DMG-PEG500 for lipid nanoparticle carrier system and synthesis method of DMG-PEG500
Through the synthesis method of DMG-PEG500, the antibody response problem caused by the existing DMG-PEG2000 in the body was solved, and DMG-PEG with high purity and low molecular weight of 500 was obtained, which reduced the vaccine response and improved the efficacy.
Patent Information
- Application Number
- CN202411752170.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-02
- Publication Date
- 2025-03-14
AI Technical Summary
The existing DMG-PEG2000 may trigger low levels of PEG-specific antibodies in the body, resulting in an enhanced clearance of nanodrugs and limiting the efficacy of the vaccine.
The synthesis method of DMG-PEG500 is adopted, and a series of specific steps are obtained by reacting compound 1 with acetone, adding MsCl, reacting with NaH, and hydrochloric acid.
The obtained DMG-PEG500 has high purity and low molecular weight, which is suitable for vaccine applications, reducing vaccine response and improving therapeutic efficacy.
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Figure CN119613704A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of polymer synthesis, and in particular relates to a method for synthesizing DMG-PEG500 for a lipid nanoparticle carrier system. Background Art
[0002] Polyethylene glycol (PEG) is a non-toxic, hydrophilic polymer with a wide range of applications in cosmetics, personal care products, and pharmaceutical formulations. PEGylation is widely used in bioconjugation and nanomedicine to maintain the colloidal stability of nanoparticles and reduce the clearance of nanomedicines in the body, thereby improving R&D efficiency and safety.
[0003] DMG-PEG2000, the full name of which is 1,2-dimyristoylglycerol-3-methoxypolyethylene glycol 2000, is a macromolecular polymer composed of a hydrophilic PEG polymer and a hydrophobic short-chain lipid. This substance is an additive in Moderna and Pfizer-BioNTech COVID-19 vaccines, which can protect the transfer of mRNA to human cells. However, current studies have found that in some cases, PEG has weak immunogenicity and produces low levels of PEG-specific antibodies in the body, which can lead to enhanced clearance of systemically delivered PEGylated nanomedicines, including therapies for the treatment of cancer, gout or patients with genetic diseases, thereby limiting the efficacy of related vaccines. Summary of the invention
[0004] The purpose of the present invention is to provide DMG-PEG500 for a lipid nanoparticle carrier system and a synthesis method thereof. The method of the present invention can obtain high-purity and low-molecular-weight DMG-PEG of 500, which provides application prospects for reducing vaccine reactions in vaccine applications.
[0005] To this end, the present invention provides the following technical solutions.
[0006] One aspect of the present invention provides a DMG-PEG500 for a lipid nanoparticle carrier system having the following structural formula:
[0007]
[0008] Another aspect of the present invention provides a method for synthesizing DMG-PEG500 for a lipid nanoparticle carrier system, the method comprising the following steps:
[0009] S1: Compound 1 and acetone are mixed and reacted in the presence of concentrated sulfuric acid to obtain compound 2;
[0010]
[0011] S2: Add DCM and TEA to compound 2, and then add MsCl to react to obtain compound 3;
[0012]
[0013] S3: adding THF to compound 4, and then adding NaH to carry out a primary reaction to obtain a reaction solution, and adding compound 3 to the obtained reaction solution to carry out a secondary reaction to obtain compound 5;
[0014]
[0015] S4: adding methanol to compound 5, and then adding hydrochloric acid to react to obtain compound 6;
[0016]
[0017] S5: Add DCM and TEA to compound 6, and then add compound 7 to react to obtain compound 8, which is DMG-PEG500;
[0018]
[0019] As a preferred embodiment of the present invention, in step S1, the reaction conditions are: temperature: room temperature, time: 1 to 3 hours.
[0020] As a preferred embodiment of the present invention, in step S1, after the reaction is completed, a saturated sodium bicarbonate aqueous solution is added to the reaction solution to remove acetone by rotary evaporation, and then dichloromethane is added for extraction. The layers are separated, and the organic phase is dried over anhydrous sodium sulfate overnight and concentrated by rotary evaporation to obtain compound 2.
