α-Carbonyl vinyl ester compounds, their preparation methods and applications

Abstract

The invention discloses more active α-carbonyl alkenyl ester compounds and their preparation method and application, such alkyne amide activated ester activity is high, without any additives just can quickly construct amide bonds in solid phase peptide synthesis, and mild conditions, simple operation, high yield, compared with traditional condensation reagents, such alkyne amide condensation reagents have simple preparation, good stability, small molecular weight, simple operation, high atom economy, no racemization occurs when activating α-chiral carboxylic acid and other advantages, is a kind of efficient amide bond and peptide bond condensation reagent. The present invention also uses such alkyne amide as condensation reagent, with carboxylic acid and amine as starting materials, and successfully develops a method for building peptide bonds using alkyne amide as condensation reagent.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthetic chemistry, and in particular to α-carbonyl alkenyl ester compounds and preparation methods and applications thereof. Background Art

[0002] Peptides play a crucial role in drug development, biotechnology, and genetic testing. Their high specificity, targeted properties, and low toxicity have led to their widespread use in the medical field. Nearly 70 peptide drugs are currently marketed worldwide, with hundreds more in preclinical and clinical development. Peptide drugs have become the most active and fastest-growing segment of drug research and development. Therefore, developing efficient methods for obtaining peptides is a key focus for peptide scientists.

[0003] Solid Phase Peptide Synthesis (SPPS) was proposed by Merrifield in the 1960s, for which he was awarded the 1984 Nobel Prize in Chemistry. Solid-phase peptide synthesis is a very powerful and very important technology in peptide synthesis, and plays an important role in the field of peptide synthesis. Solid-phase peptide synthesis actually treats each protected amino acid as a building block, the resin as the foundation, and continuously connects the building blocks like an architect to form the required biomacromolecule. Compared with other synthesis methods, solid-phase peptide synthesis has many advantages, such as high production efficiency and simple operation. It is worth mentioning that through continuous development in recent decades, solid-phase peptide synthesis technology has achieved a transition from the original manual operation to fully automatic solid-phase peptide synthesis. Unfortunately, solid-phase peptide synthesis technology is not perfect either. This is mainly reflected in the fact that the polymer resin used in SPPS undergoes a heterogeneous chemical reaction in conventional reaction media. During the aminoacid aminolysis process, an excess (3 to 5 times) of base, condensation reagent, and amino acid is required to ensure that the most efficient coupling product is obtained in each step of the reaction, which greatly increases the cost of peptide synthesis. Therefore, the development of an efficient solid-phase peptide synthesis technology remains an unresolved problem in the peptide chemistry community.

[0004] As a compound containing a special functional group, alkynamide can act as a condensation agent to promote the formation of peptide bonds between amino acids. In related art, researchers have used alkynamide as a condensation agent to synthesize a series of dipeptides and complete the synthesis of enkephalin, demonstrating that alkynamide is an effective peptide condensation agent. However, due to its low activity and the fact that the aminolysis process typically requires 24 hours for complete reaction, it has not been effectively used in solid-phase peptide synthesis. 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 more active α-carbonyl alkenyl ester compound and its preparation method and application. This type of alkynamide activated ester has high activity and can quickly construct an amide bond in solid-phase peptide synthesis without any additives, and the conditions are mild, the operation is simple, and the yield is high. Compared with traditional condensation reagents, this type of alkynamide condensation reagent has the advantages of simple preparation, good stability, small molecular weight, simple operation, high atom economy, and no racemization occurs when activating α-chiral carboxylic acid. It is an efficient amide bond and peptide bond condensation reagent. The present invention also uses this type of alkynamide as a condensation reagent and carboxylic acid and amine as starting materials to successfully develop a method for constructing a peptide bond using alkynamide as a condensation reagent.

[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 compound of formula I or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Among them, R 1 Halogen, nitro, cyano, amino, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, alkylthio, acyl, acyloxy, amino acid residues lacking a C-terminal carboxyl group, amino acid derivative residues lacking a C-terminal carboxyl group, or polypeptide fragments;

[0010] R 2 is selected from hydrogen, halogen, cyano, alkyl, acyl, aryl, heteroaryl, alkoxy-carbonyl;

[0011] R 3 、R 4 、R 5 are the same or different and are each independently selected from hydrogen, halogen, cyano, alkyl, acyl, alkyloxy-carbonyl; or R 4 、R 5 Together with the atoms to which it is attached, it forms a group selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

[0012] wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, and thioalkyl groups are optionally unsubstituted or replaced by one or more R 11 Replace; each R 11 Selected from halogen, nitro, cyano, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, C4~C 12Heteroaryl, C1-C8 alkoxy, C1-C8 halogenated alkoxy, C1-C8 alkylthio, C1-C8 halogenated alkylthio, C1-C8 acyl, C1-C8 halogenated acyl, C1-C8 acyloxy, C1-C8 halogenated acyloxy;

[0013] The acyl group and acyloxy group are optionally unsubstituted or substituted by one or more R 21 Replace; each R 21 Selected from halogen, nitro, cyano.

[0014] In some embodiments of the present invention, the compound of formula I is selected from the compound of formula IA Compound of formula IB Among them, R 1 、R 2 、R 3 The definition of R is as mentioned above; 8 Selected from H, halogen, nitro, cyano, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, C4~C 12 heteroaryl, C1-C8 alkoxy, C1-C8 halogenated alkoxy, C1-C8 alkylthio, C1-C8 halogenated alkylthio, C1-C8 acyl, C1-C8 halogenated acyl, C1-C8 acyloxy, C1-C8 halogenated acyloxy; n is selected from natural numbers of 1-4; m is selected from natural numbers of 1-10.

[0015] 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

[0016] 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.

[0017] In some embodiments of the present invention, R 1 Selected from halogen, nitro, cyano, amino, C1-C 18 Alkyl, C3~C 18 Cycloalkyl, C3~C 18 Heterocycloalkyl, C2~C 18 Alkenyl, C2~C 18 Alkynyl, C6~C 18 Aryl, C4~C 18 Heteroaryl, C1~C 18 Hydroxyl, C1~C 18 Halogenated alkyloxy, C1~C 18 Hydrocarbon sulfide, C1~C 18 Halogenated hydrocarbon thio, C1~C 18 Acyl, C1~C 18 Halogenated acyl, C1~C 18 Acyloxy, C1~C 18 Halogenated acyloxy, α-amino acid residue with missing C-terminal carboxyl group, β-amino acid residue with missing C-terminal carboxyl group or γ-amino acid residue with missing C-terminal carboxyl group, amino acid derivative residue or polypeptide fragment with missing C-terminal carboxyl group, protected amino C1~C 18 Alkyl, protected amino C3~C 18 Cycloalkyl, protected amino C3~C 18 Heterocycloalkyl, protected amino C2~C 18 Alkenyl, protected amino C2~C 18 Alkynyl, protected amino C6~C 18 Aryl, protected amino C4~C 18 Heteroaryl, protected amino C1~C 18 Hydroxyl, protected amino C1~C 18 Halogenated alkyloxy, protected amino C1~C 18 Hydrocarbon thio, protected amino C1~C 18 Halogenated alkylthio, protected amino C1~C 18 Acyl, protected amino C1~C 18 Haloacyl, protected amino C1~C 18 Acyloxy, protected amino C1~C 18Halogenated acyloxy groups, α-amino acid residues with a protected amino group C-terminal carboxyl group missing, β-amino acid residues with a protected amino group C-terminal carboxyl group missing, γ-amino acid residues with a protected amino group C-terminal carboxyl group missing, amino acid derivative residues or polypeptide fragments with a protected amino group C-terminal carboxyl group missing;

[0018] R 2 is selected from hydrogen, halogen, cyano, C1-C 16 Alkyl, C1~C 16 Acyl, C6~C 24 Aryl, C4~C 24 Heteroaryl or C1~C 16 alkoxy-carbonyl;

[0019] R 3 、R 4 、R 5 are the same or different and are independently selected from hydrogen, halogen, cyano, C1-C 16 Hydrocarbon, C1~C 16 Acyl or C1~C 16 Hydroxyl-carbonyl; or R 4 、R 5 Together with the atoms connected to it, a group selected from C3~C 10 Cycloalkyl, C4~C 10 Heterocycloalkyl, C6~C 12 Aryl, C4~C 12 heteroaryl;

[0020] Wherein, the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, alkylthio, amino acid residue with a C-terminal carboxyl group missing, amino acid derivative residue with a C-terminal carboxyl group missing or polypeptide fragment is optionally unsubstituted or replaced by one or more R 11 Replace; each R 11 Selected from halogen, nitro, cyano, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, C4~C 12 Heteroaryl, C1-C8 alkoxy, C1-C8 halogenated alkoxy, C1-C8 alkylthio, C1-C8 halogenated alkylthio, C1-C8 acyl, C1-C8 halogenated acyl, C1-C8 acyloxy, C1-C8 halogenated acyloxy, protected amino;

[0021] The acyl group and acyloxy group are optionally unsubstituted or substituted by one or more R 21 Replace; each R 21 Selected from halogen, nitro, cyano.

[0022] In some embodiments of the present invention, the protected amino group refers to an amino group protected by a protecting group; the protected amino group includes at least one of a protected α-amino group, a protected β-amino group, and a protected γ-amino group; the protecting group is a commonly used protecting group in the art for protecting amino groups, amino acids, or polypeptide chains. For example, the protecting group is at least one selected from fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), or tert-butyloxycarbonyl (Boc), allyloxycarbonyl (Alloc), acetyl (Ac), methyl (Me), ethyl (Et), tert-butyl (tBu), trityl (Trt), or benzyl (Bn).

[0023] In some embodiments of the present invention, R 1 selected from halogen, nitro, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, butenyl, adamantyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, phenylethynyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, pyrrolyl, indolyl, indolemethyl, indazolyl, furyl, benzofuranyl, thienyl, benzothienyl, styryl, phenylethynyl, benzyl, 11-hydroxyundecyl, pentadecyl, protected α-amino C2-C 10 Alkyl, protected β-amino C3~C 10 Alkyl, protected γ-amino C4~C 10 Alkyl, α-amino acid residue with a protected amino group C-terminal carboxyl group missing, β-amino acid residue with a protected amino group C-terminal carboxyl group missing, γ-amino acid residue with a protected amino group C-terminal carboxyl group missing, amino acid derivative residue or polypeptide fragment with a protected amino group C-terminal carboxyl group missing.

