A method for preparing cladoamide A

Abstract

The application relates to a preparation method of Cladoamide A. The resin is sequentially connected with Fmoc-beta-alanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-L-isoleucine, Fmoc-L-proline and L-flashing white acid to obtain a chain polypeptide compound; the chain polypeptide compound is treated by a fluorine-containing solvent to perform a cyclization reaction, and Cladoamide A is successfully prepared; the application provides a synthesis scheme of Cladoamide A, and is favorable for studying the biological activity of Cladoamide A.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemical synthesis, in particular to a preparation method of Cladoamide A. BACKGROUND

[0002] Peptolipid is a kind of oligomer composed of hydroxy acid and amino acid connected by ester bond and amide bond alternately, and the cyclic structure is the most common. Peptolipid compounds show diversified biological activities, such as anti-tumor, anti-virus, insecticidal and anti-thrombus, and have very wide application prospects. The source of peptolipid compounds is relatively wide, and they have been found in marine mollusks, coelenterates, sponges and sea squirts, and microorganisms are also an important source of such compounds.

[0003] Cladoamide A is a phenolic acid peptide compound isolated in recent years. It was first isolated by Professor Yasuhiro Igarashi's research group of Toyama Prefectural University Biological Technology Research Center from the culture solution of Cladobotrym varium, a fungal pathogen causing mushroom spider web disease. Since the abundance of Cladoamide A in nature is low, there is no synthesis scheme of Cladoamide A, which is not conducive to the study of the biological activity of Cladoamide A. SUMMARY

[0004] Therefore, it is necessary to provide a preparation method of Cladoamide A, aiming at solving the technical problem that there is no synthesis scheme of Cladoamide A in the prior art.

[0005] To achieve the above-mentioned purpose, the present application provides a technical solution:

[0006] A preparation method of Cladoamide A, comprising the following steps:

[0007] The resin is sequentially connected with Fmoc-beta-alanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-L-isoleucine, Fmoc-L-proline and L-flashing acid to obtain a chain-like polypeptide compound;

[0008] The chain-like polypeptide compound is treated with a fluorine-containing solvent, and then subjected to a cyclization reaction to obtain the Cladoamide A;

[0009] The structural formula of the Cladoamide A is as follows:

[0010]

[0011] Preferably, the cyclization reaction is carried out by a continuous flow method.

[0012] Preferably, the resin comprises any one of 2-CTC resin, Rinkamide-PS resin, Rinkamide-PEG resin and CM resin.

[0013] Preferably, the fluorine-containing solvent comprises any one of hexafluoroisopropanol, trifluoroacetic acid, trifluoroacetic acid / water / triisopropylsilane mixed reagent.

[0014] Preferably, the volume ratio of trifluoroacetic acid, water and triisopropylsilane in the trifluoroacetic acid / water / triisopropylsilane mixed reagent is (5-10):(0.1-0.3):(0.1-0.3).

[0015] Preferably, the specific steps of sequentially connecting the resin with Fmoc-β-alanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-L-isoleucine, Fmoc-L-proline and L-flashing acid to obtain the linear polypeptide compound comprise:

[0016] reacting the resin with the Fmoc-β-alanine, and obtaining a first resin after the reaction is completed;

[0017] removing the Fmoc protection from the first resin, and reacting the first resin from which the Fmoc protection is removed with the Fmoc-N-methyl-L-phenylalanine to obtain a second resin;

[0018] removing the Fmoc protection from the second resin, and reacting the second resin from which the Fmoc protection is removed again with the Fmoc-N-methyl-L-phenylalanine to obtain a third resin;

[0019] removing the Fmoc protection from the third resin, and reacting the third resin from which the Fmoc protection is removed with the Fmoc-L-isoleucine to obtain a fourth resin;

[0020] removing the Fmoc protection from the fourth resin, and reacting the fourth resin from which the Fmoc protection is removed with the Fmoc-L-proline to obtain a fifth resin;

[0021] removing the Fmoc protection from the fifth resin, and reacting the fifth resin from which the Fmoc protection is removed with the L-flashing acid to obtain the linear polypeptide compound.

[0022] Preferably, the specific steps of reacting the resin with the Fmoc-β-alanine and obtaining a first resin after the reaction is completed comprise:

[0023] swelling the resin in a first solvent, and washing the resin swollen in the first solvent with a first washing liquid to obtain a swollen resin;

[0024] dissolving the Fmoc-beta-alanine and a first basic reagent in a second solvent to obtain a first mixture;

[0025] adding the first mixture to the swollen resin to react, and bubbling with an inert gas, and after the reaction is completed, the resin is connected with Fmoc-beta-alanine to obtain a first resin.

