CN113149929B - A pleuromutilin derivative with 1,3,4-oxadiazole side chain and its preparation and application - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to a pleuromutilin derivative with a 1,3,4-oxadiazole side chain and its preparation and application. The pleuromutilin derivative with 1,3,4-oxadiazole side chain is a compound of formula 2 or a pharmaceutically acceptable salt thereof, and the compound of formula 2 or a pharmaceutically acceptable salt thereof Solvates of salts, enantiomers, diastereomers, tautomers or mixtures thereof in any proportion, including racemic mixtures. The pleuromutilin derivative has good antibacterial activity, is particularly suitable as a new type of antibacterial drug for animal or human systemic infection, and has good water solubility.

Description

A pleuromutilin derivative with 1,3,4-oxadiazole side chain and its preparation and application

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a pleuromutilin derivative with a 1,3,4-oxadiazole side chain and a preparation method and application thereof.

Background Art

As one of the major pathogens with high morbidity and mortality, multidrug-resistant Staphylococcus aureus (MRSA) often causes healthcare-associated infections, posing a serious threat to human health worldwide. Therefore, there is an urgent need to develop new antibiotics with new modes of action for the treatment of infections caused by multidrug-resistant Staphylococcus aureus (MRSA).

Natural products have been playing an important role in combating human diseases, especially in the field of infectious diseases. Despite some shortcomings, a variety of natural products or their derivatives have been developed and approved as antimicrobial agents, such as aztreonam, vancomycin, tigecycline, and penicillin G. Developing new antimicrobial agents from natural products or their semisynthetic derivatives remains the most effective approach to combat MRSA infections.

Pleuromutilin (Formula 1) is a natural tricyclic diterpenoid compound produced by culturing Pleurotus mutilus and Pleurotus Passeckerianus. It has a structure including a 5-6-8 tricyclic carbon skeleton with eight stereocenters and a glycolic acid chain at C(14).

Studies have shown that pleuromutilins and their derivatives show effective antibacterial activity against Gram-positive bacteria. Unlike other antibacterial drugs widely used in clinical practice, pleuromutilins and their derivatives can inhibit bacterial protein synthesis by binding to the V region of the peptidyl transferase center (PTC) of the 23s RNA of the bacterial 50s ribosomal subunit. Due to the unique mechanism of action, pleuromutilins and their derivatives have a low incidence of cross-resistance with other antibacterial agents and a low tendency for bacteria to develop resistance to bacteria. At the same time, they basically do not interact with mammalian cell ribosomes and do not interfere with protein synthesis in eukaryotic cells. What caught the attention of researchers is that the side chain on C14 in the pleuromutilin structural molecule can penetrate deep into the hydrophobic group of the ribosomal subunit and improve its antibacterial activity. Therefore, chemical modification of the C14 side chain has always been an important means to improve the drugability of pleuromutilin derivatives.

So far, by modifying its C14 side chain, four antibacterial drugs have been successfully launched on the market, including the veterinary antibacterial drugs Tiamulin and Valnemulin, the human skin topical drug Retapamulin, and the human drug Lefamulin, which was approved by the US FDA in 2019 for the treatment of community-acquired bacterial pneumonia (CABP).

Compared with the dozens of drugs successfully developed based on the same parent core, such as penicillin, cephalosporin, and xacin, only four antibacterial drugs have been successfully developed for pleuromutilin, and drug-resistant bacteria against pleuromutilin antibacterial drugs are still rare. Therefore, it is necessary to develop more pleuromutilin antibacterial drugs.

Summary of the invention

In order to overcome the deficiencies and shortcomings of the prior art, the primary purpose of the present invention is to provide a pleuromutilin derivative having a 1,3,4-oxadiazole side chain, which has good antibacterial activity and is particularly suitable as a new antibacterial drug for systemic infections in animals or humans.

Another object of the present invention is to provide a method for preparing the above-mentioned pleuromutilin derivative having a 1,3,4-oxadiazole side chain.

Another object of the present invention is to provide the application of the above-mentioned pleuromutilin derivative having 1,3,4-oxadiazole side chain.

