合成路线1

The intermediate quinolone boron chelate (X) is prepared as follows. Ketalization of 2’,4’-difluoroacetophenone (XII) with ethylene glycol and p-TsOH provides compound (XIII), which is hydroxylated to phenol (XIV) by ortho-metalation with BuLi in THF at –65 °C, followed by treatment with trimethyl borate in AcOH and then with aqueous H2O2. Acidic hydrolysis of the ethylene ketal moiety of compound (XIV) provides the hydroxyketone (XV), which is alkylated with dimethyl sulfate and K2CO3 in toluene to give 2’,4’-difluoro-3’-methoxyacetophenone (XVI). Carboxylation of acetophenone (XVI) with diethyl carbonate and NaH gives the 2-(benzoyl)acetate (XVII), which is further condensed with dimethylformamide dimethyl acetal (DMFDMA) to produce adduct (XVIII). Subsequent displacement of the dimethylamino group of (XVIII) with cyclopropylamine (XIX) in hot toluene furnishes the N-cyclopropyl analogue (XX) (1, 2). Then, cyclization of (XX) by means of either NaH in THF or N,O-bis(trimethylsilyl)acetamide (BSA) in boiling toluene yields the quinolone carboxylate (XXI), which is hydrolyzed to the corresponding carboxylic acid (XXII) under acidic conditions. Finally, the boron chelate (X) is obtained by complexation of the keto acid (XXII) with the reagent generated from boron oxide and acetic anhydride in AcOH (1-3). Scheme 2.