A pleuromutilin derivative with thiazole side chain and its preparation method and application

Abstract

This invention belongs to the field of medicinal chemistry and discloses a truncated pleurotin derivative with a thiazole side chain, its preparation method, and its applications. The derivative is a compound with the structure shown in Formula 2 or a pharmaceutically acceptable salt thereof. The truncated pleurotin derivative provided by this invention is a novel type of compound that has not been previously reported. It exhibits good water solubility and is particularly suitable as a novel antibacterial drug for the prevention and treatment of bacterial infections in humans or animals, especially infections caused by drug-resistant Staphylococcus aureus. The truncated pleurotin derivative with a thiazole side chain prepared by this invention has good water solubility.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and particularly relates to a truncated pleurotin derivative with a thiazole side chain, its preparation method, and its application. Background Technology

[0002] Antibiotics have long been a primary treatment for bacterial infections in clinical practice. They typically work by inhibiting the physiological functions of bacterial cells, helping the body's immune system eliminate foreign pathogens. With the widespread use of antimicrobial drugs in veterinary clinics, the problem of antibiotic resistance in animal-derived bacteria has become increasingly serious. Methicillin-resistant Staphylococcus aureus (MRSA) is a typical example of drug-resistant bacteria. MRSA is a typical zoonotic pathogen, widely distributed in nature. Besides being resistant to many disinfectants, it can survive in various harsh environments outside the body. MRSA typically colonizes moist areas such as the nasal cavity, throat, armpits, groin, perineum, and gastrointestinal tract. MRSA is a significant pathogen of bacterial sepsis, with a mortality rate as high as 40% after infection. MRSA infections have been reported worldwide, and their prevalence in communities and hospitals continues to rise, posing a serious threat to human health globally. Therefore, there is an urgent need to develop anti-MRSA drugs with unique antibacterial mechanisms to address the potential harm caused by MRSA infections.

[0003] Mycoplasma gallisepticum (MG) infection is a contagious chronic respiratory disease in chickens caused by Mycoplasma gallisepticum. Clinical symptoms of MG infection include cough, runny nose, and tracheal rales; MS infection can cause bursitis, characterized by swollen hock joints, lameness, poor growth in chicks, and decreased egg production in laying hens. Currently, almost all poultry farms have mycoplasma infections. The occurrence of mycoplasma gallisepticum in chicken farms seriously harms the profitability of the poultry industry and causes numerous problems; for example, it significantly reduces the utilization rate of breeding chickens, the egg production rate of laying hens, and the profits of commercial chickens, and severely damages the immune system and exacerbates secondary infections. Therefore, the development of new drugs for the prevention and treatment of Mycoplasma gallisepticum is particularly urgent.

[0004] Pleuroromutilin (Formula 1) is a diterpenoid natural product with fused 5-6-8 tricyclic rings. It was isolated and purified from cultures of *Pleurotus mutilu* and *Pleurotus passeckerianus* by Kavanagh et al. in the 1950s. Pleuroromutilin has a relative molecular weight of 378.51, the molecular formula C22H34O5, a melting point of 167℃–168℃, and is a milky white crystalline solid, readily soluble in ethanol and acetone, and slightly soluble in water.

[0005]

[0006] Studies have shown that truncated pleurotins and their derivatives exhibit strong antibacterial activity against most Gram-positive bacteria, some Gram-negative bacteria, and mycoplasma, unlike other widely used antibacterial drugs in clinical practice. Truncated pleurotins and their derivatives inhibit bacterial protein synthesis by binding to the V region of the peptidyl transferase center (PTC) of the 23S RNA of the 50S ribosomal subunit. Due to their unique mechanism of action, truncated pleurotins and their derivatives are less prone to cross-resistance with other drugs. Meanwhile, medicinal chemists have improved the drug-likeness of truncated pleurotins by chemically modifying multiple sites on the tricyclic backbone through biotransformation and total synthesis. Currently, most modifications focus on the C14 side chain of truncated pleurotins, typically involving the substitution of the terminal hydroxyl group or the entire side chain to produce two main types of semi-synthetic truncated pleurotins. Structural modifications to the side chain at the C-14 position of the parent nucleus yield truncated pleurotin derivatives with good antibacterial efficacy and high water solubility.

