Synthesis method of key intermediate of tilpotide

Abstract

The invention discloses a synthesis method of a key intermediate of tirpotide, and belongs to the field of polypeptide synthesis. The specific synthesis method comprises the following steps: firstly, mixing Fmoc-Ile-OH with a solvent, then reacting with an activating reagent under the action of alkali to obtain an active intermediate, and then carrying out condensation reaction on the active intermediate and H-Aib-OH to obtain Fmoc-Ile-Aib-OH, namely the key intermediate of the tilpotide; the key intermediate of the tilpotide prepared by the invention has relatively high yield and purity, the yield of the key intermediate of the tilpotide is more than 80%, the purity of the key intermediate of the tilpotide is more than 95%, and the synthesis method has few reaction steps and is beneficial to industrial production.

Description

Technical Field

[0001] The invention belongs to the field of polypeptide synthesis, and particularly relates to a method for synthesizing a key intermediate of telpotide. Background Art

[0002] Tirzepatide (CAS No.: 2023788-19-2), as a dual-target peptide drug for the treatment of diabetes and weight loss, is suitable for adult patients with type 2 diabetes whose blood sugar is still poorly controlled despite diet control, exercise, and treatment with metformin or sulfonylureas. Tirzepatide can be administered by subcutaneous injection once a week to achieve the goal of controlling blood sugar.

[0003] Fmoc-Ile-Aib-OH is a key intermediate in the synthesis of telportin. Currently, the synthesis methods of Fmoc-Ile-Aib-OH are mainly divided into liquid phase synthesis and solid phase synthesis. The solid phase synthesis method requires the use of expensive resins, excessive amino acid feeds and a large amount of solvents, which is high in cost, low in purity and has certain limitations. The currently reported liquid phase synthesis method of Fmoc-Ile-Aib-OH requires that Fmoc-Ile-OH be activated first, and then undergo a condensation reaction with H-Aib-OR (R=Me, Et) to obtain Fmoc-Gly-Arg(Pbf)-OR. During the hydrolysis of the ester group, Fmoc is removed, and the hydrolysis product H-Ile-Aib-OH needs to be protected again to obtain the final product. During the hydrolysis of the ester group, this synthetic route cannot retain the Fmoc protecting group, and needs to be protected again, which wastes materials and increases the reaction steps, and is not conducive to industrial production. Therefore, it is very necessary to improve the direct condensation process of Fmoc-Ile-Aib-OH. Summary of the invention

[0004] The object of the present invention is to provide a method for synthesizing a key intermediate of telpotide, so as to solve the problems of high cost, low purity and complicated reaction steps in the synthesis process of the key intermediate of telpotide.

[0005] In order to solve the above technical problems, the present invention specifically provides the following technical solutions: The present invention discloses a method for synthesizing a key intermediate of telpotide, comprising: First, Fmoc-Ile-OH and a solvent are mixed, and then reacted with an activating reagent under the action of a base to obtain an active intermediate, and the active intermediate is then subjected to a condensation reaction with H-Aib-OH to obtain Fmoc-Ile-Aib-OH, i.e., the key intermediate of telpotide; the base is at least one of N,N-diisopropylethylamine, N-methylimidazole, pyridine and imidazole derivatives; the imidazole derivative is prepared by reacting benzylamine, 2-methyl-1,10-phenanthroline and 2-methyl-3-phenylpyridine. The use of imidazole derivatives can better activate amino acids and generate highly active intermediates, thereby promoting the subsequent condensation reaction and improving the yield and purity of the prepared key intermediate of telpotide.

[0006] Preferably, the reaction solvent is at least one of N,N-dimethylformamide, acetonitrile and dichloromethane, and the usage ratio of Fmoc-Ile-OH to the reaction solvent is 1 g: 6-10 ml.

[0007] Preferably, the mass ratio of the amount of base used to the amount of Fmoc-Ile-OH used is 1:0.7-1.6.

[0008] Preferably, the activation reagent is at least one of HATU, PyBOP and TCFH, and the mass ratio of the amount of the activation reagent used to the amount of Fmoc-Ile-OH used is 1:0.5-1.4.

