Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-04-10
1990-06-26
Rizzo, Nicholas S.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540226, 540222, C07D50136, A61K 31545
Patent
active
049373307
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates to a novel process for preparing the alkali metal salts of an amino acid from the corresponding mineral acid salts. More specifically, the present invention relates to novel solid phase alkali metal salts of a cephalosporin antibiotic and to a process for preparing the cephalosporin alkali metal salts substantially free of impurities, from the corresponding hydrohalide salts
2. Information Disclosure
The cephalosporin antibiotic 7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino)acetamido]-3-[(fur-2-ylcarb onyl)thiomethyl]-3-cephem-4-carboxylic acid (also named 7-[2-(2-amino-4-thiazolyl-2-methoxyimino)-acetamido]-3-[2-(furanylcarbonyl thiomethyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct-2-ene-1-carboxylic acid) of formula I, its alkali metal, alkaline earth metal and amine salts of the carboxylic acid group, and easily hydrolyzable ester groups thereof are described and claimed in Labeeuw et al., U.S. Pat. No. 4.464.367. This cephalosporin free acid compound of formula I is now known by the generic name ceftiofur.
These patented free acid and cationic metal and amine salt and ester forms of this cephalosporin antibiotic are somewhat unstable chemically and are obtained as amorphous compounds which are difficult to purify, and are less desirable to work with in manufacturing pharmacuetical formulations containing them.
Methods for the conversion of cephalosporin acids to their corresponding sodium salts are known. U.S. Pat. No. 4,224,371 describes the preparation and crystallization of the crystalline sodium salt from mixing cefotaxime and sodium acetate in aqueous alcohols. U.S. Pat. No. 3,840,535 discloses the use of sodium 2-ethylhexanoate to prepare the sodium salt of cephalosporins.
Crystalline hydrohalide salts of ceftiofur are described in European Patent Application 85307417.7, published May 7, 1986 (Publication Number 0180372).
The use of polyvinylpyridine as a hydrogen chloride scavenger during cephalosporin ring cleavage reactions is described in U.S. Pat. No. 4,289,695 (1981).
A brochure, entitled "Pyridine Functionality in Polymer Form," published by Reilly Tar and Chemical Corporation, Indianapolis, IN, describes the use of derivatives of polyvinylpyridine as acid scavengers.
SUMMARY OF INVENTION
The present invention relates to a process for preparing the alkali metal salts of an amino acid from the corresponding mineral acid salts. The preferred process of this invention is to prepare the alkali metal salts of a cephalosporin antibiotic from the corresponding hydrohalide salts.
The present invention particularly provides:
A solid phase cephalosporin compound of formula III wherein M is selected from the group consisting of sodium, potassium and lithium, characterized by birefringement lath- and rod-shaped particles; comprises: organic solvent by treating it with a basic resin; earth metal; and comprises treating the salt with polyvinylpyridine.
The term "amino acid" as used in the process of this invention refers to a compound of formula NH.sub.2 -R-COOH wherein R is an aliphatic radical, derivative thereof, or a more complex radical such as those contained in cephalosporins and penicillins. Therefore, naturally, occurring as well as synthetic amino acids are included within this definition. Such compounds are well known and readily available to those skilled in the art, for example, cephalosporin, penicillin, alanine, glycine, and .alpha.-phenylglycine.
The term "cephalosporin" as used in this invention is a bicyclic, monocarboxylic acid isolated from strains of Cephalosporium or derivatives thereof and useful as an antibiotic. The term "cephalosporin" as used in this invention is understood to include its tautomers as well as the mixture of the cephalosporin and its tautomers. Cephalosporins preferred for use in this invention include those having an amino group in the moiety attached to the 7-position of the cephalosporin nucleus and especially those capable of forming hydrohalide salts. U.S. Pat. No. 4,478,749, w
REFERENCES:
patent: 3840535 (1974-10-01), Kaplan et al.
patent: 4224371 (1980-09-01), Amiard et al.
patent: 4289695 (1981-09-01), Chon
patent: 4464367 (1984-08-01), Labeeuw et al.
patent: 4478749 (1984-10-01), Koster et al.
patent: 4717768 (1988-01-01), Robinson et al.
Brochure: "Pyridine Functionality in Polymer Form", Reilly Tar & Chemical Corp., Indianapolis, Ind.
Chemistry and Biology of .beta.-Lactam Antibiotics, vol. 3, Eds R. B. Morin, M. Gorman, Acad, Press, New York (1982).* *Title page and Contents only.
Dill Loren H.
Sacks Clifford E.
Cox Martha A.
Rizzo Nicholas S.
The Upjohn Company
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