed to obtain a pure product, a white solid, with a yield of 82%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.83–7.76(m,2H),7.54–7.49(m,1H),7.47–7.39(m,2H),6.38(s,1H),4.26(q,J=5.2,2.6Hz,2H),2.28(t,J=2.6Hz,1H).

[0143] 13 C NMR (150MHz, CDCl3) δ167.1,133.8,131.8,128.6,127.0,79.5,71.9,29.8. Embodiment 20 Add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-ylbenzoate (0.2mmol), tryptamine (0.24mmol), add appropriate amount of ethyl acetate as solvent, react at 30°C for 12 hours, monitor by TLC, after the reaction, concentrate the organic layer and column chromatography to obtain pure product, purple solid, yield 98%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrum: 1 H NMR(400MHz, CDCl3)δ8.49(s,1H),7.68–7.59(m,3H),7.43(t,J=7.4Hz,1H),7.36–7.31(m,3H),7.20–7.15(m ,1H),7.09(t,J=7.5Hz,1H),6.97(d,J=1.6Hz,1H),6.39(s,1H),3.76(q,J=6.5Hz,2H),3.05(t,J=6.7Hz,2H). 13 C NMR (150MHz, CDCl3) δ167.8,136.6,134.7,131.4,128.6,127.4,126.9,122.3,122.2,119.4,118.7,112.7,111.5,40.4,25.3. Embodiment 21 Add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-ylbenzoate (0.2mmol), 3-amino-1-propanol (0.24mmol) to a clean reaction tube, add an appropriate amount of ethyl acetate as a solvent, react at 30 degrees Celsius for 12 hours, and monitor by TLC. After the reaction is completed, the organic layer is concentrated and column chromatographed to obtain a pure product, a colorless liquid, with a yield of 92%. The following is the structural formula of the product and the nuclear magnetic resonance experimental data and mass spectrometry experimental data: 1 H NMR (600MHz, CDCl3) δ7.77(d,J=7.3Hz,2H),7.49(t,J=7.4Hz,1H),7.41(t,J=7.7Hz,2H), 6.92(s,1H),3.72(t,J=5.6Hz,2H),3.62(q,J=6.1Hz,2H),1.95(s,1H),1.81–1.77(m,2H). 13 C NMR (100MHz, CDCl3) δ168.6,134.2,131.6,128.6,126.9,59.9,37.3,32.0. Embodiment 22 Add (Z)-3-(diethylamino)-3-oxo-1-phenyl-1-propene-1-yl-3,4-dimethoxybenzoate (0.2mmol), ethylamine (0.24mmol), add appropriate amount of ethyl acetate as solvent, react at 80℃ for 16 hours, monitor by TLC, after the reaction, concentrate the organic layer and column chromatography to obtain pure product, white solid, yield 99%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR(400MHz, CDCl3)δ7.43(d,J=2.0Hz,1H),7.31–7.28(m,1H),6.84(d,J=8.3H z,1H),6.34(s,1H),3.91(s,6H),3.47(q,J=6.8Hz,2H),1.24(t,J=7.2Hz,3H). 13 C NMR (150MHz, CDCl3) δ167.1,151.6,148.9,127.5,119.3,110.6,110.3,56.0,34.9,14.9. HRMS (ESI-TOF) m / z: [M+H] +Calcd for C 11 H 16 NO3 210.1125; Found 210.1120. Example 23 Add (Z)-4-(tert-butyl)-1-(3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl)(((9H-fluoren-9-yl)methoxy)carbonyl)-L-aspartic acid ester (0.1mmol), L-valine tert-butyl ester (0.12mmol) into a clean reaction tube, add an appropriate amount of ethyl acetate as solvent, react at 30°C for 16 hours, and monitor by TLC. After the reaction is completed, the organic layer is concentrated and column chromatographed to obtain a pure product, a colorless liquid, with a yield of 97% and de>99. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.76(d,J=7.5Hz,2H),7.59(d,J=7.5Hz,2H),7.40(t,J=7.5Hz,2H),7.31 (t,J=7.4Hz,2H),7.07(d,J=8.7Hz,1H),6.07(d,J=8.3Hz,1H),4.58(s,1H),4.40(d,J=7.3Hz, 2H),4.24(t,J=7.1Hz,1H),2.93(dd,J=17.2,4.1Hz,1H),2.64(dd,J=17.2,7.0Hz,1H),2.17(d t,J=14.0,7.0Hz,1H),2.04(s,1H),1.45(s,18H),0.94(d,J=6.8Hz,3H),0.91(d,J=6.9Hz,3H). 13 C NMR (150MHz, CDCl3) δ171.5,170.4,156.0,143.8,141.3,127.8,127.1,125.1,120.0,81.9,67 .3,60.4,57.8,51.0,47.1,37.6,31.2,28.1,21.1,19.0,17.5,14.2.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 32 H 43 N2O7 567.3065; Found 567.3062. Example 24 Add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl (tert-butyloxycarbonyl)-L-phenylalanine ester (0.1mmol), L-tyrosine tert-butyl ester (0.12mmol) to a clean reaction tube, add an appropriate amount of ethyl acetate as solvent, react at 30°C for 6 hours, monitor by TLC, after the reaction, concentrate the organic layer and column chromatography to obtain a pure product, a colorless viscous liquid, with a yield of 96%, de>99%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1 H NMR (400MHz, CDCl3) δ7.22(d,J=14.0Hz,2H),7.16(d,J=6.7Hz,2H),6.88(d,J=8.5Hz,2H),6.68(d,J=7.9Hz,2H),6.55(d,J=7.6H z,1H),5.11(s,1H),4.62(d,J=6.7Hz,1H),4.36(s,1H),3.03(d,J=6.0Hz,1H),2.95(d,J=5.8Hz,2H),2.05(s,2H),1.39(s,18H). 13 C NMR (100MHz, CDCl3) δ170.9,170.2,155.4,136.4,130.6,129.3,128.6,127. 