CN115286544A - Florfenicol derivative, preparation method and application thereof in resisting bacterial infection - Google Patents
Florfenicol derivative, preparation method and application thereof in resisting bacterial infection Download PDFInfo
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- CN115286544A CN115286544A CN202211219200.7A CN202211219200A CN115286544A CN 115286544 A CN115286544 A CN 115286544A CN 202211219200 A CN202211219200 A CN 202211219200A CN 115286544 A CN115286544 A CN 115286544A
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- florfenicol
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- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical class CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 208000022362 bacterial infectious disease Diseases 0.000 title claims abstract description 8
- 208000035143 Bacterial infection Diseases 0.000 title claims abstract description 7
- 229960003760 florfenicol Drugs 0.000 claims abstract description 41
- 230000032050 esterification Effects 0.000 claims abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 16
- 230000010933 acylation Effects 0.000 claims abstract description 14
- 238000005917 acylation reaction Methods 0.000 claims abstract description 14
- 238000009833 condensation Methods 0.000 claims abstract description 14
- 230000005494 condensation Effects 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000012074 organic phase Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 239000012141 concentrate Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical group ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 229940014800 succinic anhydride Drugs 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- -1 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride Chemical class 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 5
- 239000013078 crystal Substances 0.000 claims 2
- 241001465754 Metazoa Species 0.000 abstract description 13
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002552 dosage form Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 7
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WCGGWVOVFQNRRS-UHFFFAOYSA-N dichloroacetamide Chemical compound NC(=O)C(Cl)Cl WCGGWVOVFQNRRS-UHFFFAOYSA-N 0.000 description 6
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 5
- 206010059866 Drug resistance Diseases 0.000 description 5
- 241000282887 Suidae Species 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940124350 antibacterial drug Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- JILXUIANNUALRZ-UHFFFAOYSA-N n',n'-diethylbutane-1,4-diamine Chemical compound CCN(CC)CCCCN JILXUIANNUALRZ-UHFFFAOYSA-N 0.000 description 1
- GCOWZPRIMFGIDQ-UHFFFAOYSA-N n',n'-dimethylbutane-1,4-diamine Chemical compound CN(C)CCCCN GCOWZPRIMFGIDQ-UHFFFAOYSA-N 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical class CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a florfenicol derivative, a preparation method and application of the florfenicol derivative in resisting bacterial infection, and relates to the field of florfenicol derivatives. The preparation method of the florfenicol derivative comprises the following steps: esterification step and condensation acylation step. Compared with florfenicol, the antibacterial effect of the florfenicol derivative is obviously enhanced; compared with florfenicol, the water solubility is obviously improved, and the florfenicol is easy to prepare into various dosage forms; after the florfenicol derivative enters the animal body, the florfenicol derivative can be effectively converted into florfenicol and is easy to absorb.
Description
Technical Field
The invention relates to the field of heterocyclic compound preparation, and particularly relates to a florfenicol derivative, a preparation method and application thereof in resisting bacterial infection.
Background
Florfenicol (Florfenicol), chemical name 2, 2-dichloro-N- [ (1r, 2s) -3-fluoro-1-hydroxy-1- (4-methylsulfonylphenyl) -2-propyl]Acetamide with molecular formula C 12 H 14 Cl 2 FNO 4 And S. Florfenicol is a synthetic monofluoro derivative of thiamphenicol, is white or grey white crystalline powder, and is a special broad-spectrum antibacterial drug of chloramphenicol for animals, which is successfully developed in the late eighties.
Florfenicol is used as an antibiotic special for animals, has a wide antibacterial spectrum, and is widely applied to veterinary clinical prevention and treatment of bacterial infectious diseases of animals such as fish, chicken, pigs, cattle and the like. However, due to the excessive use of antibacterial drugs, a series of problems such as the generation of a large amount of drug resistance and the reduction of the curative effect of antibiotics are caused, and serious threats are caused to the health of human beings and animals; therefore, how to avoid the generation of drug resistance while ensuring the antibacterial capability of the florfenicol product is a technical problem in the field of veterinary drugs. Meanwhile, the florfenicol has poor water solubility and inconvenient clinical use, and a water-soluble florfenicol product with excellent development performance is also a research hotspot in the field of veterinary medicines.