[0007] To date, four antibacterial drugs have been successfully marketed by modifying their C14 side chains: the veterinary antibiotics tiamulin and valnemulin, the human topical antibiotic retapamulin, and the human antibiotic Lefamulin, which was approved by the US FDA in 2019 for the treatment of community-acquired bacterial pneumonia (CABP). Compared to drugs developed from the same core, such as penicillins, cephalosporins, and quinolones, which often number in the dozens, only four truncated pleurotin antibiotics have been successfully developed, and resistant bacteria against truncated pleurotin antibiotics are still relatively rare. Therefore, the development of more truncated pleurotin antibiotics is essential. Summary of the Invention

[0008] In order to overcome the shortcomings and disadvantages of the existing technology, the primary objective of this invention is to provide a truncated pleurotin derivative with a thiazole side chain. Such truncated pleurotin derivatives have good antibacterial activity and are particularly suitable for preparing novel antibacterial drugs for systemic infections in animals or humans.

[0009] Another object of the present invention is to provide a method for preparing the above-mentioned truncated pleurotin derivative having a thiazole side chain.

[0010] Another object of the present invention is to provide the use of the above-mentioned truncated pleurotin derivative having a thiazole side chain in the preparation of medicaments for treating infectious diseases, particularly infectious diseases caused by drug-resistant Staphylococcus aureus, multidrug-resistant bacteria, or mycoplasma.

[0011] The objective of this invention is achieved through the following technical solution:

[0012] A truncated pleurotin derivative having a thiazole side chain, said derivative being a compound with the structure shown in Formula 2 or a pharmaceutically acceptable salt thereof:

[0013]

[0014] Wherein, R represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0015] The specific functional groups of the compounds with the above preferred structures are summarized in Table 1:

[0016] Table 1. Compound Numbers and Specific Functions

[0017]

[0018]

[0019]

[0020] The pharmaceutically acceptable salt is a salt formed by the compound of Formula 2 with 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.

[0021] The pharmaceutically acceptable salt preferably has the following structural formula:

[0022]

[0023] The method for preparing the above-mentioned truncated pleurotin derivative with a thiazole side chain includes the following steps:

[0024] (1) The truncated pleurotin was reacted with p-methylbenzenesulfonyl chloride to obtain intermediate I with the structure shown in Formula 3;

[0025] (2) The intermediate I obtained in step (1) is reacted with sodium iodide to obtain intermediate II with the structure shown in Formula 4;

[0026] (3) Using aminoacetonitrile hydrochloride as a raw material, react with CS2 to obtain intermediate III with the structure shown in Formula 5;

[0027] (4) React intermediate II obtained in step (2) with intermediate III obtained in step (3) to obtain intermediate IV with the structure shown in Formula 6.

[0028] (5) The intermediate IV obtained in step (4) is reacted with various acyl chlorides to obtain a truncated pleurotin derivative with a thiazole side chain as shown in Formula 2.

[0029] Intermediate I, Intermediate II, Intermediate III, and Intermediate IV respectively have structural formulas 3 to 6:

[0030]

[0031] The preferred molar ratio of p-toluenesulfonyl chloride to truncated pleurotin in step (1) is 1.1:1;

[0032] The reaction described in step (2) preferably uses anhydrous methanol as a solvent, the molar ratio of intermediate I to sodium iodide is preferably 1:1, and the reaction conditions are preferably 75°C for 2-3 hours.

[0033] The preferred molar ratio of aminoacetonitrile hydrochloride to CS2 in step (3) is 1:1.1;

[0034] The specific operation of the reaction described in step (4) is as follows: intermediate II is added to intermediate III under ice bath, and then sodium methoxide is added. The molar ratio of sodium methoxide to intermediate II is preferably 1:1.

[0035] The specific operation of the reaction described in step (5) is as follows: under normal temperature conditions, acyl chloride is added dropwise to intermediate IV, the molar ratio of intermediate IV to acyl chloride is preferably 1:1.1, triethylamine is added dropwise to the reaction solution as a catalyst, and the reaction time is preferably 2 to 4 hours.