2,126.9,115.3,82.4,60.5,55.7,53.9,38.4,37.3,28.2,27.9,21.1,14.2. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 27 H 37 N2O6 485.2646; Found 485.2642. Example 25 Add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl (tert-butyloxycarbonyl)-L-phenylalanine ester (0.1mmol), L-proline tert-butyl ester (0.12mmol) to a clean reaction tube, add an appropriate amount of ethyl acetate as solvent, react at 30°C for 12 hours, monitor by TLC, after the reaction, concentrate the organic layer and column chromatography to obtain a pure product, a colorless liquid, with a yield of 93%, de>99%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1H NMR (400MHz, CDCl3) δ7.27(s,5H),5.26(d,J=8.7Hz,1H),4.65(q,J=7.4Hz,1H),4.42–4.37(m ,1H),3.15–3.09(m,1H),2.89–2.83(m,1H),1.48(s,9H),1.42(d,J=7.5Hz,6H),1.36(s,9H). 13 C NMR (150MHz, CDCl3) δ171.1,170.4,155.2,136.4,129.7,129.4,128.5,128.3,126.9,126.7,8 1.3,79.4,59.7,54.2,53.0,46.9,45.8,41.4,38.7,29.0,28.4,28.3,28.0,27.8,24.9,22.1. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 23 H 35 N2O5 419.2541; Found 419.2549. Example 26 In a clean reaction tube, add O-tert-butyl-L-serine tert-butyl ester hydrochloride (0.12mmol), sodium bicarbonate (0.12mmol), add appropriate amount of ethyl acetate as solvent, react at 30 degrees Celsius for 0.5 hours, then add (Z)-4-(tert-butyl)-1-(3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl)(((9H-fluorene-9-yl)methoxy)carbonyl)-L-aspartic acid ester (0.1mmol), react at 30℃ for 16 hours, monitor by TLC, after the reaction, the organic layer is concentrated and column chromatographed to obtain pure product, colorless liquid, yield 93%, de>99%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1H NMR (400MHz, CDCl3) δ7.75(d,J=7.5Hz,2H),7.59(d,J=7.6Hz,2H),7.39(t,J=7.5Hz, 2H),7.30(s,2H),6.02(d,J=8.2Hz,1H),4.63(d,J=6.1Hz,1H),4.55–4.51(m,1H),4. 38(d,J=7.1Hz,2H),4.23(t,J=7.2Hz,1H),3.82–3.78(m,1H),3.54–3.50(m,1H),2.9 7–2.84(m,1H),2.73–2.63(m,1H),2.03(s,1H),1.45(d,J=4.2Hz,18H),1.15(s,9H). 13 C NMR (150MHz, CDCl3) δ171.1,170.3,168.9,155.8,143.8,141.3,127.7,127.1,125.1,12 0.0,81.7,73.1,67.3,61.9,60.4,53.5,50.8,47.1,38.0,28.1,28.0,27.3,21.0,14.2. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 34 H 47 N2O8 611.3327; Found 611.3322. Example 27 Add (Z)-5-(tert-butyl)-1-(3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl)((((9H-fluoren-9-yl)methoxy)carbonyl)-L-glutamate (0.1mmol), L-valine tert-butyl ester (0.12mmol) to a clean reaction tube, add an appropriate amount of ethyl acetate as solvent, react at 30°C for 12 hours, monitor by TLC, after the reaction, concentrate the organic layer and column chromatography to obtain a pure product, a colorless liquid, with a yield of 89%, de>99%. The following is the structural formula of the product and the experimental data of nuclear magnetic resonance and mass spectrometry: 1H NMR (400MHz, CDCl3) δ7.75(d,J=7.5Hz,2H),7.59(d,J=7.5Hz,2H),7.39(t,J= 7.5Hz,2H),7.30(t,J=7.4Hz,2H),6.89(d,J=8.6Hz,1H),5.80(d,J=7.8Hz,1H) ,4.43–4.35(m,3H),4.34–4.27(m,1H),4.21(t,J=7.2Hz,1H),2.42(t,J=9.0H z,2H),2.25–2.09(m,2H),1.99–1.92(m,1H),1.46(s,18H),0.95–0.90(m,6H). 13 C NMR (150MHz, CDCl3) δ173.1,171.2,170.6,156.2,143.8,141.3,127.7,127.1,125.2,120.0,82.0 ,81.1,67.1,57.8,54.1,47.1,31.7,31.1,28.6,28.1,28.0,19.0,17.6.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 33 H 45 N2O7 581.3221; Found 581.3213. The embodiments described above are merely descriptions of preferred implementation modes of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A three-component direct synthesis method of β-acyloxy enamide compounds, characterized in that: The method comprises the following steps: adding 0.2 mmol to 6.0 mmol of α-trifluoromethyl ketone 1, 1.0 to 30.0 mmol of carboxylic acid or amino acid 2 and 30.3 to 9.0 mmol of amine into a reaction tube, and then adding 0.3 to 9.0 mmol of a base promoter, and stirring for 5 to 10 hours at a reaction temperature of 40 to 60° C. in an air atmosphere with 2.0 to 30.0 mL of an organic solvent; after the reaction is completed, extracting and purifying to obtain β-acyloxy enamide 4; the general chemical reaction formula is: Where R 1 is an aryl group or an alkyl group, R 2 is aryl, alkyl, alkenyl, alkynyl, sorbic acid, ursolic acid, ibuprofen, veratric acid, N-protected amino acid, R 3 and R 4 is an alkyl group or an aryl group.

