Synthetic method of alpinia oxyphylla dipeptide
By adopting the purification steps of organic solvent A and condensation agent, as well as Lewis acid system and ionic liquid recrystallization in the synthesis of nootropics dipeptide, the problems of low purity and yield of nootropics dipeptide are solved, the synthesis of nootropics dipeptide with high purity and high yield is achieved, the production cost is reduced and the controllability of the synthesis steps is improved.
Patent Information
- Application Number
- CN202510806045.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-17
- Publication Date
- 2025-09-26
AI Technical Summary
The current synthesis process of nootropic dipeptides has low purity and poor yield, resulting in inaccurate experimental results and reduced biological activity.
The coupling and deprotection operations are carried out sequentially from the C-terminus to the N-terminus, and the intermediate is purified using an organic solvent A and a condensing agent. The purity of the intermediate is gradually improved by combining a Lewis acid system and ionic liquid recrystallization. Finally, the intermediate is purified by recrystallization using a composite solution of organic solvent B and ionic liquid.
The synthesis of high-purity (≥99%) and high-yield alpinia dipeptide was achieved, which reduced production costs and improved the controllability and repeatability of the synthesis steps.
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Abstract
Description
Technical Field
[0001] The invention belongs to a method for synthesizing a polypeptide, and in particular relates to a method for synthesizing a nootropic dipeptide. Background Art
[0002] Peptides are compounds composed of two or more amino acids linked by peptide bonds. The solid-phase synthesis method for peptides, introduced in 1963, has rapidly developed due to its advantages, including ease of operation and ease of synthesizing long-chain peptides, while also enriching the peptide library. However, solid-phase peptide synthesis relies on a support, such as a resin, and is a heterogeneous reaction system. The synthesis process consumes significant amounts of amino acids, coupling reagents, and organic reagents, resulting in higher costs than liquid-phase synthesis.
[0003] Nootropics is a neuropeptide compound developed by researchers at Washington State University. It is primarily used as a neuroprotectant and memory enhancer. Currently, the prevalent synthesis process for Nootropics produces Nootropics with low purity and yield. However, Nootropics require high purity in experiments and applications. Low-purity Nootropics can lead to inaccurate results, reduced biological activity, and poor reproducibility.
[0004] Based on this, a new synthesis method of nootropics dipeptide is studied to improve its purity and yield. Summary of the Invention
[0005] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for synthesizing a high-purity and high-yield nootropic dipeptide.
[0006] Technical solution: The method for synthesizing the nootropic dipeptide of the present invention comprises the following steps:
[0007] (1) In the presence of an organic solvent A and a condensing agent, Fmoc-Ile-OH and H-Acp-NH2 undergo a coupling reaction. After the solid product precipitates, it is washed and purified with water and organic solvent A, and dried to obtain Fmoc-Ile-Acp-NH2;
[0008] (2) Fmoc-Ile-Acp-NH2 is added to organic solvent A, and an organic base is added to remove Fmoc protection to obtain H-Ile-Acp-NH2. After complete deprotection, the H-Ile-Acp-NH2 is washed with water and purified, and the organic layer is retained;
[0009] (3) In the presence of organic solvent A and a condensing agent, Fmoc-Tyr(tBu)-OH and H-Ile-Acp-NH2 undergo a coupling reaction. After the solid product precipitates, it is washed and purified with water and organic solvent A, and dried to obtain Fmoc-Tyr(tBu)-Ile-Acp-NH2;
[0010] (4) Fmoc-Tyr(tBu)-Ile-Acp-NH2 is added to organic solvent A, and an organic base is added to remove the Fmoc protection to obtain H-Tyr(tBu)-Ile-Acp-NH2. After the deprotection is complete, the product is washed with water and the organic layer is retained;
[0011] (5) n-hexanoic acid and H-Tyr(tBu)-Ile-Acp-NH2 undergo a coupling reaction in the presence of an organic solvent A and a condensing agent. After the solid product precipitates, it is washed and purified with water and an organic solvent A, and then dried to obtain Hexanoyl-Tyr(tBu)-Ile-Acp-NH2;
[0012] (6) The protecting group tBu of Hexanoyl-Tyr(tBu)-Ile-Acp-NH2 is cleaved by a Lewis acid system, and then precipitated in a precipitation solvent to obtain a crude nootropic dipeptide Hexanoyl-Tyr-Ile-Acp-NH2;
[0013] (7) The crude product of the nootropic dipeptide is recrystallized in a composite solution consisting of an organic solvent B and an ionic liquid, and the refined nootropic dipeptide is obtained after drying.
