A metal complex and its preparation method and application

Abstract

The present invention belongs to the technical field of organic complex synthesis, and specifically relates to a metal complex and its preparation method and application. The general formula of the metal complex is L-M, wherein L is a ligand, M is a metal salt, and the ligand is diphenylmethylbenzylamine or diphenylmethylquinuclidine-3-amine. The diphenylmethylbenzylamine is prepared by reacting imine and sodium cyanoborohydride; the diphenylmethylquinuclidine-3-amine is prepared by reacting diphenylmethylbenzylamine and ammonium formate. The preparation method of the metal complex is to dropwise add a metal salt solution to a methanol solution containing the ligand, carry out a coordination reaction, and filter to obtain a target product. The preparation method has the advantages of simple process, mild conditions, low cost, and easy industrialization. The metal complex provided by the present invention can be used to prepare an antibacterial agent, which has the advantages of high efficiency, low toxicity, and environmental protection.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic complex synthesis, and in particular relates to a metal complex and a preparation method and application thereof. Background Art

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

[0003] In 2012, Du Kai et al. synthesized Eu(III) binary luminescent complexes Eu(BTC)·2H2O, Eu2(MTA)·4H2O, and Eu2(CCA)·4H2O using 1,3,5-benzenetricarboxylic acid (H3BTC), mellitic acid (H6MTA), and 1,2,3,4,5,6-cyclohexacarboxylic acid (H6CCA) as ligands, respectively. Their chemical compositions were characterized by elemental analysis, infrared spectroscopy, and plasma atomic emission spectroscopy. (Zhang Jinli, Zhao Liping, Luo Xuan, et al. Synthesis and spectral analysis of binary complexes of europium with polycarboxylates [J]. Acta Chimica Sinica, 2012, 70(05): 679-682.)

[0004] Chitosan (abbreviated as CTS) is a product of chitin deacetylation and a linear semi-rigid polymer. Because CTS molecules contain -NH2, -OH, and -NHCOCH3, it has a strong chelating ability for transition metals. Yu Xianda et al. synthesized complexes of Cu(II), Ni(II), and Zn(II) with CTS under homogeneous reaction conditions and determined the composition of the complexes for the first time through elemental analysis. (Wang Aiqin, Zhang Pingyu, Yu Xianda. Synthesis and properties of complexes of chitosan with copper(II), nickel(II), and zinc(II) [J]. Chemical Bulletin, 1999(08):32-34. DOI:10.14159 / j.cnki.0441-3776.1999.08.006.)

[0005] The preparation cost of the above metal complexes is high, the process is complicated, the biological activity and antibacterial properties need to be improved, and there are few types of existing metal complexes. Therefore, the development of a new metal complex has important application prospects. Summary of the Invention

[0006] In view of the problems existing in the prior art, the first object of the present invention is to provide a metal complex having significant antibacterial ability.

[0007] The second object of the present invention is to provide a method for preparing the above metal complex, which is simple and the raw materials are easily available.

[0008] The third object of the present invention is to provide the use of the metal complex, which can be used in the preparation of antibacterial agents.

[0009] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0010] A metal complex having the general formula LM;

[0011] Where L is a ligand and M is a metal salt;

[0012] The metal salt is a copper salt, a zinc salt, a manganese salt, an iron salt or a nickel salt; the copper salt is copper acetate, copper sulfate or copper trifluoromethanesulfonate, etc.; the zinc salt is zinc chloride, etc.; the manganese salt is manganese sulfate, etc.; the iron salt is ferrous sulfate heptahydrate, etc.; the nickel salt is nickel chloride, etc.

[0013] The ligand is diphenylmethylbenzylamine or diphenylmethylquinuclidine-3-amine; the structural formula of the diphenylmethylbenzylamine is shown in formula (I); the structural formula of the diphenylmethylquinuclidine-3-amine is shown in formula (II):

[0014]

[0015]

[0016] The preparation method of the metal complex specifically adopts the following steps: adding a metal salt solution dropwise into a methanol solution containing a ligand to carry out a coordination reaction, and filtering to obtain the metal complex.

