A process for the preparation of a dual receptor agonist of GIP and GLP-1

Abstract

A preparation method of a dual-receptor agonist of GIP and GLP-1. The provided preparation method uses a protected polypeptide fragment containing an Aib amino acid residue to replace a single protected amino acid Aib, and in the overall preparation process, the method of first modifying the side chain of lysine and then connecting the main chain amino acid and the polypeptide fragment can effectively improve the condensation efficiency, reduce the generation of impurities, improve the product purity, more easily separate the pure product through HPLC purification, improve the yield of finished product, and at the same time make the whole reaction control process more simple, and reduce the overall production cost of the product.

Description

A preparation method of a dual receptor agonist of GIP and GLP-1 Citation of Related Applications This disclosure claims the priority of the invention patent application filed with the China Patent Office on November 2, 2023, with application number 202311449055.6 and invention name “A method for preparing a dual receptor agonist of GIP and GLP-1”, and all its contents are incorporated into this disclosure by reference. Technical Field The present invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing a dual receptor agonist of GIP and GLP-1. Background Art Obesity and diabetes are increasingly serious global health problems, which are associated with a variety of other diseases, including cardiovascular disease (CVD), obstructive sleep apnea, stroke, peripheral arterial disease, microvascular complications and osteoarthritis. Therefore, the development of new therapies and therapeutic drugs for obesity, diabetes and their complications is of great significance for improving human health. Glucose-dependent insulinotropic peptide (GIP) is a 42-amino acid gastrointestinal regulatory peptide that plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic β cells in the presence of glucose and protecting pancreatic β cells. Glucagon-like peptide-1 (GLP-1) is a 37-amino acid peptide that stimulates insulin secretion, protects pancreatic β cells, and inhibits glucagon secretion, gastric emptying, and food intake, leading to weight loss. GIP and GLP-1 are secreted by K cells and L cells of the small intestinal endothelium, respectively, and are known as incretins. Incretin receptor signaling plays a key physiologically relevant role in glucose homeostasis. Studies have shown that if blood sugar is lowered to a certain extent, sensitivity to GIP can be restored, which indicates that co-stimulation of GLP-1R / GIPR (GLP-1 receptor / GIP receptor) can exert a synergistic blood sugar-lowering effect, and dual receptor agonists of GIP and GLP-1 may produce more excellent blood sugar-lowering effects and stimulate insulin secretion. The compound of formula I below is a dual receptor agonist of GIP and GLP-1: The abbreviated formula of the compound of formula I is: The agonist exhibits an excellent hypoglycemic effect. At present, the synthesis of the compound of formula I mainly adopts the conventional Fmoc method solid phase synthesis to step-by-step couple a single protected amino acid and a side chain fragment. However, when the compound of formula I is synthesized by the step-by-step coupling method, the yield and purity of the crude product are limited. Therefore, there is an urgent need to provide a new preparation method for dual receptor agonists of GIP and GLP-1 (especially compounds of formula I) to improve the purity of the finished product. Summary of the invention Problem that the invention aims to solve Although the prior art has provided a preparation method for the compound of formula I, such as step-wise coupling, there is still a problem of limited yield and purity of the crude product obtained when the compound of formula I is prepared by this method. Therefore, the conventional Fmoc solid phase synthesis method (step-wise coupling of single protected amino acids and side chain fragments) is still not perfect for the synthesis of the compound of formula I. The present disclosure has conducted extensive research on the preparation method of the compound of formula I and found that the reason why the crude compound of formula I prepared by the conventional method has limited purity and yield is that when gradually coupling a single protected amino acid and a side chain fragment, there are mainly problems such as difficulty in amino acid condensation and generation of more impurities, for example: (1) Due to the large steric hindrance of Aib, it is difficult to condense the subsequent protected amino acids using the conventional condensation method (condensation of a single protected amino acid in sequence), the reaction time is long, the reaction is incomplete, and more impurities are generated, resulting in low purity of the crude product, difficulty in purification, and low yield; when using an onium salt type condensation reagent for condensation, the main by-product is an amino-terminated impurity. When using a typical condensation reagent HATU for condensation, the by-products are as follows: In addition, when amino detection reagents (ninhydrin, tetrachlorobenzoquinone, etc.) are used to detect the amino group of Aib, no color is developed or the color is not obvious, resulting in the inability to use colorimetric reagents for central control during the reaction process. Central control requires the use of instruments such as HPLC and LC-MS, and the central control process is complicated and has low production efficiency. (2) In conventional peptide side chain modification synthesis, Lys side chain modification is usually used, and the Lys side chain amino group is specially protected. After the peptide condensation is completed, the side chain protecting group is removed and then the side chain is modified. Commonly used Lys side chain protecting groups in peptide solid phase synthesis are Dde, ivDde, and Alloc. When Dde and ivDde are used for protection, each time piperidine is used to remove the Fmoc protecting group, a small amount of Dde and ivDde will be removed in each cycle. When the sequence is long, a series of impurities will be generated, which will eventually lead to a decrease in the purity of the crude product. This will be a huge challenge for the quality research of drugs, so Dde and ivDde are only suitable for the synthesis of short drug peptides. The removal of Alloc requires the use of Pd catalyst, and inevitably produces allylamine derivative impurities: This results in a decrease in the purity of the crude product, and the