[0014] The present invention uses H-Acp-NH2, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and n-hexanoic acid as raw materials, and adopts a coupling and deprotection operation from the C-terminus to the N-terminus in sequence to finally synthesize the fully protected peptide Hexanoyl-Tyr(tBu)-Ile-Acp-NH2. In the process of sequential cyclic coupling, organic solvent A and condensing agent are used for condensation coupling. In this process, impurities generated in each step of the reaction can be washed and removed by water and organic solvent A, so that a high-purity polysaccharide dipeptide intermediate can be obtained in each step; and based on the high-purity polysaccharide dipeptide intermediate obtained in the previous step, the reaction of the next step can be promoted to proceed in the forward direction, thereby obtaining a crude polysaccharide dipeptide with relatively high purity and yield. Finally, under the combined conditions of organic solvent B and ionic liquid, recrystallization is carried out and purified again to obtain a high-purity fine polysaccharide dipeptide.
[0015] Furthermore, in steps (1) to (5) of the synthesis method of the present invention, the molar ratio of the added amounts of Fmoc-Ile-OH, H-Acp-NH2, Fmoc-Tyr(tBu)-OH, and n-hexanoic acid is 1:(1-3):(0.9-2):(0.8-1.5), preferably 1:1.2:0.94:0.93.
[0016] Furthermore, the organic solvent A used in the synthesis method of the present invention can be one or more of ethyl acetate, tetrahydrofuran, acetonitrile, 1,2-dichloroethane, and toluene. Preferably, the organic solvent A can be ethyl acetate or 1,2-dichloroethane.
[0017] Furthermore, the condensing agent used in the synthesis method of the present invention is one or more of EDC·HCl, TBTU, PyBop, HOBt, DCC, and DIC. Preferably, the condensing agent is HOBt and EDC·HCl, and the molar ratio of the two is 1:(0.5-2). More preferably, the condensing agent is HOBt and EDC·HCl, and the molar ratio of the two is 1:(0.9-1.1).
[0018] Furthermore, in step (1), step (3) and step (5) of the synthesis method of the present invention, the coupling reaction temperature is 20-60° C., and the coupling reaction time is 2-5 h.
[0019] Furthermore, the organic base in the synthesis method of the present invention is any one or more of diethylamine, piperidine, triethylamine and piperazine.
[0020] Furthermore, the Lewis acid system used in the synthesis method of the present invention is a composite system of Lewis acid and NaI, wherein the Lewis acid is one or more of FeCl3, AlCl3, CeCl3·7H2O, and TiCl4, and the precipitation solvent is one or more of isopropyl ether, methyl tert-butyl ether, diethyl ether, and petroleum ether.
[0021] Furthermore, the molar ratio of the fully protected nootropic dipeptide to the Lewis acid system used in the synthesis method of the present invention is 1:(2-5).
[0022] Furthermore, the organic solvent B used in the synthesis method of the present invention is one of methanol and 1,2-dichloroethane; and the ionic liquid is 1,3-dimethylimidazole bis(trifluoromethanesulfonamide).
[0023] Beneficial effects: Compared with the prior art, the significant advantages of the present invention are: the production cost of the synthesis method is low, the atom economy utilization rate is high, the yield of the obtained product is high and the product purity is high, and the purity of the nootropic dipeptide is ≥99%; and the production steps of the present invention are controllable and highly reproducible; the high-purity intermediate product ensures that the reaction conversion rate can be carried out with certainty. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 This is the mass spectrum of the finished product of the nootropic dipeptide prepared in Example 2 of the present invention;
[0025] Figure 2 This is the liquid phase spectrum of the finished product of the nootropic dipeptide prepared in Example 2 of the present invention. DETAILED DESCRIPTION
[0026] The technical solution of the present invention is further described in detail below with reference to the embodiments and drawings.
