Penicillin 2-acetoxymethyl

AH cephalosporins found in nature (Tables 1 and 2) have the D-a-aminoadipic acid 7-acyl side chain (21). AH of these compounds can be classified as having rather low specific activity. A substantial amount of the early work in the cephalosporin area was unsuccessfiiHy directed toward replacing the aminoadipic acid side chain or modifying it appropriately by fermentation or enzymatic processes (6,22). A milestone ia the development of cephalosporins occurred in 1960 with the discovery of a practical chemical process to remove the side chain to afford 7-ACA (1) (1). Several related processes were subsequendy developed (22,23). The ready avaHabHity of 7-ACA opened the way to thousands of new semisynthetic cephalosporins. The cephalosporin stmcture offers more opportunities for chemical modification than does that of penicillins There are two side chains that especiaHy lend themselves to chemical manipulation the 7-acylamino and 3-acetoxymethyl substituents. 

The acetoxymethyl ester of benzylpenicillin is penamecillin (Havapen, 1). It is an almost white, free-flowing powder lacking the characteristic odour and taste which make penicillins generally unpalatable when administered in tablet or... 

Cephalosporins display an antibiotic mechanism of action identical to that of the penicillins. Cephalosporin C (Figure 1.14) is the prototypic natural cephalosporin and is produced by the fungus Cephalosporium acremonium. Most other members of this family are semi-synthetic derivatives of cephalosporin C. Chemical modification normally targets side-chains at position 3 (the acetoxymethyl group) or 7 (derived from D-a-aminoadipic acid). 

More recently reported active esters are the different acyloxymethyl esters [129]. The pharmacology of penicillin G acetoxymethyl ester (Penamecillin) was investigated in 1966 [130]. A further derivative is the acetoxymethyl ester, or preferably the pivaloyloxymethyl ester, of am-... 

After oral administration to the dog, penamecillin (VII), which is the acetoxymethyl ester of benzylpencillin, produces prolonged benzylpencillin serum levels.According to pharmacokinetic evidence O, the penamecillin is slowly absorbed unchanged throughout the intestinal tract and then is rapidly hydrolyzed to benzylpenicillin by nonspecific esterases. Compound VIII is an example of the hitherto unknown penicillin aldehydes for which a general synthesis was developed. 

Pcnamecillilt. 3,3-Di methyl-7-oxo-6-[(phenylace-tyl)amino]-4-thla-l-azabicyclo[3.2.0]heptane-2-ca rboxy lie acid (acetyloxyfmeihyl ester penicillin G hydroxymethyl ester acetate acetoxymethyl benzylpenicillinate benzylpenicillin acetoxymethyl ester Wy-20788 Havapen. C.,HKN,06S mol wt 406.48. C 56.14%. H 5.46%, N 6.89%, 6 23.62%, S 7.89%. Semi-synthetic antibiotic related to penicillin. Prepn Jansen, Russell. J. Chem. Soc. 1965, 2127 eidem, Brit. pat. 1,083,479 corresp to U,S. pet. 3,250,679 (1965, 1966 to John Wyeth A Brother). 

The 3-acetoxymethyl group, and the A2-unsaturated center of the cephalosporin structure (461) are without parallel in penicillin, and the scope of modi-... 

As previously described, one of the major advances in penicillin sulfoxide chemistry in the last few years has been the rearrangement of the sulfoxide to the exomethylenecephem. The importance of this reaction resides in its utility in the successful synthesis of the clinically important oral antibiotic, cefaclor (388) (Volume 1, Chapter 2). The exomethylene isomer has also been utilized as an intermediate for the synthesis of the naturally occurring acetoxymethyl-substituted cephems. 

A carbon analogue of penicillin V (Ic) was resistant to Bacillus cer-eus B l ctamase and moderately active against gram-positive organisms.6 ) Several 2-acetoxymethyl penicillins (2ja,y6 and 2-spirocyclopropyl cephalosporins (3 )65 vere prepared. Various chemical procedures were developed for the 7(6)a-methoxylation of B-lactam antibiotics.66-72 Conversion of penicillins to cephalosporins was achieved by new synthetic routes.73-76 Some [2,3]-fused tricyclic cephem derivatives (4a-c) were synthesized.77,78 Compound displayed significant antibiotic activity.78 Racemic cephalothin, 7-methoxycephalothin, and cefoxitin were obtained by total synthesis of a novel type.79-81 nuclear analogue of a 7-methylcephalosporin (5), prepared by total synthesis, lacked antibiotic activity,82... 

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