Further, the applicant finds that the existing florfenicol product has unsatisfactory absorption speed after entering the body of an animal, the florfenicol in the blood of the animal has long time to reach the ideal concentration, and the drug effect is slow.
Therefore, the florfenicol derivative is developed, so that the antibacterial capability of a florfenicol product can be ensured, and meanwhile, the generation of drug resistance can be avoided; meanwhile, the water solubility of the florfenicol product is improved, the absorption speed of animals on the florfenicol product is improved, the time for the florfenicol in animal blood to reach the ideal concentration is shortened, the drug effect taking speed is improved, and the florfenicol product has great significance.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a florfenicol derivative, a preparation method and application thereof in resisting bacterial infection, so as to realize the following purposes:
(1) The florfenicol antibacterial ability is ensured, and meanwhile, the generation of drug resistance is avoided;
(2) Improving the water solubility of the florfenicol product;
(3) Improve the absorption speed of animals to the florfenicol, shorten the time for the florfenicol in the blood of the animals to reach the ideal concentration, thereby improving the effect taking speed of the drug.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a florfenicol derivative having the structural formula:
wherein the structural formula of the florfenicol derivative is one of the following formulas:
n=2，a=2，b=c=0；
n=2，a=3，b=c=0；
n=2，a=3，b=c=1。
the preparation method of the florfenicol derivative comprises the following steps: esterification step and condensation acylation step.
The method of the esterification step comprises the steps of putting florfenicol and anhydride into a solvent, adding a first catalyst under the condition of stirring, heating to 40-90 ℃, and carrying out heat preservation reflux reaction for 2-8 hours; concentrating under reduced pressure at 50 deg.C under vacuum degree of 0.07-0.08MPa to obtain concentrate; adding the concentrate into 150mL of 50% ethanol water solution, crystallizing at 20-25 deg.C under stirring at 50-100rpm for 4-8h, filtering to obtain solid, and drying until the mass is unchanged to obtain compound II.
The compound II has the following structural formula:
in the structural formula of the compound II, n =2.
In the esterification step, the anhydride is succinic anhydride;
in the esterification step, the solvent is acetone;
in the esterification step, the first catalyst is 4-dimethylaminopyridine;
in the esterification step, the molar ratio of florfenicol to anhydride is 1-1.5;
in the esterification step, the ratio of the first catalyst to the florfenicol by weight part is 0.01-0.1.
Dissolving a compound II and a compound III in a solvent, adding a second catalyst, and stirring and reacting at the temperature of 0-35 ℃ and 100-200rpm for 4-8h to prepare a reaction solution; extracting the reaction solution with extractant for 2 times, and mixing organic phases; then washing the organic phase by adopting a saturated sodium bicarbonate solution or a saturated sodium chloride solution, separating out the organic phase, drying the organic phase by adopting anhydrous sodium sulfate until the moisture content is 1-2wt%, and concentrating until the quality is unchanged; then putting into 50% isopropanol solution, stirring and crystallizing at 50-100rpm for 4-8h at 20-25 ℃, filtering out solid, and drying at 50 ℃ for 8h to obtain the compound I.
The compound III has the following structural formula:
the structural formula of the compound III is one of the following: a =2,b = c =0; a =3,b = c =0; a =3,b = c =1.
The compound I is the florfenicol derivative;
in the condensation acylation step, the second catalyst is: 1-hydroxybenzotriazole, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, triethylamine;
in the condensation acylation step, an extracting agent is ethyl acetate;
in the condensation acylation step, the molar ratio of the compound II to the compound III is 1-1.5;
in the condensation acylation step, the molar ratio of the second catalyst to the compound II is 1-1.1.