[0024] In some embodiments of the present invention, R 1selected from halogen, nitro, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, butenyl, adamantyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, phenylethynyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, pyrrolyl, indolyl, indolemethyl, indole oxazolyl, furanyl, benzofuranyl, thienyl, benzothienyl, styryl, phenylethynyl, benzyl, 11-hydroxyundecyl, pentadecyl, protected glycine, protected alanine, protected phenylalanine, protected valine, protected cysteine, protected methionine, protected leucine, protected isoleucine, protected methionine, protected proline, protected tryptophan, protected serine, protected tyrosine, protected glutamine, protected asparagine, protected arginine, protected threonine, protected glutamic acid, protected aspartic acid, protected lysine, protected histidine.

[0025] In some embodiments of the present invention, R 2 Selected from hydrogen, fluorine, chlorine, bromine, methyl, formyl, acetyl, propionyl, 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, pyridyl.

[0026] In some embodiments of the present invention, R 3 、R 4 、R 5 are each independently selected from hydrogen, cyano, methyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl; or R 4 、R 5Together with the atoms to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, oxirane, thioethane, cyclonitroethane, azetidinyl, oxetanyl, thibutanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazole alkyl, tetrahydropyrazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, azepanyl, oxepanyl, thiepanyl, 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, terphenyl, triazolyl, 3-oxadiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridinyl, 1-Hydroxy-1-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-benzothiophenyl, N-indolyl, N-carbazolyl.

[0027] In some embodiments of the present invention, the compound of formula I is selected from the following compounds:

[0028] (E)-N-Fluorenylmethoxycarbonyl-L-glycine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0029]

[0030] (E)-N-Fluorenylmethoxycarbonyl-L-alanine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0031]

[0032] (E)-N-Benzyloxycarbonyl-L-alanine-1,1-dioxobenzisothiazole-2-vinyl-1-yl ester

[0033]

[0034] (E)-N-Benzyloxycarbonyl-L-phenylalanine-1,1-dioxobenzisothiazole-2-vinyl-1-yl ester

[0035]

[0036] (E)-N-Benzyloxycarbonyl-L-valine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0037]

[0038] (E)-N-tert-Butyloxycarbonyl-L-alanine-1,1-dioxobenzisothiazole-2-vinyl-1-yl ester

[0039]

[0040] (E)-N-tert-Butyloxycarbonyl-S-trityl-L-cysteine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0041]

[0042] (E)-N-tert-Butyloxycarbonyl-L-methionine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0043]

[0044] (E)-N-Fluorenylmethoxycarbonyl-L-phenylalanine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0045]

[0046] (E)-N-Fluorenylmethoxycarbonyl-L-leucine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0047]

[0048] (E)-N-Fluorenylmethoxycarbonyl-L-isoleucine-1,1-dioxobenzoisothiazole-2-vinyl-1-ester

[0049]

[0050] (E)-N-Fluorenylmethoxycarbonyl-L-methionine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0051]

[0052] (E)-N-Fluorenylmethoxycarbonyl-L-valine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0053]

[0054] (E)-N-Fluorenylmethoxycarbonyl-L-proline-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0055]

[0056] (E)-N-Fluorenylmethoxycarbonyl-L-tryptophan-1,1-dioxobenzisothiazole-2-vinyl-1-yl ester

[0057]

[0058] (E)-N-Fluorenylmethoxycarbonyl-O-tert-butyl-L-serine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0059]

[0060] (E)-N-Fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0061]

[0062] (E)-N-Fluorenylmethyloxycarbonyl-S-trityl-L-cysteine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0063]

[0064] (E)-N-Fluorenylmethoxycarbonyl-N'-trityl-L-glutamine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0065]

[0066] (E)-N-Fluorenylmethyloxycarbonyl-N'-trityl-L-asparagine-1,1-dioxobenzisothiazole-2-vinyl-1-yl ester

[0067]

[0068] (E)-N-Benzyloxycarbonyl-N',N"-dibenzyloxycarbonyl-L-arginine-1,1-dioxobenzisothiazole-2-vinyl-1-yl ester

[0069]

[0070] (E)-N-Benzyloxycarbonyl-O-tert-butyl-L-threonine-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0071]

[0072] (E)-N-Benzyloxycarbonyl-O-tert-butyl-L-aspartic acid-1,1-dioxobenzisothiazole-2-vinyl-1-yl ester

[0073]

[0074] (E)-N-tert-Butyloxycarbonyl-O-tert-butyl-L-glutamic acid-1,1-dioxobenzisothiazole-2-vinyl-1-ester

[0075]

[0076] (E)-N-tert-Butyloxycarbonyl-N'-tert-Butyloxycarbonyl-L-lysine-1,1-dioxobenzisothiazole-2-vinyl-1-yl ester

[0077]

[0078] (E)-N-tert-Butyloxycarbonyl-N'-tert-Butyloxycarbonyl-L-histidine-1,1-dioxobenzisothiazole-2-vinyl-1-yl ester

[0079]

[0080] (E)-N-tert-Butyloxycarbonyl-L-methionine-1,1-dioxoisothiazole-2-vinyl-1-ester

[0081]

[0082] The second aspect of the present invention provides a compound of formula II or a pharmaceutically acceptable salt thereof:

[0083]

[0084] Among them, R 2 、R 3 、R 4 、R 5 The definition of is as mentioned above.

[0085] In some embodiments of the present invention, the compound of formula II is selected from the following compounds:

[0086] 2-Ethynylisothiazolidine 1,1-dioxide

[0087]

[0088] 2-Ethynyl-2,3-dihydrobenzisothiazole 1,1-dioxide

[0089]

[0090] The third aspect of the present invention provides a method for preparing the compound of formula I, comprising the following steps:

[0091]

[0092] Reacting a compound of formula II with a compound of formula III to prepare a compound of formula I;

[0093] Among them, R 1 、R 2 、R 3 、R 4 、R 5 The definition of is as mentioned above.

[0094] In some embodiments of the present invention, the molar ratio of the compound of formula II to the compound of formula III is 1:(1-2); preferably 1:(1-1.5); more preferably 1:(1-1.2).

[0095] In some embodiments of the present invention, the molar ratio of the solvent in the reaction to the compound of formula II is (70-170):1, preferably (90-150):1, and more preferably (110-130):1.

[0096] In some embodiments of the present invention, the reaction solvent is an organic solvent; preferably an aprotic organic solvent. Preferably, the aprotic organic solvent includes one or more of dichloromethane, chloroform, dichloromethane, acetonitrile, tetrahydrofuran, water, ether, and toluene, preferably at least one of dichloromethane, chloroform, and dichloromethane; more preferably dichloromethane.

[0097] In some embodiments of the present invention, the reaction temperature is 0°C to 100°C; for example, 20°C to 60°C, or 30°C to 50°C.

[0098] In some embodiments of the present invention, the reaction time is 0.5 h to 320 h; for example, 1.0 h to 240 h, 5.0 h to 180 h.

[0099] The fourth aspect of the present invention provides a method for preparing a compound of formula II, characterized in that it comprises the following steps:

[0100]

[0101] reacting a compound of formula IV with a compound of formula V to prepare a compound of formula II;

[0102] Among them, R 2 、R 3 、R 4 、R 5 The definition as described in any one of claims 1 to 6; X is halogen.

[0103] In some embodiments of the present invention, the molar ratio of the compound of formula IV to the compound of formula V is 1:(1-2); preferably 1:(1-1.5); more preferably 1:(1-1.2).

[0104] In some embodiments of the present invention, the molar ratio of the solvent in the reaction to the compound of formula IV is (70-170):1, preferably (90-150):1, and more preferably (110-130):1.

[0105] In some embodiments of the present invention, the reaction solvent is an organic solvent; preferably an aprotic organic solvent. Preferably, the aprotic organic solvent includes one or more of dichloromethane, chloroform, dichloromethane, acetonitrile, tetrahydrofuran, water, ether, and toluene, preferably at least one of dichloromethane, chloroform, and dichloromethane; more preferably dichloromethane.

[0106] In some embodiments of the present invention, the reaction temperature is 0°C to 100°C; for example, 20°C to 60°C, or 30°C to 50°C.

[0107] In some embodiments of the present invention, the reaction time is 0.5 h to 320 h; for example, 1.0 h to 240 h, 5.0 h to 180 h.

[0108] A fifth aspect of the present invention provides a method for preparing a compound of formula VII, comprising the following steps:

[0109] The compound of formula I or a pharmaceutically acceptable salt thereof and the compound of formula VI The compound of formula VII is prepared by reaction

[0110] Among them, R 1 The definition of is as mentioned above;

[0111] R 6 and R 7 Each independently selected from hydrogen, amino, C1-C 24 a hydrocarbon group, an amino oligomer or amino polymer having a primary and / or secondary amine group; or 6 and R 7 Together with the N atoms to which they are connected, they form C3~C 24 Cyclic group; the hydrocarbon group is optionally unsubstituted or substituted by one or more R 31 replace;

[0112] R 31Selected from halogen, amino, hydroxyl, carboxyl, mercapto, nitro, cyano, C1~C8 hydrocarbon group, halogenated C1~C8 hydrocarbon group, C1~C8 hydrocarbonoxy group, C1~C8 halogenated hydrocarbonoxy group, C1~C8 hydrocarbonthio group, C1~C8 halogenated hydrocarbonthio group, C1~C8 acyl group, C1~C8 halogenated acyl group, C1~C8 acyloxy group, C1~C8 halogenated acyloxy group.

[0113] In the present invention, the compound of formula I is an acylating agent for synthesizing the compound of formula VI.

[0114] In some embodiments of the present invention, R 6 and R 7 Each independently selected from hydrogen, amino, C1-C 18 a hydrocarbon group, an amino oligomer or amino polymer having a primary and / or secondary amine group; or 6 and R 7 Together with the N atoms to which they are connected, they form C3~C 18 Cyclic group; the hydrocarbon group is optionally unsubstituted or substituted by one or more R 31 Replacement; R 31 The definition of is as mentioned above.

