Preparation method of Mebamamide C
Preparation of Mebamamide C by solid phase synthesis solved the problem of separation difficulties, achieved chemical synthesis, and laid the foundation for its biological activity research.
Patent Information
- Application Number
- CN202510283471.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-11
- Publication Date
- 2025-05-30
AI Technical Summary
The difficulty in isolating Mebamamide C in the prior art has led to fewer research on its biological activity and no chemical synthesis reports.
Mebamamide C was prepared by a multi-step solid-phase synthesis method using a solid-phase synthesis method, including resin bonding, deprotection, cyclization reaction and chiral fat chain fragment coupling, and the reaction conditions were optimized using specific solvents and catalysts.
The artificial synthesis of Mebamamide C is achieved, avoiding the complex process of natural product extraction and providing a basis for biological activity research.
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Figure CN120058855A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of organic synthesis, and particularly to a preparation method of Mebamamide C. Background Art
[0002] Cyclic depsipeptides are a class of oligomers composed of hydroxy acids and amino acids alternately linked by ester bonds and amide bonds. Due to their unique structural features, they exhibit diverse biological activities, including anti-tumor, anti-viral, insecticidal, and anti-thrombotic activities. Such compounds have broad application prospects, and their sources are relatively rich and have been successively discovered in marine mollusks, coelenterates, sponges, ascidians, and microorganisms.
[0003] Mebamamide compounds are a typical representative of cyclic depsipeptides. Their research began in 2015 when the Suenaga research group first isolated and identified Mebamamide A and Mebamamide B molecules from the marine green alga Derbesia marina (Journal of Natural Products, 2015, 78(4): 901 - 908). Research has shown that the Mebamamide B molecule has specific differentiation activity against HL60 cells and can induce their differentiation into macrophage-like cells, while the Mebamamide A molecule does not exhibit similar activity. However, due to the difficulty in separating natural products, only 15.6 mg and 11.0 mg of Mebamamide A and B were respectively isolated from 700 g of Derbesia marina samples, and their biological activity research is still relatively limited.
[0004] In 2024, the Takada research group first isolated Mebamamide C from the marine alga Bryopsis (Bioscience, Biotechnology, and Biochemistry, 2024, 88, 399–404). Through spectral data analysis, the research group determined its planar structure and clarified its absolute configuration using the Marfey method and the improved Mosher method. However, due to the extremely difficult separation of Mebamamide C, there is currently little research on its biological activity and no related synthetic reports.
[0005] Therefore, obtaining a sufficient amount of Mebamamide C through total chemical synthesis not only has important significance for verifying its chemical structure but also lays a foundation for its biological activity research and potential applications. Summary of the Invention
[0006] Based on this, it is necessary to provide a preparation method of Mebamamide C.
[0007] To achieve the above object, the present invention provides a technical solution:
[0008] A preparation method of Mebamamide C, the steps of which include:
[0009] S100. React the first resin with Fmoc-L-Pro-OH, Fmoc-D-Phe-OH, Boc-L-Thr-OH, Fmoc-L-Val-OH, and Fmoc-D-Leu-OH in sequence to obtain a first linear polypeptide compound, treat the first linear polypeptide compound with a first fluorinated solvent, and then carry out a cyclization reaction to obtain a first polypeptide fragment.
[0010] The specific steps of S100 include:
[0011] S110. Carry out a condensation reaction to connect the first resin with Fmoc-L-Pro-OH.
[0012] Add a green solvent to the first resin, and swell the first resin under ultrasonic treatment to obtain the swollen first resin.
[0013] Dissolve Fmoc-L-Pro and diisopropylethylamine in the green solvent, add them to the swollen first resin for reaction, and obtain Fmoc-L-Pro connected to the first resin.
[0014] In some embodiments, the green solvent is a mixed solution of N-formylmorpholine and anisole, wherein the volume ratio of N-formylmorpholine to anisole is 1:1. Preferably, the amount of the green solvent used is 20 mL;
[0015] In some embodiments, the time for swelling the first resin under ultrasonic treatment is 30 min.
