A broad-spectrum macrolide compound and its preparation and application
By introducing ester functional groups into polypeptide compounds and constructing macrolide compounds using C-H activation method, the limitations of existing antibacterial macrolide peptides in antibacterial spectrum and stability are solved, and effective inhibition of a variety of drug-resistant bacteria is achieved. New basic and therapeutic options for antibacterial drug screening are provided.
Patent Information
- Application Number
- CN202410343702.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-03-25
- Publication Date
- 2025-01-03
- Estimated Expiration
- 2044-03-25
AI Technical Summary
The existing antibacterial macrocyclic peptides have limitations in antibacterial spectrum and stability, and it is difficult to effectively inhibit a variety of drug-resistant bacteria and fungi, especially multidrug-resistant strains.
A new broad-spectrum macrolide compound is constructed by introducing ester functional groups in the polypeptide compound and using the C-H activation method, using a multi-step synthesis method under room temperature conditions, including substitution reaction, deprotection, peptide coupling and C-H activation reaction forms macrolide compounds with excellent antibacterial properties.
The prepared broad-spectrum macrolide compounds have significant antibacterial activity against a variety of bacteria such as Staphylococcus aureus and multidrug-resistant Acinetobacter baumannii. The inhibition rate increases with concentration, and their antibacterial effect is stronger than that of traditional antibiotics. Imipenem, suitable for the treatment of Gram-positive and negative bacterial infections.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of macrolide compound synthesis, and in particular to a broad-spectrum macrolide compound and a preparation method and application thereof. Background Art
[0002] Many natural peptide compounds have good antibacterial activity, especially against Gram-negative bacteria, Gram-positive bacteria, and fungi. The wide range of biological activities of antimicrobial peptides shows its good application prospects in medicine. Antimicrobial peptides have a high-efficiency and broad-spectrum killing effect on both Gram-negative and Gram-positive bacteria. At least 113 different bacteria have been reported to be killed by antimicrobial peptides at home and abroad. The first antimicrobial peptides with antifungal effects were isolated from the skin of amphibian frogs, which not only act on G+ and G-, but also have killing effects on fungi and protozoa. Defensins are endogenous bactericidal peptides in animal cells. They are isolated from phagocytes and have a wide antibacterial spectrum. The killing effect on G+ is greater than that on G-. It also acts on fungi and some eukaryotic cells. Cecropin A and its analogs, such as cecropin-melitin hybrid peptides, have a certain killing effect on fungi that infect insects.
[0003] Antimicrobial macrocyclic peptides have more outstanding advantages over traditional linear antimicrobial peptides, including higher binding affinity, target selectivity, cell permeability, proteolytic stability and the ability to regulate protein-protein interactions (PPI). In order to better understand its physiological and pharmacological functions, especially the inhibition of intracellular PPI, the construction of macrocyclic peptides has been proven to be a powerful tool and is therefore very much needed in the field of medicinal chemistry. Macrolide antibiotics (MA) are a general term for antibacterial drugs with a 12-16 carbon lactone ring in their molecular structure. They inhibit bacterial protein synthesis by blocking the activity of peptidyl transferase in the 50s ribosome and are fast antibacterial agents. Macrolide peptides are a type of macrolide compound. The cyclic peptide components are mainly derived from secondary metabolites of microorganisms, including cyanobacteria (Cyanobacterium), bacteria (Bacterium) and actinomycetes. Among them, marine bacteria mainly include Bacillus and Pseudomonas. The advantages of macrocyclic lipopeptides, including good broad-spectrum antibacterial activity and inhibitory activity, make them widely used in the treatment of bacterial and fungal infections. Summary of the invention
[0004] The invention provides a novel macrolide compound with broad-spectrum antibacterial effect.
[0005] In order to achieve the above object, the present invention provides the following technical solutions:
[0006] The present invention provides a broad-spectrum macrolide compound represented by formula (IX):
[0007]
[0008] The ester functional group is introduced into the polypeptide compound in advance, and then the broad-spectrum macrolide compound represented by formula (IX) is constructed by CH activation method. The constructed broad-spectrum macrolide compound has antibacterial properties and has obvious antibacterial activity against Staphylococcus aureus CMCC26003, Escherichia coli ATCC8099, multidrug-resistant Acinetobacter baumannii and other bacteria, and as the sample concentration increases, its inhibition rate on bacteria further increases.
