Method for synthesizing amide and / or polypeptide by taking transiently protected amino acid as ammonia component

Abstract

Provided is a method for synthesizing amide and / or polypeptide by taking a transiently protected amino acid as an ammonia component. In the method, an allenone compound is taken as a condensation reagent, a silylating reagent is used for temporarily protecting a carboxyl group of an amino acid or peptide fragment of which amino and carboxyl groups are not protected, then an α-carbonyl alkenyl ester derivative of another molecular carboxylic acid, or amino acid, or a C-terminal carboxyl group of a polypeptide is used together with same to form an amide bond, and then the temporarily protected carboxyl group can be subjected to on-site deprotection under an acidic condition to obtain a target carboxylic acid product, so as to cyclically construct a new amide bond. The allenone condensation agent 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, so that greatly excessive chemical reagents, time, manpower and energy consumption required when protecting groups are introduced and protecting groups are removed are avoided, thereby improving the step economy and atom economy of polypeptide synthesis.

Description

A method for synthesizing amides and / or polypeptides using transiently protected amino acids as ammonia components 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 ammonia components. Background Art

[0002] Peptides are compounds formed by the dehydration condensation of two or more amino acids. They are irreplaceable building blocks for active substances in the human body, such as enzymes, hormones, antibodies, and interstitial matter, and are the source of all life. Because each amino acid contains both a basic α-amino group and an acidic α-carboxyl group, condensation between amino acids can produce a wide variety of mixtures. Therefore, prior to the condensation reaction, any unneeded reactive groups must be protected to ensure a directional synthesis. Commonly used amino acid N-terminal protecting groups include fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz); and C-terminal protecting groups include methyl (Me), ethyl (Et), and tert-butyl (tBu). However, traditional peptide synthesis methods require the introduction and removal of protecting groups at each step, which not only wastes significant amounts of solvents and reagents but also significantly increases the time and effort of researchers. With the advancement of chemistry and chemical biology, rapid, efficient, economical, and environmentally friendly peptide synthesis methods have become a hot topic of research.

[0003] In 2021, 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, low molecular weight, mild reaction conditions, and does not require any additives during use. More importantly, the condensing agent does not undergo racemization during peptide chain activation and aminolysis, allowing the use of an N→C peptide synthesis strategy, greatly improving the purity and yield of the product. However, during the peptide synthesis process, this condensing agent still reacts with a carboxyl-protected amino acid as the amino component. After the reaction is completed, the protected peptide is still obtained, and further extension of the peptide chain still requires deprotection post-treatment, resulting in lengthy peptide synthesis steps, time-consuming, labor-intensive, and costly.

[0004] Summary of the Invention

[0005] 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 the amino component, in which a silanization agent is used to temporarily protect the carboxyl group of an amino acid or peptide segment whose amino and carboxyl groups are not protected, using a silanization agent, and then forming a peptide bond with another molecule of amino acid or an α-carbonyl alkenyl ester derivative of the C-terminal carboxyl group of the polypeptide. The temporarily protected carboxyl group can be deprotected on-site under acidic conditions to obtain the target carboxylic acid product, and then a new peptide bond is constructed cyclically. The condensing agents or activators used in the existing related 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 this "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 large excess of chemical reagents, time, manpower and energy consumption required for the introduction and removal of protecting groups, improving the step economy and atom economy of polypeptide synthesis, and significantly reducing the cost of polypeptide synthesis.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is:

[0007] The first aspect of the present invention provides a method for preparing an amide and / or polypeptide, comprising the following steps:

[0008] The compound of formula I and the compound of formula II are reacted in solvent I, and then subjected to a nucleophilic substitution reaction with the compound of formula III and a silanization agent in solvent II, 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 with a C-terminal carboxyl group missing, amino acid derivative residues or polypeptide fragments with a C-terminal carboxyl group missing; 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 These include 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-butyloxycarbonyl, 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 monocycle, a bridged ring or a spirocycle. 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 sulphur, 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 sulphur, 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 groups include, but are not limited to, oxirane, thioethane, and aziridine groups. Non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups. Examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups. Examples of 6-membered heterocycloalkyl groups 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 groups. Examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. The same applies to the remaining polycyclic heterocycles.