The purpose of the present invention is achieved through the following technical solutions:

A pleuromutilin derivative having a 1,3,4-oxadiazole side chain, which is a compound of formula 2 or a pharmaceutically acceptable salt thereof, and a solvent compound, an enantiomer, a diastereomer, a tautomer or a mixture thereof in any proportion, including a racemic mixture, of the compound of formula 2 or a pharmaceutically acceptable salt thereof:

Where R is _R1 or

_R1 is one of a hydrogen atom, a furyl group, a thienyl group, a phenyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group and a pyrazinyl group;

_R2 is one of a methyl group, a trifluoromethyl group, an amino group, a hydroxyl group, a hydroxyl group, a hydrogen atom, a fluorine atom, a chlorine atom and a bromine atom;

_R3 is one of a methyl group, a nitro group, an amino group, a hydrogen atom, a fluorine atom, a chlorine atom and a bromine atom;

_R4 is one of methyl, trifluoromethyl, amino, dimethylamino, hydroxyl, methoxy, hydrogen, fluorine, chlorine and bromine;

And R ₂ , R ₃ , and R ₄ cannot be hydrogen atoms at the same time;

Preferably, R ₂ is a methyl group, R ₃ is a hydrogen atom, and R ₄ is a hydrogen atom;

or R ₂ is a hydrogen atom, R ₃ is a methyl group, and R ₄ is a hydrogen atom;

or R ₂ is a hydrogen atom, R ₃ is a hydrogen atom, and R ₄ is a methyl group;

or R ₂ is a trifluoromethyl group, R ₃ is a hydrogen atom, and R ₄ is a hydrogen atom;

or R ₂ is a hydrogen atom, R ₃ is a hydrogen atom, and R ₄ is a trifluoromethyl group;

or R ₂ is a hydrogen atom, R ₃ is an amino group, and R ₄ is a hydrogen atom;

or R ₂ is a hydrogen atom, R ₃ is a hydrogen atom, and R ₄ is an amino group;

Or R ₂ is a hydrogen atom, R ₃ is a hydrogen atom, and R ₄ is a dimethylamino group;

or R ₂ is a hydrogen atom, R ₃ is a nitro group, and R ₄ is a hydrogen atom;

or R ₂ is a hydroxyl group, R ₃ is a hydrogen atom, and R ₄ is a hydrogen atom;

Or R ₂ is a hydrogen atom, R ₃ is a hydrogen atom, and R ₄ is a hydroxyl group;

or R ₂ is a hydrogen atom, R ₃ is a hydrogen atom, and R ₄ is a methoxy group;

or R ₂ is a fluorine atom, R ₃ is a hydrogen atom, and R ₄ is a hydrogen atom;

or R ₂ is a hydrogen atom, R ₃ is a fluorine atom, and R ₄ is a hydrogen atom;

or R ₂ is a hydrogen atom, R ₃ is a hydrogen atom, and R ₄ is a fluorine atom;

or R ₂ is a chlorine atom, R ₃ is a hydrogen atom, and R ₄ is a hydrogen atom;

or R ₂ is a hydrogen atom, R ₃ is a chlorine atom, and R ₄ is a hydrogen atom;

or R ₂ is a hydrogen atom, R ₃ is a hydrogen atom, and R ₄ is a chlorine atom;

or R ₂ is a hydrogen atom, R ₃ is a bromine atom, and R ₄ is a hydrogen atom;

or R ₂ is a hydrogen atom, R ₃ is a hydrogen atom, and R ₄ is a bromine atom;

The specific groups of the compounds of the above preferred structures are summarized in Table 1:

Table 1 Compound numbers and specific groups

The pharmaceutically acceptable salt is a salt formed by the compound of formula 2 and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid;

The pharmaceutically acceptable salt preferably has the following structural formula:

The preparation method of the pleuromutilin derivative having a 1,3,4-oxadiazole side chain comprises the following steps:

(1) reacting pleuromutilin with p-toluenesulfonyl chloride to obtain an intermediate I with a structure as shown in Formula 3;

(2) using carboxylic acid as a raw material and reacting it with anhydrous ethanol to obtain an intermediate II with a structure shown in Formula 4;

(3) reacting the intermediate II obtained in step (2) with hydrazine hydrate to obtain an intermediate III having a structure as shown in Formula 5;

