A quinolinephosphonate derivative and its synthesis method and application

Abstract

The invention discloses a quinoline phosphonate derivative and its synthesis method and application. The synthesis method is to add β,β-difluoro-o-isocyanophenylphosphine methylene ethylene and organic boronic acid to the corresponding solvent and mix them, and then stir under mild conditions in the presence of trivalent manganese salt and alkali to achieve efficient construction of quinoline phosphonate derivatives, and introduce fluorine groups to obtain a series of 3-fluoro-quinoline phosphonate derivatives. The present invention can efficiently realize the synthesis of 3-fluoro-quinoline phosphonate derivatives, and the promoter used is low in price and easy to operate. It can realize efficient conversion of the reaction under relatively mild environmental conditions, and the post-reaction treatment is simple; the synthesis reaction in the present invention can be fast in reaction, good in yield, and can effectively realize the amplification of the reaction scale, and has good application value and prospects in production; the prepared quinoline phosphonate derivatives have good antibacterial properties.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to a method for realizing efficient synthesis of quinoline phosphonate derivatives from β,β-difluoro-o-isocyanophenylphosphine methylene and boric acid compounds under mild conditions in the presence of a trivalent manganese salt, while introducing fluorine atoms to obtain a series of 3-fluoro-quinoline phosphonate derivatives, and discovering the application value of such compounds in antibacterial aspects. Background Art

[0002] Quinolinephosphonate derivatives are important backbone units in natural products and drug molecules, and are also widely used in organic synthesis. In the process of biological activity testing, a series of quinolinephosphonate derivatives have excellent inhibitory effects on carbapenemase, a key substance of Klebsiella pneumoniae resistance. However, the structure of quinolinephosphonate derivatives is still limited by conventional substituents at fixed sites, and the synthesis of quinolinephosphonate derivatives containing specific functional heteroatoms (functional groups) is of great significance.

[0003] Due to their excellent physicochemical properties, fluorine-substituted compounds occupy an important position in the drug development process, among which 3-fluoroquinoline compounds have shown excellent pharmacodynamic effects. The traditional method for synthesizing 3-fluoroquinoline compounds is mainly through the conversion between functional groups. For example, the Halex reaction and the Balz-Schiemann reaction are commonly used synthesis methods, but the Halex reaction prefers fluorination at the 2nd or 4th position, while the Balz-Schiemann reaction mainly relies on thermally unstable diazonium salts, which to some extent limits the practicality of this type of reaction. Although metal-catalyzed methods have been developed, these methods often require highly loaded metal catalysts or expensive catalysts.

[0004] Therefore, combining the excellent performance of quinoline phosphonate derivatives and 3-fluoroquinoline structures in antibacterial and other biological activities, the present invention develops a simple and efficient synthesis strategy for 3-fluoroquinoline phosphonate derivatives, and this type of compound exhibits good antibacterial properties. Summary of the invention

[0005] Purpose of the invention: The purpose of the present invention is to provide a quinoline phosphonate derivative with antibacterial activity and an efficient synthesis method thereof. The specific technical scheme is as follows:

[0006] The present invention provides a method for synthesizing a quinoline phosphonate derivative. The method comprises the following steps: adding β,β-difluoro-o-isocyanophenylphosphine methylene and boric acid into a corresponding solvent and mixing the mixture; and then stirring the mixture under mild conditions in the presence of a trivalent manganese salt and a base to obtain a quinoline phosphonate derivative.

[0007] The reaction scheme of the synthesis method is as follows:

[0008]

[0009] Among them, R 1 is alkyl, substituted alkyl, (hetero)aryl or substituted (hetero)aryl, R 2 is alkyl or substituted alkyl, alkoxy or substituted alkoxy, aryl or substituted aryl, (hetero)aryloxy or substituted (hetero)aryloxy, R 3 is alkyl or substituted alkyl, alkoxy or substituted alkoxy, aryl or substituted aryl, (hetero)aryloxy or substituted (hetero)aryloxy, R 4 is alkyl or substituted alkyl, aryl or substituted aryl, (hetero)aryl or substituted (hetero)aryl;

[0010] The manganese compound is a trivalent manganese salt with a structure of MnL3; wherein L is an anion;

[0011] The solvent is one or a mixture of tetrahydrofuran, acetonitrile, 1,2-dichloroethane, dichloromethane, N,N-dimethylformamide and toluene.

