20-aldehyde-23-piperidinyl-5-O-mycaminoglycan-tylonolide and its synthesis method and use

Abstract

The present invention relates to a synthesis method of 20-aldehyde-23-piperidinyl-5-O-mycamine glycosyl-tylonolide, its salt and use. The present invention has in vitro antibacterial activity against pathogenic bacteria of livestock and poultry such as Pasteurella multocida, Streptococcus suis, Streptococcus pneumoniae, Staphylococcus aureus, Bordetella bronchiseptica, Klebsiella pneumoniae, Mannheimia hemolytica, Haemophilus parasuis, Actinobacillus pleuropneumoniae, etc., and its antibacterial activity is significantly superior to that of control drugs. The present invention is also superior to macrolide control drugs in antibacterial effect on mycoplasma such as chicken, gallinulina, and pig. It can be used to prepare new high-activity veterinary antibacterial and anti-mycoplasma drugs, and has broad application prospects in livestock and poultry and aquaculture.

Description

Technical Field

[0001] The present invention belongs to the technical field of veterinary antibiotic drugs. More specifically, the present invention relates to 20-aldehyde-23-piperidinyl-5-O-mycaminoglycosyl-tylonolide and its salt, the present invention also relates to a method for synthesizing 20-aldehyde-23-piperidinyl-5-O-mycaminoglycosyl-tylonolide, and the present invention relates to the use of the compound. Background Art

[0002] Macrolide antibiotics are one of the commonly used antibacterial drugs in veterinary clinics, mainly including 14-membered ring and 16-membered ring structures. Macrolide antibiotics with a 14-membered ring structure are used in veterinary clinics, such as erythromycin, and antibiotics with a 16-membered ring structure include tylosin, tylosin, tilmicosin and tediloxine, which are used to treat infectious diseases caused by pathogens and mycoplasmas in livestock and poultry, and have achieved good results. However, with the widespread use and prolonged use of macrolide veterinary drugs, cross-resistance between drugs and with other drugs has appeared in many areas of my country to varying degrees, resulting in an increasing dosage of antibacterial drugs, but the therapeutic effect is gradually decreasing. Studies have shown that the increased resistance of Streptococcus suis and Enterococcus to erythromycin is positively correlated with the use of macrolide veterinary drugs. Therefore, new antibacterial drugs are urgently needed to replace them.

[0003] In the 20 years since macrolide antibiotics were launched, researchers have been very active in studying their structural modification. There have been many patents and articles published abroad on the synthesis of 16-membered ring mycosyl tylosin lead compounds, including modifications to positions 9, 14, 20, and 23 of the parent compound; modification of 3' deoxymycosyl; modification of the active site of 4' deoxymycosyl, etc. In 2012, the British Intervet Company modified the active sites of positions 20 and 23 of 16-membered ring macrolide compounds, added piperidine groups, and developed the third-generation macrolide veterinary drug - tylosin. It is used to treat, for example, pasteurella disease, bovine respiratory diseases and porcine respiratory diseases, and its efficacy is stronger than tylosin and tilmicosin. In recent years, there have been reports on the study of structural modification of erythromycin in China, but the research and development of the modification of position 23 of 16-membered ring macrolide compounds is relatively lacking.

[0004] In view of the technical defects of the prior art, the inventors have carried out structural modification on 16-membered ring macrolide compounds on the basis of summarizing the prior art. Through a large number of experimental studies and analytical summaries, novel 16-membered ring macrolide derivatives have been synthesized, and their anti-pathogenic and anti-mycoplasma activities have been studied, which is of great significance for further research and development of novel antibacterial and anti-mycoplasma drugs with independent intellectual property rights. Summary of the invention

[0005] [Technical issues to be solved]

[0006] The purpose of the present invention is to provide 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide and its salt.

[0007] Another object of the present invention is to provide a method for synthesizing 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide.

[0008] Another object of the present invention is to provide the use of 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide.

[0009] [Technical solution]

[0010] The present invention is achieved through the following technical solutions.

[0011] The invention relates to a method for synthesizing 20-aldehyde-23-piperidinyl-5-O-mycaminoglycan-tylonolide.

[0012] The synthesis steps of this synthesis method are as follows:

[0013] A. Preparation of Compounds of Chemical Formula (II)

[0014] The reaction of tylosin of chemical formula (I) with inorganic acid or organic acid is as follows:

[0015]

[0016] 0.04-0.10M tylosin of chemical formula (I) is reacted with 0.5-1.0M inorganic acid or organic acid solution at a weight ratio of 1:3-10, pH 1-3 and temperature of 60-95°C for 0.5-1.5h, and then the reaction solution is cooled to below 30°C, and then the pH of the reaction solution is adjusted to 9-11 using ammonia water with a concentration of 0-20.0% by volume, and then an organic extractant is used to extract 1-3 times according to a volume ratio of the reaction solution to the organic extractant of 1:0.5-1, and the extracts are combined, and then washed with water 1-3 times according to a volume ratio of the extract to water of 1:0.5-1, and the washed extract is dried with anhydrous sodium sulfate and distilled under reduced pressure to obtain 0.036-0.091M of the compound of chemical formula (II) 20-aldehyde-23-hydroxy-5-O-mycaminosyl-tylosin;

[0017] B. Preparation of Compounds of Chemical Formula (III)

[0018] The reaction of the compound of chemical formula (II) with ethylene glycol and camphorsulfonic acid is as follows:

[0019] According to the weight ratio of the compound of chemical formula (II) to dichloromethane of 1:3-10, 0.036-0.091M of the compound of chemical formula (II) obtained in step A is dissolved in dichloromethane,

[0020]

[0021] Then, 0.1-1.5M ethylene glycol and 0.05-0.40M camphorsulfonic acid are added, mixed evenly, reacted at room temperature for 2-24h, and dichloromethane is added to dilute the reaction solution according to a volume ratio of 1:1-5 to dichloromethane. Then, the diluted reaction solution is washed with a saturated sodium carbonate aqueous solution for 1-3 times according to a volume ratio of 1:1-5 to a saturated sodium carbonate aqueous solution, and then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain 0.034-0.082M of the chemical formula (III) compound 20-(1,3-dioxolane)-23-hydroxy-5-O-mycaminosyl-tylonolide;

[0022] C. Preparation of Compounds of Chemical Formula (IV)

[0023] The reaction of the compound of chemical formula (III) with ethylene glycol and a sulfonyl compound is as follows:

[0024]

[0025] 0.034-0.082M of the compound of the above chemical formula (III) and 0.05-0.20M of the sulfonyl compound are subjected to a sulfonate esterification reaction for 1-5h at a weight ratio of 1:3-10 with an organic solvent and a temperature of 20-40°C, the obtained esterification reaction liquid is cooled, water is added to the esterification reaction liquid at a volume ratio of 1:0.5-1 to the esterification reaction liquid, the organic phase is separated, and then extracted with dichloromethane 1-3 times at a volume ratio of 1:0.5-1 to the water phase and dichloromethane, the organic phase and the extract are combined, and then dried with anhydrous sodium sulfate, and distilled under reduced pressure, thereby obtaining 0.031-0.074M of the compound of the chemical formula (IV) 20-(1,3-dioxolane)-23-sulfonate-5-O-mycaminosyl-tylonolide;

[0026] D. Preparation of Compounds of Chemical Formula (V)

[0027]

[0028] The reaction of the compound of chemical formula (IV) with ethylene glycol and iodination reagent is as follows:

[0029] According to the weight ratio of the compound of chemical formula (IV) to the organic solvent being 1:3-10, an organic solvent is added to a mixture of 0.031-0.074M of the compound of chemical formula (IV) obtained in step C and 0.05-0.40M of the iodination reagent, and an iodination reaction is carried out at a reaction temperature of 30-80°C for 1-4 hours, and then the iodination reaction liquid is cooled, and water is added to the iodination reaction liquid according to a volume ratio of the iodination reaction liquid to water of 1:0.5-1, the organic phase is separated, and the volume ratio of the aqueous phase to dichloromethane is 1:0.5-1. The organic phase and the extract are combined, and then dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.028-0.067M of the compound of chemical formula (V) 20-(1,3-dioxolane)-23-iodo-5-O-mycaminosyl-tylonolide;

[0030] E. Preparation of compound of chemical formula (VI)

[0031] The reaction of the compound of chemical formula (V) and piperidine is as follows:

[0032]

[0033] According to the weight ratio of the compound of chemical formula (V) to the organic solvent of 1:3-10, an organic solvent is added to the 0.028-0.067M compound of chemical formula (V) obtained in step D, stirred and dissolved, and then 0.01-0.05M organic base or inorganic base is added, followed by dropwise addition of 0.05-0.40M piperidine, and the obtained mixture solution is heated for reaction at a temperature of 40-90°C for 2-4h, and water is added to the reaction solution according to the volume ratio of the reaction solution to water of 1:0.5-1, the organic phase is separated, and then extracted with dichloromethane 1-3 times according to the volume ratio of the aqueous phase to dichloromethane of 1:0.5-1, the organic phase and the extract are combined, and then dried over anhydrous sodium sulfate, and distilled under reduced pressure, thereby obtaining 0.025-0.062M compound of chemical formula (VI) 20-(1,3-dioxolane)-23-piperidinyl-5-O-mycaminosyl-tylonolide;

[0034] F. Preparation of Compounds of Chemical Formula (VII)

[0035] The reaction of the compound of chemical formula (VI) and camphorsulfonic acid is as follows:

[0036]

[0037] According to the weight ratio of the compound of chemical formula (VI) to the organic solvent of 1:3-10, an organic solvent is added to the 0.025-0.062M compound of chemical formula (VI) obtained in step E, stirred to dissolve, 0.05-0.25M camphorsulfonic acid is added, mixed evenly, reacted at room temperature for 2-24 hours, and then the organic solvent is removed by distillation under reduced pressure, and water is added to the remaining reaction solution according to the volume ratio of it to water of 1:1-5, and then the pH is adjusted to 9-11 with sodium hydroxide aqueous solution to generate a white precipitate, filtered, and the filter cake is stirred in 5-20 times water, and the pH is adjusted to 3-5 with an inorganic acid or an organic acid. After dissolution, the pH is adjusted to 9-11 with a sodium hydroxide aqueous solution, recrystallized, filtered, and dried under reduced pressure to obtain 0.022-0.056M compound of chemical formula (VII) 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide.