[0009] Preferably, the mass ratio of the amount of H-Aib-OH to the amount of Fmoc-Ile-OH is 1:3-3.5.

[0010] Preferably, the reaction temperature for the reaction with the activation reagent under the action of a base is 0-5°C, and the reaction time is 0.8-1.5h.

[0011] Preferably, the reaction temperature of the condensation reaction is 23-27° C., and the reaction time is 3-5 h.

[0012] The invention also discloses a key intermediate of telpotide, which is synthesized by the method.

[0013] The present invention discloses a method for synthesizing a key intermediate of telpotide, comprising: Mix Fmoc-Ile-OH and the reaction solvent, then add a base and an activating reagent at 0-5°C, and continue the reaction for 0.8-1.5h. Then add H-Aib-OH, raise the temperature to 23-27°C and react for 3-5h. After the end, add a quenching solvent and a decontamination solvent to separate the aqueous phase. Add an extraction solvent to the aqueous phase, adjust the pH to 3-4, and separate the organic phase. The organic phase is washed, dried and concentrated to obtain an oil. Add a recrystallization solvent to the oil, stir the crystals, filter out the crystals and dry them to obtain Fmoc-Ile-Aib-OH, which is the key intermediate of telpotide.

[0014] Preferably, the reaction solvent is at least one of N,N-dimethylformamide, acetonitrile and dichloromethane, and the usage ratio of Fmoc-Ile-OH to the reaction solvent is 1 g: 6-10 ml.

[0015] Preferably, the mass ratio of the amount of base used to the amount of Fmoc-Ile-OH used is 1:0.7-1.6.

[0016] Preferably, the activation reagent is at least one of HATU, PyBOP and TCFH, and the mass ratio of the amount of the activation reagent used to the amount of Fmoc-Ile-OH used is 1:0.5-1.4.

[0017] Preferably, the mass ratio of the amount of H-Aib-OH to the amount of Fmoc-Ile-OH is 1:3-3.5.

[0018] Preferably, the quenching solvent is water.

[0019] Preferably, the impurity-removing solvent is methyl tert-butyl ether.

[0020] Preferably, the extraction solvent is dichloromethane and methyl tert-butyl ether, the volume ratio of the reaction solvent to the extraction solvent is 1:4-6, and the volume ratio of dichloromethane to methyl tert-butyl ether is 1:1.3-1.6.

[0021] Preferably, the reagent used to adjust the pH is a hydrochloric acid solution, which is obtained by combining hydrochloric acid and water, and the usage ratio of hydrochloric acid to water is 1 mol: 0.15-0.2L.

[0022] Preferably, the washing reagents are water and saturated saline.

[0023] Preferably, the drying agent is anhydrous sodium sulfate.

[0024] Preferably, the recrystallization solvent is at least one of petroleum ether / methyl tert-butyl ether, n-heptane / methyl tert-butyl ether, dichloromethane / petroleum ether, and ethyl acetate / petroleum ether systems.

[0025] Preferably, the volume ratio of the reaction solvent to the recrystallization solvent is 1:0.5-1.5.

[0026] The present invention discloses a method for preparing an imidazole derivative, which specifically comprises: First, cuprous iodide and cupric acetate monohydrate are added to dimethyl sulfoxide to dissolve, and then benzylamine, 2-methyl-1,10-phenanthroline and di-tert-butyl peroxide are added, and the reaction is carried out at 100-115° C. for 20-28 hours. The reaction process is monitored by TLC. After the reaction is completed, water and ethyl acetate are added, and then the organic layer is washed. Finally, a crude product is obtained by drying and reducing pressure, and the crude product is purified to obtain an imidazole derivative.

[0027] Preferably, the usage ratio of cuprous iodide to dimethyl sulfoxide is 1 g:35-42 ml.

[0028] Preferably, the usage ratio of cupric acetate monohydrate to dimethyl sulfoxide is 1 g:35-45 ml.

[0029] Preferably, the usage ratio of cuprous iodide to benzylamine is 1 g:1.5-1.9 ml.

[0030] Preferably, the usage ratio of 2-methyl-1,10-phenanthroline to benzylamine is 1 g:4-5 ml.

