Diketopiperazine alkene fluorine derivative as well as preparation method and application thereof

Abstract

The invention provides a diketopiperazine alkene fluorine derivative as well as a preparation method and application thereof, and relates to the field of compound synthesis. The structural formula of the diketopiperazine alkene fluorine derivative is shown in the formula I, and L1 and L2 are independently selected from alkylene; x1 and X2 are respectively and independently selected from-NH,-OH and-SH; and L3 and L4 are respectively and independently selected from at least one halogen-substituted alkenylene group. The diketopiperazine alkene fluorine derivative provided by the invention is obtained by condensation and hydrolysis. The diketopiperazine alkene fluorine derivative with a specific structure can be used as a drug delivery carrier or a penetration enhancing component to promote the absorption of drugs and improve the biocompatibility. By adopting the preparation method disclosed by the invention, the yield and the purity of the diketopiperazine alkene fluorine derivative can be remarkably improved, the preparation method is simple, and raw materials are easy to obtain. Formula I

Description

Technical Field

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

[0002] Diketopiperazines (DKPs) are a class of cyclic dipeptide backbones formed by the condensation of two amino acids. Due to their inherent conformational rigidity, good metabolic stability, and ability to act as hydrogen bond donors and acceptors, this structure is widely considered a "privileged structure" in medicinal chemistry. Numerous studies have shown that derivatives based on the DKP backbone exhibit promising biological activities in antibacterial, antiviral, antitumor, and central nervous system modulation fields. For example, tazobactam (a β-lactamase inhibitor) and plerixafor (a CXCR4 antagonist) are drugs with a DKP backbone and possess good antibacterial and antitumor efficacy.

[0003] Although DKP-based compound drugs have shown promising pharmaceutical advantages in recent years, the structural diversity of existing DKP derivatives remains relatively limited. Most reported compounds focus on modifying common aliphatic or simple aromatic side chains. These structures may lead to the following problems: the activity and selectivity of existing DKP derivatives are difficult to achieve ideal levels; some DKP compounds suffer from poor solubility and low oral bioavailability.

[0004] Chinese invention patent CN113527217A discloses a diketopiperazine compound as shown in Formula I, or a pharmaceutically acceptable salt thereof:

[0005] Formula I; Where n1 and n2 are independently 0, 1, 2, 3, or 4; R a and R a， Independently selected from halogens and -LR 1 -L- is selected from linker, -O-, -S-, and -N(R). 2 ); R 2 Selected from H, C1-C6 alkyl groups, or C1-C6 alkyl groups substituted with one or more halogens; R 1The following groups are selected from H, or optionally substituted: C1-C8 alkyl, C2-C8 heteroalkyl, C6-C10 aryl, C3-C12 cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl; in the C2-C8 heteroalkyl, the heteroatom or heteroatom group is selected from one or more of N, O, and S, and the number of heteroatoms or heteroatom groups is 1-3, and they are linked to -L- through a carbon atom; in the 3-7 membered heterocycloalkyl, the heteroatom or heteroatom group is selected from -L- through a carbon atom; The atoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1-3; the heteroatoms in the 5-10 membered heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1-4; when there are multiple substituents, they may be the same or different; the substituents are independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkyl-O- groups, C1-C6 alkyl groups substituted with one or more halogens, or C1-C6 alkyl-O- groups substituted with one or more halogens. This invention provides diketopiperazine compounds with multiple structures that can be used as self-assembled drug-loaded microspheres to achieve efficient drug delivery. However, the structural choices of existing diketopiperazine compounds are still limited.

[0006] Therefore, further research is needed on the structure of diketopiperazine derivatives in order to obtain a new diketopiperazine derivative with enhanced penetration and drug delivery effects. Summary of the Invention

[0007] This invention addresses the problems existing in the prior art by providing a diketopiperazine fluoro derivative, its preparation method, and its applications. The diketopiperazine fluoro derivative with a specific structure of this invention can serve as a drug delivery carrier or permeation enhancer to promote drug absorption and improve biocompatibility. The preparation method of this invention can significantly prepare diketopiperazine fluoro derivatives with novel structures. This method improves the yield and purity of diketopiperazine fluoro derivatives, is simple to implement, and uses readily available raw materials.

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

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

[0010] Preferably, L1 and L2 are each independently selected from C1-C6 alkylene and C1-C6 alkyl groups.

