CN114685479B - Oxazolidinone compound as well as preparation method and application thereof - Google Patents

Oxazolidinone compound as well as preparation method and application thereof Download PDF

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CN114685479B
CN114685479B CN202011608121.6A CN202011608121A CN114685479B CN 114685479 B CN114685479 B CN 114685479B CN 202011608121 A CN202011608121 A CN 202011608121A CN 114685479 B CN114685479 B CN 114685479B
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oxazolidinone
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CN114685479A (en
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宁澄清
徐晶
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Southern University of Science and Technology
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    • C07—ORGANIC CHEMISTRY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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Abstract

The invention relates to an oxazolidinone compound or a stereoisomer and pharmaceutically acceptable salt thereof, and the structure of the oxazolidinone compound is shown as follows. The oxazolidinone compound is a new nifuratel impurity, and can further perfect the quality control of nifuratel bulk drugs and preparations on the basis of the research of traditional nifuratel impurities, and reduce the risk of clinical medication.

Description

Oxazolidinone compound as well as preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to an oxazolidinone compound, a preparation method and application thereof.
Background
Nifuratel (chemical structure shown below) is a drug developed by italian pride chemical company mainly for gynecological infections, chemical name: 5- [ (methylsulfanyl) methyl ] -3- { [ (5-nitro-2-furan) methylene ] amino } -2-oxazolidinone, chinese alias: nimonazole, nifuratel, english name Nifuratel. Nifuratel is a broad-spectrum antibiotic, especially has strong killing effect on common pathogens of gynecological infection such as gram positive and negative bacteria, trichomonas, mould, chlamydia, mycoplasma and the like, and has good curative effect on treating common gynecological vaginal infection caused by trichomonas, candida albicans, bacteria and the like. The composition can inhibit bacterial growth by interfering enzyme system, and is difficult to penetrate placenta without teratogenesis. In the present, the medicine is marketed in the form of tablets, capsules, suppositories and the like in many other countries.
The preparation of impurities is one of important links of raw material medicine and preparation quality research. Impurities can influence the quality of the raw materials, and then influence the safety of the medicines. The impurities should be thoroughly studied and the more comprehensive, the more thorough and better. The raw material medicine prepared by the production process of the original grinding medicine is subjected to full clinical research, the imitated medicine is not subjected to clinical test, and due to the difference of impurity mass spectra, certain untraced high-toxicity impurities can cause serious consequences, and the risk of the situation is high. The organic impurities in the impurities mainly comprise impurities, degradation products and the like introduced in the process, and may be known or unknown, volatile or nonvolatile. Since the chemical structure of such impurities is generally similar to or has a source relation with the active ingredient, the impurities can be generally called as related substances, and the control of the related substances is particularly important.
Disclosure of Invention
Based on this, the inventors discovered an oxazolidinone compound, a new nifuratel impurity, during the study of nifuratel preparation.
The specific technical scheme is as follows:
an oxazolidinone compound or a stereoisomer and pharmaceutically acceptable salt thereof, wherein the structure of the oxazolidinone compound is as follows:
the invention also provides application of the oxazolidinone compound or stereoisomer and pharmaceutically acceptable salt thereof in preparation of medicines with antibacterial activity.
The invention also provides a preparation method of the oxazolidinone compound or stereoisomer and pharmaceutically acceptable salt thereof, which comprises the following steps:
carrying out sulfonyl chloride chlorination reaction on the compound 1, and carrying out substitution reaction on the obtained product and methoxide to prepare a compound 2;
compound 2 is subjected to ring opening reaction under the action of H-X to prepare compound 3; wherein X represents a halogen group;
the compound 3 reacts with hydrazine hydrate, and the obtained product undergoes cyclization reaction with the compound A to prepare a compound 4;
performing condensation reaction on the compound 4 and 5-nitrofurfural to prepare the oxazolidinone compound;
wherein, the structural formula of the compound 1 is shown as follows:
the structural formula of compound 2 is shown below:
the structural formula of compound 3 is shown below:
the structural formula of the compound A is shown as follows:
r is independently selected from-O-C1-C5 alkyl, -O-halogen substituted C1-C5 alkyl or C3-C5 aza-aryl, said C3-C5 aza-aryl being linked to->Is connected with each other;
the structural formula of compound 4 is shown below:
in one embodiment, the chlorination reagent used in the chlorination reaction of sulfonyl chloride in the preparation of compound 2 is methylsulfonyl chloride and/or p-toluenesulfonyl chloride.