[0038] According to a preferred embodiment of the present invention, in steps A and F, the inorganic acid is one or more inorganic acids selected from hydrochloric acid, nitric acid, sulfuric acid, perchloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, chloric acid, bromic acid or phosphoric acid; the organic acid is one or more organic acids selected from 2,4,6-trinitrophenol, 2,4,6-trinitrobenzoic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, cyclohexanethiolsulfonic acid, oxalic acid or 2-chloroethanethiol.

[0039] According to another preferred embodiment of the present invention, in step A, the organic extractant is one or more organic extractants selected from ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, dichloromethane, chloroform, dichloroethane, ethyl ether, tert-butyl methyl ether, acetone, methyl ethyl ketone or methyl isobutyl ketone.

[0040] According to another preferred embodiment of the present invention, the reduced pressure distillation or reduced pressure drying is carried out under the conditions of a temperature of 20°C to 80°C and a system pressure of 0.001 to 0.02 MPa. According to another preferred embodiment of the present invention, in step C, the sulfonyl compound is p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethylsulfonyl chloride or trifluoromethylsulfonic anhydride.

[0041] According to another preferred embodiment of the present invention, in step D, the iodination agent is hydroiodic acid, iodine, potassium iodide or sodium iodide.

[0042] According to another preferred embodiment of the present invention, in steps C to F, the organic solvent is methyl formate, ethyl formate, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methanol, ethanol, acetonitrile, acetone, dichloromethane, dichloroethane, chloroform, acetone, methyl isopropyl ketone, methyl isobutyl ketone or methyl ethyl ketone.

[0043] According to another preferred embodiment of the present invention, in step E, the inorganic base is one or more inorganic bases selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; the organic base is one or more organic bases selected from pyridine, triethylamine, ethylenediamine, dimethylamine, propylamine, isopropylamine, butylamine, tert-butylamine, hexylamine or ethanolamine.

[0044] The present invention also relates to a compound of chemical formula (VII) 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide and a salt thereof synthesized by the synthesis method.

[0045] The present invention also relates to the use of the compound 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide and its salts with the chemical structural formula (VII) in the preparation of drugs for treating bacterial infections or mycoplasma infections in mammals, fish or poultry.

[0046] The present invention will be described in more detail below.

[0047] The invention relates to a method for synthesizing a compound 20-aldehyde-23-piperidinyl-5-O-mycaminoglycan-tylonolide.

[0048] The synthesis steps of this synthesis method are as follows:

[0049] A. Preparation of Compounds of Chemical Formula (II)

[0050] The reaction of tylosin of chemical formula (I) with inorganic acid or organic acid is as follows:

[0051]

[0052] 0.04-0.10M tylosin of chemical formula (I) is reacted with 0.5-1.0M inorganic acid or organic acid solution at a weight ratio of 1:3-10, pH 1-3 and temperature of 60-95°C for 0.5-1.5h, and then the reaction solution is cooled to below 30°C, and then the pH of the reaction solution is adjusted to 9-11 using ammonia water with a concentration of 0-20.0% by volume, and then an organic extractant is used to extract 1-3 times according to a volume ratio of the reaction solution to the organic extractant of 1:0.5-1, and the extracts are combined, and then washed with water 1-3 times according to a volume ratio of the reaction solution to water of 1:0.5-1, and the washed extract is dried with anhydrous sodium sulfate and distilled under reduced pressure to obtain 0.036-0.091M of the compound of chemical formula (II) 20-aldehyde-23-hydroxy-5-O-mycaminosyl-tylosin;

[0053] According to the present invention, the inorganic acid is one or more inorganic acids selected from hydrochloric acid, nitric acid, sulfuric acid, perchloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, chloric acid, bromic acid or phosphoric acid; the organic acid is one or more organic acids selected from 2,4,6-trinitrophenol, 2,4,6-trinitrobenzoic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, cyclohexanethiolsulfonic acid, oxalic acid or 2-chloroethanethiol. These inorganic acids and organic acids used in the present invention are all products currently sold on the market.

[0054] In this step, when the amount of inorganic acid or organic acid is 0.5-1.0M, if the amount of tylosin is less than 0.04M, other groups connected to the macrolide parent ring will be decomposed; if the amount of tylosin is higher than 0.10M, acidification cannot be complete; therefore, it is reasonable to use tylosin in an amount of 0.04-0.10M, preferably 0.06-0.08M; when the amount of tylosin is 0.04-0.10M, if the amount of inorganic acid or organic acid is lower than 0.5M, tylosin cannot be completely digested; if the amount of inorganic acid or organic acid is higher than 1.0M, the tylosin parent ring will be decomposed; therefore, it is reasonable to use 0.5-1.0M of inorganic acid or organic acid, preferably 0.6-0.8M.

[0055] In this step A, the main purpose of cooling the reaction solution to below 30° C. is to facilitate subsequent operations.

[0056] In this step A, the main purpose of using an organic solvent for extraction is to improve the reaction yield. The organic extractant used in the present invention is one or more organic extractants selected from ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, dichloromethane, chloroform, dichloroethane, ether, tert-butyl methyl ether, acetone, methyl ethyl ketone or methyl isobutyl ketone. These organic extractants used in the present invention are all products currently sold on the market, such as ethyl acetate sold by Merck, methyl ethyl ketone sold by Sinopharm Chemical Co., Ltd., and methyl isobutyl ketone sold by Fisher.

[0057] The basic function of washing the extract with water is to wash away excess acid.

[0058] According to the present invention, the vacuum distillation or vacuum drying is carried out at a temperature of 20°C to 80°C and a system pressure of 0.001 to 0.02 MPa. The subsequent steps are carried out in the same manner, so they will not be described in detail.

[0059] The product obtained by the reduced pressure distillation was analyzed and determined by high-resolution mass spectrometry, and the results are as follows:

[0060] HR-MS (ESI + ):(MH+ ) is 598.3595. According to the molecular formula C 31 H 51 NO 10 The obtained (MH + )The theoretical calculated value is 598.3591.

[0061] From the test results, it can be determined that the product is a compound having the chemical structural formula (II) of 20-aldehyde-23-hydroxy-5-O-mycaminosyl-tylonolide.

[0062] The conversion rate of this step can reach more than 80% according to the method described in (Meng Ke et al., Chinese Journal of Antibiotics, 2020, 45(5): 437-440 "Synthesis of Tedirosin and Its Phosphate"). The same calculation method is used for other parts of the article.

[0063] The conversion rates of steps BF can also be obtained in the same manner, and they can all reach more than 80%.

[0064] B. Preparation of Compounds of Chemical Formula (III)

[0065] The reaction of the compound of chemical formula (II) with ethylene glycol and camphorsulfonic acid is as follows:

[0066]

[0067] According to the weight ratio of the compound of chemical formula (II) to dichloromethane of 1:3-10, 0.036-0.091M of the compound of chemical formula (II) obtained in step A is dissolved in dichloromethane, and then 0.1-1.5M ethylene glycol and 0.05-0.40M camphorsulfonic acid are added, mixed evenly, and reacted at room temperature for 2-24h, and the reaction solution is diluted by adding dichloromethane according to the volume ratio of the reaction solution to dichloromethane of 1:1-5, and then washed with saturated sodium carbonate aqueous solution 1-3 times according to the volume ratio of the diluted reaction solution to saturated sodium carbonate aqueous solution of 1:1-5, and then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain 0.034-0.082M of the compound of chemical formula (III) 20-(1,3-dioxolane)-23-hydroxy-5-O-mycaminosyl-tylonolide;

[0068] In this step, if the weight ratio of the compound of the chemical formula (II) to dichloromethane is greater than 1:10, the raw material concentration is too low and the reaction is difficult to control; if the weight ratio of the compound of the chemical formula (II) to dichloromethane is less than 1:3, the viscosity of the reaction solution is too high and the reaction rate is too slow; therefore, the weight ratio of the compound of the chemical formula (II) to dichloromethane is appropriately 1:3 to 10, preferably 1:4 to 8; more preferably 1:5 to 7;