[0026] Preferably, the molar ratio of the resin to the Fmoc-beta-alanine is 1:(1.1-5).

[0027] Preferably, the specific steps for removing the Fmoc protection from the first resin and reacting the first resin from which the Fmoc protection is removed with the Fmoc-N-methyl-L-phenylalanine to obtain a second resin include:

[0028] adding a capping agent to the first resin to react, and after the reaction is completed, a capped first resin is obtained;

[0029] treating the capped first resin with a morpholine solution to remove the Fmoc protection;

[0030] dissolving Fmoc-N-methyl-L-phenylalanine, HATU and a second basic reagent in a third solvent to obtain a second mixture;

[0031] adding the first resin from which the Fmoc protection is removed to the second mixture to react, and after the reaction is completed, a second resin is obtained.

[0032] Preferably, the capping agent includes a mixture of dichloromethane / diisopropylethylamine / methanol.

[0033] Advantages of the present application:

[0034] The present application connects the resin with Fmoc-beta-alanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-L-isoleucine, Fmoc-L-proline and L-flashing acid in sequence to obtain a chain-like polypeptide compound; then the chain-like polypeptide compound is treated with a fluorine-containing solvent to perform a cyclization reaction, and Cladoamide A is successfully prepared, and the present application provides a synthesis scheme of Cladoamide A, which is beneficial to the study of the biological activity of Cladoamide A. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 a synthesis route map of Cladoamide A;

[0036] Figure 2 Figure 1 is a structural schematic diagram of a tubular microreactor;

[0037] Figure 3 Figure 1 is a structural schematic diagram of a tubular microreactor;

[0038] Figure 4 Figure 1 is a structural schematic diagram of a tubular microreactor;

[0039] In the figure, 110 is a first micro-injection pump; 120 is a second micro-injection pump; 200 is a T-shaped mixer; 300 is a micro-pipe; 400 is a sample outlet; and 500 is a collection bottle. DETAILED DESCRIPTION

[0040] For the purpose of better illustrating the present application, the technical solutions and advantages, the present application will be further described in conjunction with specific examples.

[0041] In the examples, the test methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are commercially available unless otherwise specified.

[0042] A preparation method of Cladoamide A, comprising the steps of:

[0043] The resin is sequentially connected with Fmoc-β-alanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-L-isoleucine, Fmoc-L-proline and L-flashing white acid to obtain a chain polypeptide compound.

[0044] The chain polypeptide compound is treated with a fluorine-containing solvent, and then subjected to a cyclization reaction to prepare Cladoamide A.

[0045] The structural formula of Cladoamide A is as follows:

[0046]

[0047] In an embodiment, the cyclization reaction is performed by using a continuous flow method.

[0048] In an embodiment, the fluorine-containing solvent includes any one of hexafluoroisopropanol, trifluoroacetic acid, and a trifluoroacetic acid / water / triisopropylsilane mixed reagent.

[0049] In an embodiment, the volume ratio of trifluoroacetic acid, water and triisopropylsilane in the trifluoroacetic acid / water / triisopropylsilane mixed reagent is (5-10):(0.1-0.3):(0.1-0.3).

[0050] In an embodiment, the resin is sequentially linked with Fmoc-β-alanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-L-isoleucine, Fmoc-L-proline, and L-phenylalanine to obtain a specific step of the chain polypeptide compound, which comprises the following steps:

[0051] S100, reacting the resin with Fmoc-β-alanine, and obtaining a first resin after the reaction is completed.

[0052] The specific operation steps of S100 comprise the following steps:

[0053] The resin is swelled in a first solvent, and the resin swelled in the first solvent is washed with a first washing liquid to obtain a swelled resin; more specifically, the first solvent comprises dichloromethane; the swelling time is 0.5-2 h; and the first washing liquid is dimethylformamide and dichloromethane.

[0054] Fmoc-β-alanine and a first basic reagent are dissolved in a second solvent to obtain a first mixture; the second solvent is dimethylformamide; specifically, the first basic reagent comprises at least one of isopropyl ethyl amine, triethylamine, trimethylamine, pyridine, and DBU. The first basic reagent is used for deprotonation.