allylamine derivative impurities have similar polarity to the product and are difficult to separate, causing inconvenience to purification. In this regard, the present disclosure provides a new preparation method for the compound of formula I, by replacing the single protected amino acid Aib with a protected polypeptide fragment containing the amino acid residue Aib, and in the overall preparation process, first modifying the lysine side chain and then connecting the main chain amino acids and the polypeptide fragment, the condensation efficiency can be effectively improved, the generation of impurities can be reduced, the purity of the crude product can be improved, the pure product can be more easily separated by HPLC purification, the yield of the finished product can be improved, and at the same time, the central control process of the entire reaction can be simplified, thereby reducing the overall production cost of the product. Solutions for solving problems In order to solve the above technical problems, the present disclosure provides the following technical solutions: [1] A method for preparing a dual receptor agonist of GIP and GLP-1, wherein the dual receptor agonist of GIP and GLP-1 is a compound represented by the following formula I: The preparation method comprises the following steps: (i) obtaining a Lys resin complex with a side chain modified and α-amino protected; (ii) removing the protecting group of the α-amino group to prepare a Lys resin complex with a modified α-amino group but unprotected side chain; (iii) using the Lys resin complex with the modified α-amino group of the side chain as the starting resin, and mixing it with the protected amino acid and Aib 13 Peptide fragment, Aib 2 The polypeptide fragments are condensed to prepare a fully protected resin peptide of the compound of formula I; (iv) cleaving the fully protected resin peptide of the compound of formula I to prepare the compound of formula I. [2] The preparation method according to [1], wherein (i) comprises the following steps: Connect R1-Lys(Fmoc)-OH to the resin, remove the Fmoc protecting group, and sequentially condense Fmoc-AEEEA-OH, Fmoc-AEEEA-OH, Fmoc-Glu-OtBu and tBuO-Ara(OH), or directly condense tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu fragments to obtain a Lys resin complex with a modified side chain and protected α-amino group; or, Fmoc-Lys(R1)-OH was connected to the resin, the R1 protecting group was removed, and the tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu fragment was directly condensed to obtain a Lys resin complex with a modified α-amino group on the side chain; or, Prepare Fmoc-Lys(tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu), connect it to the resin, and obtain a Lys-resin complex with a modified α-amino group and protected side chain; Wherein, the R1 is selected from any one of Dde, ivDde, Mtt, MMt, Trt, Adpoc, Bpoc and Ddz. [3] The method according to [1] or [2], wherein in (ii), a deprotecting agent is used to remove the protecting group of the α-amino group; and When the protecting group of the α-amino group is Dde or ivDde, the deprotecting agent is a DMF solution containing 0.5% to 5% by volume of hydrazine hydrate, and the removal reaction time is 1 min to 30 min; preferably, a DMF solution containing 2% by volume of hydrazine hydrate is used, and the removal reaction is repeated 3 times, each time for 5 min; When the protecting group of the α-amino group is Mtt, the deprotecting agent is a mixture of DCM, AcOH and TFE, the volume ratio of DCM, AcOH and TFE is (4-8.5): (0.5-2): (1-4), and the reaction time of the removal is 0.5h-12h; preferably, the volume ratio of DCM, AcOH and TFE is 7:1:2, and the reaction time of the removal is 2h; When the protecting group of the α-amino group is Fmoc, the deprotecting agent is a DMF solution containing 5% to 50% by volume of piperidine; preferably, a DMF solution containing 20% ​​by volume of piperidine is used; When the protecting group of the α-amino group is MMT or Trt, the deprotecting agent is a DCM solution containing 5% to 50% by volume of acetic acid or a DCM solution containing 2% to 5% by volume of TFA; When the protecting group of the α-amino group is Adpoc, Bpoc or Ddz, the deprotecting agent is TFA containing 2% to 5% by volume of DCM solution. [4] The method according to any one of [1] to [3], wherein in (iii), Aib 13 The polypeptide fragment is Fmoc-Ile-Aib-OH or Fmoc-Ile-Aib-Leu-OH; the Aib 2 The polypeptide fragment is Boc-Tyr(tBu)-Aib-OH, Boc-Tyr(tBu)-Aib-Glu(OtBu)-OH or Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-OH. [5] The preparation method according to any one of [1] to [4], wherein the (iii) comprises the following steps: According to the sequence shown in SEQ ID NO.1, the corresponding protected amino acids and Aib are sequentially condensed from the C-terminus. 13 Peptide fragment, Aib 2 The polypeptide fragment is attached to the unprotected Lys resin complex with the modified α-amino group on the side chain to obtain the fully protected resin peptide of the compound of formula I. [6] The preparation method according to any one of [1] to [5], wherein in (iii), the protected amino acid includes any one or more of Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Thr(tBu)-OH and Fmoc-Glu(OtBu)-OH. [7] The method according to any one of [1] to [6], wherein in (iii), the condensation is carried out using a condensation reagent; Preferably, the condensation reagent is selected from any one or more of HBTU, DIEA, HATU, HOAT, HOBT and DIC. [8] The preparation method according to any one of [1] to [7], wherein in (iv), the fully protected resin peptide of the compound of formula I is cleaved using a cleavage solution, and the cleavage solution is selected from any one of the following mixtures: TFA / phenol / thioanisole / TIS / water, TFA / phenol / thioanisole / water / EDT, TFA / TIS / water and TFA / TIS / EDT / water / thioanisole; Preferably, the lysis solution is a mixture of: TFA / TIS / water, or TFA / phenol / thioanisole / water / EDT; More preferably, in the lysis solution, the volume ratio of TFA / TIS / water is (90-95):(1-5):(1-5), and the volume ratio of TFA / phenol / thioanisole / water / EDT is (80-95):(1-5):(1-5):(1-5):(1-5), and further preferably, the volume ratio of TFA / TIS / water is 95:2.5:2.5, and the volume ratio of TFA / phenol / thioanisole / water / EDT is 82.5:5:5:5:2.5. [9] The preparation method according to any one of [1] to [8], wherein in (iv), after cleaving the fully protected resin peptide of the compound of formula I, the step of precipitating, washing and optionally purifying the cleavage product is also included.

