Diketopiperazine fluorolysine derivative as well as preparation method and application thereof

Abstract

The invention provides a diketopiperazine fluorolysine derivative as well as a preparation method and application thereof, and relates to the field of compound synthesis. The structural formula of the diketopiperazine fluoro-lysine derivative is shown in the formula I, and L1 and L2 are independently selected from at least one halogen-substituted alkylene group; x1 and X2 are respectively and independently selected from-NH,-OH and-SH; l3 and L4 are respectively and independently selected from an alkenylene group and a C5-C8 bridged ring group; the preparation method comprises the following steps: carrying out dehydration cyclization, oxidation, condensation and hydrolysis reaction on 2-amino-6-(((benzyloxy) carbonyl) amino)-5, 5-difluoro-hexanoic acid to obtain a compound with a structure as shown in a formula I; the obtained compound with the structure as shown in the formula I can be used as a key monomer and is modified on a polymer skeleton through polymerization or grafting, and a drug carrier is endowed with the following properties of enhancing pH responsiveness and improving biocompatibility or protein binding capacity. Formula I.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis, specifically relating to a diketopiperazine fluorolysine derivative, its preparation method, and its application. Background Technology

[0002] Diketopiperazine derivatives are a class of compounds obtained by structural modification or derivatization of diketopiperazine (DKP), such as by substituting or modifying hydrogen atoms, carbonyl groups, or nitrogen atoms on its ring to introduce different functional groups or functional groups. Studies have found that diketopiperazine derivatives possess antitumor, antibacterial, antiviral, and neuromodulatory biological activities, and have wide applications in pharmaceutical preparation.

[0003] Different diketopiperazine derivatives with different structures exhibit varying bioactivities. For example, punabulin (CHN4O2) can deprive tumor tissue of oxygen and nutrients within hours while releasing tumor-associated antigens, activating the body's anti-tumor immune response, and reducing the risk of tumor recurrence. Diketopiperazine derivatives modified with benzimidazole groups show significant antibacterial and antiviral effects. Diketopiperazine compounds are a novel type of material that can form drug-loaded microspheres by loading or adsorbing drugs onto their surfaces, thereby improving drug stability and permeability.

[0004] Extensive research has been conducted on the structure and synthesis of diketopiperazine compounds, and further pharmaceutical studies of these compounds have also been carried out. Chinese invention patent CN104721825A discloses diketopiperazine particles with a defined specific surface area and a composition containing diketopiperazine microparticles. The specific surface area of ​​the diketopiperazine microparticles is less than approximately 67 m². 2 / g, the diketopiperazine microparticles can be fumaroyl diketopiperazine and can contain drugs such as insulin. Specifically, the active ingredient in the diketopiperazine microparticles of this invention is fumaroyl diketopiperazine (di-3,6-(N-fumaryl-4-aminobutyl)-2,5-diketo-diketopiperazine (FDKP), with the following structural formula: .

[0005] This invention improves drug delivery by controlling the specific surface area of ​​diketopiperazine particles, which is beneficial for delivery to the lungs. This invention improves the problem of drugs being difficult to deliver to the lungs. However, it still uses diketopiperazine compounds with known structures and does not provide a new compound with excellent drug delivery and permeation enhancement effects.

[0006] Therefore, it is necessary to explore and study new diketopiperazine derivatives in order to obtain a new diketopiperazine fluorolysine derivative with good membrane permeability and drug delivery effect. Summary of the Invention

[0007] This invention addresses the problems existing in the prior art by providing a diketopiperazine fluorolysine derivative, its preparation method, and its applications. This invention introduces a novel structure for the diketopiperazine fluorolysine derivative. This compound can serve as a key monomer, which can be polymerized or grafted onto a polymer backbone to impart unique properties to drug carriers, such as enhanced pH responsiveness, improved biocompatibility, or stronger protein binding capacity. The preparation method of this invention can significantly improve the yield and purity of the diketopiperazine fluorolysine derivative compound. The preparation method is simple and the raw materials are readily available.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows: First, this invention provides a diketopiperazine fluorolysine derivative, the structural formula of which is shown in Formula I, specifically:

[0009] Formula I; Wherein, L1 and L2 are each independently selected from at least one halogen-substituted alkylene group; X1 and X2 are each independently selected from -NH, -OH, and -SH; and L3 and L4 are each independently selected from alkenyl and C5-C8 bridged cycloyl groups.