[0015] In some embodiments of the present invention, the cycloalkyl group refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 18-membered ring, or a 3 to 10-membered ring. Non-limiting examples of cycloalkyl groups 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-azulyl, 1-pyrenyl, 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 5-10 members, 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 with a missing C-terminal carboxyl group or the amino acid derivative residue with a missing C-terminal carboxyl group refers to the remaining portion of the amino acid or amino acid derivative after the C-terminal carboxyl group is missing; preferably, the amino acid residue with a missing C-terminal carboxyl group includes at least one of an α-amino acid residue with a missing C-terminal carboxyl group, a β-amino acid residue with a missing C-terminal carboxyl group or a γ-amino acid residue with a missing C-terminal carboxyl group; preferably, the amino acid derivative residue with a missing C-terminal carboxyl group includes an amino acid residue with a missing C-terminal carboxyl group protected by a C-terminal amino group, such as an amino acid residue with a missing C-terminal carboxyl group protected by an N-alkoxycarbonyl group and / or an N-acyl group; preferably, generally To represent α-amino acid, then R 1 In the embodiment, the amino acid residue with the C-terminal carboxyl group missing is It can be in R or S configuration; specifically, the amino acid residue with the C-terminal carboxyl group missing is selected from Preferably, the C-terminal carboxyl group-deficient amino acid derivative residue is selected from the C-terminal carboxyl group-deficient amino acid residues whose C-terminal amino group is protected by N-alkoxycarbonyl and / or N-acyl groups among the above-mentioned C-terminal carboxyl group-deficient amino acid residues.

[0019] 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.

[0020] In some embodiments of the present invention, the acidifying acidulant comprises an organic acid and / or an inorganic acid.

[0021] 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 lower (e.g., pH ≤ 4, pH ≤ 3, pH ≤ 2, pH ≤ 1) by dissolving in water.

[0022] 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, sad, lauric acid, arachidic acid, erucic acid, linoleic acid, linolenic acid, oleic acid, palmitic acid, myristic acid, edisilic acid (edisilic acid), stearic acid or any combination thereof. However, embodiments are not limited thereto.

[0023] The second aspect of the present invention provides another method for preparing an amide and / or polypeptide, comprising the following steps:

[0024] 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;

[0025] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 The definition of is as mentioned above.

[0026] In the present invention, since the compound of formula III (a compound containing both amino and carboxyl groups) exists as an intramolecular zwitterion under neutral conditions, it has poor solubility and the amino group does not have nucleophilicity, making it difficult to undergo a condensation reaction. A silanization agent (a transient protective agent) can be used to temporarily protect the carboxyl group in the compound of formula III to form a silicon ester compound, while simultaneously freeing the amino group, which can then undergo a nucleophilic substitution reaction with the compound of formula V to form a peptide bond, thereby producing a polypeptide compound of formula IV and a by-product compound of formula VI. The reaction mechanism is as follows:

[0027] 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.

[0028] 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 having both free amino and carboxyl groups, or other compounds having both amino and carboxyl groups; 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 having both unprotected amino and carboxyl groups; even more preferably, the compound of formula III 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 derivatives 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.

[0029] 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; more preferably (2-10):1.

[0030] In some embodiments of the present invention, the solvent II comprises 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.

[0031] 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.

[0032] In some embodiments of the present invention, the nucleophilic substitution reaction time is at least about 10 minutes, preferably 10 minutes to 72 hours.

[0033] 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 a silanization agent in a solvent II, and then adding the compound of formula V to carry out a nucleophilic substitution reaction to obtain a compound of formula IV.

[0034] In some embodiments of the present invention, the method for preparing the polypeptide comprises the following steps: dissolving the compound of formula III and a silanization agent in a solvent II at 20°C to 50°C with stirring for 5 minutes to 24 hours, and then adding the compound of formula V to carry out a nucleophilic substitution reaction to obtain a compound of formula IV.

[0035] 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.

[0036] In some embodiments of the present invention, the method for preparing the compound of formula V comprises the following steps:

[0037] The compound of formula I and the compound of formula II are dissolved in solvent I and stirred to react to obtain the compound of formula V;

[0038] Among them, R 1 、R 2 、R 3 、R 4 、R 5 The definition of is as mentioned above.