[0010] , a dual receptor agonist of GIP and GLP-1, wherein the dual receptor agonist of GIP and GLP-1 is prepared by the preparation method according to any one of [1] to [9], and the purity of the dual receptor agonist of GIP and GLP-1 is greater than or equal to 60%. Effects of the Invention First, unlike the existing synthesis method of the compound of formula I (modifying the side chain after synthesizing the amino acid main chain), the preparation method of the compound of formula I provided by the present disclosure first modifies the lysine side chain and then gradually connects the single amino acids or amino acid fragments of the main chain. While improving the synthesis efficiency, it effectively reduces the impurities generated in the synthesis process, thereby improving the purity and yield of the crude product, and greatly reducing the impurity content in the crude product, thereby improving the purity and safety of the final drug. Furthermore, in the preparation method provided by the present disclosure, since the lysine side chain is modified first, the impurities generated by the accidental removal of the lysine side chain protecting group in the process of connecting each amino acid when synthesizing a long main chain peptide segment are reduced. Moreover, in the preparation method provided by the present disclosure, the modification methods for the lysine side chain are flexible and diverse. The protected lysine can be connected to the resin first, and then the lysine side chain can be modified. Alternatively, the lysine side chain modified fragment and lysine can be connected in reverse first, and then connected to the resin, in preparation for the subsequent amino acid main chain synthesis. Moreover, in the preparation method provided by the present disclosure, the use of lysine containing the protecting group Alloc is avoided, so that when the protecting group is subsequently removed, there is no need to use a Pd catalyst, thereby avoiding the production of allylamine derivatives that are similar in polarity to the compound of Formula I and are difficult to separate. Biological impurities. In addition, in the preparation method provided by the present disclosure, a protected polypeptide fragment containing Aib amino acid residues is used to replace a single protected Aib, so that it is easier to condense during the amino acid main chain synthesis process and makes the reaction control process simpler and easier. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a liquid chromatogram of the crude product obtained in Example 1. FIG. 2 is a liquid chromatogram of the crude product obtained in Example 2. FIG. 3 is a liquid chromatogram of the crude product obtained in the comparative example. FIG4 is a liquid chromatogram comparison of the crude product obtained in the comparative example and the crude products obtained in Example 1 and Example 2. DETAILED DESCRIPTION The following describes the embodiments of the present disclosure, but the present disclosure is not limited thereto. The present disclosure is not limited to the various structures described below, and various changes can be made within the scope of the public request for protection, and the embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples are also included in the technical scope of the present disclosure. definition In the present disclosure, the term “a” or “an” or “the” may mean “one”, and may also mean “one or more”, “at least one” and “one or more than one”. In the present disclosure, the terms "comprising", "having", "including" or "containing" may refer to being inclusive or open-ended, not excluding additional, uncited elements or method steps. At the same time, "comprising", "having", "including" or "containing" may also refer to being closed-ended, excluding additional, uncited elements or method steps. In the present disclosure, the term "about" means that a value includes the standard deviation of the error of the device or method used to determine the value. The numerical ranges and parameters used to define the present disclosure are approximate values, and the relevant values ​​in the specific embodiments have been presented as accurately as possible. Unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in the present disclosure are modified by "about". In the present disclosure, the term "agonist" refers to a substance (ligand) that activates signaling through the target receptor type. Exemplarily, with the GLP-1 receptor as the target receptor, the agonist has the activation activity of the GLP-1 receptor, such as a GLP-1 polypeptide or an analog thereof. In the present disclosure, the term "protected amino acid" or "protected amino acid" refers to an amino acid derivative in which the activity of the amino acid functional group is blocked by the reaction of the functional group with the protecting group; the term "protected polypeptide fragment" refers to a polypeptide derivative in which the activity of the functional group of the amino acid residue in the polypeptide is blocked by the reaction of the functional group with the protecting group. 13 Peptide fragments" and "Aib 2 The "polypeptide fragment" refers to the protected polypeptide fragment of Aib containing the 13th and 2nd positions from the N-terminus to the C-terminus in the amino acid sequence, respectively. The amino acids and their abbreviations and English abbreviations in the present disclosure are shown in the following table: The English abbreviations of the compounds in this disclosure are as follows: DIEA: N,N-diisopropylethylamine; DIC: N,N-diisopropylcarbodiimide; HOBT: N-hydroxybenzotriazole; DCM: dichloromethane; TFA: trifluoroacetic acid; DMF: N,N-dimethylformamide; Fmoc-AEEEA-OH: [2-[2-[2-(Fmoc-amino)ethoxy]ethoxy]ethoxy]acetic acid; MTBE: methyl tert-butyl ether; TIS: triisopropylsilane; NMM: N-methylmorpholine; HBTU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOAT: N-hydroxy-7-azabenzotriazole; HOAc: acetic acid; HOSU: N-hydroxysuccinimide; EDT: 1,2-ethanedithiol. Unless otherwise defined, other technical and scientific terms used in the present disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. Dual receptor agonist for GIP and GLP-1 The dual receptor agonist of GIP and GLP-1 described in the present disclosure is a compound shown in the following formula I: The amino acid sequence from amino acid 1 to amino acid 39 in the compound of formula I is shown in SEQ ID NO.1: Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Ile-Ala-Gln-Lys-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser. Preparation method of dual