Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound having a 1-thia-5-aza-bicyclo
Reexamination Certificate
1999-08-26
2001-11-20
Prats, Francisco (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound having a 1-thia-5-aza-bicyclo
C435S047000, C435S049000, C435S050000
Reexamination Certificate
active
06319684
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to the recovery of fermentatively produced cephalosporin compounds.
Semi-synthetic routes to prepare cephalosporins mostly start from fermentation products such as penicillin G, penicillin V and Cephalosporin C, which are converted to the corresponding &bgr;-lactam nuclei, for instance in a manner as is disclosed in K. Matsumoto, Bioprocess. Tech., 16, (1993), 67-88, J. G. Schewale & H. Sivaraman, Process Biotechnology of August 1989, 146-154, T. A. Savidge, Industrial Antibiotics (Ed. E. J. Vandamme) Marcel Dekker, N.Y., 1984, or J. G. Shewale et al., Process Biochemistry International, June 1990, 97-103. The obtained &bgr;-lactam nuclei are subsequently converted to the desired antibiotic by coupling to a suitable side chain, as has been described in inter alia EP 0 339 751, JP-A-53005185 and CH-A-640 240. By making different combinations of side chains and &bgr;-lactam nuclei, a variety of penicillin and cephalosporin antibiotics may be obtained.
7-Amino desacetoxy cephalosporanic acid (7-ADCA) and 7-amino cephalosporanic acid (7-ACA) are know to be the most important intermediates for the production of antibiotics used in the pharmaceutical industry.
7-ADCA is for example obtained by chemical or enzymatic cleavage (deacylation) of phenlacetyl-7-ADCA yielding 7-ADCA and phenylacetic acid. Phenylacetyl-7-ADCA yielding 7-ADCA by chemical treatment of penicillin G sulfoxide, which is formed from penicillin G. In this production process a large amount of chemicals are required to ensure that the desired reaction takes place. This is both expensive and places a heavy burden on waste management. Moreover, the total yield of the process is not as high as would be desired.
To overcome some of the drawbacks of the chemical process a fermentative process has been disclosed for the production of 7-ADCA and 7-ACA, involving fermentative production of N-substituted &bgr;-lactams, such as adipyl-7-ADCA or adipyl-7-ACA, by a recombinant
Penicillin chrysogenum
strain capable of expressing a desacetoxycephalosporanic acid synthase (DAOCS) also know as “expandase” from a transgene (EP 0 532 341, EP 0 540 210, WO 93/08282, WO 95/04148, WO 95/04149). The expandase takes care of the expansion of the 5-membered ring of certain N-acylatec penicillanic acids, thereby yielding the corresponding N-acylated desacetoxycephalosporanic acids.
Known processes for recovering chemically or enzymatically produced penicillanic and cephalosporanic acids acids are not effective for the recovery of the N-substituted &bgr;-lactam intermediates and deacylated amino- &bgr;-lactams. The main problem with the recovery of the fermentatively produced N-substituted cephalosporin compounds mentioned hereinabove is the complexity of the broth, or culture filtrate. The broth usually comprises various penicillanic acids, such as &agr;-aminoadipyl-6-penicillanic acid, &agr;-hydroxyadipyl-6-penicillanic acid, 6-aminopenicillanic acid (6-APA), various cephalosporanic acids including &agr;-aminoadipyl- and &agr;-hydroxyadipyl-7-ADCA and a lot of proteinaceous material. Known recovery procedures do not give an acceptable quality of the cephalosporanic acid product in terms of purity.
In the enzymatic deacylation this leads to problems in terms of reduced enzyme half-life, slower bioconversion rate and more expenses in the recovery after bioconversion and/or unacceptable contaminant levels. Moreover, after deacylation, such impurities prevent or at least hamper the recovery of the desired deacylated cephalosporin compound with the desired specifications.
Therefore the known procedures penicillins and cephalosporins do not give an acceptable quality of end product: the end product, e.g. 7-ADCA or 7-ACA, contains an unacceptable amount of penicillin components as impurities.
REFERENCES:
patent: 3880713 (1975-04-01), Fleming et al.
patent: 5559005 (1996-09-01), Conder et al.
patent: 5731165 (1998-03-01), Bovenberg et al.
patent: 37 29 338 (1989-03-01), None
patent: 0 532 341 (1993-03-01), None
patent: 1 299 883 (1962-12-01), None
patent: WO 93 08287 (1993-04-01), None
patent: WO 95 04148 (1995-02-01), None
International Search Report dated Aug. 26, 1998 for WO 98/48036.
De Braal Henriëtte Elisabeth Anna
De Vroom Erik
Fasel Herman Pieter
Krijgsman John
Smeets Jan Willem Hubert
DMS N.V.
Morrison & Foerster / LLP
Prats Francisco
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