Tylosin derivative, preparation method therefor, and use thereof

Abstract

Disclosed in the present invention are a Tylosin derivative, a preparation method therefor, and a use thereof. The tylosin derivative provided by the present invention has the structure shown in formula 1. Also provided in the present invention are a veterinary drug composition and a pharmaceutical preparation containing the tylosin derivative, and a use of the veterinary drug composition and the pharmaceutical preparation in the treatment or prevention of bacterial infection diseases in animals. Also provided in the present invention is a feed additive comprising the tylosin derivative.

Description

A tylosin derivative and its preparation method and application Technical Field

[0001] The invention belongs to the technical field of heterocyclic compound synthesis, livestock and poultry veterinary drugs and feed additives, and particularly relates to a tylosin derivative and a preparation method and application thereof. Background Art

[0002] Tylosin is an important animal antibiotic with a 16-membered macrolide structure. It was first extracted from the culture medium of Streptomyces freundii. It has unique therapeutic effects against diseases such as Mycoplasma gallisepticum and porcine pneumonia. It can also be used as a feed additive to significantly promote livestock and poultry growth. To further expand tylosin's antimicrobial spectrum and applications and develop new drugs, researchers have modified its structure in various ways, resulting in a variety of tylosin derivatives with strong antimicrobial activity and minimal toxic side effects. Examples include 10,11,12,13-tetrahydro-decarboxamidoacetic acid tylosin derivatives, 9-oxime tylosin derivatives, tylosin, tilmicosin, and tylosin.

[0003] Summary of the Invention

[0004] The purpose of the present invention is to provide a new tylosin derivative and its preparation method and application, which can be used to treat or prevent bacterial infection and provide more selectivity for tylosin derivative treatment.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] In a first aspect, the present invention provides a tylosin derivative having a structure as shown in Formula 1:

[0007] Wherein, R is selected from 2-hydroxyethylamino, 3-hydroxypropylamino, 4-hydroxybutylamino, 5-hydroxypentylamino, bis(2-hydroxyethylamino), bis(3-hydroxypropylamino), bis(4-hydroxybutylamino), (R)-2-hydroxymethyltetrahydropyrrolyl, (S)-2-hydroxymethyltetrahydropyrrolyl, (R)-3-hydroxymethyltetrahydropyrrolyl, (S)-3-hydroxymethyltetrahydropyrrolyl, (R)-3-hydroxymethylpiperidinyl, (S)-3-hydroxymethylpiperidinyl, 4-hydroxypiperidinyl, 4-hydroxymethylpiperidinyl, 4-hydroxyethylpiperidinyl.

[0008] Exemplarily, the tylosin derivative is one of the following compounds: 20-(2-hydroxyethylamino) decarboxylase tylosin, 20-(3-hydroxypropylamino) decarboxylase tylosin, 20-(4-hydroxybutylamino) decarboxylase tylosin, 20-(5-hydroxypentylamino) decarboxylase tylosin, 20-(bis(2-hydroxyethylamino)) decarboxylase tylosin, 20-(bis(3-hydroxypropylamino)) decarboxylase tylosin, 20-(bis(4-hydroxybutylamino)) decarboxylase tylosin, 20 -((R)-2-hydroxymethyltetrahydropyrrolyl)decarbamoyl tylosin, 20-((S)-2-hydroxymethyltetrahydropyrrolyl)decarbamoyl tylosin, 20-((R)-3-hydroxymethyltetrahydropyrrolyl)decarbamoyl tylosin, 20-((S)-3-hydroxymethyltetrahydropyrrolyl)decarbamoyl tylosin, 20-((R)-3-hydroxymethylpiperidinyl)decarbamoyl tylosin, 20-((S)-3-hydroxymethylpiperidinyl)decarbamoyl tylosin, 20-(4-hydroxypiperidinyl)decarbamoyl tylosin.

