Lipid-vitamin conjugate based on amino acid structure and synthesis method therefor

Abstract

A lipid-vitamin conjugate based on an amino acid structure and a synthesis method therefor. The head of the lipid-vitamin conjugate consists of a single amino acid or a plurality of amino acids, and the tail thereof consists of a hydrophobic vitamin and a fatty chain. The molecular weight of the amino acid-based lipid-vitamin conjugate is 1000-2000 Da. The synthesis method is a solid-phase synthesis method based on polypeptide synthesis, and the method comprises: first attaching the carbon terminus of an amino acid to a 2-chlorotrityl chloride resin, then carrying out condensation-washing-deprotection-washing cycle synthesis, and finally, coupling a vitamin and a fatty chain to the nitrogen terminus to obtain a lipid-vitamin conjugate based on an amino acid structure. The synthesized lipid-vitamin conjugate is cleaved from the resin by means of a cleavage solution, and soluble by-products are removed from the organic solvent by means of a non-polar solvent. The method features ease of operation, high product purity, minimal complex factors requiring control, and high reproducibility.

Description

Lipid vitamin based on amino acid structure and synthesis method thereof TECHNICAL FIELD

[0001] The present application belongs to the field of nanomedicine, in particular relates to a class of lipid vitamins and a synthesis method thereof BACKGROUND

[0002] Vitamins are essential micronutrients for living organisms, playing a crucial role in regulating normal physiological activities of tissues and cells. Their biological activities encompass multiple aspects such as cell proliferation and differentiation, growth and development, morphogenesis, metabolism, and homeostatic regulation of internal environment. As an important component of life, vitamins not only play a crucial role in the development process of the body, but also participate in the complex regulatory network that maintains the overall health of the organism. By regulating the life cycle of cells and affecting metabolic pathways, vitamins ensure that the organism can effectively adapt and maintain internal and external balance under various environmental conditions.

[0003] However, the unsaturated bonds, relatively poor stability, relatively large molecular weight, and relatively low bioavailability of fat-soluble vitamins pose challenges in their metabolism and utilization in the body. First, the presence of unsaturated bonds increases the chemical instability of vitamin molecules, making them more susceptible to environmental factors such as oxidation. Second, the relatively large molecular weight of fat-soluble vitamins affects their efficiency during absorption in the digestive tract. Since the absorption and transport of such molecules by the organism is relatively complex, their bioavailability is relatively low compared to water-soluble vitamins. This means that only a portion of the ingested fat-soluble vitamins can be effectively absorbed and utilized, with the remainder being excreted or unable to fully participate in the metabolic processes of the organism.

[0004] Based on the fact that liposome drug delivery systems have a phospholipid bilayer structure highly similar to cell membranes, good stability, and biocompatibility, they have been shown to enhance drug penetration of biological membranes and can effectively load hydrophobic and lipophilic drugs. The vitamin liposomes reported so far are mainly in the form of liposome suspensions, which have some shortcomings. First, liposome suspensions are unstable during storage and transportation, making drug release and effectiveness difficult to predict. Second, for some highly sensitive vitamin drugs, the preparation process of liposome suspensions can lead to a decrease in drug activity. Therefore, we have researched a class of amino acid lipid vitamins with controllable structure, uniform dispersion, and high loading rate using solid-phase peptide synthesis. Compared with traditional physically encapsulated vitamin liposomes, lipid vitamins use amino acids as a biological component to increase biocompatibility and colloidal stability, while avoiding the problem of uneven dispersion caused by hydrophobic structures. SUMMARY

[0005] The present application aims to provide a kind of lipid vitamin based on amino acid structure;

[0006] Another object of the present application is to provide a synthesis method of a kind of lipid vitamin based on amino acid structure;

[0007] The amino acid lipid vitamin has the following characteristics:

[0008] (1) The head is a hydrophilic amino acid, and the tail is a hydrophobic fatty chain and a vitamin.

[0009] (2) It has a specific molecular weight range: 1000-2000 Da.