[0055] The first mixture is added to the swelled resin for reaction, the reaction time is 2-5 h, and an inert gas is bubbled during the reaction; after the reaction is completed, the resin is linked with Fmoc-β-alanine to obtain a first resin.

[0056] In an embodiment, the molar ratio of the resin to Fmoc-β-alanine is 1:(1.1-5).

[0057] In an embodiment, the resin comprises any one of 2-CTC resin, Rinkamide-PS resin, Rinkamide-PEG resin, and CM resin.

[0058] S200, removing the Fmoc protection from the first resin, and reacting the first resin from which the Fmoc protection is removed with Fmoc-N-methyl-L-phenylalanine to obtain a second resin.

[0059] The specific steps comprise the following steps:

[0060] The first resin is added with a capping agent for 0.1-1 h, and after the reaction is completed, a capped first resin is obtained; the capping agent comprises a mixture of dichloromethane / diisopropyl ethyl amine / methanol, and the volume ratio is (6-8):(5-10):(0.5-2).

[0061] The capped first resin is treated with a morpholine solution for 0.1-1 h to remove the Fmoc protection; the morpholine solution contains 5-50% morpholine by mass, and the solvent is dimethylformamide.

[0062] Fmoc-N-methyl-L-phenylalanine, HATU {2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate} and a second basic reagent are dissolved in a third solvent to obtain a second mixture; the third solvent includes dimethylformamide; specifically, the second basic reagent includes at least one of isopropyl ethyl amine, triethylamine, trimethylamine, pyridine and DBU. The second basic reagent is used for deprotonation.

[0063] The second mixture is added to the first resin from which the Fmoc protection is removed, and reacted for 1-12 h, and the reaction is completed to obtain a second resin.

[0064] In an embodiment, the capping agent includes a mixture of dichloromethane / diisopropyl ethyl amine / methanol.

[0065] S300, the second resin is removed from the Fmoc protection, and the second resin from which the Fmoc protection is removed is reacted with Fmoc-N-methyl-L-phenylalanine again to obtain a third resin.

[0066] Specifically, the molar ratio of the second resin to Fmoc-N-methyl-L-phenylalanine is 1:(1.5-5).

[0067] S400, the third resin is removed from the Fmoc protection, and the third resin from which the Fmoc protection is removed is reacted with Fmoc-L-isoleucine to obtain a fourth resin.

[0068] Specifically, the molar ratio of the third resin to Fmoc-L-isoleucine is 1:(1.5-5).

[0069] S500, the fourth resin is removed from the Fmoc protection, and the fourth resin from which the Fmoc protection is removed is reacted with Fmoc-L-proline to obtain a fifth resin.

[0070] Specifically, the molar ratio of the fourth resin to Fmoc-L-proline is 1:(1.5-5).

[0071] S600, the fifth resin is removed from the Fmoc protection, and the fifth resin from which the Fmoc protection is removed is reacted with L-flashing white acid to obtain a chain polypeptide compound.

[0072] Specifically, the molar ratio of the fifth resin to L-flashing white acid is 1:(1.5-5).

[0073] The reactions of S300, S400, S500 and S600 are performed according to a condensation cycle, and reference is made to step S200, i.e. each condensation cycle includes both condensation and removal of Fmoc protection.

[0074] S700, the chain polypeptide compound is treated with a fluorine-containing solvent, and then a cyclization reaction is performed to obtain Cladoamide A.

[0075] The specific steps of S700 include:

[0076] The fluorine-containing solvent is added to the chain polypeptide compound to remove the resin on the fourth resin, and after the reaction is completed, a crude chain hexapeptide acid product is obtained.

[0077] The crude chain hexapeptide acid product and dichloromethane are dissolved in the fourth solvent to prepare a 0.1-10 mmol / L chain polypeptide solution, thereby obtaining a third mixture. The volume ratio of the fluorine-containing solvent / dichloromethane is (1-10):20.

[0078] The third mixture and the coupling reagent solution are pumped into a continuous flow reactor at a volume ratio of 1:(1.1-3) by injection pumps to perform a cyclization reaction, the reaction time is 1-20 min, the reaction temperature is room temperature, and after the reaction is completed, Cladoamide A is obtained. Specifically, the pumping speed is 10-1000 μL / min. Specifically, the continuous flow reactor is a tubular microreactor.

[0079] Specifically, in an embodiment, as shown in Figure 1 the route for synthesizing Cladoamide A is as follows:

[0080]

[0081] wherein, is a 2-CTC resin, is added to the chain polypeptide compound, is a chain hexapeptide acid, is Cladoamide A.