[0115] In some embodiments of the present invention, R 6 and R 7 Each independently selected from hydrogen, C1 to C 12 a hydrocarbon group, an amino oligomer or amino polymer having a primary and / or secondary amine group; or 6 and R 7 Together with the N atoms to which they are connected, they form C3~C 12 Cyclic group; the hydrocarbon group is optionally unsubstituted or substituted by one or more R 31 Replacement; R 31 The definition of is as mentioned above.

[0116] In some embodiments of the present invention, the amino oligomer comprises a polypeptide chain; and the amino polymer comprises a protein or a polyamine.

[0117] In some embodiments of the present invention, R 6 and R 7 Each is independently selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, cyclooctanediyl, hydroxyethylphenyl, phenyl, ethylphenyl, phenethyl, naphthyl, 3-indoleethyl, α-acyl C1-C 20 Alkyl, β-acyl C2~C 20 Alkyl, γ-acyl C3~C 20 Alkyl, polypeptide chain C1~C20 Alkyl or polypeptide chain C1~C 20 A type of alkenyl group.

[0118] In some embodiments of the present invention, R 6 and R 7 Not amino at the same time.

[0119] In some embodiments of the present invention, the compound of formula VI is a compound having at least one NH bond. The compound of formula VI is selected from ammonia, hydrazine, C1-C1 containing primary and / or secondary amine groups. 50 Organic amine (i.e., an organic amine compound having at least one NH bond, preferably C1 to C 32 Organic amine or amino acid, more preferably C1~C 24 Organic amine, more preferably C1~C 12 organic amine); or, amino oligomers or amino polymers (including polypeptides or proteins or polyamines) having primary and / or secondary amine groups (e.g., a degree of polymerization between 2 and 1000, preferably between 3 and 500, preferably between 4 and 200, preferably between 5 and 100, and more preferably between 6 and 20).

[0120] In some embodiments of the present invention, the molar ratio of the compound of formula I to the compound of formula VI is 1:(1-2); preferably 1:(1-1.5); more preferably 1:(1-1.2).

[0121] In some embodiments of the present invention, the molar ratio of the solvent in the reaction to the compound of formula I is (30-180):1, preferably (50-150):1, and more preferably (80-120):1.

[0122] In some embodiments of the present invention, the solvent of the reaction is an organic solvent, preferably an aprotic organic solvent; the aprotic organic solvent includes at least one of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile; preferably dimethyl sulfoxide and / or N,N-dimethylformamide; more preferably N,N-dimethylformamide.

[0123] In some embodiments of the present invention, the reaction temperature is -40°C to 100°C; for example, 0°C to 60°C, or 30°C to 50°C.

[0124] In some embodiments of the present invention, the reaction time is 0.05 h to 24 h; for example, 0.5 h to 15 h, 1 h to 10 h.

[0125] In some embodiments of the present invention, the method for preparing the compound of formula VII comprises the following steps:

[0126]

[0127] The compound of formula II reacts with the compound of formula III in a first solvent to produce the compound of formula I, and the compound of formula I reacts with the compound of formula VI in a second solvent to produce the compound of formula VII;

[0128] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 The definition of is as mentioned above.

[0129] In the present invention, the above reaction does not require additives and catalysts, and a "one-pot two-step" method can also be used to obtain the compound of formula VII.

[0130] In the present invention, research has discovered that carboxylic acid compounds of Formula III can undergo a 1,4-addition reaction with alkynamide compounds of Formula II to yield the corresponding compounds of Formula I (α-carbonyl alkenyl ester compounds). These alkenyl esters are relatively active and can undergo efficient aminolysis reactions with primary or secondary amines to yield the corresponding amide compounds. Furthermore, because this aminolysis reaction is fast and requires no additional catalysts or additives, it effectively suppresses racemization of α-chiral carboxylic acids during activation. As condensation reagents, alkynamides offer the advantages of simple preparation, low molecular weight, and resistance to racemization during activation of α-chiral carboxylic acids. Furthermore, the reaction conditions are mild and the operation is simple. The byproduct, benzoylacetone, is also valuable in synthesis, aligning with the trend of green chemistry in modern chemistry and exhibiting excellent atom economy. Therefore, the use of alkynamides in the synthesis of amide and peptide bonds presents a novel, efficient, and practical synthetic method.

[0131] In some embodiments of the present invention, the first solvent and the second solvent may be the same or different.

[0132] In some embodiments of the present invention, when the first solvent and the second solvent are different, the method for preparing the compound of formula VII further comprises removing the first solvent after the reaction of the compound of formula II and the compound of formula III before continuing the reaction.

[0133] In some embodiments of the present invention, the first solvent is an organic solvent, preferably an aprotic organic solvent; the first solvent is at least one of dichloromethane, chloroform, dichloromethane, acetonitrile, tetrahydrofuran, water, ether, and toluene; preferably at least one of dichloromethane, chloroform, and dichloromethane, and more preferably dichloromethane.

[0134] In some embodiments of the present invention, the second solvent is an organic solvent, preferably an aprotic organic solvent; the second solvent is at least one of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile. Preferably, the second solvent is dimethyl sulfoxide and / or N,N-dimethylformamide. More preferably, the second solvent is N,N-dimethylformamide.

[0135] A sixth aspect of the present invention provides a method for synthesizing a polypeptide, comprising the following steps:

[0136] In the resin solid phase carrier, at least one terminal amino acid compound of formula I (α-carbonyl alkenyl ester compound) corresponding to the polypeptide chain sequence is added according to the polypeptide chain sequence to carry out a coupling reaction to obtain PG-(AA) q -resin; after removing the side chain protecting groups and the resin, the polypeptide is obtained;

[0137] Wherein, q is a natural number greater than or equal to 2; PG refers to the protecting group at the end of the main chain of the polypeptide chain on the solid phase support, and AA refers to a single amino acid on the main chain of the polypeptide chain on the solid phase support.

[0138] In some embodiments of the present invention, the method for synthesizing the polypeptide comprises the following steps: adding at least one terminal amino acid compound of formula I (α-carbonyl alkenyl ester compound) corresponding to the polypeptide chain sequence to a resin solid phase carrier according to the polypeptide chain sequence to carry out a coupling reaction to obtain PG-(AA) q -resin; after deprotection, cleavage, removal of side chain protecting groups and resin, purification is performed to obtain the polypeptide.

[0139] In some embodiments of the present invention, the lysis solution used in the lysis is trifluoroacetic acid: triisopropylsilane: water = 95:2.5:2.5 or trifluoroacetic acid: ethanedithiol: triisopropylsilane: water = 92.5:2.5:2.5:2.5.

[0140] In some embodiments of the present invention, the method for synthesizing the polypeptide further comprises the following steps: 1) removing the protective group PG on the PG-AA-resin using a deprotection reagent to obtain H-AA-resin; 2) adding a compound of formula I (α-carbonyl alkenyl ester compound) corresponding to PG-AA-OH in the presence of a catalyst, and coupling in a solvent to obtain PG-(AA)2-resin; 3) repeating steps 1) and 2) in sequence according to the sequence of the target peptide chain to obtain PG-(AA) q -resin, deprotection, cleavage, removal of side chain protecting groups and resin, and purification to obtain the polypeptide.

[0141] In some embodiments of the present invention, the amount of the deprotection reagent in step 1) is PG-(AA) q - 1 to 100 times the molar amount of the resin; for example, 2 to 80 times, 3 to 50 times.

[0142] In some embodiments of the present invention, when the protecting group at the end of the polypeptide chain main chain on the resin solid phase support is Fmoc (fluorenylmethyloxycarbonyl), the deprotection reagent is a solution of piperidine in N,N-dimethylformamide, and the amount of the added amount is PG-(AA) q -1 to 100 times the molar amount of the resin; for example, 2 to 80 times, 3 to 50 times; when the protecting group at the end of the main chain of the polypeptide chain on the solid phase carrier is Boc (tert-butyloxycarbonyl), the deprotection reagent is a dichloromethane solution of trifluoroacetic acid, and the amount added is PG-(AA) q - 1 to 100 times the molar amount of the resin; for example, 2 to 80 times, 3 to 50 times.

[0143] In some embodiments of the present invention, the solvent for the coupling reaction is an organic solvent; preferably an aprotic organic solvent; preferably, the aprotic organic solvent is N,N-dimethylformamide (DMF) and / or dimethyl sulfoxide (DMSO); preferably N,N-dimethylformamide (DMF).

[0144] In some embodiments of the present invention, the solvent of the coupling reaction is PG-(AA) q -The mass ratio of the resin is (10-300):1; for example, (20-200):1, (30-100):1.

[0145] In some embodiments of the present invention, the purification is performed by reverse-phase high performance liquid chromatography, the chromatographic column is a C18 reverse-phase silica gel column, and the mobile phase is water and acetonitrile.

[0146] In some embodiments of the present invention, PG is selected from at least one of fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), allyloxycarbonyl (Alloc), acetyl (Ac), methyl (Me), ethyl (Et), tert-butyl (tBu), trityl (Trt) or benzyl (Bn); preferably, PG is selected from one of fluorenylmethyloxycarbonyl (Fmoc) or tert-butyloxycarbonyl (Boc); preferably, fluorenylmethyloxycarbonyl (Fmoc).

[0147] In some embodiments of the present invention, the resin solid phase carrier is selected from any one of Marrifield resin, Wang resin, 2-CTC resin, and MBHA resin.

[0148] In some embodiments of the present invention, the catalyst for the coupling reaction includes any one of HOAt (1-hydroxy-7-azobenzotriazole), HOBt (1-hydroxybenzotriazole), HOOBt (3-hydroxy-1,2,3-benzotriazine-4(3H)-one), HOSu (N-hydroxysuccinimide), COMU ((2-oxime-ethyl cyanoacetate)-N,N-dimethyl-morpholinyl uronium hexafluorophosphate), and HOPHT (N-hydroxyphthalimide); preferably HOAt (1-hydroxy-7-azobenzotriazole) or HOBt (1-hydroxybenzotriazole); more preferably HOBt (1-hydroxybenzotriazole).

[0149] In some embodiments of the present invention, the amount of the catalyst used is 0.3 to 10 times the molar amount of the resin solid phase carrier; for example, 1 to 5 times, 1 to 3 times.

[0150] In some embodiments of the present invention, the coupling reaction can also be carried out under the action of a base, which includes at least one of 4-dimethylaminopyridine, pyridine, N-methylimidazole, and N,N-diisopropylethylamine (DIEA); preferably N,N-diisopropylethylamine (DIEA).