[0010] A synthesis method of a kind of lipid vitamin based on amino acid structure, characterized in that the synthesis method is by means of solid-phase peptide synthesis, the amino acid at the carbon end is connected to 2-chlorotrityl chloride resin; it is synthesized by condensation-washing-deprotection-washing cycle, and the remaining nitrogen end at the end provides a coupling site for vitamin and fatty chain, and further coupled with a hydrophobic lipid tail through amide reaction, i.e. a kind of lipid vitamin based on amino acid structure is obtained, and the synthesized lipid vitamin is removed from the resin by cleavage solution, and the soluble by-products in the organic solvent are removed by non-polar solvent.

[0011] The synthesis method of the lipid vitamin based on amino acid structure includes the following steps:

[0012] (1) Amino acid structure fixation: the resin is placed in a syringe reactor and pre-swelled in anhydrous dichloromethane (DCM) for 20-30 minutes, the reaction solution is discarded, then the first amino acid reaction solution is added, and the reaction is carried out at room temperature for 1-2 hours, then the reaction solution is removed and washed with N, N-dimethylformamide (DMF) and DCM to obtain the resin with fixed amino acid structure, i.e. resin-1;

[0013] (2) Active chlorine functional group blocking: the resin prepared in step (1) is reacted with a blocking solution containing methanol at room temperature for 30-40 minutes, washed with DMF and DCM, and then vacuum dried for 24-48 h to obtain the resin with blocked active chlorine functional group, i.e. resin-2, and the amino acid loading rate on resin-2 is measured;

[0014] (3) Amino acid structure expansion: the resin-2 prepared in step (2) is pre-swelled in anhydrous DCM, the reaction solution is discarded, and n (1≤n≤20) repeated operations are carried out, the operation steps are as follows: adding a deprotection solution, reacting at room temperature for 10-20 minutes to remove the temporary protection group of the amino acid, then adding an amino acid reaction solution, reacting at room temperature for 1-2 h, then removing the reaction solution, washing with DMF and DCM, and finally obtaining the resin with n+1 amino acid structure fixed, i.e. resin-3;

[0015] (4) Fatty acid grafting: the resin-3 of step (3) is mixed with a deprotection solution, and reacted at room temperature for 10-20 minutes. After the reaction solution is discarded, a fatty acid reaction solution is added, and reacted at room temperature for 24-36 hours to complete the fatty acid grafting, thereby obtaining a fatty acid grafted amino acid resin, i.e. resin-4;

[0016] (5) Vitamin grafting: the resin of step (4) is mixed with a 2-acetyldimethyl ketone (Dde) protecting group deprotection solution, and reacted at room temperature for 2-3 minutes. The operation is repeated for 10-20 times. After the reaction solution is discarded, a vitamin reaction solution is added, and reacted at room temperature in the dark for 4-12 hours. Then, the reaction solution is removed to complete the vitamin grafting, thereby obtaining a vitamin grafted amino acid resin, i.e. resin-5;

[0017] (6) Lipid vitamin separation: the resin of step (5) is mixed with a pre-cooled 1-2 hours at -10 to -20 °C cleavage solution, and reacted at room temperature in the dark for 20-30 minutes. The reaction solution is collected to obtain a lipid vitamin solution;

[0018] (7) The reaction solution of step (6) is collected, mixed with a precipitation solution, and centrifuged at 4000-6000 rpm at 0-4 °C. The precipitate is collected, and then vacuum freeze-dried for 24-48 hours to obtain a lipid vitamin based on an amino acid structure.

[0019] In step (1), the resin is 2-chlorotrityl chloride resin. In step (1), the first amino acid reaction solution is a mixture of Fmoc-protected amino acid, N, N-diisopropylethylamine (DIPEA) and DCM. The molar ratio of amino acid to DIPEA is 1:2-3. The amount of amino acid is 0.4-0.8 mmol / g compared with the resin in step (1). The amount of DCM is 8-12 mL / g.

[0020] In step (2), the blocking solution is a mixture of DCM, methanol and DIPEA with a volume ratio of 80-90:10-20:4-5. The amount of the mixture is 8-12 mL / g compared with the resin-1 in step (1). According to the above operation, the amino acid loading on the resin-2 is in the range of 0.15-0.35 mmol / g.

