Method for synthesizing amide and / or polypeptide by taking transient protection amino acid as ammonia component

Abstract

The invention discloses a method for synthesizing amide and / or polypeptide by taking transient protection amino acid as an ammonia component, which comprises the following steps of: temporarily protecting amino acid or carboxyl of a peptide fragment with unprotected amino and carboxyl by using a silanization reagent by taking an allene ketone compound as a condensation reagent; and forming an amido bond with another molecule carboxylic acid or amino acid or an alpha-carbonyl alkenyl ester derivative of a carboxyl group at the C end of the polypeptide, and performing field deprotection on the temporarily protected carboxyl group in an acidic aqueous solution to obtain a target carboxylic acid product, thereby circularly constructing a new amido bond. The allene ketone condensing agent used in the invention can effectively avoid racemization, and the'temporary protection 'strategy enables the'protection-condensation-deprotection' three-step reaction to be carried out in one pot, thereby avoiding the use of greatly excessive chemical reagents, time, manpower and energy consumption during the introduction and removal of the protecting group; the step economy and the atom economy of polypeptide synthesis are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthetic chemistry, and in particular to a method for synthesizing amides and / or polypeptides by using transiently protected amino acids as amino components. Background Art

[0002] Polypeptides are compounds formed by the dehydration condensation of two or more amino acids. They are irreplaceable raw materials for active substances such as enzymes, hormones, antibodies, and neural matrix in the human body, and are the source of all life. Since each amino acid contains an alkaline α-amino group and an acidic α-carboxyl group, the condensation between amino acids will produce a mixture of any combination. Therefore, before the condensation reaction, the reactive groups that do not need to participate must be protected, and then the condensation reaction is carried out to ensure the directional synthesis. Commonly used amino acid N-terminal protecting groups include fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), etc.; C-terminal protecting groups include methyl (Me), ethyl (Et), tert-butyl ( t Bu), etc. However, each step of the traditional peptide synthesis method requires the introduction and removal of protecting groups, which not only wastes a lot of solvents and reagents, but also greatly increases the time cost of researchers. With the development of chemistry and chemical biology, fast, efficient, economical and environmentally friendly peptide synthesis methods have become a hot topic in research.

[0003] In 2021, some scholars designed and developed a new type of allenone condensing agent for the synthesis of amide bonds and peptide bonds. This new condensing agent is easy to prepare, has good stability, small molecular weight, mild reaction conditions, and does not require any additives during use. More importantly, the condensing agent does not undergo racemization during the activation of the peptide chain and during the aminolysis process, and the strategy of peptide synthesis from N→C can be adopted, which greatly improves the purity and yield of the product. However, during the peptide synthesis process, the condensing agent still reacts with carboxyl-protected amino acids as the ammonia component, and the protected polypeptide is still obtained after the reaction is completed. Deprotection post-treatment is still required to continue to extend the peptide chain, which makes the polypeptide synthesis steps lengthy, time-consuming, laborious, and costly. Summary of the invention

[0004] The present invention aims to solve at least one of the above-mentioned technical problems existing in the prior art. To this end, the purpose of the present invention is to provide a method for synthesizing amides and / or polypeptides using transiently protected amino acids as ammonia components, in which a silanization agent is used to temporarily protect the carboxyl group of an amino acid or a peptide segment whose amino and carboxyl groups are not protected, and then to form a peptide bond with another molecule of amino acid or an α-carbonyl alkenyl ester derivative of the C-terminal carboxyl group of a polypeptide. The temporarily protected carboxyl group can be deprotected on-site in an acidic aqueous solution to obtain a target carboxylic acid product, and then a new peptide bond is constructed cyclically. The condensing agent or activating agent used in the prior art to synthesize polypeptides using unprotected amino acids can only synthesize dipeptides. When synthesizing tripeptides or polypeptides containing more than three amino acids, severe racemization will be induced. This is because traditional condensing agents activate long-chain polypeptides. The allenone condensation agent used in the present invention can effectively avoid racemization, and the "temporary protection" strategy enables the three-step reaction of "protection-condensation-deprotection" to be carried out in one pot, combining the original three steps into one step, avoiding the need for greatly excessive chemical reagents, time, manpower and energy consumption when introducing and removing protecting groups, improving the step economy and atom economy of polypeptide synthesis, and greatly reducing the cost of polypeptide synthesis.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] The first aspect of the present invention provides a method for preparing an amide and / or a polypeptide, comprising the following steps:

[0007]

[0008] The compound of formula I and the compound of formula II are reacted in solvent I, and then reacted with the compound of formula III and a silanization agent in solvent II for nucleophilic substitution reaction, and then acidified to obtain the compound of formula IV;

[0009] Among them, R 1 Including alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino acid residues lacking a C-terminal carboxyl group, amino acid derivative residues lacking a C-terminal carboxyl group or polypeptide fragments; R 2 Including one of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R 3 , R 4 and R 5 Each independently includes H, C1~C 18 Hydrocarbon, substituted C1~C 18 Hydrocarbon, C1~C 16 Acyl, cyano, C1~C 16 One of the hydrocarbon-carbonyl groups; R 6 It includes alkyl groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, amino acid residues or polypeptide fragments.

[0010] In some embodiments of the present invention, R 2 In the above, the substituted aryl or substituted heteroaryl includes an aryl or heteroaryl substituted by at least one selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and nitro.

[0011] In some embodiments of the present invention, R 2 Including one of phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2-methylphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3,5-dinitrophenyl, pentafluorophenyl, 4-trifluoromethylphenyl, 3,5-dichlorophenyl, 1-naphthyl, 2-naphthyl, furyl, thienyl, and pyridyl.

[0012] In some embodiments of the present invention, R 3 , R 4 and R 5 Each independently includes one of H, methyl, formyl, acetyl, propionyl, cyano, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl.

[0013] In some embodiments of the present invention, the alkyl group refers to a saturated hydrocarbon group having a specified number of carbon atoms. 18 Alkyl refers to an alkyl group having 1 to 18 carbon atoms, for example, preferably 1 to 6 carbon atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group can also be optionally substituted with one or more substituents as defined herein. Specific examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3 dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, neopentyl, hexyl, 2-methylpentyl, etc.

[0014] In some embodiments of the present invention, the heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is generally a 3 to 10 ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen, or the heterocycle is generally a 3 to 7 ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Heterocycloalkyl can be a 3 to 6 ring containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxirane, thioethane, and cyclonitroethane. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxadiazolyl, and thiadinyl. Examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. The same applies to the remaining polycyclic heterocycles.