[0151] In some embodiments of the present invention, the amount of the base is PG-(AA) q - 1 to 10 times the molar amount of the resin; for example, 1 to 6 times, 1 to 3 times.

[0152] In some embodiments of the present invention, the amount of the α-carbonyl alkenyl ester compound is PG-(AA) q - 1 to 10 times the molar amount of the resin; for example, 1 to 6 times, 1 to 3 times.

[0153] In some embodiments of the present invention, when a resin solid phase support (such as 2-CTC resin) is selected to react with the terminal amino acid of the target polypeptide chain sequence, the reaction is preferably carried out in a reaction environment in the presence of a base; and when a resin solid phase support (such as MBHA resin) is selected to react with an α-carbonyl alkenyl ester compound corresponding to the terminal amino acid of the target polypeptide chain sequence, the reaction is preferably carried out in a reaction environment in the presence of a catalyst; if other resin solid phase supports (such as Wang resin) are selected, then a more suitable condensation reagent can be optionally selected according to different combinations of the resin solid phase support and the terminal amino acid of the target polypeptide chain sequence or the α-carbonyl alkenyl ester compound corresponding to the terminal amino acid.

[0154] The seventh aspect of the present invention provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of amide compounds and / or polypeptides.

[0155] In the present invention, the protection in the protected α-aminoalkyl, protected β-aminoalkyl, protected γ-aminoalkyl, and polypeptide chain alkyl refers to protection of the terminal amino group on the main chain. The group that protects the terminal amino group on the main chain is called a main chain protecting group, and the main chain protecting group that protects the terminal amino group on the main chain is selected from one of Fmoc (fluorenylmethyloxycarbonyl), Cbz (benzyloxycarbonyl), Boc (tert-butyloxycarbonyl), Alloc (allyloxycarbonyl), and Ac (acetyl). The purpose of protecting the terminal amino group on the main chain is to prevent the terminal amino group from affecting the reaction process of synthesizing the compound of formula I using the compound of formula II and the compound of formula III.

[0156] Furthermore, the protected α-aminoalkyl, protected β-aminoalkyl, protected γ-aminoalkyl and polypeptide chain alkyl groups can also protect the functional groups on the side chains while protecting the terminal amino groups on the main chain. The functional groups to be protected on the side chains are selected from one or more of hydroxyl, sulfhydryl, amino, primary amide and carboxyl groups. The groups that protect the functional groups on the side chains are called side chain protecting groups. The side chain protecting groups that protect the functional groups on the side chains are selected from one or more of Fmoc (fluorenylmethyloxycarbonyl), Cbz (benzyloxycarbonyl), Boc (tert-butyloxycarbonyl), Alloc (allyloxycarbonyl), Ac (acetyl), Me (methyl), Et (ethyl), tBu (tert-butyl), Trt (trityl) and Bn (benzyl). The carboxylic acid compounds with main chain protecting groups or with both main chain protecting groups and side chain protecting groups can be synthesized or directly purchased. The purpose of protecting the terminal amino group on the main chain and the functional group on the side chain is to avoid the influence of the terminal amino group and the functional group on the side chain during the reaction process of synthesizing the compound of formula I using the compound of formula II and the compound of formula III (for example, the groups may react with each other or prevent the target reaction from proceeding, etc.).

[0157] The term "substituted" refers to the replacement of hydrogen atoms in a molecule by other different atoms or groups.

[0158] The term "plurality" refers to a number of two or more. Therefore, the term "substituted by multiple groups" as described in the present invention refers to substitution by two or more groups. The specific number of substituents is affected by the number of substitutable sites of the substituted group and steric hindrance, and generally refers to substitution by two, three, four, five or six groups, and more preferably substitution by two or three groups.

[0159] The term "alkyl" or "heteroalkyl" includes saturated or unsaturated straight or branched chain or cyclic alkyl groups. "Heteroalkyl" optionally contains heteroatoms such as oxygen, sulfur or nitrogen. When the alkyl group contains a cyclic group, the cyclic group can be a carbocyclic ring or a heterocyclic ring group, and the heterocyclic group is, for example, a heterocycloalkyl or heteroaryl group. The alkyl group is preferably an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl group. Specifically, the alkyl group includes an alkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkylaryl, alkenylaryl, alkynylaryl, arylalkyl, arylcycloalkyl, arylalkenyl or arylalkynyl; the heteroalkyl group includes a heteroaryl, an alkylheteroaryl, an alkenylheteroaryl, an alkynylheteroaryl, a heteroarylalkyl, a heteroarylalkenyl or a heteroarylalkynyl.

[0160] The term "alkyl" refers to a saturated hydrocarbon radical having the specified number of carbon atoms. For example, C1 to C 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.

[0161] The term "cycloalkyl" 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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0162] The term "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 typically a 3 to 10-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen, or a 3 to 7-membered 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-membered 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.

[0163] The term "alkenyl" refers to a straight or branched chain unsaturated hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon double bond (>C=C<). a ~C b The alkenyl group refers to an alkenyl-containing unsaturated hydrocarbon group having a to b carbon atoms, and specific examples of the alkenyl group include ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0164] "Alkynyl" refers to a straight or branched monovalent hydrocarbon group containing at least one carbon-carbon triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, specific examples of C2-C6 alkynyl groups include ethynyl, propynyl, and the like.

[0165] The term "aryl" 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.

[0166] The term "heteroaryl" is selected from heterocyclic groups having 1 or 2 nitrogen atoms, oxygen atoms or sulfur atoms, and preferably 5-10 members, and examples thereof include 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 and N-carbazolyl.

[0167] The term "organic amines (OA)" refers to organic amines having at least one NH bond, and is selected from the group consisting of:

[0168] amino acids;

[0169] C1~C 24 Hydrocarbylamines (primary amines), for example, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, dodecylamine, tetracosylamine, unsubstituted or substituted (e.g., halogen-substituted) aniline, methylcyclohexylamine, N-methylbenzylamine, and the like;

[0170] 2 (C1~C 16 Hydrocarbyl) amines (secondary amines, i.e., monoamines having one secondary amino group), such as dimethylamine, diethylamine, didodecylamine, or didhexadecylamine, etc.;

[0171] Choose from C2~C 14 C2~C 14 Alkylenediamines (wherein the two amine groups are each independently primary or secondary), for example, ethylenediamine, N-methylethylenediamine, N,N'-dimethylethylenediamine, 1,3-propylenediamine, N-methyl,N'ethyl-1,3-propylenediamine, butanediamine (including various isomers such as 1,2- or 1,3- or 1,4-butanediamine), 3,6-dihydroxydecanediamine, dodecanediamine, p- or m-phenylenediamine, 3,3'-dichloro-4,4'-diphenylmethanediamine (MOCA), piperazine, and the like;

[0172] Choose from C4~C 16 C4~C 16Polyalkylene polyamines, such as diethylenetriamine, triethylenetetramine, tetraethylenepentamine, pentaethylenehexamine, dipropylenetriamine, tripropylenetetramine, tris(2-hydroxy-1,3-propylene)tetramine or tetrakis(2-hydroxy-1,3-propylene)pentamine; etc.;

[0173] C3-C4 optionally substituted with hydroxyl groups having three primary amino groups 18 Organic triamines or C5-C6-C8-amino acids having four primary amino groups optionally substituted by hydroxyl groups 18 Organic tetraamines, such as 1,3,5-triaminocyclohexane, 1,3,5-tris(aminoethyl)cyclohexane, 1,3,5-tris(aminopropyl)-1,3,5-hexahydrotriazine, 1,3,5-tris(methylaminopropyl)-1,3,5-hexahydrotriazine, melamine, pentaerythritol, etc.; or

[0174] C2~C 10 Alcoholamines, such as monoethanolamine, diethanolamine, monopropanolamine, dipropanolamine, monoisopropanolamine, diisopropanolamine, monobutanolamine, dibutanolamine, etc.

[0175] The term "pharmaceutically acceptable" means chemically and physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptors.

[0176] The term "salt" refers to a compound or its stereoisomer, an acidic or basic salt formed with an inorganic acid, an organic acid or a base, and also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained by separation and purification during compound preparation, or by mixing the above-mentioned compound or its stereoisomer with a certain amount of acid or base appropriately (e.g., equivalent). These salts may be collected by forming a precipitate in solution by filtering, or recovered after solvent evaporation, or obtained by freeze-drying after reaction in an aqueous medium. The salt described in the present invention can be a hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

[0177] The beneficial effects of the present invention are:

[0178] 1. The present invention provides an α-carbonyl alkenyl ester compound and a method for synthesizing the same. The present invention also uses the acetylamide compound to react with a primary or secondary amine to prepare an amide compound, thereby developing a method for forming amide bonds and peptide bonds using carboxylic acid and amine as starting materials and acetylamide as a condensing agent. The α-carbonyl alkenyl ester of an α-amino acid is used as a peptide synthetic building block in peptide solid-phase synthesis.

[0179] 2. The synthesis method of the present invention has mild reaction conditions, simple operation, and high yield. Compared with existing amide bond condensation reagents, this type of acetylene amide has the advantages of simple preparation, good stability, low molecular weight, and no racemization when activating α-chiral carboxylic acids. It conforms to the direction of green chemistry in modern chemistry and has excellent atom economy. It is a new type of amide bond and peptide bond condensation reagent. BRIEF DESCRIPTION OF THE DRAWINGS

[0180] The present invention will be further described below with reference to the accompanying drawings and embodiments, in which:

[0181] Figure 1 This is the HPLC chart of Leucine Enkephalin of Example 15 of the present invention.

[0182] Figure 2 This is the HPLC chart of the linear skeleton of oxytocin in Example 16 of the present invention. DETAILED DESCRIPTION

[0183] 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.

[0184] Example 1

[0185] In this example, 2-ethynyl-2,3-dihydrobenzisothiazole 1,1-dioxide was prepared. The specific process is as follows:

[0186]

[0187] 2,3-Dihydrobenzisothiazole 1,1-dioxide (0.2 mmol), sodium carbonate (0.4 mmol), copper sulfate (0.02 mmol), phenanthroline (0.01 mmol), and 2 mL of toluene (PhMe) were added to a clean 4 mL reaction flask. (Bromoethynyl)triisopropylsilane (0.22 mmol) was then added. The reaction was stirred at 75° C. for 36 h, and the completion of the reaction was monitored by TLC. After the reaction, the pure product was obtained by column chromatography as a white solid. A tetrahydrofuran solution was added, followed by a tetrahydrofuran solution of tetrabutylammonium fluoride (0.2 mL). The reaction was stirred at room temperature for 10 min, and the completion of the reaction was monitored by TLC. After the reaction, the pure product was obtained by column chromatography as a white solid with a yield of 90%.