[0021] The deprotection solution in step (3) is a mixture of piperidine and DCM, the volume ratio of which is 1:3-6, and the amount of the mixture is 10-20 mL / g compared with resin-2 in step (2); the amino acid reaction solution in step (3) is a mixture of amino acid, DIPEA, HOBt, PyBop, DCM and DMF, wherein the molar ratio of the amount of amino acid, DIPEA, HOBt, PyBop to the amino acid loaded on resin-2 is 2-3:4-5:2-3:2-3:0.5-1.5, the volume ratio of DCM and DMF is 1:1-3, and the amount of DCM is 10-20 mL / g compared with resin-2;

[0022] The fatty acid reaction solution in step (4) is a mixture of fatty acid, DCM, DIPEA, HOBt, PyBop and DMF, wherein the molar ratio of the amount of fatty acid, DIPEA, HOBt, PyBop to the amino acid loaded on resin-2 is 2-3:4-5:2-3:2-3:0.5-1.5, the volume ratio of DCM and DMF is 1:1-3, and the amount of DCM is 10-20 mL / g compared with resin-2;

[0023] The Dde deprotection solution in step (5) is a mixture of hydrazine hydrate and DCM, the volume ratio of which is 1:40-60, and the amount of the mixture is 30-60 mL / g compared with resin-2 in step (2); the vitamin reaction solution in step (5) is a mixture of vitamin, DIPEA, HOBt, PyBop, DCM and DMF, and the molar ratio of the amount of vitamin, DIPEA, HOBt, PyBop to the amino acid loaded on resin-2 is 2-3:4-5:2-3:2-3:0.5-1.5, the volume ratio of DCM and DMF is 1:1-3, and the amount is 10-20 mL / g compared with resin-2;

[0024] The cleavage solution in step (6) is a mixture of trifluoroacetic acid, deionized water and triisopropylsilane, the volume ratio of which is 90-95:2.5-5:2.5-5, and the amount of the mixture is 80-120 mL / g compared with resin-5; the precipitation solution in step (7) is a mixture of methyl tert-butyl ether and n-hexane, the volume ratio of which is 1:1-3, and the amount of the mixture is 200-400 mL / g compared with resin-5;

[0025] The reaction solutions discarded in the above steps are all subjected to solid-liquid separation by using a syringe reactor, and the room temperature conditions all refer to the ambient temperature without controlling the reaction temperature.

[0026] Further, the amino acid structure fixation is to connect the carbon terminal amino acid to the resin through a connecting arm, specifically, 0.5-1 g of 2-chlorotrityl chloride resin is placed in a 5-15 mL syringe reactor and pre-swelled in anhydrous DCM for 30-60 minutes, and the DCM is discarded. Then, the first Fmoc-protected amino acid reaction solution is added, and incubated at room temperature for 1-2 hours, the components of the amino acid reaction solution include Fmoc-protected amino acid (Fmoc-amino acid), DCM and DIPEA (DIPEA). The reaction solution is removed and washed with DCM and DMF, and the resin-1 is obtained, and the washing steps are: first washed with DMF for 3-5 times, and then washed with DCM for 3-5 times.

[0027] The resin-1 is incubated with a blocking solution containing methanol at room temperature for 30-40 minutes to block the residual active chlorine functional group, and the blocking solution components include DCM, methanol and DIPEA. Again, washing and vacuum drying are performed, and the number of washing times is 3-5 times, and the resin-2 is obtained. The loading amount of amino acid on the resin-2 is measured.

[0028] Take 100-200 mg of resin-2, add 5-8 mL of DCM and pre-swelled for 30-60 minutes, and discard the DCM; repeat the following operation n times (1≤n≤20): add Fmoc deprotection solution, react for 10-20 minutes, and then discard the reaction solution, repeat 3-5 times, remove the protecting group, and the Fmoc deprotection solution is 20% v / v piperidine DCM solution; wash the resin-2 and couple Fmoc-amino acid, and the components include Fmoc-amino acid, DCM, DIPEA, HOBt, PyBop and DMF, and the resin-3 is obtained.

