Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound having a 1-thia-4-aza-bicyclo
Patent
1997-02-19
2000-04-11
Weber, Jon P.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound having a 1-thia-4-aza-bicyclo
435178, 435230, C12P 3704, C12N 1110, C12N 984
Patent
active
060487089
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a an improved process for preparation of .beta.-Lactam derivatives by enzymatic acylation of the parent amino .beta.-lactam with an acylating agent.
BACKGROUND ART
Today, semisynthetic .beta.-lactam derivatives such as ampicillin, amoxicillin, cefaclor, cephalexin, cephadroxil and cephaloglycin are, in an industrial scale, prepared by chemical methods, for example by reacting an amino .beta.-lactam such as 6-aminopenicillanic acid, usually having its carboxyl group protected, with an activated side chain derivative, followed by the removal of the protecting group by hydrolysis. For example, ampicillin (6-D-.alpha.-aminophenylacetamido-penicillanic acid) can be prepared by reacting 6-APA, having a suitable protected carboxyl group, with D-phenylglycine acid chloride, followed by removal of the protecting group by hydrolysis. These reactions typically involve costly steps such as sub zero degree Celcius conditions and organic solvents like methylene chloride and silylation reagents.
Within the last years, there has been an increasing amount of publications concerning the possibility of enzymatic preparation of penicillins and cephalosporins by reaction of an acylating agent, be it in acid form or in activated form (for example, amide or ester) and the parent amino .beta.-lactam (for example, 6-APA or 7-ADCA). For example, enzymatic production of ampicillin from 6-APA and a D-phenyl-glycine derivative (such as a lower alkyl ester) is known from West German patent application having publication No. 2,163,792, Austrian Patent No. 243,986, Dutch patent application No. 70-09138, West German patent application having publication No. 2,621,618, European patent application having publication No. 339,751 and PCT patent application having publication No. 92/01061.
The enzymatic acylation of an amino .beta.-lactam with an acylating agent may be performed in the presence of a suitable amidase or acylase whereby the desired .beta.-lactam derivative is formed. The parent amino .beta.-lactam and the .beta.-lactam derivative have the same .beta.-lactam nucleus. In the .beta.-lactam derivative endproduct the 6-NH.sub.2 side chain of the penem parent .beta.-lactam or the 7-NH.sub.2 side chain of the cephem parent .beta.-lactam are acylated.
This reaction can be illustrated by the following reaction scheme I:
Reaction Scheme I
If this process is performed batchwise, it has been discovered that at the beginning of the reaction, an increasing amount of .beta.-lactam derivative is formed whereas, after a certain period of time, the amount of .beta.-lactam derivative present in the reaction mixture is decreasing. The decomposition of the .beta.-lactam derivative formed may be due to hydrolysis thereof whereby amino .beta.-lactam and the acid form of the acylating agent is formed. In addition, the enzyme present may decompose the starting acylating agent. Consequently, at least two sorts of decomposition nay take place during such a reaction.
One object of this invention is to furnish a process whereby the molar ratio between the amount of .beta.-lactam derivative which can be recovered from the reaction mixture and the acid form of the acylating agent formed during the reaction is increased, compared with this ratio for the known processes.
BRIEF STATEMENT OF THIS INVENTION
It has now, surprisingly, been found that improved process conditions are obtained if the enzymatic acylation of the amine .beta.-lactam is performed at constantly high concentrations of both the parent amino .beta.-lactam and the corresponding acylating agent. Preferably the concentrations of the parent amino .beta.-lactam and of the corresponding acylating agent are higher than 70%, preferably higher than 85% of the lowest value of both the saturated concentration of the parent amino .beta.-lactam and of the saturated concentration of the corresponding acylating agent. which can be recovered from the reaction mixture and the amount of the acid form of the acylating agent, compared with this ratio for the kno
REFERENCES:
patent: 3763000 (1973-10-01), Abe et al.
patent: 5334497 (1994-08-01), Inaba et al.
Mou "Biochemical Engineering and Beta-lactam Antibiotic Production" in Antibiotics Containing the Beta-lactam Structure. 1983 (Springer-Verlag:Berlin) p. 255-257.
Clausen Kim
Dekkers Rocus M.
Gist-Brocades B.V.
Hanley Susan
Weber Jon P.
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