Gentiopicroside amide derivative, synthetic method and application

Abstract

The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a gentiopicroside amide derivative, a synthesis method and application. A series of gentiopicroside amide derivatives are synthesized by taking gentiopicroside as a research object, carrying out structural modification on 6 '-site hydroxyl of gentiopicroside and introducing a benzoyl chloride group into a gentiopicroside structure. The synthetic method has the beneficial effects that on one hand, the synthetic method of the gentiopicroside amide derivative, which is mild in reaction condition and environment-friendly, is established; on the other hand, the 20 synthesized gentiopicroside amide derivatives have a remarkable inhibition effect on expression of LPS-induced THP-1 macrophage IL-6 and STAT3 protein content, the anti-inflammatory activity is remarkable, the action effect is superior to that of parent compound gentiopicroside, and a new thought is provided for preparation of STAT3 small-molecule inhibitors and anti-inflammatory drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a gentiopicroside amide derivative, a synthesis method and an application thereof. Background Art

[0002] As we all know, inflammation is a defensive response of the body's tissues to damaging stimuli, and is a complex process involving multiple cells and multiple components. The currently used clinical anti-inflammatory drugs, such as coxibs, can seriously increase the risk of cardiovascular disease, as well as the risk of myocardial infarction and stroke. Therefore, it is urgent to develop an anti-inflammatory drug with high efficacy and low toxicity.

[0003] A large number of studies have shown that monomer components extracted from natural products not only have diverse chemical structures and mechanisms of action, but also have relatively good safety. Therefore, the optimization of natural anti-inflammatory active ingredients as lead compounds has attracted the attention of many pharmaceutical workers.

[0004] Signal transducer and activator of transcription 3 (STAT3) was originally discovered as a DNA-binding protein that mediates interferon-dependent gene expression. In fact, STAT3 is involved in a variety of biological processes such as cell proliferation, survival, differentiation, and angiogenesis. Interleukin-6 (IL-6) is a pleiotropic cytokine released by a variety of different cell types, such as macrophages, T cells, and fibroblasts. IL-6 plays an important role in the physiological and pathological processes of chronic inflammation, autoimmune diseases, tumors, and other diseases through a variety of mechanisms. Among them, when IL-6 binds to the soluble IL-6 receptor to form the IL-6 / sIL-6R complex, it then activates gp130 on the cell membrane surface, inducing the activation of the STAT3 transcription factor. Abnormally activated STAT3 is involved in the occurrence and development of a variety of diseases. Therefore, the physiological involvement of the IL-6 / STAT3 pathway in multiple complex diseases has made this pathway a research hotspot for drug discovery. STAT3 can be activated by the binding of various cytokines, growth factors and hormones such as IL-6 to cell surface receptors. It is of great significance in embryonic development, cell proliferation, immunity and inflammatory response. Therefore, STAT3 is a suitable target for the development of anti-inflammatory drugs.

[0005] Gentianopicroside is an iridoid glycoside compound found in Gentianaceae plants. It has a wide range of pharmacological effects in protecting the liver, anti-inflammation, anti-tumor and immunomodulation. However, its high water solubility, rapid metabolism and short half-life reduce its efficacy. These characteristics limit its clinical application to a certain extent. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a gentiopicroside amide derivative, a synthesis method and an application thereof.

[0007] The present invention takes gentiopicroside as the research object, introduces a hydrophobic group "amide group" with anti-inflammatory and anti-tumor activity to modify the structure of its 6' hydroxyl group, introduces a benzoyl chloride group into the gentiopicroside structure, and uses anti-inflammatory experiments to screen the biological activities of the synthesized gentiopicroside amide derivatives, thereby obtaining gentiopicroside amide derivatives with significant inhibitory effects on IL-6 and STAT3 and excellent anti-inflammatory activity.