[0009] Furthermore, the tylosin derivative is selected from the compounds with structures shown in the following Ia or Ib:

[0010] The present invention also provides a pharmaceutically acceptable salt of the above-mentioned tylosin derivative; the salt is obtained by reacting the tylosin derivative with an acid. The acid is hydrochloric acid, phosphoric acid, tartaric acid, salicylic acid, methanesulfonic acid, lactic acid, malic acid, formic acid, acetic acid, propionic acid, fumaric acid, citric acid, malic acid, oxalic acid, maleic acid, succinic acid, benzoic acid, ethanedisulfonic acid, etc.

[0011] In a second aspect, the present invention further provides a method for preparing the above-mentioned tylosin derivative, comprising the following steps:

[0012] S1, tylosin A reacts with amino alcohol;

[0013] S2, adding a reducing agent or acid to the system obtained by the reaction in step S1 to react to obtain a macrolide compound intermediate;

[0014] S3. Hydrolyzing the macrolide compound intermediate under acidic conditions to obtain the tylosin derivative.

[0015] Furthermore, the preparation method includes synthesis method 1 and synthesis method 2:

[0016] The synthetic method 1 comprises the following steps:

[0017] (1) Tylosin A and amino alcohol undergo condensation reaction in a polar solvent, and then a reducing agent is added to perform a reduction reaction to obtain a secondary amine-modified macrolide intermediate;

[0018] (2) hydrolyzing the secondary amine-modified macrolide compound intermediate under acidic conditions to obtain the tylosin derivative.

[0019] In step (1), the amino alcohol is 2-aminoethanol or 3-aminopropanol;

[0020] In step (1), the molar ratio of the amino alcohol to the tylosin A is 2 to 5:1, preferably 3 to 3.5:1.

[0021] In step (1), the polar solvent is one or more of methanol, ethanol, propanol, isopropanol, n-butanol and diethanol.

[0022] In step (1), the condensation reaction conditions are: temperature is room temperature, and time is 12 to 13 hours.

[0023] In step (1), the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride and LiAlH4.

[0024] In step (1), the molar ratio of the reducing agent to the tylosin A is 1 to 4: 1, preferably 2 to 2.5: 1. Before adding the reducing agent, the reaction is monitored by TLC to ensure that the raw material is completely converted into imine.

[0025] In step (1), the reduction reaction is carried out under the following conditions: room temperature, and a reaction time of 2 to 6 hours, preferably 2 hours.

[0026] In step (2), the acid is formic acid.

[0027] In step (2), the hydrolysis conditions are: the temperature is room temperature, the time is 1 to 6 hours, and the concentration of the acid aqueous solution is 0.1 to 10M, preferably 0.2M.

[0028] Furthermore, the synthesis method 1 also includes a post-treatment step; the post-treatment is carried out according to the following operations: adding an aqueous solution of an alkali to the reaction system to quench the reaction, and then concentrating under reduced pressure to remove the alcohol solvent; the remaining aqueous solution is extracted with an organic solvent, and the combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure; wherein the alkali is selected from one or more of potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; and the organic solvent is selected from one or more of dichloromethane, ethyl acetate or diethyl ether.

[0029] For example, the synthetic route of the above-mentioned synthetic method 1 is as follows:

[0030] The synthesis method 2 comprises the following steps:

[0031] Step A: Tylosin A and amino alcohol are mixed in a non-polar solvent, heated, and then acid is added to react to obtain a tertiary amine-modified macrolide intermediate;

[0032] Step B: hydrolyzing the tertiary amine-modified macrolide compound intermediate under acidic conditions to obtain the tylosin derivative.

[0033] In step A, the amino alcohol is 2-aminoethanol, 3-aminopropanol, (R)-prolinol, (S)-prolinol, 4-hydroxypiperidine, or 4-hydroxymethylpiperidine.

[0034] In step A, the molar ratio of the amino alcohol to the tylosin A is 2 to 5:1, preferably 2.5 to 3.5:1.

[0035] In step A, the non-polar solvent is one or more of ethylene glycol dimethyl ether, benzene and toluene.

[0036] In step A, the acid is formic acid.