[0031] Preferably, the volume ratio of di-tert-butyl peroxide to benzylamine is 1:0.8-0.95.

[0032] Preferably, the washing agent is saturated sodium chloride.

[0033] Preferably, the drying agent is anhydrous sodium sulfate.

[0034] Preferably, the purification method is silica gel column chromatography.

[0035] More preferably, in the synthesis process of the key intermediate of telpotide, on the basis of using imidazole derivatives, N,N-bis(hydroxymethyl)-tert-butylamine can be added. The coordinated use of N,N-bis(hydroxymethyl)-tert-butylamine can further promote the activation of amino acids, optimize and promote the subsequent condensation reaction, and improve the yield and purity of the prepared key intermediate of telpotide.

[0036] Preferably, the mass ratio of the amount of N,N-bis(hydroxymethyl)tert-butylamine used to the amount of the imidazole derivative used is 1:5.9-7.

[0037] Compared with the prior art, the present invention has the following beneficial effects: The invention provides a method for synthesizing a key intermediate of telpotide. The method comprises the following steps: firstly mixing Fmoc-Ile-OH and a solvent, then reacting with an activating reagent under the action of a base to obtain an active intermediate, and then performing a condensation reaction on the active intermediate and H-Aib-OH to obtain Fmoc-Ile-Aib-OH, i.e., the key intermediate of telpotide. The key intermediate of telpotide prepared by the invention has a high yield and purity, the yield of the key intermediate of telpotide is greater than 80%, and the purity is greater than 95%, and the synthesis method has fewer reaction steps, which is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the implementation methods of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for the implementation methods or the description of the prior art. Obviously, the drawings in the following description are only exemplary, and for ordinary technicians in this field, other implementation drawings can be derived from the provided drawings without creative work.

[0039] Figure 1 This is a graph showing the yield determination results of Fmoc-Ile-Aib-OH. DETAILED DESCRIPTION

[0040] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0041] The following first describes the concepts involved in the present application in conjunction with the accompanying drawings. It should be noted that the following description of each concept is only to make the content of the present application easier to understand, and does not limit the scope of protection of the present application; at the same time, the embodiments and features in the embodiments of the present application can be combined with each other in the absence of conflict. The present application will be described in detail with reference to the accompanying drawings and in conjunction with the embodiments.

[0042] The abbreviations used in the specification and claims have the following meanings:

[0043] Embodiment 1: Preparation of Fmoc-Ile-Aib-OH: Fmoc-Ile-OH and N,N-dimethylformamide were mixed to obtain a mixed solution. Then, N-methylimidazole and TCFH were added to the mixed solution at 4°C, and the reaction was continued for 1 hour. Then H-Aib-OH was added, and the temperature was raised to 25°C for 4 hours. After the reaction was completed, water and methyl tert-butyl ether were added to quench the reaction and remove impurities, and the aqueous phase was separated. Dichloromethane and methyl tert-butyl ether were added to the aqueous phase, and then hydrochloric acid solution was added to adjust the pH to 3.5, and the organic phase was separated. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain an oil. Dichloromethane and petroleum ether were added to the oil, stirred for crystallization, and the crystals were filtered out and dried to obtain Fmoc-Ile-Aib-OH. The usage ratio of Fmoc-Ile-OH to N,N-dimethylformamide was 1 g:8.49 ml, the mass ratio of N-methylimidazole to Fmoc-Ile-OH was 1:1.43, the mass ratio of TCFH to Fmoc-Ile-OH was 1:1.2, the mass ratio of H-Aib-OH to Fmoc-Ile-OH was 1:3.26, and N,N-dimethylformamide was 1:1. The volume ratio of the amount of amine used to the amount of dichloromethane added to the water phase is 1:2, the volume ratio of the amount of dichloromethane added to the water phase to the amount of methyl tert-butyl ether is 1:1.5, the hydrochloric acid solution is obtained by combining hydrochloric acid and water, and the usage ratio of hydrochloric acid to water is 1 mol:0.17L, the volume ratio of the amount of N,N-dimethylformamide used to the amount of dichloromethane added to the oil is 1:0.1, and the volume ratio of the amount of dichloromethane added to the oil to petroleum ether is 1:8.