[0008] The first aspect of the present invention is to provide a gentiopicroside amide derivative, the structure of the gentiopicroside amide derivative is shown in general formula 1:

[0009] General formula 1:

[0010]

[0011] Wherein, R is selected from any one of methyl, methoxy, fluoride, chloride, and bromide.

[0012] The second aspect of the present invention is to provide a method for synthesizing the gentiopicroside amide derivatives having the above structure, comprising the following steps:

[0013] (1) Using gentiopicroside and p-toluenesulfonyl chloride as raw materials, pyridine as solvent, and methanol as quencher, an esterification reaction was performed to obtain intermediate I;

[0014] (2) Using sodium azide and the intermediate I obtained in (1) as raw materials and N,N-dimethylformamide as solvent, azide substitution is performed to obtain the intermediate II;

[0015] (3) Using trimethylsilyl chloride and the intermediate II obtained in (2) as raw materials, imidazole as a catalyst, N,N-dimethylformamide as a solvent, and TMS to protect the hydroxyl group to obtain the intermediate III;

[0016] (4) using triphenylphosphine and the intermediate III obtained in (3) as raw materials, tetrahydrofuran as solvent, hydrolyzing with H2O, and undergoing Staudinger reaction to obtain the intermediate IV;

[0017] (5) using benzoyl chloride and the intermediate IV obtained in (4) as raw materials and anhydrous dichloromethane as solvent, performing an amidation reaction to obtain the intermediate V;

[0018] The structural formula of the benzoyl chloride is as follows:

[0019]

[0020] Wherein, R is selected from any one of methyl, methoxy, fluoride, chloride, and bromide;

[0021] (6) The intermediate V obtained in (5) is deprotected from the TMS protecting group to obtain a gentiopicroside amide derivative having a structure shown in Formula 1.

[0022] In the synthesis method of the gentiopicroside amide derivatives provided by the present invention, preferably, in (1), pyridine is first added to dissolve gentiopicroside, and then p-toluenesulfonyl chloride is added dropwise at 0-5° C. under N3 protection for 5-7 hours, and then methanol is added for quenching, and then purified to obtain intermediate I;

[0023] The molar ratio of gentiopicroside to p-toluenesulfonyl chloride is 1:1.5-2, and the molar ratio of solvent pyridine to gentiopicroside is 130-140:1.

[0024] More preferably, the purification operation described in (1) is: after the reaction is completed, the solvent is evaporated under reduced pressure, and the product is purified by silica gel column chromatography using a gradient elution ratio of dichloromethane:methanol v:v=(100-30):1.

[0025] Preferably, in (2), intermediate I and sodium azide are used as raw materials, N,N-dimethylformamide is used as solvent, and the reaction is carried out at 50-65°C for 8-15 hours under N3 protection, and then extracted with ethyl acetate and purified to obtain intermediate II;

[0026] The molar ratio of intermediate I to sodium azide is 1:6-7, and the molar ratio of solvent N,N-dimethylformamide to intermediate I is 130-140:1.

[0027] More preferably, in (2), the specific operation of the purification operation is: taking the organic layer obtained after extraction with ethyl acetate, adding anhydrous sodium sulfate to remove water, evaporating the solvent under reduced pressure, purifying by silica gel column chromatography, and eluting with dichloromethane: methanol v:v = 50:1.

[0028] Preferably, in (3), intermediate II and trimethylsilyl chloride are used as raw materials, imidazole is used as a catalyst, and N,N-dimethylformamide is used as a solvent. Under the protection of N3, the reaction is first carried out at 0-5°C for 3-10 minutes and then at room temperature for 0.5-1 hour, and intermediate III is obtained after purification;

[0029] The molar ratio of intermediate II: trimethylchlorosilane: imidazole is 1:6-6.5:6-6.5, and the molar ratio of solvent N,N-dimethylformamide to intermediate II is 140-150:1.