[0188] 1H NMR (400MHz, DMSO-d6) δ8.06–7.98(m,1H),7.82(tt,J=7.5,1.5Hz,1H),7.73–7.59(m,2H),4.99(s,2H),4.09(s,1H);

[0189] 13 C NMR (100 MHz, CDCl3) δ 134.5, 132.6, 132.2, 130.3, 126.0, 121.9, 72.7, 64.0, 52.5 ppm. Example 2

[0190] This example prepares 2-ethynylisothiazolidine 1,1-dioxide, and the specific process is as follows:

[0191]

[0192] To a clean 4 mL reaction flask, add isothiazolidine 1,1-dioxide (0.2 mmol), sodium carbonate (0.4 mmol), copper sulfate (0.02 mmol), phenanthroline (0.01 mmol), and 2 mL of toluene (PhMe), and then add (bromoethynyl)triisopropylsilane (0.22 mmol); then stir the reaction at 75° C. for 36 h, and monitor the completion of the reaction using a TLC plate; after the reaction, obtain the pure product as a white solid by column chromatography, add a tetrahydrofuran solution, and then add a tetrahydrofuran solution of tetrabutylammonium fluoride (0.2 mL), and then stir the reaction at room temperature for 10 min, and monitor the completion of the reaction using a TLC plate; after the reaction, obtain the pure product as a white solid by column chromatography with a yield of 90%.

[0193] 1 H NMR (400MHz, DMSO-d6) δ3.80 (s, 1H), 3.66 (t, J = 6.7Hz, 2H), 3.42 (t, J = 7.3Hz, 2H), 2.31 (p, J = 7.0Hz, 2H);

[0194] 13 C NMR (100MHz, CDCl3) δ74.4, 62.3, 50.0, 46.4, 19.7ppm.

[0195] Example 3

[0196] This example prepared (E)-N-fluorenylmethoxycarbonyl-L-alanine-1,1-dioxobenzisothiazole-2-vinyl-1-ester, and the specific process was as follows:

[0197]

[0198] To a clean 4 mL reaction flask, 2-ethynyl-2,3-dihydrobenzisothiazole 1,1-dioxide (0.22 mmol) and 2 mL of dichloromethane (DCM) were added, followed by N-9-fluorenylmethoxycarbonyl-L-alanine (0.2 mmol). The reaction was stirred at room temperature for 2 h, and completion of the reaction was monitored by TLC. After completion of the reaction, the pure product was obtained by column chromatography as a colorless oily liquid in a yield of 93%.

[0199] 1 H NMR (400MHz, CDCl3) δ7.87–7.78(m,2H),7.75(d,J=7.5Hz,2H),7.59(d,J=7.1H z,2H),7.49(dd,J=8.4,6.9Hz,2H),7.39(t,J=7.5Hz,2H),7.30(tt,J=7.5,1.4H z,2H),5.38(d,J=7.6Hz,1H),4.97–4.82(m,1H),4.73(s,2H),4.70–4.60(m,1H ),4.42–4.35(m,2H),4.21(t,J=7.0Hz,1H),2.03(s,1H),1.40(d,J=7.2Hz,3H).

[0200] 13 C NMR (100MHz, CDCl3) δ170.5,155.7,146.6,143.8,143.8,141.3,136.4,133.4,129. 0,128.0,127.8,127.1,125.1,120.0,101.5,67.1,49.7,47.1,37.3,17.9,14.2ppm.

[0201] Example 4

[0202] This example prepared (E)-N-fluorenylmethyloxycarbonyl-L-glycine-1,1-dioxobenzisothiazole-2-vinyl-1-ester. The specific process is as follows:

[0203]

[0204] To a clean 4 mL reaction flask, 2-ethynyl-2,3-dihydrobenzisothiazole 1,1-dioxide (0.22 mmol) and 2 mL of dichloromethane (DCM) were added, followed by N-9-fluorenylmethoxycarbonyl-L-glycine. The reaction was stirred at room temperature for 2 h, and the completion of the reaction was monitored by TLC. After the reaction, the pure product was obtained by column chromatography as a colorless oily liquid in a yield of 93%.

[0205] 1H NMR (400MHz, CDCl3) δ7.82(d,J=7.4Hz,2H),7.75(d,J=7.5Hz,2H),7.61–7.56(m,3H),7.52–7.48(m,2H),7.40–7.35(m,2H),7.32–7.27(m,2H),5. 41(t,J=5.6Hz,1H),4.88(d,J=2.5Hz,1H),4.61(d,J=2.5Hz,1H),4.50(s ,2H), 4.39(d,J=7.1Hz,2H), 4.22(t,J=7.0Hz,1H), 3.99(d,J=5.8Hz,2H);

[0206] 13 C NMR (100MHz, CDCl3) δ167.7,156.3,146.5,143.8,141.3,136.4,133.4,129.1,12 7.9,127.8,127.1,127.1,125.1,120.0,100.6,67.3,47.1,42.7,37.4,14.2ppm.

[0207] Example 5

[0208] This example prepared (E)-N-fluorenylmethyloxycarbonyl-L-valine-1,1-dioxobenzisothiazole-2-vinyl-1-ester. The specific process is as follows:

[0209]

[0210] To a clean 4 mL reaction flask, 2-ethynyl-2,3-dihydrobenzisothiazole 1,1-dioxide (0.22 mmol) and 2 mL of dichloromethane (DCM) were added, followed by N-9-fluorenylmethoxycarbonyl-L-valine (0.2 mmol). The reaction was stirred at room temperature for 2 h, and the completion of the reaction was monitored by TLC spot plate. After the reaction, the pure product was obtained by column chromatography as a colorless oily liquid in a yield of 92%.

[0211] 1H NMR (400MHz, CDCl3) δ7.84(d,J=7.5Hz,2H),7.77(d,J=7.5Hz,2H),7.59(d,J=10.4Hz ,2H),7.49(t,J=7.6Hz,2H),7.40(t,J=7.5Hz,2H),7.31(t,J=7.4Hz,2H),5.31(d,J=9 .1Hz,1H),4.92(s,1H),4.70(s,1H),4.48–4.35(m,2H),4.37(s,2H),4.31(dd,J=9.1, 4.6Hz, 1H), 4.24 (t, J = 6.9Hz, 1H), 1.25 (t, J = 7.1Hz, 1H), 0.94 (d, J = 30.3, 6.8Hz, 6H);

[0212] 13 C NMR (100MHz, CDCl3) δ169.7,156.2,146.6,143.9,143.7,141.3,133.3,129.0,128.0,1 27.8,127.1,125.1,120.0,120.0,102.1,67.1,59.0,47.2,37.3,30.8,19.2,17.3ppm.

[0213] Example 6

[0214] This example prepared (E)-N-fluorenylmethyloxycarbonyl-O-tert-butyl-L-serine-1,1-dioxobenzisothiazole-2-vinyl-1-ester. The specific process is as follows:

[0215]

[0216] To a clean 4 mL reaction flask, 2-ethynyl-2,3-dihydrobenzisothiazole 1,1-dioxide (0.22 mmol) and 2 mL of dichloromethane (DCM) were added, followed by N-9-fluorenylmethoxycarbonyl-L-serine (0.20 mmol). The reaction was then stirred at room temperature for 9 h, and completion of the reaction was monitored by TLC. After completion of the reaction, the pure product was obtained by column chromatography as a colorless oily liquid in a yield of 96%.

[0217] 1H NMR (400MHz, DMSO-d6) δ7.89(d,J=7.5Hz,2H),7.81(d,J=7.6Hz,2H),7.73(d,J=7.8Hz,3H),7.63(t,J=7.5Hz,2H),7.42(t,J=7.4Hz,2H) ,7.32(t,J=7.3Hz,2H),4.85(d,J=4.6Hz,2H),4.31(d,J=6.7Hz,2H),4.26–4.11(m,2H),3.52(d,J=4.7Hz,2H),2.92(s,2H),1.09(s,9H);

[0218] 13 C NMR(100MHz,DMSO-d6)δ168.8,156.4,146.0,144.2,144.1,141.1,136.9,134.0,129.8, 128.1,127.9,127.5,125.7,120.5,101.6,73.5,66.4,61.4,55.3,47.0,36.6,27.5ppm.

[0219] Example 7

[0220] This example prepared (E)-N-benzyloxycarbonyl-L-valine-1,1-dioxobenzoisothiazole-2-vinyl-1-ester. The specific process is as follows:

[0221]

[0222] To a clean 4 mL reaction flask, 2-ethynyl-2,3-dihydrobenzisothiazole 1,1-dioxide (0.22 mmol) and 2 mL of dichloromethane (DCM) were added, followed by N-benzyloxycarbonyl-L-valine. The reaction was stirred at room temperature for 2 h, and the completion of the reaction was monitored by TLC. After the reaction, the pure product was obtained by column chromatography as a colorless oily liquid in a yield of 93%.

[0223] 1 H NMR (400MHz, CDCl3) δ7.83(d,J=7.5Hz,2H),7.65–7.56(m,1H),7.51(t,J=7.6Hz,2H),7.38–7.33(m,4H),5.24(d,J=8.9Hz,1H),5.11(s, 2H), 4.91(s,1H),4.75–4.67(m,1H),4.53(s,2H),4.28(d,J=9.0,4.4Hz,1H),,2.16(m,1H),0.96(d,J=6.9Hz,3H),0.87(d,J=6.9Hz,3H).

[0224] 13 C NMR (101MHz, CDCl3) δ169.7,156.2,146.6,136.6,136.2,133.3,129.0,128.6,128.2,128.1,128.0,102.1,67.1,59.0,37.2,30.7,19.1,17.2ppm.