The application of the florfenicol derivative in resisting bacterial infection is disclosed.
Compared with the prior art, the invention has the following beneficial effects:
(1) Compared with florfenicol, the florfenicol derivative provided by the invention has a remarkably enhanced antibacterial effect.
(2) Compared with florfenicol, the florfenicol derivative provided by the invention has the advantages that the water solubility is obviously improved, and the florfenicol derivative is easy to prepare into various dosage forms.
(3) According to the florfenicol derivative disclosed by the invention, the structure of the florfenicol is modified, so that after drug molecules enter an animal body, the florfenicol derivative can be well converted into the florfenicol, and is easy to absorb; after intravenous injection for 1-1.5h, the concentration of florfenicol in animal blood can reach 20-25 mug/mL, the drug effect is quick, and the half-life period is long; the florfenicol derivative of the florfenicol derivative can penetrate cell membranes of bacteria more easily, and can avoid drug resistance while ensuring antibacterial ability.
(4) The preparation method of the florfenicol derivative has the advantages of easily available raw materials, mild reaction conditions and simple process, and can meet the requirements of large-scale industrial production.
Drawings
FIG. 1 is a reaction scheme for the preparation of florfenicol derivatives according to the present invention;
in the figure: compound I is a florfenicol derivative; compound IV is florfenicol.
FIG. 2 is a nuclear magnetic hydrogen spectrum of the compound I-1 in example 1.
FIG. 3 is the nuclear magnetic carbon spectrum of compound I-1 in example 1.
FIG. 4 is a nuclear magnetic hydrogen spectrum of Compound I-2 in example 2.
FIG. 5 is the nuclear magnetic carbon spectrum of compound I-2 in example 2.
FIG. 6 is a nuclear magnetic hydrogen spectrum of Compound I-3 in example 3.
FIG. 7 is a nuclear magnetic carbon spectrum of compound I-3 of example 3.
FIG. 8 is a graph showing the florfenicol derivative concentration, florfenicol concentration in plasma of test pigs with time after administration of compound I-1 prepared in example 1 in a predetermined dose in test example 1.
FIG. 9 is a graph showing the florfenicol derivative concentration, florfenicol concentration in plasma of test pigs over time, after administration of compound I-2 prepared in example 1 in a predetermined dose in test example 2.
FIG. 10 is a graph showing the florfenicol derivative concentration, florfenicol concentration in plasma of test pigs with time after administration of compound I-3 prepared in example 1 in a predetermined dose in test example 3.
Detailed Description
Technical features, objects, and effects of the present invention will be more clearly understood and appreciated by those skilled in the art, which are described in the following description and drawings. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Example 1
A florfenicol derivative is prepared by the following preparation method:
1. step of esterification
Dissolving 50g of florfenicol and 14g of succinic anhydride in 500mL of acetone, adding 2g of 4-dimethylaminopyridine under the condition of stirring, heating to 40 ℃, and carrying out heat preservation reflux reaction for 8 hours; concentrating under reduced pressure at 50 deg.C under 0.07MPa to obtain concentrate; the concentrate was added to 150mL of a 50% aqueous ethanol solution, crystallized with stirring at 50rpm at 20 ℃ for 8 hours, and the solid was filtered off and dried until the mass did not change, whereby 52.45g of a white solid (i.e., compound II-1) was obtained.
In the compound II-1, n =2.