[0030] More preferably, in (3), the specific operation of the purification operation is: extraction with ethyl acetate, collecting the organic layer, adding anhydrous sodium sulfate to the organic layer to remove water, evaporating the solvent under reduced pressure, and purifying by silica gel column chromatography, using petroleum ether: ethyl acetate v:v = 10:1 for elution.

[0031] Preferably, in (4), intermediate III and triphenylphosphine are used as raw materials and tetrahydrofuran is used as solvent, and after intermediate III is completely reacted for 4 to 8 hours, H2O is added for hydrolysis reaction for 1 to 3 hours, and then extracted with dichloromethane, and the solvent is evaporated under reduced pressure to obtain intermediate IV;

[0032] The molar ratio of intermediate III: triphenylphosphine: H2O is 1:1.2-1.5:70-80, and the molar ratio of solvent tetrahydrofuran to intermediate III is 160-170:1.

[0033] Preferably, in (5), intermediate IV, benzoyl chloride, and triethylamine are used as raw materials, anhydrous dichloromethane is used as solvent, and the reaction is carried out at 0-5°C for 20-40 minutes under N3 protection, and the solvent is evaporated under reduced pressure to obtain intermediate V;

[0034] The molar ratio of intermediate IV: benzoyl chloride: triethylamine is 1:2-3:1.5-2, and the molar ratio of solvent dichloromethane to intermediate IV is 410-420:1.

[0035] More preferably, in (5), the benzoyl chloride having the structure is selected from the group consisting of benzoyl chloride, o-methylbenzoyl chloride, m-methylbenzoyl chloride, p-methylbenzoyl chloride, 3,5-dimethylbenzoyl chloride, m-methoxybenzoyl chloride, 3,4-dimethoxybenzoyl chloride, 3,5-dimethoxybenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, o-fluorobenzoyl chloride, p-fluorobenzoyl chloride, 3,5-difluorobenzoyl chloride, o-chlorobenzoyl chloride, 3-chlorobenzoyl chloride, 4-chlorobenzoyl chloride, 3,4-dichlorobenzoyl chloride, 3,5-dichlorobenzoyl chloride, o-bromobenzoyl chloride, 3-bromobenzoyl chloride and 4-bromobenzoyl chloride.

[0036] Preferably, in (6), intermediate V and tetrabutylammonium fluoride are used as raw materials, tetrahydrofuran is used as solvent, and the reaction is carried out at 0-5°C for 5-10 hours under N3 protection, and then purified to obtain a gentiopicroside amide derivative having a structure shown in general formula 1;

[0037] The molar ratio of intermediate V: tetrabutylammonium fluoride: solvent tetrahydrofuran is 1:8-9:340-350.

[0038] More preferably, the purification operation described in (6) is as follows: extracting the mixture after the reaction with dichloromethane, collecting the organic layer, adding anhydrous sodium sulfate to the organic layer to remove water, evaporating the solvent under reduced pressure, and purifying by silica gel column chromatography, using a gradient elution ratio of dichloromethane:methanol v:v=(100-10):1.

[0039] Furthermore, the synthetic route of the above-mentioned gentiopicroside amide derivatives is as follows:

[0040]

[0041] The third aspect of the present invention is to provide the application of the gentiopicroside amide derivatives having the above structure, that is, to apply the gentiopicroside amide derivatives to the preparation of anti-inflammatory drugs, which is also the focus of protection of the present invention.

[0042] The beneficial effects of the present invention are:

[0043] (1) The present invention uses gentiopicroside as the research object, selects the 6'-hydroxyl group as the modification site, and introduces benzoyl chloride groups containing different substituents into the gentiopicroside structure based on the reaction mechanisms and pharmacophore splicing principles of esterification reaction, azide substitution reaction, TMS hydroxyl protection reaction, and Staudinger reaction. Twenty gentiopicroside amide derivatives were designed and synthesized, and a method for synthesizing gentiopicroside amide derivatives with mild reaction conditions and environmental friendliness was established.