[0082] In an embodiment, the condensation reagent in the coupling reagent solution includes DMAP (4-dimethylaminopyridine), the base includes DMAP (4-dimethylaminopyridine), and the solvent includes DCM.

[0083] In an embodiment, the fourth solvent includes DCM (N,N-dimethylformamide), and the preparation step of the coupling reagent solution includes:

[0084] HATU is prepared into a HATU solution with a concentration of 1-5 mmol / L using DMF, DIPEA is prepared into a DIPEA solution with a concentration of 4-20 mmol / L using DMF, and the HATU solution and the DIPEA solution are prepared into a coupling reagent solution in a volume ratio of 1:(1-3).

[0085] More specifically, as shown in Figure 2 The tubular microreactor comprises a first micro-injection pump 110, a second micro-injection pump 120, a T-shaped mixer 200, a micro-pipe 300, a sample outlet 400 and a collection bottle 500, the first micro-injection pump 110 and the second micro-injection pump 120 are connected with the T-shaped mixer 200, the T-shaped mixer 200, the micro-pipe 300, the sample outlet 400 and the collection bottle 500 are connected in sequence, the third mixture and the coupling reagent solution are pumped into the micro-pipe 300 by the first micro-injection pump 110 and the second micro-injection pump 120 respectively for reaction, the product enters the collection bottle 500 through the sample outlet 400, the material of the micro-pipe 300 comprises at least one of PTFE (polytetrafluoroethylene), PEEK (polyether ether ketone), PE (polyethylene) and PP (polypropylene), the inner diameter of the micro-pipe 300 is 0.8 mm, and the length of the micro-pipe 300 is 1 m.

[0086] It is worth noting that the Fmoc in the present application is fluorenylmethoxycarbonyl.

[0087] Example 1

[0088] Continuous flow synthesis method

[0089] S100, 1.0g of 2-CTC resin (1.08mmol) is swelled in a first solvent and placed in a 100mL solid-phase polypeptide synthesis tube, 20mL of dichloromethane, swelled for 30min, and the 2-CTC resin swelled in dichloromethane is washed with dimethylformamide (3x10mL) and dichloromethane (3x10mL) alternately to obtain the swelled 2-CTC resin.

[0090] 1.68g of Fmoc-β-alanine (5.40mmol) and 1.9mL of diisopropylethylamine (10.80mmol) are dissolved in 10mL of dimethylformamide to obtain a first mixture.

[0091] The first mixture is added to the swelled 2-CTC resin and reacted for 4h, and nitrogen is bubbled, the reaction is completed, the resin is connected with Fmoc-β-alanine to obtain a first resin.

[0092] S200, the first resin is washed alternately with dimethylformamide (3x10 mL) and dichloromethane (3x10 mL), and a capping agent is added to the first resin, and the reaction is bubbled with nitrogen for 30 min. After the reaction is completed, the capped first resin is obtained. The capping agent includes a mixture of dichloromethane / diisopropylethylamine / methanol, and the volumes are 8 mL / 1.5 mL / 5 mL, respectively.

[0093] The capped first resin is washed alternately with dimethylformamide (3x10 mL) and dichloromethane (3x10 mL), and then the second resin is treated with a 10 mL morpholine solution for 1 h to remove the Fmoc protection, and then washed alternately with dimethylformamide (3x10 mL) and dichloromethane (3x10 mL). The morpholine solution has a mass percentage of 50% morpholine, and the solvent is a dimethylformamide solution.

[0094] 2.17 g of Fmoc-N-methyl-L-phenylalanine (5.40 mmol), 2.05 g of HATU {2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate} (5.40 mmol), and 1.9 mL of diisopropylethylamine (10.80 mmol) are dissolved in 10 mL of dimethylformamide to obtain a second mixture.

[0095] The second mixture is added to the first resin from which the Fmoc protection is removed, and the reaction is carried out for 2 h. After the reaction is completed, the solvent is removed, and the solute part is washed alternately with dimethylformamide (3x10 mL) and dichloromethane (3x10 mL) to obtain the second resin.

[0096] S300, the second resin is removed from the Fmoc protection, and the second resin from which the Fmoc protection is removed is reacted again with 2.17 g of Fmoc-N-methyl-L-phenylalanine (5.40 mmol) to obtain a third resin.