[0039] In some embodiments of the present invention, the solvent I comprises at least one of dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, toluene, acetonitrile, methanol or ethanol.

[0040] 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 a fatty acid, an aromatic acid, a heterocyclic acid, an alkyne acid, an alkenoic acid, an N-acyl amino acid, an N-alkoxycarbonyl amino acid or a polypeptide carboxylic acid; further preferably, the compound of formula I includes at least one of an N-benzyloxycarbonyl amino acid, an N-tert-butyloxycarbonyl amino acid, an N-fluorenylmethoxycarbonyl amino acid, an N-acetyl amino acid or a polypeptide carboxylic acid.

[0041] 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); more preferably 1:(1-2).

[0042] In some embodiments of the present invention, the stirring reaction temperature is -20°C to 90°C; preferably 0°C to 50°C.

[0043] The third aspect of the present invention provides a method for preparing an amide and / or polypeptide, comprising the following steps:

[0044] S1: dissolving the compound of formula I and the compound of formula II in solvent I and stirring to react to obtain the compound of formula V;

[0045] 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;

[0046] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 The definition of is as mentioned above.

[0047] 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.

[0048] The beneficial effects of the present invention are:

[0049] 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 the condensation reaction, so that the "protection-condensation-deprotection" process 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, a simple acidification treatment can obtain the target polypeptide carboxylic acid, 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, this method can also completely avoid the formation of racemic by-products, ensuring the yield and purity of the product. This method saves a large amount of reagents and solvents used in the traditional methods of "introducing protective groups into amino acids" and "removing protective groups from products", reducing the generation of a large amount of chemical waste, while saving time, human resources and energy consumption, significantly reducing the cost of polypeptide synthesis, improving the atom economy and step economy of polypeptide synthesis, efficiently achieving energy conservation and emission reduction, greatly improving the efficiency of polypeptide synthesis, and having broad industrial application prospects. DETAILED DESCRIPTION

[0050] The present invention is further described in detail below using specific examples. Unless otherwise specified, the raw materials, reagents, and apparatus used in the examples and comparative examples are available from conventional commercial sources or by conventional methods. Unless otherwise specified, all experimental or testing methods are conventional in the art.

[0051] Example 1

[0052] This example prepared a polypeptide of formula 1, and the specific process was as follows: Fmco-L-Leu-L-Phe-OH (1)

[0053] Fmoc-Leu-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.2 mmol), N-methyl-N-trimethylsilyl acetamide (0.4 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 93%.

[0054] Fmoc-Leu-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. After complete consumption of the starting material, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.2 mmol), hexamethyldisilazane (0.4 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After completion of the reaction, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with water and once with saturated brine. The organic phases were dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 96%.

[0055] Fmoc-Leu-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.2 mmol), trimethylsilyl imidazole (0.4 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and an 18% yield.

[0056] Fmoc-Leu-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.2 mmol), N,O-bistrimethylsilylacetamide (0.4 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 94%.

[0057] Fmoc-Leu-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.2 mmol), N,O-bistrimethylsilylacetamide (0.4 mmol), and 1 mL of 1,2-dichloroethane. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 94%.

[0058] Fmoc-Leu-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.2 mmol), N,O-bistrimethylsilylacetamide (0.4 mmol), and 1 mL of tetrahydrofuran for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and an 83% yield.

[0059] Product NMR experimental data, mass spectrometry experimental data:

[0060] 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).

[0061] 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.

[0062] Example 2

[0063] This example prepared a polypeptide of formula 2, and the specific process was: Boc-L-Ala-L-Phe-OH (2)

[0064] Boc-Ala-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 94%.

[0065] Product NMR experimental data, mass spectrometry experimental data:

[0066] 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).

[0067] 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.

[0068] Example 3

[0069] This example prepared a polypeptide of formula 3, and the specific process was: Cbz-Gly-L-Ala-OH (3)

[0070] Boc-Gly-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Ala-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid in a 93% yield.

[0071] Product NMR experimental data, mass spectrometry experimental data:

[0072] 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).

[0073] 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.

[0074] Example 4

[0075] This example prepared a polypeptide of formula 4, and the specific process was: Cbz-L-Ser(tBu)-L-Phe-OH(4)

[0076] Cbz-Ser(tBu)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the reaction mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The product was purified by column chromatography to obtain a colorless oil with a dr ratio >99:1 and a yield of 93%.