[0069] In this step, when the amount of ethylene glycol is 0.1 to 1.5 M and the amount of camphorsulfonic acid is 0.05 to 0.40 M, if the amount of the compound of chemical formula (II) is less than 0.036 M, more by-products will be produced and the reaction rate will be difficult to control; if the amount of the compound of chemical formula (II) is higher than 0.091 M, the aldehyde group cannot be completely protected; therefore, the amount of the compound of chemical formula (II) is 0.036 to 0.091 M; when the amount of the compound of chemical formula (II) is 0.036 to 0.091 M and the amount of camphorsulfonic acid is 0.05 to 0.40 M, If the amount of ethylene glycol is less than 0.1M, the aldehyde group cannot be completely protected. If the amount of ethylene glycol is higher than 1.5M, it is not conducive to the subsequent reaction; therefore, it is desirable that the amount of ethylene glycol is 0.1-1.5M; when the amount of the compound of chemical formula (II) is 0.036-0.091 and the amount of ethylene glycol is 0.1-1.5M, if the amount of camphorsulfonic acid is lower than 0.05M, the aldehyde group protection reaction cannot be completely carried out; if the amount of camphorsulfonic acid is higher than 0.40M, it is not conducive to the occurrence of subsequent reactions; therefore, it is appropriate that the amount of camphorsulfonic acid is 0.05-0.40M;

[0070] In this step, the main function of washing with saturated sodium carbonate aqueous solution is to keep the reaction system neutral.

[0071] The diluted reaction solution should be dried with anhydrous sodium sulfate after washing to achieve a solution without lumps.

[0072] The product obtained by the reduced pressure distillation was analyzed and determined by high-resolution mass spectrometry, and the results are as follows:

[0073] HR-MS (ESI + ): the product's (MH + ) is 642.3855. According to the molecular formula C 33 H 55 NO 11 The obtained (MH + )The theoretical calculated value is 642.3853.

[0074] From this determination result, it can be determined that the product is a compound having a chemical structural formula (III) of 20-(1,3-dioxolane)-23-hydroxy-5-O-mycaminoglycansyl-tyronolide;

[0075] C. Preparation of Compounds of Chemical Formula (IV)

[0076] The reaction of the compound of chemical formula (III) with ethylene glycol and a sulfonyl compound is as follows:

[0077]

[0078] 0.034-0.082M of the compound of the above chemical formula (III) and 0.05-0.20M of a sulfonyl compound (taking p-toluenesulfonyl chloride as an example) are subjected to a sulfonate esterification reaction for 1-5 hours at a weight ratio of 1:3-10 with an organic solvent and a temperature of 20-40°C, the obtained esterification reaction liquid is cooled, water is added to the esterification reaction liquid at a volume ratio of 1:0.5-1 to the esterification reaction liquid, the organic phase is separated, and then extracted with dichloromethane 1-3 times at a volume ratio of 1:0.5-1 to the dichloromethane, the organic phase and the extract are combined, and then dried with anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.031-0.074M of the compound of the chemical formula (IV) 20-(1,3-dioxolane)-23-sulfonate-5-O-mycaminosyl-tylonolide;

[0079] In this step, the sulfonyl compound is p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethylsulfonyl chloride or trifluoromethylsulfonic anhydride. The sulfonyl compounds used in the present invention are all products currently sold on the market, such as p-toluenesulfonyl chloride sold by Shanghai Aladdin Biochemical Technology Co., Ltd. under the trade name 4-toluenesulfonyl chloride.

[0080] The organic solvent used in the present invention is methyl formate, ethyl formate, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methanol, ethanol, acetonitrile, dichloromethane, dichloroethane, chloroform, acetone, methyl isopropyl ketone, methyl isobutyl ketone or methyl ethyl ketone, which are all products currently sold on the market, such as acetone sold by Beijing Solebow Technology Co., Ltd. under the trade name of dimethyl ketone. The organic solvent used in the subsequent steps is the same as the above organic solvent, so it will not be repeated below;

[0081] According to the present invention, when the amount of the sulfonyl compound is 0.05-0.20M, if the amount of the compound of the chemical formula (III) is lower than 0.034M, the reaction is difficult to control; if the amount of the compound of the chemical formula (III) is higher than 0.082M, the sulfonate esterification reaction is incomplete; therefore, the amount of the compound of the chemical formula (III) is appropriately 0.034-0.082M, preferably 0.044-0.056M; when the amount of the compound of the chemical formula (III) is 0.034-0.082M, if the amount of the sulfonyl compound is lower than 0.05M, the sulfonate esterification reaction is incomplete; if the amount of the sulfonyl compound is higher than 0.20M, the product quality will be significantly affected; therefore, the amount of the sulfonyl compound is appropriately 0.05-0.20M, preferably 0.08-0.16M; in this step, the main purpose of extracting the esterification reaction solution with dichloromethane is to completely extract the reaction product.

[0082] The product obtained by the vacuum distillation was analyzed and determined by high-resolution mass spectrometry, and the results are as follows:

[0083] HR-MS (ESI + ):(MH + ) is 796.3946. According to the molecular formula C 40 H 61 NO 13 S obtained (MH + )The theoretical calculated value is 796.3942.

[0084] From the measurement results, it can be determined that the product is a compound having a chemical structural formula (IV) of 20-(1,3-dioxolane)-23-sulfonate-5-O-mycaminosyl-tylonolide. The conversion rate of this step is calculated to be more than 80%.

[0085] D. Preparation of Compounds of Chemical Formula (V)

[0086] The reaction of the compound of chemical formula (IV) with ethylene glycol and camphorsulfonic acid is as follows:

[0087]

[0088] According to the weight ratio of the compound of chemical formula (IV) to the organic solvent of 1:3-10, an organic solvent is added to a mixture of 0.031-0.074M of the compound of chemical formula (IV) obtained in step C and 0.05-0.40M of the iodination reagent, and an iodination reaction is carried out at a reaction temperature of 30-80°C for 1-4h, the obtained iodination reaction liquid is cooled, and water is added to the iodination reaction liquid according to a volume ratio of the iodination reaction liquid to water of 1:0.5-1, the organic phase is separated, and the volume ratio of the aqueous phase to dichloromethane is 1:0.5-1. The organic phase and the extract are combined, and then dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.028-0.067M of the compound of chemical formula (V) 20-(1,3-dioxolane)-23-iodo-5-O-mycaminosyl-tylonolide;

[0089] According to the present invention, the iodination reagent is hydroiodic acid, iodine, potassium iodide or sodium iodide, which are all products currently sold on the market.

[0090] In this step, when the amount of the iodination reagent is 0.05-0.40M, if the amount of the compound of the chemical formula (IV) is less than 0.034M, the concentration of the reactants is too low and the iodination reaction proceeds too fast; if the amount of the compound of the chemical formula (IV) is higher than 0.074M, the iodination reaction is not thorough; therefore, the amount of the compound of the chemical formula (IV) is 0.031-0.074M, preferably 0.035-0.060M; when the amount of the compound of the chemical formula (IV) is 0.031-0.074M, if the amount of the iodination reagent is less than 0.05M, the iodination reaction is not thorough; if the amount of the iodination reagent is higher than 0.40M, it is difficult to remove the excess reaction reagent after the reaction; therefore, the amount of the iodination reagent is 0.05-0.40M, preferably 0.12-0.32M;

[0091] In this step, the main purpose of extracting the iodination reaction solution with dichloromethane is to completely extract the reaction product.

[0092] The product obtained by the reduced pressure distillation was analyzed and determined by high-resolution mass spectrometry, and the results are as follows:

[0093] HR-MS (ESI + ):(MH + ) is 752.2876, according to C 33 H 54 NO 10 I molecular formula obtained (MH + )The theoretical calculated value is 752.2871.

[0094] From the measurement results, it can be determined that the product is a compound having a chemical structural formula (V) of 20-(1,3-dioxolane)-23-iodo-5-O-mycaminosyl-tylonolide. The conversion rate of this step is calculated to be more than 80%.

[0095] E. Preparation of compound of chemical formula (VI)

[0096] The reaction of the compound of chemical formula (V) and piperidine is as follows:

[0097] According to the weight ratio of the compound of chemical formula (V) to the organic solvent of 1:3-10, an organic solvent is added to the 0.028-0.067M compound of chemical formula (V) obtained in step D, stirred and dissolved, 0.01-0.05M organic base or inorganic base is added, and 0.05-0.40M piperidine is added dropwise to obtain a mixture solution, which is heated for reaction at a temperature of 40-90°C for 2-4h, water is added to the obtained reaction solution according to the volume ratio of the reaction solution to water of 1:0.5-1, the organic phase is separated, and then the solution is extracted with dichloromethane 1-3 times according to the volume ratio of the aqueous phase to dichloromethane of 1:0.5-1, the organic phase and the extract are combined, and then dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.025-0.062M compound of chemical formula (VI) 20-(1,3-dioxolane)-23-piperidinyl-5-O-mycaminosyl-tylonolide;

[0098] In this step, the inorganic base is one or more inorganic bases selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; the organic base is one or more organic bases selected from pyridine, triethylamine, ethylenediamine, dimethylamine, propylamine, isopropylamine, butylamine, tert-butylamine, hexylamine or ethanolamine. These inorganic bases and organic bases used in the present invention are products currently sold on the market, such as triethylamine sold by Shanghai MacLean Biochemical Technology Co., Ltd. under the trade name N,N-diethylethylamine.