[0036] The synthesis route is shown in the following formula:

[0037]

[0038] The above-mentioned truncated pleurotin derivatives with thiazole side chains are used in the preparation of antibacterial products.

[0039] The antibacterial product is preferably a drug for treating infectious diseases.

[0040] The infectious diseases mentioned refer to infectious diseases caused by infection with drug-resistant Staphylococcus aureus or multidrug-resistant bacteria in humans or animals.

[0041] The drug contains one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0042] The formulations of the aforementioned drugs include various clinical drug dosage forms, such as tablets, injections, liposome nanoparticles, controlled-release formulations, etc.

[0043] An antibiotic drug containing an effective amount of a truncated pleurotin derivative having a thiazole side chain, with the remainder being pharmaceutical excipients or other compatible drugs.

[0044] The pharmaceutical excipients refer to conventional pharmaceutical excipients, such as solvents, disintegrants, flavoring agents, preservatives, colorants, and binders.

[0045] The other compatible drugs refer to drugs that use an effective dose of a truncated pleurotin derivative with a thiazole side chain as the drug raw material, and then combine it with other natural drugs or chemical drugs.

[0046] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0047] (1) The truncated pleurotin derivative provided by the present invention is a new type of compound that has not been reported before.

[0048] (2) Through extensive and in-depth research, this invention has synthesized a large number of novel truncated pleurotin derivatives with thiazole side chains and conducted extensive antibacterial activity screening. It was discovered 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 novel antibacterial drug for the prevention and treatment of bacterial infectious diseases in humans or animals, especially infectious diseases caused by drug-resistant Staphylococcus aureus.

[0049] (3) The truncated pleurotin derivative with thiazole side chain prepared by the present invention has good water solubility. Attached Figure Description

[0050] Figure 1 This is the NMR spectrum of compound 2.

[0051] Figure 2 This is the NMR spectrum of compound 3.

[0052] Figure 3 This is the NMR spectrum of compound 4.

[0053] Figure 4 This is the NMR spectrum of compound 10.

[0054] Figure 5 This is the NMR spectrum of compound 19.

[0055] Figure 6 These are the results of toxicity tests on a subset of the compounds. Detailed Implementation

[0056] The present invention will be further described in detail below with reference to the embodiments and accompanying drawings, but the embodiments of the present invention are not limited thereto.

[0057] In the following examples, the R groups in thiazole are specifically shown in Table 1, all of which are commercially available, as are other reagents.

[0058] Example 1

[0059] (1) Preparation of intermediate I: 10.0 g (26.5 mmol) of truncated pleurotin was dissolved in 20 ml of pyridine and placed in an ice bath; 5.6 g (29.2 mmol) of p-methylbenzenesulfonyl chloride was dissolved in 10 ml of pyridine, and then the above truncated pleurotin pyridine solution was slowly added. The mixture was stirred in an ice bath for 3 h, and then 50 ml each of ice water and chloroform were added in sequence. The mixture was then transferred to a separatory funnel and shaken, and allowed to stand for separation. The organic phase was taken and washed in sequence with 100 ml of sulfuric acid (4 mol / L), 100 ml of saturated sodium bicarbonate solution, and 100 ml of deionized water. After washing, the organic solution was evaporated under reduced pressure. 20 ml of isopropanol was added to the remaining solid, heated to dissolve, and then cooled. A large amount of white powder precipitated. The powder was filtered, and the residue was washed with isopropanol and dried to obtain intermediate I with the structure shown in Formula 3, with a yield of 81%.

[0060] (2) Preparation of intermediate II: 11.7 g of intermediate I (80 mmol) and 3.29 g of sodium methoxide (80 mmol) were added to anhydrous methanol and stirred at 75 °C for 2 hours to obtain intermediate II with the structure shown in Formula 4, with a yield of 84.21%.

[0061] (3) Preparation of intermediate III: 10 g of aminoacetonitrile (108 mmol) was dissolved in anhydrous methanol, and 9.05 g of carbon disulfide (118 mmol) was slowly added dropwise to the reaction solution. The reaction was carried out in an ice-salt bath for 1 hour, and a large amount of solid was precipitated. The yellow solid intermediate III was obtained by filtration, with a yield of 45.17%.