[0077] Product NMR experimental data, mass spectrometry experimental data:

[0078] 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).

[0079] 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.

[0080] Example 5

[0081] This example prepared a polypeptide of formula 5, and the specific process was: Boc-L-Met-L-Phe-OH (5)

[0082] Boc-Met-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 93%.

[0083] Product NMR experimental data, mass spectrometry experimental data:

[0084] 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).

[0085] 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.

[0086] Example 6

[0087] This example prepared a polypeptide of formula 6, and the specific process was: Cbz-L-Trp-L-Phe-OH (6)

[0088] Cbz-Trp-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 92%.

[0089] Product NMR experimental data, mass spectrometry experimental data:

[0090] 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).

[0091] 13 C NMR(101MHz,DMSO-d6)δ172.8,171.8,155.7,137.4,137.0,136.1,129.2,128.3, 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.

[0092] Example 7

[0093] This example prepared a polypeptide of formula 7, and the specific process was: Boc-L-Ile-L-Phe-OH (7)

[0094] Boc-Ile-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 92%.

[0095] Product NMR experimental data, mass spectrometry experimental data:

[0096] 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).

[0097] 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.

[0098] Example 8

[0099] This example prepared a polypeptide of formula 8, and the specific process was: Fmoc-L-Cys(Trt)-L-Phe-OH(8)

[0100] Fmoc-Cys(Trt)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 93%.

[0101] Product NMR experimental data, mass spectrometry experimental data:

[0102] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=7.6Hz,2H),7.75(d,J=6.5Hz,2H),7.63(q,J=8.6 Hz,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=19.7,8.3Hz,1 H),3.08–3.00(m,1H),2.95–2.86(m,1H),2.41(dq,J=15.5,6.9,4.3Hz,2H).

[0103] 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.

[0104] Example 9

[0105] This example prepared a polypeptide of formula 9, and the specific process was: Boc-L-Asn(Trt)-L-Phe-OH(9)

[0106] Boc-Asn(Trt)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 94%.

[0107] Product NMR experimental data, mass spectrometry experimental data:

[0108] 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).

[0109] 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.

[0110] Example 10

[0111] This example prepared a polypeptide of formula 10, and the specific process was: Cbz-L-Pro-L-Phe-OH (10)

[0112] Cbz-Pro-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Phe-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 93%.

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

[0114] 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).

[0115] 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.

[0116] Example 11

[0117] This example prepared a polypeptide of formula 11, and the specific process was: Cbz-L-Asp(tBu)-L-Thr(tBu)-OH(11)

[0118] Cbz-Asp(tBu)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Thr(tBu)-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a colorless oil with a dr ratio >99:1 and a yield of 94%.

[0119] Product NMR experimental data, mass spectrometry experimental data:

[0120] 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).

[0121] 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.

[0122] Example 12

[0123] In this example, a polypeptide of formula 12 was prepared by the following process: Cbz-L-Phe-L-Asp(tBu)-OH(12)

[0124] Cbz-Phe-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Asp(tBu)-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 93%.

[0125] Product NMR experimental data, mass spectrometry experimental data:

[0126] 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=8.2,4.1Hz,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).

[0127] 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.

[0128] Example 13

[0129] This example prepared a polypeptide of formula 13, and the specific process was: Cbz-L-Phe-L-Met-OH (13)

[0130] Cbz-Phe-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Met-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 95%.

[0131] Product NMR experimental data, mass spectrometry experimental data:

[0132] 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).

[0133] 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.

[0134] Example 14

[0135] In this example, a polypeptide of formula 14 was prepared by the following process: Boc-L-Lys(Boc)-L-Tyr(tBu)-OH(14)

[0136] Boc-Lys(Boc)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Tyr(tBu)-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 93%.

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

[0138] 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).

[0139] 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.

[0140] Example 15

[0141] This example prepared a polypeptide of formula 15, and the specific process was: Cbz-Aib-Aib-OH (15)

[0142] Cbz-Aib-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Aib-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid in an 88% yield.

[0143] Product NMR experimental data, mass spectrometry experimental data:

[0144] 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).

[0145] 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.

