The reduction of 3-nitro-4-phenoxyphenol (I) with Fe, aqueous HCl gives 3-amino-4-phenoxyphenol (II), which is acylated with methanesulfonyl chloride by means of pyridine in dichloromethane affording 3-(methylsulfonamido)-4-phenoxyphenol (III). The condensation of (III) with 3-chloropropionic acid (IV) by means of NaOH in water gives 3-[3-(methylsulfonamido)-4-phenoxyphenoxy]propionic acid (V), which is cyclized by means of polyphosphoric acid at 65-70 C yielding 7-(methylsulfonamido)-6-phenoxy-3,4-dihydro-2H-1-benzopyran-4-one (VI). The bromination of (VI) with Br2 in CHCl3 affords 3-bromo-7-(methylsulfonamido)-6-phenoxy-3,4-dihydro-2H-1-benzopyran-4-one (VII), which is treated with sodium azide in DMF at 70-75 C giving 3-amino-7-(methylsulfonamido)-6-phenoxy-2H-1-benzopyran-4-one (VIII). Finally, this compound is formylated with formic acid in acetic anhydride.
A preparative-scale synthetic route for T-614 has been reported: The reaction of 4-chloro-3-nitroanisole (I) with potassium phenolate in hot DMF gives 4-phenoxy-3-nitroanisole (II), which is reduced to the corresponding 3-amino compound (III) by treatment with Fe and HCl. The reaction of (III) with mesyl chloride in pyridine affords the sulfonamide (IV), which is acylated with 2-aminoacetonitrile (V) and AlCl3 in nitrobenzene/HCl giving the 2-aminoacetophenone (VI). Formylation of (VI) at the NH2 with acetic formic anhydride yields the formamide (VII), which is demethylated with AlCl3 and NaI in acetonitrile affording the phenol (VIII). Finally, this compound is cyclized with dimethylformamide dimethylacetal in DMF.