In one embodiment, compound 2 is prepared by quenching the sulfonyl chloride with saturated aqueous ammonium chloride after the chlorination reaction, extracting the mixture with dichloromethane, concentrating the extract, and reacting with the methylthiosalt.
In one example, compound 2 was prepared by quenching with water after completion of the substitution reaction, followed by extraction with methyl tert-butyl ether, and column chromatography purification after concentration of the extract.
In one example, during the preparation of compound 3, H-X is added as an H-X solution at a concentration of 3.5M to 4.5M to perform the ring-opening reaction.
In one example, in the process of preparing the compound 3, after the ring-opening reaction is finished, the pH of the reaction solution is adjusted to 7-9, and then dichloromethane is used for extraction, and the extract is concentrated.
In one embodiment, compound a is diethyl carbonate, dimethyl carbonate, triphosgene, or N, N' -carbonyldiimidazole during the preparation of compound 4.
In one example, in the preparation of compound 4, after the completion of the cyclization reaction, the reaction solution was concentrated, ethyl acetate was added and insoluble matters were removed by filtration, and the obtained filtrate was subjected to column chromatography purification.
In one embodiment, the solvent used in the condensation reaction is a small molecule alcohol solvent.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers an oxazolidinone compound which is a new nifuratel impurity in the preparation research process of nifuratel, can further perfect the quality control of nifuratel bulk drugs and preparations on the basis of the traditional nifuratel impurity research, and reduces the risk of clinical medication.
In addition, further researches show that the oxazolidinone compound has better antibacterial activity, and the activity result shows that the impurity has stronger antibacterial activity on gram-positive bacteria and gram-negative bacteria.
Drawings
FIG. 1 is an HPLC chromatogram for purity identification of oxazolidinones prepared in example 1;
FIG. 2 is a hydrogen spectrum of structural identification of oxazolidinones prepared in example 1;
FIG. 3 is a carbon spectrum of structural identification of oxazolidinones prepared in example 1;
fig. 4 is a high resolution mass spectrum of structural identification of oxazolidinones prepared in example 1.
Detailed Description
The oxazolidinone compounds of the invention, and methods for their preparation and use are described in further detail below with reference to the specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The term "alkyl" refers to a saturated hydrocarbon containing primary (positive) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. The phrase containing the term, for example, "C1-C5 alkyl" refers to an alkyl group containing 1 to 5 carbon atoms, which may be, for each occurrence, independently of one another, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ) 2-propyl (i-Pr, i-propyl, -CH (CH) 3 ) 2 ) 1-butyl (n-Bu, n-butyl, -CH) 2 CH 2 CH 2 CH 3 ) 2-methyl-1-propyl (i-Bu, i-butyl, -CH) 2 CH(CH 3 ) 2 ) 2-butyl (s-Bu, s-butyl, -CH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH) 3 ) 3 ) 1-pentyl (n-pentyl, -CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 )。
"aryl" refers to an aromatic hydrocarbon radical derived from the removal of one hydrogen atom on the basis of an aromatic ring compound, which may be a monocyclic aryl radical, or a fused ring aryl radical, or a polycyclic aryl radical, at least one of which is an aromatic ring system for a polycyclic species. "Azaaryl" means that at least one carbon atom is replaced by a nitrogen atom on the basis of an aryl group. For example, "C3-C5 azaheteroaryl" refers to heteroaryl groups containing 3 to 5 carbon atoms and at least one nitrogen atom.
"halo" refers to-F, -Cl, -Br or-I.
By "pharmaceutically acceptable salt" is meant a salt of any of the compounds of the indicated structure with an acid or base, which is suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. One type of salt is a salt of a compound of the invention with an acid. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another class of salts are salts of the compounds of the present invention with bases, suitable for forming the salts include, but are not limited to: alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, t-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, triethylamine, and amine salts formed from morpholine, piperazine, lysine, respectively.
The dosage form and mode of administration of the compounds of the present invention are not particularly limited. It will be appreciated that in preparing the compounds into dosage forms, a pharmaceutically acceptable carrier may be introduced.