receptor agonist of GIP and GLP-1 The present disclosure provides a method for preparing a dual receptor agonist of GIP and GLP-1, wherein the dual receptor agonist of GIP and GLP-1 is a compound of formula I, and the preparation method comprises the following steps (i) to (iv): (i) obtaining a Lys resin complex with a side chain modified and α-amino protected; (ii) removing the protecting group of the α-amino group to prepare a Lys resin complex with a modified α-amino group but unprotected side chain; (iii) using the Lys resin complex with the modified α-amino group of the side chain as the starting resin, and mixing it with the protected amino acid and Aib 13 Peptide fragment, Aib 2The polypeptide fragments are condensed to prepare a fully protected resin peptide of the compound of formula I; (iv) cleaving the fully protected resin peptide of the compound of formula I to prepare the compound of formula I. The method provided by the present disclosure first modifies the lysine side chain and then gradually connects single amino acids or amino acid fragments of the main chain, which effectively reduces impurities generated during the synthesis process while improving the synthesis efficiency and improving the purity of the crude product. Step (i) In some embodiments, the (i) comprises the following steps: connecting R1-Lys(Fmoc)-OH to a resin, removing the Fmoc protecting group, sequentially condensing Fmoc-AEEEA-OH, Fmoc-AEEEA-OH, Fmoc-Glu-OtBu and tBuO-Ara(OH), or directly condensing tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu fragments to obtain a side chain-modified α-amino protected Lys resin complex, wherein R1 is selected from any one of Dde, ivDde, Mtt, MMt, Trt, Adpoc, Bpoc and Ddz. In this embodiment, when R1 is Dde, first remove Fmoc, sequentially condense Fmoc-AEEEA-OH, Fmoc-AEEEA-OH, Fmoc-Glu-OtBu and tBuO-Ara(OH) to modify the side chain, and then remove Dde, and combine it with protected amino acids and Aib. 13 Peptide fragment, Aib 2 The polypeptide fragments are condensed, and there is no accidental removal of Dde when the main chain amino acids and polypeptide fragments are condensed; compared with the method in the comparative example (the Lys side chain protecting group is Dde, and when the polypeptide is condensed, part of Dde will be removed when each amino acid removes the Fmoc protecting group, and impurities will be generated each time the condensation occurs. Since there are 39 amino acids in total, the impurities generated are numerous and complex), in this scheme, only three peptides, Fmoc-AEEEA-OH, Fmoc-AEEEA-OH, and Fmoc-Glu-OtBu, need to be condensed, and the impurities generated by the accidental removal of Dde can be ignored. In other embodiments, the (i) comprises the following steps: connecting Fmoc-Lys(R1)-OH to a resin, removing the R1 protecting group, and directly condensing tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu fragments to obtain a side chain modified α-amino protected Lys resin complex, wherein R1 is selected from any one of Dde, ivDde, Mtt, MMt, Trt, Adpoc, Bpoc and Ddz. The preparation method provided by the present disclosure avoids the use of protected Lys containing the protecting group Alloc in the above process, so that when the protecting group is subsequently removed, there is no need to use a Pd catalyst, thereby avoiding the generation of allylamine derivative impurities that are similar in polarity to the compound of formula I and are difficult to separate. In other embodiments, the (i) comprises the following steps: preparing Fmoc-Lys(tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu), connecting it to a resin, and obtaining a Lys resin complex with a side chain modified and an α-amino group protected. This scheme can further improve the purity of the crude product of the dual receptor agonist of GIP and GLP-1. In the above process, the preparation method provided by the present disclosure first synthesizes a lysine side chain fragment, then connects the side chain fragment to the lysine side chain, and finally connects to the resin. For the specific preparation process of the lysine side chain fragment, reference can be made to the conventional synthesis method of the side chain fragment in the prior art, or to ZL201510619012.7, the contents of which are incorporated into the present disclosure by reference. Step (ii) In step (ii), a deprotecting agent is used to remove the protecting group of the α-amino group. The present disclosure does not particularly limit the specific selection of the deprotecting agent, and those skilled in the art can select the deprotecting agent according to the specific protecting group to be removed. In some embodiments, when the protecting group of the α-amino group is Dde or ivDde, the deprotecting agent is a DMF solution containing 0.5% to 5% by volume of hydrazine hydrate, for example, the deprotecting agent is a DMF solution containing 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% by volume of hydrazine hydrate, and the reaction time of the removal is 1 min to 30 min, for example, the reaction time of the removal is 1 min, 5 min, 10 min, 15 min, 20 min, 25 min or 30 min, etc. In some preferred embodiments, when the protecting group of the α-amino group is Dde or ivDde, the deprotecting agent is a DMF solution containing 2% by volume of hydrazine hydrate, the deprotection reaction is performed 3 times, and the reaction time of each removal is 5 min. In some embodiments, when the protecting group of the α-amino group is Mtt, the deprotecting agent is a mixture of DCM, AcOH and TFE, the volume ratio of DCM, AcOH and TFE is (4-8.5): (0.5-2): (1-4), and the reaction time of the removal is 0.5h-12h, for example, the reaction time of the removal is 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h or 12h, etc. In some preferred embodiments, when the protecting group of the α-amino group is Mtt, the deprotecting agent is a mixture of DCM, AcOH and TFE, the volume ratio of DCM, AcOH and TFE is 7:1:2, and the reaction time of the removal is 2h. In some embodiments, when the protecting group of the α-amino group is Fmoc, the deprotecting agent is a DMF solution containing 5% to 50% piperidine by volume, for example, the deprotecting agent is a DMF solution containing 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% piperidine by volume. In some preferred embodiments, when the protecting group of the α-amino group is Fmoc, the deprotecting agent is a DMF containing 20% ​​piperidine by volume. In some embodiments, when the protecting group of the α-amino group is MMT or Trt, the deprotecting agent is