[0016] In some embodiments, the reaction time is 0.5 h.
[0017] S120. Carry out a deprotection reaction on Fmoc-L-Pro connected to the first resin.
[0018] Treat Fmoc-L-Pro connected to the first resin with a green solvent of DBU under ultrasonic treatment to remove the Fmoc protection, and wash it to obtain resin-L-Pro.
[0019] In some embodiments, in step S110, the reaction time is 30 min.
[0020] Among them, DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene, and the volume fraction of DBU is 5%.
[0021] S130. Connect (condense) the L-Pro linked to the first resin with Fmoc-D-Phe-OH to obtain resin-L-Pro-Fmoc-D-Phe-OH.
[0022] Repeat step S120 to remove the Fmoc protection to obtain resin-L-Pro-D-Phe-OH.
[0023] S140. Connect Boc-L-Thr-OH, Fmoc-L-Val-OH, and Fmoc-D-Leu-OH to resin-L-Pro-D-Phe-OH in sequence to obtain the first linear polypeptide compound. Treat the first linear polypeptide compound with a first fluorinated solvent, then carry out a cyclization reaction, and remove the Boc protecting group to prepare the first polypeptide fragment.
[0024] The specific steps include:
[0025] React resin-L-Pro-D-Phe-OH with Boc-L-Thr-OH, Fmoc-L-Val-OH, and Fmoc-D-Leu-OH in sequence. Specifically, the reactions of resin-L-Pro-D-Phe-OH with Boc-L-Thr-OH, Fmoc-L-Val-OH, and Fmoc-D-Leu-OH are all carried out according to the condensation cycle, referring to the above steps S110, S120, and step S130, that is, each condensation cycle includes two parts: condensation and removal of the Fmoc protection.
[0026] S140. Treat the first linear polypeptide compound with a first fluorinated solvent, carry out a cyclization reaction, and then remove the Boc protecting group to prepare the first polypeptide fragment.
[0027] S200. Connect Fmoc-D-Aal-OH, Fmoc-L-Pro-OH, Fmoc-L-Leu-OH, and Boc-D-Ser-(tBu)-OH to the second resin in sequence to obtain the second linear polypeptide compound. Treat the second linear polypeptide compound with a second fluorinated solvent to prepare the second polypeptide fragment.
[0028] The specific steps include:
[0029] S210. The second resin is successively linked with Fmoc-D-Aal-OH, Fmoc-L-Pro-OH, Fmoc-L-Leu-OH, and Boc-D-Ser-(tBu)-OH to obtain a second chain-like polypeptide compound.
[0030] The second resin reacts successively with Fmoc-D-Aal-OH, Fmoc-L-Pro-OH, Fmoc-L-Leu-OH, and Boc-D-Ser-(tBu)-OH. Specifically, the reactions of the second resin with Fmoc-D-Aal-OH, Fmoc-L-Pro-OH, Fmoc-L-Leu-OH, and Boc-D-Ser-(tBu)-OH are all carried out according to the condensation cycle, referring to the above steps S110 and S120, that is, each condensation cycle includes two parts: condensation and removal of the Fmoc protection.
[0031] S220. The second chain-like polypeptide compound is treated with a second fluorinated solvent to obtain a second polypeptide fragment.
[0032] S300. The first polypeptide fragment and the second polypeptide fragment are condensed to obtain a third polypeptide fragment;
[0033] S400. The third polypeptide fragment is treated with a third fluorinated solvent and then coupled with a chiral aliphatic chain fragment to obtain the Mebamamide C;
[0034] Specifically, the preparation steps of the chiral aliphatic chain fragment include:
[0035] 6- Ethyl (S)-4-chloro-3-hydroxybutyrate, N,N-dimethylformamide, and a bromide are stirred and reacted to obtain a first intermediate; specifically, this is a halogen exchange reaction, where the chloride in ethyl (S)-4-chloro-3-hydroxybutyrate is replaced by the bromide reaction to obtain the brominated product ethyl (S)-4-bromo-3-hydroxybutyrate. Among them, the bromide is a reactant that provides bromine.