[0027] The synthesis mechanism of the nootropic dipeptide of the present invention is as follows.
[0028]
[0029] The chemical names and CAS numbers of the raw materials used in this invention are listed in Table 1. During the experiments, an Agilent 1260 Infinity II HPLC system was used to monitor the reaction completion. The amounts of organic solvent A, condensing agent, organic base, precipitation solvent, and composite solution used in the examples of this invention were selected to achieve sufficient dissolution or reaction.
[0030] Table 1
[0031] Abbreviations Chemical name CAS number <![CDATA[H-Acp-NH2]]> 6-aminocaproamide 60-32-2 Fmoc-Ile-OH Fmoc-L-isoleucine 71989-23-6 Fmoc-Tyr(tBu)-OH Fmoc-O-tert-Butyl-L-tyrosine 71989-38-3 EDC·HCl 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride 25952-53-8 TBTU O-Benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborane 125700-67-6 PyBop Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate 128625-52-5 HOBT 1-Hydroxybenzotriazole 2592-95-2 DCC N,N'-Dicyclohexylcarbodiimide 538-75-0 DIC N,N'-Diisopropylcarbodiimide 693-13-0
[0032] Example 1
[0033] In the process of preparing the nootropic dipeptide in this embodiment, the organic solvent A is preferably ethyl acetate; the condensing agent is preferably HOBt and EDC·HCl, and the molar ratio of the two is 1:1; the organic base is piperidine; the Lewis acid system is preferably FeCl3·6H2O and NaI; the settling solvent is methyl tert-butyl ether; and the organic solvent B is preferably 1,2-dichloroethane. Specifically, the following steps are included:
[0034] (1) Preparation process of Fmoc-Ile-Acp-NH2
[0035] Weigh 1 kg of Fmoc-Ile-OH, 652 g of EDC·HCl, and 460 g of HOBt and add them sequentially to 10 L of ethyl acetate. Control the internal temperature at 40°C. Stir for 30 minutes, then add 442 g of H-Acp-NH2. Maintain the internal temperature and continue stirring for 2 hours. HPLC monitoring indicates that the Fmoc-Ile-OH reaction is complete, with a large amount of white solid precipitating as the reaction proceeds.
[0036] After filtration, the solid was washed twice with 5% aqueous hydrochloric acid solution, twice with purified water, and twice with ethyl acetate. The solid was dried in vacuo at 50°C to obtain 1239 g of Fmoc-Ile-Acp-NH2 as an off-white solid with a molar yield of 94.07%.
[0037] (2) Preparation process of H-Ile-Acp-NH2
[0038] The Fmoc-Ile-Acp-NH2 obtained in step (1) was added to 10 L of ethyl acetate and stirred at room temperature until it formed a slurry. 2 L of piperidine was added and stirred at room temperature until the reaction solution became clear from turbidity. After 1 hour, HPLC analysis showed that the deprotection was complete. The product was then washed with 1% aqueous hydrochloric acid three times and saturated brine twice, and the organic layer was retained to obtain H-Ile-Acp-NH2.
[0039] (3) Preparation process of Fmoc-Tyr(tBu)-Ile-Acp-NH2
[0040] 1223 g of Fmoc-Tyr(tBu)-OH, 613 g of EDC·HCl and 432 g of HOBt were weighed and added to the organic layer of step (2). The internal temperature was controlled at 50° C. and the reaction was stirred for 2 hours. HPLC monitoring showed that the reaction of H-Ile-Acp-NH2 was complete and a large amount of white solid precipitated as the reaction proceeded.
[0041] After filtration, the solid was washed twice with 5% aqueous hydrochloric acid solution, twice with purified water, and twice with ethyl acetate. The solid was dried in vacuo at 50°C to obtain 1688 g of Fmoc-Tyr(tBu)-Ile-Acp-NH2 as an off-white solid with a molar yield of 92.64%.
