Cyclic pentapeptide containing Fmoc protecting group and preparation method thereof
The method for preparing cyclic pentapeptides with Fmoc protecting groups solves the problem of high difficulty in cyclic polypeptide synthesis, achieving high yield and low cost of cyclic pentapeptide synthesis. It is applicable to a variety of amino acid sequences and enhances the binding ability with targets.
Patent Information
- Application Number
- CN202511154766.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-18
- Publication Date
- 2025-11-14
AI Technical Summary
Existing methods for synthesizing cyclic peptides are difficult, intramolecular condensation is easily affected by steric hindrance, resulting in low yields and numerous side reactions. Traditional methods are cumbersome, costly, and incompatible with complex side-chain protecting groups.
A method for preparing cyclic pentapeptides using an Fmoc protecting group is employed, which involves coupling, deprotection, and intramolecular cyclization reactions. This method avoids solid-phase carriers, adapts to various amino acid sequences, and reduces production costs.
It improves cyclization yield, reduces production costs, enhances binding ability to targets, and is suitable for the synthesis of cyclic pentapeptides with various amino acid sequences.
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Figure CN120943904A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of cyclic polypeptide technology, and more specifically, to cyclic pentapeptides containing Fmoc protecting groups and their preparation methods. Background Technology
[0002] Cyclic peptides are polypeptide compounds with closed cyclic structures formed by multiple amino acids linked by peptide bonds or other chemical bonds. Due to their rigid intramolecular conformation, resistance to enzymatic degradation, and high receptor selectivity, cyclic peptides have significant application value in antitumor, anti-inflammatory, and immunomodulatory fields. Compared to linear peptides, cyclic peptides exhibit significantly improved metabolic stability and can fix their active conformation through intramolecular hydrogen bonds or hydrophobic interactions, enhancing their binding affinity to targets. However, the synthesis of cyclic peptides in existing technologies is challenging. Intramolecular condensation is easily affected by steric hindrance, leading to low yields and numerous side reactions, such as intermolecular condensation to form decapeptides. For example, traditional solid-phase synthesis methods require multiple deprotection and coupling steps, which are cumbersome and costly. Existing cyclization methods (such as active esterification and azidation) have limited adaptability to amino acid sequences and are difficult to accommodate complex side-chain protecting groups.
[0003] In view of this, the present invention is proposed. Summary of the Invention
[0004] The purpose of this invention is to provide a cyclic pentapeptide containing an Fmoc protecting group and a method for preparing the same. The preparation method provided in this invention has a high cyclization yield, can adapt to various amino acid sequences, can synthesize cyclic polypeptides containing side-chain protecting groups, and the cyclization step does not require a solid-phase support, thus significantly reducing production costs.
[0005] This invention is implemented as follows: In a first aspect, embodiments of the present invention provide a method for preparing a cyclic pentapeptide containing an Fmoc protecting group, comprising: coupling a dipeptide containing Fmoc-Cbz-lysine with a tripeptide containing OBn-OtBu-glutamic acid to form a linear pentapeptide containing Fmoc, Cbz, OBn and OtBu. Then, Cbz and OBn are removed from the linear pentapeptide containing Fmoc, Cbz, OBn and OtBu to form a linear pentapeptide containing Fmoc and OtBu. Next, the linear pentapeptide containing Fmoc and OtBu is subjected to an intramolecular cyclization reaction to form a cyclic pentapeptide containing Fmoc and OtBu; Then, the OtBu containing Fmoc and OtBu is removed from the cyclic pentapeptide to form a cyclic pentapeptide containing the Fmoc protecting group.
[0006] In a preferred embodiment of the present invention, the method includes: mixing the dipeptide, the tripeptide, the coupling agent and the organic base to carry out a coupling reaction; Preferably, the molar ratio of the dipeptide to the tripeptide is 1:(1-1.2). The molar ratio of the dipeptide to the organic base is 1:(1.5-2.5). The molar ratio of the dipeptide to the coupling agent is 1:(1-1.2). The reaction conditions include a temperature of 10-30℃ and a time of 1-2 hours.
[0007] In a preferred embodiment of the present invention, after the coupling reaction is completed, the reaction system is post-processed, wherein the post-processing includes: mixing the reaction system with a nitrile solvent and filtering to form a filter cake, washing the filter cake multiple times, and then drying it.
[0008] In a preferred embodiment of the present invention, the dipeptide is selected from compounds with the following structural formulas: The tripeptide is selected from compounds with the following structural formulas: .