[0010] Preferably, the halogen is selected from at least one of F, Cl, Br, and At.

[0011] More preferably, the halogen is F.

[0012] Preferably, the alkylene group is selected from C1-C6 alkylene or C1-C6 alkyl; more preferably, the alkylene group is selected from C2-C4 alkylene or C2-C4 alkyl; even more preferably, the alkylene group is C2 alkylene or C3 alkylene or C2 alkyl or C3 alkyl.

[0013] Preferably, L1 and L2 are each independently selected from two halogen-substituted alkylene groups.

[0014] More preferably, the two halogens are located on the same carbon atom.

[0015] In some specific embodiments of the present invention, L1 and L2 are respectively .

[0016] Preferably, X1 and X2 are -NH.

[0017] Preferably, L3 and L4 are independently selected from C2-C6 alkenyl groups and C5-C6 bridged cyclic groups, respectively.

[0018] More preferably, L3 and L4 are independently selected from C2-C4 sub-alkenyl and C5-bridged cyclic groups, respectively.

[0019] More preferably, L3 and L4 are independently selected from C2 sub-alkenyl and C5 sub-bridged cyclic groups, respectively.

[0020] More preferably, the C2 subene group is The sub-C5 bridge ring base is .

[0021] Most preferably, the structural formula of the diketopiperazine fluorolysine derivative is: and / or .

[0022] Then, the present invention provides a method for preparing the above-mentioned diketopiperazine fluorolysine derivative, the reaction process of which is as follows:

[0023] Including the following steps: (1) Condensation reaction; Compound 2, Compound 3, condensing agent and amine compound undergo condensation reaction in the presence of solvent to obtain Compound 4; (2) Hydrolysis reaction: Compound 4 undergoes a hydrolysis reaction to obtain compound 5.

[0024] Preferably, in step (1), compound 3 is an acid with the following chemical structural formula: or .

[0025] Preferably, in step (1), the molar ratio of compound 3 to amine is 30-100:54-200.

[0026] More preferably, in step (1), the molar ratio of compound 3 to amine is 39-95.95:78-160.

[0027] Preferably, in step (1), the molar ratio of compound 2 to condensing agent is 10-50:18-300.

[0028] More preferably, in step (1), the molar ratio of compound 2 to condensing agent is 10-50:20-200.

[0029] More preferably, in step (1), the molar ratio of compound 2 to condensing agent is 19.5-45.69:30.6-114.2.

[0030] Preferably, in step (1), the solvent is tetrahydrofuran.

[0031] Preferably, in step (1), the mass-to-volume ratio of compound 2 to solvent in the condensation reaction is 6.4-15g:80-160mL.

[0032] Preferably, in step (1), the temperature of the condensation reaction is 20-30℃ and the reaction time is 8-16h.

[0033] More preferably, in step (1), the condensation reaction is carried out at room temperature for 12 hours.

[0034] Preferably, in step (1), the condensation reaction further includes the following steps: after the reaction is completed, the reaction solution is mixed with ice water, the organic layer is separated, the aqueous phase is extracted with ethyl acetate, the organic layers are then combined and dried with anhydrous sodium sulfate; after concentration, column chromatography is used to separate the compound 4.

[0035] More preferably, the column chromatography separation is performed using dichloromethane:methanol = 5-10:1.

[0036] Preferably, in step (2), the hydrolysis reaction is as follows: compound 4 is dissolved in a methanol-water mixed solution, the pH is adjusted to 11-13 and the reaction is carried out for 1-3 hours; then the pH is adjusted to 1-2 to precipitate a solid, which is filtered, washed with water until neutral, and dried to obtain compound 5.

[0037] More preferably, in step (2), the hydrolysis reaction is specifically as follows: compound 4 is dissolved in a methanol-water mixed solution, the pH is adjusted to 12 and the reaction is carried out for 2 hours; then the pH is adjusted to 1-2 to precipitate a solid, which is filtered, washed with water until neutral, and dried to obtain compound 5.