[0042] (4) Preparation process of H-Tyr(tBu)-Ile-Acp-NH2
[0043] The Fmoc-Tyr(tBu)-Ile-Acp-NH2 from step (3) was added to 10 L of ethyl acetate and stirred at room temperature to form a slurry. 2 L of piperidine was added and stirred at room temperature until the reaction solution turned from turbid to clear. After 1 hour, HPLC monitoring confirmed that the deprotection was complete.
[0044] The product was then washed with 1% aqueous hydrochloric acid solution three times and saturated brine twice, and the organic layer was retained to obtain H-Tyr(tBu)-Ile-Acp-NH2.
[0045] (5) Preparation process of Hexanoyl-Tyr(tBu)-Ile-Acp-NH2
[0046] 305 g of n-hexanoic acid, 604 g of EDC·HCl and 426 g of HOBt were weighed and added to the organic layer of step (4). The internal temperature was controlled at 50° C. and the reaction was stirred for 2 hours. HPLC monitoring showed that the reaction of H-Tyr(tBu)-Ile-Acp-NH2 was complete, and a large amount of white solid precipitated as the reaction proceeded.
[0047] After filtration, the solid was washed twice with 5% aqueous hydrochloric acid solution, twice with purified water, twice with 10% aqueous sodium carbonate solution, twice with purified water, and twice with ethyl acetate / petroleum ether (1 / 1 volume ratio). The solid was then dried in vacuo at 50°C to obtain 1276 g of Hexanoyl-Tyr(tBu)-Ile-Acp-NH2 as an off-white solid with a molar yield of 92.35%.
[0048] (6) Cleavage process of Hexanoyl-Tyr(tBu)-Ile-Acp-NH2
[0049] Add 1276 g of Hexanoyl-Tyr(tBu)-Ile-Acp-NH2 to 14 L of methanol, add 1.9 kg of FeCl3·6H2O and 1 kg of NaI, stir and react at room temperature for 2 hours, filter to remove insoluble matter, and retain the mother liquor.
[0050] The mother liquor was slowly poured into 60 L of stirred methyl tert-butyl ether to precipitate a large amount of white solid. The crude product of nootropic dipeptide was obtained by suction filtration, washed twice with purified water, and dried.
[0051] (7) Recrystallization process of nootropic dipeptide
[0052] Use 3L of 1,2-dichloroethane and 500ml of 1,3-dimethylimidazole bis(trifluoromethanesulfonamide) salt to heat to 50°C to completely dissolve the crude product, then stir and cool to 0°C, and a large amount of white solid precipitates; keep warm at 0-5°C, continue stirring for 1 hour, filter, rinse with petroleum ether; vacuum dry at 50°C to obtain 1010g of fine-quality nootropic dipeptide, which is a white solid powder after pulverization, with a molar yield of 88%.
[0053] The total yield of the Nootropics dipeptide in this example is 70.8% and the purity is 99.2%. The molecular weight of the Nootropics dipeptide is MW=504, [MW+H] + =505, [MW+Na] + =527.
[0054] Example 2
[0055] In the process of preparing the nootropic dipeptide in this embodiment, the organic solvent A is preferably 1,2-dichloroethane; the condensing agent is selected as HOBt and EDC·HCl, and the molar ratio of the two is 1:1; the organic base is selected as diethylamine; the Lewis acid system is selected as CeCl3·7H2O and NaI; the settling solvent is selected as diethyl ether; and the organic solvent B is selected as methanol. The specific preparation method includes the following steps:
[0056] (1) Preparation process of Fmoc-Ile-Acp-NH2
[0057] 1 kg of Fmoc-Ile-OH, 652 g of EDC·HCl, and 460 g of HOBt were weighed and added sequentially to 10 L of 1,2-dichloroethane. The internal temperature was controlled at 40°C, and after stirring for 30 min, 442 g of H-Acp-NH2 was added. The internal temperature was maintained and the reaction was stirred for 2 hours. HPLC monitoring indicated that the reaction of Fmoc-Ile-OH was complete, and a large amount of white solid precipitated as the reaction proceeded.