[0017] The ligand is diphenylmethylbenzylamine or diphenylmethylquinuclidine-3-amine; the metal salt is a copper salt, a zinc salt, a manganese salt, an iron salt or a nickel salt; the copper salt is copper acetate, copper sulfate or copper trifluoromethanesulfonate; the zinc salt is zinc chloride; the manganese salt is manganese sulfate; the iron salt is ferrous sulfate heptahydrate; the nickel salt is nickel chloride.

[0018] Furthermore, the molar ratio of the ligand to the metal salt is 1:2.

[0019] Furthermore, the molar volume ratio of the ligand to methanol in the methanol solution containing the ligand is 1 mmoL:2 mL; and the molar volume ratio of the metal salt to water in the metal salt solution is 2 mmoL:(1-4) mL.

[0020] Furthermore, the coordination reaction temperature is 50-60° C. and the time is 3 hours.

[0021] Furthermore, the benzhydrylbenzylamine is prepared from a THF solution containing imine and sodium cyanoborohydride by stirring, extracting, drying, filtering and desolvation. The reaction process is shown in the following formula:

[0022]

[0023] The molar volume ratio of the imine, sodium cyanoborohydride and THF is 2 mmol:1 mmol:10 mL; and the stirring conditions are 25° C. and 5 h.

[0024] Furthermore, the dibenzylquinuclidine-3-amine is prepared by heating, cooling, filtering, washing, extracting, drying and desolvating an ethanol solution containing dibenzylbenzylamine and ammonium formate in the presence of a catalyst. The reaction process is shown in the following formula:

[0025]

[0026] The molar volume ratio of the diphenylmethylbenzylamine, ammonium formate and ethanol is 1 mmol:4 mmol:17.5 mL; the catalyst is a palladium carbon catalyst; and the heating conditions are a temperature of 30-100° C. and a time of 10 h.

[0027] Furthermore, the solvent used in the extraction is dichloromethane.

[0028] The application of the metal complex is in the preparation of an antibacterial agent.

[0029] Furthermore, the antibacterial agent can be used to inhibit or kill at least one of apple rot pathogen, cucumber wilt pathogen, wheat take-all pathogen, peanut root rot pathogen, tomato wilt pathogen, peanut white rot pathogen and strawberry gray mold pathogen.

[0030] Beneficial effects:

[0031] The metal complex of the present invention uses a ligand of diphenylmethylbenzylamine or diphenylmethylquinuclidine-3-amine, which forms a complex with a metal salt and can greatly enhance the bactericidal ability of the metal complex. The preparation methods of diphenylmethylbenzylamine and diphenylmethylquinuclidine-3-amine are simple and easily available. The metal complex provided by the present invention has significant antibacterial ability and can be used to inhibit or kill apple rot pathogen, cucumber wilt pathogen, wheat take-all pathogen, peanut root rot pathogen, tomato wilt pathogen, peanut white rot pathogen, and strawberry gray mold pathogen. Moreover, the preparation process of the metal complex has readily available raw materials, high yield, low cost, high antibacterial activity, and extremely high application development value. DETAILED DESCRIPTION

[0032] To make the purpose, technical solutions and advantages of this application more clear, the embodiments of the present invention will be described in detail below. It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of this application can be combined with each other in any way.