[0021] As a preferred embodiment of the present invention, in step S2, the system is cooled to 0°C before adding MsCl.
[0022] As a preferred embodiment of the present invention, in step S2, the reaction conditions are: temperature: room temperature, time: 0.5 to 1 h.
[0023] As a preferred embodiment of the present invention, in step S2, after the reaction is completed, water is added to the reaction solution, and then DCM is added for extraction, the layers are separated, and the organic phase is dried over anhydrous sodium sulfate overnight and concentrated by rotary evaporation to obtain compound 3.
[0024] As a preferred embodiment of the present invention, in step S3, the system is cooled to 0°C before adding NaH.
[0025] As a preferred embodiment of the present invention, in step S3, the primary reaction conditions are: temperature: room temperature, time: 1 to 2 hours;
[0026] The secondary reaction conditions are: temperature: 80°C, time: 16 to 24 hours.
[0027] As a preferred embodiment of the present invention, in step S3, after the secondary reaction is completed, water is added to the reaction solution for rotary evaporation concentration, and then EA is added for extraction, the layers are separated, the organic phase is dried over anhydrous sodium sulfate overnight, rotary evaporation concentration, and column chromatography purification to obtain compound 5.
[0028] As a preferred embodiment of the present invention, in step S4, the reaction conditions are: temperature: room temperature, time: 2 to 3 hours.
[0029] As a preferred embodiment of the present invention, in step S4, after the reaction is completed, a saturated sodium bicarbonate aqueous solution is added to the reaction solution, and the mixture is concentrated by rotary evaporation. Then, the mixture is extracted with DCM, the layers are separated, and the organic phase is dried over anhydrous sodium sulfate overnight and concentrated by rotary evaporation to obtain compound 6.
[0030] As a preferred embodiment of the present invention, in step S5, the system is cooled to 0°C before adding compound 7.
[0031] As a preferred embodiment of the present invention, in step S5, the reaction conditions are: temperature: room temperature, time: 4 to 6 hours.
[0032] As a preferred embodiment of the present invention, in step S5, after the reaction is completed, the reaction solution is washed with water and saturated brine in sequence, then extracted with DCM, separated, and the organic phase is dried over anhydrous sodium sulfate overnight, concentrated by rotary evaporation, and purified by column chromatography to obtain compound 8.
[0033] By means of the above technical solution, the present invention has at least the following advantages:
[0034] The method of the present invention can obtain DMG-PEG with a small molecular weight, and the calculated molecular weight of the product is 500. The DMG-PEG500 obtained by the synthesis method of the present invention has the advantages of high purity and high yield, and is more suitable for industrial scale-up production.
[0035] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the preferred embodiments of the present invention are described in detail as follows. BRIEF DESCRIPTION OF THE DRAWINGS
[0036] Figure 1 This is the NMR spectrum of DMG-PEG500 prepared in Example 1 of the present invention;
[0037] Figure 2 This is the LC-MS spectrum of DMG-PEG500 prepared in Example 1 of the present invention. DETAILED DESCRIPTION
[0038] In order to make the technical means, creative features, objectives and effects of the present invention easy to understand, the technical solutions in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0039] Unless otherwise specified, the percentage content involved in the present invention refers to mass percentage for solid-liquid mixing and solid-solid mixing, and refers to volume percentage for liquid-liquid mixing.
[0040] Unless otherwise specified, the percentage concentrations referred to in the present invention all refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.
[0041] The temperature parameters in the present invention, if not specifically limited, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the precision range controlled by the instrument.
[0042] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.
[0043] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.