[0058] After filtration, the solid was washed twice with 5% aqueous hydrochloric acid solution, twice with purified water, and twice with 1,2-dichloroethane. The solid was dried in vacuo at 50° C. to obtain 1250 g of an off-white solid Fmoc-Ile-Acp-NH 2 with a molar yield of 94.91%.
[0059] (2) Preparation process of H-Ile-Acp-NH2
[0060] The Fmoc-Ile-Acp-NH2 prepared in step (1) was added to 10 L of 1,2-dichloroethane and stirred at room temperature to form a slurry. 981 g of diethylamine was added and stirred at room temperature until the reaction solution turned from turbid to clear. After 1 hour, the deprotection was complete as monitored by HPLC.
[0061] The product was washed twice with 1% aqueous hydrochloric acid solution and four times with saturated brine, and the organic layer was retained to obtain H-Ile-Acp-NH2.
[0062] (3) Preparation process of Fmoc-Tyr(tBu)-Ile-Acp-NH2
[0063] 1234 g of Fmoc-Tyr(tBu)-OH, 618 g of EDC·HCl and 436 g of HOBt were weighed and added to the organic layer of step (2). The internal temperature was controlled at 50° C. and the reaction was stirred for 2 hours. HPLC monitoring showed that the reaction of H-Ile-Acp-NH2 was complete, and a large amount of white solid precipitated as the reaction proceeded.
[0064] After filtration, the solid was washed twice with 5% aqueous hydrochloric acid solution, twice with purified water, and twice with 1,2-dichloroethane. The solid was vacuum dried at 50°C to obtain 1700 g of an off-white solid Fmoc-Tyr(tBu)-Ile-Acp-NH2 with a molar yield of 92.49%.
[0065] (4) Preparation process of H-Tyr(tBu)-Ile-Acp-NH2
[0066] The Fmoc-Tyr(tBu)-Ile-Acp-NH2 prepared in step (3) was added to 10 L of 1,2-dichloroethane and stirred at room temperature to form a slurry. 981 g of diethylamine was added and stirred at room temperature until the reaction solution turned from turbid to clear. After 1 hour, the deprotection was complete as monitored by HPLC.
[0067] The mixture was then washed twice with a 1% aqueous hydrochloric acid solution and four times with saturated brine, and the organic layer was retained to obtain H-Tyr(tBu)-Ile-Acp-NH2.
[0068] (5) Preparation process of Hexanoyl-Tyr(tBu)-Ile-Acp-NH2
[0069] 312 g of n-hexanoic acid, 618 g of EDC·HCl, and 436 g of HOBt were weighed and added to the organic layer of step (4). The internal temperature was controlled at 50° C. and the reaction was stirred for 2 hours. HPLC monitoring showed that the reaction of H-Tyr(tBu)-Ile-Acp-NH2 was complete, and a large amount of white solid precipitated as the reaction proceeded.
[0070] After filtration, the solid was washed twice with 5% aqueous hydrochloric acid solution, twice with purified water, twice with 10% aqueous sodium carbonate solution, twice with purified water, and twice with 1,2-dichloroethane / petroleum ether (1 / 1 volume ratio). The solid was then dried in vacuo at 50°C to obtain 1308 g of an off-white solid Hexanoyl-Tyr(tBu)-Ile-Acp-NH2 with a molar yield of 94.02%.
[0071] (6) Cleavage process of Hexanoyl-Tyr(tBu)-Ile-Acp-NH2
[0072] Add 1308 g of Hexanoyl-Tyr(tBu)-Ile-Acp-NH2 to 14 L of methanol, add 2.6 kg of CeCl3·7H2O and 1 kg of NaI, and stir at room temperature for 2 hours. Filter to remove insoluble matter and retain the mother liquor.
[0073] The mother liquor was slowly poured into 60 L of stirred ether to precipitate a large amount of white solid. The crude product of the nootropic dipeptide was obtained by suction filtration, and the crude product was washed twice with purified water and dried.