[0146] Example 16

[0147] In this example, a polypeptide of formula 16 was prepared by the following process: Boc-L-Phe-LN-Me-Ala-OH (16)

[0148] Boc-Phe-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of HN-Me-Ala-OH (0.2 mmol), N-trimethylsilylacetamide (0.2 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 95%.

[0149] Product NMR experimental data, mass spectrometry experimental data:

[0150] 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),4.40–4.13(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).

[0151] 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.

[0152] Example 17

[0153] This example prepared a polypeptide of formula 17, and the specific process was: ZL-Ala-L-Asp(tBu)-L-Val-OH(17)

[0154] Cbz-Ala-Asp(tBu)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the reaction mixture was transferred to a pre-stirred mixture of H-Val-OH (0.2 mmol), N,O-bistrimethylsilylacetamide (0.4 mmol), and 1 mL of acetonitrile. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 95%.

[0155] Cbz-Ala-Asp(tBu)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. Once the starting material was completely consumed, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Val-OH (0.2 mmol), hexamethyldisilazane (0.4 mmol), and 1 mL of acetonitrile for reaction. The reaction progress was monitored by TLC. After the reaction, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 94%.

[0156] Cbz-Ala-Asp(tBu)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Val-OH (0.2 mmol), N-methyl-N-trimethylsilyl acetamide (0.4 mmol), and 1 mL of acetonitrile for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio of >95.7:4.3 and a yield of 92%.

[0157] Cbz-Ala-Asp(tBu)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Val-OH (0.2 mmol), N,O-bistrimethylsilylacetamide (0.4 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >97:3 and a yield of 91%.

[0158] Cbz-Ala-Asp(tBu)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloroethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Val-OH (0.12 mmol), N,O-bistrimethylsilylacetamide (0.12 mmol), and 1 mL of 1,2-dichloroethane. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 95%.

[0159] Product NMR experimental data, mass spectrometry experimental data:

[0160] 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).

[0161] 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.

[0162] Example 18

[0163] This example prepared a polypeptide of formula 18, and the specific process was: ZL-Ala-L-Tyr(tBu)-L-Aal-OH(18)

[0164] Cbz-Ala-Tyr(tBu)-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Ala-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 95%.

[0165] Product NMR experimental data, mass spectrometry experimental data:

[0166] 1H 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).

[0167] 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.

[0168] Example 19

[0169] This example prepared a polypeptide of formula 19, and the specific process was: ZL-Ala-L-Phe-L-Met-OH (19)

[0170] Cbz-Ala-Phe-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Met-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 92%.

[0171] Product NMR experimental data, mass spectrometry experimental data:

[0172] 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).

[0173] 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.

[0174] Example 20

[0175] In this example, a polypeptide of formula 20 was prepared by the following process: ZL-Ala-L-Val-L-Thr(tBu)-OH(20)

[0176] Cbz-Ala-Val-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Thr(tBu)-OH (0.2 mmol), N-trimethylsilylacetamide (0.2 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 92%.

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

[0178] 1H 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=7.6Hz,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).

[0179] 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.

[0180] Example 21

[0181] This example prepared a polypeptide of formula 21, and the specific process was: Boc-L-Ala-L-Phe-L-Ile-OH (21)

[0182] Boc-Ala-Phe-OH (0.1 mmol) and 1-phenylbuta-2,3-dien-1-one (0.1 mmol) were dissolved in 1 mL of 1,2-dichloromethane and stirred at room temperature. The reaction progress was monitored by TLC. After the starting material was completely consumed, the 1,2-dichloromethane was removed by distillation under reduced pressure, and the mixture was transferred to a pre-stirred mixture of H-Ile-OH (0.12 mmol), N-trimethylsilylacetamide (0.12 mmol), and 1 mL of N,N-dimethylformamide for reaction. The reaction progress was monitored by TLC. After the reaction was completed, 10 mL of 0.2 M HCl was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was recrystallized from diethyl ether. The solid was collected by filtration to obtain the pure product as a white solid with a dr ratio >99:1 and a yield of 93%.

[0183] Product NMR experimental data, mass spectrometry experimental data:

[0184] 1H 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).

[0185] 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.

[0186] 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 considered as equivalent replacement methods and are included in the scope of protection 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 2, 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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