CN118515624B - A synthesis method and application of trifluoromethyl-containing polysubstituted oxazolidin-4-one - Google Patents
A synthesis method and application of trifluoromethyl-containing polysubstituted oxazolidin-4-one Download PDFInfo
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- CN118515624B CN118515624B CN202410529924.4A CN202410529924A CN118515624B CN 118515624 B CN118515624 B CN 118515624B CN 202410529924 A CN202410529924 A CN 202410529924A CN 118515624 B CN118515624 B CN 118515624B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
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- 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
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention provides a synthesis method and application of trifluoromethyl-containing polysubstituted oxazolidine-4-one. The trifluoromethyl-containing polysubstituted oxazolidine-4-ketone is obtained by the beta-oxo acrylamide and trifluoro-2-oxo propionic acid ethyl ester through [3+2] cycloaddition reaction, the synthesis condition is mild, the used raw materials are cheap and easy to obtain, the antibacterial activity is certain for gram-positive bacteria including staphylococcus aureus and bacillus subtilis, the Minimum Inhibitory Concentration (MIC) is 4-8 mug/mL, and the antibacterial activity is poor for gram-negative bacteria including escherichia coli and pseudomonas aeruginosa.
Description
Technical Field
The invention belongs to the technical field of synthesis and application of pharmaceutical intermediates, and particularly relates to a synthesis method and application of trifluoromethyl-containing polysubstituted oxazolidine-4-one.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Oxazolidin-4-ones exhibit a variety of important biological activities, such as Lipoxazolidinone A produced by marine actinomycete strains, as shown in FIG. 1, and exhibit good broad-spectrum antibacterial activity. Synoxazolidinone A isolated from s pulmonaria shows good antifungal and antibacterial activity. As a novel structural class of oxazolidin-4-ones, synoxazolidinone C, exhibited excellent anticancer activity. Current methods of oxazolidine-4-ones include cycloaddition of propylene oxide to ketoenes, alpha-amino acids or anhydrides, photoelectrochemical reactions involving alpha-ketoamides, domino reactions between enol ethers and alpha-bromoamidols, condensation reactions between carbonyl compounds and alpha-hydroxyamides, and cycloaddition of haloamides and aldehyde ketones, which have evolved in recent years.
Considering the cheap and easily available substrate, the atom economy of the reaction, the simplicity and easiness in purification of the product, the role of trifluoromethyl in molecular modification and the like, we provide a simple and efficient synthesis method of trifluoromethyl-containing polysubstituted oxazolidine-4-one, the structural formula of which is shown in figure 2:
Disclosure of Invention
The invention aims to provide a preparation method and application of trifluoromethyl-containing polysubstituted oxazolidine-4-one. The method has the advantages of simple and efficient steps, low cost of reagents and raw materials, mild reaction conditions, and suitability for large-scale production. The antibacterial activity test is carried out on the synthesized trifluoromethyl-containing polysubstituted oxazolidine-4-ketone, and the antibacterial activity is shown to be certain.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
The invention provides a synthesis method of trifluoromethyl-containing polysubstituted oxazolidine-4-ketone, which is characterized by comprising the following steps:
Under the catalysis of alkali, beta-oxo-acrylamide and trifluoro-2-oxo-ethyl propionate undergo [3+2] cycloaddition reaction to obtain a trifluoromethyl polysubstituted oxazolidine-4-ketone product, and the reaction equation is as follows:
preferably, the reaction temperature is 0-30 ℃ and the reaction time is 4-24 hours.
Preferably, the catalyst used is an organic or inorganic base, including one of 1, 8-diazabicyclo [ 5.4.0 ] undec-7-ene (DBU), triethylamine (Et 3 N), 4-Dimethylaminopyridine (DMAP), potassium carbonate and sodium carbonate.
Preferably, the solvent for the reaction is one of dichloromethane and chloroform.
Preferably, the molar mass ratio of the beta-oxo-acrylamide, the trifluoro-2-oxo-propionic acid ethyl ester and the catalyst is 1:1-1.5:0.1-0.2.
Preferably, the trifluoromethyl-containing polysubstituted oxazolidine-4-one shows a certain antibacterial activity against different types of staphylococcus aureus and bacillus subtilis.
The beneficial effects of the invention are as follows:
The invention provides a synthesis method of trifluoromethyl-containing polysubstituted oxazolidine-4-ketone, which comprises the step of carrying out [3+2] cycloaddition reaction on beta-oxo-acrylamide and trifluoro-2-oxo-propionic acid ethyl ester to obtain a trifluoromethyl-containing polysubstituted oxazolidine-4-ketone product. The synthesis method of trifluoromethyl polysubstituted oxazolidine-4-ketone provided by the invention has the advantages of mild reaction conditions, and cheap and easily available reagents and raw materials. Aiming at different types of staphylococcus aureus and bacillus subtilis, the trifluoromethyl-containing polysubstituted oxazolidine-4-ketone shows a certain antibacterial activity.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a representative active oxazolidin-4-one derivative
FIG. 2 is a schematic representation of trifluoromethyl-containing polysubstituted oxazolidin-4-one
FIG. 3 shows the bactericidal efficacy of trifluoromethyl-containing polysubstituted oxazolidin-4-one against Staphylococcus aureus ATCC31007
FIG. 4 is a graph showing induction of drug resistance by trifluoromethyl-containing polysubstituted oxazolidine-4-one
FIG. 5 is a nuclear magnetic resonance spectrum of trifluoromethyl-containing polysubstituted oxazolidin-4-one prepared in example 1.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
Example 1:
to 40 mL dichloromethane solution were added β -oxo acrylamide (1.1 g,5.0 mmol) and trifluoro-2-oxopropionic acid ethyl ester (1.0 g,6.0 mmol), cooled to 0 ℃, et 3 N (51 mg,0.5 mol) was added to the reaction system under stirring, and the reaction was rapidly stirred at 25 ℃ for 8 hours. The progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the organic solvent was removed by rotary evaporation, and the product containing trifluoromethyl oxazolidine-4-one was isolated by column chromatography to give 1.3 g in 69% yield.