[0062] (4) Preparation of intermediate IV: 11.7 g of intermediate III (80 mmol) and 11.9 g of sodium methoxide (80 mmol) were added to intermediate II (80 mmol). After reacting for 2 hours in an ice-salt bath, the reaction solution was evaporated to dryness by rotary evaporation. The reactants were reconstituted with dichloromethane and the reaction solution was poured into a separatory funnel. 50 ml of distilled water and 50 ml of dichloromethane were added sequentially. After shaking, the mixture was allowed to stand for separation. The organic phase was taken and washed twice with distilled water and dried with anhydrous sodium sulfate. The organic phase was then evaporated to dryness by rotary evaporation. The resulting mixture was reconstituted with dichloromethane and 10 g of 100-200 mesh silica gel was added and mixed thoroughly. After the solvent evaporated, the above crude product-silica gel powder mixture was purified by column chromatography (100-200 mesh silica gel powder was used as the stationary phase, and dichloromethane:methanol = 200:1 (V:V) was used as the mobile phase) to obtain intermediate IV with a yield of 45.65%.

[0063] Example 2 Preparation of 22-((5-(cyclopropionylamino)thiazol-2-yl)-thio)-deoxy-truncated pleurotin (compound 1)

[0064] 1 g of intermediate IV (2 mmol) prepared in Example 1 was dissolved in dichloromethane. Cyclopropyl chloride (2.2 mmol) was added dropwise to the reactants and reacted at room temperature for 3 hours. The reaction solution was poured into a separatory funnel, and 50 ml each of distilled water and dichloromethane were added sequentially. After shaking, the mixture was allowed to stand for separation. The organic phase was taken, washed twice with distilled water, and dried with anhydrous sodium sulfate. The organic phase was then evaporated by rotary evaporation to obtain a mixture, which was redissolved in dichloromethane. 1 g of 100-200 mesh silica gel was added and mixed thoroughly. After the solvent evaporated, the above crude product-silica gel powder mixture was purified by column chromatography (100-200 mesh silica gel powder was used as the stationary phase, and dichloromethane:methanol = 60:1 (V:V) was used as the mobile phase) to obtain compound 1 with the structure shown in Formula 2, as shown in Table 1, where R is... The yield of compound 1 was 48.0%.

[0065] Example 3 Preparation of compounds 2-24

[0066] Following the same method as in Example 2 (the molar amounts of each reactant, reaction conditions, purification, etc., were all the same as in Example 2), the corresponding products shown in Formula 2 were obtained, numbered sequentially from 2 to 24. Among them, Figures 1-6 These are the NMR spectra of compounds 2, 4, 10, 18, and 23.

[0067] The yields of the above compounds are summarized in Table 2.

[0068] Table 2. Compound Numbers and Yields

[0069]

[0070]

[0071] Effect Example

[0072] (1) In vitro antibacterial test

[0073] The experiment used the broth dilution method. Tiamulin was used as the control drug. Tiamulin is a truncated pleurotin class antibiotic and one of the world's top ten veterinary antibiotics.

[0074] The strains used in the experiment were methicillin-resistant Staphylococcus aureus ATCC43300, Staphylococcus aureus ATCC29213, clinical Staphylococcus aureus AD3, and clinical Staphylococcus aureus 144.

[0075] Preparation of target compound stock solution: Accurately weigh 6.4 mg of the target compound and place it in a 5 mL volumetric flask. Dissolve the compound in 0.25 mL DMSO and 0.25 mL Tween 80, then add 4.5 mL distilled water to make up to volume. Shake well to obtain the stock solution (1280 μg / mL). Sterilize the solution by filtering through a 0.22 μm filter membrane, aliquot into tubes, and store at -20 °C. The control drug tiamulin was prepared in the same manner.

[0076] Preparation of bacterial suspension: The strain, preserved intact at -20℃, was inoculated onto a new MH plate and cultured at 37℃ for 24 hours. Single colonies were then picked and inoculated into MH medium for another 24 hours. Single colonies were then transferred to sterile physiological saline and the turbidity was adjusted to 0.6 McF. At this point, the bacterial suspension concentration was 10. 6 CFU / mL.