a DCM solution containing 5% to 50% by volume of acetic acid or a DCM solution containing 2% to 5% by volume of TFA, for example, the deprotecting agent is a DCM solution containing 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% by volume of acetic acid, or a DCM solution containing 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% by volume of TFA. In some embodiments, when the protecting group of the α-amino group is Adpoc, Bpoc or Ddz, the deprotecting agent is a DCM solution containing 2% to 5% TFA by volume, for example, the deprotecting agent is a DCM solution containing 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% TFA by volume. Step (iii) In some embodiments, the step (iii) comprises the following steps: according to the sequence shown in SEQ ID NO.1, starting from the C-terminus, condensing the corresponding protected amino acids and Aib 13 Peptide fragment, Aib 2 The polypeptide fragment is attached to the unprotected Lys resin complex with the modified α-amino group on the side chain to obtain the fully protected resin peptide of the compound of formula I. The preparation method provided by the present disclosure avoids the use of a single protected Aib in the above process, thereby avoiding the problem of long and incomplete reaction time and generation of more impurities when condensing the subsequent protected amino acid due to the large steric hindrance of Aib. At the same time, the reaction mid-control process no longer needs to detect the amino group of Aib, that is, the mid-control can be achieved using a simple colorimetric reagent, thereby improving the overall production efficiency of the compound. Therefore, the present disclosure uses a protected polypeptide fragment containing Aib amino acid residues to replace a single protected Aib. The length of the fragment is not particularly limited in the present disclosure, and preferably a protected polypeptide fragment containing at least one amino acid residue at the N-terminal of the Aib amino acid residue is used, and another preferred protected polypeptide fragment containing 2 to 4 amino acid residues is used. In some embodiments, the Aib 13 The polypeptide fragment is Fmoc-Ile-Aib-OH or Fmoc-Ile-Aib-Leu-OH. In some embodiments, the Aib 2 The polypeptide fragment is Boc-Tyr(tBu)-Aib-OH, Boc-Tyr(tBu)-Aib-Glu(OtBu)-OH or Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-OH. The present disclosure does not particularly limit the use of other single protected amino acids, and those skilled in the art can select them according to actual needs. In order to prepare the compound of formula I, in some embodiments, the protected amino acid includes any one or more of Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Thr(tBu)-OH and Fmoc-Glu(OtBu)-OH. There is no particular limitation on the number of each of the above protected amino acids. A certain protected amino acid can be used once or repeatedly. As long as it can be used with the Aib 13 Polypeptide fragments and the Aib 2 The polypeptide fragments are combined to obtain the sequence shown in SEQ ID NO.1. In some specific embodiments, in said (iii), when said Aib 13The polypeptide fragment is Fmoc-Ile-Aib-OH, wherein Aib 2 When the polypeptide fragment is Boc-Tyr(tBu)-Aib-OH, the protected amino acids include Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Thr(tBu)-OH, and Fmoc-Glu(OtBu)-OH. There is no particular limitation on the number of each of the protected amino acids used, as long as they can be used with the Aib 13 Polypeptide fragments and the Aib 2 The polypeptide fragments are combined to obtain the sequence shown in SEQ ID NO.1. In some specific embodiments, in said (iii), when said Aib 13 The polypeptide fragment is Fmoc-Ile-Aib-Leu-OH, wherein Aib 2 When the polypeptide fragment is Boc-Tyr(tBu)-Aib-Glu(OtBu)-OH, the protected amino acids include Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Tyr(tBu)-OH, and Fmoc-Thr(tBu)-OH. There is no particular limitation on the number of each of the protected amino acids used, as long as they can be used with the Aib 13 Polypeptide fragments and the Aib 2 The polypeptide fragments are combined to obtain the sequence shown in SEQ ID NO.1. In some specific embodiments, in said (iii), when said Aib 13 The polypeptide fragment is Fmoc-Ile-Aib-Leu-OH, wherein Aib 2When the polypeptide fragment is Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-OH, the protected amino acids include Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Tyr(tBu)-OH, and Fmoc-Thr(tBu)-OH. There is no particular limitation on the number of each of the protected amino acids used, as long as they can be used with the Aib 13 Polypeptide fragments and the Aib 2 The polypeptide fragments are combined to obtain the sequence shown in SEQ ID NO.1. In the process of preparing the fully protected resin peptide of the compound of formula I using the protected amino acid and protected polypeptide fragment, a condensation reagent is used. In some embodiments, the condensation reagent is selected from any one or more of HBTU, DIEA, HATU, HOAT, HOBT and DIC. In some specific embodiments, the condensation reagent is selected from any one of the mixtures HBTU / DIEA, HATU / DIEA, HOAT / DIC and HOBT / DIC. Step (iv) In order to obtain the compound of formula I, in some embodiments, it is necessary to use a cleavage solution to cleave the fully protected resin peptide of the compound of formula I prepared in (iii). The present disclosure does not particularly limit the resin used. In some embodiments, the resin includes Rink Amide Resin, Rink Amide-AM Resin, Rink Amide-MBHA Resin, and Sieber Amide Resin. In order to obtain excellent cleavage effect and obtain the compound of formula I, in some embodiments, the cleavage solution is selected from any one of the following mixtures: TFA / phenol / thioanisole / TIS / water, TFA / phenol / thioanisole / water / EDT, TFA / TIS / water and TFA / TIS / EDT / water / thioanisole. In some preferred embodiments, the cleavage solution is the following mixture: TFA / TIS / water, or TFA / phenol / thioanisole / water / EDT. Further, in some specific embodiments, in the cleavage solution, the volume ratio of TFA / TIS / water is (90-95): (1-5): (1-5), preferably 95:2.5:2.5, and the volume ratio of TFA / phenol / thioanisole / water / EDT is (80-95): (1-5): (1-5): (1-5): (1-5), preferably 82.5:5:5:5:2.5. Additional Steps The preparation method provided by the present disclosure may also include other steps, such as preparing protected polypeptide fragments. In some embodiments, in order to obtain a pure compound of formula I, in