[0009] In a preferred embodiment of the present invention, the method includes: mixing the linear pentapeptide containing Fmoc, Cbz, OBn and OtBu, a palladium catalyst and a solvent in a hydrogen atmosphere to react and form a linear pentapeptide containing Fmoc and OtBu. Preferably, the reaction conditions include: a molar ratio of the linear pentapeptide containing Fmoc, Cbz, OBn and OtBu to the catalyst of 1:(0.2-0.7); and a temperature of 30-40°C.
[0010] In a preferred embodiment of the present invention, the palladium catalyst comprises Pd / C and Pd(OH)2; preferably, the molar ratio of Pd / C to Pd(OH)2 is 1:(1.5-2.5). Preferably, the solvent includes amide solvents and C1-C3 alcohol solvents, and more preferably includes DMF and methanol; Preferably, the linear pentapeptide containing Fmoc, Cbz, OBn, and OtBu is selected from compounds with the following structural formulas: .
[0011] In a preferred embodiment of the present invention, the reaction includes mixing the linear pentapeptide containing Fmoc and OtBu, a condensing agent, and a solvent.
[0012] In a preferred embodiment of the present invention, the molar ratio of the linear pentapeptide containing Fmoc and OtBu to the condensing agent is 1:(1.0-1.2). Preferably, the reaction temperature is 10-30℃; Preferably, the amount of solvent used is 60-120 times the mass of the linear pentapeptide containing Fmoc and OtBu; Preferably, the condensing agent is selected from EDCI / HOBt, TBTU / HOBT, or PyAop / HOAT; Preferably, the linear pentapeptide containing Fmoc and OtBu is selected from compounds with the following structural formulas: .
[0013] In a preferred embodiment of the present invention, the method includes: mixing a cyclic pentapeptide containing Fmoc and OtBu with an organic acidic substance and reacting it at 45°C for 20-40 minutes, and then reacting it at 60-80°C for 5-8 hours. Preferably, the cyclic pentapeptide containing Fmoc and OtBu is selected from compounds with the following structural formulas: .
[0014] Secondly, embodiments of the present invention provide a cyclic pentapeptide containing an Fmoc protecting group, which is prepared by the preparation method of the cyclic pentapeptide containing an Fmoc protecting group provided in the foregoing embodiments; Preferably, the cyclic pentapeptide containing the Fmoc protecting group is a cyclic pentapeptide with a lysine residue at the head end and a glutamic acid residue at the tail end. Preferably, the cyclic pentapeptide containing the Fmoc protecting group is selected from compounds with the following structural formulas: .
[0015] The present invention has the following beneficial effects: (1) The embodiments of the present invention reduce the coupling steps by fragment condensation, which can significantly improve the cyclization yield.
[0016] (2) The embodiments of the present invention employ a specific protecting group, which makes it applicable to a variety of amino acid sequences. That is, the preparation method provided by the embodiments of the present invention can prepare cyclic pentapeptides formed by different amino acids. In other words, the preparation method has good compatibility.
[0017] (3) The preparation method provided in this embodiment of the invention does not require a solid support for the cyclization step, which reduces production costs.
[0018] (4) The cyclic pentapeptide containing the Fmoc protecting group formed by the preparation method provided in the present invention contains the Fmoc group, and can be further modified for tumor targeted therapy or molecular probe development. Attached Figure Description
[0019] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.
[0020] Figure 1 The HPLC spectrum of the cyclic pentapeptide containing the Fmoc protecting group provided in Example 1 of the present invention; Figure 2 The NMR spectrum of the cyclic pentapeptide containing the Fmoc protecting group provided in Example 1 of the present invention; Figure 3 The mass spectrum of the cyclic pentapeptide containing the Fmoc protecting group provided in Example 1 of the present invention. Detailed Implementation
[0021] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.
[0022] In a first aspect, embodiments of the present invention provide a method for preparing a cyclic pentapeptide containing an Fmoc protecting group, comprising: S1, coupling reaction; A dipeptide containing Fmoc-Cbz-lysine is coupled with a tripeptide containing OBn-OtBu-glutamic acid to form a linear pentapeptide containing Fmoc, Cbz, OBn, and OtBu. Specifically, the dipeptide, the tripeptide, the coupling agent, and an organic base are mixed and the coupling reaction is carried out.