[0009] The present invention also provides a method for preparing a broad-spectrum macrolide compound, comprising the following steps:
[0010] S1. Under room temperature, Fmoc-Ala-OH as shown in formula (II) and dichloro resin as shown in formula (II) are added to a dichloromethane solution and mixed, diethylenetriamine is added, and after the substitution reaction is completed, the mixture is washed with dimethylformamide to obtain a compound A as shown in formula (IV).
[0011]
[0012] S2. Under room temperature, remove the Fmoc protecting group in compound A, and wash with dimethylformamide after the reaction to obtain compound B as shown in formula (V).
[0013]
[0014] S3, using a solid phase synthesis method, Fmoc-Gly-OH, a peptide coupling reagent, and compound B are mixed in dimethylformamide, and then diethylenetriamine is added; after removing the Fmoc protecting group; Boc-Trp-OH, a peptide coupling reagent, and compound B are mixed in dimethylformamide, and then diethylenetriamine is added to synthesize a tripeptide chain as shown in formula (VI); wherein the extension order from the N-terminus to the C-terminus of the amino acid is: Fmoc-Gly-OH, Boc-Trp-OH,
[0015] S4, adding the tripeptide chain obtained in S3 to a mixed solution of hexafluoroisopropanol and dichloromethane to obtain a compound C as shown in formula (VII),
[0016]
[0017] S5. At room temperature, compound C and 2-aminoethanol hydrochloride as shown in formula (I) are added to dimethylformamide, and after mixing, carbodiimide, p-hydroxybenzonitrile and diethylenetriamine are added to carry out condensation reaction to obtain compound D as shown in formula (VIII).
[0018]
[0019] S6, adding compound D to a mixed solution of 1,4-dioxane and acetic acid, mixing again, adding 1,4-benzoquinone and palladium acetate to carry out CH activation reaction, to obtain a broad-spectrum macrolide compound as shown in formula (IX),
[0020]
[0021] The preparation provided by the present invention firstly carries out a substitution reaction between Fmoc-Ala-OH (alanine containing a protective group) and dichlororesin in a dichloromethane solution under the action of diethylenetriamine to generate compound (IV), and successfully links the amino acid to the resin carrier. Then, the Fmoc protective group is removed, and the deprotection is to allow the subsequently added amino acid to be effectively coupled with the exposed amino group.
[0022] On compound (V), first add Fmoc-Gly-OH and then add Boc-Trp-OH in the order from N-terminus to C-terminus, use peptide coupling reagent as coupling agent, diethylenetriamine as base, and obtain tripeptide chain (compound VI) through solid phase synthesis of peptide resin. This step constructs a tripeptide chain of a specific sequence, which is the basis for the subsequent macrocyclization reaction. After the synthesis of the tripeptide chain is completed, the tripeptide compound is cut from the resin to release the tripeptide chain synthesized in solid phase, making it free and ready for the next reaction. Condensation is then carried out to prepare for the construction of the macrocyclic structure. Finally, compound (VIII) is dissolved in a mixed solution of 1,4-dioxane and acetic acid, 1,4-benzoquinone and palladium acetate catalyst are added, and the compound is cyclized through CH activation reaction, thereby obtaining the final target compound (IX), that is, a macrolide compound with broad-spectrum antibacterial activity.
[0023] The overall scheme proposed in this invention aims to efficiently and accurately synthesize the target molecule while retaining and enhancing its antibacterial activity. Through reasonable selection of protecting groups, deprotection timing, and specific cyclization strategies, a macrolide polypeptide compound with excellent antibacterial properties is finally prepared.
[0024] Preferably, in step S1, the molar ratio of Fmoc-Ala-OH, dichlororesin and dichloromethane is 3:1:4.
[0025] Preferably, in step S3, the molar ratio of Fmoc-Gly-OH, peptide coupling reagent, diethylenetriamine and compound B is 3:3:3:1, and the molar ratio of Boc-Trp-OH, peptide coupling reagent, diethylenetriamine and compound B is 3:3:3:1.
[0026] Preferably, in the steps S2 and S3, the Fmoc protecting group is removed by eluting the Fmoc protecting group with a mixed solution of piperidine and dimethylformamide.