(4) reacting the intermediate III obtained in step (3) with carbon disulfide to obtain the intermediate IV shown in formula 6 (corresponding to compounds 1c to 28c in the examples of the present invention);

(5) intermediate I obtained in step (1) is used as a raw material, further activated by sodium iodide, and then reacted with intermediate IV obtained in step (4) to obtain a pleuromutilin derivative having a 1,3,4-oxadiazole side chain as shown in formula 2;

The intermediates Ⅰ, Ⅱ, Ⅲ and Ⅳ have the structural formulas 3 to 6 respectively:

The molar ratio of p-toluenesulfonyl chloride to pleuromutilin in step (1) is preferably 1.1:1;

The molar ratio of the carboxylic acid to anhydrous ethanol in step (2) is preferably 1:1.1;

The reaction in step (3) preferably uses anhydrous ethanol as a solvent, the molar ratio of intermediate II to hydrazine hydrate is preferably 1:1, and the reaction conditions are preferably 25-40° C. for 2-3 hours;

The specific operation of the reaction described in step (4) is preferably:

Use 95% (v/v) ethanol as solvent to dissolve potassium hydroxide, add intermediate III in an ice bath, then add carbon disulfide dropwise, and heat under reflux at 78-80°C for 3-4h;

The amount of 95% (v/v) ethanol is preferably 5 to 20 times the mass of intermediate III, the molar ratio of potassium hydroxide to intermediate III is preferably 1.2:1, and the molar ratio of carbon disulfide to intermediate III is preferably 1.1:1;

The specific operation of activation described in step (5) is preferably:

Use acetonitrile as solvent to dissolve intermediate I first, then add sodium iodide and base, and heat under reflux at 78°C for 1 to 3 hours;

The amount of acetonitrile used is preferably 30 to 40 times the mass of the intermediate I, the molar ratio of the base to the intermediate I is preferably 2:1, and the molar number of the sodium iodide is preferably 10% of the molar number of the base;

The base is preferably sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate;

The reaction conditions in step (5) are preferably heated under reflux at 78-80° C. for 1-3 h;

The synthetic route is shown below:

Application of the pleuromutilin derivative having a 1,3,4-oxadiazole side chain in the preparation of antibacterial products;

The antibacterial product is preferably a drug for treating infectious diseases;

The antibacterial product is further preferably an antibacterial drug for treating infectious diseases caused by Gram-positive bacteria;

The infectious disease is an infectious disease caused by drug-resistant Staphylococcus aureus or multidrug-resistant bacteria infection in humans or animals;

The medicament may contain one or more pharmaceutically acceptable carriers, excipients or diluents;

The drug preparations include a variety of clinical drug dosage forms, such as tablets, injections, liposome nanoparticles, controlled release agents, etc.

An antibiotic drug, comprising an effective amount of a pleuromutilin derivative having a 1,3,4-oxadiazole side chain, and the remainder being pharmaceutical excipients or other compatible drugs;

The pharmaceutical excipients are conventional pharmaceutical excipients, such as solvents, disintegrants, flavoring agents, preservatives, colorants, and adhesives;

The other compatible drugs refer to an effective dose of a pleuromutilin derivative having a 1,3,4-oxadiazole side chain as a drug raw material, and then combined with other natural drugs or chemical drugs;

Compared with the prior art, the present invention has the following advantages and beneficial effects:

(1) The pleuromutilin derivatives provided by the present invention are new types of compounds that have never been reported.

(2) The present invention has synthesized a large number of truncated pleuromutilin derivatives with a new structure and 1,3,4-oxadiazole side chain through extensive and in-depth research, and carried out extensive antibacterial activity screening. It is found for the first time that this type of compound not only has good in vitro antibacterial activity, but also has the advantage of lower preparation cost than valnemulin and retapamulin. Therefore, it is particularly suitable as a new type of antibacterial drug for the prevention and treatment of bacterial infectious diseases in humans or animals, especially infectious diseases caused by drug-resistant Staphylococcus aureus.

(3) The pleuromutilin derivative having a 1,3,4-oxadiazole side chain prepared by the present invention has good water solubility.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is the NMR spectrum of compound 2.

Figure 2 is the NMR spectrum of compound 3.

FIG3 is the NMR spectrum of compound 15.

FIG4 is the NMR spectrum of compound 19.