[0037] In step A, the acid is added when the temperature of the reaction system reaches 75-85°C, preferably 80°C.

[0038] In step A, the molar ratio of the acid to the tylosin A is 3 to 6:1, preferably 5 to 6:1.

[0039] In step A, the reaction conditions are: temperature of 78-80° C. and time of 2-6 h.

[0040] In step B, the acid is one or more of formic acid, acetic acid, hydrochloric acid and sulfuric acid.

[0041] In step B, the hydrolysis conditions are: room temperature, 1 to 6 hours, and the concentration of the acid aqueous solution is 0.1 to 10 M, preferably 0.2 M.

[0042] Furthermore, the synthesis method 2 also includes a post-treatment step; the post-treatment is carried out according to the following operation: distilled water is added to the reaction system, the pH of the aqueous phase after separation is adjusted to 9-11 with a base, the aqueous solution is extracted with an organic solvent, the combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure; wherein the base is selected from one or more of potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; and the organic solvent is selected from one or more of dichloromethane, ethyl acetate or diethyl ether.

[0043] Furthermore, the preparation method of the macrolide compound provided by the present invention also includes a purification step: adding the obtained crude product to a silica gel chromatography column, selecting two organic solvents to form eluents of different polarities, and using gradient elution to remove impurities in the crude product, thereby obtaining a pure macrolide compound; wherein the eluent can be selected from any two of diethyl ether, ethyl acetate, methanol, isopropanol, acetone or dichloromethane.

[0044] For example, the synthetic route of the above synthetic method 2 is as follows:

[0045] In a third aspect, the present invention further provides a pharmaceutical composition or veterinary composition comprising the tylosin derivative having the structure shown in Formula I above.

[0046] In a fourth aspect, the present invention further provides a pharmaceutical preparation comprising the tylosin derivative having the structure shown in Formula I above.

[0047] The dosage forms of the pharmaceutical preparation are powder, tablet, premix, soluble powder and injection.

[0048] In a fifth aspect, the present invention further provides the use of the above-mentioned tylosin derivatives, veterinary drug compositions and pharmaceutical preparations in the preparation of drugs for treating or preventing bacterial infections in animals. For example, the anti-pathogen infection drugs are products for clinical use in livestock and poultry veterinary medicine.

[0049] In the application, the bacteria include: Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, beta-hemolytic Streptococcus, Escherichia coli, Haemophilus influenzae, Moraxella meningitidis, Pasteurella, Actinobacillus, Bordetella, Mycoplasma bovis, Actinobacillus pneumoniae, Salmonella, Erysipelothrix rhusiopathiae, Bacillus anthracis, etc.

[0050] In a sixth aspect, the present invention further provides a feed additive comprising the tylosin derivative having the structure shown in Formula I above. DETAILED DESCRIPTION

[0051] The present invention will be further described below with reference to specific examples, but the present invention is not limited to the following examples.

[0052] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0053] Unless otherwise specified, the reagents, materials, instruments, etc. used in the following examples can be obtained from commercial sources.

[0054] Example 1

[0055] Here are the steps:

[0056] (1) Dissolve tylosin A (3.00 g, 3.27 mmol) in methanol (18 mL). Add 3-amino-1-propanol (0.74 g, 9.85 mmol) at room temperature and stir to react. When no tylosin A is detected by TLC, stop the reaction to obtain a solution of the tylosin A imine derivative.

[0057] (2) Sodium triacetoxyborohydride (1.39 g, 6.56 mmol) was added at room temperature and the reaction was stirred for 2 h to stop the reaction. Aqueous NaOH solution (3 mL, 1 M) was added to quench the reaction, and the MeOH was removed by concentration on a rotary evaporator. The residue was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Concentrated on a rotary evaporator, the product was purified by silica gel column chromatography (dichloromethane / methanol = 8:1) to obtain a secondary amine-modified macrolide intermediate (1.40 g).

