Cleavage of penicillin

Chemical Cleavage of Penicillin Side Chain Amides... 

Figure 6.14 Enzymatic side chain cleavage of penicillins. 6-Aminopenicillanic acid, a valuable intermediate for the production of various semi-synthetic penicillins, can be obtained through enzyme-mediated hydrolysis of the phenylacety group of penicillin G or the phenoxyacetyl group of penicillin V. The active site of the enzyme recognises the aromatic side chain and the amide linkage, rather than the penidllin nucleus. Chemical entitles other than penicillins are therefore often good substrates, as long as they contain the aromatic acetamide moiety.

Recommended model particle systems are enzymes immobilised on carriers ([27,44,45,47,49]), oil/water/surfactant or solvent/water/surfactant emulsions ([27, 44, 45] or [71, 72]) and a certain clay/polymer floccular system ([27, 42-52]), which have proved suitable in numerous tests. The enzyme resin described in [27,44,47] (acylase immobilised on an ion-exchanger) is used on an industrial scale for the cleavage of Penicillin G and is therefore also a biological material system. In Table 3 are given some data to model particle systems. 

Microbial cleavage of Penicillin-G into 6-AMP and phenylacetate is as shown below ... 

The industrial production of 6-aminopenicillanic acid (6-APA), the key building block for all semisynthetic variations (1957) 6-APA is readily available from high-producing strains of Penidllium chrysogenum by enzymatic cleavage of penicillin G with penicillin acylase (see Section 2.03.11). 

Examples of this, in addition to the above acrylamide example and the related enzymatic conversion of 3-cyanopyridine to nicotinamide, are die amidase cleavage of penicillins to produce 6-aminopenicillanic acid (6-APA) and the corresponding (more complex) process for converting cephalosporin C to 7-aminocephalosporanic acid (7-ACA) (see Chapter 9, footnote 8.)... 

In contrast, enzymatic cleavage of penicillin G (Fig. 1.37) is performed in water at 37 °C and the only reagent used is NH3 (0.9 kg per kg of 6-APA), to adjust the pH. The enzymatic process currently accounts for the majority of the several thousand tons of 6-APA produced annually on a world-wide basis. 

This consideration is significant for hydrolytic reactions with hydrolases such as lipases, esterases, and amidases. These include penicillin amidases (synonymous with penicillin acylases) and cephalosporin acylases which are used for hydrolytic cleavage of penicillins and cephalosporins in thousands of tons per year [98]. These hydrolyses have to be performed at a pH-value of 8 which is close to the optimum pH of the enzyme. Lower pH-values lead to lower reaction rates and reversibility of the reaction, and hence to a significant loss in product formation. Higher pH-values are not advisable owing to the instability of the reaction partners. Moreover, addition of buffers is not accepted because of the costly removal of the buffer components. 

In general, virtually any process leading to 4-azetidinylthioesters from penams was put to its best use by the oxoamide-thioester coupling. Preparation of FCE-22101, FCE 22891 and related penems, could be achieved in fewer steps [81,82,92,96,153]. In particular, the silver-assisted 1,2-cleavage of penicillins is ideally suited to accompany the phosphite-mediated condensation a unique... 

Lewis Acid with Thioethers. Ag20 has been applied to the 1,2-cleavage of penicillins in a strong nonnucleophilic base, such as l,5-diazabicyclo[4.3.0]non-5-ene, and to the hydrolysis of... 

A. is a central building block of penicillins and is produced either by fermentation Penicillium chry-sogenum or Pleurotis astreatus) in the absence of suitable side-chain precursors or by chemical or enzymatic cleavage of penicilline G (phenoxy-methylpenicilline). 

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