[0011] More preferably, L1 and L2 are each independently selected from C2-C4 alkylene and C2-C4 alkyl groups.

[0012] More preferably, L1 and L2 are each independently selected from C2-C3 alkylene and C2-C3 alkyl groups.

[0013] More preferably, L1 and L2 are each independently C3 alkylene groups.

[0014] Preferably, X1 and X2 are -NH.

[0015] Preferably, L3 and L4 are each independently selected from at least one halogen-substituted alkenyl group.

[0016] More preferably, the halogen is selected from at least one of F, Cl, Br, and At; even more preferably, the halogen is F.

[0017] More preferably, when each of L3 and L4 contains two halogens, the two halogens are located on different carbon atoms.

[0018] More preferably, the sub-alkenyl group is selected from C2-C6 sub-alkenyl groups.

[0019] More preferably, the sub-alkenyl group is selected from C2-C3 sub-alkenyl groups.

[0020] More preferably, L3 and L4 are each independently selected from... , , .

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

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

[0023] The L3 or the L4 are each independently selected from , , At least one of them; The preparation method includes the following steps: (1) Condensation reaction: Compound 1, acid, condensing agent and amine compound undergo condensation reaction in the presence of solvent to obtain compound 2; (2) Hydrolysis reaction: Compound 2 undergoes a hydrolysis reaction to obtain compound 3.

[0024] Preferably, in step (1), the chemical structural formula of the acid is as follows: or or .

[0025] Preferably, in step (1), the molar ratio of the acid to the amine is 20-100:36-200.

[0026] More preferably, in step (1), the molar ratio of the acid to the amine is 30-90:60-180.

[0027] More preferably, in step (1), the molar ratio of the acid to the amine is 39-81.92:78-136.5; any point value and range within this molar ratio range can achieve the technical effect of the present invention, and the molar ratio is not limited to 39-81.92:78-136.5, 39:78, 49.15:81.29, 81.92:136.5, 50:90, 50:100, 40:120, 38-49.15:78-81.29, 49.15-81.92:81.29-136.5, 40-50:90-120.

[0028] Preferably, in step (1), the molar ratio of the acid to the condensing agent is 20-90:30-120.

[0029] More preferably, in step (1), the molar ratio of the acid to the condensing agent is 20-90:30-100; any point value and range within this molar ratio range can achieve the technical effect of the present invention, and the molar ratio is not limited to 39:30.6, 49.15:58.51, 81.92:97.52, 20:36, 20:40, 20:80, 20:120, 20:36-120, 20:40-80, 39-81.92:30.6-97.52, 20-90:30-100.

[0030] Preferably, in step (1), the condensing agent is (EDCI)1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), or dicyclohexylcarbodiimide (DCC).

[0031] Preferably, in step (1), the solvent is tetrahydrofuran.

[0032] Preferably, in step (1), the mass-to-volume ratio of compound 1 to solvent in the condensation reaction is 5-10g:80-200mL; any point value and range within this mass-to-volume ratio range can achieve the technical effect of the present invention, and the mass-to-volume ratio is not limited to 5g:80mL, 6g:100mL, 10g:200mL, 5-6g:80-100mL, 6-10g:100-200mL, or 5-10g:80-200mL.

[0033] Preferably, in step (1), the temperature of the condensation reaction is 20-30℃ and the reaction time is 8-16h.

[0034] More preferably, in step (1), the condensation reaction is carried out at room temperature for 12 hours.

[0035] 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 2.

[0036] More preferably, the column chromatography separation is performed using dichloromethane:methanol = 5-10:1.

[0037] Preferably, in step (2), the hydrolysis reaction is as follows: compound 2 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 3.

[0038] More preferably, in step (2), the hydrolysis reaction is specifically as follows: compound 2 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 3.

[0039] 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.

[0040] More preferably, in step (2), the mass-to-volume ratio of compound 2 and the mixed solution is 5-8g:70-80mL; any point value and range within this mass-to-volume ratio range can achieve the technical effect of the present invention, and the mass-to-volume ratio is not limited to 8g:80mL, 5g:70mL, 5g:80mL, 5g:70-80mL, or 5-8g:70-80mL.

[0041] 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.

[0042] Preferably, in step (2), the reaction temperature of the hydrolysis reaction is 20-60℃; more preferably 25-40℃; and even more preferably 30-35℃.