[0036] In some embodiments, the reaction solvent includes N,N-dimethylformamide.
[0037] In some embodiments, the bromide includes at least one of bromoethane, sodium bromide, potassium bromide, and bromomethane.
[0038] The first intermediate, 6-methylheptanoic acid, N-hydroxyphthalimide, 4-dimethylaminopyridine, and a first solvent are stirred and reacted to obtain a second intermediate;
[0039] The second intermediate, nickel catalyst, ligand, and second solvent are stirred and reacted to obtain a third intermediate; in some embodiments, the ligand includes at least one of 2,2':6',2”-terpyridine, 4,4'-dimethoxy-2,2'-bipyridine, and 4,4'-di-tert-butyl-2,2'-bipyridine. Preferably, the ligand is 2,2':6',2”-terpyridine.
[0040] Zn powder is added to the third intermediate, and a third solvent is added and stirred for reaction to obtain a fourth intermediate;
[0041] The fourth intermediate is hydrolyzed under alkaline conditions to obtain the chiral aliphatic chain fragment.
[0042] The structural formula of methylheptanoic acid is
[0043] In the synthesis strategy of cyclic peptides, determining the closed-loop site is a key factor determining the success or failure of the synthesis. It is recommended to avoid using N-alkyl, α,α-disubstituted, or β-substituted amino acids because obvious steric hindrance will be generated when cycling between them. Therefore, it is best to select amino acids with different configurations. In addition, the position of the intramolecular hydrogen bond will also affect the position of the cycle to a certain extent.
[0044] It should be noted that Fmoc is the protecting group fluorenylmethyloxycarbonyl, Phe is phenylalanine, Thr is threonine, Val is valine, Leu is leucine, Ala is alanine, Pro is proline, and Ser(tBu) is serine (tert-butyl).
[0045] Advantages of the present invention:
[0046] The present invention realizes the artificial synthesis of biologically active Mebamamide C for the first time, avoiding the complex process and high cost of extracting from natural products at present, and providing guarantee for its potential biological activity research in the future. Description of the drawings
[0047] Figure 1 It is the NMR characterization spectrum of Mebamamide C. Detailed implementation manners
[0048] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.
[0049] In the examples, the test methods used are all conventional methods unless otherwise specified, and the materials, reagents, etc. used can be obtained from commercial channels unless otherwise specified.
[0050] Example 1
[0051] A preparation method for efficiently synthesizing natural product Mebamamide C by solid-phase method, and the specific experimental method is as follows: Among them, the green solvent in the examples refers to a mixed solution of N-formylmorpholine and anisole, and the volume ratio of N-formylmorpholine to anisole is 1:1.
[0052] S100. React the first resin with Fmoc-L-Pro-OH, Fmoc-D-Phe-OH, Boc-L-Thr-OH, Fmoc-L-Val-OH, and Fmoc-D-Leu-OH in sequence to obtain a first chain polypeptide compound. Treat the first chain polypeptide compound with a first fluorinated solvent, and then carry out a cyclization reaction to obtain a first polypeptide fragment.
[0053] The specific steps of S100 include:
[0054] S110. Carry out a condensation reaction to connect the first resin (2-CTC resin) with Fmoc-L-Pro-OH.
[0055] Place 1.0 g of the first resin (2-CTC resin, 1.04 mmol / g) in a 50 mL solid-phase polypeptide synthesis tube, add 20 mL of the green solvent, and swell the 2-CTC resin in ultrasonic for 30 min. Pump out the green solvent with nitrogen to obtain the swollen first resin.
[0056] Dissolve Fmoc-L-Pro-OH (1.052 g, 3.12 mmol, 2 equiv.) and diisopropylethylamine (1.630 mL, 9.36 mmol, 6 equiv.) in the green solvent (10 mL), add it to the reaction tube containing the swollen first resin, and react in ultrasonic for 0.5 h to obtain Fmoc-L-Pro-OH connected to the first resin (amino acid connected to the resin).
[0057] S120. Carry out a deprotection reaction (deprotection) on the Fmoc-L-Pro connected to the first resin.
