Cephalosporin compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of synthesis of cephalosporin compounds, and particularly relates to a cephalosporin compound as well as a preparation method and application thereof. The cephalosporin compound is a compound as shown in the following structural general formula, an optical isomer and a pharmaceutically available salt, wherein R is selected from aryl, substituted aryl, 5-to 8-membered heteroaryl, 3-to 8-membered aliphatic ring and bicyclic monoterpene ketone group; the number of substituent groups of the substituted aryl is 1 to 5; substituent groups of the substituted aryl groups are independently selected from C1-C6 alkyl groups, substituted C1-C6 alkyl groups, halogen and cyano groups; the substituent of the substituted C1-C6 alkyl is selected from halogen. According to the invention, the cephalosporin compound and the sulfonyl chloride are used as raw materials for modifying the cephalosporin antibiotics for the first time, so that the antibacterial and anti-inflammatory dual functions are realized, and the effects of inhibiting bacteria and regulating inflammatory response are synchronously exerted.

Description

A cephalosporin compound, its preparation method and application Technical Field

[0001] This invention belongs to the field of cephalosporin compound synthesis technology, specifically relating to a cephalosporin compound, its preparation method, and its application. Background Technology

[0002] Since their introduction in the 1960s, cephalosporins have become one of the most widely used and important β-lactam antibiotics globally, playing a cornerstone and irreplaceable role in anti-infective therapy. Compared to other types of antibiotics, cephalosporins generally have good tolerability, a lower incidence of allergic reactions than penicillin, and lower toxicity. They hold a central position in many areas, including respiratory tract infections and skin and soft tissue infections. However, with the widespread spread of β-lactamases and the continuous emergence of multidrug-resistant strains, existing cephalosporins pose a serious challenge. In particular, the emergence of some superbugs makes the development of novel cephalosporin derivatives an urgent priority.

[0003] As β-lactam antibiotics, cephalosporins exert their bactericidal effect by inhibiting bacterial cell wall synthesis. When bacterial infection triggers an immune response, inflammatory symptoms such as redness, swelling, heat, and pain occur. Cephalosporins indirectly alleviate inflammation by eliminating the pathogenic bacteria, the root cause of inflammation, allowing the overactivated immune response to subside naturally. In recent years, a few studies have shown that some cephalosporin derivatives may have potential immunomodulatory effects, such as regulating neutrophil activation. Introducing hydrophilic or sterically hindered groups can enhance stability against β-lactamases, but these findings are still in the exploratory stage, and their clinical significance is far less than their core antibacterial effect.

[0004] The antibacterial activity of cephalosporins depends on the nature of the C-7 side chain of the cephalosporin group; modification of the C-7 amide group affects their antibacterial activity and resistance to β-lactamases. [1-7] .

[0005] Prior art CN 103396422 A A cephalosporin compound and its preparation method. The cephalosporin compound has the general structural formula (1): .

[0006] This cephalosporin compound is a cephalosporin derivative with an α-methoxy group introduced at the 7-position. Due to the steric hindrance of the methoxy group, it prevents the enzyme molecule from approaching the β-lactam ring, thus increasing the drug's stability against β-lactamases. However, it can only slightly improve the activity against anaerobic bacteria, and the increase in activity is not significant.

[0007] Prior art CN 101781318 A discloses a cephalosporin nucleus-derived compound: .

[0008] The invention uses 7β-[2-(2-alkylaminothiazol-5-yl)-2-(methoxyiminoacetamide)]-3-(hydrosulfonate)-3-cephalosporin-4-carboxylic acid (I) as a raw material and couples it with 5-alkylamino-2-(2-alkyloxyethyl)-1-pyrazole to prepare 7β-[2-(2-alkylaminothiazol-5-yl)-2-(methoxyiminoacetamide)]-3-[3-alkylamino-2-(2-alkyloxyethyl)-1-pyrazolite]methyl-3-cephalosporin-4-carboxylic acid (IV), which is then converted to cefpyrazole sulfate. However, this invention only introduces a standard aminothiazolacetamide side chain at the C-7 position and performs sulfonation and subsequent pyrazolium salt substitution at the C-3 position; the entire modification does not break through the traditional antibacterial functional framework of cephalosporin drugs.

[0009] References:

[0010] 1.Mohebbi, M. et al. Med. Chem. Res. 2014, 23, 4531-4541.

[0011] 2.Bush, K. et al. Clin. Microbiol. Rev. 2020, 33,e00047-19.

[0012] 3.Bush, K. et al.Csh. Perspect. Med. 2016, 6,a025247.

[0013] 4. Perez, F. et al. Lancet. Infect. Dis.2019, 19, 561-562.

[0014] 5.Kohanski, M A. et al. Nat. Rev. Microbiol. 2010, 8, 423-435.

[0015] 6.Drawz, S M. et al. Clin. Microbiol. Rev. 2010, 23, 160-201.

[0016] 7. Llarrull, L I. et al. Curr. Opin. Microbiol. 2010, 13, 551-557.). Summary of the Invention

[0017] The purpose of this invention is to provide a cephalosporin compound, its preparation method, and its application.

