Studies on Synthesis of the Antibacterial Agent NM441. II. Selection of a Suitable Base for Alkylation of 1-Substituted Piperazine with 4-(Bromomethyl)-5-methyl-1,3-dioxol-2-one

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Diisopropylamine (DIPA), N, N-diisopropylethylamine (DIPEA), tributylamine (TNBA) and 7-(1-piperazinyl)-4-quinolone-3-carboxylic acid (2) were titrated in water-dimethylformamide (DMF) mixtures containing 45-98% DMF. Apparent pK_a values in anhydrous DMF (pK_<DMF>) were calculated by extrapolation from the variation in the half-neutralization pH values in aqueous DMF. The validity of the relative basicity derived from the pK_<DMF>s was confirmed by examination of the kinetics of esterification of a derivative of 2 with 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (DMDO-Br). Relative basicities in DMF were : the carboxylate anion of 2≫DIPA>DIPEA>TNBA >the amino group in the piperazinyl part of 2. This order is clearly different from that observed in water.We concluded that DIPEA is a suitable agent to suppress the undesired esterification during the reaction to mask the amino group of 2 with a DMDO group, because it does not remove a proton from the carboxyl group, but only from the protonated amino group.
社団法人日本薬学会の論文
1995-11-15