Preparation method of nonapeptide-1

Abstract

The invention provides a preparation method of nonapeptide-1, which comprises the following steps: firstly synthesizing a nonapeptide-1 crude product by a solid-phase synthesis method, and then purifying by adopting a mode of combining a modified polysulfone filter membrane, a reversed-phase polymer column and a weak anion exchange column, so that the purification efficiency is greatly improved. By controlling the dosage of an acylation reagent, the modified polysulfone filter membrane achieves the effect of partial hydrophilic modification, amide groups are grafted on the surface and micropores of the filter membrane, and meanwhile, a large number of amino groups are reserved, so that the compatibility of the modified polysulfone filter membrane and polypeptide is greatly enhanced, the permeability of polypeptide molecules is enhanced, and the service life of the modified polysulfone filter membrane is prolonged. Polypeptide molecules can be quickly and efficiently separated from impurities, so that the recovery rate of polypeptide is increased; meanwhile, quaternary ammonium graphene oxide is added into modified polysulfone through a blending and phase inversion method, and then the membrane is formed through coating and casting, so that the hydrophilicity of the modified polysulfone filter membrane is effectively improved, the modified polysulfone filter membrane has a synergistic effect with amide groups, the permeability of polypeptide molecules is further improved, and the recovery rate of polypeptide is increased.

Description

Technical Field

[0001] The present invention relates to the technical field of polypeptide preparation, and in particular to a method for preparing nonapeptide-1. Background Art

[0002] In the cosmetics field, nonapeptide-1, as a beauty peptide, has attracted much attention for its significant effects in whitening and removing spots. Nonapeptide-1 inhibits the binding of melanocyte-stimulating hormone to the MCI-R receptor on melanocytes, thereby activating tyrosinase, further affecting the formation of melanin, reducing the production of melanin, and thus achieving the effect of brightening and even skin tone.

[0003] In the prior art, the synthesis of nonapeptide-1 usually adopts solid phase peptide synthesis or liquid phase peptide synthesis. These methods have been widely used in the field of peptide synthesis. However, in the process of synthesizing nonapeptide-1, there are still many challenges, mainly manifested in the presence of multiple side reactions or incomplete removal of protective agents during the synthesis process, resulting in the presence of impurity peptides of various molecular weights in the synthesized nonapeptide-1 crude product, or impurities such as protective agents are not completely removed, so it needs to be purified. Commonly used peptide separation and purification technologies include: reversed-phase high performance liquid chromatography, ion exchange chromatography, gel permeation chromatography, ultrafiltration and membrane separation. A single separation and purification technology is often difficult to separate nonapeptide-1 to obtain the ideal purity, so it is necessary to repeatedly separate or use multiple separation and purification technologies at the same time. For example, patent CN106749526B provides a low-cost method for purifying nonapeptide-1, and reversed-phase high performance liquid chromatography and weak anion exchange chromatography are used to purify nonapeptide-1 to obtain nonapeptide-1 with a purity greater than 99%. However, the yield of this method is only 79%.

[0004] In summary, it is urgent to develop a new technical solution to solve the problems existing in the prior art. The present invention provides a method for preparing nonapeptide-1, firstly synthesizing a crude nonapeptide-1 by a solid phase synthesis method, and then purifying it by combining a modified polysulfone filter membrane, a reverse phase polymer column and a weak anion exchange column, thereby greatly improving the purification efficiency. The present invention controls the amount of the acylating agent so that the modified polysulfone filter membrane achieves a partial hydrophilic modification effect, and while grafting amide groups on the filter membrane surface and micropores, a large number of amino groups are retained, thereby greatly enhancing the compatibility of the modified polysulfone filter membrane with the polypeptide, enhancing the permeability of the polypeptide molecules, and being able to quickly and efficiently separate the polypeptide molecules from impurities, thereby improving the recovery rate of the polypeptide; at the same time, the present invention adds quaternary ammonium graphene oxide to the modified polysulfone by a blending and phase conversion method, and then casts it into a film, thereby effectively improving the hydrophilicity of the modified polysulfone filter membrane, and synergizing with the amide group of the modified polysulfone, further improving the permeability of the polypeptide molecules, and improving the recovery rate of the polypeptide.