[0023] In this dipeptide, the lysine residue contains both Fmoc and Cbz; Fmoc is linked to the branched amino group of lysine, and Cbz is linked to the terminal amino group of lysine. The other end of the dipeptide contains a carboxyl group, and can be any amino acid known in the prior art. The other end of the dipeptide contains a carboxylic acid. For example, the dipeptide is selected from compounds with the following structural formula: The tripeptide is terminally composed of glutamic acid, which contains both OBn and OtBu. OBn is attached to the terminal carboxylic acid of glutamic acid, and OtBu is attached to the side-chain carboxylic acid of glutamic acid. The amino acid in the middle of the tripeptide can also be a known amino acid. The other end of the tripeptide is an existing amino acid containing an amino side chain or a terminal amino group; that is, the tripeptide contains an amino side chain or a terminal amino group. For example, the tripeptide is selected from compounds with the following structural formula: .
[0024] Furthermore, the coupling reaction conditions are as follows: the molar ratio of dipeptide to trimer is 1:(1-1.2); the molar ratio of dipeptide to said organic base is 1:(1.5-2.5); the temperature is 10-30°C; the time is 1-2 hours; and the molar ratio of dipeptide to coupling agent is 1:(1-1.2). The coupling agent can be selected from existing condensing agents, such as including but not limited to HOBT and TBTU.
[0025] Using the above conditions can facilitate the coupling reaction and improve the purity and yield of linear pentapeptides containing Fmoc, Cbz, OBn and OtBu.
[0026] After the coupling reaction is completed, the reaction system undergoes post-treatment. Specifically, the reaction system is mixed with a nitrile solvent, filtered to form a filter cake, and the filter cake is washed multiple times before drying. The solvent used for washing is also a nitrile solvent. In the embodiments of this invention, the nitrile solvent includes, but is not limited to, acetonitrile.
[0027] The specific post-processing method employed in this invention can significantly improve the yield and purity of linear pentapeptides containing Fmoc, Cbz, OBn, and OtBu.
[0028] S2, Deprotection; The Cbz and OBn of the linear pentapeptide containing Fmoc, Cbz, OBn, and OtBu formed by S1 are removed to form a linear pentapeptide containing Fmoc and OtBu. Specifically, the linear pentapeptide containing Fmoc, Cbz, OBn, and OtBu, a palladium catalyst, and a solvent are mixed and reacted under a hydrogen atmosphere to form a linear pentapeptide containing Fmoc and OtBu.
[0029] The linear pentapeptide containing Fmoc, Cbz, OBn, and OtBu has glutamic acid and lysine residues at its two ends, respectively. The amino group of the lysine side chain is connected to Fmoc, the amino terminus is connected to Cbz, the carboxyl terminus of the glutamic acid is connected to OBn, and the carboxylic acid side chain is connected to OtBu. The amino acids of the remaining tripeptide in the linear pentapeptide can be selected from existing known amino acids. Furthermore, the linear pentapeptide contains a carboxylate group and an amino group capable of reacting. For example, the linear pentapeptide containing Fmoc, Cbz, OBn, and OtBu is selected from compounds with the following structural formulas: .
[0030] Further, the reaction conditions include: a molar ratio of the linear pentapeptide to the catalyst of 1:(0.2-0.7); and a temperature of 30-40°C. The palladium catalyst comprises Pd / C and Pd(OH)₂; preferably, the molar ratio of Pd / C to Pd(OH)₂ is 1:(1.5-2.5). The solvent comprises amide solvents and C1-C3 alcohol solvents, preferably including DMF and methanol.
[0031] The embodiments of the present invention employ specific reaction temperatures, specific solvents, and specific catalysts, which can significantly enhance the reaction process, reduce the amount of reactant residue after the reaction, and improve the product yield.
[0032] S3, intramolecular cyclization reaction; An intramolecular cyclization reaction is performed on the linear pentapeptide containing Fmoc and OtBu to form a cyclic pentapeptide containing Fmoc and OtBu. Specifically, the linear pentapeptide containing Fmoc and OtBu, a condensing agent, and a solvent are mixed and reacted.
[0033] In the linear pentapeptide containing Fmoc and OtBu, Fmoc is located on the amino side chain of lysine, and OtBu is located on the carboxylic acid side chain of glutamic acid. The amino terminus of lysine reacts with the carboxylic acid terminus of glutamic acid to achieve cyclization. For example, the linear pentapeptide containing Fmoc and OtBu is selected from compounds with the following structural formulas: .