DETAILED DESCRIPTION

The present invention is further described in detail below in conjunction with embodiments and drawings, but the embodiments of the present invention are not limited thereto.

其中，具体基团R₁、R₂、R₃、R₄见表1，均为市购，其他试剂也均为市购。In the embodiment, R in R-COOCH ₂ CH ₃ is R ₁ or

The specific groups R ₁ , R ₂ , R ₃ , and R ₄ are shown in Table 1, all of which are commercially available, and other reagents are also commercially available.

Example 1

(1) Preparation of Intermediate I: 10.0 g (26.5 mmol) of pleuromutilin was dissolved in 20 ml of pyridine and placed in an ice bath; 5.6 g (29.2 mmol) of p-toluenesulfonyl chloride was dissolved in 10 ml of pyridine, and then the above pleuromutilin pyridine solution was slowly added. The mixture was stirred in an ice bath for 3 h, and then 50 ml of ice water and chloroform were added in turn. The mixture was transferred to a separatory funnel and shaken, and allowed to stand for separation; the organic phase was taken and washed with 100 ml of 4 mol/L sulfuric acid, 100 ml of saturated sodium bicarbonate solution, and 100 ml of deionized water in turn; the organic phase after washing was evaporated under reduced pressure, and 20 ml of isopropanol was added to the remaining solid. The mixture was heated to dissolve and then cooled to precipitate a large amount of white powder. The mixture was filtered, and the filter residue was washed with isopropanol and dried to obtain Intermediate I with a structure shown in Formula 3, with a yield of 81%;

(2) Preparation of intermediate II1a: 155.5 mmol of carboxylic acid (R-COOCH ₂ CH ₃ , wherein R is H) was dissolved in 10 ml of anhydrous ethanol, and the mixture was stirred in an ice bath for 3 min, and then 0.15 ml of concentrated sulfuric acid was slowly added, and the mixture was heated to reflux at 115° C. for 4 h; the reaction solution was poured into a separatory funnel, extracted with 30 ml of dichloromethane, and washed twice with deionized water, and then dried with anhydrous sodium sulfate to obtain an organic phase; the obtained organic phase was rotary evaporated to dryness to obtain an intermediate II1a with a structure shown in Formula 4, with a yield of 76.72%;

(3) Preparation of intermediate III1b: Under mechanical stirring, 2.0 g (40 mmol) of hydrazine hydrate was slowly added to 10 ml of anhydrous ethanol, and then 40 mmol of intermediate II was slowly added. The reaction was carried out at room temperature of 25°C for 2 h, and then ice-bathed. A large amount of solid was precipitated and _filtered . The product was dried with _CaCl2 in a vacuum dryer and finally dried with _P2O5 to obtain intermediate III1b with a structure shown in Formula 5, with a yield of 70.88%;

(4) Preparation of compound 1c (intermediate IV-1): 0.67 g (12 mmol) of potassium hydroxide was dissolved in 15 ml of 95% (v/v) ethanol, and 60.06 mg (10 mmol) of intermediate III was added under ice bath conditions; 0.84 g (11 mmol) of carbon disulfide was slowly added dropwise to the above reaction system, and after the addition was complete, the mixture was heated to reflux at 80°C; after heating to reflux for 3 h, concentrated hydrochloric acid was added dropwise to the reaction system under ice bath conditions, and the pH value of the reaction system was adjusted to 1, a large amount of crystals precipitated, and filtered; the crystals were dried with _CaCl2 in a vacuum dryer, _and finally dried with _P2O5 to obtain compound 1c (intermediate IV-1) with a structure shown in Formula 6, with a yield of 81.17%.

According to the method of steps (1) to (4) (the molar amount of each reactant, reaction conditions, purification, etc. are the same), intermediates II2a to II28a (yield 75.55-88.64%), intermediates III2b to III28b (yield 62.84-74.25%), and compounds 2c to 28c (yield 75.35-86.54%) were obtained respectively. The yield of each intermediate is shown in Table 2.

