1H-pyrazole-5-alcohol copper complex as well as synthesis method and application thereof
The imino group was introduced at the 4-position of the 5-pyrazolyone skeleton by solvothermal method, and the 4-position imine substituted 5-pyrazolyone derivative was prepared, which solved the problem of direct imino introduction that was difficult to achieve in the prior art. The synthetic copper complex showed excellent antibacterial properties.
Patent Information
- Application Number
- CN202510612984.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-13
- Publication Date
- 2025-07-11
AI Technical Summary
There is no report in the prior art that the 5-pyrazoleone skeleton is directly introduced into the imino-(R)C=N through 4-position CH, and the method of preparing 5-pyrazoleone derivatives is complicated, making it difficult to achieve the synthesis of 4-position imine substitution.
Using solvothermal method, using MPK, copper acetate monohydrate and nitrile as raw materials, the introduction of five-membered heterocyclic 5-pyrazoleone 4-position imino group was achieved through the addition reaction of MPK 4-position CH, and the 4-position imine substituted 5-pyrazoleone derivative was prepared. The synthesis method was simple, the raw materials were easy to obtain, and the operation was simple.
The 1H-pyrazole-5-ol copper complex Cu(L)2 was successfully synthesized, showing good antibacterial activity, and has excellent inhibitory effects on E. coli, Staphylococcus aureus, Bacillus subtilis, etc. The method is simple and efficient.
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Figure CN120289367A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a copper complex of 1H-pyrazol-5-ol, specifically to a copper complex of 3-methyl-1-phenyl-4-(1-imino-2-phenylethyl)-1H-pyrazol-5-ol and its synthesis method and application, belonging to the technical field of chemical synthesis. Background Art
[0002] Pyrazole is a nitrogen-containing heterocycle with five atoms and six π electrons, having strong reactivity. One of its important derivatives is 5-pyrazolone. 5-Pyrazolone derivatives and their metal complexes have excellent optical properties as well as biological and pharmacological activities such as antioxidant, antibacterial, antipyretic, and antitumor activities, and have always been a research hotspot in the fields of medicine, pesticides, dyes, optical materials, etc. 3-Methyl-1-phenyl-5-pyrazolone (MPK) is readily available and easy to synthesize, and is usually used as a template compound to carry out related research on pyrazolone. MPK undergoes tautomerism under different conditions and usually exists as CH-, OH-, or NH-form isomers:
[0003]
[0004] The CH at the 4-position of MPK is very active and can react with aldehydes, ketones, cobalt nitrate, imides, etc. to prepare corresponding MPK derivatives, but there is no report on the reaction with nitriles. And there is currently no report on the direct introduction of imino group -(R)C=NH into the 5-pyrazolone skeleton through the CH at the 4-position. Herein, we have discovered a method for directly introducing an imino group at the 4-position of MPK in one step by solvothermal method using MPK, copper acetate monohydrate, and nitrile as raw materials. At the same time, the corresponding OH-form imine copper complex is prepared. Based on the fact that copper complexes, imine compounds, and 5-pyrazolone derivatives generally exhibit good antibacterial, antitumor, antioxidant and other biological activities and optical properties, the copper complex of 1H-pyrazol-5-ol has extensive research and potential application value. Summary of the Invention
[0005] The object of the present invention is to provide a new copper complex of 1H-pyrazol-5-ol and its preparation method and application. Another object of the present invention is to provide a synthesis method for introducing an imino group at the 4-position of a five-membered heterocyclic 5-pyrazolone by an addition reaction of a nitrile as an amine source with the CH at the 4-position of the 5-pyrazolone skeleton to prepare a 4-imino-substituted 5-pyrazolone derivative. This method has readily available raw materials, simple operation, does not require complex multi-step reactions, and can obtain the copper complex of 1H-pyrazol-5-ol Cu(L)2 of the present invention in one step. Its new ligand is 3-methyl-1-phenyl-4-(1-imino-2-phenylethyl)-1H-pyrazol-5-ol synthesized by in-situ imination of MPK with phenylacetonitrile. And the complex Cu(L)2 has good antibacterial activity.