[0034] Furthermore, the conditions for the intramolecular cyclization reaction include: a molar ratio of the linear pentapeptide containing Fmoc and OtBu to the condensing agent of 1:(1-1.2); the condensing agent is selected from EDCI / HOBt, TBTU / HOBT, or PyAop / HOAT; the reaction temperature is 10-30°C; and the amount of solvent is 60-120 times the mass of the linear pentapeptide containing Fmoc and OtBu. The solvent can be an amide solvent, such as DMF. Using the above reaction conditions can significantly reduce the impurity content and improve the purity and yield of the cyclization.
[0035] It should be noted that the amount of solvent used is relative to the mass of the linear pentapeptide containing Fmoc and OtBu. For example, the amount of solvent used is 0.6-1.2 L per 10 g of the linear pentapeptide containing Fmoc and OtBu.
[0036] S4, Deprotection; The OtBu of the cyclic pentapeptide containing Fmoc and OtBu is removed to form a cyclic pentapeptide containing the Fmoc protecting group. Specifically, the cyclic pentapeptide containing Fmoc and OtBu is mixed with an organic acid and reacted at 45°C for 20-40 minutes, followed by reaction at 60-80°C for 5-8 hours. For example, the cyclic pentapeptide containing Fmoc and OtBu is selected from compounds with the following structural formulas: .
[0037] It should be noted that post-processing can be performed after each reaction step in the preparation method provided in this embodiment of the invention. Except for S1, which has special requirements, the post-processing methods used after the reaction of other steps can be any existing post-processing methods, including but not limited to extraction, filtration, rinsing, drying, and pulping.
[0038] In the preparation method provided in this embodiment of the invention, each reaction step is determined to be complete by TLC spot test.
[0039] Secondly, embodiments of the present invention provide a cyclic pentapeptide containing an Fmoc protecting group, which is prepared by the aforementioned method for preparing cyclic pentapeptides containing an Fmoc protecting group. The cyclic pentapeptide containing an Fmoc protecting group is a cyclic pentapeptide with a lysine residue at the head end and Fmoc located at the side chain amino group of lysine; and a glutamic acid residue at the tail end. For example, the cyclic pentapeptide containing an Fmoc protecting group is selected from compounds with the following structural formulas: .
[0040] The features and performance of the present invention will be further described in detail below with reference to embodiments.
[0041] Example 1 This invention provides a cyclic pentapeptide containing an Fmoc protecting group, the structural formula of which is shown below: .
[0042] This invention also provides a method for preparing the above-mentioned cyclic pentapeptide containing the Fmoc protecting group, comprising: synthesizing according to the following synthetic route:
[0043] The specific process is as follows: S1, coupling reaction; 1) Add 1000ml DMF and 179.6g Fmoc-Lys(Cbz)-Ala-OH to a 3L three-necked flask, and cool it to below 10℃ in an ice water bath while stirring.
[0044] 2) Add 44.4g HOBT and 120.7g TBTU sequentially. While maintaining a temperature below 15℃, add 60.7g DIEA dropwise. Dissolve 169g H-Phe-Val-Glu(OBn)-OtBu in 360ml DMF and add it dropwise while maintaining a temperature below 15℃. After the first addition, slowly add 40.5g DIEA. The system should be a pale yellow, transparent color after the addition is complete. After warming to 10-30℃ and reacting for 1.5-2 hours, a solid will precipitate. Take a sample and perform TLC to check the reaction. 3) Transfer the reaction solution to a container (approximately 2L), add 6L of acetonitrile while stirring, and after stirring for 10-20 minutes, filter to obtain a filter cake. Wash the filter cake once with approximately 2L of acetonitrile, and rinse once to obtain the wet weight of the filter cake. Place the filter cake in a forced-air drying oven at 50-55℃ and dry it. The yield is 302g, with a yield of 88.0%.
[0045] S2, Deprotection; 1) Dissolve 300g of Fmoc-Lys(Cbz)-Ala-Phe-Val-Glu(OBn)-OtBu by heating 4500ml of DMF to 65-70℃. After dissolving, cool to 30-40℃ and add 1500ml of methanol, Pd / C (45g), and Pd(OH)2 (15g). Replace with hydrogen three times and react at room temperature for 21-23h under a hydrogen atmosphere.
[0046] 2) After the TLC reaction is complete, filter the reaction solution. Wash the filter cake with a small amount of DMF. Slowly add the filtrate to 20L of water with stirring. After adding the filtrate, stir for 10-20 minutes, then filter again. Rinse the filter cake once with water. Scrape the filter cake and slurry it with 5L of acetonitrile for 20-30 minutes, then filter again. Rinse the filter cake with acetonitrile. Place the filter cake in a forced-air oven and dry at 50-55℃. The yield is 181g, yield: 75.5%.
