技术领域technical field
本发明涉及一种双-(对氟苯基)甲基哌嗪缩乙酸配合物及制备方法，属于化学技术领域。The invention relates to a bis-(p-fluorophenyl)methylpiperazine acetate complex and a preparation method thereof, belonging to the technical field of chemistry.
背景技术Background technique
有机–金属配位化合物因其独特的理化性质，在许多学领域都具有重要的应用价值。许多具有治疗作用的金属离子由于毒性大，刺激性强，难吸收等缺陷而无法直接应用于临床，但是若将其变成配合物后就能降低毒性和刺激性，进而改变吸收特性，变得容易被机体利用。1965年，Rosenberg发现顺铂(顺式二氯二氨合铂)能有效抑制大肠杆菌的分裂，随后进一步确认了其抗癌活性，并于1971年首次在临床试验中验证了顺铂对癌细胞的抑制作用，由此药物配合物成为药物分子设计及合成的一个热门领域。Organo-metallic coordination compounds have important application value in many fields of science because of their unique physical and chemical properties. Many metal ions with therapeutic effects cannot be directly used clinically due to their high toxicity, strong irritation, and difficulty in absorption. However, if they are converted into complexes, the toxicity and irritation can be reduced, and the absorption characteristics can be changed. easily used by the body. In 1965, Rosenberg discovered that cisplatin (cis-dichlorodiammine platinum) could effectively inhibit the division of Escherichia coli, and then further confirmed its anticancer activity, and verified the effect of cisplatin on cancer cells in clinical trials for the first time in 1971. Therefore, drug complexes have become a hot field in the design and synthesis of drug molecules.
许多学者研究表明，选用配合物作为新型药物开发具有许多的优势：(1)药效分子与金属离子形成配合物后，分子的亲脂性增强，可以提高药物分子穿透细胞膜的能力，进而提高药物的实际利用度；(2)新型药物分子兼有有机活性基团和无机金属离子的优势，并且两者间的协同效应还可以克服药物分子的在临床上的耐药性和毒副作用；(3)新型药物分子还可以增强药物的化学稳定性。Many scholars have shown that the use of complexes as new drug development has many advantages: (1) After the drug molecule and metal ion form a complex, the lipophilicity of the molecule is enhanced, which can improve the ability of the drug molecule to penetrate the cell membrane, thereby improving the drug. (2) The new drug molecule has the advantages of both organic active groups and inorganic metal ions, and the synergistic effect between the two can also overcome the clinical drug resistance and toxic side effects of the drug molecule; (3) ) novel drug molecules can also enhance the chemical stability of drugs.
哌嗪(Piperazine)又名六氢吡嗪，熔点为109.6℃、沸点为148.5℃，属于哌啶类的衍生物。20世纪以来，许多学者研究并发现其生物活性广泛，几十年来哌嗪类衍生物的发展取得了十分重大的成果，许多哌嗪类衍生物药物被应用于医药行业的各个领域，为人类健康事业的发展做出伟大贡献。基于上述原因，本发明设计改造了一种哌嗪的衍生物——双-(对氟苯基)甲基哌嗪，并利用改造后的分子与多种金属盐反应合成出有机-金属配合物。为新的有机-金属配位化合物新药的开发作出贡献。Piperazine, also known as hexahydropyrazine, has a melting point of 109.6°C and a boiling point of 148.5°C, and belongs to piperidine derivatives. Since the 20th century, many scholars have studied and found that it has a wide range of biological activities. In the past few decades, the development of piperazine derivatives has achieved very significant results. Great contribution to career development. Based on the above reasons, the present invention designs and transforms a derivative of piperazine—bis-(p-fluorophenyl)methylpiperazine, and utilizes the transformed molecule to react with various metal salts to synthesize an organic-metal complex . Contribute to the development of new drugs of organo-metal complexes.
