Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound having a 1-thia-5-aza-bicyclo
Patent
1996-02-07
1998-05-19
Lankford, Jr., Leon B.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound having a 1-thia-5-aza-bicyclo
435 45, 435 46, 435 50, 435 51, 435 49, C12P 3500, C12P 3504, C12P 3502, C12P 3506
Patent
active
057534586
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to an improved method for enzymatic acylation. In particular, the invention relates to the preparation of .beta.-lactam antibiotics by enzymatic acylation of the parent amino .beta.-lactam moiety with an acylating agent which is an activated derivative of the side chain acid.
BACKGROUND ART
Enzymatic production of semisynthetic .beta.-lactam antibiotics by acylation of the parent amino .beta.-lactam moiety with the side chain acid or an activated derivative, such as an amide or an ester thereof, is known e.g. 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, international patent application having publication No. WO 92/01061 and from international patent application having publication No. WO 93/12250.
From West German patent application having publication No. 3,507,403 it is known to add a lower aliphatic alcohol to the reaction mixture in order to improve the yield. According to said invention, the acylation is preferably carried out in a solvent which is water containing from about 5 to about 40 % (w/w) of methanol or ethanol. Presumably, the alcohol added lowers the activity of the water in the reaction mixture and thus the extent of the hydrolysis of the acylating agent and the desired product.
In the present specification, the moiety of the .beta.-lactam antibiotic molecule which is a condensed ring system comprising a four-membered .beta.-lactam ring which has an exocyclic amino group and a five- or six-membered ring with a sulphur atom in it and sharing a nitrogen atom with the .beta.-lactam ring is referred to as the .beta.-lactam moiety. The amino .beta.-lactam obtained on deacylation of the exocyclic amino group is referred to as the parent amino .beta.-lactam. Similarly, the acyl group to be introduced into the amino group of an amino .beta.-lactam in order to produce a .beta.-lactam antibiotic is referred to as the .beta.-lactam side chain or just the side chain. The acid corresponding to the side chain is designated the side chain acid.
The parent amino .beta.-lactams such as 6-aminopenicillanic acid (6-APA) and 7-aminodesacetoxycephalosporanic acid (7-ADCA) are commonly produced by enzymatic hydrolysis of a fermented penicillin (for example penicillin V or penicillin G). Besides impurities originating from the fermentation, the resulting crude solution typically contains unreacted traces of the .beta.-lactam antibiotic used as starting material at a concentration of 150-200 mM. The crude solution can be purified and crystallized to obtain pure 6-APA or 7-ADCA (in the 7-ADCA case, the fermented penicillin has to go through a rearrangement process before the hydrolysis step).
A drawback of the known methods for enzymatic production of .beta.-lactam antibiotics by acylation of the parent amino .beta.-lactam with an activated derivative of the side chain acid is that under the reaction conditions used part of the acylating agent hydrolyses before it has reacted with the amino .beta.-lactam. Thus, when the amide of the side chain acid is used as acylating agent, some free side chain acid and an equivalent amount of ammonia will be generated in the reaction mixture as a result of this hydrolysis. Similarly, when an ester of the side chain acid is used as acylating agent, some free side chain acid and an equivalent amount of the alcohol corresponding to the ester will be generated in the reaction mixture as a result of the hydrolysis. Also, the desired product formed hydrolyses to form free side chain acid and the parent amino .beta.-lactam.
The loss of acylating agent and of the desired product due to hydrolysis leads to a reduced yield of the process, to a more laborious work up procedure and ultimately to an economy of the process which is less than optimal. Accordingly, it is desired to find a method of avoiding or reducing the loss of a
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Clausen Kim
Nielsen Annette
Nikolov Alexander
Petersen Niels
Gist-Brocades B.V.
Lankford , Jr. Leon B.
Tate Christopher R.
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