Aminopenicillic acid

Penicillinacylase is used industrially to catalyze the hydrolytic removal of the side chain in naturally occurring penicillins such as benzylpenicillin (4.49) and phenoxymethylpenicillin (4.50). The nucleus 6-aminopenicillic acid (4.48) is then used as the starting material for the preparation of semisynthetic penicillins. Appropriate acylation of the 6-NH2 group leads to )3-lactamase-stable and broad-spectrum penicillins. 

Penicillins are the world s most important antibiotics, the production per year being worth 25 million. The quantitation of penicillin is required for control of the fermentative production of penicillin G and penicillin V and their splitting to 6-aminopenicillic acid (6-APA). 6-APA is the basic material for semisynthetic penicillins. 

Chemferm is one of among several companies which apply penicillin acylase for the kinetically controlled industrial synthesis of semisynthetic antibiotics in aqueous environments (Scheme 37) [109-111]. Ampicillin (119) and amoxicillin (120) can be obtained by the enzyme-catalyzed condensation of 6-aminopenicillic acid (6-APA, 117) with the amide or ester of D-(-)-4-hydrox-yphenylglycine and D-(-)-phenylglycine, respectively. In a similar way, cephalexin (121) can be obtained by reaction of D-(-)-phenylglycine with 7-aminodesacetoxycephalosporanic acid (7-ADCA, 118). Penicillin acylase from diverse microbial strains such as E. colU Klyveromyces citrophiluy and Bacillus megabacterium was successfully applied for this transformation and was used in its immobilized form based on a gelatin carrier. The immobilization allows an easy separation from the reaction medium and the reuse of the enzyme for at least 50 cycles. Impressive characteristics of this transformation are yields >90%, a selectivity of >95%, and an optical purity of >99% ee. The industrial manufacture takes place in repetitive batch reactors at many locations worldwide with an annual production volume of 2,000 t. 

Phenacyl-6-aminopenicillate HCI D-Phenylglycyl Chloride HCI 4-Hydro xy-1,5-naphthyridine-3-carboxylic acid-N-succinimide ester... 

Semi-Synthetic Antibiotics. In 1959, Batchelor and coworkers in the Beecham Research Laboratories in England discovered that the penicillin nucleus, 6-aminopenicil-lanic acid (6-APA), accumulated during fermentation when side chain precursors were omitted. This 6-APA could be used for the chemical synthesis of entirely new types of penicillin by coupling with new side chains. Shortly thereafter, several sources of penicillin amidase were found that would cleave the phenylacetyl side chain from penicillin G, thus producing a more economical source of 6-APA. A vast number of synthetic penicillins have been generated, and a few have achieved clinical importance. Several objectives were sought ... 

The isolation of the olivanic acids and clavulanic acid from natural sources stimulated a worldwide search for yS-lactamase inhibitors with improved biological properties. Whilst much effort was devoted to the chemical modification of the olivanic acids and clavulanic acid, perhaps the greatest success has been achieved by the chemical manipulation of 6-aminopenicil-lanic acid (6-APA) (8) and penicillin G (4). The purpose of this review is to describe some of the successful efforts that have been made to design and synthesize potent inhibitors of bacterial S-lactamases from these readily available chiral synthons. 

By 1959, Rolinson and coworkers completed the isolation of the penicillin nucleus, 6-aminopenicil-lanic acid, (Figure 1) in quantity. At about the same time the p-lactam-dihydrothiazine structure for the cephalosporin C was proposed [2] and confirmed subsequently by X-ray crystallographic analysis. In 1962, Morin and coworkers established a chemical method for the production of 7-aminocephalosporanic acid (Figure 1) from cephalosporin C in quantity. These developments opened the way to the preparation of... 

Two other developments have provided additional means for making new penicillins. A group of British scientists, Batchelor et al., reported the isolation of 6-aminopenicil-lanic acid from a culture of P. chrysogenum. This compound can be converted to penicillins by acylation of the 6-amino group. Sheehan and Ferris provided another route to synthetic penicillins by converting a natural penicillin, such as penicillin G potassium, to an intermediate (Fig. 10-1), from which the acyl side chain has been cleaved and which then can be treated to form biologically active penicillins with a variety of new side chains. By these procedures, new penicillins, superior in activity and stability to those formerly in wide use, were found, and no doubt others will be produced. The first commercial products of these research activities were phenoxyethylpenicillin (phenethicillin) (Fig. 10-2) and dimethoxyphenylpenicillin (methicillin). 

For the penicillins a one-step biocatalytic route for the production of 6-aminopenicil-lin acid (6-APA) from the fermentation product penicillin (Pen G or Pen V) was well known. Beginning at the end of 1970s the chemical process (almost similar to the... 

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... 

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