Benzylpenicilloic acid

The metabolic fate of the benzylpenicillin-human serum albumin conjugate was studied in rats [149]. The conjugate was taken up by the liver, where it underwent enzymatic cleavage to form benzylpenicilloic acid. Thus, the benzylpenicilloic acid excreted in urine may be formed either by direct hydrolysis of the /3-lactam ring, or by catabolism of protein conjugates formed in vivo. 

Synthesis of 4-amino-2-pyrazolin-5-ones is usually achieved by treatment of an a-amido-/3-aldehydo- or /9-ketoester with hydrazines according to the classical method for preparation of 2-pyrazolin-5-ones. Variants on this procedure consist of using an a-amidoester which has /9-substituents whose reaction is equivalent to that of a /9-carbonyl substituent. Such compounds are D-benzylpenicilloic acid a-methyl ester,1027 ethyl phenylpenaldate243 and the acetal of an a-amido-/9-formyl ester.59,243 Cornforth has isomerized 2-phenyl-4-hydrazino-methylidyneoxazolidone to 4-benzamido-2-pyrazolin-5-one. The same compound was obtained by treatment of 1-ethoxyvinyl-2-phenyl-oxazolidone with phenylhydrazine.319... 

Drug stability studies (i) in aged solutions of potassium penicillin G Potassium penicillin G in the presence of five of its degradation products, DL-penicillamine, benzyl penilloic acid (two isomers), benzylpenamaldic acid, benzylpenicilloic acid and benzylpenillic acid Partition Bondapak AX/ Corasil pH 3.8 buffer... 

Physical Properties of Thiazolidines. - The crystallographic data, bond lengths, and bond angles were determined for 4-ethyl-4-methyl-5-methylene-2-p-tolyliminothiazolidine (179). In the crystal, (179) is associated as a centrosymmetric dimer.The direct-current and differential-pulse polaro-graphic behaviours of benzylpenicilloic acid (180) have been discussed. The differential-pulse peak current is linearly related to concentration in the range... 

Benzylpenicillin is rapidly converted to (5R,6R)-benzylpenicilloic acid (8) when dissolved in D2O containing sodium deuteroxide as seen by absence of the closely-placed 5-H, 6-H doublets (5.4, 5.46 ppm, separation 4 Hz) characteristic of an intact ) -lactam ring, while the progressive conversion of the... 

Figure 5.35. H-NMR spectra (80 MHz) of benzylpenicilloic acids in D20-Na0D showing isomerization of the diastereoisomer (A) to the acid (E) at specific time intervals. Key (A)...

Benzylpenicillinic Acid. 3,3>Dimerhyf-7-oxo-6-[tphenylacetyllamino]-4-th ia-l-azabicyclo 3.2.0]heptane-2-carboxylic acid free benzyl penicillin free penicillin G free penicillin II. C,jHI8Nj04S mol wt 334.38, C 57.47%, H 5.43%, N 8.38%, O 19.14%, S9,59%. Obtained by extraction at ice temp of the acidified (pH 2) aq soln of sodium benzyl -penicillin with ether Or chloroform. Shows correct analytical composition only it moisture is excluded completely during iis isoln from the ether extract (by lyophilizing from benzene). When kept dry the acid retains its antibiotic potency for limited periods, bui it is rapidly inactivated by small amounts of water. The product formed on slow inactivation by moisture seems to be benzylpenicilloic acid, cf. Clarke et [., The Chemistry of Penicillin (Princeton, 1949). Prepn of methyl ester Dan. pet. 85,976 (1958 to Leo Pharm.). Pharmacokinetics in humans M. Barza, L. Weinstein, Clin. 

Fig.3. Dimerization of benzylpenicillin (/ = benzyl) via reactions between the degradation products benzylpenicillenic acid and benzylpenicilloic acid...

Fig. 12. Time courses for benzylpenicillin open circles), benzylpenicilloyl ester solid dries), and benzylpenicilloic acid squares) in the reaction between benzylpenicillin (1.4 x 10 M) and sorbitol (a), glycerol (b), or dextran 40 (c) (all 10% W/V) at pH 9.25 (0.2 M carbonate) and 35 °C. (Bundgaard and Larsen 1978 b)...