[0058] (3) Prepare 10 mL of hydrochloric acid aqueous solution (0.2 M) and add it to a 50 mL pear-shaped flask. Then add the secondary amine-modified macrolide compound intermediate (0.50 g, 0.82 mmol) obtained in step (2) and stir the reaction at room temperature for 2 h. After the reaction is completed by TLC detection, stop the reaction. Adjust the pH of the reaction solution to 10 with NaOH aqueous solution (1 M), and then extract with dichloromethane (20 mL × 3). Combine the organic phases, wash with saturated brine (10 mL), and dry over anhydrous sodium sulfate. Concentrate with a rotary evaporator and purify by silica gel column chromatography (dichloromethane / methanol = 8:1) to obtain a white solid tylosin derivative Ia (0.43 g, yield 63%).

[0059] 1H NMR(500MHz, CDCl3)δ7.35(d,J=15.0Hz,1H),6.30(d,J=15.3Hz,1H),5.92(J=10.2Hz,1H),4.95–4.93(m,1H),4.57(d,J=7.6Hz,1H), 4.29–4.27(m,1H),4.01–3.99(m,1H),3.79–3.74(m,5H),3.61–3.60(m,4H),3.55(t,J=7.9Hz,3H),3.48–3.47(m,4H),3.29–3.27(m, 2H),3.18(d,J=9.0Hz,1H),3.13–3.09(m,1H),3.02–2.95(m,3H),2.81–2.77(m,2H),2.71–2.63(m,3H),2.51–2.47(m,8H),1.98–1.8 4(m,3H),1.78–1.75(m,5H),1.65–1.61(m,3H),1.54–1.52(m,2H),1.33–1.19(m,12H),1.03(d,J=7.0Hz,3H),0.93(t,J=7.4Hz,3H).

[0060] 13 C NMR (126MHz, CDCl3) δ203.90,173.51,148.05,142.83,134.56,117.96,104.00, 101.01,81.70,79.84,79.42,74.74,73.12,72.68,70.85,70.74,70.34,70.20,6 9.03,66.52,62.31,61.64,59.51,53.43,47.60,46.25,44.97,41.64,41.28,39.41,33.50,32.31,31.03,29.54,26.80,25.19,17.68,17.57,12.80,9.55,9.24.

[0061] TLC R f =0.1 (dichloromethane / methanol=8:1)

[0062] HRMS (ESI, m / z): [M+H] + calcd for C 42 H 75 N2O 14 ,831.52128;found 831.52167.

[0063] Example 2

[0064] Here are the steps:

[0065] (1) Dissolve Tylosin A (0.50 g, 0.55 mmol) in toluene (6 mL), add (R)-prolinol (0.17 g, 1.68 mmol), and stir to dissolve.

[0066] (2) The reaction solution was then heated to 80°C, and formic acid (0.14 g, 3.04 mmol) was added. The reaction was continued at 80°C. When the raw material Tylosin A could no longer be detected by TLC, the reaction was stopped. Distilled water (5 mL) was added to quench the reaction and the layers were separated. The aqueous phase was adjusted to pH 10 with aqueous sodium hydroxide solution (5 M) and extracted with dichloromethane (15 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The product was concentrated using a rotary evaporator and purified by silica gel column chromatography (dichloromethane / methanol = 8:1) to obtain a tertiary amine-modified macrolide intermediate (0.32 g, yield 58%).

[0067] (3) Prepare 14 mL of hydrochloric acid aqueous solution (0.2 M), add it to a 50 mL pear-shaped flask, and then add the tertiary amine-modified macrolide compound intermediate (0.70 g, 0.70 mmol), and stir the reaction at room temperature for 2 h. After the reaction is completed by TLC, stop the reaction. Adjust the pH of the reaction solution to 10 with NaOH aqueous solution (1 M), and then extract it with dichloromethane (30 mL × 3). Combine the organic phases, wash with saturated brine (15 mL), and dry over anhydrous sodium sulfate. Concentrate the organic phase using a rotary evaporator and purify it by silica gel column chromatography (dichloromethane / methanol = 8:1) to obtain a white solid tylosin derivative Ib (0.58 g, yield 97%).