[0225] Example 8

[0226] In this example, (E)-N-benzyloxycarbonyl-L-phenylalanine-1,1-dioxobenzisothiazole-2-vinyl-1-ester was prepared. The specific process is as follows:

[0227]

[0228] To a clean 4 mL reaction flask, 2-ethynyl-2,3-dihydrobenzisothiazole 1,1-dioxide (0.22 mmol) and 2 mL of dichloromethane (DCM) were added, followed by N-benzyloxycarbonyl-L-alanine. The reaction was stirred at room temperature for 2 h, and completion of the reaction was monitored by TLC. After completion of the reaction, the pure product was obtained by column chromatography as a colorless oily liquid in a yield of 96%.

[0229] 1 H NMR (400MHz, CDCl3) δ7.81(d,J=7.6Hz,2H),7.57(t,J=7.4Hz,1H),7.49(t,J=7.6Hz ,2H),7.37–7.29(m,4H),7.24(dd,J=5.6,3.5Hz,3H),7.12(d,J=6.6Hz,2H),5.22(d, J=7.9Hz,1H),5.06(s,2H),4.87(d,J=3.9Hz,1H),4.69(d,J=4.0Hz,1H),4.58(q,J= 6.9Hz, 1H), 4.50 (s, 2H), 3.13 (dd, J=14.0, 5.4Hz, 1H), 2.99 (dd, J=14.1, 7.1Hz, 1H).

[0230] 13 C NMR (101MHz, CDCl3) δ169.2,155.6,146.5,136.6,136.2,135.4,133.4,129.3,129.3 ,129.0,128.7,128.6,128.2,128.1,128.0,127.3,101.9,67.1,54.9,37.6,37.1ppm.

[0231] Example 9

[0232] This example prepared (E)-N-benzyloxycarbonyl-S-trityl-L-cysteine-1,1-dioxobenzisothiazole-2-vinyl-1-ester. The specific process is as follows:

[0233]

[0234] To a clean 4 mL reaction flask, 2-ethynyl-2,3-dihydrobenzisothiazole 1,1-dioxide (0.22 mmol) and 2 mL of dichloromethane (DCM) were added, followed by N-tert-butyloxycarbonyl-L-valine. The reaction was stirred at room temperature for 2 h, and completion of the reaction was monitored by TLC. After completion of the reaction, the pure product was obtained by column chromatography as a colorless oily liquid in a yield of 98%.

[0235] 1 H NMR (400MHz, CDCl3) δ7.79(dd,J=7.4,1.2Hz,2H),7.54(t,J=7.4Hz,1H),7.44(t,J=7.6Hz,2H),7.38(d,J=7.5Hz,5H),7.30 –7.21(m,9H),4.92(d,J=10.1Hz,2H),4.81(s,1H),4.52(s,2H),4.08(d,J=6.6Hz,1H),2.55(d,J=5.2Hz,2H),1.43(s,9H).

[0236] 13 C NMR (101MHz, CDCl3) δ168.4,154.9,145.8,144.2,137.1,133.3,129.5,129.0,1 28.1,127.9,127.3,127.0,102.1,80.2,77.3,67.1,52.6,36.5,33.6,28.3ppm.

[0237] Example 10

[0238] This example prepared (E)-N-tert-butyloxycarbonyl-L-methionine-1,1-dioxobenzoisothiazole-2-vinyl-1-ester, and the specific process was as follows:

[0239]

[0240] To a clean 4 mL reaction flask, 2-ethynyl-2,3-dihydrobenzisothiazole 1,1-dioxide (0.22 mmol) and 2 mL of dichloromethane (DCM) were added, followed by N-tert-butyloxycarbonyl-L-valine. The reaction was stirred at room temperature for 2 h, and completion of the reaction was monitored by TLC. After completion of the reaction, the pure product was obtained by column chromatography as a colorless oily liquid in a yield of 98%.

[0241] 1 H NMR (400MHz, CDCl3) δ7.85(d,J=7.5Hz,2H),7.65(t,J=7.4Hz,1H),7.57(d,J=7.6Hz,1H),5.15(d,J=7.5Hz,1H),4.92(s,1 H),4.66(s,1H),4.57(s,3H),4.52–4.26(m,1H),3.01(s,2H),2.55(q,J=7.0,6.6Hz,2H),1.99–1.84(m,1H),1.45(s,9H).

[0242] 13 C NMR (101MHz, CDCl3) δ169.9,155.3,146.6,136.4,133.4,129.4,129.0,128.0,101.4,80.2,77.3,52.8,37.3,31.3,29.9,28.3,15.4ppm.

[0243] Example 11

[0244] In this example, (E)-N-tert-butyloxycarbonyl-L-methionine-1,1-dioxoisothiazole-2-vinyl-1-ester was prepared. The specific process is as follows:

[0245]

[0246] To a clean 4 mL reaction flask, 2-ethynyl-2,3-dihydroisothiazole 1,1-dioxide (0.22 mmol) and 2 mL of dichloromethane (DCM) were added, followed by N-tert-butyloxycarbonyl-L-valine. The reaction was then stirred at room temperature for 2 h, and completion of the reaction was monitored by TLC. After completion of the reaction, the pure product was obtained by column chromatography as a colorless oily liquid in a yield of 98%.

[0247] 1H NMR(500MHz,Chloroform-d)δ6.05(d,J=9.3Hz,1H),4.78(d,J=2.5Hz,1H),4.60(d,J=2.4Hz,1H),4.33(dt,J=9.3 ,5.9Hz,1H),3.68(t,J=4.8Hz,2H),3.01(t,J=4.6Hz,2H),2.62(t,J=5.3Hz,2H),2.17–2.04(m,7H),1.40(s,9H).

[0248] 13 C NMR (101MHz, CDCl3) δ129.7,122.0,102.4,80.2,77.3,52.8,37.3,34.6,31.3,29.9,28.3,26.3,15.4ppm.

[0249] Example 12

[0250] This example prepares N-Fmoc-O-tert-butyl-L-serine-L-leucine tert-butyl ester. The specific process is as follows:

[0251]

[0252] To a clean 4 mL reaction flask, (E)-N-fluorenylmethoxycarbonyl-O-tert-butyl-L-serine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (0.20 mmol) and 1.5 mL of N,N-dimethylformamide (DMF) were added, followed by O-tert-butyl-L-tyrosine tert-butyl ester (0.22 mmol). The reaction was then stirred at room temperature for 20 min, and completion of the reaction was monitored by TLC spot plate. After completion of the reaction, the pure product was obtained by column chromatography as a white solid in a yield of 99%.

[0253] 1 H NMR(400MHz, CDCl3)δ7.75(d,J=7.5Hz,2H),7.65–7.54(m,2H),7.39(t,J=7.5Hz,2H) ,7.31(t,J=7.5Hz,2H),7.23(d,1H),5.82–5.76(m,1H),4.48(q,J=7.4Hz,1H),4.43– 4.35(m,2H),4.30–4.16(m,2H),3.83(dd,J=8.5,3.8Hz,1H),3.40(t,J=8.4Hz,1H),1 .73–1.59(m,2H),1.57–1.51(m,1H),1.46(s,9H),1.22(s,9H),0.95(d,J=6.4Hz,6H).

[0254] 13 C NMR (100MHz, CDCl3) δ171.6,169.9,156.0,143.9,143.8,141.3,127.7,127.1,125.2,1 20.0,81.7,74.3,67.1,61.8,54.3,51.7,47.2,41.9,28.0,27.4,24.9,22.8,22.2ppm.

[0255] Example 13

[0256] In this example, N-tert-butyloxycarbonyl-L-threonine-L-threonine tert-butyl ester was prepared. The specific process is as follows:

[0257]

[0258] To a clean 4 mL reaction flask, (E)-N-tert-butyloxycarbonyl-L-threonine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (0.20 mmol) and 1.5 mL of N,N-dimethylformamide were added, followed by L-threonine tert-butyl ester (0.22 mmol). The reaction was then stirred at room temperature for 15 min, and completion of the reaction was monitored by TLC. After completion of the reaction, the pure product was obtained by column chromatography as a white solid in a yield of 93%.

[0259] 1 H NMR (400MHz, CDCl3) δ7.35(d,J=7.7Hz,1H),5.73(s,1H),4.42(dd,J=8.7,2.4Hz,1H),4.35–4.09(m,3H),1.43(d,J=10.9Hz,18H),1.18(t,J=6.2Hz,6H).

[0260] 13 C NMR (100MHz, CDCl3) δ171.7,169.8,156.2,82.6,80.3,68.2,67.3,58.7,58.4,28.2,27.9,20.0,18.2ppm.

[0261] Example 14

[0262] This example prepares N-fluorenylmethyloxycarbonyl-O-tert-butyl-L-glutamic acid-O-tert-butyl-L-tyrosine tert-butyl ester, and the specific process is as follows:

[0263]

[0264] To a clean 4 mL reaction flask, (E)-N-fluorenylmethyloxycarbonyl-O-tert-butyl-L-glutamic acid-1,1-dioxobenzisothiazole-2-vinyl-1-ester (from Preparation Example 18) (0.20 mmol) and 1.5 mL of N,N-dimethylformamide were added, followed by the addition of tert-butyl O-L-tyrosine (0.22 mmol). The reaction was stirred at room temperature for 5 min, and the completion of the reaction was monitored by TLC spot plate. After the reaction, the pure product was obtained as a white solid by column chromatography in a yield of 97%.

[0265] 1 H NMR (400MHz, CDCl3) δ7.75(d,J=7.5Hz,2H),7.60(d,J=7.5Hz,2H),7.39(t,J=7.5Hz,2H) ,7.30(t,J=7.3Hz,2H),7.06(d,J=8.1Hz,2H),6.94–6.77(m,3H),5.79(d,J=7.9Hz,1H), 4.78–4.61(m,1H),4.43–4.32(m,2H),4.28–4.17(m,2H),3.04(d,J=6.3Hz,2H),2.48–2. 28(m,2H),2.14–2.00(m,2H),1.98–1.80(m,1H),1.45(s,9H),1.37(s,9H),1.29(s,9H).

[0266] 13 C NMR (100MHz, CDCl3) δ172.7,170.7,170.1,156.1,154.3,143.8,143.7,141.2,130.8,129.8,127.6,127. 0,125.1,124.0,119.9,82.2,80.9,78.2,67.1,54.1,53.9,47.1,37.4,31.6,28.7,28.3,28.0,27.8ppm.

