Benzylpenicillin

The first penicillin was benzylpenicillin (penicillin G, R = C6H5 CH2 C0 NH-), which is made by growing suitable strains of Penicillium chrysogenum on a carbohydrate medium. 

PhCHa benzylpenicillin = penicillin G (usual fermentation product)... 

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. 

Confirmation of the structure of benzylpenicillin by X-ray diffraction studies (B-49MI51101). 

The nomenclature of penicillins requires special comment. Compound (2) can be named as follows (a) penicillin G (b) benzylpenicillin (note that the term penicillin may refer to the compound class (1), to the structural fragment (3) or, especially in the medical literature, to compound (2) itself) (c) 6/3-phenylacetamidopenicillanic acid (d) 2,2-dimethyl-6/3-phenylacetamidopenam-3a -carboxylic acid (e) (2S,5i ,6i )-3,3-di-methyl-7-oxo-6-(2-phenylacetamido)-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid and (f) [2S-(2a,5a,6/3)]-3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-l-azabicyclo-[3.2.0]heptane-2-carboxylic acid. The numbered system shown in (2) is the one most commonly used in the penicillin literature and will be used in this chapter note that different number is used when (2) is named according to (e) and (f) above. 

The early investigations of the reactions of the penicillin class of compounds were largely of a degradative nature, and were primarily associated with structure elucidation. These have been discussed in detail (B-49MI51102) and some of the principal transformations are outlined in Schemes 2, 3 and 4 using benzylpenicillin as an example. Some of these reactions will be discussed in greater detail later in this section. 

The acylation of 6-APA (Scheme 59) has been a very versatile way in which to generate new penicillin derivatives which differ from fermentation-produced penicillins in the 6-side chain. As will be discussed in Section 5.11.5.1, this approach has led to significant improvements in the therapeutic properties of penicillins, and, in fact, of the penicillins in medical use today, only benzylpenicillin and phenoxymethylpenicillin are produced directly by fermentation. 

All stated pK values in this book are for data in dilute aqueous solutions unless otherwise stated, although the dielectric constants, ionic strengths of the solutions and the method of measurement, e.g. potentiometric, spectrophotometric etc, are not given. Estimated values are also for dilute aqueous solutions whether or not the material is soluble enough in water. Generally the more dilute the solution the closer is the pK to the real thermodynamic value. The pK in mixed aqueous solvents can vary considerably with the relative concentrations and with the nature of the solvents. For example the pK values for V-benzylpenicillin are 2.76 and 4.84 in H2O and H20/EtOH (20 80) respectively the pK values for (-)-ephedrine are 9.58 and 8.84 in H2O and H20/Me0CH2CH20H (20 80) respectively and for cyclopentylamine the pK values are 10.65 and 4.05 in H2O and H20/EtOH (50 50) respectively. pK values in acetic acid or aqueous acetic acid are generally lower than in H2O. 

Sodium benzylpenicillin see -benzylpenicillin sodium salt on p. 514 in Chapter 6. 

PELARGONYL PEROXIDE see DI-N-HONANOYL PEROXIDE PENICILLIN see BENZYLPENICILLIN PENTABORANE... 

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... 

An alternate route to ampicillin not only circumvents the need for 6-APA but also has the advantage of providing a prodrug form of ampicillin as well as the parent compound. Reaction of benzylpenicillin (4) with the acid protecting group, 29, gives the formol ester, 30. Reaction of the product with phosphorus pentachloride leads to the corresponding imino chloride (31). 

The D- -)-o -aminobenzylpenicillin may then be recovered from the aqueous reaction mixture by concentration to small volume and recovering the product by filtration. However, due to the fact that anhydrous D- -)-a-aminobenzylpenicillin is soluble in water to the extent of about 20-25 mg/ml at 20°-25°C, it is very difficult to recover the product in high yields. Furthermore, the recovered D- -)-a-aminobenzylpenicillin may be obtained in the form of a monohydrate. The monohydrates as well as the dihydrates) of D- -)-a-amino-benzylpenicillin possess poor biological stability. 

Chemical Nama D-a-(imidazolidin-2-on-1-yl-carbonylamino)benzylpenicillin, sodium salt Common Nama —... 

Monobenzyl phenylmalonate (13.3 g) in dry benzene (100 ml) was refluxed with thionyl chloride (6.45 g) for 90 minutes, then concentrated in vacuo. The residual oil was dissolved In dry acetone (50 ml) and added to a stirred, ice-cooled solution of 6-aminopenlcillanic acid (9.7 g) in N sodium bicarbonate solution (135 ml), water (150 ml), and acetone (300 ml). The mixture was stirred for 30 minutes at 0°C and then for 90 minutes at room temperature, then concentrated under reduced pressure to remove acetone. The aqueous solution was brought to pH 2 with dilute hydrochloric acid and extracted with ether (3 X 100 ml). The ether solution was washed with water and then itself extracted with sufficient N sodium bicarbonate solution to give an aqueous phase of pH 7,5. The aqueous layer was separated and evaporated at low temperature and pressure to leave the Impure sodium salt of a-(benzyloxycarbonyl) benzylpenicillin. 

Chemicel Name Sodium D(-)-a-[(3-methvlsulfonvl-imidazolidin-2-on-1-vl)-carbonvl-amino] benzylpenicillin... 

Sjsj2 reaction and, 377-378 Benzylic radical, resonance in, 578 spin-density surface of, 578 Benzylpenicillin, discovery of, 824 structure of, 1 Benzyne, 575... 

Oxidation of phenyl hexyl sulphide with sodium metaperiodate gave also only a trace amount of the corresponding sulphoxide72. On the other hand, Hall and coworkers73 prepared benzylpenicillin and phenoxymethyl penicillin sulphoxides from the corresponding benzyl esters by oxidation with sodium metaperiodate in dioxane solution with a phosphate buffer. A general procedure for the synthesis of penicillin sulphoxides was reported later by Essery and coworkers74 which consists in the direct oxidation of penicillins or their salts with sodium metaperiodate in aqueous solution at pH 6.5-7.0. 1-Butadienyl phenyl sulphoxide 4475 and a-phosphoryl sulphoxides 4576 were also prepared by the same procedure. 

Der amorphe 6-Phenylacetylamino-penicillanylalkohol (78% d.Th.) wird ahnlich aus Benzylpenicillin-triathylammonium-Salz iiber das Kohlensaure-Carbonsaure-Anhydrid, Reaktion mit Natriumazid und Reduktion des Azids mit Natriumboranat hcrgestellt2, wobei die Aminocarbonyl-Gruppen durch das Reduktionsmittel nicht angegriffen werden. 

Penicillin Heyl (Heyl) Prevecillin (Griinenthal)-(clemizol-penicillin) Tardocillin (Bayer)-(benzathine-benzylpenicillin)... 

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