[0015] In some embodiments of the present invention, the cycloalkyl refers to a fully saturated carbocyclic ring that can exist as a monocyclic ring, a bridged ring, or a spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3 to 18-membered ring, or a 3 to 10-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.

[0016] In some embodiments of the present invention, the aryl group is selected from phenyl, o-tolyl, m-tolyl, p-tolyl, 2,4-xylyl, p-cumenyl, mesityl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthrenyl, 9-phenanthrenyl, 1-acenaphthenyl, 2-azulenyl, 1-pyrene, 2-triphenylene, o-biphenyl, m-biphenyl, p-biphenyl, and terphenyl.

[0017] In some embodiments of the present invention, the heteroaryl group is selected from a heterocyclic group having 1 or 2 nitrogen atoms, oxygen atoms or sulfur atoms, and preferably a 5-10 membered group, for example, triazolyl, 3-oxadiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-oxazolyl, 3-isoxazolyl, 2-thiazolyl, 3-isothiazolyl, 2-imidazolyl, 3-pyrazolyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, N-indolyl, N-carbazolyl.

[0018] In some embodiments of the present invention, R 1 The amino acid residue lacking a C-terminal carboxyl group or the amino acid derivative residue lacking a C-terminal carboxyl group refers to the remaining part of the amino acid or amino acid derivative after the C-terminal carboxyl group is lost; preferably, the amino acid residue lacking a C-terminal carboxyl group includes at least one of an α-amino acid residue lacking a C-terminal carboxyl group, a β-amino acid residue lacking a C-terminal carboxyl group, or a γ-amino acid residue lacking a C-terminal carboxyl group; preferably, the amino acid derivative residue lacking a C-terminal carboxyl group includes an amino acid residue lacking a C-terminal carboxyl group protected by a C-terminal amino group, such as an amino acid residue lacking a C-terminal carboxyl group whose C-terminal amino group is protected by an N-alkoxycarbonyl group and / or an N-acyl group; preferably, generally To represent α-amino acid, R 1 In the embodiment, the amino acid residue with missing C-terminal carboxyl group is It can be in R or S configuration; specifically, the amino acid residue with a missing C-terminal carboxyl group is selected from

[0019] Preferably, the amino acid derivative residue lacking a C-terminal carboxyl group is selected from the amino acid derivative residue lacking a C-terminal carboxyl group whose C-terminal amino group is protected by an N-alkoxycarbonyl group and / or an N-acyl group among the above amino acid residues lacking a C-terminal carboxyl group.

[0020] In some embodiments of the present invention, when solvent II is different from solvent I, the method for preparing the amide and / or polypeptide further comprises removing the solvent I after the reaction and then performing the nucleophilic substitution reaction.

[0021] In some embodiments of the present invention, the acidifying acidulant comprises an organic acid and / or an inorganic acid.

[0022] The term "acidifier" may refer to any material that lowers the pH of a solution by dissolving in water. In some embodiments, the acidifier may be an inorganic acid and / or organic acid that can lower the pH of a solution to 5 or less (e.g., pH≤4, pH≤3, pH≤2, pH≤1) by dissolving in water.

[0023] Inorganic acid can include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sulfonic acid, sulfamic acid, sulfuric acid, nitric acid or any combination thereof. However, embodiments are not limited thereto. Organic acid can include citric acid, lactic acid, tartaric acid, fumaric acid, trifluoroacetic acid, phthalic acid, acetic acid, oxalic acid, malonic acid, adipic acid, phytic acid, succinic acid, glutaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, capric acid, caproic acid, caprylic acid, lauric acid, arachidic acid, erucic acid, linoleic acid, linolenic acid, oleic acid, palmitic acid, myristic acid, edisilic acid, stearic acid or any combination thereof. However, embodiments are not limited thereto.

[0024] The second aspect of the present invention provides another method for preparing an amide and / or a polypeptide, comprising the following steps:

[0025]

[0026] The compound of formula V, the compound of formula III and the silanization agent are dissolved in solvent II to carry out a nucleophilic substitution reaction, and then acidified to obtain a compound of formula IV;

[0027] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 The definition of is as mentioned above.

[0028] In the present invention, since the compound of formula III (a compound having both amino and carboxyl groups) exists in the form of zwitterions in the molecule under neutral conditions, it has poor solubility and the amino group does not have nucleophilicity, making it difficult to undergo condensation reactions. The carboxyl group in the compound of formula III can be temporarily protected by a silanization agent (a transient protection agent) to form a silicon ester compound, while the amino group is freed, and then a nucleophilic substitution reaction can be performed with the compound of formula V to form a peptide bond, thereby obtaining a polypeptide compound of formula IV and forming a byproduct compound of formula VI. The reaction mechanism is as follows:

[0029]

[0030] In some embodiments of the present invention, the silanization agent includes at least one of N-trimethylsilylacetamide, N-methyl-N-trimethylsilylacetamide, N-trimethylsilylpyrrolidone, N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide, N,O-bis(tert-butyldimethylsilyl)acetamide, N,O-bistrimethylsilylacetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, hexamethyldisilazane, trimethylsilylimidazole, dimethyldichlorosilane, trimethylchlorosilane and tert-butyldimethylchlorosilane.

[0031] In some embodiments of the present invention, the compound of formula III is an organic compound having both an amino group and a carboxyl group; preferably, the compound of formula III includes any one of an amino acid compound, a polypeptide compound in which both the amino group and the carboxyl group are free, or other compounds having both an amino group and a carboxyl group; further preferably, the compound of formula III includes any one of an α-amino acid, a β-amino acid, a γ-amino acid, or a polypeptide compound in which both the amino group and the carboxyl group are not protected; further preferably, the compound of formula II includes any one of glycine, alanine, leucine, isoleucine, proline, valine, phenylalanine, tyrosine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, tryptophan, histidine, lysine, arginine, citrulline, or derivative compounds of the above amino acids. It should be understood that the twenty-one amino acids included in the compound of formula III can all be natural α-amino acids in their L-configuration and / or their corresponding D-configuration α-amino acids.

[0032] In some embodiments of the present invention, the molar ratio of the silanization agent to the compound of formula III is (0.5-20):1; preferably (1-15):1; and more preferably (2-10):1.

[0033] In some embodiments of the present invention, the solvent II includes at least one of acetonitrile, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, m-xylene, dichloromethane, 1,2-dichloroethane or chloroform.

[0034] In some embodiments of the present invention, the temperature of the nucleophilic substitution reaction is -20°C to 150°C; preferably 0°C to 90°C, and more preferably 5°C to 50°C.

[0035] In some embodiments of the present invention, the time of the nucleophilic substitution reaction is at least about 10 min; preferably 10 min to 72 h.

