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

Article abstract of DOI:10.1248/cpb.43.1872

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.

Full text of DOI:10.1248/cpb.43.1872

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