合成路线1

Two synthetic methods have been reported for the title compound. Coupling of aryl triflate (I) with thiomorpholine (II) affords the N-aryl thiomorpholine (III). Reduction of the nitroaryl group of (III) by catalytic hydrogenation in the presence of Raney nickel furnishes aniline (IV). This is then condensed with benzyl chloroformate under Schotten-Baumann conditions, yielding carbamate (V). Reaction of carbamate (V) with (S)-N-(2-acetoxy-3-chloropropyl)acetamide (VI) in the presence of lithium tert-butoxide and MeOH leads to the (S)-oxazolidine (VII). Finally, oxidation of the thiomorpholine sulfide group of (VII) with N-methylmorpholine-N-oxide in the presence of a catalytic amount of OsO4 gives rise to the title sulfone compound.

合成路线2

In an improved procedure, conjugate addition of divinyl sulfone (II) to 2,6-difluoroaniline (I) in the presence of AlCl3 leads to the N-aryl thiomorpholine sulfone (III). Aromatic nitration of (III) with fuming HNO3 in AcOH affords (IV). The nitroaryl derivative (IV) is then reduced to aniline (V) by catalytic hydrogenation over Raney Ni. Condensation of aniline (V) with isobutyl chloroformate furnishes carbamate (VI). This is finally cyclized with (S)-N-(2-acetoxy-3-chloropropyl)acetamide (VII) to generate the target oxazolidinone compound.

合成路线3

Condensation of 2-fluoro-4-nitrotoluene (I) with paraformaldehyde under basic conditions affords diol (II). Nitro group reduction in (II) by hydrogenation over Pd/C yields aniline (III), which is further protected with acetylacetone (IV), to produce the pyrrole derivative (V). After conversion of diol (V) into the mono-tosylate (VI), cyclization in the presence of BuLi furnishes the oxetane derivative (VII). Removal of the pyrrole moiety of (VII) by treatment with hydroxylamine provides amine (VIII), which is converted to the carbamate (IX) by acylation with benzyl chloroformate. Finally, condensation of (IX) with (S)-N,O-diacetyl-1-amino-3-chloro-2-propanol (X) in the presence of lithium t-butoxide produces the required oxazolidinone derivative.

合成路线4

The cyclization of 4-(benzyloxycarbonylamino)acetophenone (I) with glyoxylic acid (II) and hydrazine (III) in hot acetic acid gives the pyridazinone (IV), which is treated first with Lawesson's reagent in hot dioxane and then with MeI and TEA in DMF to yield the methylsulfanyl pyridazine (V). The cyclization of (V) with acetamide (VI) by means of t-BuOLi in methanol/DMF affords the oxazolidinone (VII), which is finally treated with Lawesson's reagent in hot dioxane to provide the target thioacetamide.

合成路线5

The cyclization of 4-(benzyloxycarbonylamino)acetophenone (I) with glyoxylic acid (II) and hydrazine (III) in hot acetic acid gives the pyridazinone (IV), which is treated first with Lawesson's reagent in hot dioxane and then with MeI and TEA in DMF to yield the methylsulfanyl pyridazine (V). The cyclization of (V) with acetamide (VI) by means of t-BuOLi in methanol/DMF affords the oxazolidinone (VII), which is finally treated with Lawesson's reagent in hot dioxane to provide the target thioacetamide.

合成路线6