[0036] In some embodiments of the present invention, the method for preparing the amide and / or polypeptide comprises the following steps: dissolving the compound of formula III and the silanization agent in solvent II, and then adding the compound of formula V to carry out a nucleophilic substitution reaction to obtain the compound of formula IV.

[0037] In some embodiments of the present invention, the method for preparing the polypeptide comprises the following steps: dissolving the compound of formula III and the silanization agent in solvent II with stirring at 20°C to 50°C for 5min to 24h, and then adding the compound of formula V to carry out a nucleophilic substitution reaction to obtain a compound of formula IV.

[0038] In some embodiments of the present invention, the method for preparing the amide and / or polypeptide further comprises a step of purifying the product after the nucleophilic substitution reaction, wherein the purification comprises at least one of extraction, recrystallization or column chromatography.

[0039] In some embodiments of the present invention, the method for preparing the compound of formula V comprises the following steps:

[0040]

[0041] The compound of formula I and the compound of formula II are dissolved in solvent I, and stirred to react to obtain a compound of formula V;

[0042] Among them, R 1 , R 2 , R 3 , R 4 , R 5 The definition of is as mentioned above.

[0043] In some embodiments of the present invention, the solvent I comprises at least one of dichloromethane, chloroform, 1,2-dichloroethane, ether, toluene, acetonitrile, methanol or ethanol.

[0044] In some embodiments of the present invention, the compound of formula I is a carboxylic acid compound; preferably, the compound of formula I includes at least one of fatty acids, aromatic acids, heterocyclic acids, acetylic acids, alkenoic acids, N-acyl amino acids, N-alkoxycarbonyl amino acids or polypeptide carboxylic acids; further preferably, the compound of formula I includes at least one of N-benzyloxycarbonyl amino acids, N-tert-butyloxycarbonyl amino acids, N-fluorenylmethoxycarbonyl amino acids, N-acetyl amino acids or polypeptide carboxylic acids.

[0045] In some embodiments of the present invention, the molar ratio of the compound of formula I to the compound of formula II is 1:(1-5); preferably 1:(1-4); and more preferably 1:(1-2).

[0046] In some embodiments of the present invention, the stirring reaction temperature is -20°C to 90°C; preferably 0°C to 50°C.

[0047] The third aspect of the present invention provides a method for preparing an amide and / or a polypeptide, comprising the following steps:

[0048]

[0049] S1: dissolving the compound of formula I and the compound of formula II in solvent I, stirring and reacting to obtain a compound of formula V;

[0050] S2: dissolving the compound of formula V, the compound of formula III, and a silanization agent in solvent II to carry out a nucleophilic substitution reaction, and then acidifying to obtain a compound of formula IV;

[0051] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 The definition of is as mentioned above.

[0052] The fourth aspect of the present invention provides an application of the method for preparing the amide and / or polypeptide in preparing the amide and / or polypeptide.

[0053] The beneficial effects of the present invention are:

[0054] In the preparation method of the polypeptide of the present invention, a cyclopentane compound is used as a condensation reagent, a low-cost unprotected amino acid is used as a raw material, and a silanization agent is used to temporarily protect the amino acid for condensation reaction, so that "protection-condensation-deprotection" is carried out in one pot, and the three-step reaction is combined into one step. After the construction of the peptide bond is achieved, the target polypeptide carboxylic acid can be obtained by simple acid treatment, which is directly used for the condensation of the next amino acid. At the same time, based on the characteristics of the cyclopentane condensation agent, the method can also completely avoid the generation of racemic by-products, ensuring the yield and purity of the product. The method saves a large amount of reagents and solvents used in the traditional method of "introducing protective groups into amino acids" and "removing protective groups from products", reduces the generation of a large amount of chemical waste, and saves time, human resources and energy consumption, greatly reduces the cost of polypeptide synthesis, improves the atomic economy and step economy of polypeptide synthesis, efficiently achieves energy conservation and emission reduction, greatly improves the efficiency of polypeptide synthesis, and has broad industrial application prospects. DETAILED DESCRIPTION

[0055] The present invention is further described in detail below by specific examples. Unless otherwise specified, the raw materials, reagents or devices used in the examples and comparative examples can be obtained from conventional commercial sources or can be obtained by prior art methods. Unless otherwise specified, the experiments or test methods are conventional methods in the art.

[0056] Example 1

[0057] This example prepares a polypeptide of formula 1, and the specific process is as follows:

[0058] Fmco-L-Leu-L-Phe-OH(1)

[0059]

[0060] Take Fmoc-Leu-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloroethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloroethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.2mmol), N-methyl-N-trimethylsilyl acetamide (0.4mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2M HCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 93%.

[0061] Take Fmoc-Leu-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloroethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloroethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.2mmol), hexamethyldisilazide (0.4mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2M HCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 96%.

[0062] Take Fmoc-Leu-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloroethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloroethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.2mmol), trimethylsilyl imidazole (0.4mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2M HCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 18%.

[0063] Take Fmoc-Leu-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloroethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloroethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.2mmol), N,O-bistrimethylsilylacetamide (0.4mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2MHCl water, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 94%.

[0064] Take Fmoc-Leu-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloroethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloroethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.2mmol), N,O-bistrimethylsilylacetamide (0.4mmol) and 1mL 1,2-dichloroethane for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2M HCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 94%.

[0065] Take Fmoc-Leu-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloroethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloroethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.2mmol), N,O-bistrimethylsilylacetamide (0.4mmol) and 1mL tetrahydrofuran for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2M HCl, extract the aqueous phase with ethyl acetate twice, combine the organic phases, wash once with water, wash the organic phase with saturated brine once, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 83%.

[0066] Product NMR experimental data, mass spectrometry experimental data:

[0067] 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=7.8Hz,1H),7.89(d,J=7.6Hz,2H),7.72(t,J=6.1Hz,2H),7.42(t,J =7.6Hz,3H),7.32(t,J=7.4Hz,2H),7.22(s,4H),7.19–7.14(m,1H),4.46(q,J=7.4Hz,1H),4.32(t,J= 8.6Hz,1H),4.29–4.18(m,2H),4.07(td,J=9.3,5.3Hz,1H),3.08(dd,J=14.0,5.2Hz,1H),2.94(dd,J= 13.9,8.6Hz,1H),1.62–1.55(m,1H),1.45–1.36(m,2H),0.88(d,J=6.6Hz,3H),0.84(d,J=6.7Hz,3H).

