合成路线1

A new synthesis for KB-5246 has been described: The reaction of 2,3,4-trifluoroaniline (I) with carbon disulfide (II) and triethylamine gives the corresponding dithiocarbamate (III), which by cyclization with 1-acetoxy-3-chloro-2-propanone (IV) in ethyl acetate yields 4-(acetoxymethyl)-3-(2,3,4-trifluorophenyl)thiazole-2(3H)-thione (V). The cyclization of (V) with potassium hydroxide in refluxing ethanol-water affords 6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazine-1-thione (VI), which is treated with trichloromethyl chloroformate in hot toluene to give the thiazolium chloride (VII), which is not isolated. The in situ reaction of (VII) with diethyl malonate by means of triethylamine in toluene gives (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonic acid diethyl ester (IX), which is cyclized again with polyphosphoric acid (PPA) at 115 C to afford 7,8-difluoro-5-oxo-9,1-(epoxymethano)-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester (X). The hydrolysis of (X) with oleum gives the corresponding acid (XI), which is finally condensed with N-methylpiperazine (XII) in hot DMSO.