[0043] Preferably, the preparation method of compound 1 includes the following steps: (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 0; (S2) Oxidation reaction: Compound 0 undergoes a Cbz removal reaction under palladium-catalyzed hydrogenation to give compound 1; The structural formula of the SM is: .

[0044] More preferably, in step (S1), the molar ratio of SM to m-cresol is 1:3-10.

[0045] More preferably, in step (S1), the molar ratio of SM to m-cresol is 1:4-5.

[0046] More preferably, in step (S1), the molar ratio of SM to m-cresol is 1:4.5-4.6.

[0047] More preferably, in step (S1), the dehydrating agent is P2O5 or calcium chloride.

[0048] More preferably, in step (S1), the molar ratio of SM to dehydrating agent is 1:0.1-10.

[0049] More preferably, in step (S1), the molar ratio of SM to dehydrating agent is 1:0.3-0.5.

[0050] More preferably, in step (S1), the molar ratio of SM to dehydrating agent is 1:0.34-0.35.

[0051] 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.

[0052] More preferably, in step (S1), the mass-to-volume ratio of SM to solvent is 10-12g:40-60mL.

[0053] More preferably, in step (S1), the mass-to-volume ratio of SM to solvent is 10-11 g: 50 mL.

[0054] More preferably, in step (S1), the mass-to-volume ratio of SM to solvent is 10.75 g: 50 mL.

[0055] More preferably, in step (S1), the reaction temperature of the dehydration and ring-closing reaction is 100-200℃.

[0056] More preferably, in step (S1), the reaction temperature of the dehydration and ring-closing reaction is 150-180°C.

[0057] More preferably, in step (S1), the reaction temperature of the dehydration and ring-closing reaction is 160-165°C.

[0058] 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.

[0059] 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 0.

[0060] More preferably, in step (S1), the structural formula of compound 0 is: .

[0061] More preferably, in step (S2), the mass ratio of compound 0 to palladium on carbon is 1:0.01-0.2.

[0062] More preferably, in step (S2), the mass ratio of compound O to palladium on carbon is 1:0.08-0.15.

[0063] More preferably, in step (S2), the mass ratio of compound O to palladium on carbon is 1:0.09-0.1.

[0064] 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.

[0065] More preferably, in step (S2), the mass-to-volume ratio of compound 0 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 0 to solvent in the Cbz removal reaction is 10.7 g: 50 mL.

[0066] More preferably, in step (S2), the solvent is a methanol and acetic acid solvent replaced by N2.

[0067] 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℃.

[0068] More preferably, in step (S2), the reaction time for the Cbz removal reaction is 8-16 hours; more preferably, it is 12 hours.

[0069] More preferably, in step (S2), the reaction apparatus for the Cbz removal reaction is connected to hydrogen gas.

[0070] 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 1.

[0071] Finally, this invention provides the application of the above-mentioned diketylpiperazine fluoro derivative in the preparation of transmembrane-related drugs.

[0072] Preferably, the transmembrane-related drug is a drug delivery drug or a permeation-enhancing drug.

[0073] 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.

[0074] Compared with the prior art, the present invention has the following beneficial effects: 1. The diketopiperazine fluoro derivatives of the structure described in this invention can be applied in 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. The novel diketopiperazine fluoro derivatives of this invention have great application potential in drugs for complex diseases such as tumors, chronic inflammation, and neurodegenerative diseases.

[0075] 2. This invention prepares the diketopiperazine fluoro derivative of the structure described above 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

[0076] 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.

[0077] 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.

[0078] 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.

[0079] Yield (%) = Actual mass of target product / Theoretical mass of target product × 100%.

[0080] Basic Implementation The preparation method of compound 1 is as follows:

[0081] 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 solution was slowly added dropwise to 100 mL of ice water, precipitating a yellow solid. After filtration and drying, 10.2 g of compound 0 was obtained, with a yield of 54.3%.

[0082] Compound 0: 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). ESI MS:573.23(M+H).

[0083] Step S2: Hydrogenation reaction Compound 0 (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 1 (3.8 g, yield 75.7%).

[0084] Compound 1: 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). ESI MS: 329.15 (M+H).

[0085] Example 1

[0086] Step 1: Compound 1 (5.0 g, 19.5 mmol), acid (5.78 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 8.52 g of white foamy solid compound 2, with a yield of 84% and a purity of 95%.

