6-Aminopenicillanic acid Amoxicillin

Aminopenicillanic acid Amoxicillin Ampicillin Azidocillin Aziocillin... 

Simultaneous impurities, 6-aminopenicillanic acid, amoxicillin penicilloic adds, p-... 

The strategy we hope you identified is to first produce 6-aminopenidllanic acid, then attempt to add different moieties to the 6-amino group. This can be achieved either chemically or enzymatically. In the following section we will consider the conversion of penicillin C into 6-aminopenicillanic acid and follow this by examining how 6-aminopenidllanic acid may be converted into ampirillin and amoxicillin. 

Figure 6.18 Chemical synthesis of amoxicillin from 6-aminopenicillanic acid via the Dane Salt of 4-hydroxyphenylglycine.

The second most important group of immobilized enzymes is still the penicillin G and V acylases. These are used in the pharmaceutical industry to make the intermediate 6-aminopenicillanic acid [551-16-6] (6-APA), which in turn is used to manufacture semisynthetic penicillins, in particular ampicillin [69-53-4] and amoxicillin [26787-78-0]. This is a remarkable example of how a complex chemical synthesis can be replaced with a simple enzymatic one ... 

Investigating the kinetically controlled synthesis of the /flactam antibiotic amoxicillin from 6-aminopenicillanic acid and D-p-hydroxyphenylglycine methyl ester in a solid suspension system in which the reaction nevertheless occurred in the liquid phase, Diender et al. found that the pH value and dissolved concentrations took a very different course at different initial substrate amounts (Diender, 2000). These results were described reasonably well by the model based on mass and charge balances, pH-dependent solubilities of the reactants, and enzyme kinetics. 

The natural penicillins, primarily G and V, have a relatively narrow spectrum. They act mostly on gram-positive organisms. The fact that proper selection of precursors could lead to new variations in the penicillin side chain offered the first source of synthetic penicillins. Penicillin V, derived from a phenoxy-acetic acid precursor, attracted clinical use because of its greater acid tolerance, which made it more useful in oral administration. Also, the widespread use of penicillin eventually led to a clinical problem of penicillin-resistant staphylococci and streptococci. Resistance for the most part involved the penicillin-destroying enzyme, penicillinase, which attacked the beta-lactam structure of the 6-aminopenicillanic acid nucleus (6-APA). Semisynthetic penicillins such as ampicillin and carbenicillin have a broader spectrum. Some, such as methicillin, orafi-cillin, and oxacillin, are resistant to penicillinase. In 1984, Beecham introduced Augmentin, which was the first combination formulation of a penicillin (amoxicillin) and a penicillinase inhibitor (clavulanic acid). Worldwide production of semisynthetic penicillins is currently around 10,000 tons/year, the major producers are Smith Kline Beecham, DSM, Pfizer, and Toyo Jozo. 

Amoxicillin (7) is a semisynthetic penicillin antibiotic. The penicillin portion is derived from fermentation of either penicillin-V or -G, and then the side chain is removed chemically to afford 6-aminopenicillanic acid (6-APA) [3,16], The D- 7-hydroxyphenylglycine is then attached as the new side chain—chemical and enzymatic methods are available to achieve this [17-21]. This amino acid is obtained by a classical resolution or by enzymatic hydrolysis of a hydantoin (Chapter 8) [22-26],... 

The starting material for the most important semi-synthetic )3-lactam antibiotics is penicillin G or adipoyl-7-aminodesacetoxycephalosporanic acid. From these, ampicUlin, amoxicillin, cephalexin and cefadroxU are obtained in considerable tonnage. [48] The essential intermediates for this are 6-aminopenicillanic acid or 7-aminodesacetoxycephalosporanic acid. 

The basic structure of penicillins is a thiazolidine ring linked to a p-lactam ring to form 6-aminopenicillanic acid, the so called penicillin nucleus (Fig. 1). This acid, obtained from Penicillium chrysogenum cultures, is a precursor for semisynthetic penicillins (ampicdlin, amoxicillin, oxacillin, cloxacillin, dicloxacillin, and methicillin) produced by attaching different side chains to the nucleus. Benzylpenicillin (penicillin G) and phenoxymethylpenicil-lin (penicillin V) are the naturally occurring penicillins. 

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