反应详情

From 4-hydroxy-2-fluoroaniline there is produced (in the manner described in published PCT International Application No. WO 85/01939 published May 9, 1985) 1-(4-hydroxy-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl) -5H-tetrazol-5-one. The latter is the nitrated by treatment with a mixture of HNO3 and H2SO4 to form 1-(4-hydroxy-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The latter is then dissolved in N,N-dimethylformamide ("DMF") and mixed with a dispersion of NaH in DMF, after which a solution of ethyl bromoacetate is added, resulting in a reaction yielding 1-(4-carboethoxy-methoxy-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The latter is then dissolved in acetic acid and then added to a hot suspension of iron powder in acetic acid and reacted at elevated temperature (e.g. 80°-90° C.) for about an hour to form 1-(7-fluoro-2H-1,4-benzoxazin-3(4H)-one-6-yl)1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The latter is then dissolved in DMF and added to a suspension of NaH in DMF and warmed to, e.g 50° C. Then a solution of 1-iodopropane in DMF is added and the mixture allowed to react to form 1-[7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one.