We prepared a number of di- and trifunctionalized quinolines by selective metalation of chloro-substituted quinolines with metal amides followed by reaction with different electrophiles. Metalation of the C-3 position of the quinolinic ring with lithium diisopropylamide at -70 °C is easy to achieve, whereas reaction with lithium-magnesium and lithium-zinc amides affords C-2 or C-8 functionalized derivatives in a regioselective fashion. These complementary methods could be rationalized by DFT calculations and are convenient strategies toward the synthesis of bioactive quinoline derivatives such as chloroquine analogues.
Propacetamol is an acetaminophen prodrug of intravenous administration used to control fever and pain of perioperative period in multimodal analgesia therapy. After injection, it is completely converted by plasma esterases into N,N-diethylglycine and acetaminophen, its active metabolite whose mechanism of action is the inhibition of prostaglandin synthesis. Herein, we report an improved protocol for the synthesis of propacetamol hydrochloride that allows the isolation of the active pharmaceutical ingredient (API) with high purity and yield. In addition, the in vitro metabolism of propacetamol in a microssomal reaction was evaluated by ion trap tandem mass spectrometry.
We have prepared some benzo-fused N-heterocycles derivatives by regioselective metalation of quinoline, isoquinoline, quinoxaline, and quinazoline with LiTMP in the presence of zinc chloride. Applying this strategy to synthesize an analog of the antitumor verubulin illustrates its relevance for medicinal chemistry. Computational calculations of the pK a values of the aromatic hydrogens have helped us to rationalize substrate reactivity and metalation regioselectivity by the complexinduced proximity effect concept.
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