Method for preparing purified erythromycin

Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives

Reexamination Certificate

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C536S007300, C536S007400, C536S127000

Reexamination Certificate

active

06767998

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a method for preparing purified erythromycin. More specifically, the present invention relates to a method for preparing purified erythromycin, characterized by removing erythromycin F for purification.
The present invention also relates to a method for preparing purified erythromycin F. More specifically, the present invention relates to a method for preparing purified erythromycin F, characterized by extracting erythromycin F for purification.
BACKGROUND ART
Erythromycin is an antibiotic with a strong antibacterial activity against Gram-positive bacteria and the like, and is important as a pharmaceutical drug.
Erythromycin is a generic name for structurally similar compounds including erythromycin A, erythromycin B, erythromycin C, erythromycin D, erythromycin E and erythromycin F. In a production of erythromycin, erythromycin A is often produced together with structurally similar erythromycins B, C and F as well as other erythromycin members. In a case where erythromycin is used as an antibacterial agent, no particular problem exists regarding the efficacy of the agent if it contains erythromycin members other than erythromycin A. However, in certain cases such as where erythromycin and/or its analogs are used as starting materials for the synthesis of N-demethyl-N-isopropyl-12-methoxy-11-oxo-8,9-anhydroerythromycin A-6,9-hemiacetal or clarithromycin, etc., it is desired that erythromycin members other than erythromycin A are not present in the starting materials.
Conventionally known techniques for purifying erythromycin from culture solutions include an extraction technique based on the nature of erythromycin A which is more soluble in an organic solvent at an alkaline pH and in water at an acidic pH, an ion-exchange technique, a technique using reverse phase adsorbents, and a technique using liquid-liquid extraction between a potassium sulfate-containing buffer and an organic solvent (Soviet Patent No. 306,669). Other purification techniques are also known, for example, a technique using recrystallization from an appropriate organic solvent and a technique in which erythromycin is dissolved in an appropriate organic solvent and then precipitated by addition of water (“Antibiotics” edited by Yusuke Sumiki, University of Tokyo Press, pages 366, 593, 926, 1056 and elsewhere, 1961).
However, no technique is known to be capable of efficient removal or isolation of erythromycin F from erythromycin for purification.
DISCLOSURE OF THE INVENTION
The present invention provides a method for preparing purified erythromycin, which involves extracting erythromycin F from erythromycin to give purified erythromycin from which erythromycin F is removed. The present invention also provides a method for preparing purified erythromycin F, which involves extracting erythromycin F from erythromycin to give purified erythromycin F.
As a result of careful studies, the inventors have found that the use of an organic solvent and water or an aqueous solution enables erythromycin F to be extracted from erythromycin and results in purified erythromycin from which erythromycin F has been removed, thereby finally completing one aspect of the invention. As a result of careful studies, the inventors have also found that the use of an organic solvent and water or an aqueous solution enables erythromycin F to be extracted from erythromycin, to provide purified erythromycin F, thereby finally completing another aspect of the invention.
Namely, the present invention relates to a method for preparing purified erythromycin and/or erythromycin analog(s), which comprises the step of removing erythromycin F and/or erythromycin F analog(s) from erythromycin and/or erythromycin analog(s) using (i) an organic solvent and (ii) water or an aqueous solution of an inorganic and/or organic material to give the purified erythromycin and/or erythromycin analog(s).
The present invention also relates to a method for preparing purified erythromycin F and/or erythromycin F analog(s), which comprises the step of extracting erythromycin F and/or erythromycin F analog(s) from erythromycin and/or erythromycin analog(s) using (i) an organic solvent and (ii) water or an aqueous solution of an inorganic and/or organic material to give the purified erythromycin F and/or erythromycin F analog(s).
PREFERRED MODE FOR CARRYING OUT THE INVENTION
This application claims the priority of Japanese Patent Application No. 2000-079455, the disclosure of which is hereby incorporated by reference in its entirety.
As used herein, the terms appearing below are defined as follows, unless otherwise specified.
“Erythromycin” encompasses erythromycin A, erythromycin B, erythromycin C, erythromycin D, erythromycin E, erythromycin F and other members. The term “erythromycin” as used herein is intended to refer to one or a mixture of these members.
“Erythromycin and/or at least one erythromycin analog” encompasses erythromycin and erythromycin derivatives. The term “erythromycin and/or at least one erythromycin analog” as used herein is intended to refer to one or a mixture of these compounds.
Examples of erythromycin derivatives include N-demethyl-erythromycin, 8,9-anhydroerythromycin 6,9-hemiketal, N-ethyl-N-demethyl-8,9-anhydroerythromycin 6,9-hemiketal, 11-oxo-8,9-anhydroerythromycin 6,9-hemiketal, and 2-O-acetyl-4-O-formyl-11-oxo-8,9-anhydroerythromycin 6,9-hemiketal, etc.
“Erythromycin F and/or at least one erythromycin F analog” encompasses erythromycin F and erythromycin F derivatives. The term “erythromycin F and/or at least one erythromycin F analog” as used herein is intended to refer to one or a mixture of these compounds.
Examples of erythromycin F derivatives include N-demethyl-erythromycin F, 8,9-anhydroerythromycin F 6,9-hemiketal, N-ethyl-N-demethyl-8,9-anhydroerythromycin F 6,9-hemiketal, 11-oxo-8,9-anhydroerythromycin F 6,9-hemiketal, and 2-O-acetyl-4-O-formyl-11-oxo-8,9-anhydroerythromycin F 6,9-hemiketal, etc.
As used herein, the term “purify(ing)” or “purified” or “purification” means either that a certain product is treated and results in reducing the content of at least one of the components (including impurities) in the untreated product as compared to the level before treatment or that a certain product is treated and results in enriching one or more components of interest.
The term “purified erythromycin and/or at least one erythromycin analog” as used herein refers to erythromycin and/or erythromycin analog(s) with a reduced content of at least one of the components (including impurities) in the unpurified erythromycin and/or erythromycin analog(s) as compared to the level before purification.
The term “purified erythromycin” as used herein refers to erythromycin with a reduced content of at least one of the components (including impurities) in the unpurified erythromycin as compared to the level before purification.
The term “purified erythromycin F and/or at least one erythromycin F analog” as used herein refers to erythromycin F and/or erythromycin F analog(s) enriched to a higher level than before purification.
The term “purified erythromycin F” as used herein refers to erythromycin F enriched to a higher level than before purification.
As used herein, “removing” erythromycin F from “erythromycin” or “erythromycin and/or at least one erythromycin analog” means reducing the content of erythromycin F in the “erythromycin” or “erythromycin and/or at least one erythromycin analog” and encompasses both complete and partial removal of erythromycin F.
Any organic solvent may be used in the present invention as long as it can dissolve erythromycin and/or erythromycin analog(s) and can be separated from water or an aqueous solution of an inorganic and/or organic material. Examples of such an organic solvent include alkyl carboxylates and alkyl ethers. Alkyl carboxylates include, but are not limited to, alkyl acetates such as ethyl acetate, propyl acetate (isopropyl acetate, n-propyl acetate) and butyl acetate (n-butyl acetate, s-butyl acetate, t-butyl acetate, isobutyl acetate), with

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