[0058] Treat the Fmoc-L-Pro connected to the first resin with a 5% DBU green solvent solution (v% volume fraction) (10 mL) in ultrasonic for 2 min for deprotection to obtain L-Pro connected to the first resin. Wash the L-Pro connected to the first resin with ethanol (3 x 10 mL) and the green solvent (3 x 10 mL) for standby.
[0059] S130. Connect L-Pro connected to the first resin with Fmoc-D-Phe-OH (condensation).
[0060] Fmoc-D-Phe (1.208 g, 3.12 mmol, 2 equiv.) and 1,3-dimethylbarbituric acid (0.057 g, 0.312 mmol, 0.6 equiv.) were pre-dissolved in a green solvent (10 mL). N,N-Diisopropylcarbodiimide (0.244 mL, 1.56 mmol, 3 equiv.) was added and shaken well, then poured into a reaction tube containing the first resin-linked L-Pro. After reacting for 12 min under ultrasound, the solution was pumped out to obtain resin-L-Pro-Fmoc-D-Phe-OH. The resin-L-Pro-Fmoc-D-Phe-OH was washed with ethanol (3 x 10 mL) and the green solvent (3 x 10 mL).
[0061] Repeat step S120 to remove the Fmoc protecting group to obtain resin-L-Pro-D-Phe
[0062] S140: The resin-L-Pro-D-Phe was successively linked with Boc-L-Thr-OH, Fmoc-L-Val-OH, and Fmoc-D-Leu-OH. The first chain polypeptide compound was treated with a first fluorinated solvent and then subjected to a cyclization reaction to obtain a first polypeptide fragment (246 mg, 82%).
[0063] The specific steps include:
[0064] The resin-L-Pro-D-Phe was successively reacted with Boc-L-Thr-OH, Fmoc-L-Val-OH, and Fmoc-D-Leu-OH. Specifically, the reactions of resin-L-Pro-D-Phe-OH with Boc-L-Thr-OH, Fmoc-L-Val-OH, and Fmoc-D-Leu-OH were all carried out according to the condensation cycle, referring to the above steps S110, S120, and S130, that is, each condensation cycle includes two parts: condensation and removal of the Fmoc protection.
[0065] The specific operations are as follows: Repeat steps S110, S120 and step S130. After connecting resin-L-Pro-Fmoc-D-Phe with Boc-L-Thr-OH, a Boc-L-Thr-D-Phe-L-Pro-resin chain is obtained. Fmoc-L-Val-OH (1.058 g, 3.12 mmol, 2 equiv.), 4-dimethylaminopyridine (0.038 g, 0.312 mmol, 0.2 equiv.) are pre-dissolved in a green solvent (10 mL), N,N-diisopropylcarbodiimide (0.244 ml, 1.56 mmol, 3 equiv.) is added and shaken for 30 s, then poured into a reaction tube containing the resin. The reaction tube is sealed with a sealing film to prevent moisture from entering. After reacting in ultrasonic for 40 min, the solution is pumped out. The resin is washed with ethanol (3 x 10 mL) and the green solvent (3 x 10 mL). Repeat steps S120 and S130 to connect D-Leu. The resin is washed with the green solvent (3 x 10 mL) and ethanol (3 x 10 mL) to obtain a resin-first chain polypeptide compound. The first chain polypeptide compound is treated with a first fluorinated solvent to obtain a first chain polypeptide, and then a cyclization reaction and a de-Boc protection group reaction are carried out to obtain a first polypeptide fragment.
[0066] Dissolve the first chain polypeptide (300 mg, 0.44 mmol) in acetonitrile (10 mL), add N-methylimidazole (166.6 mg, 1.32 mmol, 3.0 equiv.) and TCFH (135.8 mg, 0.48 mmol, 1.1 equiv.). Among them, N-methylimidazole and TCFH are coupling reagents, and react at room temperature (20 °C) for 18 h. The solvent is removed by rotary evaporation under reduced pressure, and separation by reverse-phase column chromatography is carried out to obtain a first polypeptide fragment with a Boc protection group.