Example 2 Preparation of 22-O-(1,3,4-oxadiazolyl)thioacetylthiophene (Compound 1)

Take 2.13g (4mmol) of the intermediate I prepared in Example 1 and dissolve it in 81ml of acetonitrile, add 0.12g (0.8mmol) of anhydrous sodium iodide and 1.11g (8mmol) of anhydrous potassium carbonate, heat and reflux at 78°C for 2h, then add 0.45g (4.4mmol) of 1,3,4-1,3,4-oxadiazole-2-thiol (intermediate IV-1) prepared in Example 1 to the above system, continue to react at 78°C for 3h, pour the reaction solution into a separatory funnel, add 50ml of distilled water and 50ml of chloroform in turn, shake and let stand to separate. The organic phase was washed twice with a sodium chloride aqueous solution (15% w/v) and dried with anhydrous sodium sulfate, and the organic phase was taken; the obtained organic phase was rotary evaporated to dryness to obtain a mixture, which was redissolved in dichloromethane, and 2 g of 100-200 mesh silica gel was added and fully mixed. After the solvent was evaporated, the crude product-silica gel powder mixture was purified by column chromatography (100-200 mesh silica gel powder as the stationary phase, dichloromethane: methanol = 200: 1 (V: V) as the mobile phase) to obtain a pure product of 22-O-(1,3,4-1,3,4-oxadiazolyl)thioacetylthiophene with a yield of 73.74%.

Example 3 Preparation of Compounds 2 to 28

According to the same method as Example 2 (the molar amount of each reactant, reaction conditions, purification, etc. are the same as Example 2), only compound 1c (intermediate IV-1) is replaced by compounds 2c to 28c (intermediate IV-2 to intermediate IV-28), and the corresponding products of formula 2 are obtained, which are numbered 2 to 28. Among them, Figures 1 to 4 are NMR spectra of compounds 2, 3, 15 and 19.

The yields of the above compounds are summarized in Table 2.

Table 2 Compound numbers and yields

Effect Example

(1) In vitro antibacterial test

The experiment used the broth dilution method. The experimental control drug was tylosin. Tylosin is a pleuromutilin antibiotic and one of the top ten veterinary antibiotics in the world.

The strains used in the experiment were methicillin-resistant Staphylococcus aureus ATCC43300 and Staphylococcus aureus ATCC29213, clinical Staphylococcus aureus AD3 and clinical Staphylococcus aureus 144 (clinical bacteria AD3 and 144 were isolated and identified in the Pharmacology Laboratory of the School of Veterinary Medicine of South China Agricultural University, and have been published in the literature Zhe Z A, Kang LA, Gyz A, et al. Design, synthesis and biological activities of novel pleuromutilin derivatives with a substituted triazole moiety as potent antibacterial agents-Science Direct [J]. European Journal of Medicinal Chemistry, 2020.).

Preparation of target compound stock solution: 6.4 mg of target compound was accurately weighed and placed in a 10 mL volumetric flask, dissolved with 0.25 mL DMSO, added with 9.5 mL distilled water and 0.25 mL Tween 80 to volume, shaken thoroughly to obtain a stock solution (6.4 mg/mL), sterilized with a 0.22 μm filter membrane, divided into small tubes, and stored at -20°C. The control drug tylosin was also prepared according to the above method.

Preparation of bacterial solution: Take out the strain that has been well preserved at -20℃ and inoculate it on a new MH plate. After culturing at 37℃ for 24 hours, pick out a single colony and inoculate it in MH medium and culture it again for 24 hours; select a single colony and transfer it to sterile physiological saline and adjust its turbidity to 0.6McF. At this time, the concentration of the bacterial solution is 10 ⁶ CFU/mL.

MIC plate preparation: dilute the target compound stock solution (6.4 mg/mL) 10 times to obtain a target compound solution with a concentration of 640 μg/mL; take a sterile 96-well plate, add 180 μL MH broth medium to the first well, add 100 μL MH broth medium to the second to tenth wells, add 20 μL of antibacterial drugs with a concentration of 640 μg/mL to the first well, mix well, take 100 μL and add it to the second well, mix well, and then draw 100 μL to the third well, and so on, draw 100 μL from the 12th well and discard. At this time, the drug concentrations of each well are: 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03 μg/mL, and three groups of parallel drugs are made for each concentration.