BPO-PPL = benzylpenicilloyl-polylysine BPN = bemylpenicillin BPNCO = benzylpenicilloic acid... 

Benzylpenicilloic acid is the main hydrolysis product of benzylpenicillin and is able to elicit wheal and flare reactions when used in skin tests in some patients allergic to penicillins. It has therefore been considered as one of the minor antigenic determinants of penicillin allergy (Siegel and Levine 1964 Voss et al. 1966) although the precise chemical nature of the determinant(s) derived from penicilloic acid has not been elucidated. The proportion of patients responding in skin test to penicilloic acid varies between 21% and 55% (Table 1). 

BPO, benzylpenicilloyl BPN, benzylpenicillin BPNCO, benzylpenicilloic acid PPL, penicillin-polylysine Among patients positive to BPN, PPL, or BPNCO Penicillamine-carrier conjugate used for test... 

Fig. 5. Formation of antigenic determinants from benzylpenicilloic acid...

The specificity of reactions elicited by penicilloic acid has not yet been determined with certainty. Although such reactions certainly differ in their specificity from BPO-specific reactions, they are also inhibited quite efficiently by monovalent BPO haptens. This has been the experience for skin test reactions to penicilloic acid in man (de Weck 1976) as well as for PCA reactions elicited by benzylpenicilloic acid in guinea pigs (de Weck 1976 de Weck et al. to be published). 

The immunogenicity of penicilloic acids as such has not yet been definitely established. On the one hand, the fact that a selected number of penicillin-sensitive patients very strongly react to benzylpenicilloic acid, sometimes to the exclusion of other determinants (Levine and ] dmond 1969 Gattlen and Peter 1976 ... 

Gorevic and Levine 1981), points to the immunogenicity and sensitizing capacity of this compound. On the other hand, several attempts to detect antibodies in rabbits immunized with benzylpenicilloic acid have been unsuccessful (Josephson 1960 DE Weck 1962a,b). 

However, in these studies, no serious attempts were made ot assess the antibodies specific for penamaldate and penicillamine determinants, which are precisely those which could be expected. Benzylpenicilloic acid, when applied to guinea pig skin, seems able through whatever immunochemical mechanism to induce contact hypersensitivity (Levine 1960 a). 

Levine BB (1960 c) Formation of D-penicillamine-cysteine mixed disulphide by reaction of D-benzylpenicilloic acide with cysteine Nature 187 940 Levine BB (1961) Studies on the formation of the penicillin antigen. II. Some reactions of D-benzylpenicillenic acid in aqueous solution at pH 7.5. Arch Biochem Biophys 93 50 Levine BB (1962) N(a-D-penicilloyfamines as univalent hapten inhibitors of antibody-de-pendent allergic reactions to penicillin. J Med Chem 5 1025 Levine BB (1963) Studies on the dimensions of the rabbit anti-benzyl penicilloyl antibody combining sites. J Exp Med 117 161... 

Benzylpenicilloic acid, the main hydrolysis product of benzylpenicillin, elicits wheal and flare skin reactions in some patients and was considered to be one of the so-called minor (in a quantitative sense) determinants by Levine. Decarboxylation of penicilloic acid gives rise to penilloic acid, another of the minor determinants... 

In addition to the expected hydrolysis product, benzylpenicilloic acid [30], the acid catalysed degradation of benzylpenicillin gives benzylpenicillenic... 

If the mechanisms of the reactions of penicillin involves the intermediate formation of a keten [47] or penicillenic acid [38], then the products of the reaction should show deuterium incorporation at C(6) if the reactions are carried out in DjO. The nmr spectra of benzylpenicilloic acid and penicilloyl amides obtained from the hydrolysis and aminolysis of benzylpenicillin in DjO in the presence of copper(II) ion shows no incorporation of deuterium at C(6). This indicates that the elimination-addition mechanism is not a major pathway for either of these reactions (Gensmantel et al., 1978). 

Benzylpenicilloic acid > benzylpenicillanic acid > benzylpenicillin > benzylpenicillic acid... 

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