[0067] De-Boc protection operation in liquid phase: Add a dichloromethane solution of 10% (volume fraction) trifluoroacetic acid to the polypeptide fragment 1 (246 mg, 0.37 mmol), and react at room temperature (20 °C) for 1 h. The solvent is removed by rotary evaporation under reduced pressure, and separation by reverse-phase column chromatography is carried out to obtain the first polypeptide fragment (233 mg, 95%).
[0068] S200. Connect the second resin with Fmoc-D-Aal-OH, Fmoc-L-Pro-OH, Fmoc-L-Leu-OH, Boc-D-Ser-(tBu)-OH in sequence to obtain a second chain polypeptide compound. Treat the second chain polypeptide compound with a second fluorinated solvent to obtain a second polypeptide fragment.
[0069] The specific steps include:
[0070] S210. The second resin (2-CTC resin) is successively linked with Fmoc-D-Aal-OH, Fmoc-L-Pro-OH, Fmoc-L-Leu-OH, and Boc-D-Ser-(tBu)-OH to obtain a second chain-like polypeptide compound.
[0071] The second resin reacts successively with Fmoc-D-Aal-OH, Fmoc-L-Pro-OH, Fmoc-L-Leu-OH, and Boc-D-Ser-(tBu)-OH. Specifically, the reactions of the second resin with Fmoc-D-Aal-OH, Fmoc-L-Pro-OH, Fmoc-L-Leu-OH, and Boc-D-Ser-(tBu)-OH are all carried out according to the condensation cycle, referring to the above steps S110, S120, and S130, that is, each condensation cycle includes two parts: condensation and removal of the Fmoc protection.
[0072] S220. The second chain-like polypeptide compound is treated with a second fluorinated solvent to obtain a second polypeptide fragment.
[0073] The second chain-like polypeptide compound is washed with a green solvent (3 x 10 mL) and dichloromethane (3 x 10 mL), dried by a vacuum pump, a cleavage solution (a dichloromethane solution with a volume fraction of 20 v% hexafluoroisopropanol) is added, reacted for 1.5 h, the cleavage solution is pumped under nitrogen, the solvent is removed by rotary evaporation under reduced pressure, and separation is carried out by reverse-phase column chromatography to obtain a chain-like polypeptide fragment 1.
[0074] S300. The first polypeptide fragment and the second polypeptide fragment are condensed to obtain a third polypeptide fragment; the first polypeptide fragment (15.8 mg, 0.041 mmol) and the second polypeptide fragment (22.3 mg, 0.041 mmol) are dissolved in the solvent acetonitrile (8 mL), hexafluorophosphate (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium (PyAOP, 41.7 mg, 0.08 mmol, 2 equiv.), 27 μL of N,N-diisopropylethylamine (DIPEA, 0.16 mmol, 4 equiv.) and a magnetic stir bar are added. Among them, hexafluorophosphate (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium and N,N-diisopropylethylamine are coupling reagents, stirred at room temperature for 12 h, the reaction process is detected by HPLC and LC-MS, and after the reaction is completed, the reaction solution is dried by a rotary evaporator. The reaction product is dissolved in MeCN and then separated by a reverse-phase column, and finally a white solid product, the third polypeptide fragment (28.1 mg), is obtained with a yield of 65%.
[0075] S400. Treat the third polypeptide fragment with a third fluorinated solvent and then couple it with the chiral aliphatic chain fragment to obtain the Mebamamide C. The NMR characterization spectrum of Mebamamide C is as shown in Figure 1 shown.
[0076] Specifically, first perform Boc deprotection on the third polypeptide fragment with 10% trifluoroacetic acid, and then perform fragment coupling with the chiral aliphatic chain fragment under liquid phase conditions. Finally, obtain a white solid product, mebamamide C (5.1 mg), with a yield of 19.1%.