By "pharmaceutically acceptable" is meant those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to patients and commensurate with a reasonable benefit/risk ratio.
"pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) Starches, such as corn starch, potato starch, and substituted or unsubstituted beta-cyclodextrin; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
Representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Such as suspensions, may contain suspending agents as, for example, particularly ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants. Is prepared by mixing the active ingredient under aseptic condition with pharmaceutically acceptable carrier and any preservative, buffer or propellant as required.
The invention provides an oxazolidinone compound or a stereoisomer and pharmaceutically acceptable salt thereof, wherein the structure of the oxazolidinone compound is shown as follows:
the invention discovers an oxazolidinone compound which is a new nifuratel impurity in the preparation research process of nifuratel, can further perfect the quality control of nifuratel bulk drugs and preparations on the basis of the traditional nifuratel impurity research, and reduces the risk of clinical medication.
In addition, further researches show that the oxazolidinone compound has better antibacterial activity, and the activity result shows that the impurity has stronger antibacterial activity on gram-positive bacteria and gram-negative bacteria. Therefore, the invention also provides application of the oxazolidinone compound or stereoisomer and pharmaceutically acceptable salt thereof in preparing medicines with antibacterial activity.
Furthermore, the oxazolidinone compound is used as a new nifuratel impurity, no reference substance is supplied at home and abroad, and no report on a preparation method of the impurity is disclosed in the literature and patent at home and abroad. In order to facilitate quality control of nifuratel drug substances and related substances of the preparation, reduce clinical medication risks, and provide a preparation method of a high-purity reference substance.
The invention also provides a preparation method of the oxazolidinone compound or stereoisomer and pharmaceutically acceptable salt thereof, which comprises the following steps:
carrying out sulfonyl chloride chlorination reaction on the compound 1, and carrying out substitution reaction on the obtained product and methoxide to prepare a compound 2;
compound 2 is subjected to ring opening reaction under the action of H-X to prepare compound 3; wherein X represents a halogen group;
the compound 3 reacts with hydrazine hydrate, and the obtained product undergoes cyclization reaction with the compound A to prepare a compound 4;
carrying out condensation reaction on the compound 4 and 5-nitrofurfural to prepare an oxazolidinone compound;
wherein, the structural formula of the compound 1 is shown as follows:
the structural formula of compound 2 is shown below:
the structural formula of compound 3 is shown below:
the structural formula of the compound A is shown as follows:
r is independently selected from-O-C1-C5 alkyl, -O-halogen substituted C1-C5 alkyl or C3-C5 aza-aryl, C3-C5 aza-aryl is combined with +.>Is connected with each other;
the structural formula of compound 4 is shown below:
the preparation method can rapidly, simply, conveniently and efficiently obtain the oxazolidinone compound, has the advantages of short reaction route, low energy consumption, low preparation cost, simple operation, suitability for mass preparation and high yield, and particularly the prepared nifuratel impurity has high purity, can be used as a reference substance, and is favorable for more detailed research and monitoring on the nifuratel raw material medicine and the impurity in the preparation.
In one example, the chlorination reagent used in the chlorination of sulfonyl chloride in the preparation of compound 2 is methylsulfonyl chloride and/or p-toluenesulfonyl chloride. Further, after the chlorination reaction of sulfonyl chloride is finished, the reaction is quenched by saturated ammonium chloride aqueous solution, then extracted by dichloromethane, and the extract is concentrated and then reacted with methylthiosalt. Specifically, the extract may be concentrated and reacted with a methoxide without further purification.
Further, the reaction temperature of the sulfonyl chloride chlorination reaction is 0 to 5 ℃. Still further, the sulfonyl chloride chlorination reaction is conducted under basic conditions, which may be provided by, for example, triethylamine.
In one example, the methoxide is sodium methyl mercaptide.
In one example, compound 2 is prepared by quenching with water after the substitution reaction, extracting with methyl tert-butyl ether, concentrating the extract, and purifying by column chromatography. Further, the reaction temperature of the sulfonyl chloride chlorination reaction is room temperature (such as 20 ℃ to 30 ℃). Further, the eluent used in the column chromatography purification is petroleum ether and ethyl acetate with the volume ratio of (10-20): 1.
