Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-10
2003-04-29
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06555680
ABSTRACT:
FIELD OF THE INVENTION
The present invention discloses a new process for the preparation of Ceftiofur sodium by the condensation of 3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid as represented by formula (II) with 5-phenyl-1,3,4-oxadiazole-2-thio-2-(2-aminothiazol-4-yl)2-methoxyimino)acetate as represented by formula (III) and the Ceftiofur amine salt thus obtained is converted into its sodium salt.
BACKGROUND OF INVENTION
Ceftiofur is a generic name given to the compound of formula (Ia)
Ceftiofur acid, its alkali metal, alkaline earth metal and amines salts were reported for the first time in U.S. Pat. No. 4,464,367. During the course of further investigation, later on, it was discovered that all these derivatives of Ceftiofur are known to have stability problems. Further, it was difficult to purify the derivative of Ceftiofur due to amorphous nature of the compound. In fact, from the beginning, preparation of Ceftiofur sodium has posed challenges to organic chemists regarding purity, stability and crystallinity.
Several attempts have been made to prepare Ceftiofur sodium for obviating above-mentioned problems. One of the solutions was provided in U.S. Pat. No. 4,877,782 by preparing zinc complexes of Ceftiofur which have better dispersibility in water and can be used in pharmacological preparations. U.S. Pat. No. 4,902,683 also explains the isolation of more stable Ceftiofur in the form of crystalline hydrohalide salts which has better solubility and other physical properties, as compared to parent compounds. During the isolation of Ceftiofur hydrochloride salt most of the impurities present in the compound are removed during filtration. The hydrohalide salts as such cannot be used for parenteral administration, therefore it is necessary to convert a hydrohalide salt to sodium salt in order to use the drug as injectable.
Several methods are reported in chemical literature for converting cephalosporanic acids to their corresponding alkali metal salts. This step is of special importance in case of injectable antibiotics. Surprisingly, very few methods are disclosed for preparing Ceftiofur sodium starting from either Ceftiofur hydrohalide salt or Ceftiofur acid. Using conventional method, it is extremely difficult to get pure Ceftiofur sodium from Ceftiofur hydrochloride without isolating Ceftiofur acid as intermediate. During the neutralization of Ceftiofur hydrochloride with any sodium base, one molecule of hydrochloric acid attached to Ceftiofur also get neutralized resulting in the formation of sodium chloride which is very difficult to remove from the required compound. Till date, there is no chemical method reported to separate the sodium chloride from Ceftiofur sodium since both have very similar properties, especially, solubility. Alternatively, one can isolate Ceftiofur acid first and then treat it with sodium base but it is also problematic due to its amorphous nature of Ceftiofur acid and severe problems during filtration of Ceftiofur acid are also encountered.
U.S. Pat. No. 4,937,330 describes the use of polyvinylpyridine for neutralization of hydrohalide salt to get free acid and then treating the free acid, in situ with sodium-2-ethylhexanoate. The use of sodium-2-ethyl hexanoate for this purpose is subject of several patents in field of cephalosporin antibiotics. The polyvinyl pyridine resin loses activity after certain batches and needs replacement, which makes the process expensive.
In general, the process for liberation of Ceftiofur free acid from hydrohalide salt using either resin bases or non-resin bases is associated with above problems. Keeping all these problems in mind, the applicant disclose a simple, economical and commercially viable process for preparing Ceftiofur sodium which obviates all the above mentioned limitations. In this regard, a reference to applicants co-pending U.S. patent application Ser. No. 09/754,302 is also made herewith.
OBJECTS OF THE INVENTION
Therefore, the primary object of the invention is to provide a process for preparing Ceftiofur sodium without the preparation of Ceftiofur hydrochloride as an intermediate.
Another object of the invention is to concentrate the aqueous solution of Ceftiofur amine salt as well as Ceftiofur sodium salt by employing evaporation under reduced pressure using effective heat transfer methods.
Yet another object of this invention is to prevent the deterioration of product during evaporation process.
Still another object of the invention is to prepare Ceftiofur Sodium from Ceftiofur amine by treating with sodium-2-ethylhexanote, sodium acetate, sodium-bi-carbonate or sodium lactate.
One more object of the invention is to precipitate Ceftiofur sodium using an organic solvent.
Further object of the present invention is to prepare buffered Ceftiofur sodium from Ceftiofur amine salt.
Still another object of the invention is to provide Ceftiofur sodium from Ceftiofur amine salt solution by neutralizing the Ceftiofur amine salt solution with stoichiometric equivalent of mineral acid in presence of sodium chloride and organic solvent, followed by treating the organic layer with sodium base.
SUMMARY OF THE INVENTION
To meet the above objectives, the present invention provides a process for the preparation of Ceftiofur sodium by the condensation of 3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid with 5-phenyl-1,3,4-oxadiazole-2-thio-2-(2-aminothiazol-4-yl)2-methoxyimino)acetate. The Ceftiofur amine salt obtained during the condensation is converted in situ into its sodium salt. The solution thus obtained is concentrated without subjecting to high temperature by using highly efficient evaporation techniques which hitherto not been used for this class of compounds. The Ceftiofur amine salt is converted into its sodium salt by using sodium-2-ethylhexanoate, sodium acetate or sodium bicarbonate. Finally, Ceftiofur sodium can be isolated by crystallizing out by the addition of an organic solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of Ceftiofur sodium (I),
the said process comprising the steps of:
(a) condensing 3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid represented by formula (II) with 5-phenyl-1,3,4-oxadiazole-2-thio-2-(2-aminothiazol-4-yl)2-methoxyimino)acetate represent by formula (III) in a mixture of water and an organic solvent, in the presence of an amine base, at a pH range of 7.0 to 8.5 and at a temperature between −25° C. and 30° C. and
subsequent extraction with a solvent selected from dichloromethane or ethylacetate to get Ceftiofur amine salt which is isolated in the aqueous phase,
(b) treating the aqueous solution of Ceftiofur amine salt of step(a) with charcoal, filtering and evaporating the aqueous solution by employing a highly efficient evaporation technique under vacuum to remove water to yield a slurry of Ceftiofur amine salt,
(c) treating the slurry of step (b) containing Ceftiofur amine salt with sodium base and precipitating and isolating Ceftiofur sodium by adding organic solvent, followed by filtering the precipitated solid and drying the filtered solid, and
(d) treating Ceftiofur sodium of step (c) with a potassium dihydrogen phosphate buffer at pH 7.5, followed by sterile filtration using micron filter and lyophilisation to get sterile buffer Ceftiofur sodium.
A process wherein Ceftiofur sodium is obtained alternatively by adding an organic solvent to Ceftiofur amine salt solution, the mixture is neutralized with stoichiometric amount of mineral acid and sodium chloride is added in order to separate organic layer which is treated with charcoal, filtered and treated with a sodium base to precipitate Ceftiofur sodium which is filtered, dried and treating it with potassium dihydrogen phosphate buffer at pH 7.5, followed by sterile filtration using micron filter and lyophilisation to get sterile buffer Ceftiofur sodium.
In the above process, the condensation reaction of step (a) is quenched by adding dichloromethane or ethylacetate into the re
Deshpande Pandurang Balwant
Deshpande Pramod Narayan
Kulkarni Milind Ramkrishna
Luthra Parven Kumar
Berch Mark L.
Burns Doane Swecker & Mathis L.L.P.
Orchid Chemicals & Pharmaceuticals Ltd.
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