[0044] Embodiment 2: Preparation of Fmoc-Ile-Aib-OH: The preparation of Fmoc-Ile-Aib-OH is different from that in Example 1, except that the N-methylimidazole in Example 1 is replaced by N,N-diisopropylethylamine, and the mass ratio of the amount of N,N-diisopropylethylamine used to the amount of Fmoc-Ile-OH used is 1:0.91. Other conditions and parameters are the same as in Example 1.

[0045] Embodiment 3: Preparation of Fmoc-Ile-Aib-OH: The preparation of Fmoc-Ile-Aib-OH is different from that in Example 1, except that N-methylimidazole in Example 1 is replaced by pyridine, and the mass ratio of pyridine to Fmoc-Ile-OH is 1:1.49. Other conditions and parameters are the same as in Example 1.

[0046] Embodiment 4: Preparation of Fmoc-Ile-Aib-OH: The preparation of Fmoc-Ile-Aib-OH was compared with that in Example 1, except that N,N-dimethylformamide in Example 1 was replaced by acetonitrile, the usage ratio of Fmoc-Ile-OH to acetonitrile was 1 g:8.49 ml, and other conditions and parameters were the same as in Example 1.

[0047] Embodiment 5: Preparation of Fmoc-Ile-Aib-OH: The preparation of Fmoc-Ile-Aib-OH was different from that in Example 1, except that the mass ratio of TCFH used to Fmoc-Ile-OH used was 1:1.15, and the other conditions and parameters were the same as in Example 1.

[0048] Embodiment 6: Preparation of Fmoc-Ile-Aib-OH: The preparation of Fmoc-Ile-Aib-OH was different from that in Example 1, except that TCFH in Example 1 was replaced by HATU, and the mass ratio of HATU to Fmoc-Ile-OH was 1:0.71. Other conditions and parameters were the same as in Example 1.

[0049] Embodiment 7: Preparation of Fmoc-Ile-Aib-OH: The preparation of Fmoc-Ile-Aib-OH was compared with that in Example 1, except that TCFH in Example 1 was replaced with PyBOP, the mass ratio of HATU used to Fmoc-Ile-OH used was 1:1.15, and other conditions and parameters were the same as in Example 1.

[0050] Embodiment 8: Preparation of imidazole derivatives: First, cuprous iodide and cupric acetate monohydrate are added to dimethyl sulfoxide to obtain a solution, benzylamine, 2-methyl-1,10-phenanthroline and di-tert-butyl peroxide are added to the solution, the temperature is raised to 105°C for reaction for 24 hours, and the reaction process is monitored by TLC. After the reaction is completed, water and ethyl acetate are added, the organic layer is washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and finally treated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain an imidazole derivative. The ratio of cuprous iodide to dimethyl sulfoxide is 1g:39ml, the ratio of cupric acetate monohydrate to dimethyl sulfoxide is 1g:38ml, the ratio of cuprous iodide to benzylamine is 1g:1.72ml, the ratio of 2-methyl-1,10-phenanthroline to benzylamine is 1g:4.37ml, and the volume ratio of di-tert-butyl peroxide to benzylamine is 1:0.89.

