Nemonoxacin

Nemonoxacin is a novel nonfluorinated quinolone and broad-spectrum antibiotic for the treatment of drug-resistant bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA) and quinolone- resistant MRSA as well as quinolone-resistant Streptococcus pneumonia. The drug was originally discovered by Procter & Gamble Pharmaceuticals (P&GP). It was codeveloped by TaiGen Biotechnology for development in Asia and by Warner Chilcott for development in the United States and Europe and was first approved by the China Food and Drug Administration (CFDA).

ChEBI: Nemonoxacin is a member of quinolines.

Although several synthetic approaches to marketed quinolone antibiotics similar in structure to nemonoxacin have been reported, two dedicated synthetic routes to nemonoxacin have been reported. Condensation of commercial 2,4- difluoroacetophenone (57) with ethylene glycol furnished ketal 58 in 86% yield. This was followed by fluorine-directed olithiation with n-butyllithium and trimethylborate quench. Acidification followed by oxidation of the boron species rendered hydroxyketone 59 in 79% yield from 58. Next, phenol methylation with dimethyl sulfate followed by deprotonation and reaction with diethyl carbonate (60) gave rise to the keto-ester intermediate, which underwent condensation with dimethylformamide-dimethylacetal (DMFDMA) in refluxing toluene to provide the corresponding vinylogous amide 61. An addition-elimination reaction with cyclopropylamine (55) and subjection of this intermediate to acetimidate 62 in refluxing toluene presumably facilitated alkene isomerization with concomitant cyclization to produce the quinolinone derivative 63 in 82% yield over five steps. Acidic hydrolysis followed by treatment with diboron trioxide and acetic anhydride generated triacetoxyborate 64, which served as a unique protecting group for the next step of the synthesis. Exposure of 64 to aminopiperidine 65 under SNAr conditions provided aniline derivative 66. This was followed by basemediated borate removal, acidic quench with concomitant Boc deprotection, and basification to furnish nemonoxacin (V) in 79% yield from 64.
For the preparation of aminopiperidine fragment 65 of nemonoxacin, commercial proline derivative 67 was converted to the corresponding ester 68 in 52% yield prior to treatment with Bredereck?ˉs reagent to give enamine 69 . Next, catalytic hydrogenation of 69 using a Pfaudler reactor and 5% Pd/C converted the vinylogous amide to the corresponding methyl group, delivering 70 in nearly quantitative yield and 93:7 diastereomeric excess in favor of the desired geometry. Further reduction of 70 using NaBH4 followed by treatment with calcium chloride dihydrate gave the corresponding diol 71 in 66% yield. Mesylation of diol 71 followed by cyclization with benzylamine and hydrogenation to remove the N-benzyl group provided aminopiperidine 65. The yields of the last three steps were not reported.