[0027] More preferably, in the mixed solution of piperidine and dimethylformamide, the volume ratio of piperidine to dimethylformamide is 1:3.
[0028] Preferably, in step S4, in the mixed solution of hexafluoroisopropanol and dichloromethane, the volume ratio of hexafluoroisopropanol to dichloromethane is 1:3.
[0029] Preferably, in step S5, the molar ratio of compound C, 2-aminoethanol hydrochloride, carbodiimide and diethylenetriamine is 1:1:1.5:3.
[0030] Preferably, in step S5, compound C and 2-aminoethanol hydrochloride are added to dimethylformamide at room temperature, and after mixing, carbodiimide, p-hydroxybenzonitrile and diethylenetriamine are added to carry out condensation reaction, and after the reaction is completed, the compound D as shown in formula (VIII) is separated and purified.
[0031] Further preferably, the separation and purification conditions are: column chromatography, using a mixed solution of dichloromethane:methanol in a volume ratio of (15-20):1 as an eluent, collecting the target component, and spinning it to obtain a broad-spectrum macrolide compound.
[0032] Preferably, in step S6, the molar ratio of compound D, 1,4-benzoquinone and palladium acetate is 1:2:0.1.
[0033] Preferably, in step S6, in the mixed solution of 1,4-dioxane and acetic acid, the volume ratio of 1,4-dioxane to acetic acid is 3:1; and the reaction temperature is 70-90°C.
[0034] Preferably, in step S6, compound D is added to a mixed solution of 1,4-dioxane and acetic acid and mixed again, 1,4-benzoquinone and palladium acetate are added to carry out CH activation reaction, and after the reaction is completed, the broad-spectrum macrolide compound as shown in formula (IX) is separated and purified.
[0035] Further preferably, the separation and purification conditions are: column chromatography, using a mixed solution of dichloromethane:methanol in a volume ratio of (15-20):1 as an eluent, collecting the target component, and spinning it to obtain a broad-spectrum macrolide compound.
[0036] The invention provides an antibacterial application of a broad-spectrum macrolide compound.
[0037] The broad-spectrum macrolide compound shown in formula (IX) has stronger bactericidal activity against multidrug-resistant strains of Acinetobacter baumannii than imipenem, and has a strong antibacterial effect on Staphylococcus aureus CMCC26003, Escherichia coli ATCC8099, and multidrug-resistant Acinetobacter baumannii. Based on the antibacterial properties of macrolide compounds, they can be used in many antibacterial scenarios, such as as antibacterial drugs to treat infections caused by Gram-positive bacteria and Gram-negative bacteria.
[0038] Therefore, the present invention has the following beneficial effects:
[0039] (1) The present invention introduces an ester bond into the molecular structure of the polypeptide compound in advance, and then constructs a new broad-spectrum macrolide compound in one step through a CH activation reaction.
[0040] (2) The broad-spectrum macrolide compound provided by the present invention has broad-spectrum antibacterial activity, providing a research basis for the screening of new antibacterial drugs.
[0041] (3) The method for preparing the broad-spectrum macrolide compound provided by the present invention has a simple preparation process, high yield, and is easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS
[0042] Figure 1 This is the H NMR spectrum of a broad-spectrum macrolide compound;
[0043] Figure 2 This is the NMR carbon spectrum of a broad-spectrum macrolide compound. DETAILED DESCRIPTION
[0044] The present invention is further described below in conjunction with specific embodiments. Those of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work should fall within the scope of protection of the present invention.
[0045] Example 1: Synthesis of broad-spectrum macrolide compounds
[0046] Fmoc-Ala-OH and dichlororesin as shown in formula (II) are added to a dichloromethane solution and mixed, and diethylenetriamine is added. After the substitution reaction is completed, the solution is washed with dimethylformamide to obtain a compound A as shown in formula (IV).
[0047] (1) Compound (II) Fmoc-Ala-OH 2.8 g (9 mmol) and compound III dichlororesin 3 g (3 mmol, degree of substitution 1.0 mmol / g) were placed in a solid phase synthesis reactor, 30 mL of dichloromethane was added, and finally 1.55 g (12 mmol) of diethylenetriamine was added. After nitrogen was blown for 2 hours, 3 mL of methanol was added and reacted for 10 minutes. The reaction solution was washed with dimethylformamide 3 times, 30 mL each time, and directly used in the next step.