[0006] To achieve the above object, the technical solution of the present invention is as follows:
[0007] A copper complex of 1H-pyrazol-5-ol, the complex having the structure of formula I, with the molecular formula Cu(L)2, where L is the anionic ligand obtained by dehydrogenating the hydroxyl group of 3-methyl-1-phenyl-4-(1-imino-2-phenylethyl)-1H-pyrazol-5-ol:
[0008]
[0009] A crystal of a copper complex of 1H-pyrazol-5-ol, the complex being in the triclinic system, space group P-1, and the volume
[0010] The preparation method of the complex according to any one of the above, putting MPK, copper acetate monohydrate, and nitrile into a 25 mL stainless steel reaction vessel with a polytetrafluoroethylene liner, sealing it well, reacting at a constant temperature in an oven at 120–160 °C for 24–72 h, then cooling to room temperature at a cooling rate of 10 °C / hour, closing the oven, opening the reaction vessel the next day, filtering, and standing for 7 - 15 days to obtain flaky green crystals, namely the target product Cu(L)2 single crystal. The synthesis route is as follows:
[0011]
[0012] Using the above preparation method, with MPK and copper acetate monohydrate as raw materials and phenylacetonitrile as the amine source, through the addition reaction of the 4-position CH of MPK, the introduction of the imino group at the 4-position of the five-membered heterocyclic 5-pyrazolone is achieved, and the 4-iminated MPK derivative is synthesized in one step. The 4-iminated MPK derivative has the following structure:
[0013]
[0014] Further, the organic solvent is acetonitrile or phenylacetonitrile.
[0015] Further, the molar ratio of MPK to copper acetate monohydrate is 1:1–3:1, and the volume of nitrile is 5–15 mL.
[0016] Further, the cooling rate is not limited, and it can be cooled in a gradient or directly close the oven and cool naturally.
[0017] The application of the complex or crystal according to any one of the above in the preparation of antibacterial or bactericidal drugs.
[0018] Further, the bacteria are selected from Staphylococcus aureus, Bacillus subtilis, or Escherichia coli.
[0019] Beneficial effects:
[0020] The present invention synthesizes a previously unreported copper complex of 1H-pyrazol-5-ol. This complex has excellent inhibitory effects on three tested strains, namely Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. At the same time, the present invention provides a novel method for introducing an imine group at the 4-position of the five-membered heterocyclic 5-pyrazolone skeleton by using phenylacetonitrile and acetonitrile as amine sources in one step. This method is different from common imination methods, does not require raw materials such as aldehydes / ketones and primary amines, nor does it require cumbersome and complex reaction steps, and has the advantages of easily available raw materials, simple operation, and one-step in-situ synthesis. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 is the crystal structure diagram of the target complex.
[0022] Figure 2 is the crystal cell packing diagram of the target complex along the a-axis.
[0023] Figure 3 is the infrared spectrum diagram of the target complex.
[0024] Figure 4 is the infrared spectrum diagram of copper complex 2 with acetonitrile as the solvent.
[0025] Figure 5 is the crystal structure diagram of copper complex 2 with acetonitrile as the solvent. DETAILED DESCRIPTION OF THE EMBODIMENTS
[0026] The technical solutions of the present invention will be clearly and completely described below in conjunction with the specific embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and in no way constitutes a limitation on the present invention and its application or use. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the scope of protection of the present invention.
[0027] Example 1
[0028] This example provides a method for synthesizing and preparing single crystals of a copper complex of 1H-pyrazol-5-ol, specifically including:
[0029] 2 mmol (0.349 g) of MPK, 1 mmol (0.1997 g) of copper(II) acetate monohydrate, and 15 mL of benzonitrile were placed in a 25 mL stainless steel reaction vessel with a PTFE liner, sealed, and reacted at 150 °C in an oven for 72 h. Then, the temperature was decreased to room temperature at a rate of 10 °C / h, the oven was turned off, and the reaction vessel was opened the next day. After filtration and standing for 10 days, plate-like green crystals were obtained. After filtration and washing with methanol, the target copper complex of 1H-pyrazol-5-ol, Cu(L)2, was obtained, with a melting point of 289 - 291 °C and a yield of approximately 43%.