[0077] MIC plate preparation: Take a sterile 96-well plate, add 180 μL of LMH broth to well 1, and add 100 μL of LMH broth to wells 2 through 12 respectively. Add 20 μL of the target compound solution at a concentration of 1280 μg / mL to well 1, mix well, and then add 100 μL to well 2, mix well, and then add 100 μL to well 3, and so on, until 100 μL is added to well 12 and discarded. At this point, the drug concentrations in each well are: 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.06 μg / mL, respectively. Each concentration is prepared in triplicate.

[0078] Inoculation: Add 100 μL of bacterial solution to each of wells 1 to 12, so that the final bacterial concentration in each well is approximately 5 × 10⁻⁶. 5 The drug concentrations in wells 1 through 12 were 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, and 0.03 μg / mL, respectively. The inoculated 96-well plates were incubated at 37°C for 24 hours, and bacterial growth was observed. The control drug, tiamulin, was determined using the same method, with the lowest drug concentration (MIC) required to completely inhibit bacterial growth in each well. In the positive control wells (i.e., without drug), significant bacterial growth was required. If a single well skipped in the microbroth dilution method, the highest drug concentration inhibiting bacterial growth was recorded. If multiple wells skipped, the experiment needed to be repeated.

[0079] The MIC results of the target compound for the test strains are shown in Table 3.

[0080] Table 3. Antimicrobial susceptibility results of the target compounds against four drug-resistant Staphylococcus aureus strains.

[0081]

[0082]

[0083]

[0084]

[0085] As can be seen from the data in Table 3, most of the compounds of this invention exhibit good antibacterial activity against Staphylococcus aureus. The antibacterial activity of most compounds against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus is close to or better than that of tiamulin, which is widely used in clinical practice. Among them, compounds 3 and 4 have the best overall antibacterial effect.

[0086] (2) In vitro mycoplasma activity inhibition experiment

[0087] The experiment used the broth dilution method. Tiamulin was used as the control drug. Tiamulin is a truncated pleurotin antibiotic, mainly used to prevent porcine mycoplasma pneumonia, and its activity against mycoplasma is stronger than that of macrolides.

[0088] The strains used in the experiment were Mycoplasma gallisepticum 352, Mycoplasma tamiflu 352, and Mycoplasma gallisepticum M47.

[0089] Preparation of stock solution for target compound: Dissolve the compound in 1 mL DMSO, then dilute to 250 mL in a volumetric flask and shake well to obtain the stock solution (5120 μg / mL).

[0090] The stock solution was serially diluted in petri dishes, with each dish containing 2 ml of the drug solution, to a final concentration of 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.0313, 0.0152, 0.00075, and 0.0004 μg / mL.

[0091] Fifteen sterile 2mL EP tubes were prepared. 0.9mL of liquid culture medium was added to the first tube, and 0.5mL to each of the remaining tubes. 0.1mL of the prepared culture solution was added to the first tube and mixed thoroughly. Then, 0.5mL of the mixture was added to the second tube, and so on. The last 0.5mL was discarded. Finally, 0.5mL of diluted bacterial culture was added to each tube. The tubes were capped, and a blank control was prepared. The tubes were incubated at 37℃, and the growth of mycoplasma was observed.

[0092] Table 4 shows the MIC results of some target compounds against Mycoplasma gallisepticum.

[0093] Table 4 In vitro antibacterial data

[0094]

[0095] As shown in the table above, most of the derivatives of this invention have good inhibitory activity against Mycoplasma gallisepticum.

[0096] (3) Cytotoxicity test

[0097] The experiment used the MTT method.

[0098] The cell line used in the experiment was mouse mononuclear macrophages (RAW264.7).

[0099] Preparation of target compound stock solution: Accurately weigh 8 mg of the target compound, dissolve it in 1 mL of DMSO, shake well to obtain stock solution (8 mg / mL), filter through a 0.22 μm filter membrane for sterilization, and store at -20 °C.