[0012] As a preferred embodiment of the synthesis method of the present invention, stirring is performed to achieve efficient construction of quinoline phosphonate derivatives, and a fluorine group is introduced to obtain a fluorine-based quinoline phosphonate derivative.

[0013] As a preferred embodiment of the synthesis method of the present invention, the specific operation steps of the synthesis method are as follows: β,β-difluoro-o-isocyanophenylphosphine methylene ethylene, boronic acid, trivalent manganese salt, base and solvent are added to a reaction container, and the reaction is stirred under mild conditions. After the reaction is completed, the solvent is removed, and the target product quinoline phosphonate derivative is obtained by simple separation by column chromatography.

[0014] Furthermore, the aromatic structure of the β,β-difluoro-o-isocyanatophenylphosphine methyleneethylene has one or more substituents selected from the group consisting of alkyl, halogen, substituted alkoxy, and substituted aryloxy.

[0015] Furthermore, the organic boronic acid is a substituted or unsubstituted alkyl boronic acid, alkenyl boronic acid or aryl boronic acid.

[0016] Further, the trivalent manganese salt is a trivalent manganese salt compound having a MnL3 structure, wherein L is an anion. Specifically, L includes but is not limited to a halogen anion, a carboxylate anion or an acetylacetonate anion, and more preferably, L is M(acac)3 (i.e., manganese(III) acetylacetonate).

[0017] Preferably, the base is an organic base or an inorganic base. Further preferably, the base includes but is not limited to triethylamine, pyridine, triethylenediamine, 1,8-diazobispiro[5.4.0]undec-7-ene, tert-butoxide and carbonate, and further preferably, the base is 1,8-diazobispiro[5.4.0]undec-7-ene.

[0018] Preferably, the mass ratio of the β,β-difluoro-o-isocyanophenylphosphine methyleneethylene, the organic boronic acid, the manganese compound and the base is 1.0:(1.0-2.0):(1.0-2.0):(1.0-2.0). More preferably, the mass ratio is 1.0:2.0:2.0:2.0.

[0019] Preferably, the reaction temperature under mild conditions is 25 to 100° C. More preferably, the reaction temperature is 80° C.

[0020] Preferably, the reaction time is 5-60 minutes, and more preferably, the reaction time is 10 minutes.

[0021] Compared with the prior art, the present invention has at least one or more of the following advantages:

[0022] 1. The present invention can achieve structural optimization of quinoline phosphonate derivatives in the presence of trivalent manganese salts, introduce 3-fluoro-quinoline phosphonate derivatives that are difficult to construct under conventional environmental conditions, and has mild conditions, does not require the participation of precious metals, and does not require harsh conditions such as high temperature.

[0023] 2. The reaction involved in the present invention has high reaction efficiency, and the target structure can be constructed in just a few minutes. Moreover, the post-processing of the reaction is simple, the yield is good, and the reaction can be effectively amplified, which has good application value and prospects in production.

[0024] 3. The quinoline phosphonate derivatives prepared by the present invention have good antibacterial properties and good sterilization effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The structure of Example 1 prepared by the present invention 1 H NMR spectrum;

[0026] Figure 2 The structure of Example 2 prepared by the present invention 1 H NMR spectrum. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present invention will be described clearly and completely below so that those skilled in the art can better understand the advantages and features of the present invention, thereby making a clearer definition of the protection scope of the present invention. The embodiments described in the present invention are only a part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention.

[0028] Example 1

[0029]

[0030] β,β-difluoro-o-isocyanophenyldiphenylphosphine ethylene (0.2 mmol, 1.0 equiv.), phenylboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), and 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. for 10 minutes under an argon atmosphere, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain pure product (yield 61%). 1 H NMR (400MHz, Chloroform-d) δ8.16 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.81–7.71 (m, 6H), 7.66 (t, J = 7.6 Hz, 1H), 7.58–7.50 (m, 3H), 7.48–7.40 (m, 7H), 4.18 (d, J = 14.1 Hz, 2H), the specific spectrum is shown in Figure 1 shown.