[0005] An object of the present invention is to provide a method for preparing nonapeptide-1, the method for preparing nonapeptide-1 comprising the following steps: S1. Preparation of modified polysulfone filter membrane, the preparation of modified polysulfone filter membrane comprises the following steps: L1. Add graphene oxide to N,N-dimethylformamide, disperse by ultrasonication, then add a tertiary amine modifier, stir to react, purify and dry to obtain tertiary amine graphene oxide; L2, adding the tertiary amine graphene oxide to ethanol, ultrasonically dispersing, then adding a quaternary ammonium modifier, heating for reaction, purifying, and drying to obtain quaternary ammonium graphene oxide; L3, placing polysulfone in a plasma treatment device, introducing nitrogen and hydrogen for plasma treatment to obtain amino polysulfone; blending the amino polysulfone with an acylating agent for reaction, purifying, and drying to obtain modified polysulfone; L4, adding the modified polysulfone into a solvent, adding the quaternary ammonium graphene oxide, ultrasonicating, heating and stirring, and then casting into a membrane to obtain a modified polysulfone filter membrane; S2, synthesizing the crude product of nonapeptide-1 by solid phase synthesis method; S3, adding the nonapeptide-1 crude product into water, ultrasonicating, and filtering with the modified polysulfone filter membrane to obtain a nonapeptide-1 mixture; S4, purifying the nonapeptide-1 mixture by reverse phase high performance liquid chromatography to obtain crude nonapeptide-1; S5. Purifying the crude nonapeptide-1 by anion exchange chromatography to obtain highly pure nonapeptide-1.

[0006] Further, in step L1, the tertiary amine modifier is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, triethylamine, N,N-dimethyl-1,3-propylenediamine, N,N-disalicylidenepropylenediamine, N,N'-dimethyl-1,4-butanediamine, 1,4-bis(dimethylamino)butane, N,N'-dihydroxy-2,3-dimethyl-2,3-butanediamine, N-hydroxysuccinimide, N-hydroxysulfosuccinimide, 4-dimethylaminopyridine, N-hydroxybenzotriazole, N,N-dicyclohexylcarbodiimide or one or more of 3-dimethylaminopropylamine.

[0007] Furthermore, in step L1, the molar ratio of the graphene oxide to the tertiary amine modifier is 1:(1-10).

[0008] Furthermore, in step L2, the quaternary ammonium modifier is selected from one or more of butyl chloride, pentyl chloride, hexyl chloride, heptyl chloride, butyl bromide, pentyl bromide, hexyl bromide, and heptyl bromide.

[0009] Furthermore, in step L2, the molar ratio of the tertiary amine graphene oxide to the quaternary ammonium modifier is 1:(1-5).

[0010] Furthermore, in step L3, the plasma treatment conditions are: excitation by high-frequency and high-voltage discharge, with a frequency of 20-30 KHz and a power of 10-15 W.

[0011] Furthermore, in step L3, the volume ratio of nitrogen to hydrogen is 1:(2-5).

[0012] Furthermore, in step L3, the acylating agent is selected from one or more of pentanoyl chloride, hexanoyl chloride, heptanoyl chloride or octanoyl chloride.

[0013] Furthermore, in step L3, the molar ratio of the aminopolysulfone to the acylating agent is 1:(0.1-0.5).

[0014] Furthermore, in step L4, the mass ratio of the modified polysulfone to the quaternary ammonium graphene oxide is 100:(0.1-1).

[0015] Furthermore, in step L4, the solvent is selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

[0016] Furthermore, the preparation method of the crude nonapeptide-1 comprises the following steps: P1, mixing the resin with dichloromethane, soaking and swelling, and purifying to obtain an activated resin; P2, dissolving the first amino acid protected by Fmoc, HBTU and DMAP in DMF, adding DIEA, mixing evenly, then adding to the activated resin, shaking for reaction, purifying, and obtaining the resin coupled with the first amino acid; P3, adding a mixed solution of acetic anhydride, pyridine and DMF to the resin coupled with the first amino acid, shaking the reaction to block the unreacted functional groups on the resin; then washing with DMF, DCM and DMF in sequence, adding a mixed solution of piperidine and DMF to deprotect the functional groups of the resin; P4. Repeat steps P2-P3 to carry out peptide grafting reaction, then remove the resin, purify and dry to obtain the crude product of nonapeptide-1.