[0048] (2) Add 30 mL of 25% piperidine / dimethylformamide solution to compound (IV) and deprotect for 30 minutes. Wash with dimethylformamide 4 times, 30 mL each time, and use it directly in the next reaction.
[0049] (3) Compound (V) to Compound (VI) The conventional solid phase synthesis operation steps are as follows: 3 mmol of compound (V), 2.8 g (9 mmol) of Fmoc-Gly-OH, 3.42 g (9 mmol) of peptide coupling reagent, 30 mL of dimethylformamide, and finally 1.16 g (9 mmol) of diethylenetriamine for 1 hour. The ninhydrin test solution shows a colorless state, indicating that the reaction is safe. The mixture is washed with dimethylformamide 3 times, 30 mL each time, and directly used in the next step. 30 mL of 25% piperidine / dimethylformamide solution is added for deprotection for 30 minutes, and the mixture is washed with dimethylformamide 4 times, 30 mL each time, and directly used in the next step.
[0050] Add Boc-Trp-OH 2.73 g (9 mmol), peptide coupling reagent 3.42 g (9 mmol), dimethylformamide 30 mL, and finally add diethylenetriamine 1.16 g (9 mmol) to react for 1 hour. The ninhydrin test solution shows colorless, indicating that the reaction is safe. Wash with dimethylformamide 3 times and methanol 3 times, 30 mL each time, drain and use directly in the next reaction.
[0051] (4) Compound (VI) was suspended in 50 mL of 25% hexafluoroisopropanol / dichloromethane solution, reacted for 2 hours, filtered, and the resin was washed with dichloromethane three times, 50 mL each time. The organic phases were combined and dried to obtain 1.1 g of a white foamy solid, which was compound (VII).
[0052] (5) 864 mg (2 mmol) of compound (VII), 209 mg (2 mmol) of compound (I), 298 mg (3 mmol) of carbodiimide and 200 mg (3 mmol) of p-hydroxybenzonitrile were accurately weighed and placed in a 100 mL round-bottom flask, added to 20 mL of dimethylformamide solution, and finally added 774 mg (6 mmol) of diethylenetriamine to react at room temperature for 3 hours. After the reaction was completed as monitored by TLC, dichloromethane and water were added to extract and collect the organic phase. The organic phase was washed once with 3% phosphoric acid aqueous solution, saturated sodium bicarbonate and saturated sodium chloride, 50 mL each time, and dried over anhydrous sodium sulfate. Filtered, the solvent was removed by vacuum rotary evaporation, and the concentrate was separated by silica gel column (dichloromethane: methanol = 20:1, v / v) to collect 650 mg of white foamy compound, which was compound VIII.
[0053] (6) Accurately weigh 117 mg (0.2 mmol) of compound (VIII), 1,4-benzoquinone (43.3 mg, 0.4 mmol), and 9 mg (0.02 mmol) of palladium acetate into a 100 mL round-bottom flask, and add 10 mL of a mixed solution of 1,4-dioxane / acetic acid (1,4-dioxane: acetic acid = 3:1, v / v). Cover with a rubber stopper and heat the reaction mixture to 80°C for 24 hours. Add 40 mL of ethyl acetate and 20 mL of water to the reaction mixture. Wash the organic layer with 20 mL of 1N hydrochloric acid, 20 mL of saturated sodium bicarbonate, and 20 mL of saturated sodium chloride solution, respectively, and dry with anhydrous sodium sulfate, filter, and concentrate in vacuo. The concentrate is separated by a silica gel column (dichloromethane: methanol = 20:1, v / v) to obtain 50 mg of a white foamy compound, which is compound IX: a broad-spectrum macrolide compound.
[0054] NMR spectrum see Figure 1 and Figure 2 , 1H NMR (600MHz, DMSO) δ11.37(s,1H),8.40(d,J=7.6Hz,1H),8.31(dd,J=7.4,4.7Hz,1H),8.12(d,J=7.5Hz,1H),7.87 (d,J=8.0Hz,1H),7.82(d,J=15.9Hz,1H),7.31(d,J=8.2Hz,1H),7.19(t,J=7.6Hz,1H),7.04–6.97(m,2H),6.38(d ,J=15.9Hz,1H),4.65–4.56(m,1H),4.51(dd,J=11.1,3.0Hz,1H),4.46–4.41(m,1H),4.36–4.32(m,1H),4.16–4.0 1(m,2H),3.69(s,3H),3.55–3.49(m,1H),3.45(dd,J=14.4,4.1Hz,1H),3.08(dd,J=14.4,8.9Hz,1H),1.22(s,9H). 13 C NMR (151MHz, DMSO) δ172.22,171.67,169.94,169.76,166.16,155.63,137.96,133.72,130.97,129.03,127.47, 124.66,120.86,119.32,114.26,110.73,78.52,62.62,57.35,52.74,52.25,48.82,43.01,29.46,28.43,18.13.