[0051] Preparation of Fmoc-Ile-Aib-OH: Fmoc-Ile-OH and N,N-dimethylformamide are mixed to obtain a mixed solution. Then, imidazole derivatives and TCFH are added to the mixed solution at 4°C, and the reaction is continued for 1 hour. Then H-Aib-OH is added, and the temperature is raised to 25°C for reaction for 4 hours. After the reaction is completed, water and methyl tert-butyl ether are added to quench the reaction and remove impurities, and the aqueous phase is separated. Dichloromethane and methyl tert-butyl ether are added to the aqueous phase, and then hydrochloric acid solution is added to adjust the pH to 3.5, and the organic phase is separated. The organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain an oily substance. Dichloromethane and petroleum ether are added to the oily substance to stir and crystallize, and the crystals are filtered out and dried to obtain Fmoc-Ile-Aib-OH. The usage ratio of Fmoc-Ile-OH to N,N-dimethylformamide was 1 g:8.49 ml, the mass ratio of the usage of imidazole derivative to the usage of Fmoc-Ile-OH was 1:1.43, the mass ratio of the usage of TCFH to the usage of Fmoc-Ile-OH was 1:1.2, the mass ratio of the usage of H-Aib-OH to the usage of Fmoc-Ile-OH was 1:3.26, and N,N-dimethylformamide was 1:1. The volume ratio of the amount of amine used to the amount of dichloromethane added to the water phase is 1:2, the volume ratio of the amount of dichloromethane added to the water phase to the amount of methyl tert-butyl ether is 1:1.5, the hydrochloric acid solution is obtained by combining hydrochloric acid and water, and the usage ratio of hydrochloric acid to water is 1 mol:0.17L, the volume ratio of the amount of N,N-dimethylformamide used to the amount of dichloromethane added to the oil is 1:0.1, and the volume ratio of the amount of dichloromethane added to the oil to petroleum ether is 1:8.

[0052] Embodiment 9: The preparation of imidazole derivatives is the same as in Example 8.

[0053] Preparation of Fmoc-Ile-Aib-OH: Fmoc-Ile-OH and N,N-dimethylformamide are mixed to obtain a mixed solution. Then, imidazole derivatives, N,N-bis(hydroxymethyl)tert-butylamine and TCFH are added to the mixed solution at 4°C, and the reaction is continued for 1 hour. Then H-Aib-OH is added, and the temperature is raised to 25°C for reaction for 4 hours. After the reaction is completed, water and methyl tert-butyl ether are added to quench the reaction and remove impurities, and the aqueous phase is separated. Dichloromethane and methyl tert-butyl ether are added to the aqueous phase, and then hydrochloric acid solution is added to adjust the pH to 3.5, and the organic phase is separated. The organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain an oily substance. Dichloromethane and petroleum ether are added to the oily substance to stir and crystallize, and the crystals are filtered out and dried to obtain Fmoc-Ile-Aib-OH. The usage ratio of Fmoc-Ile-OH to N,N-dimethylformamide is 1g:8.49ml, the usage ratio of imidazole derivative to Fmoc-Ile-OH is 1:1.43, the usage ratio of N,N-bis(hydroxymethyl)tert-butylamine to imidazole derivative is 1:6.67, the usage ratio of TCFH to Fmoc-Ile-OH is 1:1.2, the usage ratio of H-Aib-OH to Fmoc-Ile-OH is 1:1.3, the usage ratio of N,N-bis(hydroxymethyl)tert-butylamine to Fmoc-Ile-OH is 1:1.6 ... N,N-bis(hydroxymethyl)tert-butylamine to Fmoc-Ile-OH is 1:1.6 The ratio is 1:3.26, the volume ratio of N,N-dimethylformamide used and the amount of dichloromethane added to the aqueous phase is 1:2, the volume ratio of dichloromethane added to the aqueous phase and methyl tert-butyl ether is 1:1.5, the hydrochloric acid solution is obtained by combining hydrochloric acid and water, the dosage ratio of hydrochloric acid to water is 1 mol:0.17L, the volume ratio of N,N-dimethylformamide used and the amount of dichloromethane added to the oil is 1:0.1, and the volume ratio of dichloromethane added to the oil to petroleum ether is 1:8.

[0054] Embodiment 10: Preparation of Fmoc-Ile-Aib-OH: The preparation of Fmoc-Ile-Aib-OH was different from that in Example 8, except that no imidazole derivative was used. Other conditions and parameters were the same as in Example 8.

[0055] Embodiment 11: The preparation of imidazole derivatives is the same as in Example 8.

[0056] Preparation of Fmoc-Ile-Aib-OH: The preparation of Fmoc-Ile-Aib-OH is different from that in Example 8, except that the mass ratio of the amount of imidazole derivative used to the amount of Fmoc-Ile-OH used is 1:1.1, and the other conditions and parameters are the same as in Example 8.

[0057] Embodiment 12: The preparation of imidazole derivatives is the same as in Example 8.