said (iv), after using a cleavage solution to cleave the fully protected resin peptide of the compound of formula I, the cleavage product containing the compound of formula I is further included to precipitate, wash and optionally purify the cleavage product. At the same time, the present disclosure also provides a dual receptor agonist of GIP and GLP-1 prepared by the above method. In some embodiments, the dual receptor agonist of GIP and GLP-1 prepared by the above method is an enrichment, that is, a crude dual receptor agonist of GIP and GLP-1, which inevitably contains impurities generated during the preparation process. Compared with the crude dual receptor agonist of GIP and GLP-1 prepared by the preparation method provided by the prior art, the types and quantities of impurities in the dual receptor agonist of GIP and GLP-1 (crude product) prepared by the above method provided by the present disclosure are significantly reduced, and the purity of the dual receptor agonist of GIP and GLP-1 is higher. In some embodiments, in the dual receptor agonist of GIP and GLP-1 (crude product), the purity of the dual receptor agonist of GIP and GLP-1 is greater than or equal to 60%; preferably greater than or equal to 63%, more preferably greater than or equal to 65%. Example The embodiments of the present disclosure will be described in detail below in conjunction with the examples, but those skilled in the art will understand that the following examples are only used to illustrate the present disclosure and should not be considered to limit the scope of the present disclosure. If no specific conditions are specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the materials or instruments used are all conventional products that can be obtained commercially. Example 1 (Side chain fragments are condensed sequentially) The preparation of the compound of formula I in this embodiment comprises the following steps: 1) connecting the protected amino acid R1-Lys(Fmoc)-OH (R1=Dde) to Rink MBHA Amide resin (using HOBT / DIC as condensation reagent); removing the Fmoc protecting group with DMF containing 20% ​​by volume of piperidine, and connecting Fmoc-AEEEA-OH, Fmoc-AEEEA-OH, Fmoc-Glu-OtBu, and tBuO-Ara(OH) to the resin in sequence (using HBTU / DIEA as condensation reagent) to obtain a Lys resin complex with a modified α-amino group on the side chain; 2) Removal of the α-amino protecting group Dde: Deprotection reaction was performed using DMF containing 2% by volume of hydrazine hydrate for 5 min, 3 times for a total of 15 min, and after deprotection, washing was performed with DMF to obtain a Lys resin complex with a modified α-amino group but not protected; 3) Sequentially connect the following protected amino acids and dipeptide fragments to the unprotected Lys resin complex with modified α-amino groups on the side chains (condensation reagents used are HOBT / DIC): Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmo c-Gly-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Ala-OH, Fmoc-Lys(Boc)-OH, Fmoc-G ln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Ile-Aib-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Boc-Tyr(tBu)-Aib-OH to obtain a fully protected resin peptide of compound formula I; 4) The resin was cleaved with 95% (V / V) TFA / 2.5% (V / V) water / 2.5% (V / V) TIS, followed by icy tert-methyl The crude product was purified by HPLC and freeze-dried to obtain the target compound of formula I. Table 1 Liquid chromatography data of crude product of formula I obtained by the method of Example 1 Wherein, the preparation of Fmoc-Ile-Aib-OH is as follows: Dissolve Fmoc-Ile-OH (1.0 eq) in dichloromethane, add DIEA (2.0 eq), DIC (1.5 eq), HOBT (1.5 eq), H-Aib-OtBu.HCl (1.1 eq), monitor the reaction by TLC, concentrate to remove DCM, add ethyl acetate, wash with dilute hydrochloric acid, wash with saturated sodium bicarbonate, dry with anhydrous sodium sulfate, and concentrate to dryness to obtain Fmoc-Ile-Aib-OtBu; Fmoc-Ile-Aib-OtBu was dissolved in dichloromethane, TFA was added, and after the reaction was completed under TLC monitoring, the mixture was washed with purified water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain Fmoc-Ile-Aib-OH. The preparation of Boc-Tyr(tBu)-Aib-OH is as follows: Dissolve Boc-Tyr(tBu)-OH (1.0 eq) in dichloromethane, add DIEA (2.0 eq), DIC (1.5 eq), HOBT (1.5 eq), H-Aib-OBzl.HCl (1.1 eq), monitor the reaction by TLC, concentrate to remove DCM, add ethyl acetate, wash with dilute hydrochloric acid, wash with saturated sodium bicarbonate, dry with anhydrous sodium sulfate, and concentrate to dryness to obtain Boc-Tyr(tBu)-Aib-OBzl; Boc-Tyr(tBu)-Aib-OBzl was dissolved in methanol, Pd / C was added, hydrogen was introduced under normal pressure, and after the reaction was completed under TLC monitoring, the mixture was filtered and concentrated to dryness to obtain Boc-Tyr(tBu)-Aib-OH. Example 2 (the entire side chain is condensed together) The preparation of the compound of formula I in this embodiment comprises the following steps: 1) Synthesis of protective side chain fragment Fmoc-Lys(tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu): 2) Connecting the protected side chain fragment Fmoc-Lys (tBuO-Ara-Glu (AEEEA-AEEEA)-OtBu) to Rink MBHA Amide resin (using HBTU / DIEA or HATU / DIEA or HOAT / DIC as condensation reagent) to obtain a Lys resin complex with a modified α-amino group and protected side chain; 3) removing the Fmoc protecting group with DMF containing 20% ​​by volume of piperidine to obtain a Lys resin complex with a modified α-amino group on the side chain and no protection; 4) Sequentially connect the following protected amino acids and dipeptide fragments to the unprotected Lys resin complex with modified α-amino groups on the side chains (HOBT / DIC is used as the condensation reagent): Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmo c-Gly-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Ala-OH, Fmoc-Lys(Boc)-OH, Fmoc-G ln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Ile-Aib-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Boc-Tyr(tBu)-Aib-OH to obtain a fully protected resin peptide of compound formula I; 5) The resin was cleaved using 95% (V / V) TFA / 2.5% (V / V) water / 2.5% (V / V) TIS, and then precipitated and washed with icy methyl tert-butyl ether (MTBE) to obtain a crude product of a high-purity compound of formula I (the liquid chromatogram of the crude product of formula I is shown in Figure 2, and the corresponding peak data are shown in Table 2). The purification method was the same as in Example 1. Table 2 Liquid