Cephalosporins manufacture

For the analogous side-chain removal reaction required for semi-synthetic cephalosporin manufacture more complicated processes have been developed. The side-chain of cephalosporin C can be split off enzymatically, but only after its amino group has been removed by a combined enzymatic and spontaneous reaction sequence (Matsumoto, 1993). Amongst other companies, Hoechst has replaced their chemical process by a two-enzyme process, thus reducing the amount of waste from 31 ton to 0.3 ton per ton of 7-... 

Barr and Biocraft, which have valid cephalosporin manufacturing facilities in the U. S., may also try to skirt Lilly s process patents, Mr. Flynn says. Such a strategy would give these companies a meaningful cost advantage over importing firms, he adds. 

Antibiotics. Solvent extraction is an important step in the recovery of many antibiotics (qv) such as penicillin [1406-05-9] streptomycin [57-92-17, novobiocin [303-81-1J, bacitracin [1405-87-4] erythromycin, and the cephalosporins. A good example is in the manufacture of penicillin (242) by a batchwise fermentation. Amyl acetate [628-63-7] or -butyl acetate [123-86-4] is used as the extraction solvent for the filtered fermentation broth. The penicillin is first extracted into the solvent from the broth at pH 2.0 to 2.5 and the extract treated with a buffet solution (pH 6) to obtain a penicillin-rich solution. Then the pH is again lowered and the penicillin is re-extracted into the solvent to yield a pure concentrated solution. Because penicillin degrades rapidly at low pH, it is necessary to perform the initial extraction as rapidly as possible for this reason centrifugal extractors are generally used. 

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). 

Pharmaceutical. Ion-exchange resins are useful in both the production of pharmaceuticals (qv) and the oral adrninistration of medicine (32). Antibiotics (qv), such as streptomycin [57-92-17, neomycin [1404-04-2] (33), and cephalosporin C [61-24-5] (34), which are produced by fermentation, are recovered, concentrated, and purified by adsorption on ion-exchange resins, or polymeric adsorbents. Impurities are removed from other types of pharmaceutical products in a similar manner. Resins serve as catalysts in the manufacture of intermediate chemicals. 

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. 

Antibiotics, e.g. cephalosporins, hydralizine, ampicilli ns. Manufacture, dispensing... 

In the organic chemicals industry, H2O2 is used in the production of epoxides, propylene oxide, and caprolactones for PVC stabilizers and polyurethanes, in the manufacture of organic peroxy compounds for use as polymerization initiators and curing agents, and in the synthesis of fine chemicals such as hydroquinone, pharmaceuticals (e.g. cephalosporin) and food products (e.g. tartaric acid). 

Before we leave our discussion of preparing 6-aminopenicillanic acid for use as a starting material in the manufacture of semi-synthetic penicillins, we should point out that similar processes are used in the manufacture of semi-synthetic cephalosporins. Here tire key intermediate is 7-aminodeacetoxycephalosporanic add (7-ADCA). We have drawn outline schemes comparing the production of semi-synthetic penicillins and cephalosporins in Figure 6.15. You will see that the two schemes are very similar. 

Manufacturing processes for cephalosporin C and benzylpenicilhn are broadly similar. In common with mai other antibiotic fermentations, no specific precursor feed is necessary for cephalosporin C. There is sufficient acetyl group substrate for the terminal acetyltransferase reaction available fiom the organism s metabolic pool. 

July 2002, Wyeth Pharmaceutical discontinued manufacturing cefixime, at the time of publication, Lupin, Ltd, which has FDA approval to market cefixime, had marketed only a suspension formulation of the drug and not the 400-mg tablet dosage form. Another recommended IM or po cephalosporin also can be used. 

Scheme 6.7). Penicillin G amidase from Mcaligenes faecalis, which is used in the manufacture of semisynthetic penicillins and cephalosporins, was used in both steps to afford a one-pot cascade process [21]. The acylation was performed in an aqueous medium at pH 10-11 and, after separation of the remaining amine enantiomer, the acylated amine was hydrolyzed with the same enzyme by lowering the pH to 7. 

The manufacture of several semisynthetic oral cephalosporin antibiotics involves the chemical ring expansion of penicillin V to 7-aminodeacetoxycephalosporanic acid (7-ADCA Fig. 2 [68]). This is a costly and potentially environmentally damaging process [69], Cloning of the C. acremonium cefEF gene (DAOCS/ DACS [47]) and the S. clavuligerus cefD (IPNE) and cefE gene (DAOCS [43]) opened the possibility for biosynthetic/enzymatic processes for production of 7-ADCA. 

CA Bunnell, WD Luke, FM Perry. Industrial manufacture of cephalosporins. In SF Queener, Weber JA, SW Queener, eds. Beta-lactam Antibiotics for Clinical Use. New York Marcel Dekker, 1986, pp 255-284. 

Previous efforts have failed to identify an enzyme with robust Ceph C amidase activity. Some glutaryl-7-ACA acylases can directly convert Ceph C to 7-ACA, but they do so with very poor efficiency and have not been considered for a single-enzyme manufacturing process.30-33 Nonetheless, glutary 1-7-AC A acylases with measurable activity on Ceph C are classified as cephalosporin C acylases. Mutagenesis approaches such as ePCR have been used in an attempt to improve the activity of these enzymes on Ceph C, but only marginal improvements in the desired activity have... 

Our own interest in applying electrochemistry grew from the highly successful process developed for the manufacture of the third-generation cephalosporin antibiotic, Ceftibuten.93 The electrochemical reduction component of the process and the product extraction step are, in outline, as follows ... 

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