[0044] Example 1: Synthesis and detection of DMG-PEG500
[0045] 1) Compound 2 is obtained by reacting compound 1 with acetone
[0046]
[0047] Compound 1 (10.0 g, 0.11 mol, 1.0 eq.) and acetone (31.5 g, 0.54 mol, 5 eq.) were added to a flask, and then 3 drops of concentrated sulfuric acid were added to obtain a mixture. The obtained mixture was stirred at room temperature for 2 hours to obtain a reaction solution. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the obtained reaction solution, and the acetone in the reaction solution was rotary evaporated. The remaining reaction solution was extracted with dichloromethane, separated, and the organic phase was dried over anhydrous sodium sulfate, and then rotary evaporated to obtain compound 2 (11.2 g, yield: 77%).
[0048] After testing, the NMR data of compound 2 is: 1H NMR(400MHz,cdcl3)δ4.22(tdd,J=6.5,5.3,3.8Hz,1H),4.02(dd,J=8.2,6.7Hz,1H),3.7 5(ddd,J=22.8,9.9,5.1Hz,2H),3.57(dd,J=11.7,5.1Hz,1H),1.42(s,3H),1.35(s,3H).
[0049] 2) Compound 3 is obtained by reacting compound 2 with MsCl
[0050]
[0051] Compound 2 (10.0 g, 0.08 mol, 1.0 eq.) and DCM (100 mL) were added to a flask, and TEA (10.0 g, 0.10 mol, 1.3 eq.) was added to obtain a reaction solution. The obtained reaction solution was cooled to 0°C, and MsCl (10.4 g, 0.09 mol, 1.2 eq.) was slowly added dropwise to obtain a mixture. The obtained mixture was stirred at room temperature for 0.5 h to obtain a reaction solution. Water (100 mL) was added to the obtained reaction solution, and the reaction solution was extracted with DCM, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain compound 3 (14.5 g, yield: 91%).
[0052] 3) Compound 3 is reacted with compound 4 to obtain compound 5;
[0053]
[0054] Compound 4 (20.0 g, 0.04 mol, 1.0 eq.) and THF (200 mL) were added to a flask to obtain a reaction solution. The reaction solution was cooled to 0°C, and NaH (1.7 g, 0.04 mol, 1.2 eq.) was added in two batches within 15 mins to obtain a mixture. The mixture was stirred at room temperature for 1 h to obtain a reaction solution. Compound 3 (9.0 g, 0.04 mol, 1.2 eq.) was added to the reaction solution, and the mixture was refluxed at 80°C for 16 h to obtain a reaction solution. Water (100 mL) was then added to the reaction solution, and the mixture was concentrated by rotary evaporation, extracted with EA, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain a crude product. The crude product was purified by column chromatography to obtain compound 5 (8.4 g, yield: 35%).
[0055] After testing, the NMR data of compound 5 is: 1H NMR(400MHz,cdcl3)δ4.29–4.23(m,1H),4.06–4.00(m,1H),3.73–3.51(m, 50H), 3.48 (dd, J = 10.0, 5.5Hz, 1H), 3.36 (s, 3H), 1.40 (s, 3H), 1.34 (s, 3H).
[0056] 4) Compound 6 is obtained by reacting compound 5 with hydrochloric acid
[0057] Compound 5 (9.0 g, 0.01 mol, 1.0 eq.) and MeOH (20 mL) were added to a flask, and then 1 M HCl (20 mL) was added to obtain a mixture. The obtained mixture was stirred at room temperature for 2 h to obtain a reaction solution. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the obtained reaction solution, and the reaction solution was concentrated by rotary evaporation, extracted with DCM, and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain compound 6 (5.8 g, yield: 68%).
[0058] 5) Compound 8 is obtained by reacting compound 6 with compound 7
[0059] Compound 6 (5 g, 0.008 mol, 1.0 eq.) and DCM (50 mL) were added to a flask, and then TEA (8.0 g, 0.09 mol, 10 eq.) was added to obtain a mixture. The mixture was cooled to 0°C, and compound 7 (11.0 g, 0.04 mol, 6.0 eq.) was slowly added dropwise, and stirred at room temperature for 5 h to obtain a reaction solution. The reaction solution was washed twice with water, and then washed twice with saturated brine, and then extracted with DCM, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain a crude product. The crude product was purified by column chromatography to obtain compound 8 (2.5 g, yield: 32%).