[0068] 1H NMR (500MHz, CDCl3) δ7.35(d,J=15.3Hz,1H),6.29(d,J=15.1Hz,1H),5.94(s,1H),4.96(d,J=9.2Hz,1H),4.59–4.56(m,1H),4.33–4.29( m,1H),4.01–3.98(m,1H),3.83–3.81(m,1H),3.76–3.73(m,1H),3.62–3.57(m,6H),3.47–3.46(m,2H),3.34–3.30(m,1H),3.18–3.13(m, 2H),3.04–2.94(m,3H),2.73–2.63(m,3H),2.58–2.51(m,13H),2.39–2.38(m,1H),2.29(s,1H),2.00–1.85(m,4H),1 .81–1.72(m,6H),1.63–1.57(m,4H),1.31–1.25(m,6H),1.20–1.19(m,3H),1.06–1.03(m,9H),0.92(t,J=7.2Hz,3H).

[0069] 13 C NMR (126MHz, CDCl3) δ204.10,173.60,148.01,143.05,134.37,117.96,104.21,100 .98,82.18,81.64,79.86,77.38,77.13,76.87,74.87,73.22,72.65,70.71,70.29,7 0.25,69.06,66.49,65.06,63.12,61.59,59.43,55.05,54.66,45.95,45.08,41.61,39.35,34.96,34.20,27.51,26.73,25.17,23.43,17.81,17.65,12.70,11.19,9.56.

[0070] TLC R f =0.1 (dichloromethane / methanol=8:1)

[0071] HRMS (ESI, m / z): [M+H] + calcd for C 44 H 77 N2O 14 ,857.53693;found857.53705.

[0072] Test Example 1 Determination of antibacterial activity of the compounds of the present invention

[0073] The antibacterial activities of the tylosin derivatives Ia and Ib of the present invention were determined by the broth microdilution method using tylosin as a positive control.

[0074] The specific test methods are as follows:

[0075] Add broth culture medium to a 96-well plate, dilute the prepared drug solution in a micro-two-fold decreasing concentration, then inoculate an appropriate amount of bacterial solution. After incubation for 24 hours, observe the minimum inhibitory concentration of the drug.

[0076] The culture medium used in the experiment was CAMHB broth and CAMHB+5% defibrinated sheep blood broth.

[0077] The preserved bacteria were inoculated into serum plate medium and cultured at 37℃ for 16-18 hours. The appropriate amount of bacteria and physiological saline after subculture were placed in a turbidimetric tube. The McFarland turbidimeter was calibrated to the McFarland turbidimetric standard. The bacterial suspension was diluted 10 times with physiological saline to prepare a certain concentration (5×10 5 ~5×10 6 cfu / mL) of the test bacterial solution for later use.

[0078] Dissolve tylosin and the compounds obtained in the examples in methanol to the desired concentration (1.0 mg / mL). Store in sterile brown vials, stopper, and seal until ready for use. The working concentration range for Gram-negative bacteria is 0.25 μg / mL to 128 μg / mL; for Gram-positive bacteria, the working concentration range is 0.098 μg / mL to 50 μg / mL.

[0079] The 96-well plate micro-dilution method was used. Broth culture medium was added to the 96-well plate, and the prepared drug solution was diluted in micro-dilution in a two-fold decreasing manner, so that the drug solution concentration in the first well to the tenth well showed a two-fold decreasing relationship. No drug solution was added to the eleventh and twelfth wells. Finally, the prepared bacterial solution (concentration of 5×10 5 ~5×10 6 cfu / mL). The twelfth well was left untreated as a blank control. The 96-well plate was placed in a 37°C incubator and incubated for 24 hours. Bacterial growth in each well was observed. The solution in wells that inhibited bacterial growth was transparent, while the solution in wells that did not inhibit bacterial growth was turbid. The concentration corresponding to the well with a transparent solution was the minimum antimicrobial concentration (MIC) for that sample.

[0080] The results are shown in the following table.