[0047] S3, intramolecular cyclization reaction; 1) Add 4000ml of DMF and 81g of Fmoc-Lys-Ala-Phe-Val-Glu-OtBu to a 5L three-necked flask, stir and cool in an ice water bath to below 10℃, but it failed to dissolve completely.
[0048] 2) Add 13.1g HOBT and 33.6g TBTU sequentially, rinse the funnel with 150ml DMF, dissolve 43.1g DIEA in 710ml DMF, add dropwise while controlling the temperature below 10℃, and add completely in about 30min. After the temperature is restored to 10-30℃, react for 1.5-2h until the system is clear; take a sample and spot it on a TLC plate.
[0049] 3) After filtering the reaction solution to remove the linear peptides, slowly add it to 15L of 2% sodium bicarbonate aqueous solution under stirring. After stirring for 10-20 minutes, filter. Scrape off the filter cake, slurry it with 1L of water for 30 minutes, and filter again. Rinse the filter cake with water, scrape off the filter cake again, slurry it with 1L of acetonitrile for 30 minutes, and filter again to obtain the filter cake. Place the solid in a forced-air drying oven at 50-55℃ and collect 64g of off-white solid, yield: 80.7%.
[0050] S4, Deprotection; 1) Add 640ml of acetonitrile and 640ml of DCM to a 2L single-necked flask, and add 64g of Fmoc-Cyclo(Lys-Ala-Phe-Val-Glu)-OtBu, 64g of TFA and 64g of 85% phosphoric acid while stirring. Heat to 45℃ and react for 0.5h, then heat to 70℃ and continue reacting.
[0051] 2) After reacting at a constant temperature for 6-7 hours, the system initially showed signs of dissolution, followed by the precipitation of a large amount of solid. A sample was taken and visualized by TLC under UV light. After the reaction was complete, the reaction solution was cooled to 20-30℃, filtered, and the filter cake was washed with acetonitrile. The filter cake was then slurried with 1L of water for 30 minutes and filtered again. The filter cake was then slurried again with a mixture of 500ml acetonitrile and 500ml THF for 30 minutes and filtered. The solid was dried in a forced-air oven at 50-55℃, yielding 50g of a white solid, with a yield of 83.7%.
[0052] Characterization The cyclic pentapeptide containing the Fmoc protecting group prepared in Example 1 was characterized, and the results are shown in [reference needed]. Figures 1-3 .in, Figure 1 This is an HPLC chromatogram; Figure 2 This is an NMR spectrum; Figure 3 This is a mass spectrum. According to... Figures 1-3 It is understood that the compound formed in the embodiments of the present invention is the desired cyclic pentapeptide containing the Fmoc protecting group.
[0053] Process optimization 1 This optimized process was performed following S1 of the preparation method provided in Example 1. Specifically, using Fmoc-Lys(Cbz)-Ala-OH, H-Phe-Val-Glu(OBn)-OtBu, DIPEA, and DMF as standard substrates, and with reaction conditions such as temperature and reaction time consistent with S1 of Example 1, the post-reaction processing method was investigated, and the results are shown in the table below:
[0054] The yield and purity in the table above refer to the yield and purity of the product of S1, respectively.
[0055] As shown in the table above, the purity of the linear pentapeptide containing Fmoc, Cbz, OBn and OtBu formed by the coupling reaction is greatly affected by the post-treatment. If the solvent used in the post-treatment is changed, the yield and purity of the product may be significantly reduced, and it may even affect the filtration performance, thus affecting the actual production time and efficiency.
[0056] Process optimization 2 This process optimization refers to the synthesis in S2 of the preparation method provided in Example 1. Specifically, using Fmoc-Lys(Cbz)-Ala-Phe-Val-Glu(OBn)-OtBu as the starting material, the reaction solvent, reaction temperature, and catalyst were investigated. Except for the changes in temperature, solvent, and catalyst in the table below, all other operations and conditions were consistent with those of S2. The results are shown in the table below:
[0057] As can be seen from the table above, if the solvent, temperature and catalyst are changed, there may be a large amount of residual raw materials in the S2 reaction, resulting in incomplete S2 reaction, which in turn leads to high impurity content and low yield of S2 product.
[0058] Process optimization 3 This optimized process was performed following step S3 of the preparation method provided in Example 1. Specifically, all other operations and conditions in S3 remained unchanged, except for the volumes of the condensing agent and the reaction solvent, to investigate the results, which are shown in the table below.
