Penicillins 3- substituted carboxyl

The beta-lactam antibiotics are commonly used because of their safety, efficacy, relatively low cost and the variety of dosage forms available. Both penicillins and cephalosporins have a four-membered beta-lactam ring that is responsible for the instability of these compounds. The penicillins are also relatively insoluble they are prepared as various salts by the substitution of the hydroxyl group or the hydrogen of the carboxyl group with sodium, potassium, benzathine or procaine. 

A variety of other monoanionic ligands that contain O and N functional groups have been reported to complex Zr and Hf. For example, hydroxy-pyridionate,707 substituted-thiazolidin-4-ones,708,709 cycloserine,710 V-furfurylidnearylamines711 azopyrazolones,712-714 substituted aroylhydrazone,715 benzoyl hydrazones,716-718 6-amino-penicillinic acid,719 aniline-carboxylate,720 aminoantipyrine,721 and bis-salicyloyl hydrazides722 have been employed in the preparation of various halide and oxide derivatives. The majority of these complexes have been characterized by IR spectroscopy and elemental analysis alone. 

From carboxyl substituted polystyrene (cf. Schemes 1.5.4.5 and 1.5.4.10) by treatment with 85% HjO in methan sulfonic acid. - Epoxides from di- and tri-subsiituted olefins. Sulfoxides and sulfones from sulfides some sulfides (penicillins, deacetoxycephalosporins) could be oxidised selectively to give sulfoxides. Stereoselectivities of epoxide or sulfoxide formation compare well with the results observed for monomeric m-CPBA.-"- -... 

The above, as well as other substitution reactions, both electrophilic and nucleophilic, has been taken advantage of in studies of penicillin analogues, particularly in an exploration of possible synthetic routes to 5-methyl-3-phenylisothiazole-4-carboxylic acid (100) (Scheme 6). 

The reactivity of ketenimines such as 146 is related to substituent R. Ketenimines were isolable when R was phenyl or alkyl. In contrast, ketenimines wherein R was halogen, thienyl, phenylthio, methylthio, or methylsulfonyl were sufficiently reactive to afford iminoethers (147) at -78°C in the presence of excess lithium methoxide. The trimethyl-chlorosilane-quinoline procedure satisfactorily converted all these substituted iminoethers to amides in good yields. The overall sequence proved amenable for use with cephalosporin acids, by prior protection of the carboxyl group as a silyl ester. Extension of this method to the penicillin series permitted the preparation of 6a-methoxyketenimine 149 and 6a-methoxyimino ether 150 from the corresponding methyl 6p-(2-chlorophenyl)acetamido and fi -dichloroacetamidopenicillanates, respectively. No further transformations of these substances were reported. 

Type C (C—C—N—C + S) Syntheses.—A synthesis of 5-substituted A -thiazoline-4-carboxylates that is useful for the preparation of penicillin derivatives involves the interaction of isocyano-acrylates (60) with hydrogen sulphide. Depending on the nature of R and R , the reaction proceeds via either intermediate (61) (as shown by i.r. spectroscopy) or intermediate (62 X = S isolable... 

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