[0267] Example 15

[0268] In this example, leucine enkephalin was prepared, and the specific process was as follows:

[0269] 1) Using 2-CTC resin as a carrier, Fmoc-Leu-OH protected by an N-terminal Fmoc group is added, and coupling is carried out in a solvent in the presence of a base to obtain Fmoc-Leu-resin.

[0270] 2) Using a DMF solution containing piperidine to remove the Fmoc protecting group on the Fmoc-Leu-resin to obtain H-Leu-resin.

[0271] 3) In the presence of a catalyst, an α-carbonyl alkenyl ester compound corresponding to Fmoc-Phe-OH is added and reacted in a solvent until complete (ninhydrin detection resin becomes colorless). After the reaction is complete, the resin is washed with a solvent (sequentially with DCM and DMF) and dried to obtain Fmoc-Phe-Leu-resin.

[0272] 4) Repeat steps 2 and 3 to sequentially add α-carbonyl alkenyl ester compounds corresponding to amino acids such as Gly and Tyr according to the amino acid sequence.

[0273] 5) Deprotection, cleavage, removal of side chain protecting groups and resin, and then precipitation in diethyl ether to obtain crude peptide H-Tyr-Gly-Gly-Phe-Leu-OH.

[0274] 6) Purification and lyophilization to obtain the target polypeptide chain.

[0275] Among them, the structure of the H-Tyr-Gly-Gly-Phe-Leu-OH sequence is:

[0276]

[0277] The first amino acid is coupled to the 2-CTC resin by adding the first amino acid into a solid phase reaction vessel, and the protected amino acid is connected to the 2-CTC resin under the action of a base.

[0278] Specifically, the following methods can be used:

[0279] 1) Synthesis of Fmoc-Leu-resin:

[0280] Add 64.9 mg of 2-CTC resin (loading 0.77 mmol / g) to a solid-phase synthesis tube and soak in 3 mL of dichloromethane for 20 minutes. After soaking, filter out excess solvent and add 0.15 mmol of Fmoc-Leu-OH, 0.15 mmol of N,N-diisopropylethylamine (DIEA), 1.5 mL of DMF, and 1.5 mL of DCM. Stir and react for 2 hours. Filter the reaction solution, wash with DMF, and drain to obtain Fmoc-Leu-resin.

[0281] 2) Synthesis of H-Leu-resin:

[0282] 0.75 mL of 20% piperidine in DMF solution was added to the solid phase synthesis tube containing Fmoc-Leu-resin, and the mixture was stirred for 20 min. The reaction solution was filtered off, washed with solvent (DMF), and dried to obtain H-Leu-resin.

[0283] 3) Synthesis of Fmoc-Phe-Leu-resin:

[0284] In a solid-phase synthesis tube containing H-Leu-resin, add 0.015 mmol HOBt, 0.15 mmol α-carbonyl alkenyl ester compound corresponding to Fmoc-Phe-OH, and 3 mL DMF. Stir and react until complete (ninhydrin detection resin becomes colorless). Filter the reaction solution, wash with solvent (DMF), and dry to obtain Fmoc-Phe-Leu-resin.

[0285] 4) Synthesis of H-Tyr(tBu)-Gly-Gly-Phe-Leu-resin:

[0286] Repeat steps 2) and 3) according to the sequence of H-Tyr(tBu)-Gly-Gly-Phe-Leu-resin, and sequentially access the α-carbonyl alkenyl ester compounds corresponding to the sequence such as Tyr, Gly, etc. until H-Tyr(tBu)-Gly-Gly-Phe-Leu-resin is obtained.

[0287] 5) Cleavage of leucine enkephalin resin to obtain crude enkephalin:

[0288] A cleavage solution (TFA:TIS:H2O=95:2.5:2.5) was added to a solid phase synthesis tube containing H-Tyr(tBu)-Gly-Gly-Phe-Leu-resin, and the reaction was carried out at room temperature for 2 h. The solution was filtered out, and the resin was washed 3 times with TFA. The filtrate was filtered and combined, 10 mL of ether was added thereto to precipitate the crude product, which was washed with 3×10 mL of ether and dried to obtain a crude leucine enkephalin product.

[0289] 6) Purification of crude leucine enkephalin:

[0290] Dissolve 2 mg of crude leucine enkephalin in 0.25 mL of water and filter to obtain a crude aqueous solution for later use. Separate using a C18 reverse phase column with mobile phase A: 0.1% TFA, 10% H₂O, 90% MeCN and mobile phase B: 0.1% TFA, 100% H₂O. Gradient elution yields a pure leucine enkephalin solution. Concentrate the solution to 2 mL and freeze-dry to obtain pure leucine enkephalin.

[0291] The obtained pure leucine enkephalin was subjected to high performance liquid chromatography detection. The results were as follows. Figure 1 shown.

[0292] Example 16

[0293] This embodiment is a solid phase synthesis method of the linear skeleton of oxytocin, and the specific process is as follows:

[0294] 1) MBHA resin is used as a carrier, and an α-carbonyl alkenyl ester compound corresponding to the Fmoc-Gly-OH protected by the N-terminal Fmoc group is added in the presence of a catalyst in a solvent for coupling to obtain Fmoc-Gly-resin.

[0295] 2) Using a DMF solution containing piperidine to remove the Fmoc protecting group on the Fmoc-Gly-resin to obtain H-Gly-resin.

[0296] 3) In the presence of a catalyst, an α-carbonyl alkenyl ester compound corresponding to Fmoc-Leu-OH is added and reacted in a solvent until complete (ninhydrin detection resin becomes colorless). After the reaction is complete, the resin is washed with a solvent (sequentially with DCM and DMF) and dried to obtain Fmoc-Leu-Gly-resin.

[0297] 4) Repeating the two-step reaction of 2) and 3) to sequentially introduce α-carbonyl alkenyl ester compounds corresponding to amino acids such as Cys(Me), Tyr, Ile, Gln, Asn, Cys(Me), and Pro according to the amino acid sequence.

[0298] 5) Deprotection, cleavage, removal of side chain protecting groups and resin, and then precipitation in diethyl ether to obtain the crude peptide H-Cys(Me)-Tyr-Ile-Gln-Asn-Cys(Me)-Pro-Leu-Gly-OH.

[0299] 6) Purification and lyophilization to obtain the target polypeptide chain.

[0300] Among them, the structure of the H-Cys(Me)-Tyr-Ile-Gln-Asn-Cys(Me)-Pro-Leu-Gly-NH2 sequence is:

[0301]

[0302] The first amino acid is coupled to the MBHA resin by adding an α-carbonyl alkenyl ester compound corresponding to the first amino acid into a solid phase reaction vessel, and then the protected amino acid is connected to the MBHA resin in the presence of a catalyst.

[0303] Specifically, the following methods can be adopted:

[0304] 1) Synthesis of Fmoc-Gly-resin:

[0305] 39.0 mg of MBHA resin (loading 0.77 mmol / g) was added to a solid-phase synthesis tube and soaked in 3 mL of dichloromethane for 20 minutes. After soaking, the excess solvent was filtered off. 0.15 mmol of the α-carbonyl alkenyl ester corresponding to Fmoc-Gly-OH, 0.015 mmol of HOBt, and 3 mL of DMF were added. The reaction was stirred until complete (the resin turned colorless when tested with ninhydrin). The reaction solution was filtered off, washed with DMF, and dried to obtain Fmoc-Gly-resin.

[0306] 2) Synthesis of H-Gly-resin:

[0307] 0.75 mL of 20% piperidine in DMF solution was added to the solid phase synthesis tube containing Fmoc-Leu-resin, and the mixture was stirred for 20 min. The reaction solution was filtered off, washed with solvent (DMF), and dried to obtain H-Gly-resin.

[0308] 3) Synthesis of Fmoc-Leu-Gly-resin:

[0309] In a solid-phase synthesis tube containing H-Gly-resin, add 0.015 mmol HOBt, 0.15 mmol α-carbonyl alkenyl ester compound corresponding to Fmoc-Leu-OH, and 3 mL DMF, and stir until the reaction is complete (ninhydrin detection resin appears colorless). Filter the reaction solution, wash with solvent (DMF), and dry to obtain Fmoc-Leu-Gly-resin.

[0310] 4) Synthesis of H-Cys(Me)-Tyr-Ile-Gln-Asn-Cys(Me)-Pro-Leu-Gly-resin:

[0311] Repeat steps 2) and 3) according to the sequence of H-Cys(Me)-Tyr-Ile-Gln-Asn-Cys(Me)-Pro-Leu-Gly-resin, and sequentially access α-carbonyl alkenyl ester compounds corresponding to amino acids such as Cys(Me), Tyr(tBu), Ile, Gln(Trt), Asn(Trt), and Pro until H-Cys(Me)-Tyr-Ile-Gln-Asn-Cys(Me)-Pro-Leu-Gly-resin is obtained.

[0312] 5) Resin cracking of the oxytocin linear skeleton to obtain a crude oxytocin linear skeleton product:

[0313] A lysis buffer (TFA:EDT:TIS:H2O=92.5:2.5:2.5:2.5) was added to a solid phase synthesis tube containing H-Cys(Me)-Tyr-Ile-Gln-Asn-Cys(Me)-Pro-Leu-Gly-resin, and the reaction was carried out at room temperature for 2 h. The solution was filtered and the resin was washed three times with TFA. The filtrate was filtered and combined, 10 mL of ether was added thereto to precipitate the crude product, which was washed with 3×10 mL of ether and dried to obtain a crude linear skeleton of oxytocin.

[0314] 6) Purification of crude oxytocin linear backbone:

[0315] Dissolve 2 mg of crude oxytocin linear backbone product in 0.25 mL of water and filter the resulting solution to obtain a crude aqueous solution for later use. Separate the solution using a C18 reverse phase chromatography column with mobile phase A: 0.1% TFA, 10% H2O, 90% MeCN and mobile phase B: 0.1% TFA, 99.9% H2O. Gradient elution yields a solution of pure oxytocin linear backbone product. Concentrate the solution to 2 mL and freeze-dry to obtain pure oxytocin linear backbone product.

[0316] The obtained pure oxytocin straight chain skeleton was subjected to high performance liquid chromatography detection. The results were as follows: Figure 2 shown.