[0031] Example 2

[0032]

[0033] β,β-difluoro-o-isocyanophenyldiphenylphosphine ethylene (0.2 mmol, 1.0 equiv.), 4-methylphenylboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), and 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. under an argon atmosphere for 10 minutes, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain pure product (yield 56%). 1 H NMR (400MHz, Chloroform-d) δ8.16 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.79–7.73 (m, 4H), 7.68–7.62 (m, 3H), 7.57–7.51 (m, 3H), 7.47–7.41 (m, 4H), 7.27–7.24 (m, 2H), 4.19 (d, J = 14.1 Hz, 2H), 2.41 (s, 3H). The specific spectrum is shown in Figure 2 shown.

[0034] Example 3

[0035]

[0036] β,β-difluoro-o-isocyanophenyldiphenylphosphine ethylene (0.2 mmol, 1.0 equiv.), 4-nitrobenzeneboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), and 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. under an argon atmosphere for 10 minutes, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain a pure product (yield 80%). 1 H NMR(400MHz,Chloroform-d)δ8.29(d,J=8.6Hz,2H),8.17–8.08(m,2H),7.94(d,J=8.0H z,2H),7.80–7.68(m,5H),7.62–7.53(m,3H),7.50–7.42(m,4H),4.22(d,J=13.9Hz,2H).

[0037] Example 4

[0038]

[0039] β,β-difluoro-o-isocyanophenyldiphenylphosphine ethylene (0.2 mmol, 1.0 equiv.), 3-cyanophenylboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), and 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. under an argon atmosphere for 10 minutes, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain a pure product (yield 67%). 1 H NMR(400MHz,Chloroform-d)δ8.14(d,J=8.3Hz,1H),8.08(d,J=8.4Hz,1H),8.04(d,J=7.7Hz,1H),7.96(s ,1H),7.80–7.73(m,4H),7.71–7.66(m,2H),7.60–7.53(m,4H),7.50–7.42(m,4H),4.19(d,J=13.9Hz,2H).

[0040] Example 5

[0041]

[0042] In a Schlenk test tube (25 mL), β,β-difluoro-o-isocyanophenyldiphenylphosphine ethylene (0.2 mmol, 1.0 equiv.), 2-methylphenylboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), and 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added. The mixture was stirred at 80° C. under an argon atmosphere for 10 minutes, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain a pure product (yield 64%). 1H NMR(400MHz,Chloroform-d)δ8.31(d,J=8.0Hz,1H),8.09(d,J=8.1Hz,1H),7.83–7.73(m,4H),7.70–7.61(m,2H),7.50(d,J=6.9 Hz,2H),7.47–7.38(m,4H),7.34–7.29(m,1H),7.24(t,J=7.5Hz,2H),7.17(d,J=7.0Hz,1H),4.21(d,J=14.1Hz,2H),1.93(s,3H).

[0043] Example 6

[0044]

[0045] β,β-difluoro-o-isocyanophenyldiphenylphosphine ethylene (0.2 mmol, 1.0 equiv.), 3-thiopheneboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), and 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. under an argon atmosphere for 10 minutes, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain pure product (yield 44%). 1 H NMR(400MHz,Chloroform-d)δ8.05(t,J=7.5Hz,2H),7.87(s,1H),7.81–7.70(m,5H),7.62(t,J= 7.4Hz, 1H), 7.54–7.47 (m, 3H), 7.46–7.39 (m, 4H), 7.36 (t, J = 4.2Hz, 1H), 4.16 (d, J = 13.8Hz, 2H).

[0046] Example 7

[0047]

[0048] β,β-difluoro-o-isocyanophenyldiphenylphosphine ethylene (0.2 mmol, 1.0 equiv.), 1-cyclopenteneboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), and 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. for 10 minutes under an argon atmosphere, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain pure product (yield 56%). 1 H NMR(400MHz,Chloroform-d)7.98(t,J=8.9Hz,2H),7.72(t,J=9.4Hz,4H),7.57(t,J=7.7Hz,1H),7.48(d,J=7.6Hz,2H) ,7.41(s,5H),6.51(s,1H),4.10(d,J=14.0Hz,2H),2.91(d,J=8.0Hz,2H),2.59(d,J=7.8Hz,2H),1.95(t,J=7.6Hz,2H).