2. The method according to claim 1, characterized in that: The carboxylic acid is an aryl group, an alkyl carboxylic acid, sorbic acid, ursolic acid, ibuprofen, or veratric acid; and the amino acid is an N-protected amino acid.

3. The method according to claim 1, characterized in that The organic solvent is ethanol, ethyl acetate, acetone, or DMSO.

4. The method according to claim 1, characterized in that The alkaline promoter is tetra-tert-butylammonium hydroxide, sodium tert-butoxide, sodium carbonate, sodium hydroxide, lithium hydroxide, and cesium carbonate.

5. The method according to claim 1, characterized in that The amine is a secondary amine, and the molar ratio of the α-trifluoromethyl ketone, carboxylic acid and secondary amine is 1:5:1.5; the base promoter is cesium carbonate, and the molar ratio of cesium carbonate to α-trifluoromethyl ketone is 1.5:1; the organic solvent is DMSO, and the amount is 2-10 mL; the reaction temperature is 40-45° C., and the stirring is 5-6 hours.

6. Use of the β-acyloxy enamide prepared according to any one of claims 1 to 5, characterized in that: The β-acyloxyenamides can be used to synthesize amides or peptides.

7. The specific method of application according to claim 6, characterized in that: The following steps are involved: (1) 0.2 mmol of the β-acyloxy enamide 4, 0.12-0.24 mmol of an amine or amino acid 5, and 1 mL of ethyl acetate are mixed and stirred continuously at a temperature of 30-80° C. for 3-24 hours; (2) Column chromatography separation and purification to obtain amide or peptide product 6, and at the same time obtain by-product β-ketoamide 7, the reaction equation is as follows: Where R 1 is an aryl group or an alkyl group, R 2 is aryl, alkyl, alkenyl, sorbic acid, ursolic acid, ibuprofen, veratric acid, N-protected amino acid, R 3 and R 4 Alkyl, aryl and carboxyl protected amino acids.

8. The specific method of application according to claim 7, characterized in that: The following steps are involved: The molar ratio of β-acyloxy enamide 4 to amine or amino acid 5 is 1:1.2.

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