[0044] (2) The gentiopicroside amide derivatives provided by the present invention have a significant inhibitory effect on the expression of IL-6 and STAT3 proteins in inflammatory cells, providing a new idea for the preparation of anti-inflammatory drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The optical microscope pictures (100×) of the morphological changes of THP-1 cells induced by PMA at different concentrations at 24h and 48h in Experimental Example 1 of the present invention;

[0046] Figure 2 The effect of the gentiopicroside amide derivatives in Experimental Example 1 of the present invention on the survival rate of THP-1 macrophages at a concentration of 10 μM;

[0047] Figure 3 The effect of the gentiopicroside amide derivatives in Experimental Example 1 of the present invention on the survival rate of THP-1 macrophages at a concentration of 40 μM;

[0048] Figure 4 The effect of the gentiopicroside amide derivatives in Experimental Example 1 of the present invention on the survival rate of THP-1 macrophages at a concentration of 80 μM;

[0049] Figure 5 The effect of the gentiopicroside amide derivatives in Experimental Example 1 of the present invention on the survival rate of THP-1 macrophages at a concentration of 120 μM;

[0050] Figure 6 The effect of the gentiopicroside amide derivatives in Experimental Example 1 of the present invention on the survival rate of THP-1 macrophages at a concentration of 160 μM;

[0051] Figure 7The effect of the gentiopicroside amide derivatives in Experimental Example 1 of the present invention on the survival rate of THP-1 macrophages at a concentration of 200 μM;

[0052] Figure 8 The effect of different concentrations of LPS on the IL-6 content of THP-1 macrophages in Experimental Example 1 of the present invention;

[0053] Fig. 9 This is the effect of different concentrations of LPS on the STAT3 content of THP-1 macrophages in Experimental Example 1 of the present invention. DETAILED DESCRIPTION

[0054] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in conjunction with specific implementation methods.

[0055] Example 1

[0056] A gentiopicroside amide derivative having a structure of general formula 1:

[0057] General formula 1:

[0058]

[0059] The gentiopicroside amide derivatives are prepared by the following method:

[0060] (1) Weigh gentiopicroside (1.40 mmol) into a 50 mL round-bottom flask, place a magnetic bar, add 10 mL of pyridine to dissolve, weigh p-toluenesulfonyl chloride (2.53 mmol) into a constant pressure dropping funnel, add 5 mL of pyridine to dissolve, under N3 protection, ice bath at 0°C, slowly add p-toluenesulfonyl chloride dropwise, react for 6 h, after the reaction is completed, add 5 mL of methanol to quench, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography (dichloromethane: methanol v: v = 100 to 30: 1) with gradient elution to obtain intermediate I.

[0061] (2) The intermediate I in (1) was used as a raw material (1.00 mmol), added to a 50 mL round-bottom flask, placed in a magnetic bar, and then 5 mL of N,N-dimethylformamide was added to dissolve. After sodium azide (6.00 mmol) was added, 5 mL of N,N-dimethylformamide was added to dissolve. The mixture was heated to 60°C under N3 protection for 10 h. The reaction was detected by thin layer chromatography until the reaction was complete. The mixture was cooled to room temperature, extracted with ethyl acetate, and the organic layer was collected. Anhydrous sodium sulfate was added to remove water, and the solvent was evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (dichloromethane: methanol v:v = 50:1) to obtain intermediate II.

[0062] (3) Intermediate II in (2) was used as a raw material (0.90 mmol) in a 50 mL two-necked flask, a magnetic bar was placed, 10 mL of N,N-dimethylformamide was added to dissolve, imidazole (5.42 mmol) was added, and the mixture was placed in an ice bath at 0°C under N3 protection to react for 5 min. Trimethylsilyl chloride (5.42 mmol, 0.5 mL) was slowly added dropwise, and the mixture was reacted at room temperature for 0.5 h. The mixture was extracted with ethyl acetate, the organic layer was collected, anhydrous sodium sulfate was added to remove water, the solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate v:v = 10:1) to obtain intermediate III.