[0049] Example 8

[0050]

[0051] β,β-difluoro-o-isocyanophenyldiphenylphosphine ethylene (0.2 mmol, 1.0 equiv.), cyclohexylboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), and 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. for 10 minutes under an argon atmosphere, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain pure product (yield 38%). 1H NMR(400MHz,Chloroform-d)8.09(d,J=7.8Hz,1H),7.98(d,J=8.0Hz,1H),7.78–7.66(m,4H),7.62–7.56(m,1H),7.49(d,J=6.4Hz,3H),7.41(d, J=7.8Hz,4H),4.10(d,J=14.0Hz,2H),2.92(t,J=10.3Hz,1H),1.82(d,J=10.7Hz,2H),1.76–1.66(m,3H),1.65–1.56(m,2H),1.41–1.24(m,3H).

[0052] Example 9

[0053]

[0054] β,β-difluoro-o-isocyanophenylbis(3,5-dimethyl)phenylphosphine oxide methyleneethylene (0.2mmol, 1.0equiv.), phenylboronic acid (0.4mmol, 2.0equiv.), manganese acetylacetonate (2equiv.), toluene (4mL), 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0equiv.) were added to a Schlenk tube (25mL). The mixture was stirred at 80°C for 10 minutes under an argon atmosphere, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain a pure product (yield 64%). 1 H NMR(400MHz,Chloroform-d)δ8.16(d,J=8.3Hz,1H),8.10(d,J=8.3Hz,1H),7.79–7.73(m,2H),7.68–7.63(m,1H) ,7.56(t,J=7.6Hz,1H),7.48–7.41(m,3H),7.35(d,J=12.0Hz,4H),7.14(s,2H),4.18–4.11(m,2H),2.29(s,12H).

[0055] Example 10

[0056]

[0057] β,β-difluoro-o-isocyanophenyl (3,5-dimethyl)phenyl phosphite ethyl methylene vinyl (0.2 mmol, 1.0 equiv.), phenylboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. for 10 minutes under an argon atmosphere, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain pure product (yield 62%). 1 HNMR(400MHz,Chloroform-d)δ8.10(d,J=8.4Hz,1H),7.97(d,J=8.4Hz,1H),7.82(d,J=7.4Hz,2H),7.61(q,J=10.2,8.1Hz,3H ),7.53–7.41(m,5H),7.38–7.32(m,2H),4.13–4.04(m,1H),3.98–3.85(m,1H),3.82(d,J=18.6Hz,2H),1.23(t,J=7.0Hz,3H).

[0058] Embodiment 11

[0059]

[0060] β,β-difluoro-o-isocyanophenyl dimethyl phosphite methylene vinyl (0.2 mmol, 1.0 equiv.), phenylboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. under an argon atmosphere for 10 minutes, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain pure product (yield 56%). 1H NMR(400MHz,Chloroform-d)δ8.16(d,J=8.4Hz,1H),8.07–8.00(m,3H),7.71–7.66(m,1H) ,7.61(t,J=7.6Hz,1H),7.54–7.47(m,3H),3.75(d,J=2.1Hz,2H),3.71(d,J=11.0Hz,6H).

[0061] Example 12

[0062]

[0063] β,β-difluoro-o-isocyanato-m-methylphenylphosphite diethyl methylene ethylene (0.2 mmol, 1.0 equiv.), phenylboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. under an argon atmosphere for 10 minutes, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚 =1:2 solvent as developing solvent, purified by flash column chromatography to obtain pure product (yield 54%). 1 H NMR (400MHz, Chloroform-d) δ8.05–8.02(m,2H),7.81(s,1H),7.55–7.45(m,4H),4.12–4.00(m,4H),3.75–7.66(m,2H),2.59(s,3H),1.22(s,6H).