[0018] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0019] A cephalosporin compound, which is a compound, optical isomer, or pharmaceutically usable salt represented by the following general structural formula: Wherein, R is selected from aryl, substituted aryl, 5-8 membered heteroaryl, 3-8 membered aliphatic ring, bicyclic monoterpene ketone; the number of substituents in the substituted aryl group is 1-5; the substituents in the substituted aryl group are independently selected from C1-C6 alkyl, substituted C1-C6 alkyl, halogen, cyano; the substituents in the substituted C1-C6 alkyl group are selected from halogen.

[0020] According to embodiments of the present invention, the present invention can be further optimized, and the optimized technical solution is as follows:

[0021] In one preferred embodiment, the aryl group is phenyl, naphthyl, tetrahydronaphthyl, indene, or hydroindene.

[0022] In one preferred embodiment, the 5-8 heteroaryl group is thienyl, pyridyl, furanyl, thienyl, pyrroleyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or indoleyl.

[0023] In one preferred embodiment, the 3-8 member aliphatic ring is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0024] In one preferred embodiment, the bicyclic monoterpene ketone group is .

[0025] In one preferred embodiment, R is selected from methylphenyl, trifluoromethylphenyl, fluorophenyl, chlorophenyl, tert-butylphenyl, cyanophenyl, 3,5-ditrifluoromethylphenyl, 3,5-dichlorophenyl, naphthyl, thiophenyl, pyridyl, cyclopropyl, propyl, .

[0026] In one preferred embodiment, R is selected from substituted aryl, 5-8 membered heteroaryl; the number of substituents in the substituted aryl is 1-5; the substituents in the substituted aryl are independently selected from substituted C1-C6 alkyl, halogen, cyano; the substituents in the substituted C1-C6 alkyl are selected from halogen; when the substituent in the substituted aryl is one chlorine, the substitution position is not at position 2; when the substituent in the substituted aryl is two chlorines, the substitution positions are not simultaneously at positions 3 and 5.

[0027] Based on the same inventive concept, this invention also claims a method for preparing the cephalosporin compound, comprising the following steps: S1, reacting compound 1, compound 2, and solvent under N2 protection at room temperature with stirring for 15-20 hours, cooling to room temperature after the reaction, removing the solvent to obtain compound 3; S2, reacting compound 3, compound 4, alkali, and solvent at room temperature with stirring for 4-8 hours, followed by vacuum distillation, extraction, acidification, and purification to obtain the cephalosporin compound; the structural formula of compound 1 is: The structural formula of compound 2 is: The structural formula of compound 3 is: The structural formula of compound 4 is: .

[0028] In one preferred embodiment, the synthetic route of the cephalosporin compound is as follows: ; .

[0029] In one preferred embodiment, in step S1, the molar ratio of compound 1 to compound 2 is 1-2:1-2.

[0030] In one preferred embodiment, in step S1, the solvent is dichloromethane.

[0031] In one preferred embodiment, in step S2, the base is one or a mixture of two of triethylamine and pyridine.

[0032] In one preferred embodiment, in step S2, the solvent is tetrahydrofuran.

[0033] In one preferred embodiment, in step S2, purification is performed by thin-layer chromatography, using a dichloromethane and methanol mixture in a volume ratio of (20-50):1 as the developing solvent.

[0034] Based on the same inventive concept, the present invention also claims protection for the use of the cephalosporin compound in antibacterial applications.

[0035] In one preferred embodiment, the bacteria are drug-resistant bacteria.

[0036] In one preferred embodiment, the bacteria is MRSA or ESBL-producing Klebsiella pneumoniae.

[0037] Compared with the prior art, the beneficial effects of the present invention are:

[0038] This invention is the first to modify cephalosporin antibiotics using cephalosporin compounds and sulfonyl chlorides as raw materials. The sulfonamide bond possesses chemical stability, is not easily hydrolyzed or enzymatically degraded, and can ensure the structural integrity of the drug molecule during in vivo delivery. Secondly, this stable chemical bond is the key structural basis for achieving a synergistic "antibacterial-anti-inflammatory" dual function, and is expected to enable the precise delivery of the sulfonyl anti-inflammatory fragment to the infection site via bacterial targeting from the cephalosporin parent, where it can simultaneously inhibit bacteria and regulate the inflammatory response after local enrichment. From a synthetic chemistry perspective, the formation of the sulfonamide bond has mild reaction conditions, high selectivity, and a well-defined product structure, which is beneficial for subsequent purification and structural characterization.

[0039] This invention innovatively employs tert-butyl-N,N'-diisopropylcarbodiimide as a protecting agent, successfully achieving efficient and highly selective tert-butyl ester protection of the carboxyl group of cephalosporin parent material. Secondly, this invention utilizes sulfonyl chloride to sulfonate the protected C-7 amino group of the cephalosporin parent material, successfully introducing a series of structurally diverse sulfonyl fragments into the cephalosporin skeleton. This invention overcomes the fundamental chemical challenge of selectively modifying the C-7 amino and carboxyl groups of cephalosporin parent material, achieving the core challenge of directly selectively modifying a cephalosporin parent material possessing both highly active amino and carboxyl groups. It also overcomes the problem of limited chemical space in existing cephalosporin modification methods, pioneering the application of sulfonyl chloride chemistry to the modification of the C-7 amino group of cephalosporins, greatly expanding the chemical modification space and function of cephalosporin drugs.

