Starting from 2-bromo-4,5-difluoroacetylaniline, it was reacted with crotonaldehyde under Skraup-Doeber-VonMiller reaction conditions to generate quinoline 2 in 67% yield. Pd-on-carbon catalytic hydrogenation was used to reduce the carbon-bromine bond in 2, and the catalyst was removed by filtration. Platinum-on-carbon was added to the reaction mixture and the hydrogenation conditions were again applied to give tetrahydroquinoline 3 in 97% yield. Tetrahydroquinoline 3 was reacted with 2,3-di-O-benzyl-L-tartaric acid (L-DBTA) and subsequently recrystallized from 60% methanol-water solution to give S-isomer 4 in 35% yield and 100% enantiomeric excess. The recovered R-isomer could be racemized by treatment with methanesulfonic acid. Compound 4 was reacted with diethylethoxymethylvinylmalonate in polyphosphoric acid and subsequently treated with hydrochloric acid to give tricyclic acid 5 in 88% yield. The tricyclic acid 5 chelates with the in situ generated borotriacetate to form the cyclic boronic ester complex 6. The cyclic boronic ester complex 6 is reacted with 4-hydroxypiperidine to afford levonadifloxacin 8 in good yield in a two-step reaction.Levonadifloxacin 8 was coupled with Boc-alanine, followed by removal of the Boc protecting group and salt formation with methanesulfonic acid to afford alalevonadifloxacin (I) in 95% yield.