[0029] Subsequently, a stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid or hydroxyl-modified stearic acid solution is added as a lipid hydrophobic fatty tail. Specifically, a fatty acid reaction solution is added, and incubated at room temperature for 24-36 h. After the reaction, the reaction solution is removed after washing, and the resin-4 is obtained. The components of the fatty acid reaction solution include fatty acid, DCM, DIPEA, HOBt, PyBop and DMF.

[0030] The Dde semi-permanent protecting group of the amino acid side chain is removed, and a carboxylated vitamin is added. Specifically, by reacting with 8-10 mL of Dde deprotection solution for 2-3 minutes, the protecting group at the carbon terminal amino acid ε-amine is removed for 15-20 times, and the Dde deprotection solution is 2% v / v hydrazine hydrate DCM solution; then a vitamin reaction solution is added, and reacted at room temperature for 4-12 h in the dark, and after the reaction is completed, the residual reaction solution is removed after washing again, and the resin-5 is obtained.

[0031] Finally, cleavage solution was added to remove the t-butyloxycarbonyl (Boc) protecting group and cut the synthesized lipid vitamin from the resin-5; then it was immediately added to the precipitation solution which was a mixture of methyl t-butyl ether and n-hexane; centrifuged for 10-20 minutes to remove the soluble reaction byproducts, collected the precipitate and vacuum freeze-dried to obtain a series of lipid vitamins based on amino acid structure.

[0032] The present application first synthesizes a class of lipid vitamins based on amino acid structure, which has good biocompatibility and colloidal stability (no significant change in particle size distribution within one week, Figure 4) compared with traditional physical encapsulation liposomes. The amino acid biological scaffold can be selected from various chemical modification structures to realize antibody coupling and other multiple specific effects, thereby improving the in vivo targeting of the drug. At the same time, the problem of drug loading limitation is solved, and efficient and controllable vitamin loading is realized. In addition, by adjusting the ratio of lipid vitamins, the problem of uneven dispersion caused by hydrophobic structure in physical encapsulation can be avoided. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1: Chemical structure diagram of Example 1 of the present application.

[0034] Figure 2: Mass spectrum diagram of Example 1 of the present application.

[0035] Figure 3: Transmission electron microscope pictures of liposomes (a) and vitamin liposomes (b) of Example 1 of the present application.

[0036] Figure 4: Particle size test (0, 3, 7 days) of liposomes (a) and vitamin liposomes (b) synthesized in Example 1 of the present application. DETAILED DESCRIPTION

[0037] Example 1

[0038] (1) 1 g of 2-chlorotrityl chloride resin was placed in a 15 mL syringe reactor and pre-swelled in 5 mL of calcium chloride-dried DCM for 30 minutes, and the DCM was discarded. 0.45 mmol of Boc-protected Fmoc-lysine (Fmoc-Lys(Boc)-OH) and 0.9 mmol of DIPEA were dissolved in 5 mL of DCM, sucked into the syringe and incubated at room temperature for 1 h. Then the reaction solution was removed and the resin was washed with DMF and DCM, and the washing steps were first washed with DMF three times and then washed with DCM three times. 8 mL of DCM, 1.5 mL of methanol and 0.5 mL of DIPEA were mixed and sucked into the syringe and incubated at room temperature for 30 minutes. Then it was washed with DMF and DCM and vacuum dried, and the amino acid loading on the resin was measured to be 0.3 mmol / g.

[0039] (2) Take 100 mg resin from step (1), pre-swell in 5 mL DCM for 30 min, discard DCM. Take 20% v / v piperidine in DCM, repeat for 3 times, 15 min each time. Remove the reaction solution and wash the resin with DMF and DCM.

[0040] (3) Dissolve 0.12 mmol Dde-protected Fmoc-Lysine Fmoc-Lys(Dde)-OH and 0.24 mmol DIPEA in 1 mL DCM, dissolve 0.12 mmol HOBt and 0.12 mmol PyBop in 1 mL DMF, mix and inject into the syringe of step (2), discard the reaction solution after 1 h and wash the resin with DMF and DCM. Take 20% v / v piperidine in DCM, repeat for 3 times, 15 min each time. Remove the reaction solution and wash the resin with DMF and DCM.

