The reaction of 7-fluoro-1-methyl-3,1-benzoxazine-2,4-dione (I) with trimethylsulfoxonium iodide and NaH in DMSO gives the corresponding ylide (II), which is cyclized with methyl orthoformate (III) in refluxing ethanol-acetic acid.
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.
The synthesis of the two enantiomers of flosequinan has been described: The reaction of 7-fluoro-3-(methylsulfanyl)quinolin-4(1H)-one (I) with POCl3 in refluxing CHCl3 gives the corresponding chloroquinoline (II), which by oxidation with m-chloroperbenzoic acid (m-CPBA) in CHCl3/water yields 4-chloro-7-fluoro-3-(methylsulfinyl)quinoline (III). The condensation of (III) with (R)-1-phenylethylamine (IV) affords the secondary amine (V) as a diastereomeric mixture that is separated by fractional crystallization to afford the two diastereomers (VI)-(S) and (VI)-(R). Both compounds are treated with hot 1N HCl to afford (S)-4-amino-7-fluoro-3-(methylsulfinyl)quinoline (VII)-(S) and (R)-4-amino-7-fluoro-3-(methylsulfinyl)quinoline (VII)-(R), respectively. Finally, (VII)-(S) and (VII)-(R) are treated with methyl iodide in hot butanone to afford (S)-flosequinan and (R)-flosequinan, respectively.