[0068] 13 C NMR(101MHz,DMSO-d6)δ172.7,172.2,155.8,143.9,143.7,140.7,137.4,129.1,128.1,1 27.6,127.0,126.33,125.3,120.1,65.5,53.2,53.0,46.7,40.7,36.7,24.1,23.0,21.5.

[0069] Example 2

[0070] This example prepares a polypeptide of formula 2, and the specific process is as follows:

[0071] Boc-L-Ala-L-Phe-OH(2)

[0072]

[0073] Take Boc-Ala-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2MHCl, extract the aqueous phase with ethyl acetate twice, combine the organic phases, wash with water once, wash the organic phase with saturated brine once, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 94%.

[0074] Product NMR experimental data, mass spectrometry experimental data:

[0075] 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=7.7Hz,1H),7.28-7.18(m,J=15.1,8.1Hz,5H),6.83(d,J=7.3Hz,1H),4.44(q,J=7.9Hz ,1H),4.06–3.86(m,1H),3.06(dd,J=13.8,5.0Hz,1H),2.92(dd,J=13.8,8.4Hz,1H),1.36(s,9H),1.13(d,J=7.0Hz,3H).

[0076] 13 C NMR (101MHz, DMSO) δ172.7,172.5,154.9,137.3,129.2,128.1,126.4,78.0,53.2,49.6,36.7,28.2,18.1.

[0077] Example 3

[0078] This example prepares a polypeptide of formula 3, and the specific process is as follows:

[0079] Cbz-Gly-L-Ala-OH(3)

[0080]

[0081] Take Boc-Gly-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Ala-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2MHCl water, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with a yield of 93%.

[0082] Product NMR experimental data, mass spectrometry experimental data:

[0083] 1 H NMR (400MHz, DMSO-d6) δ12.64(s,1H),8.15(d,J=7.2Hz,1H),7.44(t,J=5.9Hz,1H),7.38– 7.30(m,5H),5.05(s,2H),4.24(p,J=7.1Hz,1H),3.71–3.63(m,2H),1.28(d,J=7.2Hz,3H).

[0084] 13 C NMR (101MHz, DMSO-d6) δ174.1,168.9,156.5,137.1,128.4,127.9,127.7,65.5,47.5,43.3,17.4.

[0085] Example 4

[0086] This example prepares a polypeptide of formula 4, and the specific process is as follows:

[0087] Cbz-L-Ser( t Bu)-L-Phe-OH(4)

[0088]

[0089] Take Cbz-Ser( tBu)-OH (0.1mmol), 1-phenylbuta-2,3-diene-1-one (0.1mmol) were dissolved in 1mL 1,2-dichloromethane, stirred at room temperature for reaction, and the reaction process was monitored by TLC. After the raw materials were completely consumed, 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a system pre-stirred and mixed with H-Phe-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and the reaction process was monitored by TLC. After the reaction was completed, 10mL 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The mixture was purified by column chromatography to obtain a colorless oil with dr>99:1 and a yield of 93%.

[0090] Product NMR experimental data, mass spectrometry experimental data:

[0091] 1 H NMR(400MHz,DMSO-d6)δ8.01(d,J=7.7Hz,1H),7.38–7.16(m,11H),5.05(s,2H),4.51–4.45(m,1H),4.15– 4.10(m,1H),3.43–3.39(m,2H),3.06(dd,J=13.8,5.3Hz,1H),2.93(dd,J=13.8,8.0Hz,1H),1.09(s,9H).

[0092] 13 C NMR (101MHz, DMSO-d6) δ172.4,169.6,155.7,137.2,136.9,129.1,128.3,128.1,127.7,127.6,126.4,72.8,65.4,61.8,55.3,53.3,36.8,27.1.

[0093] Example 5

[0094] This example prepares a polypeptide of formula 5, and the specific process is as follows:

[0095] Boc-L-Met-L-Phe-OH(5)

[0096]

[0097] Take Boc-Met-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2MHCl, extract the aqueous phase with ethyl acetate twice, combine the organic phases, wash with water once, wash the organic phase with saturated brine once, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 93%.

[0098] Product NMR experimental data, mass spectrometry experimental data:

[0099] 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=7.8Hz,1H),7.30–7.21(m,5H),6.91(d,J=8.2Hz,1H),4.42–4.48(m,1H),4.00(d,J=7.1Hz,1H),3.07 (dd,J=13.9,5.0Hz,1H),2.92(dd,J=13.9,8.7Hz,1H),2.43–2.35(m,2H),2.02(s,3H),1.74(dq,J=13.7,7.6,6.6Hz,2H),1.37(s,9H).

[0100] 13 C NMR (101MHz, DMSO-d6) δ172.8,171.6,155.2,137.3,129.2,128.1,126.4,78.2,53.6,53.2,36.7,31.9,29.6,28.2,14.6.

[0101] Example 6

[0102] This example prepares a polypeptide of formula 6, and the specific process is as follows:

[0103] Cbz-L-Trp-L-Phe-OH(6)

[0104]

[0105] Take Cbz-Trp-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. After the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2MHCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 92%.

[0106] Product NMR experimental data, mass spectrometry experimental data:

[0107] 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.26(s,1H),7.65(d,J=6.7Hz,1H),7.39–6.90(m,15H),4.96(s,2 H),4.53(td,J=8.1,4.1Hz,1H),4.36(dt,J=9.2,4.5Hz,1H),3.11(t,J=13.1Hz,2H),3.04–2.85(m,2H).

[0108] 13 C NMR (101 MHz, DMSO-d6) δ 172.8, 171.8, 155.7, 137.4, 137.0, 136.1, 129.2, 128.3, 128.2, 127.7, 127.4, 127.3, 126.4, 123.8, 120.9, 118.5, 118.2, 111.3, 110.2, 65.3, 55.4, 53.4, 36.8, 27.8. Example 7

[0109] This example prepared a polypeptide of formula 7, and the specific process was as follows:

[0110] Boc-L-Ile-L-Phe-OH(7)

[0111]

[0112] Take Boc-Ile-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2MHCl, extract the aqueous phase with ethyl acetate twice, combine the organic phases, wash with water once, wash the organic phase with saturated brine once, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 92%.

[0113] Product NMR experimental data, mass spectrometry experimental data:

[0114] 1 H NMR(400MHz,DMSO-d6)δ12.72(s,1H),8.06(d,J=7.9Hz,1H),7.28–7.17(m,5H),6.61 (d,J=9.3Hz,1H),4.50–4.44(m,1H),3.82(t,J=8.4Hz,1H),3.06(dd,J=13.9,4.9Hz, 1H),2.90(dd,J=13.9,9.2Hz,1H),1.61(q,J=6.3Hz,1H),1.38(s,9H),1.03(dq,J=13 .9,8.1,7.6Hz,1H),0.88–0.82(m,1H),0.77(t,J=7.4Hz,3H),0.72(d,J=6.7Hz,3H).

