A synthesis method and application of trifluoromethyl-containing polysubstituted oxazolidin-4-one

Abstract

The present invention provides a synthesis method and application of a trifluoromethyl-containing polysubstituted oxazolidine-4-one. The trifluoromethyl-containing polysubstituted oxazolidine-4-one is obtained by a [3+2] cycloaddition reaction of β-oxoacrylamide and ethyl trifluoro-2-oxopropionate; the synthesis conditions are mild, and the raw materials used are cheap and readily available; it exhibits certain antibacterial activity against Gram-positive bacteria including Staphylococcus aureus and Bacillus subtilis, and its minimum inhibitory concentration (MIC) is 4-8 μg / mL; the antibacterial activity against Gram-negative bacteria including Escherichia coli and Pseudomonas aeruginosa is poor.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis and application of pharmaceutical intermediates, and specifically relates to a synthesis method and application of a trifluoromethyl-containing multi-substituted oxazolidin-4-one. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Oxazolidin-4-ones exhibit a variety of important biological activities, such as Figure 1 As shown, Lipoxazolidinone A produced by marine actinomycete strains exhibits good broad-spectrum antibacterial activity. Synoxazolidinone A isolated from S. pulmonaria exhibits good antifungal and antibacterial activity. Synoxazolidinone C, a novel structural class of the oxazolidinone series, exhibits excellent anticancer activity. The current synthesis methods of oxazolidinones include: cycloaddition reactions between epoxyaziridines and ketoenes, α-amino acids or anhydrides, photoelectrochemical reactions involving α-ketoamides, domino reactions between enol ethers and α-bromoamide alcohols, condensation reactions between carbonyl compounds and α-hydroxyamides, and cycloaddition reactions of halogenated amides and aldehydes and ketones developed in recent years.

[0004]

[0005] Considering the cheapness and availability of the substrate, the atom economy of the reaction, the simplicity and ease of purification of the product, and the role of the trifluoromethyl group in molecular modification, we provide a simple and efficient method for synthesizing trifluoromethyl-containing polysubstituted oxazolidin-4-ones, whose structural formula is as follows Figure 2 As shown:

[0006] Summary of the invention

[0007] The present invention aims to provide a preparation method and application of a trifluoromethyl-containing multi-substituted oxazolidine-4-one. The advantages of the method include simple and efficient steps, cheap reagents and raw materials, mild reaction conditions, and the method is more suitable for large-scale production. The synthesized trifluoromethyl-containing multi-substituted oxazolidine-4-one was tested for antibacterial activity and showed certain antibacterial activity.

[0008] In order to achieve the above object, the technical solution of the present invention is:

[0009] The present invention provides a method for synthesizing a trifluoromethyl-containing multi-substituted oxazolidin-4-one, characterized in that it comprises the following steps:

[0010] Under the catalytic action of base, β-oxyacrylamide and ethyl trifluoro-2-oxopropionate undergo [3+2] cycloaddition reaction to obtain a trifluoromethyl-containing multi-substituted oxazolidin-4-one product, and the reaction equation is as follows:

[0011]

[0012] Preferably, the reaction temperature is 0-30°C and the reaction time is 4-24 h.

[0013] Preferably, the catalyst used is an organic base or an inorganic base, including one of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (Et3N), 4-dimethylaminopyridine (DMAP), potassium carbonate and sodium carbonate.

[0014] Preferably, the reaction solvent is one of dichloromethane and chloroform.

[0015] Preferably, the molar mass ratio of β-oxyacrylamide, ethyl trifluoro-2-oxopropionate and the catalyst is 1:1-1.5:0.1-0.2.

[0016] Preferably, the trifluoromethyl-containing multi-substituted oxazolidin-4-one exhibits certain antibacterial activity against different types of Staphylococcus aureus and Bacillus subtilis.

[0017] The beneficial effects of the present invention are:

[0018] The present invention provides a method for synthesizing a trifluoromethyl-containing polysubstituted oxazolidine-4-one, comprising: a [3+2] cycloaddition reaction of β-oxyacrylamide and trifluoro-2-oxopropionic acid ethyl ester to obtain a trifluoromethyl-containing polysubstituted oxazolidine-4-one product. The method for synthesizing a trifluoromethyl-containing polysubstituted oxazolidine-4-one provided by the present invention has mild reaction conditions, and the reagents and raw materials used are cheap and readily available. The trifluoromethyl-containing polysubstituted oxazolidine-4-one exhibits certain antibacterial activity against different types of Staphylococcus aureus and Bacillus subtilis. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0020] Figure 1 Representative active oxazolidin-4-one derivatives

[0021] Figure 2The structural formula is trifluoromethyl-containing polysubstituted oxazolidin-4-one

[0022] Figure 3 The bactericidal effect of trifluoromethyl-containing polysubstituted oxazolidin-4-one on Staphylococcus aureus ATCC31007

[0023] Figure 4 The drug resistance-inducing oxazolidin-4-one containing trifluoromethyl multi-substituted

[0024] Figure 5 This is the H NMR spectrum of the trifluoromethyl-containing multi-substituted oxazolidin-4-one prepared in Example 1. DETAILED DESCRIPTION

[0025] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments. Embodiment 1:

[0027] β-Oxyacrylamide (1.1 g, 5.0 mmol) and ethyl trifluoro-2-oxopropionate (1.0 g, 6.0 mmol) were added to 40 mL of dichloromethane solution, and the temperature was lowered to 0°C. Under stirring conditions, Et3N (51 mg, 0.5 mol) was added to the reaction system, and the temperature was raised to 25°C and stirred rapidly for 8 hours. The reaction progress was monitored by thin layer chromatography. After the reaction was complete, the organic solvent was removed by rotary evaporation and separated by column chromatography to obtain 1.3 g of a product containing trifluoromethyloxazolidin-4-one with a yield of 69%.