[0060] After testing, the NMR data of compound 8 is: 1 H NMR(400MHz,cdcl3)δ5.22–5.16(m,1H),4.32(dd,J=11.9,3.5Hz,1H),4.13(dd,J=11.9,6.5Hz,1H),3.87–3.56(m,46H),3.55–3 .51(m,2H),3.36(s,3H),2.29(dd,J=14.8,7.4Hz,4H),1.70(s,6H),1.58(d,J=4.6Hz,4H),1.23(s,36H),0.86(t,J=6.6Hz,6H).
[0061] The NMR spectrum and LC-MS spectrum of compound 8 are shown in Figure 1-2 shown.
[0062] Example 2: Synthesis of DMG-PEG500
[0063] 1) Compound 2 is obtained by reacting compound 1 with acetone
[0064]
[0065] Compound 1 (10.0 g, 0.11 mol, 1.0 eq.) and acetone (31.5 g, 0.54 mol, 5 eq.) were added to a flask, and then 3 drops of concentrated sulfuric acid were added to obtain a mixture. The obtained mixture was stirred at room temperature for 1 hour to obtain a reaction solution. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the obtained reaction solution, and the acetone in the reaction solution was rotary evaporated. The remaining reaction solution was extracted with dichloromethane, separated, and the organic phase was dried over anhydrous sodium sulfate, and then rotary evaporated to obtain compound 2 (10.4 g, yield: 72%).
[0066] 2) Compound 3 is obtained by reacting compound 2 with MsCl
[0067]
[0068] Compound 2 (10.0 g, 0.08 mol, 1.0 eq.) and DCM (100 mL) were added to a flask, and then TEA (10.0 g, 0.10 mol, 1.3 eq.) was added to obtain a reaction solution. The obtained reaction solution was cooled to 0°C, and MsCl (10.4 g, 0.09 mol, 1.2 eq.) was slowly added dropwise to obtain a mixture. The obtained mixture was stirred at room temperature for 0.5 h to obtain a reaction solution. Water (100 mL) was added to the obtained reaction solution, and the reaction solution was extracted with DCM, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain compound 3 (13.1 g, yield: 82%).
[0069] 3) Compound 3 is reacted with compound 4 to obtain compound 5;
[0070]
[0071] Compound 4 (20.0 g, 0.04 mol, 1.0 eq.) and THF (200 mL) were added to a flask to obtain a reaction solution. The reaction solution was cooled to 0°C, and NaH (1.7 g, 0.04 mol, 1.2 eq.) was added in two batches within 15 mins to obtain a mixture. The mixture was stirred at room temperature for 1.5 h to obtain a reaction solution. Compound 3 (9.0 g, 0.04 mol, 1.2 eq.) was added to the reaction solution, and the mixture was refluxed at 80°C for 20 h to obtain a reaction solution. Water (100 mL) was then added to the reaction solution, and the mixture was concentrated by rotary evaporation, extracted with EA, separated into layers, and the organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain a crude product. The crude product was purified by column chromatography to obtain compound 5 (7.5 g, yield: 31%).
[0072] 4) Compound 6 is obtained by reacting compound 5 with hydrochloric acid
[0073] Compound 5 (9.0 g, 0.01 mol, 1.0 eq.) and MeOH (20 mL) were added to a flask, and then 1 M HCl (20 mL) was added to obtain a mixture. The obtained mixture was stirred at room temperature for 2.5 h to obtain a reaction solution. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the obtained reaction solution, and the reaction solution was concentrated by rotary evaporation, extracted with DCM, and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain compound 6 (5.6 g, yield: 66%).