[0115] 13 C NMR (101MHz, DMSO-d6) δ172.8,171.4,155.2,137.5,129.1,128.1,126.4,78.0,58.7,53.2,36.8,36.7,28.2,24.3,15.2,10.9.

[0116] Example 8

[0117] This example prepares a polypeptide of formula 8, and the specific process is as follows:

[0118] Fmoc-L-Cys(Trt)-L-Phe-OH(8)

[0119]

[0120] Take Fmoc-Cys(Trt)-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. After the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2M HCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 93%.

[0121] Product NMR experimental data, mass spectrometry experimental data:

[0122] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=7.6Hz,2H),7.75(d,J=6.5Hz,2H),7.63(q,J= 8.6Hz,1H),7.41(t,J=7.5Hz,2H),7.37–7.22(m,18H),7.17–7.10(m,5H),4.48– 4.38(m,1H),4.33(d,J=9.5Hz,1H),4.25(d,J=5.6Hz,2H),4.04(dt,J=19.7,8.3 Hz,1H),3.08–3.00(m,1H),2.95–2.86(m,1H),2.41(dq,J=15.5,6.9,4.3Hz,2H).

[0123] 13 C NMR(101MHz,DMSO-d6)δ172.3,169.6,155.5,144.3,143.6,140.7,137.1,129.1,128.0,1 28.0,127.6,127.0,126.7,126.3,125.3,120.0,65.9,53.9,53.3,46.6,36.6,33.9,26.3.

[0124] Example 9

[0125] This example prepares a polypeptide of formula 9, and the specific process is as follows:

[0126] Boc-L-Asn(Trt)-L-Phe-OH(9)

[0127]

[0128] Take Boc-Asn(Trt)-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. After the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2M HCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 94%.

[0129] Product NMR experimental data, mass spectrometry experimental data:

[0130] 1 H NMR(400MHz,Chloroform-d)δ7.36(s,1H),7.27–7.16(m,20H),7.06(d,J=6.8Hz,2H),6.16(d,J=6.5Hz,1H),4.59(q,J=6.3Hz,1H),4.45(q, J=5.7Hz,1H),3.01(dd,J=13.9,5.6Hz,1H),2.92(dd,J=13.7,6.0Hz,1H),2.84(d,J=10.2Hz,1H),2.60(dd,J=14.7,4.5Hz,1H),1.37(s,9H).

[0131] 13 C NMR (101MHz, CDCl3-d) δ173.6,171.8,170.6,155.9,144.3,135.9,129.4,128.8,128.6,128.0,127.1,127.0,70.9,53.7,51.5,38.1,37.4,28.3.

[0132] Example 10

[0133] This example prepares a polypeptide of formula 10, and the specific process is as follows:

[0134] Cbz-L-Pro-L-Phe-OH(10)

[0135]

[0136] Take Cbz-Pro-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Phe-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2MHCl water, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 93%.

[0137] Product NMR experimental data, mass spectrometry experimental data:

[0138] 1 H NMR(400MHz, DMSO-d6)δ8.15(dd,J=39.2,8.0Hz,1H),7.41–7.14(m,10H),5.13–4.84(m,2H),4.54–4.44(m,1H ),4.28–4.21(m,1H),3.41–3.30(m,2H),3.10–3.00(m,1H),2.98–2.86(m,1H),2.13–1.96(m,1H),1.76–1.66(m 3H).

[0139] 13 C NMR(101MHz,DMSO-d6)δ171.9,171.8,171.0,170.8,153.1,152.8,136.6,136.5,136.0,128.2,128.0,127.4,127.2,127.1,127.0, 126.7,126.4,126.0,125.4,125.3,64.9,64.7,58.7,58.3,52.4,52.1,46.0,45.4,38.3,38.1,37.9,35.6,29.9,28.6,22.6,21.8.

[0140] Embodiment 11

[0141] This example prepares a polypeptide of formula 11, and the specific process is as follows:

[0142] Cbz-L-Asp( t Bu)-L-Thr( t Bu)-OH(11)

[0143]

[0144] Take Cbz-Asp( t Bu)-OH (0.1 mmol) and 1-phenylbuta-2,3-diene-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction process was monitored by TLC. After the raw materials were completely consumed, 1,2-dichloromethane was removed by vacuum distillation and the mixture was transferred to a pre-stirred mixture of H-Thr( t Bu)-OH (0.12mmol), N-trimethylsilyl acetamide (0.12mmol) and 1mL N,N-dimethylformamide were reacted in a system, and the reaction process was monitored by TLC. After the reaction was completed, 10mL of 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, recrystallized with ether, and the solid was collected by filtration to obtain a pure product in the form of a colorless oil with dr>99:1 and a yield of 94%.

[0145] Product NMR experimental data, mass spectrometry experimental data:

[0146] 1 H NMR (400MHz, DMSO-d6) δ7.91–7.63(m,2H),7.37–7.26(m,10H),5.09–5.02(m,2H),4.61–4.48(m,2H),4.46 –4.38(m,2H),4.17–4.08(m,1H),2.78–2.68(m,1H),2.52–2.45(m,1H),1.37(s,9H),1.10(d,J=6.1Hz,3H).

[0147] 13 C NMR(101MHz,DMSO-d6)δ171.7,171.2,169.3,155.9,138.4,136.9,128.3,128.1, 127.8,127.7,127.4,127.4,80.1,74.5,70.2,65.6,56.4,51.4,37.4,27.7,16.1.

[0148] Example 12

[0149] This example prepares a polypeptide of formula 12, and the specific process is as follows:

[0150] Cbz-L-Phe-L-Asp( t Bu)-OH(12)

[0151]

[0152] Cbz-Phe-OH (0.1 mmol) and 1-phenylbuta-2,3-diene-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction process was monitored by TLC. After the raw materials were completely consumed, 1,2-dichloromethane was removed by vacuum distillation and the mixture was transferred to a pre-stirred mixture of H-Asp( t Bu)-OH (0.12mmol), N-trimethylsilyl acetamide (0.12mmol) and 1mL N,N-dimethylformamide were reacted in a system, and the reaction process was monitored by TLC. After the reaction was completed, 10mL of 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, recrystallized with ether, and the solid was collected by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 93%.