[0058] Preparation of Fmoc-Ile-Aib-OH: The preparation of Fmoc-Ile-Aib-OH is different from that in Example 9, except that the mass ratio of the amount of N,N-bis(hydroxymethyl)tert-butylamine used to the amount of the imidazole derivative used is 1:6.1, and the other conditions and parameters are the same as in Example 9.

[0059] Comparative Example 1: The preparation of imidazole derivatives is the same as in Example 8.

[0060] Preparation of Fmoc-Ile-Aib-OH: The preparation of Fmoc-Ile-Aib-OH was compared with that in Example 8, except that the mass ratio of the amount of the imidazole derivative used to the amount of Fmoc-Ile-OH used was 1:4, and the other conditions and parameters were the same as in Example 8.

[0061] Experimental Example 1: Determination of yield: The Fmoc-Ile-Aib-OH prepared in Examples 1-12 and Comparative Example 1 was statistically calculated to obtain the yield.

[0062] The results are as follows Figure 1As shown, compared with Example 2, Example 1 of the present invention shows that replacing N-methylimidazole with N,N-diisopropylethylamine as a base in the reaction process will reduce the yield of Fmoc-Ile-Aib-OH; compared with Example 3, Example 1 shows that replacing N-methylimidazole with pyridine will also reduce the yield of Fmoc-Ile-Aib-OH; compared with Example 4, Example 1 shows that compared with acetonitrile, N,N-dimethylformamide as a reaction solvent has a better effect, that is, it has a higher yield of Fmoc-Ile-Aib-OH; compared with Example 5, Example 1 shows that the reduction in the amount of TCFH used will reduce the yield of Fmoc-Ile-Aib-OH; compared with Examples 6 and 7, Example 1 shows that TCFH has a better effect than HATU and PyBOP, and the yield of Fmoc-Ile-Aib-OH is higher; compared with Example 8, Example 1 shows that the imidazole derivative The use of can improve the yield of Fmoc-Ile-Aib-OH; Example 8 compared with Example 10 shows that without the use of imidazole derivatives, the yield of Fmoc-Ile-Aib-OH will be inhibited; Example 8 compared with Example 11 shows that within a certain range, the increase in the amount of imidazole derivatives used can improve the yield of Fmoc-Ile-Aib-OH; Example 8 compared with Example 9 shows that on the basis of the use of imidazole derivatives, N,N-bis(hydroxymethyl)-tert-butylamine is added, and the use of both together can further improve the yield of Fmoc-Ile-Aib-OH; Example 9 compared with Example 12 shows that within a certain range, the increase in the amount of N,N-bis(hydroxymethyl)-tert-butylamine used can improve the yield of Fmoc-Ile-Aib-OH; Example 8 compared with Comparative Example 1 shows that the amount of imidazole derivatives used needs to be within a certain range, and if the amount is small, the yield of Fmoc-Ile-Aib-OH will be inhibited.

[0063] Experimental Example 2: Purity determination: The Fmoc-Ile-Aib-OH prepared in Examples 1-12 and Comparative Example 1 was subjected to HPLC analysis to obtain the purity.