[0038] More preferably, in step (2), the solid-liquid ratio of methanol to water in the methanol-water mixed solution is 15-25:1; even more preferably, in step (2), the solid-liquid ratio of methanol to water in the methanol-water mixed solution is 20:1.

[0039] More preferably, in step (2), the mass-to-volume ratio of compound 4 and the mixed solution is 8.5-10.5 g: 80 mL.

[0040] More preferably, in step (2), the components used to adjust the pH are not limited to sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid; the concentration of each component has no effect on the technical effect.

[0041] Preferably, in step (2), the reaction temperature of the hydrolysis reaction is 20-60℃; more preferably 25-40℃; and even more preferably 30-35℃.

[0042] Preferably, the preparation method further includes the step of preparing compound 2, specifically: (S1) Dehydration cyclization reaction: SM and m-cresol undergo a dehydration cyclization reaction in the presence of a dehydrating agent and a solvent to give compound 1; (S2) Oxidation reaction: Compound 1 undergoes a Cbz removal reaction under palladium-catalyzed hydrogenation to obtain compound 2; The structural formula of the SM is: .

[0043] More preferably, in step (S1), the molar ratio of SM to m-cresol is 1:3-10.

[0044] More preferably, in step (S1), the molar ratio of SM to m-cresol is 1:4-5.

[0045] More preferably, in step (S1), the molar ratio of SM to m-cresol is 1:4.5-4.6.

[0046] More preferably, in step (S1), the dehydrating agent is P2O5 or calcium chloride.

[0047] More preferably, in step (S1), the molar ratio of SM to dehydrating agent is 1:0.1-10.

[0048] More preferably, in step (S1), the molar ratio of SM to dehydrating agent is 1:0.3-0.5.

[0049] More preferably, in step (S1), the molar ratio of SM to dehydrating agent is 1:0.34-0.35.

[0050] More preferably, in step (S1), the solvent is selected from at least one of N-methylpyrrolidone (NMP), N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dioxane, and tetrahydrofuran.

[0051] More preferably, in step (S1), the mass-to-volume ratio of SM to solvent is 10-12g:40-60mL.

[0052] More preferably, in step (S1), the mass-to-volume ratio of SM to solvent is 10-11 g: 50 mL.

[0053] More preferably, in step (S1), the mass-to-volume ratio of SM to solvent is 10.75 g: 50 mL.

[0054] More preferably, in step (S1), the reaction temperature of the dehydration and ring-closing reaction is 100-200℃.

[0055] More preferably, in step (S1), the reaction temperature of the dehydration and ring-closing reaction is 150-180°C.

[0056] More preferably, in step (S1), the reaction temperature of the dehydration and ring-closing reaction is 160-165°C.

[0057] More preferably, in step (S1), the reaction time of the dehydration and ring-closing reaction is 5-15 h; even more preferably, it is 10 h.

[0058] More preferably, in step (S1), after the dehydration and ring-closing reaction, a post-processing step is further included, comprising: cooling to room temperature, precipitating a solid in ice water, drying, and obtaining compound 1.

[0059] More preferably, in step (S1), the structural formula of compound 1 is as follows: .

[0060] More preferably, in step (S2), the mass ratio of compound 1 to palladium on carbon is 1:0.01-0.2.

[0061] More preferably, in step (S2), the mass ratio of compound 1 to palladium on carbon is 1:0.08-0.15.

[0062] More preferably, in step (S2), the mass ratio of compound 1 to palladium on carbon is 1:0.09-0.1.

[0063] More preferably, in step (S2), the Cbz removal reaction is carried out under conditions where methanol and acetic acid are used as solvents; the volume ratio of methanol to acetic acid is 1:0.5-2; even more preferably, the volume ratio of methanol to acetic acid is 1:1.

[0064] More preferably, in step (S2), the mass-to-volume ratio of compound 1 to solvent in the Cbz removal reaction is 10-11 g: 40-60 mL; more preferably, in step (S2), the mass-to-volume ratio of compound 1 to solvent in the Cbz removal reaction is 10.7 g: 50 mL.

[0065] More preferably, in step (S2), the solvent is a methanol and acetic acid solvent replaced by N2.