[0099] In this step, the main function of adding 0.01-0.05 M of organic base or inorganic base is to allow the reaction of the compound of chemical formula (V) with piperidine to be carried out under alkaline conditions.

[0100] In this step, when the amount of the compound of chemical formula (V) is 0.028-0.067M, if the amount of piperidine is less than 0.05M, the reaction is not carried out completely; if the amount of piperidine is higher than 0.40M, it is difficult to remove the excess reactants after the reaction is completed; therefore, it is reasonable to use piperidine in an amount of 0.05-0.40M, preferably 0.12-0.34M; when the amount of piperidine is 0.05-0.40M, if the amount of the compound of chemical formula (V) is lower than 0.028M, the concentration of the reactants is too low and the reaction progresses too fast; if the amount of the compound of chemical formula (V) is higher than 0.067M, the reaction is not carried out completely; therefore, it is reasonable to use the compound of chemical formula (V) in an amount of 0.028-0.067M, preferably 0.030-0.060M;

[0101] In this step, the basic purpose of extracting the mixture solution with dichloromethane is to completely extract the reaction product.

[0102] The product obtained by the reduced pressure distillation was analyzed and determined by high-resolution mass spectrometry, and the results are as follows:

[0103] HR-MS (ESI + ):(MH + ) is 709.4642. According to the molecular formula C 38 H 64 N2O 10 The obtained (MH + )The theoretical calculated value is 709.4639;

[0104] From the test results, it can be determined that the product is a compound having a chemical structural formula (VI) of 20-(1,3-dioxolane)-23-piperidinyl-5-O-mycaminoglycan-tylonolide. The conversion rate of this step is calculated to be more than 80%.

[0105] F. Preparation of Compounds of Chemical Formula (VII)

[0106] The reaction of the compound of chemical formula (VI) and camphorsulfonic acid is as follows:

[0107]

[0108] According to the weight ratio of the compound of chemical formula (VI) to the organic solvent of 1:3-10, an organic solvent is added to the 0.025-0.062M compound of chemical formula (VI) obtained in step D, stirred and dissolved, 0.05-0.25M camphorsulfonic acid is added, reacted at room temperature for 2-24 hours, and then the organic solvent is removed by distillation under reduced pressure. Water is added to the remaining reaction solution according to the volume ratio of it to water of 1:1-5, and then the pH is adjusted to 9-11 with sodium hydroxide aqueous solution to generate a white precipitate, which is filtered. The filter cake is stirred in 5-20 times water, and the pH is adjusted to 3-5 with an inorganic acid or an organic acid. After dissolution, the pH is adjusted to 9-11 with a sodium hydroxide aqueous solution, recrystallized, filtered, and dried under reduced pressure to obtain 0.022-0.056M compound of chemical formula (VII) 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide.

[0109] In this step, when the amount of camphorsulfonic acid is 0.05-0.25M, if the amount of the compound of chemical formula (VI) is less than 0.025M, the concentration of the reactants is too low and the reaction progresses too fast; if the amount of the compound of chemical formula (VI) is higher than 0.062M, the reaction is not thorough; therefore, it is desirable that the amount of the compound of chemical formula (VI) is 0.025-0.062M, preferably 0.030-0.050M; when the amount of the compound of chemical formula (VI) is 0.025-0.062M, if the amount of camphorsulfonic acid is lower than 0.05M, the reaction progresses too slowly; if the amount of camphorsulfonic acid is higher than 0.25M, it is difficult to remove the excess reactants after the reaction is completed; therefore, it is desirable that the amount of camphorsulfonic acid is 0.05-0.25M, preferably 0.05-0.20M;

[0110] In this step, the reduced pressure drying is carried out in a vacuum drying oven under a system pressure of 0.02 MPa, and the drying should reach a moisture content ratio of less than or equal to 2%. The conversion rate of this step is calculated to be more than 80%.

[0111] The product was analyzed and determined by high-resolution mass spectrometry, and the results are as follows:

[0112] HR-MS (ESI + ):(MH + ) is 665.4383. According to the molecular formula C 36 H 60 N2O9 (MH + )The theoretical calculated value is 665.4377;

[0113] The white crystalline product prepared by the present invention was subjected to the following nuclear magnetic resonance spectrum and mass spectrometry analysis:

[0114] (I) H NMR spectrum analysis

[0115] Analytical equipment: NMR instrument sold by Bruker Corporation under the trade name Avance DRX 500;

[0116] Analysis conditions: 500 Hz, pulse zg30, scan number (ns) 8, relaxation time (D1) 1 s, CDCl3 solvent. The analysis results are shown in the attached Figure 1 .

[0117] The chemical shifts of H NMR spectrum were assigned as follows: δ7.321 (1H, H-11), δ6.343 (1H, H-10), δ6.312 (1H, H-13), δ4.732 (1H, H-15), δ4.29 (1H, H-2'), δ3.08 (1H, H-5'), δ3.54 (1H, H-4'), δ2.41 (1H, H-3'), δ1.024 (6H, H-18), δ3.799 (1H, H-3), δ3.559 (1H, H-5), δ2.918 (1H, H-14), δ2.706 (2H ,H-8), δ2.338(2H×5), δ2.412(2H,H-2), δ2.003(3H×2,-NCH3), δ2.424(2H,H-17), δ1.792(3H,H-22), δ1.492(H,H-4,6), δ1.7 12(2H,H-19), δ1.878(2H,H-16), δ9.719(H,H-20), δ1.712(2H,H-7), δ0.950(3H,H-18), δ1.250(3H,H-21), δ0.978(3H,H-5').

[0118] (II) Mass spectrometry analysis

[0119] Analytical equipment: High-resolution mass spectrometer sold by Waters Corporation under the trade name Synapt HDMS;

[0120] Analytical conditions: QTOF MS used ESI positive ionization scanning; capillary voltage 3.0 kV, cone voltage 15 V; ion source and desolvation gas temperatures were 120 °C and 350 °C, respectively; the desolvation gas flow rate was set to 650 L / hr. TOF MS mass acquisition range was m / z 80 to 1000 Da;

[0121] The samples were mass calibrated with sodium formate solution before analysis; leucine-enkephalin solution (LE, m / z 566.2771) was used as Lock mass for real-time calibration of accurate mass.

[0122] The results of this analysis are shown in the Appendix Figure 2 .

[0123] In the time-of-flight mass spectrometry, 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tyrosol was detected according to the molecular formula C 36 H 60 N2O9 (MH + ) The theoretical calculated value is 665.4377; [MH + ]m / z665.4383 molecular ion peak, fragment ion [MH +]m / z 492.3328, which is the fragment ion peak of the molecule after the removal of mycosylamine. The fragment ion [MH + ]m / z 174.1147 is the fragment ion peak of mycosylamine, and the fragment ion [MH + ]m / z98.0991 is the fragment ion peak of methylenepiperidine.

[0124] The above-mentioned nuclear magnetic resonance hydrogen spectrum analyzed the nuclear magnetic resonance signals of the sample molecules, the size and cause of chemical shifts, the connection mode and configuration between atomic structures; the mass spectrometry analysis results showed that the molecular weight of the measured samples was consistent with the theoretical results.

[0125] The results of the above analytical test data show that the chemical structure of the product prepared by the method of the present invention is consistent with the spectral analysis data. Therefore, it can be determined that the product prepared by the method of the present invention is a compound 20-aldehyde-23-piperidinyl-5-O-mycaminoglycansyl-tylonolide having a chemical structural formula (VII).

[0126] According to the method described in (Meng Ke et al., Chinese Journal of Antibiotics, 2020, 45(5): 437-440 "Study on the Synthesis of Tediloxine and Its Phosphate"), the conversion rate of the reactants in each step of the preparation method of the present invention can reach more than 80%; with reference to the method described in ("Pharmacopoeia of the People's Republic of China", 2020, 219-220 "Tylosin" and (Chen Hongli et al., Animal Husbandry and Veterinary Medicine, 2016, 48(6): 86-88 "Study on the Determination of Tediloxine by High Performance Liquid Chromatography"), an HPLC content detection method was formulated, and the purity of the compound 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylosin having the chemical formula (VII) can reach 98.7%.

[0127] HPLC content detection method.

[0128] Chromatographic column: C 18 4.6×150mm,1.7μm; Flow rate: 1.0mL / min; Injection volume: 10μL; Column temperature: 30℃, Detection wavelength: 290nm;

[0129] Mobile phase: 0.3% formic acid acetonitrile solution-0.3% formic acid aqueous solution (18:82)

[0130] The determination method is as follows: accurately measure about 10 mg of the sample prepared in this example, accurately weigh it, place it in a 50 mL volumetric flask, add the mobile phase to dilute it to the scale, shake it well, and prepare it into a 0.2 mg / mL test solution. Accurately measure 10 μL and inject it into the liquid chromatograph to record the chromatogram. According to the area normalization method, the purity of the compound 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide of the chemical formula (VII) prepared in Example 1 is 98.7%.

