The Synthesis Of {2-Amino-7-[5-(4-Isopropoxy-3-Trilfuoro Methyl-Phenyl)-[l-,394]Oxadiazol-2-yl]-l,2,394-Tetrahydro Naphthalen-2-yl} Methanol

Immune inhibitor developed from the70′s of last century is a kind of drugs used inclinical treatment of organ transplant rejection reactions and human autoimmune diseases.Nowadays, immunosuppressants clinical commonly used mostly have strong side effects inthe treatment of disease, and they might cause infections and tumors. Therefore thedevelopment of new immunosuppressive agents provided with specificity, efficiency andlow toxicity become the focus of the medical workers.1994, Professor Fujita team in JapanKyoto University isolated the ISP-1from the active ingredient of cordyceps sinensis. Afterthe molecular modification according to the structure-activity relationship and furtheroptimization, they got a more active new immunosuppressant FTY720. According to thestructure-activity relationship of FTY720compounds, our lab team members designed andsynthesized a series of amino alcohol derivatives (FC compounds). We have completed theactivity tests and got a plurality of screened compounds with FTY720activity, whichprovided a theoretical basis for the research and development of new immunosuppressants.Heterocyclic chemistry is an important component of organic chemistry. Nowadays,heterocyclic compounds are widely distributed in nature. Many important compounds relatedto the biology are mostly heterocyclic compounds, such as nucleic acids, certain vitamins,hormones, and alkaloids, etc. Among them, nitrogenous heterocyclic compounds as animportant branch of heterocyclic compounds, are widely used in material, pesticide,medicine and other fine chemical fields. In view of the nitrogenous heterocyclic compoundson the physiological action of human life and a wide range of uses, synthesis, structuralmodification and pharmacological activity research of nitrogenous heterocyclic compoundshas become an important field of organic chemistry and medicinal chemistry. Fivemembered heterocyclic derivatives1,3,4-oxadiazoles containing oxygen and nitrogen atomshave showed many unique physiological activities in drug research and development, whichinclude anticancer, antidiabetic, anti-inflammatory, antibacterial, antituberculous and so on.At the same time,1,3,4-oxadiazoles heterocyclic derivatives have been widely used in thetreatment of symptoms of rheumatic fever and arthritis (rheumatoid, osteoarthritis andjaundice), myocardial infarction and primary dysmenorrhea. A large number of research hasproved that1,3,4-oxadiazoles compounds has played a decisive position in medicine. Based on the design concept of FC compound, we preserved the parent structureof naphthalene-methanol, and1,3,4-oxadiazole groups possessing extensive biologicalactivities was introduced, two kinds of bioactive groups connected by a covalentbond into a new molecular compound. This paper focuses on the design and synthes-is of the new immunosuppressive agents:{2-Amino-7-[5-(4-isopropoxy-3-trifluoromethyl-phenyl)-[1,3,4]oxadiazol-2-yl]-1,2,3,4-tetrahydro-naphthalen-2-yl}methanol (FC-99). Ta-rget molecules based on4-hydroxy-3-(trifluoromethyl)benzoic acid as the initial rawmaterials, via demethylation, esterification, etherification, acylation to obtain the intermediate1:3-methyl-4-isopropoxide benzoyl hydrazine;3-bromo phenyl acetic as rawmaterial by Friedel-Crafts reaction, Borch reduction, cyano addition, hydrol, reduction,Grignard reaction, reaction with thionyl chloride become the intermediate2. The twointermediate acylated dehydration, phosphorus oxychloride as cyclizing agent, diacylh-ydrazine dehydration and cyclization by the traditional method of ‘Diacylhydrazine C-yclization’, and followed by hydrolysis, catalyzed hydrogenation to obtain the objecti-ve compound FC-99. The key intermediates obtained in the course of the experimentand the ultimate objective product was confirmed by1H NMR,13C NMR.