Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound having a 1-thia-4-aza-bicyclo
Patent
1998-02-25
2000-08-29
Marx, Irene
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound having a 1-thia-4-aza-bicyclo
435 44, 435 46, C12P 3700
Patent
active
061106992
DESCRIPTION:
BRIEF SUMMARY
The invention comprises a new alternative process for obtaining and fundamentally recovering 6-aminopenicillanic acid (6-APA) by ultrafiltration of the culture broth and fractionated recovery of the enzyme hydrolysis products using ion exchange resins.
STATE OF THE ART
One of 6-APA is an integral b-lactam compound of the various penicillins. Penicillins consist of the heterocyclic group consisting of a thiazolidine ring (with 5 members including one sulphur atom) fused with a beta-lactam ring (with 4 members), which are distinguished from each other by the nature of the side chain attached to the amine group in position 6 through a peptide link. The formula of 6-APA is: ##STR2##
Even when the formation and presence of 6-APA has been detected in the course of the fermentation of penicillins, and consequently in the broth, and given that the quantities are merely traces, the processes in use are based on the concept that the manner of obtaining this product should proceed by other routes and usually follow the following sequence.
The fermentation of microorganisms of the Penicillium chrysogenum type under optimum conditions for use of nutrients and energy makes it possible to obtain the greatest output of the corresponding penicillin, depending on the precursor used, which is normally PenG or PenV. Other reactions forming other metabolites, as well as the difficult-to-avoid degradation reactions of penicillin to penicillanic acid, oxidation of the phenylacetic acid precursor to oxidized derivatives such as o-hydroxyphenyl acetic acid, which must be controlled, take place during this type of fermentation and alongside the penicillin biosynthesis reactions.
Once fermentation is complete, the culture broth contains the compounds mentioned plus the biomass of the microorganism and the normal process basically consists of removing this biomass by known physical procedures: filtration, centrifuging, etc., to yield a filtered broth which has been clarified to a greater or lesser extent and contains no biomass.
Starting from this solution the most widely-used process comprises performing a liquid-liquid extraction at acid pH using appropriate equipment capable of dealing with the emulsions which form between the broth and the organic solvent, which in most cases require the use of surfactants. The solvents normally used, which have to be immiscible with the broth, include: esters, of the ethyl acetate, n-butyl acetate, etc., type; ketones, of the methyl isobutyl ketone type; alcohols of the n-butanol, etc., type. The efficiency of this stage is affected by temperature control, loss of activity in the broth, which is exhausted both through deactivation at acid pH and the physical loss connected with inadequate separation of the organic phase, which may remain included, and which in any case requires costly equipment, the use of surfactants, with consequences on costs and environmental problems, and the use of solvents.
The organic-rich phase obtained in this way normally requires purification stages: centrifuging, washing, treatment with active carbon, etc., to remove impurities. Penicillin is crystallized out from this organic phase by introducing the corresponding cation, normally K.sub.+, in an appropriate form to render it insoluble and to allow it to be subsequently separated by filtration, ending with drying, packaging and inspection.
The resulting penicillin, which normally has a high degree of purity, even though it is not free from some impurities which can give rise to problems on some occasions, is converted into 6-APA by the reaction of removing the side chain linked to the amino group in position 6. This reaction was initially performed by chemical processes, but now it is frequently being carried out through enzyme processes using enzymes of the penicillin acylase or amidase (3.5.1.11) type immobilized by different procedures, and which in brief can be grouped together as trapping, ionic or covalent bonding to a support, as described for example in Spanish patent No. 369,125. The source of the enzyme
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patent: 3787288 (1974-01-01), Miyamura
patent: 3887432 (1975-06-01), Cawthorne
patent: 5500352 (1996-03-01), Lopez
Batchelor et al., Proc. Roy. Soc. (London) B154, 1961, pp. 498-508.
Chemical Abstracts, vol. 101, No. 15 (1984) Columbus, Ohio Abstract No. 128857 "6 Aminopenicillanic Acid" Abstract & JP 59082097 A (Toyo Jozo Co., Ltd.) May 11, 1984.
Chemical Abstracts, vol. 116, No. 17 (1992) Columbus, Ohio Abstract No. 168965 , "Separation of Enzymes from Fermentation Medium from Penicillin Productikon by Ultrafiltration" Abstract & CS 268591 A (P. Brokes et al.) Jul. 31, 1990.
Database WPI Section Ch, Week 9043 Derwent Publications Ltd. London, GB, Class B02, AN 90-321113 & DD 277088 A (VEB JENAPHARM) Mar. 21, 1990.
Chemical Abstracts No. 258679 of CN 11106861Dated Nov. 19, 1996.
Fraile Yecora Nieves
Gonzalez de Prado Emiliano
Oliver Ruiz Manuel
Salto Maldonado Francisco
Vitaller Alba Alejandro
Antibioticos S.A.
Marx Irene
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