Penicillins, semisynthetic synthesis

Other Reactions. The reaction of Thydioxybenzaldehyde with sodium cyanide and ammonium chloride, Strecker synthesis, yields /J-hydroxyphenylglycine [938-97-6] a key intermediate in the manufacture of semisynthetic penicillins and cephalosporins (see Antibiotics, p-LACTAMs). 

Pharmaceuticals. -Hydroxybenzaldehyde is often a convenient intermediate in the manufacture of pharmaceuticals (qv). For example, 2-(p-hydroxyphenyl)glycine can be prepared in a two-step synthesis starting with -hydroxybenzaldehyde (86). This amino acid is an important commercial intermediate in the preparation of the semisynthetic penicillin, amoxicillin (see ANTIBIOTICS, P-LACTAMs). Many cephalosporin-type antibiotics can be made by this route as well (87). The antiemetic trimethobenzamide [138-56-7] is convenientiy prepared from -hydroxybenzaldehyde (88) (see Gastrointestinal agents). 

The second most important group of immobilized enzymes is stiU the penicillin G and V acylases. These are used in the pharmaceutical industry to make the intermediate 6-aminopenici11anic acid [551-16-6] (6-APA), which in turn is used to manufacture semisynthetic penicillins, in particular ampicilHn [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 ... 

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

These defects have spurred attempts to prepare analogs. The techniques used have been (1) natural fermentation (in which the penicillin-producing fungus is allowed to grow on a variety of complex natural nutrients from which it selects acids for incorporation into the side chain), (2) biosynthetic production (in which the fermentation medium is deliberately supplemented with unnatural precursors from which the fungus selects components for the synthesis of "unnatural" penicillins), (3) semisynthetic production (in which 6-aminopenicillanic acid (2) is obtained by a process involving fermentation, and suitably activated acids are subsequently reacted chemically with 6-APA to form penicillins with new side chains) and (4) total synthesis (potentially the most powerful method for making deep-seated structural modifications but which is at present unable to compete economically with the other methods). 

Semisynthetic heterocycles are also important dmg molecules. These compounds attempt to capture the best of both worlds, being synthetic derivatives of natural products. The use of a natural product in the preliminary stages of the synthesis enables the elimination of numerous costly synthetic steps. The subsequent synthetic modifications enable further fine tuning of the natural product pharmacophore. There are a number of semisynthetic penicillin derivatives available. Similarly, there are also semisynthetic hormone analogs, especially of estrogens and gestagens. 

After the first successful attempts in 1928 to identify the active biochemicals found in antibacterial molds, followed the rediscovery of penicillin by Fleming, identification of its chemical structure by Hodgkin, and subsequent synthesis by Chain, Heatley, and Florey, which led to the commercial production of penicillin in the mid 1940s [1], Since then, other families of (3-lactam antibiotics have been developed [2, 3], and their massive use worldwide continues to be a forefront line of action against infectious pathogens [4-6]. In recent years, (3-lactams have found other biomedical applications, such as inhibitors of serine protease ([7, 8] for a review, see [9]) and inhibitors of acyl-CoA cholesterol acyltransferasa (ACAT) [10]. Encouraged by their bioactivity, the synthesis and chemistry of (3-lactam antibiotics have been the focus of active research, and chemical modification of some basic structures available from biosynthesis (semisynthetic approaches) as well as the discovery of fully chemical routes to de novo synthesis of (3-lactam... 

Bamberg, P. Ekstrom, B. Sjoberg, B. Semisynthetic penicillins VII. The use of phenacyl 6-aminopenicillinates in penicillin synthesis. Aeta Chem. Scand. 1967, 21, 2210-2214. 

Nowadays, all the therapeutically relevant penems are equipped with the lf/ 3-hydroxyethyl side chain, characteristic of the thienamycin (carbapenem) family (see Table 1). Accordingly, they are prepared by hemisynthesis from the chiral acetoxyazetidinone 76, which is industrially produced on a large scale by chemical methods (see Section 2.03.9). This chiron plays a similar role as 6-APA for the synthesis of semisynthetic penicillins, but here for the synthesis of non-natural penems and carbapenems <1996T331>. 

Recently a number of enzymatic systems have been developed at several chemical companies including Upases (synthesis of enantiotrope alcohols, R-amid, S-amin), nitrilases (R-mandehc acid), amidases (non-proteinogenic L-amino acids), aspartic acid ammonia lyase (L-aspartic add), penicilin acylase (6-Aminopenicilanic acid), acylases (semisynthetic penicillins), etc.( Koeller and Wong, 2001 and references therin). 

The overwhelming majority of semisynthetic beta-lactam antibiotics, the penicillins and cephalosporin, currently available to physicians trace their origins to the intense research effort devoted to this field several decades ago. The emergence of pathogens resistant to those antibiotics has led some laboratories to revisit this field. The modified cephalosporin ceftobiprole (220), a compound with a rather complex extended side chain, has shown activity in the clinic against some strains of multidrug resistant bacteria. The synthesis starts with the well-precedented acylation of the of the cephalosporin (215), available in several steps from the commercially available 7-acetoxy cephalosporanic acid, with the activated... 

In 1958-60, Beechams managed to isolate a biosynthetic intermediate of penicillin which was also one of Sheehan s synthetic intermediates. The compound was 6-APA and it allowed the synthesis of a huge number of analogues by a semisynthetic... 

Figure 14.15 Synthesis of semisynthetic penicillins using penicillin G acylase.

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