发明内容Contents of the invention
本发明的目的在于提供一种合成方法简单、提纯工艺简便、产率较高、并且在空气中稳定性好的双-(对氟苯基)甲基哌嗪缩乙酸配合物及制备方法。其技术方案为：The object of the present invention is to provide a bis-(p-fluorophenyl)methylpiperazine acetal complex with simple synthesis method, simple and convenient purification process, high yield and good stability in air and a preparation method thereof. Its technical solution is:
一种双-(对氟苯基)甲基哌嗪缩乙酸配合物，其特征在于：配合物是二价金属与双-(对氟苯基)甲基哌嗪缩乙酸的配合物，其分子通式为(L)2M，其中M代表金属原子，为二价的Cu、Ni或Zn；L代表双-(对氟苯基)甲基哌嗪缩乙酸。A kind of bis-(p-fluorophenyl) methylpiperazine acetic acid complex, is characterized in that: complex is the complex of divalent metal and bis-(p-fluorophenyl) methylpiperazine acetic acid complex, its molecule The general formula is (L)2 M, wherein M represents a metal atom, which is divalent Cu, Ni or Zn; L represents bis-(p-fluorophenyl)methylpiperazine acetic acid.
一种根据权利要求1所述的双-(对氟苯基)甲基哌嗪缩乙酸配合物的制备方法，其特征在于采用以下步骤：A preparation method of two-(p-fluorophenyl) methylpiperazine acetal complex according to claim 1, characterized in that the following steps are adopted:
1)双-(对氟苯基)甲基哌嗪缩乙酸的制备，其过程为：将原料双-(对氟苯基)甲基哌嗪溶于弱碱的乙醇溶液中，再加入氯乙酸并充分搅拌均匀，置于65～75℃油浴锅，回流16h，减压蒸干溶剂得固体产物；再加入等体积的水，使固体溶解，并用盐酸溶液调节溶液pH值为3.0，析出沉淀，过滤干燥，得到粉末状固体的双-(对氟苯基)甲基哌嗪缩乙酸。1) The preparation of bis-(p-fluorophenyl)methylpiperazine acetic acid, the process is: dissolving the raw material bis-(p-fluorophenyl)methylpiperazine in ethanol solution of weak base, then adding chloroacetic acid And fully stir evenly, put in an oil bath at 65-75°C, reflux for 16 hours, evaporate the solvent to dryness under reduced pressure to obtain a solid product; then add an equal volume of water to dissolve the solid, and adjust the pH of the solution to 3.0 with hydrochloric acid solution to precipitate out , filtered and dried to obtain bis-(p-fluorophenyl)methylpiperazine acetal as a powdery solid.
2)将浓度为0.02mol/L的金属盐水溶液与0.02mol/L双-(对氟苯基)甲基哌嗪缩乙酸甲醇溶液等体积混合，室温下静置3-7天，得到双-(对氟苯基甲基)哌嗪缩乙酸的配合物。2) The metal salt aqueous solution with a concentration of 0.02mol/L and the methanol solution of 0.02mol/L bis-(p-fluorophenyl)methylpiperazine acetal acetal are mixed in equal volumes, and left standing at room temperature for 3-7 days to obtain bis- Complexes of (p-fluorophenylmethyl)piperazine acetic acid.
所述的双-(对氟苯基)甲基哌嗪缩乙酸配合物的制备方法，步骤1)中，所用的弱碱为碳酸钾、碳酸钠或碳酸氢钠无机弱碱，双-(对氟苯基)甲基哌嗪与弱碱的摩尔比为1:4；双-(对氟苯基)甲基哌嗪与氯乙酸的摩尔比为1:1.5。The preparation method of described bis-(p-fluorophenyl)methylpiperazine acetate complex, in step 1), the weak base used is potassium carbonate, sodium carbonate or sodium bicarbonate inorganic weak base, two-(p The molar ratio of fluorophenyl)methylpiperazine to weak base is 1:4; the molar ratio of bis-(p-fluorophenyl)methylpiperazine to chloroacetic acid is 1:1.5.
所述的双-(对氟苯基)甲基哌嗪缩乙酸配合物的制备方法，步骤2)中，金属盐指的是醋酸铜、醋酸锌和醋酸镍中的一种。In the preparation method of the bis-(p-fluorophenyl)methylpiperazine acetate complex, in step 2), the metal salt refers to one of copper acetate, zinc acetate and nickel acetate.
本发明与现有技术相比，具有以下优点：Compared with the prior art, the present invention has the following advantages:
1、原料低毒易得、成本低廉；1. The raw materials are low-toxic and easy to obtain, and the cost is low;
2、合成方法简单、操作简便；2. The synthesis method is simple and easy to operate;
3、产品产率较高、提纯工艺简单；3. The product yield is high and the purification process is simple;
4、产品的水溶性、稳定性良好。4. The product has good water solubility and stability.
