The Preparation Of Platinum Anti-tumor Drug Miplatin And Its Physical And Chemical Properties

Cancer is a serious threat to human life,chemotherapy is one of the most important means to treat cancer.Since its approval by FDA,cisplatin has been widely used in the chemotherapy of various cancers,such as ovarian cancer,testicular cancer,lung cancer,and so on.Unfortunately,severe side effects and drug resistance limit the continuous use of cisplatin.Therefore,developing platinum drugs which have lower toxicity with higher effect and can overcome cisplatin-resistant is very important in the future.Liver cancer is one of the highest mortality cancers in China.However,cisplatin and other drugs are not effective for advanced hepatocellular carcinoma.The molecular targeted drugs introduced in recent years are also difficult to cure.In this case,the Japanese Sumitomo Co.,Ltd.developed miriplatin for lipiodoiling for the treatment of liver cancer.The clinical datas showed that the efficacy and safety of miriplatin were better than the only approved drug zinostatin stimalamer for the treatment of liver cancer.Miriplatin is currently approved in Japan only.At the same time,the systematic research of miriplatin is deficiency in China,and due to the patent protection of Japan,there are few reports on the technology,detection methods and physical&chemical properties of miriplatin.This paper developed a simple,quality based,economical and environmental friendly preparation process of miriplatin which can be used in industry.The structure of the miriplatin was characterized by a variety of instruments,and the detection method of the miriplatin was established,especially the HPLC method.Finally,the physicochemical properties of miriplatin were systematically studied,which laid the foundation for the development of new dosage and the follow up quality research.The main contents are as follows:1.Combined with the general preparation methods of platinum drugs and ralated literatures at home and abroad,the Sodium Salt Method is optimized and innovated to prepare three batches of miriplatin.The yield of miriplatin crude can be 74%,the yield of recrystallization can be 87%,and the total yield can be 65%.2.The structure of miriplatin was confirmed by EA,MS,TGA,IR,UV,¹H-NMR and¹³C-NMR,which shows that the structure of the sample is in accordance with the theoretical structure.3.A high performance liquid chromatography（HPLC）method was established for the determination of the content of miriplatin.The results show that the content of the miriplatin samples are all above 99%.4.Combined with a variety of experimental instruments and high performance liquid chromatography,we studied the physicochemical properties of miriplatin,including properties,oil-water partition coefficient,stability and so on.Description:white or almost white solid powder,insoluble in water and DMF,almost insoluble in methanol,dissolved in anhydrous ethanol and n-butanol,dissolved in dichloromethane,dissolved in trichloromethane,the specific rotation was between 29-30 degrees,and the melting point was between 213-215℃.Under the condition of heating,the miriplatin solution is yellow in thiourea and red brown in three ketone and yellow green in nitric acid.The oil water separation coefficient Log P is 1.66 under this experimental condition,and the miriplatin is unstable under light and unstable at high temperature.The higher the temperature,the faster miriplatin degrades,the higher the concentration,the faster miriplatin degrades.The miriplatin solution is very unstable under acidic conditions,is more stable under oxidizing conditions,is more stable under reducing conditions and is most stable under alkaline conditions.