[0066] More preferably, in step (S2), the reaction temperature of the Cbz removal reaction is 10-60℃; more preferably 20-40℃; and even more preferably 25-35℃.

[0067] More preferably, in step (S2), the reaction time for the Cbz removal reaction is 8-16 hours; more preferably, it is 12 hours.

[0068] More preferably, in step (S2), the reaction apparatus for the Cbz removal reaction is connected to hydrogen gas.

[0069] More preferably, in step (S2), the Cbz removal reaction further includes a post-processing step: after the reaction is completed, the mixture is filtered through diatomaceous earth, the filtrate is concentrated under reduced pressure, then suspended in dichloromethane, and the precipitated solid is washed with ethyl acetate and filtered to obtain compound 2.

[0070] Finally, this invention provides the application of the above-mentioned diketopiperazine fluorolysine derivative in the preparation of transmembrane-related drugs.

[0071] Preferably, the transmembrane-related drug is a drug delivery drug or a permeation-enhancing drug.

[0072] Preferably, the drug comprises a compound of Formula I, an isomer thereof, a prodrug, a stable isotope derivative thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable carrier.

[0073] Compared with the prior art, the present invention has the following beneficial effects: 1. The diketopiperazine fluorolysine derivative with the structure described in this invention can be applied to the preparation of drugs with enhanced penetration and improved drug delivery, thereby improving drug solubility and bioavailability, achieving targeted drug delivery, controlled drug release, and enhanced cell penetration. This novel diketopiperazine fluorolysine derivative is expected to play a more significant role in precision drug delivery and personalized treatment, and has great application potential in drugs for complex diseases such as tumors, chronic inflammation, and neurodegenerative diseases.

[0074] 2. This invention prepares the diketopiperazine fluorolysine derivative of the aforementioned structure through a specific reaction pathway and reaction conditions, which can improve the yield and purity of the compound product. The raw materials are readily available, the reaction process is simple, and the reaction is green and efficient. Detailed Implementation

[0075] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0076] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0077] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention are obtained through conventional commercial channels. Products from different manufacturers do not have a significant impact on the effectiveness.

[0078] Yield (%) = Actual mass of target product / Theoretical mass of target product × 100%.

[0079] Example 1

[0080] Step S1: Dehydration cyclization reaction 2-Amino-6-(((benzyloxy)carbonyl)amino)-5,5-difluorohexanoic acid (SM, 10.75 g, 34 mmol) and m-cresol (16.7 g, 154 mmol) were dissolved in NMP (50 mL), and P2O5 (1.67 g, 11.8 mmol) was added. The mixture was heated to 160-165 °C and reacted for 10 h. After cooling to room temperature, the mixture was slowly added dropwise to 100 mL of ice water, precipitating a yellow solid. After filtration and drying, 10.2 g of compound 1 was obtained, with a yield of 54.3%.

[0081] Compound 1: 1 H NMR (500 MHz, DMSO- d 6, ppm):8.10(s, 2H, NH), 7.33-7.37(m, 8H),7.22(t, 2H), 6.76(s, 2H, NH),5.05(s, 4H, CH2), 3.80-3.99(m, 2H, COCH), 3.18-3.26(m, 4H, CF2CH2), 1.57-2.09(m, 8H, CH2).

[0082] ESI MS: 573.23 (M+H).

[0083] Step S2: Hydrogenation reaction Compound 1 (10.7 g, 18.57 mmol) was suspended in a 1:1 mixture of methanol and acetic acid (50 mL) replaced with N2, and 10% Pd / C (1.0 g) was added. The reaction apparatus was connected to a hydrogen balloon system, and the needle was suspended above the liquid surface after a brief bubbling of hydrogen gas. The reaction was stirred overnight at 30 ± 5 °C, and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The resulting viscous substance was resuspended in a minimal amount of dichloromethane (10 mL), washed with ethyl acetate to precipitate a white solid, and then filtered under vacuum to obtain compound 2 (3.8 g, yield 75.7%).

[0084] Compound 2: 1 H NMR (500 MHz, DMSO- d 6, ppm): 8.26 (s, 2H, CONH), 3.90-3.99 (m, 2H, COCH), 2.68-2.95 (m, 4H, CH2), 1.50-2.09 (m, 12H).