[0097] S400, the third resin is removed from the Fmoc protection, and the third resin from which the Fmoc protection is removed is reacted with 2.89 g of Fmoc-L-isoleucine (5.40 mmol) to obtain a fourth resin.

[0098] S500, the fourth resin is removed from the Fmoc protection, and the fourth resin from which the Fmoc protection is removed is reacted with 1.82 g of Fmoc-L-proline (5.40 mmol) to obtain a fifth resin.

[0099] S600, the fifth resin is removed from the Fmoc protection, and the fifth resin from which the Fmoc protection is removed is reacted with 0.71 g of L-flashing acid (5.40 mmol) to obtain a chain polypeptide compound.

[0100] The reactions of S300, S400, S500 and S600 are performed according to a condensation cycle, and reference is made to step S200, i.e. each condensation cycle comprises condensation and removal of Fmoc protection.

[0101] S700, the chain polypeptide compound is treated with a fluorine-containing solvent, and then a cyclization reaction is performed to obtain Cladoamide A.

[0102] The specific steps of S700 include:

[0103] The chain polypeptide compound is washed with dimethylformamide (3 x 10 mL) and dichloromethane (3 x 10 mL) alternately, and after the washing is completed, the chain polypeptide compound is transferred from the synthesis tube to a round-bottom flask. The chain polypeptide compound is added to a mixture of trifluoroacetic acid / water / triisopropylsilane, and the reaction is performed for 2 h. After the reaction is completed, the solid part is removed by filtration, and the solution is blown dry with nitrogen to obtain the crude chain hexapeptide acid product. The volumes of trifluoroacetic acid / water / triisopropylsilane are 9.5 mL, 0.25 mL and 0.25 mL, respectively.

[0104] The 65 mg of the crude chain hexapeptide acid product (0.09 mmol) is dissolved in dichloromethane to prepare a 2 mmol / L chain polypeptide solution, thereby obtaining a third mixture.

[0105] The third mixture and the coupling reagent solution are pumped into the microchannel 300 through the first microsyringe pump 110 and the second microsyringe pump 120 at a volume ratio of 1:2 to perform a cyclization reaction. The reaction time is 10 min, the reaction temperature is room temperature, and the pumping speed is 50 μL / min. After the reaction is completed, Cladoamide A is obtained, and the yield is 52%.

[0106] Specifically, the preparation steps of the coupling reagent solution include:

[0107] The 6 mg of DMAP (0.045 mmol) is dissolved in DCM to prepare a 1 mmol / L DMAP solution, and the 46 mg of MNBA (0.135 mmol) is dissolved in DCM to prepare a 3 mmol / L NMI solution. The DMAP solution and the NMI solution are mixed at a volume ratio of 1:1 to prepare the coupling reagent solution.

[0108] The nuclear magnetic resonance hydrogen spectrum of the product Cladoamide A is as shown in Figure 3 , and the nuclear magnetic resonance carbon spectrum is as shown in Figure 4 .

[0109] Example 2

[0110] Conventional solid-phase synthesis method

[0111] The other steps are the same as those in Example 1, and the different parts are as follows:

[0112] 65 mg of crude linear hexapeptide acid product (0.09 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, 6 mg of DMAP (0.045 mmol) and 46 mg of MNBA (0.135 mmol) were added, and the reaction was carried out at room temperature (20°C) for 24 h. The solvent was removed by rotary evaporation under reduced pressure, and HPLC separation was performed to obtain Cladoamide A as a white solid, with a yield of 37%.

[0113] The reaction for preparing Cladoamide A was studied in terms of temperature, solvent, and reaction concentration. The following experiments were performed under the conditions indicated, and the reaction steps are shown in Examples 1 and 2, and the reaction data is shown in Table 1.

[0114] Table 1 Reaction data

[0115]

[0116] In Table 1, the molar ratio refers to the ratio of the molar values of the condensation reagent and the crude linear hexapeptide acid product.

[0117] As can be seen from Table 1, continuous flow reaction can significantly improve the reaction rate and yield.

[0118] The above are only preferred embodiments of the present application, and do not limit the patent scope of the present application. Any equivalent structural transformation made under the inventive concept of the present application, using the content of the present application specification and drawings, or directly / indirectly applied in other related technical fields is included in the patent protection scope of the present application.