In one example, during the preparation of compound 3, H-X is added as an H-X solution at a concentration of 3.5M to 4.5M to perform the ring-opening reaction. Specifically, H-X is hydrochloric acid, and the solvent used may be dioxane. Further, after the ring-opening reaction is finished, the pH of the reaction solution is adjusted to 7-9, and then dichloromethane is used for extraction, and the extract is concentrated. Specifically, the extract may be concentrated and then subjected to the next step without further purification.
In one example, compound a is diethyl carbonate, dimethyl carbonate, triphosgene, or N, N' -carbonyldiimidazole during the preparation of compound 4. Further, the reaction temperature of the cyclization reaction is 75-85 ℃. Further, the cyclization reaction adopts sodium methoxide for catalytic reaction. Further, after the completion of the cyclization reaction, the reaction solution was concentrated, ethyl acetate was added and insoluble matters were removed by filtration, and the obtained filtrate was purified by column chromatography. Specifically, the eluent adopted by the column chromatography purification is petroleum ether and ethyl acetate with the volume ratio of 1 (2-5).
In one example, the solvent used in the condensation reaction is a small molecule alcohol solvent. Further, the small molecule alcohol solvent is ethanol. Specifically, a large amount of solids are separated out from the solvent after the condensation reaction is finished, and the separated solids are collected, washed and dried to obtain the oxazolidinone compounds.
The following are specific examples, and all materials used in the examples are commercially available products unless otherwise specified. The preparation route of the oxazolidinone compound in the examples can be shown as follows:
example 1
The embodiment is a preparation method of an oxazolidinone compound, which comprises the following steps:
(1) Preparation of oxetane-3-methylthio (2)
10g of oxetan-3-ol was dissolved in 100mL of anhydrous Dichloromethane (DCM), 29.2mL of Triethylamine (TEA) was added, the temperature of the reaction solution was controlled at 0-4℃in an ice bath, 11.48mL of methylsulfonyl chloride (MsCl) was slowly dropped, the reaction was quenched by adding saturated aqueous ammonium chloride solution for 3 times after 1 hour, the dichloromethane layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and used directly for the next reaction without purification.
The reaction product obtained in the previous step was dissolved in 180mL of DMF, 13.3g of sodium methyl mercaptide was added and stirred at room temperature overnight. After the TLC was followed by completion of the reaction, the reaction was quenched with water, extracted 3 times with methyl t-butyl ether, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 10.6g (petroleum ether: ethyl acetate=15:1) of a colorless oily liquid in 76% yield.
(2) Preparation of 3-chloro-2-methylsulfanyl-propanol (3)
1.5g of oxetane-3-methylthio was dissolved in 20mL of anhydrous DCM, and a 4M hydrochloric acid-dioxane solution was added dropwise under ice-bath conditions, and after the addition, the ice bath was removed and the reaction was carried out at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to adjust the pH to about 8, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and used directly in the next reaction without purification.
(3) Preparation of N-amino-5-methylsulfanyl-2-oxazinidinone (4)
The reaction product obtained in the previous step was dissolved with 20mL of ethanol-water (v/v=1:1), 10mL of hydrazine hydrate was added, and reacted at room temperature, and after half an hour, concentrated under reduced pressure, and the obtained product was directly used in the next step.
20mL of Tetrahydrofuran (THF) is added to dissolve the product obtained in the last step, 16.5mL of diethyl carbonate is added under stirring, the temperature is raised to 80 ℃, then 5.2mL of 30% sodium methoxide methanol solution is slowly added dropwise, the reaction is maintained at the temperature for overnight, after the TLC monitoring reaction is finished, the reaction is cooled to room temperature, after the solvent is removed after decompression concentration, 20mL of ethyl acetate is added, filtration is carried out, and after the filtrate is decompressed concentration, the product of 0.9g (petroleum ether: ethyl acetate=1:3) is obtained after purification by silica gel column chromatography. ESI-MS m/z 163[ M+H ]] + .
(4) Preparation of oxazolidinones (nifuratel impurity)
Dissolving 150mg of N-amino-5-methylthio-2-oxazinidone in 5mL of absolute ethanol solution, adding 131mg of 5-nitrofurfural, stirring at room temperature for reaction, separating out yellow solid after 10min, filtering after the reaction is monitored by LC-MS, washing filter residues with glacial ethanol, and drying to obtain 210mg of yellow solid.