[0040] This invention has the advantages of simple synthesis steps, easy operation, inexpensive and readily available raw materials, good compatibility of the synthesis method with functional groups, high chemical selectivity and atom economy. Detailed Implementation

[0041] This invention is not limited to the specific embodiments listed below. Those skilled in the art can implement this invention using various other specific embodiments based on the content disclosed herein. Any modifications or alterations made to the design structure and concept of this invention fall within the protection scope of this invention. It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other.

[0042] The following are definitions of some of the terms used in this invention:

[0043] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0044] “CF3” refers to trifluoromethyl.

[0045] When "alkyl" is used as a group or part of a group, it refers to a straight-chain or branched aliphatic hydrocarbon group. Preferred alkyl groups are C1-C14 alkyl groups; more preferred are C1-C10 alkyl groups; and most preferred are C1-C6 alkyl groups, unless otherwise specified. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, hexyl, etc.

[0046] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, or spirocyclic carbon ring. Rings consisting of 3-9 carbon atoms are preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] "Aryl" as a group or part of a group refers to: (1) an aromatic monocyclic or fused ring; preferably an aromatic carbocyclic ring with 5-12 carbon atoms (a cyclic structure in which all ring atoms are carbon). Examples of aryl groups include, but are not limited to: phenyl, naphthyl; (2) a group that can be connected to a partially saturated carbocyclic ring, for example: a phenyl group and a C5-7 cycloalkyl or C5-7 cycloalkenyl group fused together to form a cyclic structure. Examples include, but are not limited to: tetrahydronaphthyl, indenyl, or hydroindenyl. An aryl group may be substituted by one or more substituents.

[0048] "Heteroaryl" refers to a monocyclic or fused polycyclic aromatic heterocyclic group, preferably an aromatic group having one or more (preferably 3 to 14, more preferably 5 to 10, especially preferably 5 or 6) carbon atoms and one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N) as cyclic atoms. Preferably, the aromatic group is a 4-15 membered heteroaryl, more preferably a 5-8 membered heteroaryl. Examples of the heteroaryl groups include, for example: furanyl, thiopheneyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, pyridyl, imidazolyl, 3-phenylpyrrolyl, thiazolyl-oxazolyl, tetrazolyl, isoxazolyl, inzolyl, pyridazinyl, quinolinyl, purinyl, carbazoleyl, acridineyl, pyrimidinyl, 2,3'-bifuranyl, and isoquinolinyl.

[0049] This invention includes compounds represented by general formula (I) and their various possible isomers. These include: non-mirror image isomers, mirror image isomers, tautomers, and geometric isomers of "E" or "Z" configuration isomers. Any chemist with a basic understanding can isolate the above-mentioned optically pure or stereoisomerically pure compounds.

[0050] The term "pharmaceutically acceptable salt" refers to certain salts of the aforementioned compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of compounds represented by general formula (I) can be formed in two forms: one is a salt formed with an acid; the other is a salt formed with a base or alkali metal. Acids that form pharmaceutically acceptable salts with compounds represented by general formula (I) include inorganic acids and organic acids. Suitable inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic acids, and sulfonic acids; examples include, but are not limited to, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkyl sulfonic acids, and aromatic sulfonic acids. Alkali metals that form pharmaceutically acceptable salts with compounds represented by general formula (I) include lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, etc.; bases that form pharmaceutically acceptable salts with compounds represented by general formula (I) include choline, diethanolamine, morpholine, etc.

[0051] The compounds of this invention can be used alone or in combination with one or more other drugs; or in combination with surgery or radiotherapy; or formulated into a specific dosage form with pharmaceutically acceptable carriers, diluents, or excipients for administration. The specific dosage form depends on the route of administration.

[0052] The non-enteric injectable drug formulations of the present invention include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersants, suspending agents or emulsifiers, and powder injections that are prepared into injectable sterile aqueous solutions only before use.

[0053] If needed, and for more efficient distribution, the compounds of the present invention can be incorporated into slow-release or targeted delivery systems, such as polymer matrices, liposomes, and microspheres.

[0054] Oral solid dosage forms include capsules, tablets, pills, powders, and granules. These solid dosage forms contain an active compound represented by general formula (I) mixed with at least one inert and pharmaceutically acceptable excipient or carrier. These excipients or carriers include sodium citrate or dicalcium phosphate and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) disintegrants, such as agar gum, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; d) dissolution delayers, such as paraffin wax; e) absorption accelerators, such as quaternary ammonium compounds; f) wetting agents, such as cetyl alcohol and glyceryl monostearate; g) adsorbents, such as kaolin and bentonite; and h) lubricants, such as talc, calcium stearate, magnesium stearate, and solid polyethylene glycol.

[0055] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with a coating or shell.

[0056] The active compound can also be administered in microcapsule form. If desired, one or more of the excipients mentioned above may be included.

[0057] Orally administered liquid dosage forms include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, etc. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in this art, such as water or other solvents, stabilizers, and emulsifiers, such as ethyl alcohol, ethyl carbonate, ethyl acetate, benzoic acid alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerin, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, etc.

[0058] In addition to inert diluents, oral compositions may also include excipients such as humectants, emulsifiers and suspending agents, sweeteners, flavorings and fragrances.