[0017] The present invention has the following beneficial effects: (1) In the purification process of nonapeptide-1, the present invention uses a modified polysulfone filter membrane, a reverse phase polymer column and a weak anion exchange column to greatly improve the purification efficiency. The modified polysulfone filter membrane is obtained by amination of polysulfone, reacting with an acylating agent and then blending with quaternary ammonium graphene oxide to form a cast membrane. The present invention controls the amount of the acylating agent so that the modified polysulfone filter membrane achieves a partial hydrophilic modification effect, while retaining a large number of amino groups while grafting amide groups on the surface and micropores of the filter membrane, greatly enhancing the compatibility of the modified polysulfone filter membrane with the polypeptide, increasing the filtration area, and enhancing the permeability of the polypeptide molecules. The polypeptide molecules can be quickly and efficiently separated from impurities, thereby improving the recovery rate of the polypeptide.

[0018] (2) The quaternary ammonium graphene oxide of the present invention is obtained by reacting graphene oxide with a tertiary ammonium modifier and a quaternary ammonium modifier, and has a large number of quaternary ammonium salt groups and hydroxyl groups on its surface and edges, and has good hydrophilicity. The present invention adds quaternary ammonium graphene oxide to modified polysulfone by a blending and phase conversion method, and then casts it into a membrane, which effectively improves the hydrophilicity of the modified polysulfone filter membrane, and greatly improves its permeability, adsorption and anti-pollution performance, and synergizes with the amide group of the modified polysulfone to further improve the permeability of polypeptide molecules and improve the recovery rate of polypeptides. DETAILED DESCRIPTION

[0019] In order to more clearly illustrate the technical solution of the present invention, the following examples are listed. Unless otherwise stated, the raw materials, reactions and post-treatment methods shown in the examples are common raw materials on the market and technical methods well known to those skilled in the art.

[0020] The words "preferred", "preferably", "more preferably", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain circumstances. However, other embodiments may also be preferred under the same circumstances or other circumstances. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not applicable, nor is it intended to exclude other embodiments from the scope of the present invention.

[0021] It should be understood that, except in any operating examples, or where otherwise indicated, all numbers indicating, for example, the amounts of ingredients used in the specification and claims should be understood to be modified in all cases by the term "about". Therefore, unless indicated to the contrary, the numerical parameters set forth in the following specification and the appended claims are approximate values ​​that vary depending on the desired properties to be obtained by the present invention.

[0022] The present invention uses the following raw materials: Wang resin in the examples and comparative examples of the present invention was purchased from Jier Biochemical (Shanghai) Co., Ltd.

[0023] The Fmoc-Val-OH in the examples and comparative examples of the present invention was purchased from Merck KGaA.

[0024] The polysulfones in the examples and comparative examples of the present invention were purchased from Hubei Kewode Chemical Co., Ltd.

[0025] The graphene oxide in the examples and comparative examples of the present invention was purchased from Anhui Kerun Nanotechnology Co., Ltd.

