Penicillins semi synthesis

Amides and iS-lactams semi-synthesis and hydrolysis of penicillins and cephalosporins... 

Enzymatic processes also advance in the area of large-scale pharma intermediates /flactam antibiotics can now be produced in a fully biotechnological process, including the semi-synthesis from the /flactam core to the penicillin or cephalosporin. A precursor to ephedrine, long produced by a whole-cell process in yeast, can be obtained from benzaldehyde and acetaldehyde with the help of pyruvate dehydrogenase acting as a carboligase. 

Tetracyclines are a family of antibiotics which display a characteristic 4-fused-core ring structure (Figure 1.16). They exhibit broad antimicrobial activity and induce their effect by inhibiting protein synthesis in sensitive microorganisms. Chlortetracycline was the first member of this family to be discovered (in 1948). Penicillin G and streptomycin were the only antibiotics in use at that time, and chlortetracycline was the first antibiotic employed therapeutically that retained its antimicrobial properties upon oral administration. Since then, a number of additional tetracyclines have been discovered (all produced by various strains of Streptomyces), and a variety of semi-synthetic derivatives have also been prepared (Table 1.18). 

D-p-Hydroxyphenylglycine is an important component of certain semi-synthetic antibiotics such as the semi-synthetic cephalosporins cefadroxil and cefatrizine and the semi-synthetic penicillin amoxicillin, with a combined world market in excess of 3 x 10 /a. Synthesis was possible from DL-5-monosubstituted hydantoins (cyclic ureides of amino acids) provided that a selective D-hydantoinase could be found, which would be competitive with chemical methods. 

Sulbactam sodium is semi-synthetic antibiotic of penicillinic group. Start material for it s synthesis is 6-aminopenicillanic acid. First 6-aminopenicillanic acid was isolated in 1957 year from benzylpenicilline as resalt of treating of it by penicillinaze. Benzylpenicilline is produced by microorganism of genus Streptomyces. 

Carboxylic acid 3.46 has been extensively used in the preparation of semi-synthetic penicillins and cephalosporins. Devise a synthesis of 3.46 from ester 3.45. 

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 ... 

To date, the number of penicillin and cephalosporin-based molecules produced by semi- and total synthesis is well in excess of 20000. Most started with modification of the fermentation product, 6-amino-penicillanic acid 20 or the corresponding cephalosporin, 7-amino-cephalosporanic acid 21, both of which can be produced by simple chemical or biochemical deacylation from penicillin or cephalosporin C. The number above is only approximate as a significant proportion of structures from industry were never formally published, or were only mentioned in the patent literature—particularly if they had marginal or no significant activity levels over those which had been reported previously. 

More recently, a biocatalytic manufacturing route was developed in which deacylation was accomplished by penicillin G acylase in water at room temperature, requiring no protection and deprotection (Scheme 8.9) [58]. Moreover, through reaction engineering, penicillin G acylase also catalyzes the acylation of 6-APA with either amino esters or aminoamides to produce a wide range of semi-synthetic P-lactam antibiotics such as amoxicillin and ampicillin. A similar approach could be applied to the synthesis of the 7-ADCA derivatives cefaclor, cephalexin, and cefadroxil. 

D-phenylglycine and D-p-hydroxy-phenylglycine esters have been investigated in the enzymatic process to semi-synthetic penicillins and cephalosporins (3). Phenylalanine methyl ester was used in the Holland Sweetener Company (DSM-Tosoh joint venture) for enzymatic synthesis of the artifical sweetener aspartame (4). 

The industrial manufacture of semi-synthetic penicillins and cephalosporins is an outstanding example of the integration of chemistry and biocatalysis. The impact of biocatalysis shortens the synthesis for Cefalexin from ten to six steps is a successful example (Fig. 16) [55,56]. 

In the crucial final step in the Cefalexin synthesis, the cephalosporin nucleus 7-ADCA is coupled with phenylglycine amide or ester. This is one of the first industrial examples of a synthesis reaction performed by enzymes. Until then, enzymes were mainly employed for hydrolysis the deacylation of penicillin G to give 6-APA (not shown), that of cephalosporin G to give 7-ADCA (Fig. 16) as well as the kinetic resolution of the DL-phenylglycine derivatives (Fig. 16) are examples. Also, similar processes were developed for other semi-synthetic antibiotics derived from phenylglycine and 4-hydroxyphenyl-glycine (Fig. 17). 

Bruggink A (2000), Green solutions for chemical challenges biocatalysis in the synthesis of semi-synthetic antibiotics. In Zwanenburg B, Mikolajczyk M, Kielbasinsky P (eds) Enzymes in action. NATO sciences series 1/33, Kluwer Academic, pp 449-458 Bruggink A, Roos EC, de Vroom E (1998) Penicillin acylase in the industrial production of lactam antibiotics.Org Process Res Dev2 128-133... 

The nocardicin nucleus 3-aminonocardicinic acid (3-ANA) (7) has not been found in nature, but can be prepared by deacylation of nocardicin C using microbial amidases 10). The first chemical method leading to (7) involved acid treatment of the bisthiourea derivative (8) of nocardicin C 11). A more recent method 12) makes use of the reaction of the oxime grouping of nocardicin A with di-/-butyl dicarbonate. This results in (9) which on treatment with trifluoroacetic acid gives (7). Further confirmation of the structure and stereochemistry of the nocardicins was the identification of the acylamino-derivative (10) derived from 3-ANA, with a compound obtained by partial synthesis from penicillin G 11). Another semi-synthetic approach (75) to the nocardicins from penicillin is by way of the thiazoline (11), the final step being Raney nickel desulphurisation of (12). 

A potentially useful route to semi-synthetic penicillins by direct acylation of penicillin G imino-chloride esters (187) proceeds through the intermediate diacyl derivatives (188). Selective removal of the phenylacetyl group and ester deblocking with thiophenolate ion afford penicillins (189). A practical application of this route for the synthesis of carbenicillin [189 R = PhCH(COaH)] has been developed. A route to a-carboxyphenylacetamido-cephalosporins (191), by the reaction of isocyanate (190 R = 4-nitrobenzyl) with the anion of t-butyl phenylacetate, has been described. ... 

---