chromatography data of crude product of formula I obtained by the method of Example 2 Example 3 The preparation of the compound of formula I in this embodiment comprises the following steps: 1) The protected amino acid Fmoc-Lys(R1)-OH (R1 = Mtt) was connected to Rink MBHA Amide resin (HOBT / DIC was used as the condensation reagent), and the Mtt protecting group was removed by reacting with DCM / AcOH / TFE = 7:1:2 (volume ratio) for 2 h, and then the tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu fragment was directly condensed (HBTU / DIEA was used as the condensation reagent) to obtain a Lys resin complex with a modified α-amino group on the side chain; 2) Removal of the protective group Fmoc of the α-amino group: using DMF containing 20% ​​by volume of piperidine to remove the protective group Fmoc, to obtain a Lys resin complex with a modified α-amino group but not protected; 3) Sequentially connect the following protected amino acids and polypeptide fragments to the unprotected Lys resin complex with modified α-amino groups on the side chains (condensation reagents used are HOBT / DIC): Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH , Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Ala-OH, Fmoc-Lys(Boc)-O H, Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ile-Aib-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Boc-Tyr(tBu)-Aib-Glu(OtBu)-OH to obtain a fully protected resin peptide of compound formula I; 4) The resin was cleaved by TFA / phenol / thioanisole / water / EDT (volume ratio of 82.5:5:5:5:2.5), and then precipitated and washed with icy methyl tert-butyl ether (MTBE) to obtain a crude product of high-purity compound of formula I. The purity of the crude product was comparable to that in Example 1. The synthesis of tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu fragment in step 1) of this example was carried out by referring to the method in step 1) of example 2. Example 4 The preparation of the compound of formula I in this embodiment comprises the following steps: 1) preparing a Lys resin complex with a modified α-amino group protected on the side chain, the specific process is the same as step 1) in Example 3; 2) preparing a Lys resin complex with a modified α-amino group but not protected on the side chain, the specific process is the same as step 2) of Example 3; 3) preparing a fully protected resin peptide of the compound of formula I, the specific process is the same as step 3) of Example 3, wherein the difference is that Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-OH is used instead of Boc-Tyr(tBu)-Aib-Glu(OtBu)-OH; 4) The cleavage of the resin and the acquisition of the crude product of Formula I are the same as step 4) of Example 3. The purity of the crude product obtained in this example is comparable to that in Example 1. In addition, in other embodiments of the present disclosure, the α-amino protecting group and the side-chain amino protecting group in the Lys-protected amino acid can also be ivDde, MMt, Trt, Adpoc, Bpoc or Ddz, and it is sufficient to ensure that the α-amino protecting group and the side-chain amino protecting group are different, and the corresponding deprotecting agent can be used for deprotection in the subsequent steps. Comparative Example (Existing Technology Process) The preparation of the compound of formula I in this comparative example comprises the following steps: Fmoc-Rink MBHA Amide resin was used to remove the Fmoc protecting group using DMF containing 20% ​​piperidine by volume, HOBT / DIC was used as coupling reagent, DMF was used as reaction solvent, and the reaction was monitored using the ninhydrin detection method. (1) Connect the following protected amino acids to Rink MBHA Amide resin in sequence: Fmoc-Lys(Alloc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, F moc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Ala-OH, Fmoc-Lys(Boc)- OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Aib-OH, Fmoc-Ile-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tB u)-OH, Fmoc-Asp(OtBu)OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Aib-OH, Boc-Tyr(tBu)-OH; (2) Removal of the Alloc protecting group: add 3 eq of a solution of Pd(PPh3)4 in CHCl3:AcOH:NMM (18:1:0.5), react for 2 h, then wash with chloroform (6×30 ml), 20% HOAc in DCM solution (6×30 ml), DCM (6×30 ml) and DMF (6×30 ml), monitor with ninhydrin to be positive, then condense Fmoc-AEEEA-OH, Fmoc-AEEEA-OH, Fmoc-Glu-OtBu and mono-tert-butyl eicosanedioate in sequence to obtain a fully protected resin of compound Formula I; (3) Resin cleavage: using 95% (V / V) TFA / 2.5% (V / V) water / 2.5% (V / V) TIS, followed by icy MTBE The crude product was precipitated and washed (the liquid chromatogram is shown in FIG3 , and the corresponding peak data are shown in Table 3), purified by HPLC, and freeze-dried to obtain the target compound of formula I. In the comparative example, the removal of Alloc in step (2) requires the use of a Pd catalyst and inevitably produces an allylamine derivative impurity (the relative retention time of the impurity in FIG. 3 corresponds to RRT=1.02), resulting in a decrease in the purity of the crude product. In addition, the allylamine impurity has a similar polarity to the product and is difficult to separate, which brings inconvenience to the purification. Table 3 Liquid chromatography data of crude product of Formula I obtained by comparative method The impurity transfer caused by removing Alloc is as follows: The retention time of the impurity in FIG3 is 19.883 min, and the relative retention time corresponds to RRT=1.02. The following impurities can be avoided by using dipeptides: The retention time of the impurity in FIG3 is 22.035 min, and the relative retention time corresponds to RRT=1.13. FIG4 is a liquid chromatogram comparison of the crude product obtained in the comparative example and the crude products obtained in Example 1 and Example 2. As shown in Figures 1-4, the purity of the compound of formula I obtained by the prior art process is about 49%, and the purity of the compound of formula I in the crude product obtained by the process provided by the present disclosure is 66-73%, and the purity of the crude product is increased by 17-24%. It can be seen that the present invention improves the existing preparation method by first modifying the lysine side chain and then performing amino acid condensation, and using short peptides to replace some single amino acids, avoiding the use of the protecting group Alloc, avoiding the generation of two impurities, and effectively improving the purity of the crude product.