[0026] Example 1 A method for preparing nonapeptide-1, comprising the following steps: S1. Preparation of modified polysulfone filter membrane, the preparation of modified polysulfone filter membrane comprises the following steps: L1, add 0.2 g of graphene oxide to 100 g of N,N-dimethylformamide, ultrasonically disperse for 2 h, then add 3 g of N,N-dicyclohexylcarbodiimide and 0.2 g of 4-dimethylaminopyridine, activate for 30 min, then add 4.5 g of 3-dimethylaminopropylamine, stir in a water bath at room temperature for 24 h, centrifuge, wash, and dry to obtain tertiary amine graphene oxide; L2, adding 0.1 g of the tertiary amine graphene oxide to 100 g of ethanol, ultrasonically dispersing for 30 min, then adding 5 g of butyl bromide, stirring in a water bath at 70° C. for 12 h, centrifuging, washing, and drying to obtain quaternary ammonium graphene oxide; L3, placing 5 g of polysulfone in a plasma treatment device, introducing nitrogen and hydrogen (volume ratio of 1:3, gas flow rate of 30 ml / min), and plasma treatment at a frequency of 20 KHz and a power of 15 W to obtain amino polysulfone; the amino polysulfone, 0.5 mL of triethanolamine and 60 mL of dichloromethane were mixed and stirred evenly, and then placed in an ice water bath, 0.5 mL of hexanoyl chloride was added, and the ice water bath was removed after completion, and the reaction was stirred at room temperature for 2 h, filtered, washed, and dried to obtain modified polysulfone; L4, adding the modified polysulfone to N-methylpyrrolidone, and then adding the quaternary ammonium graphene oxide (the mass ratio of modified polysulfone, N-methylpyrrolidone and quaternary ammonium graphene oxide is m / m / m=100:1000:0.5), ultrasonicating for 20 min, stirring at 70°C for 12 h, cooling to room temperature, and then casting into a membrane to obtain a modified polysulfone filter membrane; S2, synthesizing the crude product of nonapeptide-1 by solid phase synthesis method; S3, adding 0.5 g of the crude nonapeptide-1 to 10 mL of distilled water, dispersing by ultrasonication to completely dissolve it, and then filtering with a modified polysulfone filter membrane to obtain a nonapeptide-1 filtrate; S4. Using high performance liquid chromatography, the nonapeptide-1 filtrate is crudely purified using a reverse phase polymer column to obtain crude nonapeptide-1. The purification conditions are as follows: Chromatographic column packing: F-type SBC MCI GEI reversed-phase chromatography packing with a particle size of 30-50 μm (Chengdu Kepu Biotechnology); chromatographic column filling volume: 30 mL; Mobile phase A: 0.1 mol / L trifluoroacetic acid in water; Mobile phase B: 0.1 mol / L trifluoroacetic acid in methanol; Flow rate: 4 mL / min; column temperature: 40°C; detection wavelength: 215 nm; Gradient: 0-10 min: A:B from 70:30 to 55:45; 15-40 min: A:B from 55:45 to 40:60; Before injection, the column was equilibrated with 0.1 mol / L trifluoroacetic acid aqueous solution, and then the sample was loaded and the target peak was collected. The solution was concentrated by rotary evaporation at 40°C under reduced pressure until the content of nonapeptide-1 was 50 mg / mL; S5. The concentrated solution obtained in step S4 was subjected to a weak anion exchange column to remove trifluoroacetic acid to obtain highly pure nonapeptide-1 with a purity greater than 99% and a yield of 93%. The purification conditions are as follows: Chromatographic column packing: DEAE high-flow agarose microspheres with a particle size of 50-160 μm (Xi'an Jiaotong University Baosai Biotechnology); Chromatographic column filling volume: 30 mL; Mobile phase: 2% acetic acid aqueous solution; Flow rate: 4 mL / min; column temperature: 40°C; detection wavelength: 215 nm; Before injection, the chromatographic column was equilibrated with an aqueous acetic acid solution having a volume concentration of 2%, and then the sample was loaded, and the target peak was collected, concentrated under reduced pressure, and freeze-dried.

[0027] The method for synthesizing the crude nonapeptide-1 in step S2 comprises the following steps: A crude nonapeptide-1, wherein the amino acid sequence of the nonapeptide-1 is Met-Pro-D-Phe-Arg-D-Trp-Phe-Lys-Pro-Val.

[0028] The synthesis method of the above-mentioned crude nonapeptide-1 comprises the following steps: P1, 1.5 g Wang resin was mixed with 8.0 mL anhydrous dichloromethane (DCM), soaked and swollen for 20 h, and the solvent DCM was removed under reduced pressure to obtain an activated resin; P2, 0.15 mmol Fmoc-Val-OH, 0.15 mmol HBTU and 15 mg DMAP were dissolved in 4.0 mL DMF, 0.15 mL DIEA was added, and then added to the activated resin, and the reaction was oscillated at room temperature for 20 h, the solvent was blown dry with nitrogen, and then washed 5 times with 4.0 mL DMF to obtain a resin connected to the first amino acid; P3, adding a mixed solution of acetic anhydride, pyridine and DMF (v / v / v=2:1:3) to the resin connected to the first amino acid, shaking for 30 minutes, to obtain a resin with blocked unreacted functional groups; washing the resin with blocked unreacted functional groups with DMF, DCM and DMF in sequence for 3 times, each time for 5 minutes; then deprotecting with 20% pyridine-DMF solution for 2 times, each time for 20 minutes; to obtain a resin with deprotected functional groups; P4. Wash the resin with deprotected functional groups three times with DMF, and then repeat steps P2-P3 to connect the remaining amino acids in sequence to obtain a resin containing a polypeptide; wash the polypeptide-containing resin with DMF, DCM, and DMF three times respectively, and then dry it under vacuum; then slowly add 5.0 mL of a mixed solution of trifluoroacetic acid, pure water, thioanisole, EDT, and phenol (v / v / v / v / v=82.5:5:5:2.5:5) at room temperature, react for 4 h, filter, and blow dry the solvent with nitrogen until 1 / 10 volume of the solution remains, pour 5.0 mL of anhydrous ether into the residual liquid, and a white flocculent precipitate appears. Centrifuge at 5000 rpm for 10 min, remove the supernatant, add 5.0 mL of anhydrous ether to the precipitate, shake, centrifuge for 10 min under the same conditions, repeat once, and vacuum dry the precipitate for 24 h to obtain a crude product of nonapeptide-1.