[0087] Compound 2: 1 H NMR (500 MHz, DMSO- d6, ppm): 9.22 (s, 2H, NH), 8.27 (s, 2H, NH), 5.96 (s, 2H), 3.91-3.99 (s, 2H, COCH), 3.65 (s, 6H, CH3), 3.12-3.19 (s, 4H,CH2), 1.71-1.79 (m, 4H, CH2), 1.49-1.55 (m, 4H, CH2), 1.21-1.28 (m, 4H, CH2). ESI MS:517.20 (M+H).

[0088] Step 2: Dissolve compound 2 (8.0 g, 13.5 mmol) in 80 mL of a methanol:water (volume ratio 20:1), 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 a solid, filter, wash with water until neutral, dry to obtain a white solid compound 3 in an amount of 6.2 g, yield: 82%, purity: 98%.

[0089] Compound 3 (diketopiperazine fluorine derivative): 1 H NMR (500 MHz, DMSO- d 6, ppm): 9.21 (s, 2H, NH), 8.26 (s, 2H, NH), 5.95 (s, 2H), 3.90-3.99 (s, 2H, COCH), 3.10-3.19 (s, 4H, CH2), 1.70-1.79 (m,4H, CH2), 1.48-1.53 ​​(m, 4H, CH2), 1.20-1.25 (m, 4H, CH2). ESI MS:489.17 (M+H).

[0090] Example 2 A diketopiperazine fluoro derivative, with the following structural formula:

[0091] Step 1: Compound 1 (6.0 g, 23.41 mmol), acid (7.28 g, 49.15 mmol), EDCI (9.08 g, 58.51 mmol), and triethylamine (8.29 g, 81.9 mmol) were dissolved in 100 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 80 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 11.0 g of white foamy solid compound 2, with a yield of 79% and a purity of 96%.

[0092] Compound 2: 1 H NMR (500 MHz, DMSO- d 6, ppm): 9.22 (s, 2H, NH), 8.24 (s, 2H, NH), 6.40 (s, 2H), 3.91-3.96 (s, 2H, COCH), 3.68 (s, 6H, CH3), 3.12-3.19 (s, 4H,CH2), 1.72-1.79 (m, 4H, CH2), 1.46-1.58 (m, 4H, CH2), 1.22-1.28 (m, 4H, CH2). ESI MS:517.20 (M+H).

[0093] Step 2: Compound 2 (5.0 g, 8.43 mmol) was dissolved in 70 mL of a methanol:water (volume ratio 20:1). The temperature was adjusted to 30-35 °C, and the pH was adjusted to 12 with 10% sodium hydroxide aqueous solution. After reacting for 2 h, the pH was adjusted to 1-2 with 6N hydrochloric acid, and a solid precipitated. The solid was filtered, washed with water until neutral, and dried to obtain a white solid compound 3 with an amount of 5.8 g. The yield was 76.7% and the purity was 98%.

[0094] Compound 3 (diketopiperazine fluorine derivative): 1 H NMR (500 MHz, DMSO- d 6, ppm): 9.21 (s, 2H, NH), 8.26 (s, 2H, NH), 6.44 (s, 2H), 3.90-3.95 (s, 2H, COCH), 3.10-3.18 (s, 4H, CH2), 1.71-1.78 (m,4H, CH2), 1.45-1.56 (m, 4H, CH2), 1.21-1.26 (m, 4H, CH2). ESI MS:489.17 (M+H).

[0095] Example 3

[0096] Step 1: Compound 1 (10.0 g, 39 mmol), acid (13.61 g, 81.92 mmol), EDCI (15.14 g, 97.52 mmol), and triethylamine (13.82 g, 136.5 mmol) were dissolved in 200 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 100 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 17.5 g of white foamy solid compound 2, with a yield of 81% and a purity of 96%.

[0097] Compound 2: 1 H NMR (500 MHz, DMSO- d 6, ppm): 9.23 (s, 2H, NH), 8.27 (s, 2H, NH), 3.91-3.97 (s, 2H, COCH), 3.68 (s, 6H, CH3), 3.12-3.19 (s, 4H, CH2), 1.72-1.79(m, 4H, CH2), 1.43-1.52 (m, 4H, CH2), 1.21-1.29 (m, 4H, CH2). ESI MS:553.18 (M+H).