[0033] Example 1 Synthesis of Diphenylmethylbenzylamine

[0034] To a dry 100 mL three-necked flask, add imine (4 mmol), sodium cyanoborohydride (2 mmol), and 20 mL of dry THF. Stir and react at 25°C. Monitor the reaction progress by TLC. After 5 h of reaction, the starting material spot disappears. Post-treatment: Add 10 mL of distilled water, adjust the solution to pH 10-11 with 20% NaOH, and extract three times with 50 mL of dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate for 1 h, filter, and desolventize to obtain 0.8 g of a white solid (yield 82.3%). 1H NMR (500 MHz, DMSO-d6) δ8.31 (t, J = 6.0 Hz, 1H), 7.53–6.93 (m, 14H), 5.53 (s, 1H), 4.44 (d, J = 13.1 Hz, 1H), 4.23 (d, J = 5.9 Hz, 2H), 4.05 (d, J = 13.8 Hz, 1H), 2.94 (d, J = 10.9 Hz, 1H), 2.79–2.59 (m, 1H), 1.73 (d, J = 15.1 Hz, 1H), 1.55 (d, J = 13.1 Hz, 1H), 1.39 (qd, J = 12.3, 4.1 Hz, 1H), 1.14 (qd, J = 12.1, 3.8 Hz, 2H). The synthetic route is as follows:

[0035]

[0036] Example 2 Synthesis of Benzhydrylquinuclidine-3-amine

[0037] In a dry 250mL four-necked flask, benzhydrylbenzylamine (14.2mmol), 1g 10% palladium carbon catalyst, 70mL ethanol solution and ammonium formate (56.8mmol) were added, and the temperature was gradually raised to reflux for reaction. The reaction was carried out for 10h. The reaction was monitored by TLC and the raw material spot disappeared. Post-treatment: cooled to room temperature, filtered, the catalyst was filtered off, and the filter cake was washed with 40mL ethanol. The filtrate was combined, 10mL water was added, and the pH of the solution was adjusted to 10-11 with 20% NaOH. The solution was extracted three times with 80mL dichloromethane. The organic phases were combined, dried with 4g anhydrous sodium sulfate, filtered, and desolvated to obtain 1.5g of a white solid with a yield of 63.3%. 1H NMR (500 MHz, CDCl3) δ7.34 (d, J = 7.6 Hz, 2H), 7.23–7.06 (m, 7H), 7.01 (t, J = 7.1 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 3.56 (dd, J = 12.1, 7.6 Hz, 1H), 3.23–3.04 (m, 2H), 2.72 (t, J = 7.8 Hz, 2H), 2.55 (t, J = 12.8 Hz, 1H), 1.75 (d, J = 41.8 Hz, 2H), 1.61–1.45 (m, 2H), 1.19 (q, J = 11.6, 9.9 Hz, 1H), 0.98 (s, 2H). The synthetic route is as follows:

[0038]

[0039] Example 3

[0040] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylquinuclidine-3-amine (1 mmol, 292 mg). Heat to 50°C and stir for 30 minutes until the solid is completely dissolved. After dissolution, add zinc chloride (2 mmol, 272.6 mg) in 1 mL of water dropwise. After complete addition, react at 50°C for 3 hours. TLC monitoring of the starting material spot disappears. After standing for 1 hour, filter and obtain a metal complex named S1 in a yield of 55%. The structural characterization data of the product are as follows: Anala.Calc / %: C, 56.03; H, 5.64; N, 6.53; Found: C, 56.31; H, 5.31; N, 6.23. The synthetic route is as follows:

[0041]

[0042] Example 4

[0043] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylquinuclidine-3-amine (1 mmol, 292 mg). Heat to 50°C and stir for 30 minutes until the solid is completely dissolved. After dissolution, add nickel chloride (2 mmol, 259.2 mg) in 1 mL of water dropwise. After complete addition, react at 50°C for 3 hours. TLC monitoring of the starting material spot disappears. After standing for 1 hour, filter and obtain the metal complex, named S2, in a yield of 44%. The structural characterization data of the product are as follows: Anala. Calc / %: C, 56.92; H, 5.73; N, 6.64. Found: C, 56.71; H, 5.48; N, 6.35. The synthetic route is as follows:

[0044]