[0100] MTT incubation and OD value determination: Healthy cells were collected and seeded into 96-well plates with 100 μL of cells at a density of approximately 5 × 10⁵ cells / mL per well. The 96-well plates were incubated overnight in a 5% CO₂ incubator. The complete culture medium was discarded, and the test compound (dissolved in DMSO to prepare a 4 mg / mL stock solution) was added to a final concentration of 4 μg / mL. The plates were then incubated in a 5% CO₂ incubator for 24 h. The supernatant was discarded, and freshly prepared 0.5 mg / mL MTT solution (dissolved in DMEM to prepare a 5 mg / mL stock solution, aliquoted at -20℃) was added and incubated in the dark for 4 h. The supernatant was discarded, and 150 μL of DMSO was added. The plates were then shaken at 70 rpm for 10 min at room temperature. The absorbance was measured at 490 nm using a microplate reader, and cell viability was calculated. The experiment was performed in triplicate. The formula is as follows:

[0101] Cell viability (%) = OD drug group / OD control group × 100%

[0102] Figure 6 The results of toxicity tests on a subset of the compounds show that the target compounds are not toxic to the selected cell lines at a concentration of 8 μg / mL, and have a certain growth-promoting effect, making them suitable as novel antibacterial drugs for the prevention and treatment of infectious diseases in humans or animals, or caused by drug-resistant Staphylococcus aureus or multidrug-resistant bacteria.

[0103] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A pleuromutilin derivative having a thiazole side chain, characterized in that: The derivative is a compound of the structure shown in Formula 2 or a pharmaceutically acceptable salt thereof: ； Formula 2; wherein R is , 。 2. The pleuromutilin derivative with thiazole side chain according to claim 1, characterized in that: The pharmaceutically acceptable salt is a salt of the compound of Formula 2 with 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 thiazole side chain according to claim 2, characterized in that: The pharmaceutically acceptable salt has the following structural formula: 。 4. Process for the preparation of a pleuromutilin derivative with a thiazole side chain according to any one of claims 1 to 3, characterized in that The method comprises the following steps: (1) the reaction of pleuromutilin with p-toluenesulfonyl chloride to obtain an intermediate of the structure shown in Formula 3 ; (2) reacting the intermediate prepared in step (1) with sodium iodide to obtain an intermediate having a structure as shown in formula 4 ; (3) Aminoacetonitrile hydrochloride is used as a raw material to react with CS2 to obtain an intermediate with a structure as shown in Formula 5 ; (4) reacting the intermediate prepared in step (2) with the intermediate prepared in step (3) to obtain an intermediate having a structure as shown in formula 6 ; (5) reacting the intermediate prepared in step (4) with various acyl chlorides to obtain a pleuromutilin derivative having a thiazole side chain of the structure shown in Formula 2; and various acyl chlorides to obtain a pleuromutilin derivative having a thiazole side chain of the structure shown in Formula 2; The intermediate I, intermediate II, intermediate III and intermediate IV have the structural formulas of Formula 3-6 respectively: 。 5. The preparation method according to claim 4, characterized in that: In step (1), the molar ratio of the p-toluenesulfonyl chloride to the pleuromutilin is 1.1:1; In step (2), the reaction uses anhydrous methanol as the solvent, the molar ratio of the intermediate I to sodium iodide is 1:1, and the reaction condition is 75℃ for 2-3h; In step (3), the molar ratio of the aminoacetonitrile hydrochloride to CS2 is 1:1.1; The specific operation of the reaction in Step (4) is as follows: under ice-bath, intermediate is added into intermediate , then sodium methoxide is added, and the molar ratio of sodium methoxide to intermediate is 1:

1. The reaction in step (5) is carried out by adding the acyl chloride dropwise to the intermediate at room temperature, and the reaction is carried out for 2-4 hours. The molar ratio of the intermediate (V) and the acyl chloride is 1:1.1, and triethylamine is added dropwise to the reaction solution as a catalyst.

6. Use of the pleuromutilin derivative with thiazole side chain according to any one of claims 1-3 in the preparation of an antibacterial product.

7. Use according to claim 6, characterized in that: The antibacterial product is a drug for treating infectious diseases.

8. Use according to claim 7, characterized in that: The infectious disease is an infectious disease caused by infection of a drug-resistant Staphylococcus aureus or a multi-drug resistant bacteria in a human or an animal.

9. Use according to claim 7, characterized in that: The drug contains one or more pharmaceutically acceptable carriers, excipients or diluents.

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