Purity and structure identification patterns are shown in figures 1-4. It can be seen that the HPLC purity of the nifuratel impurity>99％。ESI-MS m/z:286[M+H] + ； 1 H NMR(DMSO-d 6 ,400MHz)δ8.11(s,1H),7.78(d,J＝4.0Hz,1H),7.12(d,J＝4.0Hz,1H),4.49(m,1H),4.25(t,J＝8.0Hz,1H),4.02(m,1H),3.59(m,2H),2.21(s,3H)； 13 C NMR(DMSO-d 6 ,100MHz)δ152.8,152.2,149.4,131.6,115.2,115.1,68.5,49.9,36.8,13.5；HRMS m/z:calcd.for C 10 H 12 N 3 O 5 S[M+H]286.0492,found 286.0490.
Example 2
The present embodiment is a method for preparing an oxazolidinone compound, and the steps are the same as those in embodiment 1, and the main difference is that: in the step (3), triphosgene is used for replacing diethyl carbonate to carry out a cyclization reagent.
The method comprises the following specific steps:
(1) As in example 1.
(2) Preparation of 3-chloro-2-methylsulfanyl-propanol (3)
1.5g of oxetane-3-methylthio was dissolved in 20mL of anhydrous DCM, and a 4M hydrochloric acid-dioxane solution was added dropwise under ice-bath conditions, and after the addition, the ice bath was removed and the reaction was carried out at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to adjust the pH to about 8, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and used directly in the next reaction without purification.
(3) Preparation of N-amino-5-methylsulfanyl-2-oxazinidinone (4)
The reaction product obtained in the previous step was dissolved with 20mL of ethanol-water (v/v=1:1), 10mL of hydrazine hydrate was added, and reacted at room temperature, after half an hour, concentrated under reduced pressure, and the obtained product (compound 7) was directly used in the next step of reaction.
The product from the previous step was dissolved in 15mL of methylene chloride, TEA (2.12 g) was added, triphosgene (1 g) was then added dropwise under ice bath, and after the addition was completed, the reaction was continued under ice bath, and TLC was used to detect the progress of the reaction. After the reaction, the reaction mixture was quenched by adding a saturated aqueous ammonium chloride solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 42mg of the product (petroleum ether: ethyl acetate=1:3).
Antibacterial activity experiment:
antibacterial drug to be tested: oxazolidinone compound prepared in example 1.
The determination of the Minimum Inhibitory Concentration (MIC) is determined by a double dilution method, and the specific operation method is as follows: 10 test tubes with the diameter of 13mm multiplied by 100mm are adopted; the first test tube is a blank tube, and 2mL of LB culture solution is added into each test tube from the second test tube; an ethanol solution (20 mM) of the antibacterial agent to be tested was diluted with LB medium to a concentration of 128. Mu.g/mL to be tested, and 2mL was added to the first and second test tubes, respectively. After the antibacterial drug to be detected is added, the antibacterial drug to be detected in the second pipe is evenly mixed with LB culture solution, then 2mL is sucked out and added into the third pipe, the mixture is analogically diluted to the 10 th pipe, the 10 th pipe is evenly mixed, and then 2mL is sucked out and discarded, namely the final concentration of the antibacterial drug in each pipe is 128 mug/mL, 64 mug/mL, 32 mug/mL, 16 mug/mL, 8 mug/mL, 4 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL and 0.25 mug/mL in sequence.
10 test tubes were taken and blank solvent control tubes of different concentrations were prepared as described above. And taking 3 test tubes, and respectively making an LB culture solution control (only LB), a detection bacteria growth control (LB+bacteria) and an LB+medicine control (LB+medicine).
Inoculating: taking 0.1mL of bacterial liquid with proper concentration, sequentially adding the bacterial liquid from low concentration to high concentration into a test tube, and finally inoculating bacterial amount to be 5 multiplied by 10 -5 CFU/mL. After incubation for 24h at 35℃the results were observed.
After the incubation, the lowest drug concentration at which no bacterial growth was observed visually was the MIC of the drug for the test bacteria.