[0077] Specifically, the preparation steps of the chiral aliphatic chain fragment include:
[0078] Add ethyl (S)-4-chloro-3-hydroxybutyrate (16.70 g, 100 mmol), the solvent N,N-dimethylformamide (100 mL), bromoethane (22.4 mL, 3 mol, 30 equiv.), NaBr (10.29 g, 100 mmol, 1 equiv.) and a magnetic stir bar into a 500 mL pear-shaped flask. Stir and reflux at 65 °C for 7 days. After the reaction is completed, quench the reaction with water, extract, dry, filter, and rotary evaporate to obtain 19.25 g of a yellow liquid target product 4-2 (91 mmol, yield 91%).
[0079] Add compound 4-3 (420 mg, 2.91 mmol, 1 equiv.), NHP (522 mg, 3.2 mmol, 1.1 equiv.), DMAP (35.6 mg, 0.29 mmol, 0.1 equiv.) and a magnetic stir bar into a 25 mL pear-shaped flask. Replace the atmosphere with nitrogen through a double-tube. Add 10 mL of anhydrous DCM and stir. Subsequently, add DIC (404 mg, 3.2 mmol, 1.1 equiv.) with a syringe. After reacting for 12 h, filter by suction and rotary evaporate the filtrate to obtain the intermediate.
[0080] Precisely weigh the NiBr 2 (dme) catalyst (89.8 mg, 0.291 mmol, 0.1 equiv.) and the ligand 2,2':6',2”-terpyridine (0.349 mmol, 0.12 equiv.) into a 10 mL pear-shaped flask, add DMA solvent (4 mL) and a magnetic stir bar, and stir at room temperature for 2 h.
[0081] In the glove box, transfer the intermediate to a 25 mL pear-shaped flask, and add Zn powder (570.8 mg, 8.73 mmol, 3 equiv.), compound 4-2 (1.54 g), DMA solvent (3 mL) and a magnetic stir bar. Then, combine the previously pre-stirred catalyst solution using a glass dropper and rinse with 3 mL of DMA solvent. Take the mixture out of the glove box, stir at 50 °C for 12 h. After the reaction is completed, extract, dry, filter, rotary evaporate, and separate the crude product through a silica gel column (EA:PE = 1:10) to finally obtain the target product 4-4 as a pale yellow liquid (161 mg, 0.699 mmol, yield 24%).
[0082] Add compound 4-4 (100 mg, 0.434 mmol, 1 equiv.), KOH (48.7 mg, 0.868 mmol, 2 equiv.), water (5 mL), ethanol (5 mL) and a magnetic stir bar to a 25 mL pear-shaped flask, stir at room temperature for 4 h. After the reaction is completed, add 1 mol / L HCl aqueous solution to adjust the pH to 2. Extract with EA three times and collect the organic phase. Dry the organic phase over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate to finally obtain the chiral aliphatic chain fragment as a pale yellow liquid with a yield of 90% (79.3 mg).
[0083] Note:
[0084] In the esterification synthesis strategy on resin, generally, the carboxyl group needs to be activated. At the same time, since this is a heterogeneous reaction and the reaction time is long, after using ultrasonic assistance for process intensification, a sealing film needs to be added during the reaction to avoid a decrease in esterification efficiency caused by an increase in water content during ultrasonic treatment. At the same time, as the ultrasonic treatment progresses, the temperature will rise, and too high a temperature will also induce side reactions. Therefore, it is necessary to pay attention to maintaining room temperature during the esterification process.
[0085] I. To study the effect of different ligands on the yield of the chiral aliphatic chain fragment, the following experiment is conducted. Without special indication, the experimental steps for preparing the chiral aliphatic chain fragment are the same as those in Example 1. The effect of different ligands on the yield of the chiral aliphatic chain fragment is shown in Table 1.
[0086] Table 1 Effect of different ligands on the yield of the chiral aliphatic chain fragment
[0087]
[0088] II. Effects of temperature and solvent
[0089] The increase in temperature is beneficial for linear peptides to overcome the torsional tension, thereby improving the cyclization efficiency. However, excessively high temperatures can also induce side reactions, so the temperature must be reduced at the beginning. This method can effectively increase the yield of cyclic peptides in solid-phase synthesis, and then gradually raise the temperature to room temperature. The solubility of the resin varies in different solvents, which illustrates the importance of selecting solvents with high solubility in the synthesis of cyclic peptides. In solid-phase synthesis, the solubility of the resin is different in different solvents, so choosing a solvent with good solubility is a key step in the synthesis of cyclic peptides. The results of the swelling degree of the resin and the related standard deviation values in different solvents are shown in Table 2.