[0131] The present invention also relates to a compound of chemical formula (VII) synthesized by the synthesis method, 20-aldehyde-23-piperidinyl-5-O-mycaminoglycan-tylonolide and its salt. Wherein, the pharmaceutically acceptable salt of the compound of chemical formula (VII) is a salt prepared by conventional preparation methods with an inorganic acid or an organic acid. The inorganic acid is hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, metaphosphoric acid, sulfurous acid, perchloric acid or phosphoric acid; the organic acid is trifluoroacetic acid, acetic acid, glycolic acid, propionic acid, pyruvic acid, acrylic acid, malonic acid, γ-hydroxybutyric acid, hexanoic acid, cyclopentanepropionic acid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, methoxybenzoic acid, hydroxybenzoic acid, benzenesulfonic acid, tartaric acid, stearic acid, mandelic acid, succinic acid, maleic acid, citric acid, (D) or (L) malic acid, lactic acid, salicylic acid, gluconic acid, cinnamic acid, glutamic acid, dodecyl sulfuric acid, phthalic acid, or oxalic acid.

[0132] The present invention also relates to the use of the compound 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide and its salts with the chemical structural formula (VII) in the preparation of drugs for treating bacterial infections or mycoplasma infections in mammals, fish or poultry.

[0133] The mammals are, for example, pigs, cattle, sheep, horses, dogs, rabbits or cats; the drugs used to treat these mammals are, for example, erythromycin, tylosin, tylosin, tilmicosin, streptomycin, gentamicin, streptomycin, neomycin, spectinomycin, lincomycin or tediloxine; the amount of the compound of the chemical formula (VII) of the present invention added to these drugs is generally based on weight / volume (2.5-20 g) / 100 mL. For a detailed preparation method, see: the invention patent titled "A pharmaceutical composition containing 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylosin and its use".

[0134] The poultry is, for example, chicken, duck, pigeon or goose; the drugs used to treat poultry are, for example, florfenicol, tilmicosin, tylosin, tulathromycin, oxytetracycline, or ceftriaxone sodium; the amount of the compound of the chemical formula (VII) of the present invention added to these drugs is generally (2.5-20) g / 100 mL by weight / volume. For a detailed preparation method, see: the invention patent titled "A pharmaceutical composition containing 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide and its use".

[0135] [Beneficial Effects]

[0136] The beneficial effects of the present invention are:

[0137] In terms of the synthesis process: (1) The hydrolysis reaction of the two pyranose groups connected to the parent ring of the raw material tylosin is simple and efficient, and can be completed in only one step and 0.5 to 1.5 hours. (2) The method of iodination after sulfonation reaction is simple and easy to operate, and the reaction by-products are easy to remove. The unreacted sulfonylation reagent directly adds water to generate water-soluble sulfonic acid, which can be separated from the product by conventional extraction methods, and is conducive to the complete amination reaction in the next step, with obvious results. (3) The method of generating piperidine group by amination at position 23 of the parent ring described in the present invention has mild reaction conditions, is safe for equipment and operating environment, avoids the use of toxic solvent toluene, has no special requirements for reaction temperature and pressure, has high reaction yield, low cost, and less wastewater discharge. (4) The reaction yield is high, and the conversion rate of each step of the reaction can reach more than 80%, and the purity of the product can reach 98.7%. (5) The reaction reagents are all conventional reagents, which are very easy to obtain and inexpensive in the market. The process operation is simple and does not require high temperature or high pressure equipment. It avoids the use of reagents that are highly toxic to the human body and need to be stored at ultra-low temperatures. It is not dangerous, improves the reaction yield, reduces costs, and has industrial application value. If it is put into production, it will produce huge social and economic benefits.

[0138] In terms of veterinary antibacterial effect, 66 strains of 10 bacterial species, including pathogenic bacteria of livestock and poultry, such as Pasteurella multocida, Streptococcus suis, Streptococcus pneumoniae, Staphylococcus aureus, Bordetella bronchiseptica, Klebsiella pneumoniae, Mannheimia hemolytica, Haemophilus parasuis, and Actinobacillus pleuropneumoniae, were tested respectively. The results showed that 20-aldehyde-23-piperidinyl-5-O-mycaminoglycans-tylosin showed sensitive characteristics to the above 66 strains, among which the antibacterial effect on 63.6% of the tested strains was better than that of the third-generation macrolide veterinary drug tediluosin currently used in veterinary clinical practice.

[0139] In terms of veterinary anti-mycoplasma effect, the minimum inhibitory concentration of the compound 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylosin of the chemical formula (VII) of the present invention on pig BTS-7 is 1 / 4 of the tested control drugs: tylosin, tilmicosin, tedilosin, which has the best antibacterial effect, tilmicosin, and the antibacterial effect on chicken-S6, chicken poison BG44T, and chicken poison-0912 is comparable to them.

[0140] In summary, the compound 20-aldehyde-23-piperidinyl-5-O-mycaminoglycansyl-tylonolide prepared by the present invention is sensitive to a variety of pathogens and can be used to prepare new highly effective antibacterial and antimycoplasma veterinary drugs to better control the occurrence and spread of animal infectious diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0141] Figure 1 The H NMR spectrum of the compound 20-aldehyde-23-piperidinyl-5-O-mycaminoglycansyl-tylonolide of the chemical formula (VII);

[0142] Figure 2 It is a full scan mass spectrum of the compound 20-aldehyde-23-piperidinyl-5-O-mycaminoglycansyl-tylonolide of chemical formula (VII). DETAILED DESCRIPTION

[0143] The present invention will be better understood through the following examples.

[0144] Example 1: Synthesis of the compound 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide (VII) of the present invention

[0145] The implementation steps of this embodiment are as follows:

[0146] A. Preparation of Compounds of Chemical Formula (II)

[0147] 0.04M tylosin of chemical formula (I) and 0.5M hydrochloric acid solution are reacted at a weight ratio of 1:10, pH 2 and temperature of 95°C for 0.5h, and then the reaction solution is cooled to below 30°C, and then the pH of the reaction solution is adjusted to 10 using ammonia water with a concentration of 10% by volume, and then ethyl acetate is used as an organic extractant to extract twice according to a volume ratio of the reaction solution to the organic extractant of 1:1, and the extracts are combined, and then washed with water twice according to a volume ratio of the extract to water of 1:0.5, and the washed extract is dried with anhydrous sodium sulfate and distilled to obtain 0.036M chemical formula (II) compound 20-aldehyde-23-hydroxy-5-O-mycaminosyl-tylosin; the high-resolution mass spectrometry analysis results of the product refer to the technical solution part of this specification.

[0148] According to the method described in this specification, the conversion rate of the reactant in this step is 90.0%.

[0149] B. Preparation of Compounds of Chemical Formula (III)

[0150] According to the weight ratio of the compound of chemical formula (II) to dichloromethane of 1:10, 0.036M of the compound of chemical formula (II) obtained in step A is dissolved in dichloromethane, and then 0.1M ethylene glycol and 0.05M camphorsulfonic acid are added, mixed evenly, reacted at room temperature for 12 hours, and dichloromethane is added to dilute it at a volume ratio of 1:1, and then the diluted reaction solution is washed three times with a saturated sodium carbonate aqueous solution at a volume ratio of 1:5 to a saturated sodium carbonate aqueous solution, and then dried with anhydrous sodium sulfate, filtered, and distilled to obtain 0.034M of the compound of chemical formula (III) 20-(1,3-dioxolane)-23-hydroxy-5-O-mycaminosyl-tylonolide; the high-resolution mass spectrometry analysis results of the product refer to the technical solution section of this specification.

[0151] According to the method described in this specification, the conversion rate of the reactant in this step is 94.4%.

[0152] C. Preparation of Compounds of Chemical Formula (IV)

[0153] 0.034M of the compound of the above chemical formula (III) and 0.10M of p-toluenesulfonyl chloride and acetone solvent are subjected to sulfonation reaction at a weight ratio of 1:3 and a temperature of 20°C for 3 hours, and water is added to the obtained esterification reaction liquid at a volume ratio of 1:0.5-1 between the esterification reaction liquid and water, and the organic phase is separated, and then extracted twice with dichloromethane at a volume ratio of 1:1 between the aqueous phase and dichloromethane, and the organic phase and the extract are combined, dried over anhydrous sodium sulfate, and distilled, thereby obtaining 0.031M of the compound of the chemical formula (IV) 20-(1,3-dioxolane)-23-sulfonate-5-O-mycaminosyl-tylonolide;

[0154] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0155] According to the method described in this specification, the conversion rate of the reactants in this step is 91.2%.

