6-Aminopenicillanic acid, oxidation

When 6/3-aminopenicillanic acid (6-APA) is diazotized in the presence of chloride ion, the principal product obtained is 6a-chloropenicillanic acid (38) (62JOC2668), presumably by way of the diazo intermediate (39 Scheme 29) (72JCS(P1)895). If the diazotization is carried out in the presence of excess bromide instead of chloride, significant amounts of the 6,6-dibromo derivative are obtained, and in the case of excess iodide the 6,6-diiodopenicillanic acid becomes the predominant product (69JCS(C)2123). The 6,6-dihalo products presumably arise from nitrous acid oxidation of halide to halogen, which then reacts with (39). 

Amino-2,5-dinitrotoluene, 2783 2-Amino-5-nitrothiazole, 1117 6-Aminopenicillanic acid 5-oxide, 3010... 

Aminopenicillanic acid (8) was converted to 6(5)-bromopenicillanic acid by trapping of the diazo-intermediate with hydrogen bromide. Esterification of the dicyclohexylamine salt (93) with p-methoxybenzyl bromide, followed by oxidation, afforded the sulphoxide (94) in 60% yield from 6-APA. Elaboration of this sulphoxide to the disulphide (96) was effected by the procedure established by Kamiya et al. [98] the sulphenic acid (95), formed by heating the sulphoxide to reflux in toluene, was intercepted by reaction with 2-mercaptobenzothiazole to yield the disulphide (96). The latter was transformed by base-catalysed double bond isomerization to the conjugated ester disulphide (97) [95% yield from (94)]. Reductive formylation of disulphide (97) then provided the formylthio-derivative (98). Cyclization of the oxalimide (99), obtained by ozonolysis of... 

The penicillins, from the fungus Penicillium chryso-genum, are the oldest and most widely used antibiotics. They are formed through stepwise build-up from a tripeptide (ACV) derived from a-Amino adipic acid, cysteine, and valine. Successive oxidation steps form the p-lactam and close the thiazolidine ring to form isopenicillin N. Action of an acyltransferase then yields penicillin G (Fig. 47). Alternatively, hydrolysis of isopenicillin N (or penicillin G) yields 6-aminopenicillanic acid, a key precursor for the wide range of semisynthetic pencillins used therapeutically. 

Using this method, 6-aminopenicillanic acid (6-APA) was successively subjected to benzoylation, esterification with benzhydrol, S-oxidation, and subsequent epimerization at the C-6 position, giving epi-penicillin 1 P-oxide ester (49). 

Carrington TR (1971) The development of commercial processes for the production of 6-aminopenicillanic acid. Proc R Soc Lond [Biol] 179 321-333 Daly JW, Jerina DM, Witkop B (1972) Arene oxides and the NIH shift The metabolism, toxicity and carcinogenicity of aromatic compounds. Experientia 28 1129-1264 Dennen DW (1967) Degradation kinetics of 6-aminopenicillanic acid. J Pharm Sci 56 1273-1276... 

The direct oxidation of 6-aminopenicillanic acid (5) or ampicillin (6) to their sulfoxides (7 and 8, respectively) could be accomplished either using peracetic acid on their p-toluenesulfonate salts (Micetich, 1976a) or with ozone (Spry, 1972). However, in the latter case, a mixture of the sulfoxide stereoisomers of 6-APA S R 4 1) (7 and 9) was obtained. 

A copper-catalysed CDC of benzothiazoles with thiazoles and polyfluoroarene leads to the synthesis of the 2,2 -linkage of thiazoles and 2-polyfluoroarylthiazoles. Silver carbonate has been used as a terminal oxidant. Palladium-catalysed dual C-H functionalization of benzophenones to form fluorenones by oxidative dehydrogenative cyclization has been developed using silver oxide as the oxidant. The reaction is postulated to involve a five-membered palladacycle intermediate. Os(VIII)-catalysed oxidation of 6-aminopenicillanic acid and chlorpheniramine by diperiodatoar-gentate(III) involves an initial formation of an Os(VIII)-reductant complex followed... 

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