[0055] Example 2: Detection of fungicidal activity of broad-spectrum macrolide compound (IX)
[0056] The various strains used in the following examples were purchased from the China National Institute for the Control of Biological Products. The bactericidal activity of the cationic antibacterial cyclic peptide was detected by the agar punching method, and the straight-chain peptide (VIII) was used as a control to evaluate the bactericidal activity of the broad-spectrum macrolide compound (IX) in the present invention. The bactericidal activity of the antimicrobial peptide was determined according to the following steps: Strain recovery: Inoculate resistant Acinetobacter baumannii and streak it on NA nutrient agar medium, place it in a constant temperature incubator for culture, the temperature is 37°C, and the culture time is 16-20 hours. Strain culture: Pick a single colony and place it in 100mL MHB medium for culture. The culture temperature is also the optimal growth temperature of bacteria, 37°C, the shaker speed is 160 rpm, and the shaking culture (16-20h) is performed to allow the bacterial growth state to reach the logarithmic phase. Preparation of bacterial suspension: The concentration of bacteria is generally determined by McFarland turbidimetric tube. The turbidity of the McFarland turbidimetric tube is about 0.5 McFarland turbidity, and the number of bacterial colonies is about 1.5x10 8cfu / mL, and then diluted to 10 at 1:1000. 5 -10 6 cfu / mL bacterial suspension. Antibacterial experiment: The diluted bacterial suspension was evenly applied to 25mL NA culture medium at a volume of 0.1mL / plate; after the bacterial solution solidified, a hole (9mm in diameter) was punched. For the positive control, 50μL (0.4mg / mL, 0.2mg / mL, 0.1mg / mL) of imipenem was added; for the negative control, 50μL of deionized water was added; for the other holes, 50μL (0.4mg / mL, 0.2mg / mL, 0.1mg / mL) of IX antibacterial cyclic peptide solution was added. The bacteria were cultured in a 37°C constant temperature incubator, and the size of the bacterial inhibition zone was measured after 16 hours, so that the size of the bacterial antibacterial activity could be preliminarily determined, and three groups of parallel experiments were performed. It can be seen from Table 1 above that the broad-spectrum macrolide compound IX of the present invention has obvious bactericidal ability and is better than the control linear peptide VIII, especially at a high concentration of 0.4mg / mL, it is better than imipenem.
[0057] Table 1 Inhibition zone diameters (mm) of different concentrations of broad-spectrum macrolide compounds against multidrug-resistant strains of Acinetobacter baumannii
[0058]
[0059] Example 3: Antibacterial activity detection of broad-spectrum macrolide compound (IX)
[0060] The various strains used in the following examples were purchased from the China National Institute for the Control of Biological Products. The minimum inhibitory capacity of the broad-spectrum macrolide compound was determined, and the linear peptide VIII before cyclization was used as a control to evaluate the antibacterial capacity of the broad-spectrum macrolide compound of the present invention. The antibacterial activity of the broad-spectrum macrolide compound IX was determined according to the following steps: bacteria growing in the logarithmic phase were collected, centrifuged at 4°C and 8000 rpm for 2 min, washed 3 times with physiological saline, and fresh broth medium was added to make the bacterial suspension concentration 2.0x10 5cfu / mL. Add 50 μL of bacterial suspension to the experimental wells of the 96-well cell culture plate (add 100 μL PBS to the surrounding wells), and then add 50 μL of peptide solutions (imipenem solutions) of different concentrations, so that the final concentrations (μg / mL) of the peptide solutions (imipenem solutions) in the horizontal wells are: 512, 256, 128, 64, 32, 16, 12, 4. The same volume of PBS buffer was used as the growth control group, and three parallel groups were set up in each group. After the cell culture plate was covered, it was placed in a biochemical incubator at 37°C for 12 hours, and the bacterial growth in each well was determined by fully automatic enzyme labeling (OD600nm). The minimum inhibitory concentration (MIC) is defined as the peptide concentration in the well where bacterial growth is completely inhibited. The smaller the minimum inhibitory concentration value in the table, the stronger the antibacterial ability of the peptide. As can be seen from Table 2, compared with the control straight-chain peptide, the macrolide peptide IX of the present invention has a lower minimum inhibitory concentration, and the MIC is much smaller than that of VIII, indicating that the antibacterial ability of the macrolide peptide IX of the present invention is much stronger than that of the control straight-chain peptide VIII.