[0045] Example 5

[0046] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylquinuclidine-3-amine (1 mmol, 292 mg). Heat to 50°C and stir for 30 minutes until the solid is completely dissolved. After dissolution, add 1 mL of copper sulfate (2 mmol, 499.4 mg) in water dropwise. After complete addition, react at 50°C for 3 hours. TLC monitoring of the starting material spot disappears. After standing for 1 hour, filter and obtain a metal complex named S3 in a 61% yield. The structural characterization data of the product are as follows: Anala. Calc / %: C, 53.14; H, 5.35; N, 6.20. Found: C, 53.45; H, 5.67; N, 6.51. The synthetic route is as follows:

[0047]

[0048] Example 6

[0049] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylquinuclidine-3-amine (1 mmol, 292 mg). Heat to 50°C and stir for 30 min until the solid is completely dissolved. After dissolution, add 1 mL of an aqueous solution of manganese sulfate (2 mmol, 302 mg) dropwise. After completion, react at 50°C for 3 h. TLC monitoring of the starting material spot disappears. After standing for 1 h, filter and obtain a metal complex named S4 in a 48% yield. The structural characterization data of the product are as follows: Anala. Calc / %: C, 54.17; H, 5.46; N, 6.32. Found: C, 54.38; H, 5.74; N, 6.52. The synthetic route is as follows:

[0050]

[0051] Example 7

[0052] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylquinuclidine-3-amine (1 mmol, 292 mg). Heat to 50°C and stir for 30 min until the solid is completely dissolved. After dissolution, add 1 mL of ferrous sulfate heptahydrate (2 mmol, 556 mg) in water dropwise. After completion of the addition, react at 50°C for 3 h. TLC monitoring of the starting material spot disappears. After standing for 1 h, filter and obtain a metal complex named S5 in a 64% yield. The structural characterization data of the product are as follows: Anala. Calc / %: C, 54.06; H, 5.44; N, 6.30. Found: C, 54.31; H, 5.23; N, 6.51. The synthetic route is as follows:

[0053]

[0054] Example 8

[0055] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylbenzylamine (1 mmol, 383 mg), heat to 60°C, and stir for 30 minutes. Once the solution becomes clear, add a mixture of 2 mmol, 400 mg of copper acetate and 4 mL of water dropwise. After complete addition, stir at 60°C for 3 hours. TLC monitors the disappearance of the starting material spot. After standing for 1 hour, filter and obtain a metal complex, designated T1, in a 62% yield. The structural characterization data of the product are as follows: Anala. Calc / %: C, 66.00; H, 6.43; N, 4.97. Found: C, 66.24; H, 6.14; N, 4.66. The synthetic route is as follows:

[0056]

[0057] Example 9

[0058] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylbenzylamine (1 mmol, 383 mg). Heat to 60°C and stir for 30 minutes. Once the solution becomes clear, add a mixture of 2 mmol, 302 mg of manganese sulfate and 4 mL of water dropwise. After complete addition, stir at 60°C for 3 hours. TLC monitoring reveals the disappearance of the starting material spot. After standing for 1 hour, filter and obtain a metal complex, designated T2, in a yield of 53%. The structural characterization data of the product are as follows: Anala. Calc / %: C, 60.78; H, 5.67; N, 5.25. Found: C, 60.47; H, 5.38; N, 5.64. The synthetic route is as follows:

[0059]

[0060] Example 10

[0061] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylbenzylamine (1 mmol, 383 mg). Heat to 60°C and stir for 30 minutes. Once the solution becomes clear, add a mixture of 2 mmol, 272.6 mg of zinc chloride and 4 mL of water dropwise. After complete addition, stir at 60°C for 3 hours. The starting material spot disappears as monitored by TLC. After standing for 1 hour, filter and obtain a metal complex, designated T3, in a 47% yield. The structural characterization data of the product are as follows: Anala. Calc / %: C, 62.51; H, 5.83; N, 5.40. Found: C, 62.21; H, 5.51; N, 5.14. The synthetic route is as follows:

[0062]

[0063] Example 11

[0064] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylbenzylamine (1 mmol, 383 mg). Heat to 60°C and stir for 30 minutes. Once the solution becomes clear, add a mixture of 2 mmol, 499.4 mg of copper sulfate and 4 mL of water dropwise. After complete addition, stir at 60°C for 3 hours. After TLC monitoring, the starting material spot disappears. After standing for 1 hour, filter and obtain a metal complex, designated T4, in a 64% yield. The structural characterization data of the product are as follows: Anala. Calc / %: C, 59.82; H, 5.58; N, 5.17. Found: C, 59.51; H, 5.78; N, 5.46. The synthetic route is as follows:

[0065]

[0066] Example 12

[0067] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylbenzylamine (1 mmol, 383 mg). Heat to 60°C and stir for 30 minutes. Once the solution becomes clear, add a mixture of ferrous sulfate heptahydrate (2 mmol, 556 mg) and 4 mL of water dropwise. After complete addition, stir at 60°C for 3 hours. The starting material spot disappears as monitored by TLC. After standing for 1 hour, filter and obtain a metal complex, designated T5, in a 53% yield. The structural characterization data of the product are as follows: Anala. Calc / %: C, 60.68; H, 5.66; N, 5.24. Found: C, 60.38; H, 5.33; N, 5.54. The synthetic route is as follows:

[0068]

[0069] Example 13

[0070] In a 10mL round-bottom flask, add 2mL of methanol and diphenylmethylbenzylamine (1mmol, 383mg), heat to 60°C, and stir for 30 minutes. Once the solution becomes clear, add a mixture of nickel chloride (2mmol, 259.2mg) and 4mL of water dropwise. After complete addition, stir at 60°C for 3 hours. TLC monitoring reveals the disappearance of the starting material spot. After standing for 1 hour, filter and obtain a metal complex, designated T6, in a 41% yield. The structural characterization data of the product are as follows: Anala. Calc / %: C, 63.32; H, 5.90; N, 5.47. Found: C, 63.53; H, 5.68; N, 5.76. The synthetic route is as follows:

[0071]

[0072] Example 14

[0073] In a 10 mL round-bottom flask, add 2 mL of methanol and diphenylmethylbenzylamine (1 mmol, 383 mg). Heat to 60°C and stir for 30 minutes. Once the solution becomes clear, add a mixture of copper trifluoromethanesulfonate (2 mmol, 723.4 mg) and 4 mL of water dropwise. After complete addition, stir at 60°C for 3 hours. TLC monitoring reveals the disappearance of the starting material spot. After standing for 1 hour, filter and obtain a metal complex, designated T7, in a 51% yield. The structural characterization data of the product are as follows: Anala. Calc / %: C, 46.80; H, 4.06; N, 3.76. Found: C, 46.53; H, 4.37, N, 3.42. The synthetic route is as follows:

[0074]

[0075] Example 15

[0076] First, seal the PDA prepared in a conical flask according to the proportion with a breathable sealing film, put it into a high-pressure sterilizer at a temperature of 120°C, and sterilize it for 30 minutes. Before inoculating the bacteria, different concentrations of target compound and control drug solutions must be prepared, using acetone as the solvent. In the experiment, each drug concentration culture dish was measured with 3 parallel replicates. The colony diameter was measured using the cross-cross method, and the inhibition rate was calculated. The formula for the inhibition rate of antibacterial activity is as follows: mycelium growth inhibition rate = (control colony diameter - treated colony diameter) / control colony diameter × 100%. The antibacterial activity of the metal complex prepared in Example 3-14 is shown in Table 1 and Table 2:

[0077] Table 1 Antibacterial activity of the metal complexes prepared in Examples 3-14 (inhibition rate %)

[0078]