Claims

1. A process for the preparation of Cladoamide A, characterized in that, The steps include: The resin is sequentially connected with Fmoc-beta-alanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-L-isoleucine, Fmoc-L-proline, and L-flashing white acid to obtain a chain polypeptide compound; The chain polypeptide compound is treated with a fluorine-containing solvent and then subjected to a cyclization reaction to obtain the Cladoamide A; The specific steps include: After the resin is swelled, the resin is sequentially connected with Fmoc-beta-alanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-L-isoleucine, Fmoc-L-proline, and L-flashing white acid to form a chain polypeptide compound, and then subjected to a fluorine-containing solvent reaction for 2 hours, the solid part is removed, and the solution is blown dry with nitrogen to obtain a chain hexapeptide acid crude product; The chain hexapeptide acid crude product is dissolved in dichloromethane to obtain a chain polypeptide solution, and a third mixture is obtained; The third mixture and a coupling reagent solution are pumped into a microchannel at a volume ratio of 1:2 through a first microsyringe pump and a second microsyringe pump to perform a cyclization reaction, the reaction time is 10 minutes, the reaction temperature is room temperature, and the pumping speed is 50 μL / min, and the reaction is completed to obtain the Cladoamide A; The resin is a 2-CTC resin; The fluorine-containing solvent is a mixture of trifluoroacetic acid / water / triisopropylsilane; The coupling reagent solution contains a condensation reagent 2-methyl-6-nitrobenzoic anhydride and a solvent dichloromethane, and the molar ratio of the condensation reagent 2-methyl-6-nitrobenzoic anhydride to the chain hexapeptide acid crude product is 1.5:1; The structural formula of the Cladoamide A is as follows:

2. The process for the preparation of Cladoamide A according to claim 1, characterized in that, The volume ratio of trifluoroacetic acid, water, and triisopropylsilane in the trifluoroacetic acid / water / triisopropylsilane mixed reagent is (5-10):(0.1-0.3):(0.1-0.3).

3. The method of claim 1, wherein the Cladoamide A is prepared by the process comprising the steps of: The specific steps for connecting the resin with Fmoc-beta-alanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-N-methyl-L-phenylalanine, Fmoc-L-isoleucine, Fmoc-L-proline, and L-flashing white acid to obtain a chain polypeptide compound include: The resin is reacted with the Fmoc-beta-alanine, and the reaction is completed to obtain a first resin; The first resin is removed from Fmoc protection, and the first resin removed from Fmoc protection is reacted with the Fmoc-N-methyl-L-phenylalanine to obtain a second resin; The second resin is removed from Fmoc protection, and the second resin removed from Fmoc protection is again reacted with the Fmoc-N-methyl-L-phenylalanine to obtain a third resin; The third resin is removed from Fmoc protection, and the third resin removed from Fmoc protection is reacted with the Fmoc-L-isoleucine to obtain a fourth resin; The fourth resin is removed from Fmoc protection, and the fourth resin removed from Fmoc protection is reacted with the Fmoc-L-proline to obtain a fifth resin; The fifth resin is deprotected from Fmoc, and the deprotected fifth resin is reacted with the L-flashing acid to obtain a chain polypeptide compound.

4. The process for the preparation of Cladoamide A according to claim 3, characterized in that, The specific steps for reacting the resin with the Fmoc-β-alanine and ending the reaction to obtain the first resin include: swelling the resin in a first solvent, and washing the resin swelled in the first solvent with a first washing solution to obtain a swelled resin; dissolving the Fmoc-β-alanine and a first basic reagent in a second solvent to obtain a first mixture; adding the first mixture to the swelled resin for reaction, and bubbling with an inert gas, and ending the reaction, and the resin is connected with the Fmoc-β-alanine to obtain the first resin.

5. The method for preparing Cladoamide A according to claim 3, characterized in that, The molar ratio of the resin to the Fmoc-β-alanine is 1:(1.1-5).

6. The method for preparing Cladoamide A according to claim 3, characterized in that, The specific steps for deprotecting the first resin from Fmoc and reacting the deprotected first resin with the Fmoc-N-methyl-L-phenylalanine to obtain the second resin include: adding a capping agent to the first resin for reaction, and obtaining a capped first resin after ending the reaction; treating the capped first resin with a morpholine solution to remove the Fmoc protection; dissolving the Fmoc-N-methyl-L-phenylalanine, HATU and a second basic reagent in a third solvent to obtain a second mixture; adding the deprotected first resin to the second mixture for reaction, and obtaining the second resin after ending the reaction.

7. The method for preparing Cladoamide A according to claim 6, characterized in that, The capping agent includes a mixture of dichloromethane / diisopropylethylamine / methanol.

Images