[0059] In addition to the active compounds, the suspension may contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan anhydride esters.

[0060] Compositions for rectal or vaginal administration are preferably suppositories. Preparation can be achieved by mixing the compounds of the invention with suitable non-irritating excipients or carriers.

[0061] The dosage forms for topical administration of the compounds of this invention include powders, patches, sprays, ointments, and inhalers. The active compounds are prepared under sterile conditions by mixing with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

[0062] The method for modifying cephalosporin antibiotics of the present invention includes the following steps:

[0063] 1. Protection of carboxyl groups in the cephalosporin parent:

[0064] Compound 1, Compound 2, and solvent were added to the reactor and stirred at room temperature for 18 h under N2 protection. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the tert-butyl ester protected raw material.

[0065] Compound 1 refers to the cephalosporin parent compound having the structure of formula (1); Compound 2 refers to the tert-butyl ester protecting agent having the structure of formula (2); .

[0066] The reaction equations involved in the above synthesis method are shown below: .

[0067] The reactor is preferably a two-necked flask.

[0068] The molar ratio of compound 1 to compound 2 is 1:1.

[0069] The solvent is dichloromethane.

[0070] 2. Modification of cephalosporin parent material using sulfonyl chloride derivatives:

[0071] Compound 3, compound 4, alkali, and solvent were added to the reactor and stirred at room temperature for 6 hours. THF was removed by vacuum distillation, followed by extraction, acidification, vacuum distillation, and purification by thin-layer chromatography.

[0072] Compound 3 refers to a cephalosporin parent compound with protected substituents having the structure of formula (3); Compound 4 refers to a sulfonamide compound having the structure of formula (4); .

[0073] The reaction equations involved in the above synthesis method are shown below: .

[0074] Wherein, R is selected from aryl, substituted aryl, 5-8 membered heteroaryl, 3-8 membered aliphatic ring, bicyclic monoterpene ketone; the number of substituents in the substituted aryl is 1-5; the substituents in the substituted aryl are independently selected from C1-C6 alkyl, substituted C1-C6 alkyl, halogen, cyano; the substituents in the substituted C1-C6 alkyl are selected from halogen.

[0075] The base is one or a mixture of two of triethylamine and pyridine.

[0076] The solvent is tetrahydrofuran.

[0077] The extent of reaction was determined by thin-layer chromatography. The developing solvent used in the thin-layer chromatography was a mixed solvent of dichloromethane and methanol in a volume ratio of (20-50):1.

[0078] Specifically, Example 1 of the synthesis of compound 3 is as follows:

[0079] 5 mmol of (6R,7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid was added to a two-necked flask and dissolved in 25.0 ml of CH2Cl2. Then, 5 mmol of 2-tert-butyl-1,3-diisopropylisourea was slowly added to the solution. After mixing for 18 hours at room temperature under a nitrogen atmosphere, the precipitate was removed by filtration, and the filtrate was then evaporated under vacuum to give compound 3 protected by tert-butyl ester.

[0080] Example 1

[0081] Preparation of Compound 1

[0082]

[0083] In a reactor, 0.65 mmol of p-toluenesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0084] The structural characterization data of the obtained product are as follows:

[0085] 1 H NMR(600 MHz, Chloroform-d) δ 7.78 (d, J = 8.1 Hz, 2H), 7.32 (d, J= 8.0 Hz, 2H), 5.13 (d, J = 4.6 Hz, 1H), 4.83 (d, J = 4.6 Hz, 1H), 3.45 –3.39 (m, 1H), 3.14 (d, J = 18.3 Hz, 1H), 2.43 (s, 3H), 2.06 (s, 3H), 1.49 (s,9H).

[0086] 13 C NMR(151 MHz, Chloroform-d) δ 162.8, 161.1, 144.1, 136.7, 129.9,129.5, 127.1, 123.8, 82.8, 62.0, 57.2, 30.0, 27.9, 21.6, 19.8.

[0087] Example 2

[0088] Preparation of compound 2

[0089]

[0090] In a reactor, 0.65 mmol of p-trifluoromethylbenzenesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0091] The structural characterization data of the obtained product are as follows:

[0092] 1 H NMR(600 MHz, Chloroform-d) δ 8.05 (d, J = 8.1 Hz, 2H), 7.80 (d, J= 8.2 Hz, 2H), 5.19 (d, J = 4.7 Hz, 1H), 4.86 (d, J = 4.6 Hz, 1H), 3.44 (d, J= 18.4 Hz, 1H), 3.16 (d, J = 18.4 Hz, 1H), 2.07 (s, 3H), 1.49 (s, 9H).

[0093] 13 C NMR (151 MHz, Chloroform-d) δ 162.5, 161.0, 143.4, 129.6, 127.6, 126.5, 126.5, 126.5, 123.8, 83.0, 61.9, 57.0, 30.0, 27.9, 19.8.

[0094] 19 F NMR (565 MHz, Chloroform-d) δ -63.15.