[0074] 5) Compound 8 is obtained by reacting compound 6 with compound 7
[0075] Compound 6 (5 g, 0.008 mol, 1.0 eq.) and DCM (50 mL) were added to a flask, and then TEA (8.0 g, 0.09 mol, 10 eq.) was added to obtain a mixture. The mixture was cooled to 0°C, and compound 7 (11.0 g, 0.04 mol, 6.0 eq.) was slowly added dropwise, and stirred at room temperature for 4 h to obtain a reaction solution. The reaction solution was washed twice with water, and then washed twice with saturated brine, and then extracted with DCM, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain a crude product. The crude product was purified by column chromatography to obtain compound 8 (2.4 g, yield: 31%).
[0076] Example 3: Synthesis and detection of DMG-PEG500
[0077] 1) Compound 2 is obtained by reacting compound 1 with acetone
[0078]
[0079] Compound 1 (10.0 g, 0.11 mol, 1.0 eq.) and acetone (31.5 g, 0.54 mol, 5 eq.) were added to a flask, and then 3 drops of concentrated sulfuric acid were added to obtain a mixture. The obtained mixture was stirred at room temperature for 3 hours to obtain a reaction solution. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the obtained reaction solution, and the acetone in the reaction solution was rotary evaporated. The remaining reaction solution was extracted with dichloromethane, separated, and the organic phase was dried over anhydrous sodium sulfate, and then rotary evaporated to obtain compound 2 (9.5 g, yield: 66%).
[0080] 2) Compound 3 is obtained by reacting compound 2 with MsCl
[0081]
[0082] Compound 2 (10.0 g, 0.08 mol, 1.0 eq.) and DCM (100 mL) were added to a flask, and then TEA (10.0 g, 0.10 mol, 1.3 eq.) was added to obtain a reaction solution. The obtained reaction solution was cooled to 0°C, and MsCl (10.4 g, 0.09 mol, 1.2 eq.) was slowly added dropwise to obtain a mixture. The obtained mixture was stirred at room temperature for 1 h to obtain a reaction solution. Water (100 mL) was added to the obtained reaction solution, and the reaction solution was extracted with DCM, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain compound 3 (13.2 g, yield: 83%).
[0083] 3) Compound 3 is reacted with compound 4 to obtain compound 5;
[0084]
[0085] Compound 4 (20.0 g, 0.04 mol, 1.0 eq.) and THF (200 mL) were added to a flask to obtain a reaction solution. The obtained reaction solution was cooled to 0°C, and NaH (1.7 g, 0.04 mol, 1.2 eq.) was added in two batches within 15 mins to obtain a mixture. The obtained mixture was stirred at room temperature for 1 h to obtain a reaction solution. Compound 3 (9.0 g, 0.04 mol, 1.2 eq.) was added to the obtained reaction solution, and refluxed at 80°C for 24 h to obtain a reaction solution. Water (100 mL) was then added to the obtained reaction solution, and after rotary evaporation concentration, EA was extracted, and the organic phase was dried over anhydrous sodium sulfate and rotary evaporation concentration was performed to obtain a crude product. The obtained crude product was purified by column chromatography to obtain compound 5 (6.8 g, yield: 28%).
[0086] 4) Compound 6 is obtained by reacting compound 5 with hydrochloric acid
[0087] Compound 5 (9.0 g, 0.01 mol, 1.0 eq.) and MeOH (20 mL) were added to a flask, and then 1 M HCl (20 mL) was added to obtain a mixture. The obtained mixture was stirred at room temperature for 3 h to obtain a reaction solution. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the obtained reaction solution, and the reaction solution was concentrated by rotary evaporation, extracted with DCM, and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain compound 6 (6.1 g, yield: 72%).