[0153] Product NMR experimental data, mass spectrometry experimental data:

[0154] 1 H NMR(400MHz,Chloroform-d)δ7.52–7.31(m,1H),7.23(s,2H),7.18–7.08(m,8H),5.59(d,J=7.8Hz,1H),4.94(t,J=8.8Hz,2H),4.71(dd,J=8.2,4.1H z,1H),4.57–4.34(m,1H),3.04(dd,J=13.5,5.7Hz,1H),2.94(dd,J=12.9, 7.7Hz,1H),2.87–2.79(m,1H),2.67(dd,J=17.0,4.7Hz,1H),1.32(s,9H).

[0155] 13 C NMR (101MHz, CDCl3-d) δ174.0,171.5,170.4,156.3,136.2,136.2,129.5,1 28.8,128.7,128.3,128.1,127.2,82.3,67.2,56.1,49.0,38.6,37.3,28.1.

[0156] Embodiment 13

[0157] This example prepares a polypeptide of formula 13, and the specific process is as follows:

[0158] Cbz-L-Phe-L-Met-OH(13)

[0159]

[0160] Take Cbz-Phe-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Met-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2MHCl, extract the aqueous phase with ethyl acetate twice, combine the organic phases, wash with water once, wash the organic phase with saturated brine once, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 95%.

[0161] Product NMR experimental data, mass spectrometry experimental data:

[0162] 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=8.1Hz,1H),7.53(d,J=8.6Hz,1H),7.28(dt,J=24.6,8.9Hz,10H),4.95(s,2H),4.49–4.25(m,2H) ,3.08–2.99(m,1H),2.75(t,J=12.4Hz,1H),2.06(s,3H),2.02(s,1H),1.96–1.77(m,1H),1.38(s,1H),1.20(q,J=10.7,6.9Hz,1H).

[0163] 13 C NMR (101MHz, DMSO-d6) δ173.3,171.9,155.9,138.2,137.1,129.3,128.4,128.1,127.7,127.5,126.3,65.2,56.1,51.0,37.4,30.8,29.7,14.7.

[0164] Embodiment 14

[0165] This example prepares a polypeptide of formula 14, and the specific process is as follows:

[0166] Boc-L-Lys(Boc)-L-Tyr( t Bu)-OH(14)

[0167]

[0168] Take Boc-Lys(Boc)-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane. Stir the reaction at room temperature and monitor the reaction process by TLC. After the raw materials are completely consumed, remove 1,2-dichloromethane by vacuum distillation and transfer to a pre-stirred mixture of H-Tyr( t Bu)-OH (0.12mmol), N-trimethylsilyl acetamide (0.12mmol) and 1mL N,N-dimethylformamide were reacted in a system, and the reaction process was monitored by TLC. After the reaction was completed, 10mL of 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, recrystallized with ether, and the solid was collected by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 93%.

[0169] Product NMR experimental data, mass spectrometry experimental data:

[0170] 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=8.0Hz,1H),7.12(d,J=8.4Hz,2H),6.85(d,J=8.3Hz,2H),6.77–6.67(m,2H),4.42(td,J=8.4,5. 0Hz,1H),3.86(d,J=8.0Hz,1H),3.01(dd,J=14.0,5.0Hz,1H),2.95–2.86(m,2H),2.84(d,J=9.3Hz,1H),1.38(s,18H),1.26(s,9H).

[0171] 13 C NMR(101MHz,DMSO-d6)δ172.9,172.1,155.6,155.2,153.6,131.9,129.7,12 3.4,78.0,77.6,77.3,54.4,53.1,36.1,31.7,29.2,28.6,28.3,28.2,22.8.

[0172] Embodiment 15

[0173] This example prepares a polypeptide of formula 15, and the specific process is as follows:

[0174] Cbz-Aib-Aib-OH(15)

[0175]

[0176] Take Cbz-Aib-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Aib-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2MHCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with a yield of 88%.

[0177] Product NMR experimental data, mass spectrometry experimental data:

[0178] 1 H NMR (400MHz, DMSO-d6) δ7.45(s,1H),7.35(d,J=4.3Hz,4H),7.31(dd,J=5.0,3.6Hz,1H),7.27(s,1H),5.02(s,2H),1.34(s,12H).

[0179] 13 C NMR (101MHz, DMSO-d6) δ175.8,173.3,154.6,137.1,128.2,127.6,127.5,65.0,56.0,55.1,25.0,24.4.

[0180] Example 16

[0181] This example prepares a polypeptide of formula 16, and the specific process is as follows:

[0182] Boc-L-Phe-LN-Me-Ala-OH(16)

[0183]

[0184] Take Boc-Phe-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with HN-Me-Ala-OH (0.2mmol), N-trimethylsilylacetamide (0.2mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2M HCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 95%.

[0185] Product NMR experimental data, mass spectrometry experimental data:

[0186] 1 H NMR(400MHz, DMSO-d6)δ7.02-6.95(m,J=29.2Hz,5H),6.76(d,J=8.6Hz,1H),4.73–4.46(m,1H),4.4 0–4.13(m,1H),2.67(d,J=11.3Hz,3H),2.34(d,J=67.9Hz,1H),1.05(s,9H),0.89(d,J=35.5Hz,3H).

[0187] 13 C NMR (101MHz, DMSO) δ172.9,171.6,155.2,137.7,129.4,128.1,126.3,78.1,52.3,52.1,36.8,31.2,28.2,14.1.

[0188] Embodiment 17

[0189] This example prepares a polypeptide of formula 17, and the specific process is as follows:

[0190] ZL-Ala-L-Asp( t Bu)-L-Val-OH(17)

[0191]

[0192] Take Cbz-Ala-Asp( tBu)-OH (0.1mmol), 1-phenylbuta-2,3-diene-1-one (0.1mmol) were dissolved in 1mL 1,2-dichloroethane, stirred at room temperature, and the reaction process was monitored by TLC. After the raw materials were completely consumed, 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a system pre-stirred and mixed with H-Val-OH (0.2mmol), N,O-bistrimethylsilylacetamide (0.4mmol) and 1mL acetonitrile for reaction, and the reaction process was monitored by TLC. After the reaction was completed, 10mL 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, recrystallized with ether, and the solid was collected by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 95%.

[0193] Take Cbz-Ala-Asp( t Bu)-OH (0.1mmol), 1-phenylbuta-2,3-diene-1-one (0.1mmol) were dissolved in 1mL 1,2-dichloroethane, stirred at room temperature, and the reaction process was monitored by TLC. After the raw materials were completely consumed, 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a system pre-stirred and mixed with H-Val-OH (0.2mmol), hexamethyldisilazide (0.4mmol) and 1mL acetonitrile for reaction, and the reaction process was monitored by TLC. After the reaction was completed, 10mL 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, recrystallized with ether, and the solid was collected by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 94%.