[0095] Example 3

[0096] Preparation of compound 3

[0097]

[0098] In a reactor, 0.65 mmol of p-fluorobenzenesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0099] The structural characterization data of the obtained product are as follows:

[0100] 1 H NMR (600 MHz, Chloroform-d) δ 7.97 – 7.88 (m, 2H), 7.20 (t, J =8.5 Hz, 2H), 5.15 (d, J = 4.6 Hz, 1H), 4.83 (d, J = 4.6 Hz, 1H), 3.42 (d, J =18.3 Hz, 1H), 3.15 (d, J = 18.3 Hz, 1H), 2.06 (s, 3H), 1.49 (s, 9H).

[0101] 13 C NMR (151 MHz, Chloroform-d) δ 166.2, 164.5, 162.7, 161.0, 135.9,135.9, 129.9, 129.9, 129.5, 123.8, 116.6, 116.5, 82.9, 61.9, 57.0, 30.0,27.9, 19.8.

[0102] 19 F NMR (565 MHz, Chloroform-d) δ -104.27.

[0103] Example 4

[0104] Preparation of compound 4

[0105]

[0106] In a reactor, 0.65 mmol of p-chlorobenzenesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0107] The structural characterization data of the obtained product are as follows:

[0108] 1 H NMR (600 MHz, Chloroform-d) δ 7.85 (d, J = 8.3 Hz, 2H), 7.50 (d, J= 8.3 Hz, 2H), 5.15 (d, J = 4.6 Hz, 1H), 4.83 (d, J = 4.6 Hz, 1H), 3.42 (d, J= 18.4 Hz, 1H), 3.15 (d, J = 18.4 Hz, 1H), 2.07 (s, 3H), 1.49 (s, 9H).

[0109] 13 C NMR (151 MHz, Chloroform-d) δ 162.6, 161.0, 139.7, 138.4, 129.6,128.5, 123.8, 82.9, 61.9, 57.0, 30.0, 27.9, 19.8.

[0110] Example 5

[0111] Preparation of compound 5

[0112]

[0113] In a reactor, 0.65 mmol of p-tert-butylbenzenesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0114] The structural characterization data of the obtained product are as follows:

[0115] 1 H NMR (600 MHz, Chloroform-d) δ 7.83 (d, J = 8.3 Hz, 2H), 7.52 (d, J= 8.3 Hz, 2H), 5.12 (d, J = 4.6 Hz, 1H), 4.84 (d, J = 4.6 Hz, 1H), 3.41 (d, J= 18.3 Hz, 1H), 3.15 (d, J = 18.3 Hz, 1H), 2.06 (s, 3H), 1.48 (s, 9H), 1.33(s, 9H).

[0116] 13 C NMR (151 MHz, Chloroform-d) δ 162.8, 161.0, 157.0, 136.5, 129.8,127.0, 126.2, 123.8, 82.8, 62.0, 57.4, 35.1, 31.0, 30.1, 27.9, 19.8.

[0117] Example 6

[0118] Preparation of compound 6

[0119]

[0120] In a reactor, 0.65 mmol of p-cyanobenzenesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0121] The structural characterization data of the obtained product are as follows:

[0122] 1H NMR (600 MHz, Chloroform-d) δ 8.03 (d, J = 8.4 Hz, 2H), 7.83 (d, J= 8.2 Hz, 2H), 5.18 (d, J = 4.7 Hz, 1H), 4.84 (d, J = 4.6 Hz, 1H), 3.42 (d, J= 18.4 Hz, 1H), 3.16 (d, J = 18.4 Hz, 1H), 2.06 (s, 3H), 1.49 (s, 9H).

[0123] 13 C NMR (151 MHz, Chloroform-d) δ 162.6, 160.9, 144.3, 133.1, 129.6,127.66, 123.7, 117.3, 116.8, 83.0, 61.9, 56.9, 30.0, 27.9, 19.8.

[0124] Example 7

[0125] Preparation of compound 7

[0126]

[0127] In a reactor, 0.65 mmol of 2-chlorobenzenesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0128] The structural characterization data of the obtained product are as follows:

[0129] 1H NMR (600 MHz, Chloroform-d) δ 8.09 (dd, J = 7.9, 1.6 Hz, 1H), 7.59– 7.50 (m, 2H), 7.42 (td, J = 7.5, 7.1, 1.7 Hz, 1H), 5.19 (d, J = 4.7 Hz,1H), 4.86 (d, J = 4.7 Hz, 1H), 3.44 (d, J = 18.3 Hz, 1H), 3.17 (d, J = 18.3Hz, 1H), 2.07 (s, 3H), 1.49 (s, 9H).

[0130] 13 C NMR (151 MHz, Chloroform-d) δ 162.4, 161.0, 137.4, 134.2, 131.9,130.5, 127.1, 123.9, 82.9, 62.1, 57.1, 30.1, 27.9, 19.8

[0131] Example 8

[0132] Preparation of compound 8

[0133]

[0134] In a reactor, 0.65 mmol of 3,5-ditrifluoromethylbenzenesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0135] The structural characterization data of the obtained product are as follows:

[0136] 1H NMR (600 MHz, Chloroform-d) δ 8.36 (d, J = 1.6 Hz, 2H), 8.08 (s,1H), 5.23 (d, J = 4.7 Hz, 1H), 4.85 (d, J = 4.7 Hz, 1H), 3.43 (d, J = 18.8Hz, 1H), 3.16 (d, J = 18.4 Hz, 1H), 2.07 (s, 3H), 1.48 (s, 9H).