[0059]
[0060] The results above show that if the amount of solvent is too small, it can easily lead to the formation of a large number of impurities, reducing the yield and purity of the S3 product.
[0061] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A method for preparing a cyclic pentapeptide containing an Fmoc protecting group, characterized in that, include: A dipeptide containing Fmoc-Cbz-lysine is coupled with a tripeptide containing OBn-OtBu-glutamic acid to form a linear pentapeptide containing Fmoc, Cbz, OBn and OtBu. Then, Cbz and OBn are removed from the linear pentapeptide containing Fmoc, Cbz, OBn and OtBu to form a linear pentapeptide containing Fmoc and OtBu. Next, the linear pentapeptide containing Fmoc and OtBu is subjected to an intramolecular cyclization reaction to form a cyclic pentapeptide containing Fmoc and OtBu; Then, the OtBu containing Fmoc and OtBu is removed from the cyclic pentapeptide to form a cyclic pentapeptide containing the Fmoc protecting group.
2. The preparation method according to claim 1, characterized in that, include: The dipeptide, the tripeptide, the coupling agent, and the organic base are mixed and a coupling reaction is carried out. Preferably, the molar ratio of the dipeptide to the tripeptide is 1:(1-1.2). The molar ratio of the dipeptide to the organic base is 1:(1.5-2.5). The molar ratio of the dipeptide to the coupling agent is 1:(1-1.2). The reaction conditions include a temperature of 10-30℃ and a time of 1-2 hours.
3. The preparation method according to claim 2, characterized in that, After the coupling reaction is completed, the reaction system is post-processed, which includes: mixing the reaction system with a nitrile solvent, filtering to form a filter cake, washing the filter cake multiple times, and then drying it.
4. The preparation method according to any one of claims 1-3, characterized in that, The dipeptide is selected from compounds shown in the following structural formulas: The tripeptide is selected from compounds with the following structural formulas: .
5. The preparation method according to claim 1, characterized in that, include: The linear pentapeptide containing Fmoc, Cbz, OBn and OtBu, palladium catalyst and solvent are mixed and reacted in a hydrogen atmosphere to form a linear pentapeptide containing Fmoc and OtBu. Preferably, the reaction conditions include: a molar ratio of the linear pentapeptide containing Fmoc, Cbz, OBn and OtBu to the catalyst of 1:(0.2-0.7); and a temperature of 30-40°C.
6. The preparation method according to claim 5, characterized in that, The palladium catalyst comprises Pd / C and Pd(OH)2; preferably, the molar ratio of Pd / C to Pd(OH)2 is 1:(1.5-2.5). Preferably, the solvent includes amide solvents and C1-C3 alcohol solvents, and more preferably includes DMF and methanol; Preferably, the linear pentapeptide containing Fmoc, Cbz, OBn, and OtBu is selected from compounds with the following structural formulas: 。 7. The preparation method according to claim 1, characterized in that, include: The linear pentapeptide containing Fmoc and OtBu, a condensing agent, and a solvent are mixed and reacted.
8. The preparation method according to claim 7, characterized in that, The molar ratio of the linear pentapeptide containing Fmoc and OtBu to the condensing agent is 1:(1.0-1.2). Preferably, the reaction temperature is 10-30℃; Preferably, the amount of solvent used is 60-120 times the mass of the linear pentapeptide containing Fmoc and OtBu; Preferably, the condensing agent is selected from EDCI / HOBt, TBTU / HOBT, or PyAop / HOAT; Preferably, the linear pentapeptide containing Fmoc and OtBu is selected from compounds with the following structural formulas: 。 9. The preparation method according to claim 1, characterized in that, include: Cyclic pentapeptides containing Fmoc and OtBu are mixed with organic acidic substances and reacted at 45°C for 20-40 minutes, followed by reaction at 60-80°C for 5-8 hours. Preferably, the cyclic pentapeptide containing Fmoc and OtBu is selected from compounds with the following structural formulas: 。 10. A cyclic pentapeptide containing an Fmoc protecting group, characterized in that, It is prepared by the method for preparing cyclic pentapeptides containing Fmoc protecting groups as described in any one of claims 1-9; Preferably, the cyclic pentapeptide containing the Fmoc protecting group is a cyclic pentapeptide with a lysine residue at the head end and a glutamic acid residue at the tail end. Preferably, the cyclic pentapeptide containing the Fmoc protecting group is selected from compounds with the following structural formulas: 。