Inoculation of bacterial solution: Add 100 μL of bacterial solution to each well from 1 to 12, so that the final bacterial solution concentration in each well is about 5×10 ⁵ CFU/mL, and the drug concentrations in wells 1 to 12 are 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, and 0.015 μg/mL, respectively. The inoculated 96-well plate was placed in a 37°C incubator for culture, and the growth of the bacterial solution was observed for 24 hours. The control drug tylosin was determined in the same way, and the lowest drug concentration that completely inhibited bacterial growth in the small well was MIC. The bacteria in the positive control well (i.e., without drug) needed to grow significantly. When a single jump hole appeared in the microbroth dilution method, the highest drug concentration that inhibited the bacteria was recorded. If multiple jump holes appeared, the test needed to be repeated.

Table 3 shows the MIC results, which shows that the target compound has good antibacterial activity against the selected strains and has good inhibitory activity against drug-resistant Staphylococcus aureus. It is particularly suitable as a new antibacterial drug for the prevention and treatment of infectious diseases caused by human or animal or drug-resistant Staphylococcus aureus or multidrug-resistant bacteria.

Table 3 In vitro antibacterial data

(2) Determination of compound solubility

Compounds 2, 3, 15 and 19 were converted into sulfates, and the sulfate of Retamulin was used as a control. The solubility in water was determined by high performance liquid chromatography. The test results are shown in Table 4.

Table 4 Solubility of Compounds 2, 3, 15, 19 and Sulfate of Retamulin

Compound Solubility (mg/mL, pH=7.0 in water) 2 1.42 3 1.57 15 1.85 19 2.32 Retapamulin 0.11

As shown in Table 4, the tested compounds all have good water solubility, which is better than the solubility of retamulin salt and improves the solubility of pleuromutilin derivatives. The solubility of the sulfate salt of compound 19 in water reaches 2.32 mg/mL.

The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims (8)

1. A pleuromutilin derivative with 1,3,4-oxadiazole side chain, characterized in that it is a compound of formula 2 or a pharmaceutically acceptable salt thereof:

Wherein, R is furyl, thienyl, phenyl, 2-pyridyl, 4-pyridyl, pyrazinyl,

2. The pleuromutilin derivative with 1,3,4-oxadiazole side chain according to claim 1, characterized in that: Described pharmaceutically acceptable salt is formula 2 compound and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid , Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid. 3. The pleuromutilin derivative with 1,3,4-oxadiazole side chain according to claim 2, characterized in that: Described pharmaceutically acceptable salt has following structural formula:

4. The preparation method of pleuromutilin derivatives having 1,3,4-oxadiazole side chains according to any one of claims 1 to 3, characterized in that it comprises the following steps: (1) reacting pleuromutilin with p-toluenesulfonyl chloride to obtain intermediate I of the structure shown in formula 3; (2) Carboxylic acid is used as a raw material to react with absolute ethanol to obtain the intermediate II of the structure shown in formula 4; (3) reacting the intermediate II prepared in step (2) with hydrazine hydrate to obtain intermediate III of the structure shown in formula 5; (4) react the intermediate III prepared in step (3) with carbon disulfide to obtain intermediate IV as shown in formula 6; (5) The intermediate I prepared in step (1) is used as a raw material, further activated by sodium iodide, and then reacted with the intermediate IV prepared in step (4), to obtain a compound having the structure shown in formula 2. , a truncated pleuromutilin derivative of the 4-oxadiazole side chain; The intermediates I, II, III and IV have the structural formulas 3-6 respectively:

5. The application of the pleuromutilin derivative with 1,3,4-oxadiazole side chain according to any one of claims 1 to 3 in the preparation of antibacterial products. 6. according to claim 5 there is 1,3, the application of the pleuromutilin derivative of 4-oxadiazole side chain in the preparation antibacterial product, it is characterized in that: The antibacterial product is a medicine for treating infectious diseases. 7. according to claim 6 there is 1,3, the application of the pleuromutilin derivative of 4-oxadiazole side chain in the preparation antibacterial product, it is characterized in that: The infectious disease is an infectious disease caused by human or animal infection by drug-resistant Staphylococcus aureus or multidrug-resistant bacteria. 8. according to claim 6 there is 1,3, the application of the pleuromutilin derivative of 4-oxadiazole side chain in the preparation antibacterial product, it is characterized in that: The medicine contains one or more pharmaceutically acceptable carriers, excipients or diluents.

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