[0137] 13 C NMR (151 MHz, Chloroform-d) δ 160.9, 133.1, 132.9, 129.8, 127.4,123.8, 123.3, 121.5, 83.0, 62.1, 56.8, 30.1, 27.8, 19.8.

[0138] 19 F NMR (565 MHz, Chloroform-d) δ -62.97.

[0139] Example 9

[0140] Preparation of compound 9

[0141]

[0142] In a reactor, 0.65 mmol of 3,5-dichlorobenzenesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0143] The structural characterization data of the obtained product are as follows:

[0144] 1H NMR (600 MHz, Chloroform-d) δ 7.78 (d, J = 1.9 Hz, 2H), 7.58 (s,1H), 5.17 (d, J = 4.6 Hz, 1H), 4.86 (d, J = 4.6 Hz, 1H), 3.45 (d, J = 18.3Hz, 1H), 3.18 (d, J = 18.3 Hz, 1H), 2.08 (s, 3H).

[0145] 13 C NMR (151 MHz, Chloroform-d) δ 162.1, 160.9, 142.7, 136.2, 133.2,129.8, 125.5, 123.8, 83.0, 61.9, 56.9, 30.1, 27.9, 19.8.

[0146] Example 10

[0147] Preparation of compound 10

[0148]

[0149] In a reactor, 0.65 mmol of 1-naphthalenesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0150] The structural characterization data of the obtained product are as follows:

[0151] 1H NMR (600 MHz, Chloroform-d) δ 8.64 (d, J = 8.6 Hz, 1H), 8.30 (d, J= 7.3 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.69 (t, J= 7.7 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 5.16 (d, J= 4.5 Hz, 1H), 4.74 (d, J = 4.5 Hz, 1H), 3.34 (d, J = 18.3 Hz, 1H), 3.07 (d,J = 18.4 Hz, 1H), 2.03 (s, 3H), 1.47 (s, 9H).

[0152] 13 C NMR (151 MHz, Chloroform-d) δ 162.5, 161.0, 134.9, 134.5, 134.3,129.3, 129.1, 129.1, 128.6, 128.2, 127.1, 124.4, 124.1, 123.8, 82.8, 62.0,57.3, 30.0, 27.9, 19.7.

[0153] Example 11

[0154] Preparation of compound 11

[0155]

[0156] In a reactor, 0.65 mmol of 2-thiophene sulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0157] The structural characterization data of the obtained product are as follows:

[0158] 1H NMR (600 MHz, Chloroform-d) δ 7.69 (d, J = 2.4 Hz, 1H), 7.66 –7.60 (m, 1H), 7.14 – 7.08 (m, 1H), 5.22 (d, J = 4.6 Hz, 1H), 4.87 (d, J = 4.6Hz, 1H), 3.43 (d, J = 18.3 Hz, 1H), 3.15 (d, J = 18.3 Hz, 1H), 2.07 (s, 3H), 1.50 (s, 9H).

[0159] 13 C NMR (151 MHz, Chloroform-d) δ 162.4, 161.0, 140.3, 132.8, 132.8,129.5, 127.7, 123.9, 82.9, 62.1, 57.1, 30.1, 27.9, 19.8.

[0160] Example 12

[0161] Preparation of compound 12

[0162]

[0163] In a reactor, 0.65 mmol of pyridine-3-sulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0164] The structural characterization data of the obtained product are as follows:

[0165] 1H NMR (600 MHz, Chloroform-d) δ 9.09 (d, J = 2.4 Hz, 1H), 8.80 (dd,J = 4.9, 1.6 Hz, 1H), 8.20 (dt, J = 8.1, 2.0 Hz, 1H), 7.48 (dd, J = 8.1, 4.8Hz, 1H), 5.21 (d, J = 4.6 Hz, 1H), 4.84 (d, J = 4.6 Hz, 1H), 3.39 (d, J =18.3 Hz, 1H), 3.13 (d, J = 18.3 Hz, 1H), 2.04 (s, 3H), 1.47 (s, 9H).

[0166] 13 C NMR (151 MHz, Chloroform-d) δ 162.5, 161.0, 153.4, 147.7, 137.1,134.9, 129.5, 124.0, 123.7, 82.9, 61.9, 57.1, 30.0, 27.9, 19.7.

[0167] Example 13

[0168] Preparation of compound 13

[0169]

[0170] In a reactor, 0.65 mmol of cyclopropanesulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0171] The structural characterization data of the obtained product are as follows:

[0172] 1H NMR (600 MHz, Chloroform-d) δ 5.25 (d, J = 4.8 Hz, 1H), 4.97 (d, J= 4.7 Hz, 1H), 3.51 (dd, J = 18.3, 1.3 Hz, 1H), 3.22 (d, J = 18.3 Hz, 1H), 2.60 (tt, J = 8.0, 4.8 Hz, 1H), 2.10 (s, 3H), 1.53 (s, 9H), 1.48 (d, J = 4.4Hz, 2H), 1.28 (t, J = 4.6 Hz, 2H).

[0173] 13 C NMR (151 MHz, Chloroform-d) δ 162.5, 161.0, 133.3, 120.5, 81.2, 61.9, 58.5, 39.3, 27.9, 16.7.