附图说明Description of drawings
图1为实施例1的双-(对氟苯基)甲基哌嗪缩乙酸铜的配合物结构图；Fig. 1 is the complex structural figure of two-(p-fluorophenyl) methylpiperazine copper acetate of embodiment 1;
图2为实施例2的双-(对氟苯基)甲基哌嗪缩乙酸镍的配合物结构图；Fig. 2 is the complex structural figure of two-(p-fluorophenyl) methylpiperazine nickel acetate of embodiment 2;
图3为实施例3的双-(对氟苯基)甲基哌嗪缩乙酸锌的配合物结构图。Fig. 3 is a structural diagram of the complex of bis-(p-fluorophenyl)methylpiperazine zinc acetate in Example 3.
具体实施方案specific implementation plan
下面结合实施例对本发明做进一步说明，但本发明的范围并不受这些实施例的任何限制。The present invention will be further described below in conjunction with the examples, but the scope of the present invention is not limited by these examples.
实施例1，其具体操作为：Embodiment 1, its concrete operation is:
1)将2g双-(对氟苯基)甲基哌嗪，溶于含有3.835g碳酸钾的50mL乙醇中，并加入0.9832g氯乙酸,充分搅拌均匀后置于65～75℃油浴锅，回流16h，减压蒸干溶剂得固体产物；再加入50mL水，使固体溶解，并用盐酸溶液调节溶液pH值为3.0，析出沉淀，过滤干燥，得到2.162g双-(对氟苯基)甲基哌嗪缩乙酸，收率为90％。1) Dissolve 2g of bis-(p-fluorophenyl)methylpiperazine in 50mL of ethanol containing 3.835g of potassium carbonate, add 0.9832g of chloroacetic acid, stir well and place in an oil bath at 65-75°C, Reflux for 16 hours, evaporate the solvent to dryness under reduced pressure to obtain a solid product; then add 50 mL of water to dissolve the solid, and adjust the pH value of the solution to 3.0 with hydrochloric acid solution, precipitate out, filter and dry to obtain 2.162 g of bis-(p-fluorophenyl)methyl Piperazine acetic acid, the yield is 90%.
2)将2mL浓度为0.02mol/L的醋酸铜水溶液与2mL浓度为0.02mol/L双-(对氟苯基)甲基哌嗪缩乙酸甲醇溶液混合，室温下静置3天，得到18.63mg蓝色的双-(对氟苯基)甲基哌嗪缩乙酸与铜的配合物。2) Mix 2 mL of 0.02 mol/L copper acetate aqueous solution with 2 mL of 0.02 mol/L bis-(p-fluorophenyl)methylpiperazine acetal methanol solution, and let stand at room temperature for 3 days to obtain 18.63 mg Blue bis-(p-fluorophenyl)methylpiperazine acetal complex with copper.
实施例2，其具体操作为：Embodiment 2, its concrete operation is:
1)步骤1)与实施例1中的步骤1)完全相同；1) Step 1) is exactly the same as step 1) in Example 1;
2)将2mL浓度为0.02mol/L的醋酸镍水溶液与2mL浓度为0.02mol/L双-(对氟苯基)甲基哌嗪缩乙酸甲醇溶液混合，室温下静置5天，产生17.691mg碧绿色的双-(对2) Mix 2mL of 0.02mol/L nickel acetate aqueous solution with 2mL of 0.02mol/L bis-(p-fluorophenyl)methylpiperazine acetal methanol solution, and let stand at room temperature for 5 days to produce 17.691mg Emerald double-(right
氟苯基甲基)哌嗪缩乙酸与镍的配合物，产率为53％。The complex of fluorophenylmethyl)piperazine acetic acid and nickel, the yield is 53%.
实施例3，其具体操作为：Embodiment 3, its concrete operation is:
1)步骤1)与实施例1中的步骤1)完全相同；1) Step 1) is exactly the same as step 1) in Example 1;
2)将2mL浓度为0.02mol/L的醋酸锌水溶液与2mL浓度为0.02mol/L双-(对氟苯基)甲基哌嗪缩乙酸甲醇溶液混合，室温下静置7天，产生15.087mg无色的双-(对氟苯基甲基)哌嗪缩乙酸与锌的配合物，产率为45％。2) Mix 2 mL of 0.02 mol/L zinc acetate aqueous solution with 2 mL of 0.02 mol/L bis-(p-fluorophenyl)methylpiperazine acetal methanol solution, and let stand at room temperature for 7 days to produce 15.087 mg A colorless complex of bis-(p-fluorophenylmethyl)piperazine acetic acid and zinc with a yield of 45%.