[0085] ESI MS: 329.15 (M+H).

[0086] Example 2

[0087] Step 1: Compound 2 (6.4 g, 19.5 mmol), compound 3 (6.63 g, 39 mmol), EDCI (9.08 g, 30.6 mmol), and triethylamine (7.99 g, 78 mmol) were dissolved in 80 mL of anhydrous THF. The reaction mixture was allowed to react overnight (12 h) at room temperature. The reaction solution was then poured into ice water, and the organic layer was separated. The organic layers were extracted once with 50 mL of ethyl acetate in the aqueous phase. The combined organic layers were dried over anhydrous sodium sulfate. After concentration, the mixture was separated by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 9.4 g of white foamy solid compound 4, with a yield of 76% and a purity of 95%.

[0088] Compound 4: 1 H NMR (500 MHz, DMSO- d6, ppm): 8.27 (s, 2H, NH), 8.06 (s, 2H, NH), 3.91-3.99 (m, 2H, COCH), 3.67 (s, 6H, CH3), 3.46-3.55 (m, 4H, CH2), 1.85-2.46 (m,10H, CH2), 1.71-1.79 (m, 4H, CH2), 1.50-1.57 (m, 4H, CH2). ESI MS: 632.25 (M+H).

[0089] Step 2: Dissolve compound 4 (8.5 g, 13.5 mmol) in 80 mL of a methanol:water (20:1) mixture, adjust the temperature to 30-35 °C, adjust the pH to 12 with 10% sodium hydroxide aqueous solution, react for 2 h, adjust the pH to 1-2 with 6 N hydrochloric acid, precipitate the solid, filter, wash with water until neutral, dry to obtain 6.5 g of white solid compound 5, yield: 85.3%, purity: 98%.

[0090] Compound 5: 1 H NMR (500 MHz, DMSO- d6 , ppm): 8.26 (s, 2H, NH), 8.05 (s, 2H, NH), 3.90-3.99 (m, 2H, COCH), 3.45-3.52 (m, 4H, CH2), 1.88-2.44 (m, 10H, CH2), 1.70-1.77(m, 4H, CH2), 1.50-1.57 (m, 4H, CH2). ESI MS:605.28 (M+H).

[0091] Example 3

[0092] Step 1: Compound 2 (15.0 g, 45.69 mmol), compound 3 (12.48 g, 95.95 mmol), EDCI (17.73 g, 114.2 mmol), and triethylamine (16.18 g, 160 mmol) were dissolved in 160 mL of anhydrous THF. The reaction mixture was reacted overnight (12 h) at 25-30 °C. The reaction mixture was then poured into ice water, and the organic layer was separated. The organic layers were extracted once with 50 mL of ethyl acetate in the aqueous phase. The combined organic layers were dried over anhydrous sodium sulfate. After concentration, the mixture was separated by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 20.0 g of white foamy solid compound 4, with a yield of 79.2% and a purity of 95%.

[0093] Compound 4: 1 H NMR (500 MHz, DMSO- d 6, ppm): 9.21 (s, 2H, NH), 8.28 (s, 2H, NH), 6.25 (2H, d, J =12Hz), 5.93 (2H, d, J =12.2Hz), 3.92-3.99 (m, 2H, COCH), 3.65 (s,6H, CH3), 3.21-3.28 (m, 4H, CH2), 1.58-1.79 (m, 8H, CH2).

[0094] ESI MS: 553.20 (M+H).

[0095] Step 2: Dissolve compound 4 (10.5 g, 15.3 mmol) in 80 mL of a methanol:water (20:1) mixture, adjust the temperature to 30-35 °C, adjust the pH to 12 with 10% sodium hydroxide aqueous solution, react for 2 h, adjust the pH to 1-2 with 6 N hydrochloric acid, precipitate the solid, filter, wash with water until neutral, dry to obtain 7.2 g of white solid compound 5, yield: 89.5%, purity: 98%.

[0096] Compound 5: 1 H NMR (500 MHz, DMSO- d 6, ppm): 9.21 (s, 2H, NH), 8.26 (s, 2H, NH), 6.24 (2H, d, J =12Hz), 5.92 (2H, d, J =12.2Hz), 3.90-3.99 (m, 2H, COCH), 3.20-3.26 (m, 4H, CH2), 1.57-1.77 (m, 8H, CH2). ESI MS:525.15 (M+H).