[0029] Example 2 A method for preparing nonapeptide-1, the difference between this embodiment and embodiment 1 is that in step L4, the mass ratio of the modified polysulfone to the quaternary ammonium graphene oxide is 100:0.3, and the amounts of other components and the preparation method are the same as those in embodiment 1. This embodiment obtains high-purity nonapeptide-1 with a purity greater than 99% and a purification yield of 90%.

[0030] Example 3 A method for preparing nonapeptide-1, the difference between this embodiment and embodiment 1 is that in step L3, 0.5 mL of valeryl chloride is added, and the amounts of other components and the preparation method are the same as those in embodiment 1. This embodiment obtains high-purity nonapeptide-1 with a purity greater than 99% and a purification yield of 91%.

[0031] Comparative Example 1 A method for preparing nonapeptide-1, the difference between this comparative example and Example 1 is that steps L1 and L2 are omitted, and in step L4, the mass of quaternary ammonium graphene oxide is replaced by commercially available graphene oxide, and the amounts of other components and the preparation method are the same as those in Example 1. This comparative example obtains high-purity nonapeptide-1 with a purity greater than 99% and a purification yield of 78%.

[0032] Comparative Example 2 A method for preparing nonapeptide-1, the difference between this comparative example and Example 1 is that in step L3, the polysulfone plasma treatment step is omitted, the aminopolysulfone is replaced by polysulfone, and the amount of other components and the preparation method are the same as those in Example 1. This comparative example obtains high-purity nonapeptide-1 with a purity greater than 99% and a purification yield of 73%.

[0033] Comparative Example 3 A method for preparing nonapeptide-1, the difference between this comparative example and Example 1 is that in step L3, no acylation reaction is performed, the aminopolysulfone is used as a modified polysulfone for subsequent reaction, and the amounts of other components and the preparation method are the same as those in Example 1. This comparative example obtains high-purity nonapeptide-1 with a purity greater than 99% and a purification yield of 72%.

[0034] Comparative Example 4 A method for preparing nonapeptide-1, the difference between this comparative example and Example 1 is that in step L3, 5 mL of hexanoyl chloride is added, and the amounts of other components and the preparation method are the same as those in Example 1. This comparative example obtains high-purity nonapeptide-1 with a purity greater than 99% and a purification yield of 77%.

[0035] It can be seen from the above results that the present invention synthesizes the crude product of nonapeptide-1 by a solid phase synthesis method, and then purifies it by combining a modified polysulfone filter membrane, a reverse phase polymer column and a weak anion exchange column, and the obtained high-purity nonapeptide-1 has a purity greater than 99% and a yield greater than 90%. Comparative Example 1 uses a modified polysulfone filter membrane prepared by commercially available graphene oxide, and the hydrophilicity is relatively poor; Comparative Example 2 omits the polysulfone plasma treatment step, and replaces the amino polysulfone isotope with polysulfone, and Comparative Example 3 does not perform an acylation reaction, and uses the amino polysulfone as a modified polysulfone for subsequent reactions, and the prepared modified polysulfone filter membrane has poor compatibility with the polypeptide; Comparative Example 4 adds an excess of hexanoyl chloride, and the modified polysulfone filter membrane is more completely amidated, has fewer amino groups, and has poor hydrophilicity, so its purification yield for nonapeptide-1 is low, and the purification effect is not as good as the present invention.

