Penicillin V

Certain factors and product precursors are occasionally added to various fermentation media to iacrease product formation rates, the amount of product formed, or the type of product formed. Examples iaclude the addition of cobalt salts ia the vitamin fermentation, and phenylacetic acid and phenoxyacetic acid for the penicillin G (hen ylpenicillin) and penicillin V (phenoxymethylpenicillin) fermentations, respectively. Biotin is often added to the citric acid fermentation to enhance productivity and the addition of P-ionone vastly iacreases beta-carotene fermentation yields. Also, iaducers play an important role ia some enzyme production fermentations, and specific metaboHc inhibitors often block certain enzymatic steps that result in product accumulation. 

Most of the new commercial antibiotics have resulted from semisynthetic studies. New cephalosporkis, a number of which are synthesized by acylation of fermentation-derived 7-amkiocephalosporanic acid, are an example. Two orally active cephalosporkis called cefroxadine and cephalexin are produced by a synthetic ring-expansion of penicillin V. 

At present all of the cephalosporins ate manufactured from one of four P-lactams, cephalosporin C (2), penicillin V [87-08-17, penicillin G [113-98-4] and cephamycin C (8), which ate all produced in commercial quantities by fermentation (87). The manufacturing process consists of three steps fermentation, isolation, and chemical modification. 

The only penicillins used in their natural form are benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V). The remainder of penicillins in clinical use are derived from 6-APA and most penicillins having useful biological properties have resulted from acylation of 6-APA using standard procedures. 

The pharmacology of penicillins differs markedly from compound to compound but has been well reviewed (57). The majority of derivatives, including penicillin G and the antipseudomonal penicillins, ate unstable in gastric acid and ate not available orally. The isoxazolyl penicillins ate relatively acid stable but not consistendy well absorbed by the oral route. Nafcillin and oxacillin ate poody absorbed orally cloxacillin, dicloxacillin, and ducloxacillin ate more teUable. Penicillin V, ampicillin, and patticulady amoxicillin ate relatively well absorbed orally. Esters of ampicillin such as bacampicillin, pivampicillin, and talampicillin improve the level of oral absorption of ampicillin to that achieved by amoxicillin. Absorption can be diminished by food after oral adruinistration, however, and peak blood levels, usually achieved after 1 to 2 h, ate somewhat delayed after ingestion of food. 

Table 2. Typical Operating Parameters for Immobilized Glucose Isomerase and Penicillin V Acylase...

Immobilized enzyme Glucose isomerase Penicillin V acylase... 

En2yme techniques are primarily developed for commercial reasons, and so information about immobilisation and process conditions is usually Limited. A commercially available immobilised penicillin V acylase is made by glutaraldehyde cross-linking of a cell homogenate. It can be used ia batch stirred tank or recycled packed-bed reactors with typical operating parameters as iadicated ia Table 2 (38). Further development may lead to the creation of acylases and processes that can also be used for attaching side chains by ensymatic synthesis. 

In an unusual application of the Wittig reaction, treatment of clavulanic acid derivatives and esters of penicillin V with methoxycarbonylmethylenetriphenylphosphorane afforded the corresponding exo-alkylideneazetidines. Thus penicillin V benzyl ester (104) gave (lOS) as a mixture of E and Z isomers. The /3-lactam could be regenerated by low-temperature ozonolysis (81CC929). 

The importance of the penicillins as a class of heterocyclic compounds derives primarily from their effectiveness in the treatment of bacterial infections in mammals (especially humans). It has been estimated that, in 1980, the worldwide production of antibiotics was 25 000 tons and, of this, approximately 17 000 tons were penicillins (81MI51103). The Food and Drug Administration has estimated that, in 1979 in the U.S.A., 30.1 x 10 prescriptions of penicillin V and 44.3 x 10 prescriptions of ampicillin/amoxicillin were dispensed. This level of usage indicates that, compared to other methods of dealing with bacterial infection, the cost-benefit properties of penicillin therapy are particularly favorable. Stated differently, penicillin treatment leads to the elimination of the pathogen in a relatively high percentage of cases of bacterial infection at a relatively low cost to the patient in terms of toxic reactions and financial resources. 

Penicillin V—see Penicillin, phenoxymethyl-, 7, 300 Penicilloate, benzyl-, 7, 303 Penicilloate, D-a-benzyl-a-methyl ester, 7, 303 Penillamine, benzyl-, 7, 303 Penillic acid, benzyl-, 7, 303 Penilloaldehyde, benzyl-, 7, 303 Penilloic acid, benzyl-, 7, 303 Penillonic acid, benzyl-methyl ester, 7, 303 1,2,3,4,6-Pentaazaindene nomenclature, 1, 18 Pentadeca-5,10-dienols synthesis, 1, 428 Pentadienol, tetrachloro-2H-pyran synthesis from, 3, 740 Pentadienonitrile, 5-(l,2-benzoselenazol-3-yl)-X-ray diffraction, 6, 334 Penta-2,4-dienonitrile, 5-(dimethylamino)-2-(2-thienyl)-... 

In the post-World War II years, synthesis attained a different level of sophistication partly as a result of the confluence of five stimuli (1) the formulation of detailed electronic mechanisms for the fundamental organic reactions, (2) the introduction of conformational analysis of organic structures and transition states based on stereochemical principles, (3) the development of spectroscopic and other physical methods for structural analysis, (4) the use of chromatographic methods of analysis and separation, and (5) the discovery and application of new selective chemical reagents. As a result, the period 1945 to 1960 encompassed the synthesis of such complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward, R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork, 1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll (R. Woodward, 1960) (page 5). ... 

Following the realization that the presence of phenylacetic acid in the fermentation led to a simplification of the mixture of penicillins produced by the fungus due to preferential uptake of this acid and its incorporation into benzylpenicillin (4), a wide variety of other acids were added to the growing culture. Inclusion of the appropriate acids in the culture medium thus afforded, respectively, phenoxymethylpenicillin (5, penicillin V), phenethicillin propicillin (7), and phehbencillin... 

Approximately 1,000 g of phenoxymethylpenicillin acid (Penicillin V) is dissolved directly in about 5 liters of ethyl acetate to a concentration of 20% w/v. The resulting solution Is fil-... 

Epicillln Floxaclllin Methicillin sodium Nafcillin sodium Oxacillin sodium Penicillin V... 

Penicillin G hydrabamine Dehydroabietyl ethylene diamine Penicillin V hydrabamine 1 -Dehydro-6tt-methyl-9a-fluorohydro-cortisone Fluorometholone 6-Dehydro-17-methyltestosterone Calusterone... 

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