[0194] Take Cbz-Ala-Asp( t Bu)-OH (0.1mmol), 1-phenylbuta-2,3-diene-1-one (0.1mmol) were dissolved in 1mL 1,2-dichloroethane, stirred at room temperature, and the reaction process was monitored by TLC. After the raw materials were completely consumed, 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a system pre-stirred and mixed with H-Val-OH (0.2mmol), N-methyl-N-trimethylsilyl acetamide (0.4mmol) and 1mL acetonitrile for reaction, and the reaction process was monitored by TLC. After the reaction was completed, 10mL 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, recrystallized with ether, and the solid was collected by filtration to obtain a pure product as a white solid with dr>95.7:4.3 and a yield of 92%.

[0195] Take Cbz-Ala-Asp( t Bu)-OH (0.1mmol), 1-phenylbuta-2,3-diene-1-one (0.1mmol) were dissolved in 1mL 1,2-dichloroethane, stirred at room temperature, and the reaction process was monitored by TLC. After the raw materials were completely consumed, 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a system pre-stirred and mixed with H-Val-OH (0.2mmol), N,O-bistrimethylsilylacetamide (0.4mmol) and 1mL N,N-dimethylformamide for reaction, and the reaction process was monitored by TLC. After the reaction was completed, 10mL 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, recrystallized with ether, and the solid was collected by filtration to obtain a pure product as a white solid with dr>97:3 and a yield of 91%.

[0196] Take Cbz-Ala-Asp( t Bu)-OH (0.1mmol), 1-phenylbuta-2,3-diene-1-one (0.1mmol) were dissolved in 1mL 1,2-dichloroethane, stirred at room temperature for reaction, and the reaction process was monitored by TLC. After the raw materials were completely consumed, 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a system pre-stirred and mixed with H-Val-OH (0.12mmol), N,O-bistrimethylsilylacetamide (0.12mmol) and 1mL 1,2-dichloroethane for reaction, and the reaction process was monitored by TLC. After the reaction was completed, 10mL 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, recrystallized with ether, and the solid was collected by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 95%.

[0197] Product NMR experimental data, mass spectrometry experimental data:

[0198] 1H NMR (400MHz, DMSO-d6) δ8.28(d,J=8.1Hz,1H),7.62(d,J=8.6Hz,1H),7.52(d,J=7.3 Hz,1H),7.43–7.27(m,5H),5.11–4.94(m,2H),4.63(q,J=7.4Hz,1H),4.14(dd,J=8.6 ,5.5Hz,1H),4.05(q,J=7.2Hz,1H),2.70(dd,J=16.1,5.9Hz,1H),2.47(d,J=7.9Hz,1 H), 2.05 (q, J = 6.7Hz, 1H), 1.37 (s, 9H), 1.21 (d, J = 7.1Hz, 3H), 0.86 (d, J = 6.8Hz, 6H).

[0199] 13 C NMR (101MHz, DMSO-d6) δ173.1,170.7,169.7,156.2,137.4,128.8,128.3,128.2,80.6,65.9,57.6,50.6,49.8,37.4,30.4,28.1,19.5,18.6,18.2.

[0200] Embodiment 18

[0201] This example prepares a polypeptide of formula 18, and the specific process is as follows:

[0202] ZL-Ala-L-Tyr( t Bu)-L-Aal-OH(18)

[0203]

[0204] Take Cbz-Ala-Tyr( t Bu)-OH (0.1mmol), 1-phenylbuta-2,3-diene-1-one (0.1mmol) were dissolved in 1mL 1,2-dichloromethane, stirred at room temperature, and the reaction process was monitored by TLC. After the raw materials were completely consumed, 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a system pre-stirred and mixed with H-Ala-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and the reaction process was monitored by TLC. After the reaction was completed, 10mL 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, recrystallized with ether, and the solid was collected by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 95%.

[0205] Product NMR experimental data, mass spectrometry experimental data:

[0206] 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=7.1Hz,1H),7.89(d,J=8.5Hz,1H),7.42(d,J=7.3Hz,1H), 7.38–7.26(m,5H),7.16(d,J=8.3Hz,2H),6.83(d,J=8.2Hz,2H),5.08–4.97(m,2H),4.55(dt ,J=8.5,4.4Hz,1H),4.24(p,J=7.1Hz,1H),4.00(q,J=7.0Hz,1H),3.04(dd,J=13.8,3.6Hz,1 H), 2.78 (dd, J = 13.7, 9.7Hz, 1H), 1.31 (d, J = 7.2Hz, 3H), 1.25 (s, 9H), 1.11 (d, J = 7.1Hz, 3H).

[0207] 13 C NMR(101MHz,DMSO-d6)δ174.0,172.2,170.9,155.7,153.4,137.0,132.4,129.9, 128.4,127.9,127.8,123.4,77.6,65.5,53.4,50.5,47.7,36.9,28.6,18.2,17.2.

[0208] Embodiment 19

[0209] This example prepares a polypeptide of formula 19, and the specific process is as follows:

[0210] ZL-Ala-L-Phe-L-Met-OH(19)

[0211]

[0212] Take Cbz-Ala-Phe-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Met-OH (0.12mmol), N-trimethylsilyl acetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2M HCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 92%.

[0213] Product NMR experimental data, mass spectrometry experimental data:

[0214] 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=7.3Hz,1H),7.95(d,J=7.7Hz,1H),7.44(d,J= 7.0Hz,1H),7.41–7.13(m,10H),5.11–4.94(m,2H),4.61–4.52(m,1H),4.42–4.3 5(m,1H),4.06–3.99(m,1H),3.15–3.04(m,1H),2.92–2.80(m,1H),2.53–2.43(m ,2H),2.05(s,3H),2.03–1.96(m,1H),1.94–1.86(m,1H),1.14(d,J=7.1Hz,3H).

[0215] 13 C NMR (101MHz, DMSO-d6) δ173.0,172.3,170.9,154.9,137.5,129.3,127.9,126.2,78.1,53.2,50.9,49.9,37.5,30.8,29.6,28.2,18.1,14.6.

[0216] Embodiment 20

[0217] This example prepares a polypeptide of formula 20, and the specific process is as follows:

[0218] ZL-Ala-L-Val-L-Thr( t Bu)-OH(20)

[0219]

[0220] Cbz-Ala-Val-OH (0.1 mmol) and 1-phenylbuta-2,3-diene-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction process was monitored by TLC. After the raw materials were completely consumed, 1,2-dichloromethane was removed by vacuum distillation and the mixture was transferred to a pre-stirred mixture of H-Thr( t Bu)-OH (0.2mmol), N-trimethylsilyl acetamide (0.2mmol) and 1mL N,N-dimethylformamide were reacted in a system, and the reaction process was monitored by TLC. After the reaction was completed, 10mL of 0.2M HCl was added, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, recrystallized with ether, and the solid was collected by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 92%.