[0041] (4) Dissolve 0.12 mmol stearic acid and 0.24 mmol DIPEA in 1 mL DCM, dissolve 0.12 mmol HOBt and 0.12 mmol PyBop in 1 mL DMF, mix and inject into the syringe of step (3), discard the reaction solution after 24 h and wash the resin with DMF and DCM. Take 5 mL 2% v / v hydrazine hydrate in DCM, react for 2 min, remove the reaction solution and repeat for 15 times. Remove the reaction solution and wash the resin with DMF and DCM.

[0042] (5) Dissolve 0.12 mmol D-α-tocopheryl succinate and 0.24 mmol DIPEA in 1 mL DCM, dissolve 0.12 mmol HOBt and 0.12 mmol PyBop in 1 mL DMF, mix and inject into the syringe of step (4), discard the reaction solution after 4 h in dark and wash the resin with DMF and DCM.

[0043] (6) Mix 9.5 mL trifluoroacetic acid, 0.25 mL water and 0.25 mL triisopropylsilane, inject into a syringe and react for 20 min at room temperature in dark. Take 40 mL methyl tert-butyl ether and n-hexane mixed solution pre-cooled at -20 °C for 1 h, the volume ratio is 1:1. Centrifuge at 4 °C, 4000 rpm for 15 min, remove the supernatant, dissolve in water, and freeze at -80 °C for 24 h to obtain the lipid vitamin based on amino acid structure.

[0044] (7) Take the lipid vitamin synthesized above, mix with cholesterol in chloroform solvent, remove the solvent by rotary evaporation in a round-bottom flask at 60 °C, and dry under vacuum at room temperature overnight; then add PBS and treat under ultrasonic condition for 30 min to obtain a liposome solution (Figure 3), which can be maintained relatively stable within a week (Figure 4).

[0045] Example 2

[0046] (1) 1 g of 2-chlorotrityl chloride resin was placed in a 15 mL syringe reactor and pre-swollen in 5 mL of DCM dried with calcium chloride for 30 minutes, and the DCM was discarded. 0.45 mmol of Fmoc-Lys(Dde)-OH and 0.9 mmol of DIPEA were dissolved in 5 mL of DCM, sucked into the syringe, and incubated at room temperature for 1 h. Then the reaction solution was removed and the resin was washed with DMF and DCM, and the washing steps were first washed with DMF for three times and then washed with DCM for three times. 8 mL of DCM, 1.5 mL of methanol, and 0.5 mL of DIPEA were mixed, sucked into the syringe, and incubated at room temperature for 30 minutes. The resin was washed with DMF and DCM again and vacuum dried, and the amino acid loading on the resin was measured to be 0.3 mmol / g of resin.

[0047] (2) 100 mg of the resin obtained in step (1) was taken and pre-swollen in 5 mL of DCM for 30 minutes, and the DCM was discarded. 20% v / v piperidine DCM solution was sucked, and after 15 minutes of reaction, the reaction solution was discarded and the operation was repeated three times. The reaction solution was removed and the resin was washed with DMF and DCM.

[0048] (3) 0.12 mmol of oleic acid and 0.24 mmol of DIPEA were dissolved in 1 mL of DCM, 0.12 mmol of HOBt and 0.12 mmol of PyBop were dissolved in 1 mL of DMF, and after mixing, they were sucked into the syringe of step (2). After 24 h of reaction, the reaction solution was discarded and the resin was washed with DMF and DCM. 5 mL of 2% v / v hydrazine hydrate DCM solution was sucked and reacted for 2 minutes, the reaction solution was removed, and the operation was repeated 15 times by re-sucking. The reaction solution was removed and the resin was washed with DMF and DCM.

[0049] (4) 0.12 mmol of L-L-threo-hex-2-ene dioic acid 1,4-lactone (carboxylated vitamin C) and 0.24 mmol of DIPEA were dissolved in 1 mL of DCM, 0.12 mmol of HOBt and 0.12 mmol of PyBop were dissolved in 1 mL of DMF, and after mixing, they were sucked into the syringe of step (3). After 4 h of reaction in the dark, the reaction solution was discarded and the resin was washed with DMF and DCM.