[0030] Figure 3 For the IR spectrum of the target complex (KBr / pellet, cm -1 ), its main IR characteristic peaks are as follows: 3434m, 3318m, 3060w, 3028w, 2966w, 2924w, 2853w, 1610s, 1589s, 1528s, 1499s, 1454m, 1407s, 1381s, 1273w, 1072s, 1030m, 1003m, 904w, 754s, 742w, 627m, 509w (cm -1 ). The sharp peak at 3318 cm -1 is attributed to the stretching vibration of imine N-H; the strong absorption peak at 1610 cm -1 is attributed to the stretching vibration of imine C=N; the peak at 2966 cm -1 is generated by the asymmetric stretching vibration of the methyl group, while the peaks at 2824 and 2853 cm -1 are generated by the symmetric and asymmetric stretching vibrations of the methylene group; the peaks at 1381 and 1072 cm -1 can be respectively attributed to the stretching vibrations of C-N and C-O; the peaks in the range of 1600 - 1407 cm -1 are the skeletal vibrations of the benzene ring and pyrazole ring.
[0031] A single crystal of the obtained copper complex Cu(L)2 with a size of approximately 0.21 mm × 0.11 mm × 0.05 mm was placed on a BRUKER SMART 1000CCD diffractometer, and graphite-monochromated Mo-K α (λ = 0.71073 nm) radiation was used to measure in the range of 1.357° < θ < 25.016° in the ω-2θ scanning mode at 298(2) K. All intensity data were reduced on the BrukerSAINT program. The data were corrected with the L p factor. The crystal structure was solved by the direct method using SHELEXS 97 software, with theoretical hydrogenation. The coordinates and anisotropic thermal parameters of all non-hydrogen atoms were refined to convergence by full-matrix least-squares method. The detailed crystallographic data are shown in Table 1.
[0032] 10. Crystallographic data of complex Cu(L)2 in Table 1
[0033]
[0034] The target copper complex Cu(L)2 belongs to the triclinic system, space group P-1. The results of single crystal X-ray diffraction analysis show that the complex consists of 2 newly formed ligands L in situ and 1 Cu 2+ atom. Among them, the new ligand L, 3-methyl-1-phenyl-4-(1-imino-2-phenylethyl)-1H-pyrazol-5-ol, is an imine compound formed by the addition of the CH at the 4-position of the raw material MPK to the cyano group of phenylacetonitrile. Using phenylacetonitrile as the amine source, an imino group is introduced at the 4-position of 5-pyrazolone. The new ligand L coordinates with Cu 2+ through the imine N atom and the O atom of the 5-enol hydroxyl group on the OH-form pyrazolone ring, forming a square planar coordination structure. The ORTEP diagram and atomic numbering of the target copper complex Cu(L)2 are shown in the attached figure Figure 1 , and its crystal cell packing diagram along the a-axis is shown in the attached figure Figure 2 .
[0035] Example 2:
[0036] In this example, acetonitrile was used to replace phenylacetonitrile in Example 1, and the reaction was carried out at a constant temperature of 120 °C in an oven for 48 h. Other conditions were the same as those in Example 1, and black blocky copper complex 2 crystals were obtained, with a melting point greater than 300 °C and a yield of 52%.
[0037] Figure 4 This is the infrared spectrum of copper complex 2 obtained in this example (KBr / pellet, cm -1 -1), and its main infrared characteristic peaks are: 3356m, 2987w, 2930w, 1608s, 1594s, 1580s, 1494s, 1450m, 1410s, 1379s, 1281w, 1071s, 1029m, 977m, 905w, 792m, 754s, 620m, 547w (cm -1 -1). The sharp peak at 3356 cm -1 is attributed to the stretching vibration of imine N-H; the strong absorption peak at 1608 cm -1 is attributed to the stretching vibration of imine C=N; the peaks at 2987 and 2930 cm -1 are produced by the symmetric and asymmetric stretching vibrations of methyl; the peaks at 1379 and 1071 cm -1 can be attributed to the stretching vibrations of C-N and C-O respectively; the peaks at 1600–1410 cm -1 are the skeletal vibrations of the benzene ring and pyrazole ring.
[0038] Select a single crystal of the copper complex 2 obtained in this example with a size of approximately 0.16 mm × 0.08 mm × 0.05 mm, and analyze its structure using the same single crystal X-ray diffraction technique as in Example 1. The results show that the copper complex 2 is monoclinic, space group P2(1) / c, and the molecular structure is as shown in the attached figure Figure 5 as follows.
[0039] Through characterization and analysis, it can be known that the ligand of this copper complex 2 is not the raw material MPK, but a ligand obtained by using acetonitrile as the amine source, and its cyano group undergoes an addition reaction with the 4-position C-H of MPK, and the anionic ligand obtained by dehydrogenation of the hydroxyl group of 3-methyl-1-phenyl-4-(1-imino-2-methyl)-1H-pyrazol-5-ol. Further confirmation shows that with the method of the present invention, either acetonitrile or phenylacetonitrile can be used as the amine source to achieve the one-step introduction of an imino group at the 4-position of the five-membered heterocyclic 5-pyrazolone skeleton, and the corresponding 5-pyrazolone 4-iminated derivative is prepared.
