Process for the preparation of cefuroxime

Details Process for the preparation of cefuroxime Process for the preparation of cefuroxime

1999-03-09

2001-05-22

Berch, Mark L. (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06235896

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed generally to a process for the preparation of cefuroxime axetil and more specifically to such a process, the starting ingredient being one of predominantly S-cefuroxime axetil, R,S mixture of cefuroxime axetil or R-cefuroxime axetil not meeting the purity criteria.
BACKGROUND OF THE INVENTION
Cefuroxime is a cephalosporin antibiotic with a broad spectrum of activity against both gram-positive and gram-negative microorganisms. Due to poor absorption from the gastrointestinal tract following oral administration, its salt, cefuroxime sodium, is ideally suited to formulation as injectables. The need for a more convenient and broader therapeutic use of cefuroxime led to the synthesis of 1-acetoxyethyl ester of cefuroxime, which is referred to as cefuroxime axetil. Cefuroxime axetil is a prodrug of cefuroxime and is suitable for oral administration. As a result, it permits a more convenient and broader therapeutic use of cefuroxime.
Cefuroxime axetil possesses an asymmetric carbon atom at the 1-position of the 1-acetoxyethyl group and, therefore, can exist as R- and S-isomers and mixtures thereof. Cefuroxime axetil is marketed as a mixture of R- and S-isomers in an approximately 1:1 ratio.
While cefuroxime axetil well suited to formulation for oral administration, it suffers from several deficiencies. Cefuroxime axetil is rapidly hydrolyzed in the intestine, thereby resulting in the formation of cefuroxime, which is poorly absorbed from the gastrointestinal tract. It has also been observed that oral administration of the R,S-mixture results in only about 50% bioavailability of the cefuroxime antibiotic, which is due to low overall solubility and the rapid hydrolysis of the ester portion of cefuroxime axetil by the esterase enzyme located in the gut. The non-absorbable cefuroxime remaining in the gut accounts for a partial loss of therapeutic activity and possibly the cause of side effects generally observed.
The rate of cleavage of ester group of the individual R- and S-isomers of cefuroxime axetil by esterase enzyme is different and it has been discovered that the individual S-isomer is hydrolyzed in animals much more rapidly than the R-isomer. U.S. Pat. No. 5,063,224 provides a process for preparing substantially pure R-cefuroxime axetil. It embodies the invention by claiming the superior stability to esterases and greater bioavailability of R-cefuroxime axetil over S-isomer, thus reducing the amount of non-absorbable cefuroxime remaining in the gut lumen, thereby diminishing the side effects attributable to cefuroxime. However, said patent does not describe the use of the undesirable S-isomer. Accordingly, there has been a need for a process whereby the undesirable S-isomer could be recycled. Such a process would not only be useful in minimizing the waste should R-cefuroxime axetil be used as a drug, but also be advantageous from a commercial standpoint.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a process for the preparation of cefuroxime from predominantly S-cefuroxime axetil, R, S mixture of cefuroxime axetil or R-cefuroxime axetil not meeting the purity criteria.
The present invention provides a process for the conversion of cefuroxime axetil as seen in Formula I as follows:
into cefuroxime as seen in Formula II as follows:
which comprises treating cefuroxime axetil with alkoxides in the presence of a suitable solvent(s) as described herein and isolating cefuroxime from the reaction mixture. The reaction is carried out at a temperature ranging from approximately −80 to +40° C., most preferably at approximately −65 to +20° C. After completion of the reaction, aqueous hydrochloric acid is added to the reaction mixture, the solvent is removed under reduced pressure and water is added to the reaction mixture. Cefuroxime is extracted with a water-immiscible solvent. A basifying agent is added and cefuroxime is precipitated from the aqueous layer by acidification.
The term “suitable solvent(s)” denotes any lower alkanol or non-alcoholic polar solvent(s) and mixture thereof, which is capable of homogenizing the reaction mixture. The lower alkanol includes those primary, secondary and tertiary alcohols having from one to six carbon atoms. Preferably, the lower alkanol solvents used are methyl, ethyl and isopropyl alcohol. The non-alcoholic polar solvents include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and dimethylsulfoxide. Preferably, tetrahydrofuran and 1,4-dioxane are used. Mixtures of two or more lower alkanols and/or other non-alcoholic polar solvents can also be used.
Any alkali alkoxides may be used, however, sodium alkoxides, such as sodium methoxide and sodium ethoxide, which are commercially available, are preferred. Any water-immiscible solvent may be used for extraction purposes, however, keeping in mind commercial availability and cost benefits, it is preferred that the solvent be selected from the group consisting of ethyl acetate, ether or dichloromethane.
The cefuroxime prepared according to the present invention may be converted into cefuroxime axetil or cefuroxime sodium by methods known per se.


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