Development of a manufacturing process for (S)-3-(aminomethyl)-5-methylhexanoic acid, an anticonvulsant, is described. Initial preparation employed an Evans chiral alkylation on (4R,5S)-4-methyl-3-(1-oxo-4-methylpentyl)-5-phenyl-2-oxazolidinone, using benzyl bromoacetate. Use of tert-butyl bromoacetate proved advantageous for large-scale preparation. Route selection for a low-cost manufacturing process was based on "ideal process" cost projections. Four routes were evaluated in the laboratory. Of the four, two were scaled up in the pilot plant, resulting in selection of a route based on synthesis of racemic 3-(aminomethyl)-5-methylhexanoic acid, followed by resolution with (S)-(+)-mandelic acid.

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A series of 5-amino- and 5-hydroxyquinolone antibacterials substituted at C7 with a select group of common piperazinyl and 3-aminopyrrolidinyl side chains was prepared. These 5-substituted derivatives were compared to the analogous 5-hydrogen compounds for antiinfective activity by using DNA gyrase inhibition, minimum inhibitory concentrations against a variety of bacteria, and in vivo efficacy in the mouse infection model. The influence on the structure-activity relationships of varied substituents at C8 (H, F, Cl) and N1 (ethyl, cyclopropyl, difluorophenyl) was also studied. The results showed that several of the structure-activity conclusions regarding side-chain bulk at C7, the effect of halogen at C8, and the effect of the C5-amino group were greatly influenced by the choice of the N1-substituent. Several outstanding broad spectrum quinolones were identified in this work. In particular, the spectrum and potency of the 7-piperazinyl quinolones could be greatly enhanced by the judicious choice of C5-, C8-, and N1-substituents.

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