Synthesis Of Key Intermediates In Antineoplastic Drug TNBG

TNBG(Tetrazanbigen) is non cytotoxic antineoplastic drug whichhas been innovated by our group independently, it involves the key intermediates and derivatives of quinoxaline-2,3-dione compounds and1-aminomethylisoquinoline compounds, and both of the key intermediates and derivatives also have high biological activity, quinoxaline-2,3-dione compounds are often used as hypoglycemic agents, reducing agents, receptor of excitatory amino acids receptor antagonists and so on;Isoquinoline compounds are frequently used as antitumor drugs,analgesic drugs, antithrombotic drugs, antifungal/antibacterial drugs and soon. Therefore, the research on the two key intermediates and derivatives will be of great significance.According to the principles that request raw material easily found,convenient manipulate, environment friendly and available to the industrialization. The new compounds6-acetyl-1,4-dihydroquinoxaline-2,3-dione(15),6-[3-(phenyl)allyl-1-one)-1,4-dihydro-quinoxaline-2,3-dione(16)as well as1-[(N-acetyl) aminomethyl]-2-acetyl-1,2,3,4-tetrahydroisoquinoline(17),1-[(N-methylsulfanyl)aminomethyl]-2-Methylsulfanyl-1,2,3,4 -tetrahydroisoquinoline(18),1-aminomethy-3,4-dihydroisoquinoline(19)which designed in the research have been synthesized. Linking to therelated literatures,the study has used retro-synthetic analysis to get routes to synthesize them, and specific focused on their synthetic steps.The results are as follows:1. A concise, efficient route for the synthesis of a new compound15have been established.Acetanilide have been used as the raw material, through the acetylation reaction, the nitration reaction,the hydrolysis reaction, and the one-step method of reduction and cyclization, fourstep in all. It can get15finally. The total yield can get27.4%.2.16was synthetized via using15and benzaldehyde, with sodiumethylate as catalysator, and refluxing in the ethanol.3. The synthetic methods of new compounds:17,18and19wereestablished,1-aminomethyl-1,2,3,4-tetrahydroisoquinoline dihydrochloride(AMTIQ) as the raw material,at room temperature with acetyl chloride and methyl sulfonyl chloride can get new compounds17and18, the yield are95.7%and63.3%; N-[(1-methylene)-3,4-dihydroisoquinoline]phthalimide(DIQA) as the raw material, through hydrazinolysis,canget the new compound19, the yield is15.5%, which have made the preparations for the next steps of the project.4. The synthetic methods of N-acetyl-3nitro-4-aminoacetophenonewas established, using nitric acid as nitration agent and acetic anhydr ideas the solvent. The study has considered its influencing factors:theamounts ofsolvent, the amounts of nitrate,reaction temperature,and have got the optimum reaction conditions which are: N-acetyl-4-Aminoacetophenone (mol):nitric acid(mol)=1:6, N-acetyl-4-aminoacetophenone:acetic anhydride=1g:10ml, under5℃, the yield can reach67.5%. TheAdvantage ofthe method overcoming the reaction temperature of the document is operation more simple(especially using sodium hydroxide solution or sodium carbonate solution adjust the pH of aqueous layer to7), the yield canreach91.5%, increase26.5%than that in the literature.5. The study has studied the products of N-acetyl-3-nitro-4-aminoacetophenone hydrolysis in the different conditions, found that at70℃using HCl solution in hydrolysis reaction, the yield and controllabilityof reaction are higher than those using NaOH solution in hydrolysis reaction, the optimum synthesizing conditions of4-acetyl-2-nitroanilineis: in8mol/L HCl solution at70℃, the yield can get79%.5new compounds have been synthesized in this thesis, and haven’t been seen in literatures in hand. The desired productions all havebeen authenticated by IR, LC-MSand1H NMR. It lays a solid foundation in the study that will proclaim the structure-activity relationship ofnon cytotoxic antineoplastic drugs-the derivatives of TNBG.