下面对实施例1-3进行检测：Embodiment 1-3 is detected below:
测试仪器为Bruker Smart Apex CCD单晶衍射仪，以Mo-Kα(λ＝0.071073nm)射线，在20℃时用ω/2θ的扫描模式进行测试。数据通过SAINT修正，Lorentz修正和极化效应的消除得到。吸收修正使用Bruker的SADABS补充。用SHELXL-97直接解出了分子结构。金属原子及其周围相连原子的位置用直接E-maps的方法测出，其他非氢原子通过傅立叶变换，最小二乘法修正逐步确定其精细结构。氢原子则最后确定于计算所得的位置，并有统一的Uiso值，溶剂的氢原子由差值傅里叶图中确定。检测结果如表1所示。The test instrument is a Bruker Smart Apex CCD single crystal diffractometer, which uses Mo-Kα (λ=0.071073nm) rays to conduct tests at 20°C in the scanning mode of ω/2θ. The data were obtained by SAINT correction, Lorentz correction and elimination of polarization effects. Absorption correction is supplemented with Bruker's SADABS. The molecular structure was solved directly with SHELXL-97. The positions of metal atoms and their surrounding atoms are directly measured by E-maps method, and the fine structures of other non-hydrogen atoms are gradually determined through Fourier transform and least square correction. The hydrogen atoms are finally determined at the calculated position, and have a unified Uiso value, and the hydrogen atoms of the solvent are determined by the difference Fourier map. The test results are shown in Table 1.
表1实施例1-3单晶衍射数据表Table 1 Example 1-3 single crystal diffraction data table
a R1＝Σ||C|-|Fc||/ΣFo|.b wR2＝[Σw(Fo2-Fc2)2/Σw(Fo2)]1/2。a R1＝Σ||C|-|Fc||/ΣFo|.b wR2＝[Σw(Fo2-Fc2)2/Σw(Fo2)]1/2.
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|---|---|
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6127467A (en)* | 1989-10-06 | 2000-10-03 | Cosan Chemical Corporation | Aminocarboxylate salts as corrosion inhibitors in coating applications |
| CN101235019A (en)* | 2008-03-06 | 2008-08-06 | 徐锁平 | 3,5-diiodo salicylaldehyde-4-(omega-aminoalkyl)morpholine metal complexes, preparation method and use thereof |
| CN102827192A (en)* | 2012-09-16 | 2012-12-19 | 罗梅 | Zinc complex |
| CN103288857A (en)* | 2013-06-08 | 2013-09-11 | 山东理工大学 | Sarafloxacin metal complex and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6127467A (en)* | 1989-10-06 | 2000-10-03 | Cosan Chemical Corporation | Aminocarboxylate salts as corrosion inhibitors in coating applications |
| CN101235019A (en)* | 2008-03-06 | 2008-08-06 | 徐锁平 | 3,5-diiodo salicylaldehyde-4-(omega-aminoalkyl)morpholine metal complexes, preparation method and use thereof |
| CN102827192A (en)* | 2012-09-16 | 2012-12-19 | 罗梅 | Zinc complex |
| CN103288857A (en)* | 2013-06-08 | 2013-09-11 | 山东理工大学 | Sarafloxacin metal complex and preparation method thereof |
| Title |
|---|
| BERGEL, F.等: "Some potentially cytotoxic methylnitrosamines", 《JOURNAL OF THE CHEMICAL SOCIETY》* |
| IRVING, H.等: "The stability of metal complexes of 1,4-piperazinediacetic acid", 《JOURNAL OF THE CHEMICAL SOCIETY》* |
| TIEN-YAU LUH等: "Synthesis and X-Ray Crystal Structure (4-morpholino)acetatocopper(II)", 《TRANSITION METAL CHEMISTRY》* |
| 李清寒等: "微波辐射下2-[4-二-(4-氟苯)甲基]哌嗪乙酰腙化合物的合成", 《有机化学》* |
| Publication | Publication Date | Title |
|---|---|---|
| Dhahagani et al. | Crystal structure, optical properties, DFT analysis of new morpholine based Schiff base ligands and their copper (II) complexes: DNA, protein docking analyses, antibacterial study and anticancer evaluation | |
| CN102268046B (en) | 9-anthracenecarboxaldehyde-4,5-dihydro-1H-imidazol-2-yl-hydrazone cisplatin complex and synthesis method and use thereof | |
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