[0174] Example 14

[0175] Preparation of compound 14

[0176]

[0177] In a reactor, 0.65 mmol of propylsulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0178] The structural characterization data of the obtained product are as follows:

[0179] 1H NMR (600 MHz, Chloroform-d) δ 5.23 (d, J = 4.9 Hz, 1H), 4.99 (d, J= 3.8 Hz, 1H), 3.51 (dd, J = 18.2, 1.3 Hz, 1H), 3.20 (s, 1H), 3.18 – 3.11 (m,2H), 2.11 (s, 3H), 1.91 (qd, J = 7.4, 3.7 Hz, 2H), 1.53 (s, 9H), 1.08 (t, J =7.4 Hz, 3H).

[0180] 13 C NMR (151 MHz, Chloroform-d) δ 163.7, 161.1, 129.4, 83.0, 62.2, 57.0, 56.3, 29.9, 27.9, 19.9, 17.4, 12.8.

[0181] Example 15

[0182] Preparation of compound 15

[0183]

[0184] In a reactor, 0.65 mmol of (1S)-(+)-camphor-10-sulfonyl chloride was added in batches to a stirred mixture of 0.5 mmol of compound 3, 1.3 mmol of triethylamine, 1.0 ml of water, and 0.5 ml of tetrahydrofuran (THF). After stirring the mixture at room temperature for 6 h, THF was removed by vacuum distillation. The reaction mixture was then extracted with ethyl acetate. The aqueous phase was acidified with 5 mol% hydrochloric acid and then extracted again with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by vacuum distillation and thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain the target product.

[0185] The structural characterization data of the obtained product are as follows:

[0186] 1H NMR (600 MHz, Chloroform-d) δ 5.29 (d, J = 5.2 Hz, 1H), 5.03 (d, J= 5.3 Hz, 1H), 4.04 (d, J = 15.2 Hz, 1H), 3.47 (d, J = 18.1 Hz, 1H), 3.24 (d,J = 18.1 Hz, 1H), 3.12 (d, J = 15.2 Hz, 1H), 2.45 (ddd, J = 18.7, 4.9, 2.3Hz, 1H), 2.21 – 2.17 (m, 1H), 2.11 (d, J = 4.5 Hz, 1H), 2.10 (s, 3H), 2.05 –1.95 (m, 3H), 1.91 (d, J = 18.7 Hz, 1H), 1.50 (s, 9H), 1.25 (s, 6H).

[0187] 13 C NMR (151 MHz, Chloroform-d) δ 218.3, 164.8, 161.5, 130.7, 124.2,82.9, 63.0, 60.3, 56.3, 54.4, 49.8, 43.5, 43.2, 30.3, 29.9, 28.5, 28.2, 27.3,20.4, 20.2, 19.6.

[0188] Example 16

[0189] Beneficial effects and experimental data in terms of bioactivity

[0190] To demonstrate the positive effects and pharmaceutical application potential of the compounds of general formula (I) prepared in this invention, the in vitro antibacterial activity of representative compounds of this invention was evaluated.

[0191] 1. Experimental Materials and Methods

[0192] 1. Test strains: Representative standard quality control strains and clinical drug-resistant strains were selected, including: (1) Gram-positive bacteria: Methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300; (2) Gram-negative bacteria: Klebsiella pneumoniae (ESBL) ATCC 700603.

[0193] 2. Test compounds: The final products prepared in Examples 1-23 of this invention were selected as test samples. Meanwhile, unmodified cephalosporin parent compound (compound 1) and the commercially available first-line drug cefazolin were used as control standards.

[0194] 3. Activity Assay Method: The minimum inhibitory concentration (MIC) was determined using the microbroth dilution method recommended by the Clinical Laboratory Standards Institute (CLSI). A simplified procedure is as follows: The test compound was serially diluted in Mueller-Hinton broth, inoculated with a prepared bacterial suspension (final concentration approximately 5 × 10⁵ CFU / mL), and incubated at 37 °C for 20 hours. The lowest drug concentration at which visible bacterial growth was completely inhibited was then observed and recorded.

[0195] 6.2.2 Experimental Results The table below summarizes the in vitro antibacterial activity results (MIC, μg / mL) of some representative compounds:

[0196] The structural formula of the cephalosporin parent is as follows: .

[0197] The structural formula of cefazolin is as follows: .

[0198] Results Analysis and Conclusions

[0199] 1. Practicality Confirmation: The data in Table 1 clearly show that the series of cefsulfonamide modified compounds prepared in this invention exhibit significant inhibitory activity against a variety of pathogens, proving that these compounds can produce a positive bactericidal effect.

[0200] 2. Outstanding Effect in Overcoming Drug Resistance: Compared with unmodified cephalosporin and cefazolin, several compounds of the present invention (particularly Examples 1, 2, 6, and 8) exhibit significantly enhanced antibacterial activity against clinically challenging drug-resistant strains. For example, unmodified cephalosporin and cefazolin were completely ineffective against MRSA and ESBL-producing Klebsiella pneumoniae (MIC > 64 μg / mL), while compound 2 achieved MIC values ​​of 4 μg / mL and 16 μg / mL against these two drug-resistant bacteria, respectively, representing an activity increase of more than 16-fold. This result demonstrates the effectiveness of the present invention's unique C-7 sulfonation modification strategy in overcoming resistance to β-lactam antibiotics.