[0221] Product NMR experimental data, mass spectrometry experimental data:

[0222] 1 H NMR(400MHz,Chloroform-d)δ7.48–7.35(m,1H),7.36–7.28(m,5H),7.07–7.02(m,1H),5.99–5.83(m,1H),5.15–5.01(m,2H),4.48(d,J=7.6H z,1H),4.45–4.31(m,2H),4.27–4.20(m,1H),2.13–1.99(m,1H),1.33( d,J=6.8Hz,3H),1.17(s,9H),1.10(d,J=6.0Hz,3H),0.98–0.86(m,6H).

[0223] 13 C NMR (101MHz, CDCl3-d) δ173.1,172.7,172.0,156.2,136.5,128.7,128.3,12 8.2,75.5,67.1,67.0,58.8,57.8,50.6,31.5,28.4,19.8,19.1,19.0,18.3.

[0224] Embodiment 21

[0225] This example prepares a polypeptide of formula 21, and the specific process is as follows:

[0226] Boc-L-Ala-L-Phe-L-Ile-OH(21)

[0227]

[0228] Take Boc-Ala-Phe-OH (0.1mmol) and 1-phenylbuta-2,3-diene-1-one (0.1mmol) and dissolve them in 1mL 1,2-dichloromethane, stir and react at room temperature, and monitor the reaction process by TLC. When the raw materials are completely consumed, remove 1,2-dichloromethane by distillation under reduced pressure, and transfer to a system pre-stirred and mixed with H-Ile-OH (0.12mmol), N-trimethylsilylacetamide (0.12mmol) and 1mL N,N-dimethylformamide for reaction, and monitor the reaction process by TLC. After the reaction is completed, add 10mL 0.2M HCl, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with water, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, recrystallize with ether, and collect the solid by filtration to obtain a pure product as a white solid with dr>99:1 and a yield of 93%.

[0229] Product NMR experimental data, mass spectrometry experimental data:

[0230] 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.73(d,J=6.1Hz,1H),7.20(d,J=14.5Hz,5H),6.96–6.62(m,1H),4.63(s,1H),4.20(s,1H),3.9 0(s,1H),3.03(d,J=12.5Hz,1H),2.90–2.73(m,1H),1.77(s,1H),1.36(s,9H),1.26–1.16(m,2H),1.09(d,J=5.4Hz,3H),0.85(s,6H).

[0231] 13 C NMR (101MHz, DMSO-d6) δ172.7,172.4,170.8,154.9,137.4,129.3,127.9,126.1,78.1,56.3,53.1,49.9,37.5,36.5,28.1,24.6,18.1,15.5,11.2.

[0232] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A method for preparing an amide and / or a polypeptide, characterized in that: The following steps are involved: The compound of formula I and the compound of formula II are reacted in solvent I, and then reacted with the compound of formula III and a silanization agent in solvent II for nucleophilic substitution reaction, and then acidified to obtain the compound of formula IV; Among them, R 1 Including alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino acid residues lacking a C-terminal carboxyl group, amino acid derivative residues lacking a C-terminal carboxyl group, or polypeptide fragments; R 2 Including one of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R 3 , R 4 and R 5 Each independently includes H, C1~C 18 Hydrocarbon, substituted C1~C 18 Hydrocarbon, C1~C 16 Acyl, cyano, C1~C 16 One of the hydrocarbon-carbonyl groups; R 6 It includes alkyl groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, amino acid residues or polypeptide fragments.

2. A method for preparing an amide and / or a polypeptide, characterized in that: The following steps are involved: The compound of formula V, the compound of formula III and the silanization agent are dissolved in solvent II to carry out a nucleophilic substitution reaction, and then acidified to obtain a compound of formula IV; Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 The definition as in claim 1.

3. The method for preparing an amide and / or polypeptide according to claim 3, characterized in that: The preparation method of the compound of formula V comprises the following steps: The compound of formula I and the compound of formula II are dissolved in solvent I, and stirred to react to obtain a compound of formula V; Among them, R 1 , R 2 , R 3 , R 4 , R 5 The definition as in claim 1.

4. A method for preparing an amide and / or a polypeptide, characterized in that: The following steps are involved: S1: dissolving the compound of formula I and the compound of formula II in solvent I, stirring and reacting to obtain a compound of formula V; S2: dissolving the compound of formula V, the compound of formula III, and a silanization agent in solvent II to carry out a nucleophilic substitution reaction, and then acidifying to obtain a compound of formula IV; Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 The definition as in claim 1.

5. The method for preparing the amide and / or polypeptide according to any one of claims 1, 3 or 4, characterized in that: When solvent II is different from solvent I, the method for preparing the amide and / or polypeptide further comprises removing the solvent I after the reaction and then performing the nucleophilic substitution reaction.

6. The method for preparing an amide and / or polypeptide according to any one of claims 1, 2 or 4, characterized in that: The silanization agent includes at least one of N-trimethylsilylacetamide, N-methyl-N-trimethylsilylacetamide, N-trimethylsilylpyrrolidone, N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide, N,O-bis(tert-butyldimethylsilyl)acetamide, N,O-bistrimethylsilylacetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, hexamethyldisilazane, trimethylsilylimidazole, dimethyldichlorosilane, trimethylchlorosilane and tert-butyldimethylchlorosilane.

7. The method for preparing an amide and / or polypeptide according to any one of claims 1, 2 or 4, characterized in that: The molar ratio of the silanization agent to the compound of formula III is (0.5-20):

1.

8. The method for preparing an amide and / or polypeptide according to any one of claims 1, 2 or 4, characterized in that: The solvent II includes at least one of acetonitrile, ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, m-xylene, dichloromethane, 1,2-dichloroethane or chloroform.

9. The method for preparing an amide and / or polypeptide according to any one of claims 1, 3 or 4, characterized in that: The solvent I comprises at least one of dichloromethane, chloroform, 1,2-dichloroethane, ether, toluene, acetonitrile, methanol or ethanol.

10. The method for preparing an amide and / or polypeptide according to any one of claims 1, 3 or 4, characterized in that: The molar ratio of the compound of formula I to the compound of formula II is 1:(1-5).

11. Use of the method for preparing the amide and / or polypeptide in preparing the amide and / or polypeptide.

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