2. Condensation acylation step
Dissolving 46g of compound II-1 and 9g of compound III-1 (N, N-dimethylethylenediamine) in 500mLN, N-dimethylformamide, adding 15g of 1-hydroxybenzotriazole, 21.1g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 50g of triethylamine, stirring at the temperature of 0 ℃ and 100rpm for 8 hours, and preparing a reaction solution after the reaction is finished; extracting the reaction solution with ethyl acetate for 2 times, each time with 100mL, and combining organic phases; then washing the organic phase for 1 time by adopting 100mL saturated salt solution, separating out the organic phase, drying the organic phase by using anhydrous sodium sulfate until the moisture content is between 1 and 2 weight percent, and concentrating until the mass is unchanged; then, the mixture was added to a 50% isopropyl alcohol solution, crystallized with stirring at 50rpm at 20 ℃ for 8 hours, and the solid was filtered off and dried at 50 ℃ for 8 hours to obtain 47g of Compound I-1 (2- (2, 2-dichloroacetamide) -3-fluoro-1- (4-methanesulfonylphenyl) propyl 3- { [2- (dimethylamino) ethyl ] carbamoyl } propionate) as an off-white solid.
In the compound III-1, a =2,b = c =0.
In the compound I-1, n =2,a =2,b = c =0.
The nuclear magnetic resonance results of the compound I-1 are as follows:
1 H NMR（CDCl 3 ）δ7.96（s，1H）、7.86（d，J＝6Hz，2H）、7.6（d，J＝6Hz，2H）、7.28（d，J＝6Hz，1H）、5.88（s，1H）、4.67-4.47（m，2H）、4.34（d，J=12Hz，1H）、3.63（d，J＝6Hz，2H）、3.06（s，3H）、2.71（s，4H）、2.5 （t，J＝6Hz，2H）、2.23 （s，6H）。
13 C NMR（CDCl 3 ） δ29.7，31.5，36.6，45.4，55，55.1，56.2，66.2，70.1，81.9，127.1，127.5，139.9，147.4，162.6，164.5，177.4。
example 2
A florfenicol derivative is prepared by the following preparation method:
1. step of esterification
Dissolving 50g of florfenicol and 17.5g of succinic anhydride in 500mL of acetone, adding 2g of 4-dimethylaminopyridine under the condition of stirring, heating to 60 ℃, and carrying out heat preservation reflux reaction for 4 hours; concentrating under reduced pressure at 50 deg.C under 0.075MPa to obtain concentrate; the concentrate was added to 150mL of a 50% aqueous ethanol solution, crystallized with stirring at 80rpm at 22 ℃ for 6 hours, and the solid was filtered off and dried until the mass did not change, whereby 53.23g of a white solid (i.e., compound II-2) was obtained.
In the compound II-2, n =2.
2. Condensation acylation step
Dissolving 23g of compound II-2 and 6.15g of compound III-2 (4-dimethylaminobutylamine) in 250mLN and N-dimethylformamide, adding 7.5g of 1-hydroxybenzotriazole, 10.5g of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride and 25g of triethylamine, stirring for 6h at the temperature of 20 ℃ and the rpm of 150, and preparing a reaction solution after the reaction is finished; extracting the reaction solution with ethyl acetate for 2 times, 50mL each time, and combining organic phases; then washing the organic phase for 1 time by adopting 40mL of saturated saline solution, separating the organic phase out, drying the organic phase by using anhydrous sodium sulfate until the moisture content is between 1 and 2 weight percent, and concentrating until the quality is unchanged; then, the mixture was added to a 50% aqueous isopropanol solution, crystallized with stirring at 80rpm at a temperature of 22 ℃ for 6 hours, and the solid was filtered off and dried at a temperature of 50 ℃ for 8 hours to obtain 21.5g of an off-white solid, i.e., compound I-2 (2- (2, 2-dichloroacetamide) -3-fluoro-1- (4-methanesulfonylphenyl) propyl 3- { [3- (dimethylamino) propyl ] carbamoyl } propionate).
In the compound III-2, a =3,b = c =0.
In the compound I-2, n =2, a =3, b = c =0.