[0156] D. Preparation of Compounds of Chemical Formula (V)

[0157] According to the weight ratio of the compound of chemical formula (IV) to the organic solvent being 1:10, an organic solvent of isopropyl acetate is added to a mixture of 0.031M of the compound of chemical formula (IV) obtained in step C and 0.05M of hydroiodic acid, and an iodination reaction is carried out at a reaction temperature of 80°C for 1h, followed by cooling, and water is added in a volume ratio of the reaction solution to water of 1:1, and the organic phase is separated, and extracted twice with dichloromethane in a volume ratio of the aqueous phase to dichloromethane of 1:0.8, and the organic phase and the extract are combined and dried over anhydrous sodium sulfate, and distilled under reduced pressure, thereby obtaining 0.028M of the compound of chemical formula (V) 20-(1,3-dioxolane)-23-iodo-5-O-mycaminosyl-tylonolide;

[0158] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0159] According to the method described in this specification, the conversion rate of the reactant in this step is 90.3%.

[0160] E. Preparation of compound of chemical formula (VI)

[0161] According to the weight ratio of the compound of chemical formula (V) to the organic solvent of 1:5, tert-butyl methyl ether organic solvent is added to the 0.028M compound of chemical formula (V) obtained in step D, stirred to dissolve, 0.01M sodium carbonate is added, and 0.05M piperidine is added dropwise to obtain a mixture solution, which is heated to react for 4 hours at a temperature of 40°C, and then water is added according to the volume ratio of the reaction solution to water of 1:1, the organic phase is separated, and the mixture is extracted twice with dichloromethane according to the volume ratio of the aqueous phase to dichloromethane of 1:0.6, the combined extracts are dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.025M compound of chemical formula (VI) 20-(1,3-dioxolane)-23-piperidinyl-5-O-mycaminosyl-tylonolide;

[0162] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0163] According to the method described in this specification, the conversion rate of the reactant in this step is 89.3%.

[0164] F. Preparation of Compounds of Chemical Formula (VII)

[0165] According to the weight ratio of the compound of chemical formula (VI) to the organic solvent of 1:5, methyl acetate, an organic solvent, is added to the 0.025M compound of chemical formula (VI) obtained in step D, stirred to dissolve, 0.15M camphorsulfonic acid is added, and the reaction is carried out at room temperature for 2 hours. The organic solvent is removed by distillation under reduced pressure, and water is added to the remaining reaction solution according to the volume ratio of 1:5 to water, and then the pH is adjusted to 9 with aqueous sodium hydroxide solution to generate a white precipitate, which is filtered. The filter cake is stirred in 20 times water, the pH value is adjusted to 3 with hydrochloric acid, and after dissolution, the pH is adjusted to 10 with aqueous sodium hydroxide solution, recrystallized, filtered, and dried under reduced pressure at 60°C in a vacuum drying oven to obtain 0.022M compound of chemical formula (VII) 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide.

[0166] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0167] According to the method described in this specification, the conversion rate of the reactant in this step is 88.0%.

[0168] According to the method described in this specification, the purity of the compound of chemical formula (VII) prepared in this example is 98.7%.

[0169] Example 2: Synthesis of 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide (VII) of the present invention The implementation steps of this example are as follows:

[0170] A. Preparation of Compounds of Chemical Formula (II)

[0171] 0.07M tylosin of chemical formula (I) and 0.7M sulfuric acid solution are reacted at a weight ratio of 1:6, pH 1 and temperature of 60°C for 1.5h, and then the reaction solution is cooled to below 30°C, and then the pH of the reaction solution is adjusted to 10 using ammonia water with a concentration of 20.0% by volume, and then extracted 3 times with dichloroethane at a volume ratio of 1:0.5 between the reaction solution and the organic extractant, and the extracts are combined, and then washed with water 3 times at a volume ratio of 1:0.5 between the extract and water, and the washed extract is dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 0.060M compound 20-aldehyde-23-hydroxy-5-O-mycaminosyl-tylosin of chemical formula (II);

[0172] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0173] According to the method described in this specification, the conversion rate of the reactant in this step is 85.7%.

[0174] B. Preparation of Compounds of Chemical Formula (III)

[0175] According to the weight ratio of the compound of chemical formula (II) to dichloromethane of 1:6, 0.060M of the compound of chemical formula (II) obtained in step A was dissolved in dichloromethane, and then 0.8M ethylene glycol and 0.19M camphorsulfonic acid were added, mixed evenly, reacted at room temperature for 2h, diluted according to the volume ratio of the reaction solution to dichloromethane of 1:3, then washed twice with saturated sodium carbonate aqueous solution at a volume ratio of 1:5, and then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain 0.054M of the compound of chemical formula (III) 20-(1,3-dioxolane)-23-hydroxy-5-O-mycaminosyl-tylonolide;

[0176] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0177] According to the method described in this specification, the conversion rate of the reactant in this step is 90.0%.

[0178] C. Preparation of Compounds of Chemical Formula (IV)

[0179] 0.054M of the compound of the above chemical formula (III) and 0.05M of methylsulfonyl chloride and methyl isopropyl ketone in a weight ratio of 1:7 at a temperature of 30°C for sulfonation reaction for 1h, the obtained esterification reaction solution is then cooled, water is added in a volume ratio of 1:1 between the reaction solution and water, the organic phase is separated, and then extracted twice with dichloromethane in a volume ratio of 1:0.8 between the aqueous phase and dichloromethane, the organic phase and the extract are combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure, thereby obtaining 0.044M of the compound of the chemical formula (IV) 20-(1,3-dioxolane)-23-sulfonate-5-O-mycaminosyl-tylonolide;

[0180] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0181] According to the method described in this specification, the conversion rate of the reactant in this step is 81.5%.

[0182] D. Preparation of Compounds of Chemical Formula (V)

[0183] According to the weight ratio of the compound of chemical formula (IV) to the organic solvent being 1:5, dichloroethane organic solvent is added to the mixture of 0.044M compound of chemical formula (IV) obtained in step C and 0.20M potassium iodide, and iodination reaction is carried out at a reaction temperature of 30°C for 4 hours, followed by cooling, and water is added according to a volume ratio of the reaction solution to water of 1:0.5, the organic phase is separated, and then extracted with dichloromethane three times according to a volume ratio of the aqueous phase to dichloromethane of 1:0.5, the organic phase and the extract are combined and then dried over anhydrous sodium sulfate, and distilled under reduced pressure, thereby obtaining 0.036M compound of chemical formula (V) 20-(1,3-dioxolane)-23-iodo-5-O-mycaminosyl-tylonolide;

[0184] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0185] According to the method described in this specification, the conversion rate of the reactant in this step is 81.8%.

[0186] E. Preparation of compound of chemical formula (VI)

[0187] According to the weight ratio of the compound of chemical formula (V) to the organic solvent of 1:10, ethyl acetate is added as an organic solvent to the 0.036M compound of chemical formula (V) obtained in step D, the mixture is stirred and dissolved, 0.03M potassium carbonate is added, and 0.24M piperidine is added dropwise to obtain a mixture solution, which is heated to react for 3 hours at a temperature of 65°C, water is added according to a volume ratio of the reaction solution to water of 1:1, the organic phase is separated, and then the mixture is extracted with dichloromethane three times according to a volume ratio of the aqueous phase to dichloromethane of 1:0.7, the organic phase and the extract are combined, and then dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.029M of the compound of chemical formula (VI) 20-(1,3-dioxolane)-23-piperidinyl-5-O-mycaminosyl-tylonolide;

[0188] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0189] According to the method described in this specification, the conversion rate of the reactant in this step is 80.6%.

[0190] F. Preparation of Compounds of Chemical Formula (VII)

[0191] According to the weight ratio of the compound of chemical formula (VI) to the organic solvent of 1:5, butyl acetate was added to the 0.029M compound of chemical formula (VI) obtained in step D, stirred and dissolved, 0.25M camphorsulfonic acid was added, and the reaction was carried out at room temperature for 24 hours. The organic solvent was removed by distillation under reduced pressure, and water was added to the remaining reaction solution according to the volume ratio of 1:3 to water, and then the pH was adjusted to 10 with sodium hydroxide aqueous solution to generate a white precipitate, which was filtered. The filter cake was stirred in 10 times water, and the pH was adjusted to 4 with nitric acid. After dissolution, the pH was adjusted to 9 with sodium hydroxide aqueous solution, recrystallized, filtered, washed, and dried under reduced pressure in a vacuum drying oven at 0.08MPa and 60°C to obtain 0.024M compound of chemical formula (VII) 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide.

[0192] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0193] According to the method described in this specification, the conversion rate of the reactant in this step is 82.8%.

[0194] According to the method described in this specification, the purity of the compound of chemical formula (VII) prepared in this example is 98.2%.

[0195] Example 3: The present invention: Synthesis of 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide (VII)

[0196] The implementation steps of this embodiment are as follows:

[0197] A. Preparation of Compounds of Chemical Formula (II)

[0198] 0.10M tylosin of chemical formula (I) and 1.0M methanesulfonic acid solution are reacted at a weight ratio of 1:3, pH 3 and temperature of 78°C for 1 hour, and then the reaction solution is cooled to below 30°C, and then the pH of the reaction solution is adjusted to 11 using ammonia water with a concentration of 16.0% by volume, and then methyl ethyl ketone is used as an organic extractant to extract 3 times at a volume ratio of 1:0.8 between the reaction solution and the organic extractant, and the extracts are combined, and then washed once with water at a volume ratio of 1:0.5 between the extract and water, and the washed extract is dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 0.081M compound 20-aldehyde-23-hydroxy-5-O-mycaminosyl-tylosin of chemical formula (II);

[0199] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0200] According to the method described in this specification, the conversion rate of the reactant in this step is 81.0%.