[0061] Table 2 Comparison of MIC of broad-spectrum macrolide compound IX against different bacteria
[0062]
Claims
1. A broad-spectrum macrolide compound represented by formula (IX):
2. A method for preparing the broad-spectrum macrolide compound as claimed in claim 1, characterized in that: The following steps are involved: S1. Under room temperature, Fmoc-Ala-OH and dichloro resin are added to a dichloromethane solution and mixed, and diethylenetriamine is added. After the substitution reaction is completed, the solution is washed with dimethylformamide to obtain a compound A as shown in formula (IV). S2. Under room temperature, remove the Fmoc protecting group in compound A, and wash with dimethylformamide after the reaction to obtain compound B as shown in formula (V). S3, using a solid phase synthesis method, Fmoc-Gly-OH, a peptide coupling reagent, and compound B are mixed in dimethylformamide, and then diethylenetriamine is added; after removing the Fmoc protecting group; Boc-Trp-OH, a peptide coupling reagent, and compound B are mixed in dimethylformamide, and then diethylenetriamine is added to synthesize a tripeptide chain as shown in formula (VI); wherein the extension order from the N-terminus to the C-terminus of the amino acid is: Fmoc-Gly-OH, Boc-Trp-OH, S4, adding the tripeptide chain obtained in S3 to a mixed solution of hexafluoroisopropanol and dichloromethane to obtain a compound C as shown in formula (VII), S5. Under room temperature, compound C and a substance represented by formula (I): Add to dimethylformamide, mix, then add carbodiimide, p-hydroxybenzonitrile and diethylenetriamine for condensation reaction to obtain compound D as shown in formula (VIII), S6, adding compound D to a mixed solution of 1,4-dioxane and acetic acid, mixing again, adding 1,4-benzoquinone and palladium acetate to carry out CH activation reaction, to obtain a broad-spectrum macrolide compound as shown in formula (IX), 3. The method according to claim 2, characterized in that In the step S1, the molar ratio of Fmoc-Ala-OH, dichlororesin and dichloromethane is 3:1:
4.
4. The method according to claim 2, characterized in that: In the step S3, the molar ratio of Fmoc-Gly-OH, peptide coupling reagent, diethylenetriamine, and compound B is 3:3:3:1, and the molar ratio of Boc-Trp-OH, peptide coupling reagent, diethylenetriamine, and compound B is 3:3:3:
1.
5. The method according to claim 2 or 4, characterized in that: In the steps S2 and S3, the Fmoc protecting group is removed by eluting the Fmoc protecting group with a mixed solution of piperidine and dimethylformamide.
6. The method according to claim 2, characterized in that In the step S4, in the mixed solution of hexafluoroisopropanol and dichloromethane, the volume ratio of hexafluoroisopropanol to dichloromethane is 1:
3.
7. The method according to claim 2, characterized in that In the step S5, the molar ratio of compound C, 2-aminoethanol hydrochloride, carbodiimide, and diethylenetriamine is 1:1:1.5:
3.
8. The method according to claim 2, characterized in that: In step S6, the molar ratio of compound D, 1,4-benzoquinone and palladium acetate is 1:2:0.
1.
9. The method according to claim 2 or 8, characterized in that: In the step S6, in the mixed solution of 1,4-dioxane and acetic acid, the volume ratio of 1,4-dioxane to acetic acid is 3:1; and the reaction temperature is 70-90°C.
10. Use of the broad-spectrum macrolide compound according to claim 1 or the broad-spectrum macrolide compound prepared by the method according to any one of claims 2 to 9 in the preparation of therapeutic antibacterial drugs.