[0074] (7) Purification process of nootropic dipeptide
[0075] The crude product was completely dissolved in 3L of methanol and 300mL of 1,3-dimethylimidazole bis(trifluoromethanesulfonamide) at 50°C. The mixture was then cooled to 0°C with stirring, resulting in the precipitation of a large amount of white solid. The mixture was maintained at 0-5°C and stirred for 1 hour before filtration and rinsing with petroleum ether. The mixture was then dried under vacuum at 50°C to yield 1063g of the finely crafted nootropic dipeptide. The product, after pulverization, was a white solid powder with a molar yield of 90.33%.
[0076] The total yield of the finished product in this embodiment is 74.55%, and the purity is 99.86%; and the mass spectrum of the polysaccharide dipeptide is as follows: Figure 1 As shown, the liquid phase spectrum is as Figure 2 As shown; the molecular weight of the nootropic dipeptide MW = 504, [MW + H] + =505, [MW+Na] + =527.
[0077] Comparative Example 1
[0078] The method for preparing the nootropic dipeptide in this comparative example is basically the same as that in Example 2, except that the organic solvent B and the ionic liquid are different. In this comparative example, the organic solvent B used in the purification process of the nootropic dipeptide is ethanol, and the ionic liquid used is 1-ethyl-3-methylimidazolium hexafluorophosphate. The purification method of the nootropic dipeptide is as follows:
[0079] (7) Purification process of nootropic dipeptide
[0080] The crude product was completely dissolved in 10L of ethanol and 1L of 1-ethyl-3-methylimidazolium hexafluorophosphate at 50°C, then cooled to 0°C with stirring. A large amount of white solid precipitated. The mixture was kept at 0-5°C and stirred for 1 hour before filtration and rinsing with petroleum ether. 1165g of fine-quality nootropic dipeptide was obtained by vacuum drying at 50°C. The product was pulverized into a white solid powder. The molar yield of nootropic dipeptide in this step of its purification was 98.9%, and its purity was 96.5%. The crystal purity was unqualified.
[0081] In the present invention, methanol and 1,3-dimethylimidazole bis(trifluoromethanesulfonamide) salt are preferably used in combination to recrystallize and purify the nootropic dipeptide. The solubility of the nootropic dipeptide in methanol is limited. After the addition of 1,3-dimethylimidazole bis(trifluoromethanesulfonamide) salt, the nootropic dipeptide forms hydrogen bonds and ion-dipole interactions with the nootropic dipeptide, thereby increasing the solubility of the nootropic dipeptide in methanol. With the combination of the two, the dissolved nootropic dipeptide precipitates and is crystallized and purified after the temperature drops. In Comparative Example 1, the solubility of the 1-ethyl-3-methylimidazole hexafluorophosphate ionic liquid in ethanol is reduced. During the cooling process, impurities are precipitated together with the nootropic dipeptide, resulting in the inability to remove impurities such as deprotected groups, thereby reducing the purity of the nootropic dipeptide.
[0082] In addition to the above embodiments, it should be noted that the organic solvent A can be one or more of ethyl acetate, tetrahydrofuran, acetonitrile, 1,2-dichloroethane, and toluene; the condensing agent can be one or more of EDC·HCl, TBTU, PyBop, HOBt, DCC, and DIC, and if the condensing agent is HOBt and EDC·HCl, the molar ratio of the two can be 1:(0.5-2), and the effect is best when the molar ratio of the two is 1:1; in steps (1), (3), and (5), the coupling reaction temperature can be 20-60°C, and the coupling reaction time can be 0-5h; the organic base can be any one or more of triethylamine and piperazine; the Lewis acid can be AlCl3, TiCl4, and the sedimentation solvent can be one or more of isopropyl ether, methyl tert-butyl ether, ether, and petroleum ether; the molar ratio of the fully protected nootropic dipeptide and the Lewis acid can be 1:(2-5), and the optimal molar ratio of the two is 1:3. The technical effects claimed in the present invention can be achieved by adopting the preparation process of the present invention and the specified parameter range, and therefore no further examples are given for verification.