[0081] Table 1 MIC values ​​of compounds of the present invention (μg / mL)

[0082] As shown in Table 1, compared with tylosin, compound Ia obtained in Example 1 and compound Ib obtained in Example 2 have higher in vitro antibacterial activity against Streptococcus pneumoniae (a representative of Gram-positive bacteria), and compound Ib obtained in Example 2 has higher in vitro antibacterial activity against Escherichia coli (a representative of Gram-negative bacteria).

[0083] Table 2 In vitro antibacterial effect of compound Ia on different strains

[0084] As shown in Table 2, compound Ia has comparable antibacterial effects against Streptococcus pneumoniae and Escherichia coli before and after hydrolysis, but has stronger antibacterial activity against Streptococcus agalactiae before hydrolysis and stronger antibacterial activity against Staphylococcus aureus after hydrolysis.

[0085] Table 3 In vitro antibacterial effect of compound Ib on different strains

[0086] As shown in Table 3, the antibacterial effect of compound Ib against Escherichia coli was comparable before and after hydrolysis, but the antibacterial activity against Streptococcus pneumoniae was doubled after hydrolysis.

[0087] Although the present invention has been described in detail above using general descriptions and specific embodiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

[0088] Cross-reference to related applications:

[0089] This application claims priority to the Chinese patent application (application number 202311620626.8) filed on November 30, 2023, the entire contents of which are incorporated herein by reference.

[0090] Industrial Applications

[0091] The present invention has the following technical advantages: the present invention provides a tylosin derivative having a structure as shown in Formula I, which can be used to treat or prevent bacterial infection in animals, providing more selectivity for tylosin derivative treatment.

Claims

1. A tylosin derivative, characterized in that: It has a structure as shown in Formula 1: Wherein, R is selected from 2-hydroxyethylamino, 3-hydroxypropylamino, 4-hydroxybutylamino, 5-hydroxypentylamino, di(2-hydroxyethylamino), di(3-hydroxypropylamino), di(4-hydroxybutylamino), (R)-2-hydroxymethyltetrahydropyrrolyl, (S)-2-hydroxymethyltetrahydropyrrolyl, (R)-3-hydroxymethyltetrahydropyrrolyl, (S)-3-hydroxymethyltetrahydropyrrolyl, (R)-3-hydroxymethylpiperidinyl, (S)-3-hydroxymethylpiperidinyl, 4-hydroxypiperidinyl, 4-hydroxymethylpiperidinyl, 4-hydroxyethylpiperidinyl.

2. The tylosin derivative according to claim 1, characterized in that: The tylosin derivative is selected from the following compounds with structures shown in Ia or Ib:

3. The method for preparing the tylosin derivative according to claim 1 or 2, characterized in that: The steps include: S1, tylosin A reacts with amino alcohol; S2, adding a reducing agent or an acid to the system obtained by the reaction in step S1, and reacting to obtain a macrocyclic endo Ester compound intermediates; S3, hydrolyzing the macrolide compound intermediate under acidic conditions to obtain the tylosin derivative.

4. The method for preparing the tylosin derivative according to claim 3, characterized in that: The preparation method includes synthesis method 1 and synthesis method 2: The synthesis method 1 comprises the following steps: (1) tylosin A and amino alcohol are subjected to a condensation reaction in a polar solvent, and then a reducing agent is added to carry out a reduction reaction to obtain a secondary amine-modified macrolide compound intermediate; (2) hydrolyzing the secondary amine-modified macrolide compound intermediate under acidic conditions to obtain the tylosin derivative; The synthesis method 2 comprises the following steps: Step A: Tylosin A and amino alcohol are mixed in a non-polar solvent, and then acid is added after heating to obtain a tertiary amine-modified macrolide compound intermediate; Step B: hydrolyzing the tertiary amine-modified macrolide compound intermediate under acidic conditions to obtain the tylosin derivative.