[0201] B. Preparation of Compounds of Chemical Formula (III)

[0202] According to the weight ratio of the compound of chemical formula (II) to dichloromethane of 1:3, 0.081M of the compound of chemical formula (II) obtained in step A was dissolved in dichloromethane, and then 1.5M ethylene glycol and 0.40M camphorsulfonic acid were added, mixed evenly, reacted at room temperature for 24 hours, and diluted with dichloromethane at a volume ratio of 1:5, followed by washing 3 times with a saturated sodium carbonate aqueous solution at a volume ratio of 1:3, and then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain 0.065M of the compound of chemical formula (III) 20-(1,3-dioxolane)-23-hydroxy-5-O-mycaminosyl-tylonolide;

[0203] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0204] According to the method described in this specification, the conversion rate of the reactant in this step is 80.2%.

[0205] C. Preparation of Compounds of Chemical Formula (IV)

[0206] 0.065M of the compound of the above chemical formula (III) and 0.20M of trifluoromethylsulfonyl chloride and methyl isobutyl ketone in a weight ratio of 1:10 at a temperature of 40°C were subjected to a sulfonation reaction for 5 hours, and the obtained esterification reaction solution was then cooled, and water was added in a volume ratio of 1:1 between the reaction solution and water, and the organic phase was separated, and then extracted with dichloromethane three times in a volume ratio of 1:0.5 between the aqueous phase and dichloromethane, and the organic phase and the extract were combined and dried over anhydrous sodium sulfate, and distilled under reduced pressure, thereby obtaining 0.059M of the compound of the chemical formula (IV) 20-(1,3-dioxolane)-23-sulfonate-5-O-mycaminosyl-tylonolide;

[0207] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0208] According to the method described in this specification, the conversion rate of the reactant in this step is 90.8%.

[0209] D. Preparation of Compounds of Chemical Formula (V)

[0210] According to the weight ratio of the compound of chemical formula (IV) to the organic solvent being 1:3, methyl acetate is added to the mixture of 0.059M compound of chemical formula (IV) obtained in step C and 0.40M sodium iodide, and iodination reaction is carried out at a reaction temperature of 55°C for 3 hours, followed by cooling, and water is added according to a volume ratio of the reaction solution to water of 1:1, the organic phase is separated, and the mixture is extracted three times with dichloromethane according to a volume ratio of the aqueous phase to dichloromethane of 1:1, the organic phase and the extract are combined, and then dried over anhydrous sodium sulfate, and distilled under reduced pressure, thereby obtaining 0.053M compound of chemical formula (V) 20-(1,3-dioxolane)-23-iodo-5-O-mycaminosyl-tylonolide;

[0211] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0212] According to the method described in this specification, the conversion rate of the reactant in this step is 89.8%.

[0213] E. Preparation of compound of chemical formula (VI)

[0214] According to the weight ratio of the compound of chemical formula (V) to the organic solvent of 1:10, methyl isobutyl ketone is added to the 0.053M compound of chemical formula (V) obtained in step D, stirred and dissolved, 0.05M ethanolamine is added, and 0.40M piperidine is added dropwise to obtain a mixture solution, which is heated to react for 2h at a temperature of 90°C, and then water is added according to the volume ratio of the reaction solution to water of 1:0.5, the organic phase is separated, and the mixture is extracted with dichloromethane three times according to the volume ratio of the aqueous phase to dichloromethane of 1:0.5, the organic phase and the extract are combined, and then dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.045M compound of chemical formula (VI) 20-(1,3-dioxolane)-23-piperidinyl-5-O-mycaminosyl-tylonolide;

[0215] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0216] According to the method described in this specification, the conversion rate of the reactant in this step is 84.9%.

[0217] F. Preparation of Compounds of Chemical Formula (VII)

[0218] According to the weight ratio of the compound of chemical formula (VI) to the organic solvent of 1:6, isopropyl acetate is added to the 0.045M compound of chemical formula (VI) obtained in step D, stirred and dissolved, 0.05M camphorsulfonic acid is added, and the reaction is carried out at room temperature for 12 hours. The organic solvent is removed by distillation under reduced pressure, and water is added to the remaining reaction solution according to the volume ratio of 1:1 with water, and the pH is adjusted to 11 with sodium hydroxide aqueous solution to generate a white precipitate, which is filtered. The filter cake is stirred in 10 times water, the pH value is adjusted to 5 with sulfuric acid, and after dissolution, the pH is adjusted to 11 with sodium hydroxide aqueous solution, recrystallized, filtered, washed, and dried under reduced pressure in a vacuum drying oven at 0.08MPa and 60°C to obtain 0.040M compound of chemical formula (VII) 20-aldehyde-23-piperidinyl-5-O-mycaminoglycosyl-tylonolide.

[0219] The high-resolution mass spectrometry analysis results of the product are shown in the technical solution section of this specification.

[0220] According to the method described in this specification, the conversion rate of the reactant in this step is 88.9%.

[0221] According to the method described in this specification, the purity of the compound of chemical formula (VII) prepared in this example is 98.5%.

[0222] Experimental Example 1: Study on the antibacterial activity of the compound of the chemical formula (VII) of the present invention

[0223] The implementation method of this test example is as follows:

[0224] The antibacterial activity of the compound of the chemical formula (VII) of the present invention was tested according to the US NCCLS antimicrobial drug sensitivity test operating standards. The minimum inhibitory concentration (MIC) of the compound of the chemical formula (VII) against the following experimental strains was determined by the microbroth dilution method.

[0225] (1) Culture medium and preparation method

[0226] MHB agar medium and MHB broth medium were purchased from Beijing Zhonghai Biotechnology Co., Ltd. They were prepared according to the instructions before use. Streptococcus culture medium required adding 10% calf serum by volume after the sterilization temperature of the culture medium dropped below 60°C.

[0227] (2) Test strains

[0228] Pasteurella multocida, Streptococcus suis, Streptococcus pneumoniae, Staphylococcus aureus, Bordetella bronchiseptica, Klebsiella pneumoniae, Mannheimia hemolytica, Haemophilus parasuis, and Actinobacillus pleuropneumoniae were purchased from the Culture Collection Center of the China Veterinary Drug Administration, and the other strains were isolated by the drug resistance group of the Safety Evaluation Laboratory of the China Veterinary Drug Administration, and were identified by the VITEK-32 fully automatic bacterial identification system.

[0229] (3) Experimental drugs

[0230] Test drug: 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide compound having the chemical structural formula (VII) prepared in Example 1 of the present invention.

[0231] Control drugs: Tylosin (sold by China Veterinary Drug Administration, batch number K0161305), Tilmicosin (sold by China Veterinary Drug Administration, batch number K11109, content 93.7%), Tedirosin (Toronto Research Chemicals, content 98.0%).

[0232] (4) Test methods

[0233] The MIC of the antibacterial drugs against the above test strains was determined by the microbroth dilution method recommended by the American Committee for Clinical Laboratory Standards. The macrolide antibacterial drugs were accurately weighed and dissolved and diluted in multiples with 20% ethanol as solvent. The dilution range of the final drug concentration was: for Klebsiella pneumoniae 3699 and Bordetella bronchiseptica 718, the drug concentration range was 1000-0.488 μg / mL; for Salmonella enteritidis 3379 and Escherichia coli 204, the drug concentration range was 100-0.049 μg / mL; for other pathogens, the concentration range was 50-0.024 μg / mL. The mixture was shaken evenly with a micro-oscillator and incubated at 37°C for 24 hours. The lowest concentration of sterile growth was observed to be the MIC of the drug.

[0234] (5) Measurement results

[0235] The MIC values ​​of the compound of the chemical formula (VII) of the present invention (20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylosin) and other three macrolide control drugs, tylosin, tilmicosin and tedilosin, against common animal pathogens are shown in Table 1, where the MIC unit is μg / mL.

[0236] Table 1: MICs of compound (VII) and macrolide control drugs against animal pathogens

[0237]

[0238]

[0239] As can be seen from Table 1, the in vitro antibacterial test on 66 strains of the above 10 species showed that compound (VII) showed sensitive characteristics to all tested strains, among which the antibacterial effect on 63.6% of the tested strains was better than that of the third-generation macrolide veterinary drug tediluoxin, and the antibacterial effect on 18.2% of the strains was equivalent to that of the third-generation macrolide veterinary drug tediluoxin. Therefore, the in vitro antibacterial activity of 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide was significantly superior to that of the control drug.

[0240] Test Example 2: Study on the anti-mycoplasma activity of the compound of the chemical formula (VII) of the present invention (20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide). The implementation method of this test example is as follows:

[0241] In order to further verify the anti-mycoplasma activity of the compound of the chemical formula (VII) of the present invention (20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide), sensitivity tests were performed on gallisepticum, chicken and porcine mycoplasma.

[0242] (1) Determination of mycoplasma:

[0243] Chicken (S6), gallisepticum (BG44T), gallisepticum-0912, and porcine (BTS-7) mycoplasmas were purchased from the Culture Collection Center of the China Veterinary Drug Administration.