[0090] Table 2 Results of the swelling degree of the resin and the related standard deviation values
[0091]
[0092] It should be noted that the specific parameters or some reagents in the above embodiments are specific embodiments or preferred embodiments under the concept of the present invention, rather than limitations thereof; those skilled in the art can make adaptive adjustments within the concept and protection scope of the present invention.
Claims
1. A method for preparing Mebamamide C, characterized in that: Includes steps: Sequentially reacting the first resin with Fmoc-L-Pro-OH, Fmoc-D-Phe-OH, Boc-L-Thr-OH, Fmoc-L-Val-OH, and Fmoc-D-Leu-OH to obtain a first chain polypeptide compound, treating the first chain polypeptide compound with a first fluorinated solvent, performing a cyclization reaction, and then removing the Boc protecting group to obtain a first polypeptide fragment; connecting the second resin with Fmoc-D-Aal-OH, Fmoc-L-Pro-OH, Fmoc-L-Leu-OH, and Boc-D-Ser-(tBu)-OH in sequence to obtain a second chain polypeptide compound, and treating the second chain polypeptide compound with a second fluorinated solvent to obtain a second polypeptide fragment; Condensing the first polypeptide fragment and the second polypeptide fragment to obtain a third polypeptide fragment; The third polypeptide fragment is treated with a third fluorinated solvent, and then coupled with a chiral fatty chain fragment to obtain Mebamamide C; Wherein, the structural formula of the chiral fatty chain fragment is as follows: The structural formula of the Mebamamide C is as follows:
2. The method for preparing Mebamamide C according to claim 1, characterized in that: The preparation steps of the chiral fatty chain fragment include: (S)-4-chloro-3-hydroxybutyric acid ethyl ester, a reaction solvent and a bromide are stirred to react to obtain a first intermediate; The first intermediate, 6-methylheptanoic acid, N-hydroxyphthalimide, 4-dimethylaminopyridine and the first solvent are stirred to react to obtain a second intermediate; The second intermediate, the nickel catalyst, the ligand, and the second solvent are stirred to react to obtain a third intermediate; Adding Zn powder to the third intermediate, and adding a third solvent to stir and react, to obtain a fourth intermediate; The fourth intermediate is subjected to a hydrolysis reaction under alkaline conditions to obtain the chiral fatty chain fragment.
3. The method for preparing Mebamamide C according to claim 2, characterized in that: The first solvent includes dichloromethane, the second solvent includes dimethylacetamide, and the third solvent includes dimethylacetamide.
4. The method for preparing Mebamamide C according to claim 2, characterized in that: The nickel catalyst includes NiBr2.
5. The method for preparing Mebamamide C according to claim 2, characterized in that: The ligand includes at least one of 2,2':6',2"-terpyridine, 4,4'-dimethoxy-2,2'-bipyridine and 4,4'-di-tert-butyl-2,2'-bipyridine.
6. The method for preparing Mebamamide C according to claim 1, characterized in that: The first resin includes 2-CTC resin; The second resin includes 2-CTC resin.
7. The method for preparing Mebamamide C according to claim 1, characterized in that: The first fluorine-containing solvent includes hexafluoroisopropanol; The second fluorine-containing solvent includes hexafluoroisopropanol; The third fluorine-containing solvent includes a mixed solvent of trifluoroacetic acid and dichloromethane.
8. The method for preparing Mebamamide C according to claim 7, characterized in that: The volume ratio of trifluoroacetic acid to water in the trifluoroacetic acid / water / triisopropylsilane mixed reagent is 90:
5.
9. The method for preparing Mebamamide C according to claim 2, characterized in that: The bromide includes at least one of ethyl bromide, sodium bromide, potassium bromide and methyl bromide.
10. The method for preparing Mebamamide C according to claim 2, characterized in that: The reaction solvent includes N,N-dimethylformamide.