[0063] (4) Intermediate III in (3) was used as a raw material (0.73 mmol) in a 50 mL round-bottom flask. A magnetic bar was placed in the flask. 10 mL of tetrahydrofuran was added to dissolve the mixture. Triphenylphosphine (1.09 mmol) was added and the mixture was heated to 40 °C under N3 protection for 5 h. The reaction was detected by thin layer chromatography until the reaction was complete. 1 mL of H2O was added for 2 h. The mixture was cooled to room temperature and extracted with dichloromethane. The organic layer was collected and anhydrous sodium sulfate was added to remove water. The solvent was evaporated under reduced pressure to obtain intermediate IV.

[0064] (5) Intermediate IV in (4) was used as a raw material (0.36 mmol) in a 50 mL round-bottom flask. A magnetic bar was placed in the flask. 10 mL of anhydrous dichloromethane was added to dissolve the mixture. Triethylamine (0.75 mmol, 0.10 mL) was added. The mixture was placed in an ice bath at 0°C under N3 protection. Benzoyl chloride (1.13 mmol, 131 μL) was slowly added dropwise. The mixture was allowed to react at room temperature for 40 min. The solvent was evaporated under reduced pressure to obtain intermediate V.

[0065] (6) The intermediate V in (5) was used as a raw material (0.22 mmol) in a 50 mL round-bottom flask. A magnetic bar was placed in a 50 mL round-bottom flask. 6 mL of tetrahydrofuran was added to dissolve the mixture. Tetrabutylammonium fluoride (1.78 mmol, 0.5 mL) was added. The mixture was placed in an ice bath at 0°C under N3 protection for 8 h. The mixture was extracted with dichloromethane. The organic layer was collected. Anhydrous sodium sulfate was added to remove water. The solvent was evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (dichloromethane: methanol v:v = 100 to 10:1) with gradient elution to obtain the target product.

[0066] Example 1-1

[0067] The only difference from Example 1 is:

[0068] In (5), the selected benzoyl chloride is p-methylbenzoyl chloride; the other steps are the same as those in Example 1.

[0069] Example 1-2

[0070] The only difference from Example 1 is:

[0071] In (5), the selected benzoyl chloride is m-methoxybenzoyl chloride; the other steps are the same as those in Example 1.

[0072] As can be seen from the above, changing the benzoyl chloride in Example 1 can achieve the purpose of synthesizing the target product. Therefore, in addition to the benzoyl chloride in Example 1, it can also be any one of o-methylbenzoyl chloride, m-methylbenzoyl chloride, p-methylbenzoyl chloride, 3,5-dimethylbenzoyl chloride, m-methoxybenzoyl chloride, 3,4-dimethoxybenzoyl chloride, 3,5-dimethoxybenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, o-fluorobenzoyl chloride, p-fluorobenzoyl chloride, 3,5-difluorobenzoyl chloride, o-chlorobenzoyl chloride, 3-chlorobenzoyl chloride, 4-chlorobenzoyl chloride, 3,4-dichlorobenzoyl chloride, 3,5-dichlorobenzoyl chloride, o-bromobenzoyl chloride, 3-bromobenzoyl chloride, and 4-bromobenzoyl chloride.

[0073] Furthermore, the method in Example 1 was used to prepare the gentiopicroside amide derivatives in F-1 to F-20. The specific structures of the obtained gentiopicroside amide derivatives are shown in Table 1 below.

[0074] Table 1 Structures of gentiopicroside amide derivatives

[0075]

[0076]

[0077]

[0078] Test Example 1 Evaluation of the anti-inflammatory activity of gentiopicroside amide derivatives

[0079] The ELISA method was used to determine the effects of different concentrations (low concentration: 40 μM, medium concentration: 80 μM, high concentration: 120 μM) of gentiopicroside amide derivatives on the levels of IL-6 and STAT3 in the supernatant of THP-1 macrophages. The results are shown in Table 2-3 and the attached Figure 1-9 shown.