The results obtained according to the experimental method show that the antibacterial drug to be tested has stronger antibacterial activity on staphylococcus aureus and escherichia coli, and MIC values are 8 mug/mL and 2 mug/mL respectively.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (10)

1. An oxazolidinone compound or a pharmaceutically acceptable salt thereof, the oxazolidinone compound having the structure shown below:
2. the use of an oxazolidinone compound or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a medicament with antibacterial activity against staphylococcus aureus and escherichia coli.
3. The method for preparing an oxazolidinone compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the method for preparing the oxazolidinone compound comprises the following steps:
carrying out sulfonyl chloride chlorination reaction on the compound 1, and carrying out substitution reaction on the obtained product and methoxide to prepare a compound 2;
compound 2 is subjected to ring opening reaction under the action of H-X to prepare compound 3; wherein X represents a halogen group;
the compound 3 reacts with hydrazine hydrate, and the obtained product undergoes cyclization reaction with the compound A to prepare a compound 4;
performing condensation reaction on the compound 4 and 5-nitrofurfural to prepare the oxazolidinone compound;
wherein, the structural formula of the compound 1 is shown as follows:
the structural formula of compound 2 is shown below:
the structural formula of compound 3 is shown below:
the structural formula of the compound A is shown as follows:
r is independently selected from-O-C1-C5 alkyl, -O-halogen substituted C1-C5 alkyl or C3-C5 aza-aryl, said C3-C5 aza-aryl being attached to->Is connected with each other;
the structural formula of compound 4 is shown below:
4. a process for the preparation of an oxazolidinone compound or a pharmaceutically acceptable salt thereof according to claim 3 where the chlorinating reagent used in the sulfonyl chloride chlorination reaction is methylsulfonyl chloride and/or p-toluenesulfonyl chloride in the process of preparing compound 2.
5. The process for preparing oxazolidinone compounds or pharmaceutically acceptable salts thereof according to claim 4, wherein in the process of preparing compound 2, the sulfonyl chloride is quenched with saturated aqueous ammonium chloride solution after chlorination, extracted with dichloromethane, and the extract is concentrated and then reacted with the methylthiosalt.
6. The process for preparing oxazolidinone compounds or pharmaceutically acceptable salts thereof according to claim 4, wherein in the process of preparing compound 2, water quenching reaction is carried out after the substitution reaction is finished, then methyl tertiary butyl ether extraction is carried out, and the extract is concentrated and then subjected to column chromatography purification.
7. A process for the preparation of an oxazolidinone compound or a pharmaceutically acceptable salt thereof according to claim 3 where H-X is formulated in a solution of H-X at a concentration of 3.5M to 4.5M for ring opening reaction during the preparation of compound 3.
8. The process for preparing an oxazolidinone compound or pharmaceutically acceptable salt thereof according to claim 7, wherein the pH of the reaction solution is adjusted to 7-9 after the ring opening reaction is completed in the process of preparing the compound 3, and then the reaction solution is extracted with dichloromethane, and the extract solution is concentrated.
9. The method for preparing an oxazolidinone compound or pharmaceutically acceptable salt thereof according to any of claims 3 to 8, wherein compound a is diethyl carbonate, dimethyl carbonate, triphosgene or N, N' -carbonyldiimidazole during the process of preparing compound 4.
10. The process for producing an oxazolidinone compound or pharmaceutically acceptable salt thereof according to claim 9, wherein in the process for producing compound 4, after the cyclization reaction is completed, the reaction solution is concentrated, ethyl acetate is added and insoluble matter is removed by filtration, and the obtained filtrate is purified by column chromatography.
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US2702292A (en) * 1953-08-05 1955-02-15 Norwich Pharma Co Nu-(5-nitro-2-furfurylidene)-3-amino-3, 4, 5, 6,-tetrahydro-1, 3,-oxazine-2-one
CN1169488A (en) * 1996-07-03 1998-01-07 天津服装研究所 Anti-bacterial odour-proof and easy-to-remove-dirt fabric, preparation method and products thereof
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US2702292A (en) * 1953-08-05 1955-02-15 Norwich Pharma Co Nu-(5-nitro-2-furfurylidene)-3-amino-3, 4, 5, 6,-tetrahydro-1, 3,-oxazine-2-one
CN1169488A (en) * 1996-07-03 1998-01-07 天津服装研究所 Anti-bacterial odour-proof and easy-to-remove-dirt fabric, preparation method and products thereof
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