[0028] 1 H 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 = 7.4Hz, 3H), 3.57 – 3.29 (m, 2H), 2.34 (s, 3H), 1.32 – 1.20 (m, 3H). Embodiment 2:

[0029] β-Oxyacrylamide (1.1 g, 5.0 mmol) and ethyl trifluoro-2-oxopropionate (1.0 g, 6.0 mmol) were added to 40 mL of chloroform, and the temperature was lowered to 0°C. Under stirring conditions, Et3N (51 mg, 0.5 mol) was added to the reaction system, and the temperature was raised to 25°C and stirred rapidly for 6 hours. The reaction progress was monitored by thin layer chromatography. After the reaction was complete, the organic solvent was removed by rotary evaporation, and 1.1 g of the product containing trifluoromethyloxazolidin-4-one was obtained by column chromatography separation with a yield of 56%. Embodiment 3:

[0030] β-Oxyacrylamide (1.1 g, 5.0 mmol) and ethyl trifluoro-2-oxopropionate (1.0 g, 6.0 mmol) were added to 40 mL of dichloromethane solution, and the temperature was lowered to 0°C. DBU (76 mg, 0.5 mol) was added to the reaction system under stirring, and the temperature was raised to 25°C and stirred rapidly for 8 hours. The reaction progress was monitored by thin layer chromatography. After the reaction was complete, the organic solvent was removed by rotary evaporation and separated by column chromatography to obtain 1.2 g of a product containing trifluoromethyloxazolidin-4-one with a yield of 63%.

[0031] We conducted relevant in vitro antibacterial activity evaluation on the synthesized trifluoromethyl polysubstituted oxazolidin-4-one (product in Example 1) (Table 1). The antibacterial activity results showed that the trifluoromethyl polysubstituted oxazolidin-4-one exhibited certain antibacterial activity against the tested Gram-positive bacteria including Staphylococcus aureus and Bacillus subtilis, and its minimum inhibitory concentration (MIC) was 4-8 μg / mL; the antibacterial activity against Gram-negative bacteria including Escherichia coli and Pseudomonas aeruginosa was poor.

[0032]

[0033] Bactericidal kinetics test:

[0034] Staphylococcus aureus ATCC31007 was cultured overnight to allow the bacteria to grow to the logarithmic phase, and the bacterial solution was diluted to a concentration of 108CFU / mL, and different concentrations of the test compound were added. At 0 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h after drug addition, 100 μL of bacterial solution was taken from each group with different concentrations at different time points, and ten-fold gradient dilution was performed, and 10 μL was dropped onto the MHA agar plate, with three parallels for each concentration. The agar plate was cultured in an incubator for 24 hours, and the number of colonies was calculated according to the dilution multiple.

[0035] Oxazolidine-4-one was selected to study its bactericidal efficacy against Staphylococcus aureus ATCC31007 at different concentrations over time. Figure 3The results showed that oxazolidin-4-one had a rapid bactericidal effect and could kill all Staphylococcus aureus within 1 hour at a concentration of 32 µg / mL.

[0036] Resistance induction test:

[0037] First, the MIC values ​​of the compound and the positive control drug norfloxacin against Staphylococcus aureus ATCC31007 were determined. The compound and the control drug were added to the LB medium containing Staphylococcus aureus ATCC31007 to a final concentration of 1 / 2 MIC, and cultured at 37°C for 18 h. The MIC values ​​were determined for 20 consecutive days in this way.

[0038] The compound oxazolidin-4-one was selected to study its evaluation on the induction of drug resistance in Staphylococcus aureus. The results showed that the compound oxazolidin-4-one performed better than the control drug norfloxacin in inhibiting bacterial resistance induction. By inducing drug resistance in bacteria at the drug MIC / 2 concentration for 20 generations, it was found that the MIC of the compound oxazolidin-4-one against Staphylococcus aureus increased by 16 times, while the MIC of the control drug norfloxacin increased by 128 times. Figure 4 As shown, this indicates that the compound has good bacterial tolerance.

[0039] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a trifluoromethyl-containing polysubstituted oxazolidin-4-one, characterized in that: The steps include: Under the catalytic action of a base, β-oxyacrylamide and ethyl trifluoro-2-oxopropionate undergo a [3+2] cycloaddition reaction to obtain a trifluoromethyl-containing multi-substituted oxazolidin-4-one product; the reaction equation is as follows: .

2. The synthesis method according to claim 1, characterized in that The reaction temperature is 0~30°C and the reaction time is 4~24h.

3. The synthesis method according to claim 1, characterized in that The solvent for the synthesis reaction is one of dichloromethane and chloroform.

4. The synthesis method according to claim 1, characterized in that The catalyst used is an organic base or an inorganic base, including one of DBU, Et3N, DMAP, K2CO3 and Na2CO3.

5. The synthesis method according to claim 1, characterized in that The molar mass ratio of β-oxyacrylamide, ethyl trifluoro-2-oxopropionate and the catalyst is 1:1~1.5:0.1~0.2.

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