[0097] Application examples The compounds with the structures described in the examples are used in the preparation of drug delivery materials to improve the stability and permeability of the drug.

[0098] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A diketopiperazine fluorolysine derivative, characterized in that, The structural formula of the diketopiperazine fluorolysine derivative is shown in Formula I, specifically: Formula I; Wherein, L1 and L2 are each independently selected from at least one halogen-substituted alkylene group; X1 and X2 are each independently selected from -NH, -OH, and -SH; and L3 and L4 are each independently selected from alkenyl and C5-C8 bridged cyclic groups.

2. The diketopiperazine fluorolysine derivative according to claim 1, characterized in that, The halogen is selected from at least one of F, Cl, Br, and At; The alkylene group is selected from C1-C6 alkylene or C1-C6 alkyl; preferably, the alkylene group is selected from C2-C4 alkylene or C2-C4 alkyl; more preferably, the alkylene group is C2 alkylene or C3 alkylene or C2 alkyl or C3 alkyl.

3. The diketopiperazine fluorolysine derivative according to claim 1, characterized in that, L1 and L2 are each independently selected from two halogen-substituted alkylene groups.

4. The diketopiperazine fluorolysine derivative according to claim 1, characterized in that, L3 and L4 are independently selected from C2-C6 alkenyl and C5-C6 bridged cyclic groups, respectively; Preferably, L3 and L4 are independently selected from C2-C4 sub-alkenyl and C5-bridged cyclic groups, respectively.

5. The diketopiperazine fluorolysine derivative according to claim 4, characterized in that, L3 and L4 are independently selected from C2-olefinic and C5-bridged cyclic groups, respectively; Preferably, the C2 sub-olefin is The sub-C5 bridge ring base is .

6. The diketopiperazine fluorolysine derivative according to any one of claims 1-5, characterized in that, The structural formula of the diketopiperazine fluorolysine derivative is: and / or 。 7. The method for preparing the diketopiperazine fluorolysine derivative according to any one of claims 1-6, characterized in that, The reaction process is as follows: Including the following steps: (1) Condensation reaction; Compound 2, Compound 3, condensing agent and amine compound undergo condensation reaction in the presence of solvent to obtain Compound 4; (2) Hydrolysis reaction: Compound 4 undergoes a hydrolysis reaction to obtain compound 5.

8. The preparation method according to claim 7, characterized in that, In step (1), compound 3 is an acid with the following chemical structural formula: or ; In step (1), the molar ratio of compound 3 to amine is 30-100:54-200; in step (1), the molar ratio of compound 2 to condensing agent is 10-50:18-300; in step (1), the solvent is tetrahydrofuran; in step (1), the mass-volume ratio of compound 2 to solvent in the condensation reaction is 6.4-15g:80-160mL, the temperature of the condensation reaction is 20-30℃, and the reaction time is 8-16h. In step (2), the hydrolysis reaction is specifically as follows: compound 4 is dissolved in a methanol-water mixed solution, the pH is adjusted to 11-13 and the reaction is carried out for 1-3 hours; then the pH is adjusted to 1-2 to precipitate solid, which is filtered, washed with water until neutral, and dried to obtain compound 5; the reaction temperature of the hydrolysis reaction is 20-60℃.

9. The preparation method according to claim 8, characterized in that, In step (1), the molar ratio of compound 3 to amine is 39-95.95:78-160; in step (1), the molar ratio of compound 2 to condensing agent is 10-50:20-200; in step (1), the condensation reaction is carried out at room temperature for 12 hours. In step (2), the hydrolysis reaction is specifically as follows: compound 4 is dissolved in a methanol-water mixed solution, the pH is adjusted to 12 and the reaction is carried out for 2 hours; then the pH is adjusted to 1-2 to precipitate solid, which is filtered, washed with water until neutral, and dried to obtain compound 5; the reaction temperature of the hydrolysis reaction is 25-40℃.

10. The use of the diketopiperazine fluorolysine derivative according to any one of claims 1-6 in the preparation of transmembrane-related drugs.

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