[0079] Table 2 Antibacterial activity of the metal complexes prepared in Examples 3-14 (inhibition rate %)

[0080]

[0081]

[0082] The results showed that at a drug concentration of 50 mg / L, most target compounds exhibited inhibition rates exceeding 43% against peanut root rot, tomato wilt, peanut white rot, and strawberry gray mold. At a drug concentration of 100 mg / L, 12 target compounds exhibited inhibition rates exceeding 64% against wheat take-all pathogen. Compounds S1, S2, S5, and T6 exhibited significant inhibition against wheat take-all pathogen, while compound T4 exhibited the best inhibition against apple rot pathogen. Compounds S3, S4, and T3 exhibited significant inhibition against cucumber wilt pathogen, compound S1 exhibited significant inhibition against strawberry gray mold, compound S3 exhibited significant inhibition against peanut root rot pathogen, compound T3 exhibited significant inhibition against tomato wilt pathogen, and compound T4 exhibited significant inhibition against peanut white rot pathogen.

Claims

1. A metal complex, characterized in that The general formula of the metal complex is LM; Wherein, L is a ligand and M is a metal salt; The ligand is diphenylmethylbenzylamine or diphenylmethylquinuclidine-3-amine; the structural formula of the diphenylmethylbenzylamine is shown in formula (I); the structural formula of the diphenylmethylquinuclidine-3-amine is shown in formula (II): (I)； (II); The metal salt is a copper salt, a zinc salt, a manganese salt, an iron salt or a nickel salt.

2. The metal complex according to claim 1, characterized in that The copper salt is copper acetate, copper sulfate or copper trifluoromethanesulfonate; the zinc salt is zinc chloride; the manganese salt is manganese sulfate; the iron salt is ferrous sulfate heptahydrate; and the nickel salt is nickel chloride.

3. A method for preparing the metal complex according to claim 1 or 2, characterized in that: The preparation method comprises the steps of dropwise adding a metal salt solution into a methanol solution containing a ligand to carry out a coordination reaction to obtain the metal complex.

4. The preparation method according to claim 3, characterized in that The molar ratio of the ligand to the metal salt is 1:

2.

5. The preparation method according to claim 3, characterized in that The molar volume ratio of the ligand to methanol in the methanol solution containing the ligand is 1 mmoL:2 mL; the molar volume ratio of the metal salt to water in the metal salt solution is 2 mmoL:(1-4) mL.

6. The preparation method according to claim 3, characterized in that The temperature of the coordination reaction is 50-60° C. and the time is 3 h.

7. The preparation method according to claim 3, characterized in that The benzhydryl benzylamine is prepared from a THF solution containing imine and sodium cyanoborohydride by stirring, extracting, drying, filtering and desolvation. The reaction process is shown in the following formula: The molar volume ratio of the imine, sodium cyanoborohydride and THF is 2 mmol:1 mmol:10 mL.

8. The preparation method according to claim 3, characterized in that The benzhydrylquinuclidine-3-amine is prepared by heating, cooling, filtering, washing, extracting, drying and desolvating an ethanol solution containing benzhydrylbenzylamine and ammonium formate in the presence of a catalyst. The reaction process is shown in the following formula: The molar volume ratio of the diphenylmethylbenzylamine, ammonium formate and ethanol is 1 mmol:4 mmol:17.5 mL; the catalyst is a palladium-carbon catalyst; and the heating conditions are a temperature of 30-100° C. and a time of 10 h.

9. Use of the metal complex according to claim 1 or 2 or / and the metal complex prepared by the method according to any one of claims 3 to 8 in the preparation of an antibacterial agent, characterized in that: The antibacterial agent is used for inhibiting or killing at least one of apple rot pathogen, cucumber wilt pathogen, wheat take-all pathogen, peanut root rot pathogen, tomato wilt pathogen, peanut white rot pathogen and strawberry gray mold pathogen.

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