[0050] (5) 9.5 mL of trifluoroacetic acid, 0.25 mL of water, and 0.25 mL of triisopropylsilane were mixed, sucked into the syringe, and reacted at room temperature in the dark for 20 minutes. 40 mL of a mixture of methyl tert-butyl ether and n-hexane with a volume ratio of 1:1 was pre-cooled at -20°C for 1 h. Centrifugation was performed at 4°C, 4000 rpm, for 15 minutes, the supernatant was removed, and the operation was repeated by re-dissolving in water and vacuum freezing at -80°C for 24 h to obtain the lipid vitamin based on the amino acid structure.

[0051] Example 3

[0052] (1) 1 g of 2-chlorotrityl chloride resin was placed in a 15 mL syringe reactor and pre-swollen in 5 mL of DCM dried over calcium chloride for 30 minutes, and the DCM was discarded. 0.45 mmol of Fmoc-Lys(Dde)-OH, 0.9 mmol of DIPEA were dissolved in 5 mL of DCM, taken up in the syringe and incubated at room temperature for 1 h. The reaction was then removed and the resin was washed with DMF and DCM, with the washing steps being three washes with DMF followed by three washes with DCM. 8 mL of DCM, 1.5 mL of methanol, 0.5 mL of DIPEA were mixed and taken up in the syringe and incubated at room temperature for 30 minutes. The resin was again washed with DMF and DCM and vacuum dried, and the amino acid loading on the resin was measured to be 0.3 mmol / g of resin.

[0053] (2) 100 mg of the resin from step (1) was taken up in 5 mL of DCM and pre-swollen for 30 minutes, and the DCM was discarded. 20% v / v piperidine in DCM was taken up and the reaction was allowed to proceed for 15 minutes, after which the reaction was discarded and the resin was washed with DMF and DCM.

[0054] (3) 0.12 mmol of Fmoc-Lys(Boc)-OH and 0.24 mmol of DIPEA were dissolved in 1 mL of DCM, 0.12 mmol of HOBt and 0.12 mmol of PyBop were dissolved in 1 mL of DMF, and after mixing, the syringe from step (2) was taken up and the reaction was allowed to proceed for 1 h, after which the reaction was discarded and the resin was washed with DMF and DCM. 20% v / v piperidine in DCM was taken up and the reaction was allowed to proceed for 15 minutes, after which the reaction was discarded and the resin was washed with DMF and DCM. The reaction was repeated three times. The reaction was removed and the resin was washed with DMF and DCM.

[0055] (4) 0.12 mmol of stearic acid and 0.24 mmol of DIPEA were dissolved in 1 mL of DCM, 0.12 mmol of HOBt and 0.12 mmol of PyBop were dissolved in 1 mL of DMF, and after mixing, the syringe from step (3) was taken up and the reaction was allowed to proceed for 24 h, after which the reaction was discarded and the resin was washed with DMF and DCM. 5 mL of 2% v / v hydrazine hydrate in DCM was taken up and the reaction was allowed to proceed for 2 minutes, after which the reaction was removed and the resin was taken up again and the reaction was repeated 15 times. The reaction was removed and the resin was washed with DMF and DCM.

[0056] (5) 0.12 mmol of retinoic acid (carboxylated vitamin A) and 0.24 mmol of DIPEA were dissolved in 1 mL of DCM, 0.12 mmol of HOBt and 0.12 mmol of PyBop were dissolved in 1 mL of DMF, and after mixing, the syringe from step (4) was taken up and the reaction was allowed to proceed for 4 h in the dark, after which the reaction was discarded and the resin was washed with DMF and DCM.

[0057] (6) 9.5 mL trifluoroacetic acid, 0.25 mL water, 0.25 mL triisopropylsilane were mixed, sucked into a syringe and reacted at room temperature for 20 minutes in the dark. 40 mL of a mixture of methyl tert-butyl ether and n-hexane at a volume ratio of 1:1 pre-cooled at -20°C for 1 h was taken. Centrifugation was carried out at 4°C, 4000 rpm for 15 minutes, the supernatant was removed, redissolved in water, and vacuum frozen at -80°C for 24 h to obtain the lipid vitamin based on the amino acid structure.