[0040] Example 3:
[0041] This example provides an evaluation of the antibacterial activity of the target copper complex Cu(L)2 of the present invention
[0042] Referring to the antibacterial experiment steps and methods in the reference (Xu R.B., J. Chem. Crystallogr. 2012, 42(9): 928-932), the inhibitory effects of the copper complex Cu(L)2 on three tested bacteria, Escherichia coli, Staphylococcus aureus, and Bacillus subtilis, were measured. Take 34 g of nutrient agar, add 1 L of distilled water, dissolve it and place it in an autoclave, and sterilize it at 120 °C for 30 min. Cool to 50-60 °C to make a plate. Take 0.1 mL of the activated bacterial solution, spread it evenly on the plate, and place 5 Oxford cups evenly and vertically at equal distances. Add 0.1 mL of the copper complex Cu(L)2 solution to the Oxford cups, cover the petri dish, and place it in a biochemical incubator at 37 °C for 24 h. After taking it out, measure the diameter (mm) of the clear antibacterial zone generated around each Oxford cup. The results are listed in Table 2. 11. Table 2 Antibacterial experiment results of the copper complex Cu(L)2
[0043] 12.
[0045] As can be seen from Table 2, the copper complex Cu(L)2 of the present invention shows excellent inhibitory effects on all three tested strains. Within the tested concentration range, the inhibitory effects on Bacillus subtilis and Escherichia coli are stronger than those on Staphylococcus aureus; as the concentration of the complex increases, the inhibitory effects on the three bacteria also increase.
[0046] The above-described embodiments merely represent several implementation manners of the present invention. The description thereof is relatively specific and detailed, but it should not be construed as a limitation to the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention.
Claims
1. A 1 H -pyrazole-5-ol copper complex, characterized in that: The molecular formula of the complex is Cu(L)2, where L represents the anionic ligand obtained by dehydrogenating the hydroxyl group of 3-methyl-1-phenyl-4-(1-imino-2-phenylethyl)-1 H -pyrazol-5-ol, and has the structure of Formula I: I。 2. A 1 H -pyrazol-5-ol copper complex according to claim 1, characterized in that: The crystal of the complex is triclinic, P space group -1, and the a of the crystal is 6.0890(7) Å, b is 8.7361(8) Å, c is 15.0588(16) Å, and the volume V is 795.69(14) Å 3 .
3. A 1 H -pyrazole-5-ol copper complex synthesis method, characterized in that, The synthesis method is as follows: 3-methyl-1-phenyl-5-pyrazolone, copper(II) acetate monohydrate, and phenylacetonitrile are placed in a 25 mL stainless steel reaction vessel with a PTFE liner, sealed, and reacted at a constant temperature of 120 – 160 °C in an oven for 24 – 72 h. Then, it is cooled to room temperature at a cooling rate of 10 °C / hour, the oven is turned off, and the reaction vessel is opened the next day. After filtration and standing for 7 - 15 days, block-shaped green crystals, namely the target product Cu(L)2, are obtained.
4. The synthesis method according to claim 3, wherein: Using this method, with phenylacetonitrile as the amine source, the introduction of an imine group at the 4-position of the five-membered heterocyclic 5-pyrazolone is achieved in one step to prepare 4-imine-substituted 5-pyrazolone derivatives.
5. The synthesis method according to claim 3, characterized in that: The organic solvent is phenylacetonitrile or acetonitrile.
6. The synthesis method according to claim 3, wherein: The molar ratio of 3-methyl-1-phenyl-5-pyrazolone to copper(II) acetate monohydrate is 1:1 – 3:1, and the volume of phenylacetonitrile is 5 – 15 mL.
7. The synthesis method according to claim 3, characterized in that: The cooling rate is not limited. It can be cooled in a gradient manner or the oven can be directly turned off for natural cooling.
8. Use of a copper complex of 1 H -pyrazol-5-ol in the preparation of antibacterial or bactericidal drugs.
9. The application according to claim 8, wherein: The bacteria are selected from Staphylococcus aureus, Bacillus subtilis, or Escherichia coli.