[0098] Step 2: Dissolve compound 2 (5.0 g, 9 mmol) in 80 mL of a methanol:water (volume ratio 20:1), adjust the temperature to 30-35 °C, adjust the pH to 12 with 10% sodium hydroxide aqueous solution, and after reacting for 2 h, adjust the pH to 1-2 with 6 N hydrochloric acid, precipitate a solid, filter, wash with water until neutral, and dry to obtain a white solid compound 3 with an amount of 3.56 g, yield: 75%, purity: 98%.

[0099] Compound 3 (diketopiperazine fluorine derivative): 1 H NMR (500 MHz, DMSO- d6, ppm): 9.21 (s, 2H, NH), 8.26 (s, 2H, NH), 3.92-3.99 (s, 2H, COCH), 3.12-3.19 (s, 4H, CH2), 1.72-1.79 (m, 4H, CH2), 1.42-1.51 (m, 4H, CH2), 1.22-1.28 (m, 4H, CH2). ESI MS:525.17 (M+H).

[0100] Application examples Compound 3, with the structure described in the examples, is used in the preparation of drug delivery materials to improve the stability and permeability of the drug. Simultaneously, compound 3, with this structure, can serve as a key monomer, which can be polymerized or grafted onto a polymer backbone to endow the drug carrier with unique properties, such as enhanced pH responsiveness, improved biocompatibility, or stronger protein binding capacity.

[0101] 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 fluoro derivative, characterized in that, The structural formula of the diketylpiperazine fluoro derivative is shown in Formula I, specifically: Formula I; Wherein, L1 and L2 are each independently selected from alkylene groups; X1 and X2 are each independently selected from -NH, -OH, and -SH; and L3 and L4 are each independently selected from at least one halogen-substituted alkenyl group.

2. The diketopiperazine fluoro derivative according to claim 1, characterized in that, The L1 and L2 are each independently selected from C1-C6 alkylene and C1-C6 alkyl; preferably, the L1 and L2 are each independently selected from C2-C4 alkylene and C2-C4 alkyl; more preferably, the L1 and L2 are each independently selected from C2-C3 alkylene and C2-C3 alkyl; even more preferably, the L1 and L2 are each independently C3 alkylene.

3. The diketopiperazine fluoro derivative according to claim 1, characterized in that, X1 and X2 are respectively -NH; L3 and L4 are each independently selected from at least one halogen-substituted alkenyl group.

4. The diketopiperazine fluoro derivative according to claim 3, characterized in that, The halogen is selected from at least one of F, Cl, Br, and At; when each of L3 and L4 contains two halogens, the two halogens are located on different carbon atoms.

5. The diketopiperazine fluoro derivative according to claim 3, characterized in that, The alkenyl group is selected from C2-C6 alkenyl groups; Preferably, the alkenyl group is selected from C2-C3 alkenyl groups.

6. The diketopiperazine fluoro derivative according to claim 3, characterized in that, L3 and L4 are each independently selected from , , .

7. The diketopiperazine fluoro derivative according to any one of claims 1-6, characterized in that, The structural formula of the diketopiperazine fluorolysine derivative is: and / or and / or 。 8. The method for preparing the diketopiperazine fluoro derivative according to any one of claims 1-7, characterized in that, The reaction process is as follows: ； The preparation method includes the following steps: (1) Condensation reaction: Compound 1, acid, condensing agent and amine compound undergo condensation reaction in the presence of solvent to obtain compound 2; (2) Hydrolysis reaction: Compound 2 undergoes a hydrolysis reaction to obtain compound 3; The L3 or the L4 are each independently selected from , , At least one of them.

9. The preparation method according to claim 8, characterized in that, In step (1), the chemical structural formula of the acid is: or or ; In step (1), the molar ratio of the acid to the amine is 20-100:36-200; In step (1), the molar ratio of the acid to the condensing agent is 20-90:30-120; In step (1), the condensing agent is EDCI, HATU or DCC, and the solvent is tetrahydrofuran; In step (1), the mass-volume ratio of compound 1 to solvent in the condensation reaction is 5-10g:80-200mL, 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 2 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 3; In step (2), the mass-to-volume ratio of compound 2 and the mixed solution is 5-8g:70-80mL; in step (2), the reaction temperature of the hydrolysis reaction is 20-60℃.

10. The use of the diketopiperazine fluoro derivative according to any one of claims 1-7 in the preparation of transmembrane-related drugs.

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