[0058] The above merely describes preferred specific embodiments of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art should be covered within the protection scope of the present application according to the technical solution and the inventive concept of the present application, and any equivalent replacement or change is within the technical range disclosed by the present application.

Claims

1. A class of lipid vitamins based on amino acid structures, characterized in that, The head of the lipid vitamin is composed of an amino acid structure, and the tail is composed of a vitamin and a fatty acid branched chain.

2. The lipid vitamin according to claim 1, wherein The amino acid structure is composed of single or multiple amino acids; the vitamin includes vitamin A, vitamin C, and vitamin E; and the fatty acid includes stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid, and hydroxyl-modified stearic acid.

3. The method for preparing lipid vitamins according to claim 1, wherein The amino acid skeleton is fixed by chloro resin, and then the residual active chlorine functional groups are blocked by a blocking solution; the protecting groups of the amino acid are removed by a deprotection solution, and then the amino acid reaction solution, the fatty acid reaction solution, and the vitamin reaction solution are mixed respectively to obtain the expansion of the amino acid skeleton and the grafting of the vitamin and the fatty acid chain; and then the lipid vitamin and the resin are separated by a cleavage solution, and the specific conditions and steps are as follows: (1) Amino acid structure fixation: the resin is placed in a syringe reactor and pre-swelled in anhydrous dichloromethane for 20-30 minutes, the reaction solution is discarded, and then the first amino acid reaction solution is added, and the reaction is carried out at room temperature for 1-2 hours; then the reaction solution is removed, and N,N-dimethylformamide and dichloromethane are used for washing to obtain the amino acid structure fixed resin, i.e., resin-1; (2) Active chlorine functional group blocking: the resin prepared in step (1) is reacted with the blocking solution containing methanol at room temperature for 30-40 minutes, washed with N,N-dimethylformamide and dichloromethane, and then vacuum dried for 24-48 h to obtain the active chlorine functional group blocked resin, i.e., resin-2, and the amino acid loading rate is measured; (3) Amino acid structure expansion: the resin-2 prepared in step (2) is pre-swelled in anhydrous dichloromethane, and after the reaction solution is discarded, n times of repeated operations are carried out, 1≤n≤20; each operation step is as follows: the deprotection solution is added, the reaction is carried out at room temperature for 10-20 minutes to remove the temporary protecting groups of the amino acid, and then the amino acid reaction solution is added, and the reaction is carried out at room temperature for 1-2 hours; then the reaction solution is removed, and N,N-dimethylformamide and dichloromethane are used for washing, and finally n+1 amino acid structure fixed resins, i.e., resin-3, are obtained; (4) Fatty acid grafting: the resin-3 of step (3) is mixed with the deprotection solution, and the reaction is carried out at room temperature for 10-20 minutes; after the reaction solution is discarded, the fatty acid reaction solution is added, and the reaction is carried out at room temperature for 24-36 h to complete the fatty acid grafting, and the fatty acid grafted amino acid resin, i.e., resin-4, is obtained; (5) Vitamin grafting: the resin of step (4) is mixed with the 2-acetyldimethyl ketone protecting group deprotection solution, and the reaction is carried out at room temperature for 2-3 minutes, repeated for 10-20 times; after the reaction solution is discarded, the vitamin reaction solution is added, and the reaction is carried out at room temperature in the dark for 4-12 h; then the reaction solution is removed to complete the vitamin grafting, and the vitamin grafted amino acid resin, i.e., resin-5, is obtained; (6) Separation of the lipid vitamin: the resin of step (5) is