[0244] (2) Test drug: Same as in Test Example 1, except that the drug concentration range is 25 to 0.001 μg / mL.

[0245] (3) Determination method: Referring to the test tube double dilution method described in (Zhang Chunping et al., Chinese Journal of Veterinary Drugs, 2013, 47(4): 10-12 "Study on the in vitro antimicrobial susceptibility test of Mycoplasma hyopneumoniae"), the in vitro antibacterial activity of compound (VII) and control drugs tylosin, tilmicosin and tedilosin against the above mycoplasmas was determined. The determination results are shown in Table 2.

[0246] Table 2: MIC of compound (VII) and macrolide control drugs against animal mycoplasma

[0247]

[0248] The results in Table 2 clearly show that among the three macrolide control drugs: tylosin, tilmicosin, and tedilosin, tilmicosin has a stronger inhibitory effect on mycoplasma, while the minimum inhibitory concentration of the compound 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylosin on pig BTS-7 is 1 / 4 of that of tilmicosin, and its antibacterial effect on chicken-S6, chicken poison BG44T, and chicken poison-0912 is comparable. Therefore, the compound 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylosin of the chemical structural formula (VII) of the present invention has a higher in vitro antibacterial activity against the tested mycoplasma.

Claims

1. A method for synthesizing 20-aldehyde-23-piperidinyl-5-O-mycaminoglycan-tylonolide, characterized in that The synthesis steps of this synthesis method are as follows: A. Preparation of Compounds of Chemical Formula (II) The reaction of tylosin of chemical formula (I) with inorganic acid or organic acid is as follows: 0.04-0.10M tylosin of chemical formula (I) and 0.5-1.0M inorganic acid or organic acid solution are mixed in a weight ratio of 1:3-10, pH 1-3 reacts with a temperature of 60-95° C. for 0.5-1.5 h, then cools the reaction solution to below 30° C., then uses ammonia water with a concentration of 0-20.0% by volume to adjust the pH of the reaction solution to 9-11, then uses an organic extractant to extract 1-3 times according to a volume ratio of the reaction solution to the organic extractant of 1:0.5-1, and combines the extracts, wherein the organic extractant is one or more organic extractants selected from ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, dichloromethane, chloroform, dichloroethane, ether, tert-butyl methyl ether, acetone, methyl ethyl ketone or methyl isobutyl ketone; then washes with water 1-3 times according to a volume ratio of 1:0.5-1 to water, and the washed extract is dried with anhydrous sodium sulfate and distilled under reduced pressure to obtain 0.036-0.091M of the compound of chemical formula (II) 20-aldehyde-23-hydroxy-5-O-mycaminosyl-tylonolide; B. Preparation of Compounds of Chemical Formula (III) The reaction of the compound of chemical formula (II) with ethylene glycol and camphorsulfonic acid is as follows: According to the weight ratio of the compound of chemical formula (II) to dichloromethane of 1:3-10, 0.036-0.091M of the compound of chemical formula (II) obtained in step A is dissolved in dichloromethane, and then 0.1-1.5M ethylene glycol and 0.05-0.40M camphorsulfonic acid are added, mixed evenly, and reacted at room temperature for 2-24h, and the reaction solution is diluted with dichloromethane according to the volume ratio of the compound to dichloromethane of 1:1-5, and then washed 1-3 times according to the volume ratio of the compound to saturated sodium carbonate aqueous solution of 1:1-5, and then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain 0.034-0.082M of the compound of chemical formula (III) 20-(1,3-dioxolane)-23-hydroxy-5-O-mycaminosyl-tylonolide; C. Preparation of Compounds of Chemical Formula (IV) The reaction of the compound of chemical formula (III) and the sulfonyl compound is as follows: 0.034-0.082M of the compound of the above chemical formula (III) and 0.05-0.20M of the sulfonyl compound, in a weight ratio of 1:3-10 to an organic solvent, are subjected to a sulfonate esterification reaction at a temperature of 20-40°C for 1-5h, the obtained esterification reaction liquid is cooled, water is added to the esterification reaction liquid at a volume ratio of 1:0.5-1 to the esterification reaction liquid, the organic phase is separated, and then extracted with dichloromethane 1-3 times at a volume ratio of 1:0.5-1 to the water phase to dichloromethane, the organic phase and the extract are combined, and then dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.031-0.074M of the compound of the chemical formula (IV) 20-(1,3-dioxolane)-23-sulfonate-5-O-mycaminosyl-tylonolide; D. Preparation of Compounds of Chemical Formula (V) The reaction of the compound of chemical formula (IV) with the iodination reagent is as follows: According to the weight ratio of the compound of chemical formula (IV) to the organic solvent of 1:3-10, an organic solvent is added to a mixture of 0.031-0.074M of the compound of chemical formula (IV) obtained in step C and 0.05-0.40M of an iodination reagent, and an iodination reaction is carried out at a reaction temperature of 30-80°C for 1-4h, wherein the iodination reagent is hydroiodic acid, iodine, potassium iodide or sodium iodide; then the iodination reaction liquid is cooled, and water is added to the iodination reaction liquid according to a volume ratio of the reaction liquid to water of 1:0.5-1, the organic phase is separated, and then extracted with dichloromethane 1-3 times according to a volume ratio of the water phase to dichloromethane of 1:0.5-1, the organic phase and the extract are combined, and then dried with anhydrous sodium sulfate, and distilled under reduced pressure, thereby obtaining 0.028-0.067M of the compound of chemical formula (V) 20-(1,3-dioxolane)-23-iodo-5-O-mycaminosyl-tylonolide; E. Preparation of compound of chemical formula (VI) The reaction of the compound of chemical formula (V) and piperidine is as follows: According to the weight ratio of the compound of chemical formula (V) to the organic solvent of 1:3-10, an organic solvent is added to the 0.028-0.067M compound of chemical formula (V) obtained in step D, and the mixture is stirred and dissolved, and then 0.01-0.05M organic base or inorganic base is added, and then 0.05-0.40M piperidine is added dropwise, and the obtained mixture solution is heated at a temperature of 40-90°C for reaction for 2-4h, and water is added to the reaction solution according to the volume ratio of the reaction solution to water of 1:0.5-1, and the organic phase is separated, and then extracted with dichloromethane 1-3 times according to the volume ratio of the aqueous phase to dichloromethane of 1:0.5-1, and the organic phase and the extract are combined, and then dried with anhydrous sodium sulfate, and distilled under reduced pressure, so as to obtain 0.025-0.062M compound of chemical formula (VI) 20-(1,3-dioxolane)-23-piperidinyl-5-O-mycaminosyl-tylonolide; F. Preparation of Compounds of Chemical Formula (VII) The reaction of the compound of chemical formula (VI) and camphorsulfonic acid is as follows: According to the weight ratio of the compound of chemical formula (VI) to the organic solvent of 1:3-10, an organic solvent is added to the 0.025-0.062M compound of chemical formula (VI) obtained in step E, stirred to dissolve, 0.05-0.25M camphorsulfonic acid is added, mixed evenly, reacted at room temperature for 2-24 hours, and then the organic solvent is removed by distillation under reduced pressure, and water is added to the remaining reaction solution according to the volume ratio of it to water of 1:1-5, and then the pH is adjusted to 9-11 with sodium hydroxide aqueous solution to generate a white precipitate, filtered, and the filter cake is stirred in 5-20 times water, and the pH value is adjusted to 3-5 with an inorganic acid or an organic acid. After dissolution, the pH value is adjusted to 9-11 with a sodium hydroxide aqueous solution, recrystallized, filtered, and dried under reduced pressure to obtain 0.022-0.056M compound 20-aldehyde-23-piperidinyl-5-O-mycaminosyl-tylonolide of chemical formula (VII).

2. The synthesis method according to claim 1, characterized in that In steps A and F, the inorganic acid is one or more inorganic acids selected from hydrochloric acid, nitric acid, sulfuric acid, perchloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, chloric acid, bromic acid or phosphoric acid; the organic acid is one or more organic acids selected from 2,4,6-trinitrophenol, 2,4,6-trinitrobenzoic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, cyclohexanethiolsulfonic acid, oxalic acid or 2-chloroethanethiol.

3. The synthesis method according to claim 1, characterized in that In steps AF, the reduced pressure distillation or reduced pressure drying is carried out at a temperature of 20° C. to 80° C. and a system pressure of 0.001 to 0.02 MPa.

4. The synthesis method according to claim 1, characterized in that In step C, the sulfonyl compound is p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethylsulfonyl chloride or trifluoromethylsulfonic anhydride.

5. The synthesis method according to claim 1, characterized in that In steps C to F, the organic solvent is methyl formate, ethyl formate, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methanol, ethanol, acetonitrile, dichloromethane, dichloroethane, chloroform, acetone, methyl isopropyl ketone, methyl isobutyl ketone or methyl ethyl ketone.

6. The synthesis method according to claim 1, characterized in that In step E, the inorganic base is one or more inorganic bases selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; the organic base is one or more organic bases selected from pyridine, triethylamine, ethylenediamine, dimethylamine, propylamine, isopropylamine, butylamine, tert-butylamine, hexylamine or ethanolamine.

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