The nuclear magnetic resonance results of the compound I-2 are as follows:
1 H NMR（CDCl 3 ） δ7.98（s，1H）、7.88（d，J＝6Hz，2H）、7.63（d，J＝6Hz，2H）、7.47（d，J＝12Hz，2H）、5.93（s，1H）、5.16（s，1H）、4.68-4.35（m，2H）、3.18（t，J=Hz，2H）、3.04（s，3H）、2.33（d，J=6Hz，2H）、2.29（d，J=6Hz，2H）、2.23（d，J=6Hz，2H）、2.18（s，6H）、1.74（t，J=6Hz，2H）。
13 C NMR（CDCl 3 ） δ25.6，28.2，31.4，36.5，44.5，45.3，55.0，57.0，66.2，69.8，81.7，127.1，127.4，139.7，147.8，162.6，164.5，177.3。
example 3
A florfenicol derivative is prepared by the following preparation method:
1. step of esterification
Dissolving 50g of florfenicol and 17.5g of succinic anhydride in 500mL of acetone, adding 2g of 4-dimethylaminopyridine under the stirring condition, heating to 90 ℃, and carrying out heat preservation reflux reaction for 2 hours; concentrating under reduced pressure at 50 deg.C under 0.08MPa to obtain concentrate; adding the concentrate into 150mL 50% ethanol solution, stirring at 100rpm at 25 deg.C for crystallization for 4h, filtering to obtain solid, and drying until the mass is unchanged to obtain white solid 55.23g compound II-3;
in the compound II-3, n =2.
2. Condensation acylation step
Dissolving 23g of compound II-3 and 7.6g of compound III-3 (N, N-diethylbutane-1, 4-diamine) in 250mLN, N-dimethylformamide, adding 7.5g of 1-hydroxybenzotriazole, 10.5g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 25g of triethylamine, stirring at the temperature of 35 ℃ and 200rpm for 4 hours, and obtaining a reaction solution after the reaction is finished; extracting the reaction solution with ethyl acetate for 2 times, 50mL each time, and combining organic phases; then washing the organic phase for 1 time by adopting 40mL of saturated saline solution, separating the organic phase out, drying the organic phase by using anhydrous sodium sulfate until the moisture content is between 1 and 2 weight percent, and concentrating until the quality is unchanged; then, the mixture was added to a 50% aqueous isopropanol solution, crystallized with stirring at 100rpm at 25 ℃ for 4 hours, filtered off the solid, and dried at 50 ℃ for 8 hours to obtain 22.65g of Compound I-3 (2- (2, 2-dichloroacetamide) -3-fluoro-1- (4-methanesulfonylphenyl) propyl 3- { [3- (diethylamino) propyl ] carbamoyl } propionate).
In the compound III-1, a =3,b = c =1.
In the compound I-1, n =2, a =3, b = c =1.
The nuclear magnetic resonance results of the compound I-3 are as follows:
1 H NMR（CDCl 3 ） δ7.99（s，1H）、7.89（d，J＝6Hz，2H）、7.62（d，J＝6Hz，2H）、7.28（d，J＝12Hz，1H）、7.27（d，J=6Hz，1H）、5.87 （s，1H）、5.17（m，1H）、4.67-4.47（m，2H）、3.69（s，2H）、3.53（s，3H）、2.51（d，J=6Hz，2H）、2.49（d，J=6Hz，2H）、2.44（t，J=6Hz，2H）、1.74（t，J=6Hz，2H）、1.70（t，J=6Hz，4H）、0.99（t，J=6Hz，6H）。
13 C NMR（CDCl 3 ） δ11.5，25.1，28.2，31.5，37.4，46.6，50.3，55.0，55.1，66.2，69.9，81.8，127.0，127.5，140.0，162.6，164.4，177.3。
test example 1
The florfenicol derivatives prepared in examples 1-3 were each dissolved in distilled water to prepare a solution having a concentration of 500mg/mL. Selecting 3 healthy test pigs with the weight of 15-18kg, and carrying out intravenous injection according to the dose of 10mg/kg of body weight. Within 12h after the administration, blood of each test pig was collected every hour, plasma was separated, and the concentration of the florfenicol derivative and the concentration of florfenicol in the plasma were measured. The specific result is shown in figures 8-10 in the specification.
All percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described above, or equivalents may be substituted for elements thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. A florfenicol derivative is characterized by having a structural formula as follows:
wherein the structural formula of the florfenicol derivative is one of the following formulas:
n=2，a=2，b=c=0；
n=2，a=3，b=c=0；
n=2，a=3，b=c=1；
the preparation method of the florfenicol derivative comprises the following steps: esterification step, condensation acylation step;
the method of the esterification step comprises the steps of putting florfenicol and anhydride into a solvent, adding a first catalyst under the condition of stirring, heating to 40-90 ℃, and carrying out heat preservation reflux reaction for 2-8 hours; concentrating at 50 deg.C under vacuum degree to obtain concentrate; adding the concentrate into ethanol water solution, stirring at 20-25 deg.C for crystallizing until no crystal is precipitated, filtering to obtain solid, and drying until the quality is unchanged to obtain compound II;
the compound II has the following structural formula:
in the structural formula of the compound II, n =2;
dissolving a compound II and a compound III in a solvent, adding a second catalyst, and stirring for reacting for 4-8h at the temperature of 0-35 ℃ to prepare a reaction solution; extracting the reaction solution with extractant for 2 times, and mixing organic phases; then washing an organic phase by adopting a saturated sodium bicarbonate solution or a saturated sodium chloride solution, separating the organic phase, drying the organic phase by adopting anhydrous sodium sulfate until the moisture content is 1-2wt%, and concentrating until the quality is unchanged; then putting the mixture into 50% isopropanol solution, stirring and crystallizing at the temperature of 20-25 ℃ until no crystal is separated out, filtering out solid, and drying until the mass is unchanged to prepare a compound I;
the compound III has the following structural formula:
the structural formula of the compound III is one of the following: a =2,b = c =0; a =3, b = c =0; a =3, b = c =1;
the compound I is a florfenicol derivative.
2. A florfenicol derivative according to claim 1 wherein in the esterification step, the anhydride is succinic anhydride; the solvent is acetone; the first catalyst is 4-dimethylaminopyridine.
3. A florfenicol derivative according to claim 1 wherein in the esterification step, the molar ratio of florfenicol to anhydride is from 1 to 1.5;
in the esterification step, the weight part ratio of the first catalyst to the florfenicol is 0.01-0.1.
4. A florfenicol derivative according to claim 1 wherein in the condensation acylation step, the second catalyst is: a mixture of 1-hydroxybenzotriazole, 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride, triethylamine;
the weight ratio of the 1-hydroxybenzotriazole to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the triethylamine is 7.5-15.
5. The florfenicol derivative of claim 1 wherein in the condensation acylation step, the molar ratio of compound ii to compound iii is 1;
in the condensation acylation step, the molar ratio of the second catalyst to the compound II is 1-1.1.
6. The florfenicol derivative of claim 1 wherein in the step of condensation acylation, the extractant is ethyl acetate.
7. Use of a florfenicol derivative for combating bacterial infections, using a florfenicol derivative according to any of claims 1-6.
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| CN116178309A (en) * | 2023-02-20 | 2023-05-30 | 华中农业大学 | Florfenicol derivative with good water solubility and preparation method and application thereof |
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| US20050182031A1 (en) * | 2003-12-23 | 2005-08-18 | Schering-Plough Animal Health Corporation | Florfenicol prodrug having improved water solubility |
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| US20050182031A1 (en) * | 2003-12-23 | 2005-08-18 | Schering-Plough Animal Health Corporation | Florfenicol prodrug having improved water solubility |
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| CN116178309A (en) * | 2023-02-20 | 2023-05-30 | 华中农业大学 | Florfenicol derivative with good water solubility and preparation method and application thereof |
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