studied the diazotization/halogenation of 6-aminopenicillanic acid (II) in aqueous media. Accordingly, Clayton was able to generate 6,6-dibromopenicillanic acid (Ilia), a most useful ¡3-lactam intermediate,7 in approximately 34% yield and was able to convert this product via a reduction to penicillanic acid (Illb). While this diazotization/halogenation procedure conceptually provided a solution to our problem, the low yield for this transformation was unacceptable for our purposes and similarly has plagued those who have used Ilia in ¡8-lactam syntheses.This diazotization reaction, in our hands, generated varying amounts of -bromopenicillanic acid (IIIc) in addition to the desired 6,6-dibromopenicillanic acid (Ilia).8 The inefficiency of this transformation, we thought, could be attributed to the presence of hydrogen bromide in the reaction media, which was intercepting the diazo intermediate to form IIIc, and also to the prolonged exposure of the desired dihalogenated product Ilia to strongly acidic conditions. We therefore reasoned that a high-yield conversion of 6-APA ( ) to 6,6-dibromopenicillanic acid (Ilia)
Attachment of p-benzophenone side chains at N1 was found to be one of the most effective modifications for enhancing the potency of 6-azauracil against a broad spectrum of coccidia in chickens. Compound 20 was about 1000-fold more potent than 6-azauracil. Structure-activity relationships paralleled those found in a previously reported series of related analogues containing diphenyl sulfide and sulfone side chains. Drug metabolism studies showed the ketones to be reduced rapidly to carbinols, which are the prevalent species in vivo.
In the presence of sodium hydroxide or a β‐lactamase, 6‐APA has been shown to hydrolyze rapidly at room temperature to penicic acid 3, the kinetic product of the reaction. In a subsequent equilibration 3 isomerizes at C‐5, by way of intermediate imine 4, affording 5‐epi‐penicic acid 6 as the major hydrolysis product (∼ 95% at equilibrium). The pH and temperature parameters of equilibration are discussed and HPLC, optical rotation, proton nmr and 13C nmr data are presented.
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