Synthesis Study And Production Process Optimization Of Antineoplastic Drug Melphalan

Cancer is a disease seriously threatening human health.Millions of people die from cancer every year around the world.China is the most populous country in the world and has the most cancer patients.Therefore,it is very urgent to find a method that can treat cancer effectively.The main treatment methods for cancer are surgery,radiation therapy,drug therapy(chemotherapy)and immunotherapy(biotherapy).But to a large extent,drug therapy is the main treatment,namely chemotherapy.Alkylation agents,also known as bio-alkylating agents,are among the earliest and most widely used antitumor drugs.The nitrogen mustard antitumor drug is the most important alkylating agent and is an important class of antitumor drugs for clinical application.Melphalan is an anticancer drug of amino acid nitrogen mustard,which has strong cytotoxicity.It can directly act on the DNA in biological cells,causing the alkylation of the electron-rich groups of DNA,thus making the DNA lose its original physiological activity,unable to replicate and divide,and ultimately leading to cell death.Melphalan has been widely used since its appearance in 1952,and its curative effect is worthy of affirmation.The development of this product has an excellent market prospect.The current synthetic routes of melphalan have certain disadvantages,such as too long synthetic route or low yield or costly starting material.In this paper,we found a better production process by consulting the reported literature and detailed experimental comparison.Firstly,we choose the cheap p-nitro-L-phenylalanine as the starting material.The amino group was protected by phthalic anhydride,and the effects of different additives on the product yield were emphatically investigated.Triethylamine was selected as the additive,and the amount of triethylamine was also screened in the meantime.Secondly,carboxylic acid was esterified with thionyl chloride in alcohol,which simplified the reaction operation,reduced the production of by-products and improved the product yield compared with the previous process.Thirdly,we choose palladium on activated carbon as the catalyst to reduce the nitro group in the presence of hydrogen,which reduced environmental pollution compared with the previous process,and the amount of catalyst and reaction temperature were also screened in the meantime.Fourthly,the hydroxyethylation reaction of amino group is carried out by injecting ethylene oxide gas.Compared with the previous process,the operation is simplified and the production safety is improved.Fifthly,thionyl chloride was used to replace the commonly used phosphorous chloride reagents for chlorination reaction,which improved the reaction yield and reduced the difficulty of workup.Finally,the product was directly obtained by removing the protective group with hydrochloric acid and adjusting the pH with aqueous ammonia.Compared with the previous process,the operation procedure was simplified.Melphalan hydrochloride was obtained from p-nitro-L-phenylalanine as the starting material through six steps of amino protection,esterification,catalytic reduction of nitrogroup,hydroxyethylation,chlorination and deprotection.After the above optimization,the total yield can reach 48.0%.