[0064] Embodiment 13

[0065]

[0066] β,β-difluoro-o-isocyanato-m-tert-butylphenylphosphite-diethyl methyleneethylene (0.2 mmol, 1.0 equiv.), phenylboronic acid (0.4 mmol, 2.0 equiv.), manganese acetylacetonate (2 equiv.), toluene (4 mL), and 1,8-diazobispiro[5.4.0]undec-7-ene (DBU, 2.0 equiv.) were added to a Schlenk tube (25 mL). The mixture was stirred at 80° C. under an argon atmosphere for 10 minutes, and then the reaction system was cooled to room temperature. The solvent was then distilled off under reduced pressure to obtain V 乙酸乙酯 / V 石油醚=1:2 solvent as developing solvent, purified by flash column chromatography to obtain pure product (yield 56%). 1 H NMR(400MHz,Chloroform-d)δ8.07(d,J=8.9Hz,1H),8.03–7.97(m,2H),7.94(d,J=1.8Hz,1H),7.78–7. 71(m,1H),7.52–7.39(m,3H),4.09–4.00(m,4H),3.76–3.64(m,2H),1.43(s,9H),1.19(t,J=7.1Hz,6H).

[0067] Embodiment 14

[0068]

[0069] In a dry round-bottom flask (25 mL), the product of Example 1 (0.44 mmol) was added, followed by 1,4-dioxane (10 mL) and hydrochloric acid (HCl, 4M, 5 mL). After stirring at 100° C. for 18 hours, the reaction mixture was concentrated to dryness, washed with ethyl acetate, and dried to obtain the product (yield 95%). 1 H NMR(400MHz,Chloroform-d)δ8.56(d,J=8.5Hz,1H),8.39(d,J=8.5Hz,1H),8.13( t,J=7.7Hz,1H),8.02(d,J=7.5Hz,3H),7.82–7.70(m,3H),4.06(d,J=22.9Hz,2H).

[0070] Embodiment 15

[0071] Take 0.1 g of the sample obtained in Example 1, add 10 ml of sterile saline, heat it in an autoclave at 130°C for half an hour, and then add 1x10 7 1 ml of CFU per ml of E. coli solution was cultured at 36-37 degrees Celsius for 48 hours, and then the number of bacteria was calculated and compared with the control experiment to obtain a sterilization rate of 89.51%.

[0072] Example 16

[0073] Take 0.1 g of the sample obtained in Example 1, add 10 ml of sterile saline, heat it in an autoclave at 130°C for half an hour, and then add 1x10 7 1 ml of Staphylococcus aureus liquid with CFU per ml was cultured at 36-37 degrees Celsius for 48 hours, and then the number of bacteria was calculated and compared with the control experiment to obtain a sterilization rate of 91.43%.

[0074] Embodiment 17

[0075] Take 0.1 g of the sample obtained in Example 14, add 10 ml of sterile saline, heat it in an autoclave at 130°C for half an hour, and then add 1x10 7 1 ml of CFU per ml of E. coli solution was cultured at 36-37 degrees Celsius for 48 hours, and then the number of bacteria was calculated and compared with the control experiment to obtain a sterilization rate of 96.37%.

[0076] Embodiment 18

[0077] Take 0.1 g of the sample obtained in Example 14, add 10 ml of sterile saline, heat it in an autoclave at 130°C for half an hour, and then add 1x10 7 1 ml of Staphylococcus aureus liquid with CFU per ml was cultured at 36-37 degrees Celsius for 48 hours, and then the number of bacteria was calculated and compared with the control experiment to obtain a sterilization rate of 92.19%.

[0078] Obviously, the above embodiments are merely examples for clear description and are not limitations of the implementation methods.

[0079] Although the above disclosure discusses some of the invention embodiments currently considered useful through various examples, it should be understood that such details are for illustrative purposes only, and the appended claims are not limited to the disclosed embodiments. On the contrary, the claims are intended to cover all modifications and equivalent combinations that are consistent with the essence and scope of the embodiments of the present application.