[0317] 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 compound of formula I or a pharmaceutically acceptable salt thereof: in, R 1 Selected from halogen, nitro, cyano, amino, C1~C 18 Alkyl, C3~C 18 Cycloalkyl, C3~C 18 Heterocycloalkyl, C2~C 18 Alkenyl, C2~C 18 Alkynyl, C6~C 18 Aryl, C4~C 18 Heteroaryl, C1~C 18 Hydroxyl, C1~C 18 Halogenated alkyloxy, C1~C 18 Hydrocarbon sulfide, C1~C 18 Halogenated hydrocarbon thio, C1~C 18 Acyl, C1~C 18 Halogenated acyl, C1~C 18 Acyloxy, C1~C 18 Haloacyloxy, C Carboxyl-terminal missing α -Amino acid residues, C Carboxyl-terminal missing β -Amino acid residues or C Carboxyl-terminal missing γ -Amino acid residues, C Amino acid derivative residues or polypeptide fragments with missing terminal carboxyl groups, protected amino C1~C 18 Alkyl, protected amino C3~C 18 Cycloalkyl, protected amino C3~C 18 Heterocycloalkyl, protected amino C2~C 18 Alkenyl, protected amino C2~C 18 Alkynyl, protected amino C6~C 18 Aryl, protected amino C4~C 18 Heteroaryl, protected amino C1~C 18 Hydroxyl, protected amino C1~C 18 Halogenated alkyloxy, protected amino C1~C 18 Hydrocarbon thio, protected amino C1~C 18 Halogenated alkylthio, protected amino C1~C 18 Acyl, protected amino C1~C 18 Haloacyl, protected amino C1~C 18 Acyloxy, protected amino C1~C 18 Haloacyloxy, protected amino C Carboxyl-terminal missing α -Amino acid residues, protected amino groups C Carboxyl-terminal missing β -Amino acid residues, protected amino groups C Carboxyl-terminal missing γ -Amino acid residues, protected amino groups C Amino acid derivative residues or polypeptide fragments lacking a terminal carboxyl group; R 2 is selected from hydrogen, halogen, cyano, alkyl, acyl, aryl, heteroaryl, alkoxy-carbonyl; R 3 、R 4 、R 5 are the same or different and are independently selected from hydrogen, halogen, C1~C 16 Hydrocarbyl; or R 4 、R 5 Together with the atoms connected to it, it forms C6~C 12 aryl; Among them, the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkylthio, C Amino acid residues lacking a terminal carboxyl group, C The amino acid derivative residue or polypeptide fragment lacking the terminal carboxyl group is optionally unsubstituted or replaced by one or more R 11 Replace; each R 11 Selected from halogen, nitro, cyano, C1~C8 alkyl, C2~C8 alkenyl, C2~C8 alkynyl, C6~C 12 Aryl, C4~C 12 Heteroaryl, C1~C8 alkoxy, C1~C8 haloalkoxy, C1~C8 alkylthio, C1~C8 haloalkylthio, C1~C8 acyl, C1~C8 haloacyl, C1~C8 acyloxy, C1~C8 haloacyloxy, protected amino; The acyl group and acyloxy group are optionally unsubstituted or substituted by one or more R 21 Replace; each R 21 Selected from halogen, nitro, cyano.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 1 selected from halogen, nitro, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, butenyl, adamantyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, phenylethynyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, pyrrolyl, indolyl, indolemethyl, indazolyl, furyl, benzofuranyl, thienyl, benzothienyl, styryl, phenylethynyl, benzyl, 11-hydroxyundecyl, pentadecyl, protected α -amino C2~C 10 Alkyl, protected β -Amino C3~C 10 Alkyl, protected γ -Amino C4~C 10 Alkyl, protected amino C Carboxyl-terminal missing α -Amino acid residues, protected amino groups C Carboxyl-terminal missing β -Amino acid residues, protected amino groups C Carboxyl-terminal missing γ -Amino acid residues, protected amino groups C Amino acid derivative residues or polypeptide fragments lacking a terminal carboxyl group.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 1 selected from halogen, nitro, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, butenyl, adamantyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, phenylethynyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, pyrrolyl, indolyl, indolemethyl, indole oxazolyl, furanyl, benzofuranyl, thienyl, benzothienyl, styryl, phenylethynyl, benzyl, 11-hydroxyundecyl, pentadecyl, protected glycine, protected alanine, protected phenylalanine, protected valine, protected cysteine, protected methionine, protected leucine, protected isoleucine, protected methionine, protected proline, protected tryptophan, protected serine, protected tyrosine, protected glutamine, protected asparagine, protected arginine, protected threonine, protected glutamic acid, protected aspartic acid, protected lysine, protected histidine.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The protected amino groups include protected α -amino, protected β -amino, protected γ -amino group; its protecting group is selected from fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), allyloxycarbonyl (Alloc), acetyl (Ac), methyl (Me), ethyl (Et), tert-butyl ( t at least one of Bu), trityl (Trt) or benzyl (Bn).

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 2 Selected from H, fluorine, chlorine, bromine, methyl, formyl, acetyl, propionyl, 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, pyridyl.

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 3 、R 4 、R 5 are each independently selected from H, methyl; or R 4 、R 5 Together with the atoms connected to it, it forms C6~C 12 Aryl.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound of formula I is selected from the following compounds: (E)- N -Fluorenylmethoxycarbonyl- L -Glycine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- L -Alanine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Benzyloxycarbonyl- L -Alanine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Benzyloxycarbonyl- L -phenylalanine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Benzyloxycarbonyl- L -Valine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -tert-Butyloxycarbonyl- L -Alanine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -tert-Butyloxycarbonyl- S -trityl- L -Cysteine-1,1-dioxobenzoisothiazole-2-vinyl-1-ester (E)- N -tert-Butyloxycarbonyl- L -Methionine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- L -phenylalanine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- L -Leucine-1,1-dioxobenzoisothiazol-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- L -Isoleucine-1,1-dioxobenzoisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- L -Methionine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- L -Valine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- L -Proline-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- L -Tryptophan-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- O -tert-butyl- L -Serine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- O -tert-butyl- L -1,1-dioxobenzisothiazole-2-vinyl-1-tyrosine ester (E)- N -Fluorenylmethoxycarbonyl- S -trityl- L -Cysteine-1,1-dioxobenzoisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- N’ -trityl- L -Glutamine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Fluorenylmethoxycarbonyl- N '-trityl- L -Asparagine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Benzyloxycarbonyl- N',N ''-dibenzyloxycarbonyl- L -Arginine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Benzyloxycarbonyl- O -tert-butyl- L -Threonine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -Benzyloxycarbonyl- O -tert-butyl- L -Aspartic acid-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -tert-Butyloxycarbonyl- O -tert-butyl- L -Glutamic acid-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -tert-Butyloxycarbonyl- N '-tert-butyloxycarbonyl- L -Lysine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -tert-Butyloxycarbonyl- N '-tert-butyloxycarbonyl- L -histidine-1,1-dioxobenzisothiazole-2-vinyl-1-ester (E)- N -tert-Butyloxycarbonyl- L -Methionine-1,1-dioxoisothiazole-2-vinyl-1-ester 。 8. A method for preparing a compound of formula I according to any one of claims 1 to 7, characterized in that: The following steps are involved: Reacting a compound of formula II with a compound of formula III to prepare a compound of formula I; Among them, R 1 、R 2 、R 3 、R 4 、R 5 The definition as described in any one of claims 1 to 7.

9. A method for preparing a compound of formula VII, characterized in that: The following steps are involved: The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 and the compound of formula VI The compound of formula VII is prepared by reaction ; Among them, R 1 The definition as set forth in any one of claims 1 to 7; R 6 and R 7 Each independently selected from H, amino, C1~C 24 a hydrocarbon group, an amino oligomer or amino polymer having a primary and / or secondary amine group; or 6 and R 7 connected to them N The atoms together form C3~C 24 Cyclic group; the hydrocarbon group is optionally unsubstituted or substituted by one or more R 31 replace; R 31 Selected from halogen, amino, hydroxyl, carboxyl, mercapto, nitro, cyano, C1~C8 hydrocarbon group, halogenated C1~C8 hydrocarbon group, C1~C8 hydrocarbonoxy group, C1~C8 halogenated hydrocarbonoxy group, C1~C8 hydrocarbonthio group, C1~C8 halogenated hydrocarbonthio group, C1~C8 acyl group, C1~C8 halogenated acyl group, C1~C8 acyloxy group, C1~C8 halogenated acyloxy group.

10. The method for preparing the compound of formula VII according to claim 9, characterized in that: The preparation method of the compound of formula VII comprises the following steps: The compound of formula II reacts with the compound of formula III in a first solvent to produce the compound of formula I, and the compound of formula I reacts with the compound of formula VI in a second solvent to produce the compound of formula VII; Among them, R 1 、R 2 、R 3 、R 4 、R 5 The definition as defined in any one of claims 1 to 7; R 6 、R 7 The definition of is as described in claim 9.

11. The method for preparing the compound of formula VII according to claim 10, characterized in that: The first solvent and the second solvent may be the same or different; and / or, when the first solvent and the second solvent are different, the method for preparing the compound of formula VII further comprises removing the first solvent after the reaction of the compound of formula II and the compound of formula III before continuing the reaction.

12. A method for synthesizing a polypeptide, characterized in that: The following steps are involved: In the resin solid phase carrier, at least one terminal amino acid corresponding to the polypeptide chain sequence is added according to the polypeptide chain sequence to carry out a coupling reaction with the compound of formula I according to any one of claims 1 to 7 to obtain PG-(AA) q -resin; after removing the side chain protecting groups and the resin, the polypeptide is obtained; Wherein, q is a natural number greater than or equal to 2; PG refers to the protecting group at the end of the main chain of the polypeptide chain on the solid phase support, and AA refers to a single amino acid on the main chain of the polypeptide chain on the solid phase support.

13. The method for synthesizing a polypeptide according to claim 12, wherein: The polypeptide synthesis method further includes the following steps: 1) removing the protective group PG on the PG-AA-resin using a deprotection reagent to obtain H-AA-resin; 2) adding a compound of formula I corresponding to PG-AA-OH in the presence of a catalyst, and coupling in a solvent to obtain PG-(AA)2-resin; 3) repeating steps 1) and 2) in sequence according to the sequence of the target peptide chain to obtain PG-(AA) q -resin, decapping, cleavage, removal of side chain protecting groups and resin, and purification to obtain the polypeptide.

14. Use of the compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 in the preparation of amide compounds and / or polypeptides.

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