[0201] 3. Structure-Activity Relationship and Innovation: The sulfonyl group (R group) with different structures has a certain influence on the activity. Aromatic sulfonyl modified compounds containing strong electron-withdrawing groups (such as trifluoromethyl and cyano groups) (Examples 2 and 7) exhibited superior antibacterial spectrum and activity against drug-resistant bacteria. This reveals a certain structure-activity relationship, which not only proves the inventiveness of the present invention, but also provides a scientific basis and clear direction for subsequent drug optimization targeting specific drug-resistant bacteria.

[0202] In summary, this invention not only provides an innovative method for modifying cephalosporins, but also demonstrates through biological experimental data that a novel class of compounds created by this method possesses good antibacterial activity, particularly showing great application potential and market value in combating clinically resistant bacteria.

[0203] In contrast, this invention uses a thionyl chloride / methanol system (referencing existing technology Wang S, Korenchan DE, Perez PM, et al. Amino Acid-Retained Sensors For Specific Zn2+ Detection Using Hyperpolarized 13C Magnetic Resonance Spectroscopy[J]. Chemistry – A European Journal, 2019, 25(51).DOI:10.1002 / chem.201902771.) to protect the carboxyl group of the cephalosporin parent material to a methyl ester. However, no methyl ester-protected intermediate was obtained, indicating insufficient chemical stability in this synthetic route.

[0204] In contrast, this invention refers to existing methods for the protection of tert-butyl ester (refer to prior art Gragan, N., Musel, D., Veinberg, GA, & Lukevics, E. (1996). A Simple Preparative Method fortert-Butyl Protection of Aminocephalosporanic Acid. Synthetic Communications, 26(6), 1183–1185. https: / / doi.org / 10.1080 / 00397919608003727), using a tert-butyl acetate / boron trifluoride diethyl ether system for the protection of tert-butyl ester, and no tert-butyl ester protected intermediate was obtained.

[0205] It should be noted that the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is impossible to exhaustively list all possible implementations here. All obvious variations or modifications derived from the technical solutions of this invention are still within the scope of protection of this invention.

Claims

1. A cephalosporin compound, characterized in that, It includes compounds, optical isomers, and pharmaceutically usable salts represented by the following general structural formulas: Wherein, R is selected from aryl, substituted aryl, 5-8 membered heteroaryl, 3-8 membered aliphatic ring, bicyclic monoterpene ketone; the number of substituents in the substituted aryl group is 1-5; the substituents in the substituted aryl group are independently selected from C1-C6 alkyl, substituted C1-C6 alkyl, halogen, cyano; the substituents in the substituted C1-C6 alkyl group are selected from halogen.

2. The cephalosporin compound according to claim 1, characterized in that, The aryl group is phenyl, naphthyl, tetrahydronaphthyl, indene, or hydroindene.

3. The cephalosporin compound according to claim 1, characterized in that, The 5-8 membered heteroaryl groups are thienyl, pyridyl, furanyl, thienyl, pyrroleyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, and indoleyl.

4. The cephalosporin compound according to claim 1, characterized in that, The 3-8 membered aliphatic rings are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the bicyclic monoterpene ketone group is... 。 5. The cephalosporin compound according to claim 1, characterized in that, R is selected from methylphenyl, trifluoromethylphenyl, fluorophenyl, chlorophenyl, tert-butylphenyl, cyanophenyl, 3,5-ditrifluoromethylphenyl, 3,5-dichlorophenyl, naphthyl, thiophene, pyridyl, cyclopropyl, propyl, 。 6. The cephalosporin compound according to claim 1, characterized in that, R is selected from substituted aryl groups and 5-8-membered heteroaryl groups; the number of substituents in the substituted aryl group is 1-5; the substituents in the substituted aryl group are independently selected from substituted C1-C6 alkyl groups, halogens, and cyano groups; the substituents in the substituted C1-C6 alkyl groups are selected from halogens; when the substituent in the substituted aryl group is one chlorine, the substitution position is not at position 2; when the substituent in the substituted aryl group is two chlorines, the substitution positions are not simultaneously at positions 3 and 5.

7. A method for preparing a cephalosporin compound as described in any one of claims 1-6, characterized in that, Includes the following steps: S1. Compound 1, Compound 2, and solvent were stirred at room temperature under N2 protection for 15-20 h. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed to obtain Compound 3. S2. Compound 3, Compound 4, base, and solvent were stirred at room temperature for 4-8 h. The mixture was then subjected to vacuum distillation, extraction, acidification, and purification to obtain the cephalosporin compound. The structural formula of Compound 1 is: The structural formula of compound 2 is: The structural formula of compound 3 is: The structural formula of compound 4 is: 。 8. The preparation method according to claim 7, characterized in that, In step S1, the molar ratio of compound 1 to compound 2 is 1-2:1-2; the solvent is dichloromethane.

9. The preparation method according to claim 7, characterized in that, In step S2, the base is one or a mixture of two of triethylamine and pyridine; the solvent is tetrahydrofuran.

10. The application of the cephalosporin compound as described in claim 1 in antibacterial activity, characterized in that, The bacteria in question are drug-resistant.

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