[0080] Similarly, it should be noted that in order to simplify the description of the disclosure of this application and thus facilitate the understanding of one or more embodiments of the invention, in the foregoing description of the embodiments of this application, multiple features are sometimes combined into one embodiment, drawing or description thereof. However, this disclosure method does not mean that the features required by the object of this application are more than the features mentioned in the claims.

[0081] In some embodiments, numbers describing the number of components and attributes are used. It should be understood that such numbers used in the description of the embodiments are modified by the modifiers "about", "approximately" or "substantially" in some examples. Unless otherwise specified, "about", "approximately" or "substantially" indicate that the numbers are allowed to vary by ±. Accordingly, in some embodiments, the numerical parameters used in the specification and claims are approximate values, which may vary according to the required features of individual embodiments.

[0082] Finally, it should be understood that the embodiments described in this application are only used to illustrate the principles of the embodiments of the present application. Other variations may also fall within the scope of the present application. Therefore, as an example and not a limitation, the alternative configurations of the embodiments of the present application may be considered to be consistent with the teachings of the present application. Accordingly, the embodiments of the present application are not limited to the embodiments explicitly introduced and described in the present application.

Claims

1. A method for synthesizing a quinolinephosphonate derivative, characterized in that: After adding β,β-difluoro-o-isocyanophenylphosphine methylene ethylene and organic boronic acid into a corresponding solvent and mixing, stirring under mild conditions in the presence of a trivalent manganese salt and a base, the quinoline phosphonate derivative is efficiently constructed, and a fluorine group is introduced to obtain a quinoline phosphonate derivative; The reaction scheme of the synthesis method is as follows: Among them, R 1 is alkyl, substituted alkyl, (hetero)aryl or substituted (hetero)aryl, R 2 is alkyl or substituted alkyl, alkoxy or substituted alkoxy, aryl or substituted aryl, (hetero)aryloxy or substituted (hetero)aryloxy, R 3 is alkyl or substituted alkyl, alkoxy or substituted alkoxy, aryl or substituted aryl, (hetero)aryloxy or substituted (hetero)aryloxy, R 4 is alkyl or substituted alkyl, aryl or substituted aryl, (hetero)aryl or substituted (hetero)aryl; The manganese compound is a trivalent manganese salt with a structure of MnL3; wherein L is an anion; The solvent is one or more of tetrahydrofuran, acetonitrile, 1,2-dichloroethane, dichloromethane, N,N-dimethylformamide and toluene.

2. The method for synthesizing a quinolinephosphonate derivative according to claim 1, wherein: The aromatic structure of the β,β-difluoro-o-isocyanophenylphosphine methylene ethylene has one or more substituent groups selected from the group consisting of alkyl, halogen, substituted alkoxy and substituted aryloxy.

3. The method for synthesizing a quinolinephosphonate derivative according to claim 1, characterized in that: The organic boronic acid is a substituted or unsubstituted alkyl boronic acid, alkenyl boronic acid or aryl boronic acid.

4. The method for synthesizing a quinolinephosphonate derivative according to claim 1, wherein: L includes a halogen anion, a carboxylate anion, or an acetylacetonate anion.

5. The method for synthesizing a quinolinephosphonate derivative according to claim 1, wherein: The base is an organic base or an inorganic base, including triethylamine, pyridine, triethylenediamine, 1,8-diazobispiro[5.4.0]undec-7-ene, tert-butoxide and carbonate.

6. The method for synthesizing a quinolinephosphonate derivative according to claim 1, characterized in that: The mass ratio of the β,β-difluoro-o-isocyanoarylethylene, organic boronic acid, trivalent manganese salt and base is 1.0:(1.0-2.0):(1.0-2.0):(1.0-2.0).

7. The method for synthesizing a quinolinephosphonate derivative according to claim 1, characterized in that: The reaction temperature under mild conditions is 25-100°C.

8. The method for optimizing the structure of a quinoline phosphonate derivative according to claim 1, wherein: The reaction time is 5-60 minutes.

9. A quinolinephosphonate derivative prepared by the synthesis method according to any one of claims 1 to 8.

10. Use of the quinolinephosphonate derivative prepared by the synthesis method according to any one of claims 1 to 8 in antibacterial activity.

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