Penicilloic acid derivatives

Examples of such an approach are found in the synthesis of strychnine [22] and morphine [23], labours which have been said to bear resemblance to Sysiphus s torment [24], since they involve linear sequences of more than 25 steps. However, the most illustrative example is found, perhaps, in the synthesis of penicillin (10 ). in the course of which the penicilloic acid derivative JJL was synthesised, though through a laborious and lenghty route. Because this intermediate was easily available from natural penicillin, it was convenient to resort to such a method of degradation in order to make it available in sufficient quantities for studying the last step -that requires the formation of a P-lactam- and thus accomplishing successfully the total synthesis [25]. 

Holt and Stewart (1965) have studied the breakdown of ) -lactam antibiotics by infrared spectroscopy. The method is based on observation of the rupture of the integral lactam ring by penicillinase, )S-lactamase, with the production of penicilloic acid derivatives totally lacking in antibiotic activity. Figure 15.18 is the spectrum of benzylpenicillin before hydrolysis by a staphylococcal suspension, and Fig. 15.19 is the spectrum after rupture of the lactam ring by )3-lactamase of the bacteria. Figure 15.20 is the spectrum of 6-APA before hydrolysis, and Fig. 15.21 after lactam ring... 

Penicilloic acid 5, the substrate for the projected lactamization reaction, could be derived from the suitably protected intermediate 6. Retrosynthetic disassembly of 6, in the manner illustrated, provides D-penicillamine hydrochloride (7) and tert-butyl phthalimido-malonaldehydate (8) as potential building blocks. In the synthetic direction, it is conceivable that the thiol and amino groupings in 7 could be induced to converge upon the electrophilic aldehyde carbonyl in 8 to give thiazolidine 6 after loss of a molecule of water. 

Derivative UV spectrophotometry at 275 to 305 nm can be used to measure amoxicillin in urine down to 2 pg/ml [185], but the possibility of interference by the penicilloic acid and other metabolites appears not to have been investigated. 

Synthetic penicilloic acids can be derived from D-, DL-, or L-penicillamine and are designated accordingly. The Four stereoisomers which can be derived from D-pentcillamine are arbitrarily desigaated as , 0, >, 6. Review and bibliography Chain in Antibiotics, vol. 2, H. W. Florey et al.. Eds. (Oxford University Press, New York, 1949) p 839. 

Everett et al. first reported the application of NMR spectroscopy in metabolism studies. In 1984, they studied the metabolites of ampicillin in rats using spin-echo H NMR spectroscopy [4]. Apart from the unchanged penicillin, the natural (5R)-isomer of penicilloic acid, the epimerized (55)-isomer as well as a new metabolite, a diketopiperazine derivative, were identified in urine. Reinvestigation of ampicillin and corresponding penicillins ten years later confirmed the results in the case of amoxycillin, a dimeric metabolite was additionally found [5]. 

Reactive derivatives and degradation products benzylpenicillenic acid, benzyl-penicilloic acid in aged penicillin solutions penicillin (especially ampicillin) polymers... 

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). 

D-Penicillamine may arise directly from penicilloic acid or through formation of a penicillamine-cysteine mixed disulfide, following a penamaldate rearrangement (Levine 1960 c Yemal et al. 1978). This reaction also occurs with functional derivatives of the alpha-carboxylic group of penicilloic acid (Schneider et al. 1973). The penicillamine determinant may therefore arise in vivo from any penicilloyl conjugate. 

Polymerization of benzylpenicillin has been described by several authors (Batchelor et al. 1967 Stewart 1967 a de Weck et al. 1968 Butcher and Stewart 1969, 1970 Dewdney et al. 1971 Smith et al. 1971 Smith and Marshall 1971 Bungaard and Larsen 1977). Polymerization probably involves hydrolysis of the beta-lactam ring to form penicilloic acid, followed by acylation of the exposed thiazolidine nitrogen by another intact penicillin molecule or a benzyl-penicillenic acid derivative (Stewart 1973 Smith and Marshall 1971 Schneider and de Weck, 1970) (Fig. 8) Such polymers have been isolated by Sephadex gel chromatography (Smith et al. 1971) or by high-pressure liquid chromatography (Bundgaard 1977 b). Polymers have been isolated also from other semisynthetic penicillins such as hetacillin and carbenicillin (Smith et al. 1971), methicillin and pheneticillin (Butcher and Stewart 1970). 

The penicillinase of the title is the penicillin ) -lactamase (EC S.5.2.6) which hydrolyzes the substituted amide bond in the four-membered ring in penicillin, producing penicilloic add. Bacterial penicillinases show a general group spedlicity in hydrolyzing, as well as the naturally produced penicillins, many synthetic acyl derivatives of 6-aminopenicil-lanic acid, though the rate of destruction depends both on the nature of the acyl side chain and on the source of the penicillinase. The products of the reaction have no antibiotic activity, and both the discovery and... 

Prior to the complete structural elucidation of penicillin some effort was directed towards the preparation of the erroneous oxazolone-thiazolidine structure (48) using (52) and penicillamine (53). Surprisingly trace amounts of bioactive penicillins corresponding to the fused P-lactam structure (49) were obtained 40). The first cyclisation of a penicilloate derivative was described by Sheehan 41) using the acid chloride of the phthalimido derivative (54) to give (55). 

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