mixed with the pre-cooled 1-2 h cleavage solution at-10 to-20℃, and the reaction is carried out at room temperature in the dark for 20-30 minutes; the reaction solution is collected to obtain the lipid vitamin solution. (7) Collecting the reaction solution of step (6), mixing with the precipitate solution, centrifuging at 4000-6000 rpm under 0-4 ℃, collecting the precipitate, and then vacuum freeze-drying for 24-48 h to obtain the lipid vitamin based on the amino acid structure; In the step (1), the resin is 2-chlorotrimesyl chloride resin; the first amino acid reaction solution in the step (1) is a mixture of amino acid, N, N-diisopropyl ethylamine and dichloromethane, the molar ratio of the amino acid and N, N-diisopropyl ethylamine is 1:2-3, the amount of the amino acid is 0.4-0.8 mmol / g compared with the resin in the step (1), and the amount of dichloromethane is 8-12 mL / g; In the step (2), the blocking solution is a mixture of dichloromethane, methanol and N, N-diisopropyl ethylamine, the volume ratio is 80-90:10-20:4-5, and the amount of the mixture is 8-12 mL / g compared with the resin-1 in the step (1); In the step (3), the deprotection solution is a mixture of piperidine and dichloromethane, the volume ratio of the components is 1:3-6, and the amount of the mixture is 10-20 mL / g compared with the resin-2 in the step (2); the amino acid reaction solution in the step (3) is a mixture of amino acid, N, N-diisopropyl ethylamine, hydroxybenzotriazole, benzotriazole-1-yl-oxytripyrrolidinophosphonium-hexafluorophosphate, dichloromethane and N, N-dimethylformamide, wherein the molar ratio of the amounts of the amino acid, N, N-diisopropyl ethylamine, hydroxybenzotriazole, benzotriazole-1-yl-oxytripyrrolidinophosphonium-hexafluorophosphate to the amino acid loaded on the resin-2 is 2-3:4-5:2-3:2-3:0.5-1.5, the volume ratio of dichloromethane and N, N-dimethylformamide is 1:1-3, and the amount of dichloromethane is 10-20 mL / g; In the step (4), the fatty acid reaction solution is a mixture of fatty acid, dichloromethane, N, N-diisopropyl ethylamine, hydroxybenzotriazole, benzotriazole-1-yl-oxytripyrrolidinophosphonium-hexafluorophosphate and N, N-dimethylformamide, wherein the molar ratio of the amounts of the fatty acid, N, N-diisopropyl ethylamine, hydroxybenzotriazole, benzotriazole-1-yl-oxytripyrrolidinophosphonium-hexafluorophosphate to the amino acid loaded on the resin-2 is 2-3:4-5:2-3:2-3:0.5-1.5, the volume ratio of dichloromethane and N, N-dimethylformamide is 1:1-3, and the amount of dichloromethane is 10-20 mL / g compared with the resin-2; The deprotection solution of the 2-acetyldimethylketone protecting group in step (5) is a mixture of hydrazine hydrate and dichloromethane with a volume ratio of 1:40-60, and the amount of the mixture used is 30-60 mL / g compared with the resin-2 in step (2); the vitamin reaction solution in step (5) is a mixture of vitamin, N, N-diisopropyl ethylamine, hydroxybenzotriazole, benzotriazole-1-yl-oxytripyrrolidinophosphonium-hexafluorophosphate, dichloromethane and N, N-dimethylformamide, and the molar ratio of vitamin, N, N-diisopropyl ethylamine, hydroxybenzotriazole, benzotriazole-1-yl-oxytripyrrolidinophosphonium-hexafluorophosphate to the amino acid loaded on the resin-2 is 2-3:4-5:2-3:2-3:0.5-1.5, the volume ratio of dichloromethane and N, N-dimethylformamide is 1:1-3, and the amount used is 10-20 mL / g compared with the resin-2; The cleavage solution in step (6) is a mixture of trifluoroacetic acid, deionized water and triisopropylsilane with a volume ratio of 90-95:2.5-5:2.5-5, and the amount of the mixture used is 80-120 mL / g compared with the resin-2; the precipitation solution in step (7) is a mixture of methyl tert-butyl ether and n-hexane with a volume ratio of 1:1-3, and the amount of the mixture used is 200-400 mL / g compared with the resin-2; The reaction solutions abandoned in the above steps are all subjected to solid-liquid separation by using a syringe reactor, and the room temperature conditions are not specially controlled.

4. The lipid vitamin prepared by the method of claim 3.

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