[0080] Figure 1 The morphological changes of THP-1 cells induced by different concentrations of phorbol ester (PMA) at 24h and 48h under an optical microscope (100×). Note: The arrows point to typical differentiated macrophages.

[0081] Figure 2-7 The effects of gentiopicroside amide derivatives on the survival rate of THP-1 macrophages at concentrations of 10μM, 40μM, 80μM, 120μM, 160μM, and 200μM, respectively.

[0082] Figure 8 , Fig. 9 These are the effects of different concentrations of LPS on the IL-6 content and STAT3 content of THP-1 macrophages.

[0083] Table 2 Effects of gentiopicroside amide derivatives on IL-6 content in THP-1 macrophages induced by LPS

[0084]

[0085]

[0086] Note: Compared with gentiopicroside, *P<0.05, **P<0.01, n=3

[0087] Table 3 Effects of gentiopicroside amide derivatives on STAT3 content in THP-1 macrophages induced by LPS

[0088]

[0089]

[0090] Note: Compared with gentiopicroside, *P<0.05, **P<0.01, n=3

[0091] As shown in Tables 2 and 3, compared with the LPS group, the expression of IL-6 and STAT3 was inhibited after the action of gentiopicroside and its derivatives and the positive drug naftifine hydrochloride (Stattic).

[0092] When the compound concentration was 120 μM, the inhibitory effects of derivatives F-1, F-4, F-5, and F-15 on cell IL-6 were better than those of the parent compound gentiopicroside (P < 0.05 or P < 0.01); when the compound concentration was 80 μM, the inhibitory effects of derivatives F-1, F-3, F-5, F-7, F-9, and F-14 were better than those of the parent compound gentiopicroside (P < 0.05 or P < 0.01); when the compound concentration was 40 μM, the inhibitory effects of derivatives F-1, F-2, F-3, F-5, F-13, F-14, F-15, F-17, and F-18 were better than those of the parent compound gentiopicroside (P < 0.05 or P < 0.01). Based on the above experiments, it can be seen that the inhibitory effects of compounds F-1 and F-5 on cell IL-6 are generally better than those of the parent compound gentiopicroside.

[0093] In addition, when the compound concentration was 120 μM, the inhibitory effect of derivatives F-1, F-2, F-3, and F-14 on cell STAT3 was better than that of the parent compound gentiopicroside (P < 0.05 or P < 0.01); when the compound concentration was 80 μM, the inhibitory effect of derivatives F-1, F-6, F-7, F-14, and F-15 was better than that of the parent compound gentiopicroside (P < 0.05 or P < 0.01); when the compound concentration was 40 μM, the inhibitory effect of derivatives F-1, F-12, F-13, F-14, and F-15 was better than that of the parent compound gentiopicroside (P < 0.05 or P < 0.01). From the above, it can be seen that the inhibitory effect of compounds F-1 and F-14 on cell STAT3 is generally better than that of the parent compound gentiopicroside.

Claims

1. A gentiopicroside amide derivative, characterized in that: The structure of the gentiopicroside amide derivatives is shown in general formula 1: General formula 1: Wherein, R is selected from any one of methyl, methoxy, fluoride, chloride, and bromide.