[0064] Table 1 Purity determination results of Fmoc-Ile-Aib-OH

[0065] The results are shown in Table 1. Compared with Example 2, Example 1 of the present invention shows that replacing N-methylimidazole with N,N-diisopropylethylamine as a base in the reaction process will reduce the purity of Fmoc-Ile-Aib-OH; compared with Example 3, Example 1 shows that replacing N-methylimidazole with pyridine will also reduce the purity of Fmoc-Ile-Aib-OH; compared with Example 4, Example 1 shows that compared with acetonitrile, N,N-dimethylformamide is used as a reaction solvent, and the prepared Fmoc-Ile-Aib-OH has higher purity; compared with Example 5, Example 1 shows that the reduction in the amount of TCFH used will reduce the purity of Fmoc-Ile-Aib-OH; compared with Examples 6 and 7, Example 1 shows that TCFH has a better effect than HATU and PyBOP, and the purity of Fmoc-Ile-Aib-OH is higher; compared with Example 8, Example 1 shows that the purity of imidazole derivatives The purity of Fmoc-Ile-Aib-OH can be improved by using the imidazole derivatives; Example 8, compared with Example 10, indicates that without using the imidazole derivatives, the purity of Fmoc-Ile-Aib-OH will be inhibited; Example 8, compared with Example 11, indicates that within a certain range, the increase in the amount of imidazole derivatives used can improve the purity of Fmoc-Ile-Aib-OH; Example 8, compared with Example 9, indicates that on the basis of using the imidazole derivatives, N,N-bis(hydroxymethyl)-tert-butylamine is added, and the use of the two together can further improve the purity of Fmoc-Ile-Aib-OH; Example 9, compared with Example 12, indicates that within a certain range, the increase in the amount of N,N-bis(hydroxymethyl)-tert-butylamine used can improve the purity of Fmoc-Ile-Aib-OH; Example 8, compared with Comparative Example 1, indicates that the amount of imidazole derivatives used needs to be within a certain range, and if the amount is small, the purity of Fmoc-Ile-Aib-OH will be inhibited.

[0066] The embodiments and / or implementation methods described above are only used to illustrate the preferred embodiments and / or implementation methods for realizing the technology of the present invention, and are not intended to limit the implementation methods of the technology of the present invention in any form. Any technical personnel in this field may make slight changes or modifications to other equivalent embodiments without departing from the scope of the technical means disclosed in the content of the present invention, but they should still be regarded as technologies or embodiments that are essentially the same as the present invention.

[0067] This article uses specific examples to illustrate the principles and implementation methods of this application. The description of the above embodiments is only used to help understand the method and its core ideas of this application. The above is only the preferred implementation method of this application. It should be pointed out that due to the limitations of textual expression and the objective existence of infinite specific structures, ordinary technicians in this technical field can make several improvements, modifications or changes without departing from the principles of this application, and can also combine the above technical features in an appropriate manner; these improvements, modifications, changes or combinations, or the direct application of the concept and technical solution of the invention to other occasions without improvement, should be regarded as the scope of protection of this application.

Claims

1. A method for synthesizing a key intermediate of tepote, comprising: First, Fmoc-Ile-OH and a reaction solvent are mixed, and then reacted with an activation reagent under the action of a base to obtain an active intermediate, and the active intermediate is then subjected to a condensation reaction with H-Aib-OH to obtain Fmoc-Ile-Aib-OH, i.e., a key intermediate of telpotide; the base is at least one of N,N-diisopropylethylamine, N-methylimidazole, pyridine and an imidazole derivative; the imidazole derivative is prepared by reacting benzylamine, 2-methyl-1,10-phenanthroline and 2-methyl-3-phenylpyridine.

2. The method for synthesizing a key intermediate of telpotide according to claim 1, characterized in that: The reaction solvent is at least one of N,N-dimethylformamide, acetonitrile and dichloromethane, and the usage ratio of Fmoc-Ile-OH to the reaction solvent is 1g:6-10ml.

3. The method for synthesizing a key intermediate of telpotide according to claim 1, characterized in that: The mass ratio of the amount of the base used to the amount of Fmoc-Ile-OH used is 1:0.7-1.

6.

4. The method for synthesizing a key intermediate of telpotide according to claim 1, characterized in that: The activation reagent is at least one of HATU, PyBOP and TCFH, and the mass ratio of the amount of the activation reagent used to the amount of Fmoc-Ile-OH used is 1:0.5-1.

4.

5. The method for synthesizing a key intermediate of telpotide according to claim 1, characterized in that: The mass ratio of the amount of H-Aib-OH used to the amount of Fmoc-Ile-OH used is 1:3-3.

5.

6. The method for synthesizing a key intermediate of telpotide according to claim 1, characterized in that: The reaction temperature of the reaction with the activation reagent under the action of the base is 0-5°C, and the reaction time is 0.8-1.5h.

7. The method for synthesizing a key intermediate of telpotide according to claim 1, characterized in that: The reaction temperature of the condensation reaction is 23-27° C., and the reaction time is 3-5 h.

8. The key intermediate of telpotide synthesized by the method according to any one of claims 1 to 7.

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