1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 7.5 Hz, 2H), 7.20 (s, 2H), 5.20 (t, J = 10.0 Hz, 1H), 4.27 (dd, J = 13.6, 6.7 Hz, 2H), 3.90 (d, J = 7.4 Hz, 3H), 3.57 – 3.29 (m, 2H), 2.34 (s, 3H), 1.32 – 1.20 (m, 3H).
Example 2:
To 40 mL chloroform were added β -oxo-acrylamide (1.1 g,5.0 mmol) and ethyl trifluoro-2-oxopropionate (1.0 g,6.0 mmol), cooled to 0 ℃, et 3 N (51 mg,0.5 mol) was added to the reaction system with stirring, and the reaction was stirred rapidly to 25 ℃ for 6 hours. The progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the organic solvent was removed by rotary evaporation, and the product 1.1 g containing trifluoromethyl oxazolidin-4-one was obtained by column chromatography, with a yield of 56%.
Example 3:
to 40 mL dichloromethane solution, β -oxo-acrylamide (1.1 g,5.0 mmol) and ethyl trifluoro-2-oxopropionate (1.0 g,6.0 mmol) were added, cooled to 0 ℃, DBU (76 mg,0.5 mol) was added to the reaction system under stirring, and the temperature was raised to 25 ℃ and the reaction was rapidly stirred for 8 hours. The progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the organic solvent was removed by rotary evaporation, and the product 1.2 g containing trifluoromethyl oxazolidin-4-one was obtained by column chromatography, and the yield was 63%.
The in vitro antibacterial activity evaluation (Table 1) is carried out on the synthesized trifluoromethyl polysubstituted oxazolidine-4-ketone (the product of the example 1), and the antibacterial activity result shows that the trifluoromethyl polysubstituted oxazolidine-4-ketone has certain antibacterial activity on gram-positive bacteria including staphylococcus aureus and bacillus subtilis, the minimum antibacterial concentration (MIC) is 4-8 mug/mL, and the antibacterial activity on gram-negative bacteria including escherichia coli and pseudomonas aeruginosa is poor.
Sterilization kinetics test:
Staphylococcus aureus ATCC31007 was cultured overnight to grow bacteria to log phase, diluted bacteria solution concentration was 108CFU/mL, and test compounds of different concentrations were added. After dosing, 0h, 0.5 h, 1h, 2h, 4h, 6 h, 100 μl of bacterial liquid was removed from each group at different time nodes and diluted ten-fold gradient, 10 μl was dropped onto MHA agar plates, three in parallel, the plates were incubated in an incubator for 24h, and colony numbers were calculated from dilution factors.
Oxazolidin-4-one was selected for its bactericidal efficacy against Staphylococcus aureus ATCC31007 at various concentrations over time, as shown in FIG. 3. The result shows that the oxazolidine-4-one has a rapid sterilization effect, and can kill staphylococcus aureus completely within 1 hour at the concentration of 32 mug/mL.
Drug resistance induction test:
MIC values of the compound and the positive control norfloxacin against staphylococcus aureus ATCC31007 were first determined. The compound and the control agent were added to LB medium containing Staphylococcus aureus ATCC31007 at a final concentration of 1/2MIC and incubated at 37℃of 18 h. MIC values were determined in this way for 20 consecutive days.
The compound oxazolidin-4-one was selected for evaluation in terms of resistance induction against Staphylococcus aureus. The result shows that the compound oxazolidin-4-one shows better performance than the control drug norfloxacin in inhibiting bacterial induced drug tolerance, and the MIC of the compound oxazolidin-4-one to staphylococcus aureus is increased by 16 times through bacterial induced drug tolerance passage for 20 generations under the concentration of the drug MIC/2, and the MIC of the control drug norfloxacin is increased by 128 times respectively, so that the compound has better bacterial tolerance as shown in figure 4.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105705147A (en) * | 2013-11-08 | 2016-06-22 | 李药业有限公司 | Novel oxazolidinone antibacterial compound |
| CN110372624A (en) * | 2019-08-13 | 2019-10-25 | 北京海美桐医药科技有限公司 | A kind of Oxazolidinone derivative, preparation method and application |
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| FR2850377B1 (en) * | 2003-01-23 | 2009-02-20 | Sanofi Synthelabo | ARYLALKYLCARBAMATE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| WO2014108832A1 (en) * | 2013-01-09 | 2014-07-17 | Actelion Pharmaceuticals Ltd | Antibacterial oxazolone derivatives |
| JP7039025B2 (en) * | 2018-05-22 | 2022-03-22 | 学校法人東京農業大学 | Method for producing 2-oxazolidinone compound |
| WO2022135601A1 (en) * | 2020-12-25 | 2022-06-30 | 杭州百新生物医药科技有限公司 | 5-alkyl-2-pyrazole-oxazolidine-4-ketone derivative and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105705147A (en) * | 2013-11-08 | 2016-06-22 | 李药业有限公司 | Novel oxazolidinone antibacterial compound |
| CN110372624A (en) * | 2019-08-13 | 2019-10-25 | 北京海美桐医药科技有限公司 | A kind of Oxazolidinone derivative, preparation method and application |
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