[0088] 5) Compound 8 is obtained by reacting compound 6 with compound 7
[0089] Compound 6 (5 g, 0.008 mol, 1.0 eq.) and DCM (50 mL) were added to a flask, and then TEA (8.0 g, 0.09 mol, 10 eq.) was added to obtain a mixture. The mixture was cooled to 0°C, and compound 7 (11.0 g, 0.04 mol, 6.0 eq.) was slowly added dropwise, and stirred at room temperature for 6 h to obtain a reaction solution. The reaction solution was washed twice with water, and then washed twice with saturated brine, and then extracted with DCM, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain a crude product. The crude product was purified by column chromatography to obtain compound 8 (2.6 g, yield: 33%).
[0090] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technician familiar with this profession can make some changes or modifications to equivalent embodiments of equivalent changes by using the methods and technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.
Claims
1. A lipid nanoparticle carrier system using DMG-PEG500, characterized in that: It has the following structural formula:
2. The synthetic method of DMG-PEG500 for lipid nanoparticle carrier system according to claim 1, characterized in that, The method comprises the following steps: S1: Compound 1 and acetone are mixed and reacted in the presence of concentrated sulfuric acid to obtain compound 2; S2: Add DCM and TEA to compound 2, and then add MsCl to react to obtain compound 3; S3: adding THF to compound 4, and then adding NaH to carry out a primary reaction to obtain a reaction solution, and adding compound 3 to the obtained reaction solution to carry out a secondary reaction to obtain compound 5; S4: adding methanol to compound 5, and then adding hydrochloric acid to react to obtain compound 6; S5: Add DCM and TEA to compound 6, and then add compound 7 to react to obtain compound 8, which is DMG-PEG500; 3. The synthesis method according to claim 2, characterized in that In step S1, the reaction conditions are: temperature: room temperature, time: 1 to 3 hours.
4. The synthesis method according to claim 2, characterized in that In step S1, after the reaction is completed, a saturated sodium bicarbonate aqueous solution is added to the reaction solution to remove acetone by rotary evaporation, and then dichloromethane is added for extraction. The layers are separated, and the organic phase is dried over anhydrous sodium sulfate overnight and concentrated by rotary evaporation to obtain compound 2.
5. The synthesis method according to claim 2, characterized in that In step S2, the reaction conditions are: temperature: room temperature, time: 0.5 to 1 h.
6. The synthesis method according to claim 2, characterized in that In step S2, after the reaction is completed, water is added to the reaction solution, and then DCM is added for extraction. The layers are separated, and the organic phase is dried over anhydrous sodium sulfate overnight and concentrated by rotary evaporation to obtain compound 3.
7. The synthesis method according to claim 2, characterized in that In step S3, the primary reaction conditions are: temperature: room temperature, time: 1 to 2 hours; The secondary reaction conditions are: temperature: 80°C, time: 16 to 24 hours.
8. The synthesis method according to claim 2, characterized in that In step S3, after the secondary reaction is completed, water is added to the reaction solution for rotary evaporation and then EA is added for extraction. The organic phase is dried over anhydrous sodium sulfate overnight, concentrated by rotary evaporation, and purified by column chromatography to obtain compound 5.
9. The synthesis method according to claim 2, characterized in that: In step S4, the reaction conditions are: temperature: room temperature, time: 2 to 3 hours.
10. The synthesis method according to claim 2, characterized in that: In step S4, after the reaction is completed, a saturated sodium bicarbonate aqueous solution is added to the reaction solution, and the mixture is concentrated by rotary evaporation. The mixture is then extracted with DCM, separated, and the organic phase is dried over anhydrous sodium sulfate overnight and concentrated by rotary evaporation to obtain compound 6.
11. The synthesis method according to claim 2, characterized in that: In step S5, the reaction conditions are: temperature: room temperature, time: 4 to 6 hours.
12. The synthesis method according to claim 2, characterized in that: In step S5, after the reaction is completed, the reaction solution is washed with water and saturated brine in sequence, then extracted with DCM, separated, and the organic phase is dried over anhydrous sodium sulfate overnight, concentrated by rotary evaporation, and purified by column chromatography to obtain compound 8.