[0036] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0037] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A method for preparing nonapeptide-1, characterized in that: The preparation method of nonapeptide-1 comprises the following steps: S1. Preparation of modified polysulfone filter membrane, the preparation of modified polysulfone filter membrane comprises the following steps: L1. Add graphene oxide to N,N-dimethylformamide, disperse by ultrasonication, then add a tertiary amine modifier, stir to react, purify and dry to obtain tertiary amine graphene oxide; L2, adding the tertiary amine graphene oxide to ethanol, ultrasonically dispersing, then adding a quaternary ammonium modifier, heating for reaction, purifying, and drying to obtain quaternary ammonium graphene oxide; L3, placing polysulfone in a plasma treatment device, introducing nitrogen and hydrogen for plasma treatment to obtain amino polysulfone; blending the amino polysulfone with an acylating agent for reaction, purifying, and drying to obtain modified polysulfone; L4, adding the modified polysulfone into a solvent, adding the quaternary ammonium graphene oxide, ultrasonicating, heating and stirring, and then casting into a membrane to obtain a modified polysulfone filter membrane; S2, synthesizing the crude product of nonapeptide-1 by solid phase synthesis method; S3, adding the nonapeptide-1 crude product into water, ultrasonicating, and filtering with the modified polysulfone filter membrane to obtain a nonapeptide-1 mixture; S4, purifying the nonapeptide-1 mixture by reverse phase high performance liquid chromatography to obtain crude nonapeptide-1; S5. Purifying the crude nonapeptide-1 by anion exchange chromatography to obtain highly pure nonapeptide-1.

2. The method for preparing nonapeptide-1 according to claim 1, characterized in that: In step L1, the tertiary amine modifier is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, triethylamine, N,N-dimethyl-1,3-propylenediamine, N,N-disalicylidenepropylenediamine, N,N'-dimethyl-1,4-butanediamine, 1,4-bis(dimethylamino)butane, N,N'-dihydroxy-2,3-dimethyl-2,3-butanediamine, N-hydroxysuccinimide, N-hydroxysulfosuccinimide, 4-dimethylaminopyridine, N-hydroxybenzotriazole, N,N-dicyclohexylcarbodiimide or 3-dimethylaminopropylamine. One or more.

3. The method for preparing nonapeptide-1 according to claim 1, characterized in that: In step L1, the molar ratio of graphene oxide to tertiary amine modifier is 1:(1-10).

4. The method for preparing nonapeptide-1 according to claim 1, characterized in that: In step L2, the quaternary ammonium modifier is selected from one or more of butyl chloride, pentyl chloride, hexyl chloride, heptyl chloride, butyl bromide, pentyl bromide, hexyl bromide, and heptyl bromide.

5. The method for preparing nonapeptide-1 according to claim 1, characterized in that: In step L2, the molar ratio of the tertiary amine graphene oxide to the quaternary ammonium modifier is 1:(1-5).

6. The method for preparing nonapeptide-1 according to claim 1, characterized in that: In step L3, the volume ratio of nitrogen to hydrogen is 1:(2-5).

7. The method for preparing nonapeptide-1 according to claim 1, characterized in that: In step L3, the acylating agent is selected from one or more of pentanoyl chloride, hexanoyl chloride, heptanoyl chloride or octanoyl chloride.

8. The method for preparing nonapeptide-1 according to claim 1, characterized in that: In step L3, the molar ratio of the aminopolysulfone to the acylating agent is 1:(0.1-0.5).

9. The method for preparing nonapeptide-1 according to claim 1, characterized in that: In step L4, the mass ratio of the modified polysulfone to the quaternary ammonium graphene oxide is 100:(0.1-1).

10. The method for preparing nonapeptide-1 according to claim 1, characterized in that: The preparation method of the crude nonapeptide-1 comprises the following steps: P1, mixing the resin with dichloromethane, soaking and swelling, and purifying to obtain an activated resin; P2, dissolving the first amino acid protected by Fmoc, HBTU and DMAP in DMF, adding DIEA, mixing evenly, then adding to the activated resin, shaking for reaction, purifying, and obtaining the resin coupled with the first amino acid; P3, adding a mixed solution of acetic anhydride, pyridine and DMF to the resin coupled with the first amino acid, shaking the reaction to block the unreacted functional groups on the resin; then washing with DMF, DCM and DMF in sequence, adding a mixed solution of piperidine and DMF to deprotect the functional groups of the resin; P4. Repeat steps P2-P3 to carry out peptide grafting reaction, then remove the resin, purify and dry to obtain the crude product of nonapeptide-1.