5. The method for preparing the tylosin derivative according to claim 4, characterized in that: In the synthetic method 1: In step (1): The amino alcohol is 2-aminoethanol or 3-aminopropanol; The molar ratio of the amino alcohol to the tylosin A is 2 to 5:1; The polar solvent is one or more of methanol, ethanol, propanol, isopropanol, n-butanol and ethylene glycol; The conditions of the condensation reaction are: room temperature, time 12 to 13 hours; The reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride and LiAlH4; The molar ratio of the reducing agent to the tylosin A is 1 to 4:1; The reduction reaction conditions are: room temperature, time 2 to 6 hours; In step (2): The acid is formic acid; The hydrolysis conditions are: room temperature, time 1 to 6 hours, the concentration of the aqueous solution of the acid The depth is 0.1~10M.

6. The method for preparing the tylosin derivative according to claim 4, characterized in that: In the synthetic method 2: In step A: The amino alcohol is one or more of 2-aminoethanol, 3-aminopropanol, (R)-prolinol, (S)-prolinol, 4-hydroxypiperidine, and 4-hydroxymethylpiperidine; The molar ratio of the amino alcohol to the tylosin A is 2 to 5:1; The non-polar solvent is one or more of ethylene glycol dimethyl ether, benzene and toluene; The acid is formic acid; The acid is added at a time when the temperature of the reaction system reaches 75 to 85°C; The molar ratio of the acid to the tylosin A is 3 to 6:1; The reaction conditions are: temperature of 78-80°C and time of 2-6h; In step B: The acid is one or more of formic acid, acetic acid, hydrochloric acid and sulfuric acid; The hydrolysis conditions are as follows: the temperature is room temperature, the time is 1 to 6 hours, and the concentration of the acid aqueous solution is 0.1 to 10M.

7. A veterinary drug composition, characterized in that: The veterinary composition comprises the tylosin derivative according to claim 1 or 2.

8. A veterinary drug composition for treating or preventing bacterial infection in animals, characterized in that: The veterinary composition comprises the tylosin derivative according to claim 1 or 2.

9. The veterinary drug composition according to claim 8, characterized in that: The bacteria are selected from one or more of the following: Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, beta-hemolytic Streptococcus, Escherichia coli, Haemophilus influenzae, Moraxella meningitidis, Pasteurella, Actinobacillus, Bordetella, Mycoplasma bovis, Actinobacillus pneumoniae, Salmonella, Erysipelothrix rhusiopathiae, and Bacillus anthracis.

10. A pharmaceutical preparation, characterized in that: The pharmaceutical preparation comprises the tylosin derivative according to claim 1 or 2.

11. A pharmaceutical preparation for treating or preventing bacterial infection in animals, characterized in that: The pharmaceutical preparation comprises the tylosin derivative according to claim 1 or 2.

12. The pharmaceutical preparation according to claim 11, characterized in that: The bacteria are selected from one or more of the following: Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, beta-hemolytic Streptococcus, Escherichia coli, Haemophilus influenzae, Moraxella meningitidis, Pasteurella, Actinobacillus, Bordetella, Mycoplasma bovis, Actinobacillus pneumoniae, Salmonella, Erysipelothrix rhusiopathiae, and Bacillus anthracis.

13. Use of the tylosin derivative according to claim 1 or 2, the veterinary composition according to claim 7, or the pharmaceutical preparation according to claim 10 in the preparation of a medicament for treating or preventing bacterial infection in animals.

14. A feed additive, characterized in that: The feed additive comprises the tylosin derivative according to claim 1 or 2.

15. A feed additive for treating or preventing bacterial infection in animals, characterized in that: The feed additive comprises the tylosin derivative according to claim 1 or 2.

16. The feed additive according to claim 15, characterized in that: The bacteria are selected from one or more of the following: Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, beta-hemolytic Streptococcus, Escherichia coli, Haemophilus influenzae, Moraxella meningitidis, Pasteurella, Actinobacillus, Bordetella, Mycoplasma bovis, Actinobacillus pneumoniae, Salmonella, Erysipelothrix rhusiopathiae, and Bacillus anthracis.

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