Claims

1. A method for preparing a dual receptor agonist of GIP and GLP-1, characterized in that: The dual receptor agonist of GIP and GLP-1 is a compound shown in the following formula I: The preparation method comprises the following steps: (i) obtaining a Lys resin complex with a side chain modified and α-amino protected; (ii) removing the protecting group of the α-amino group to prepare a Lys resin complex with a modified α-amino group but unprotected side chain; (iii) using the Lys resin complex with the modified α-amino group of the side chain as the starting resin, and mixing it with the protected amino acid and Aib 13 Peptide fragment, Aib 2 The polypeptide fragments are condensed to prepare a fully protected resin peptide of the compound of formula I; (iv) cleaving the fully protected resin peptide of the compound of formula I to prepare the compound of formula I.

2. The preparation method according to claim 1, characterized in that: The (i) comprises the following steps: Connect R1-Lys(Fmoc)-OH to the resin, remove the Fmoc protecting group, and sequentially condense Fmoc-AEEEA-OH, Fmoc-AEEEA-OH, Fmoc-Glu-OtBu and tBuO-Ara(OH), or directly condense tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu fragments to obtain a Lys resin complex with a modified side chain and protected α-amino group; or, Fmoc-Lys(R1)-OH was connected to the resin, the R1 protecting group was removed, and the tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu fragment was directly condensed to obtain a Lys resin complex with a modified α-amino group on the side chain; or, Prepare Fmoc-Lys(tBuO-Ara-Glu(AEEEA-AEEEA)-OtBu), connect it to the resin, and obtain a Lys-resin complex with a modified α-amino group and protected side chain; Wherein, the R1 is selected from any one of Dde, ivDde, Mtt, MMt, Trt, Adpoc, Bpoc and Ddz.

3. The preparation method according to claim 1 or 2, characterized in that: In said (ii), a deprotecting agent is used to remove the protecting group of the α-amino group; and, When the protecting group of the α-amino group is Dde or ivDde, the deprotecting agent is a DMF solution containing 0.5% to 5% by volume of hydrazine hydrate; preferably, a DMF solution containing 2% by volume of hydrazine hydrate is used; When the protecting group of the α-amino group is Mtt, the deprotecting agent is a mixture of DCM, AcOH and TFE, and the volume ratio of DCM, AcOH and TFE is (4-8.5): (0.5-2): (1-4); preferably, the volume ratio of DCM, AcOH and TFE is 7:1:2; When the protecting group of the α-amino group is Fmoc, the deprotecting agent is a DMF solution containing 5% to 50% by volume of piperidine; preferably, a DMF solution containing 20% ​​by volume of piperidine is used; When the protecting group of the α-amino group is MMT or Trt, the deprotecting agent is a DCM solution containing 5% to 50% by volume of acetic acid or a DCM solution containing 2% to 5% by volume of TFA; When the protecting group of the α-amino group is Adpoc, Bpoc or Ddz, the deprotecting agent is TFA containing 2% to 5% by volume of DCM solution.

4. The preparation method according to any one of claims 1 to 3, characterized in that In said (iii), Aib 13 The polypeptide fragment is Fmoc-Ile-Aib-OH or Fmoc-Ile-Aib-Leu-OH; the Aib 2 The polypeptide fragment is Boc-Tyr(tBu)-Aib-OH, Boc-Tyr(tBu)-Aib-Glu(OtBu)-OH or Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-OH.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The (iii) step comprises the following steps: According to the sequence shown in SEQ ID NO.1, the corresponding protected amino acids and Aib are sequentially condensed from the C-terminus. 13 Peptide fragment, Aib 2 The polypeptide fragment is attached to the unprotected Lys resin complex with the modified α-amino group on the side chain to obtain the fully protected resin peptide of the compound of formula I.

6. The preparation method according to any one of claims 1 to 5, characterized in that In (iii), the protected amino acid includes any one or more of Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Thr(tBu)-OH and Fmoc-Glu(OtBu)-OH.

7. The preparation method according to any one of claims 1 to 6, characterized in that: In said (iii), said condensation is carried out using a condensation reagent; Preferably, the condensation reagent is selected from any one or more of HBTU, DIEA, HATU, HOAT, HOBT and DIC.

8. The preparation method according to any one of claims 1 to 7, characterized in that In (iv), the fully protected resin peptide of the compound of formula I is cleaved by a cleavage solution, wherein the cleavage solution is selected from any one of the following mixtures: TFA / phenol / thioanisole / TIS / water, TFA / phenol / thioanisole / water / EDT, TFA / TIS / water and TFA / TIS / EDT / water / thioanisole; Preferably, the lysis solution is a mixture of: TFA / TIS / water, or TFA / phenol / thioanisole / water / EDT; More preferably, in the lysis solution, the volume ratio of TFA / TIS / water is (90-95):(1-5):(1-5), and the volume ratio of TFA / phenol / thioanisole / water / EDT is (80-95):(1-5):(1-5):(1-5):(1-5).

9. The preparation method according to any one of claims 1 to 8, characterized in that In the step (iv), after cleaving the fully protected resin peptide of the compound of formula I, the step further includes precipitating, washing and optionally purifying the cleavage product.

10. A dual receptor agonist of GIP and GLP-1, characterized in that: The dual receptor agonist of GIP and GLP-1 is prepared by the preparation method according to any one of claims 1 to 9, and the purity of the dual receptor agonist of GIP and GLP-1 is greater than or equal to 60%.

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