Claims
1. A method for synthesizing a nootropic dipeptide, characterized in that: The following steps are involved: (1) In the presence of an organic solvent A and a condensing agent, Fmoc-Ile-OH and H-Acp-NH2 undergo a coupling reaction. After the solid product precipitates, it is washed and purified with water and organic solvent A, and dried to obtain Fmoc-Ile-Acp-NH2; (2) Fmoc-Ile-Acp-NH2 is added to organic solvent A, and an organic base is added to remove Fmoc protection to obtain H-Ile-Acp-NH2. After complete deprotection, the H-Ile-Acp-NH2 is washed and purified with water, and the organic layer is retained; (3) In the presence of organic solvent A and a condensing agent, Fmoc-Tyr(tBu)-OH and H-Ile-Acp-NH2 undergo a coupling reaction. After the solid product precipitates, it is washed and purified with water and organic solvent A, and dried to obtain Fmoc-Tyr(tBu)-Ile-Acp-NH2; (4) Fmoc-Tyr(tBu)-Ile-Acp-NH2 is added to organic solvent A, and an organic base is added to remove the Fmoc protection to obtain H-Tyr(tBu)-Ile-Acp-NH2. After the deprotection is complete, the product is washed with water and the organic layer is retained; (5) n-hexanoic acid and H-Tyr(tBu)-Ile-Acp-NH2 undergo a coupling reaction in the presence of an organic solvent A and a condensing agent. After the solid product precipitates, it is washed and purified with water and an organic solvent A, and then dried to obtain Hexanoyl-Tyr(tBu)-Ile-Acp-NH2; (6) The protecting group tBu of Hexanoyl-Tyr(tBu)-Ile-Acp-NH2 is cleaved by a Lewis acid system, and then precipitated in a precipitation solvent to obtain a crude nootropic dipeptide Hexanoyl-Tyr-Ile-Acp-NH2; (7) The crude product of the nootropic dipeptide is recrystallized in a composite solution consisting of an organic solvent B and an ionic liquid, and the refined nootropic dipeptide is obtained after drying.
2. The method for synthesizing the nootropic dipeptide according to claim 1, wherein: In steps (1) to (5), the molar ratio of the added amounts of Fmoc-Ile-OH, H-Acp-NH2, Fmoc-Tyr(tBu)-OH, and n-hexanoic acid is 1:(1-3):(0.9-2):(0.8-1.5).
3. The method for synthesizing the nootropic dipeptide according to claim 1, wherein: The organic solvent A is one or more of ethyl acetate, tetrahydrofuran, acetonitrile, 1,2-dichloroethane, and toluene.
4. The method for synthesizing the nootropic dipeptide according to claim 3, wherein: The organic solvent A is ethyl acetate or 1,2-dichloroethane.
5. The method for synthesizing the nootropic dipeptide according to claim 1, wherein: The condensing agent is one or more of EDC·HCl, TBTU, PyBop, HOBt, DCC, and DIC.
6. The method for synthesizing the nootropic dipeptide according to claim 5, wherein: The condensing agents are HOBt and EDC·HCl, and the molar ratio of the two is 1:(0.5-2).
7. The method for synthesizing the nootropic dipeptide according to claim 1, wherein: In step (1), step (3) and step (5), the coupling reaction temperature is 20-60° C., and the coupling reaction time is 2-5 h.
8. The method for synthesizing the nootropic dipeptide according to claim 1, wherein: In step (2) and step (4), the organic base is any one or more of diethylamine, piperidine, triethylamine, and piperazine.
9. The method for synthesizing the nootropic dipeptide according to claim 1, wherein: In step (6), the Lewis acid system is a composite system of Lewis acid and NaI, wherein the Lewis acid is one or more of FeCl3, AlCl3, CeCl3·7H2O, and TiCl4, and the sedimentation solvent is one or more of isopropyl ether, methyl tert-butyl ether, diethyl ether, and petroleum ether.
10. The method for synthesizing the nootropic dipeptide according to claim 1, wherein: The organic solvent B is one of methanol and 1,2-dichloroethane; and the ionic liquid is 1,3-dimethylimidazole bis(trifluoromethanesulfonamide).