合成路线1

Flosequinan has been synthesized by two new related ways: 1) The reaction of 2-chloro-4-fluorobenzoic acid (I) with refluxing aqueous methylamine Cu powder and CuCl2 gives 4-fluoro-2-(methylamino)benzoic acid (II), which is cyclized with phosgene to yield 7-fluoro-1-methyl-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (III). The reaction of (III) with dimethyl sulfoxide and NaH in toluene affords 4-fluoro-2-(methylamino)-alpha-(methylsulfinyl)acetophenone (IV), which is finally cyclized with refluxing triethyl orthoformate. 2) The reaction of 2-amino-4-fluorobenzoic acid (V) with phosgene as before gives the corresponding benzoxazine (VI), which is treated with dimethyl sulfoxide and NaH in refluxing toluene to afford 2-amino-4-fluoro-alpha-(methylsulfinyl)acetophenone (VII). The cyclization of (VII) with refluxing trimethyl orthoformate gives 7-fluoro-3-(methylsulfinyl)quinolin-4(1H)-one (VIII), which is finally methylated with dimethyl sulfate and KOH in water.