2. The method for synthesizing the gentiopicroside amide derivatives according to claim 1, characterized in that: The steps include: (1) Using gentiopicroside and p-toluenesulfonyl chloride as raw materials, pyridine as solvent, and methanol as quencher, an esterification reaction was performed to obtain intermediate I; (2) Using sodium azide and the intermediate I obtained in (1) as raw materials and N,N-dimethylformamide as solvent, azide substitution is performed to obtain the intermediate II; (3) Using trimethylsilyl chloride and the intermediate II obtained in (2) as raw materials, imidazole as a catalyst, N,N-dimethylformamide as a solvent, and TMS to protect the hydroxyl group to obtain the intermediate III; (4) using triphenylphosphine and the intermediate III obtained in (3) as raw materials, tetrahydrofuran as solvent, hydrolyzing with H2O, and undergoing Staudinger reaction to obtain the intermediate IV; (5) using benzoyl chloride and the intermediate IV obtained in (4) as raw materials and anhydrous dichloromethane as solvent, performing an amidation reaction to obtain the intermediate V; The structural formula of the benzoyl chloride is as follows: Wherein, R is selected from any one of methyl, methoxy, fluoride, chloride, and bromide; (6) The intermediate V obtained in (5) is deprotected from the TMS protecting group to obtain a gentiopicroside amide derivative having a structure shown in Formula 1.

3. The synthesis method according to claim 2, characterized in that In (1), pyridine is first added to dissolve gentiopicroside, and then p-toluenesulfonyl chloride is added dropwise at 0-5°C under N3 protection for 5-7 hours. After quenching with methanol, the reaction is purified to obtain intermediate I. The molar ratio of gentiopicroside to p-toluenesulfonyl chloride is 1:1.5-2, and the molar ratio of solvent pyridine to gentiopicroside is 130-140:

1.

4. The synthesis method according to claim 2, characterized in that (2), using intermediate I and sodium azide as raw materials and N,N-dimethylformamide as solvent, reacting at 50-65°C for 8-15h under N3 protection, extracting with ethyl acetate, and purifying to obtain intermediate II; The molar ratio of intermediate I to sodium azide is 1:6-7, and the molar ratio of solvent N,N-dimethylformamide to intermediate I is 130-140:

1.

5. The synthesis method according to claim 2, characterized in that (3), using intermediate II and trimethylsilyl chloride as raw materials, imidazole as catalyst, and N,N-dimethylformamide as solvent, under N3 protection, the reaction is first carried out at 0-5°C for 3-10 minutes and then at room temperature for 0.5-1 hour, and intermediate III is obtained after purification; The molar ratio of intermediate II: trimethylchlorosilane: imidazole is 1:6-6.5:6-6.5, and the molar ratio of solvent N,N-dimethylformamide to intermediate II is 140-150:

1.

6. The synthesis method according to claim 2, characterized in that (4), using intermediate III and triphenylphosphine as raw materials and tetrahydrofuran as solvent, the reaction is continued until intermediate III is completely reacted for 4 to 8 hours, and then H2O is added for hydrolysis reaction for 1 to 3 hours, and then extracted with dichloromethane, and the solvent is evaporated under reduced pressure to obtain intermediate IV; The molar ratio of intermediate III: triphenylphosphine: H2O is 1:1.2-1.5:70-80, and the molar ratio of solvent tetrahydrofuran to intermediate III is 160-170:

1.

7. The synthesis method according to claim 2, characterized in that (5), using intermediate IV, benzoyl chloride, and triethylamine as raw materials and anhydrous dichloromethane as solvent, the reaction was carried out at 0-5°C for 20-40 min under N3 protection, and the solvent was evaporated under reduced pressure to obtain intermediate V; The molar ratio of intermediate IV: benzoyl chloride: triethylamine is 1:2-3:1.5-2, and the molar ratio of solvent dichloromethane to intermediate IV is 410-420:

1.

8. The synthesis method according to claim 2, characterized in that (6), using intermediate V and tetrabutylammonium fluoride as raw materials and tetrahydrofuran as solvent, under N3 protection, reacting at 0-5°C for 5-10 hours, followed by extraction and purification to obtain gentiopicroside amide derivatives having the structure shown in general formula 1; The molar ratio of intermediate V: tetrabutylammonium fluoride: solvent tetrahydrofuran is 1:8-9:340-350.

9. Use of a gentiopicroside amide derivative as claimed in claim 1 in the preparation of anti-inflammatory drugs.

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