Method of preparing highly pure cefpodoxime proxetil

Details Method of preparing highly pure cefpodoxime proxetil Method of preparing highly pure cefpodoxime proxetil

2002-04-24

2003-10-28

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

06639068

ABSTRACT:

BACKGROUND OF THE INVENTION
Cefpodoxime proxetil, (R,S)-1-(isopropoxycarbonyloxy)ethyl-(+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-((Z)-methoxyimino)acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate, is a cephalosporin ester pro-drug which, when orally administered, converts to cefpodoxime, an antibacterial agent, through rapid hydrolysis by esterases present on the intestinal wall. Cefpodoxime exhibits a wide range of antibacterial activity against gram positive and negative bacteria, e.g.,
Staphylococcus aureus, Streptococcus aureus, E. coli, Klebsiella pneumonia
and
Proteuse vulgaris
, and also a high degree of &bgr;-lactamase stability.
The cefpodoxime proxetil of formula (I) is a &Dgr;
3
-isomer prepared by various methods.
Hideo Nakao and Koich Huzimoto et al. reported a method of preparing cefpodoxime proxetil by reacting cefpodoxime with iodoalkylcarbonate in the presence of a base such as dicyclohexylamine (see
J. of Antibiotics
, vol. 40, pp. 370 (1987)). But the product obtained by this method is contaminated by about 3 weight % of the &Dgr;
2
-isomers of formula (II) formed as a by-product. Due to the structure similarity, it is very difficult to separate the undesired by-product from the &Dgr;
3
-isomer. The conversion of the &Dgr;
2
-isomer to the &Dgr;
3
-isomer has been attempted, but this process requires a series of reactions, and thus is not economically feasible.
U.S. Pat. No. 5,498,787 discloses a method of preparing cefpodoxime proxetil from a cefpodoxime salt using a quaternary ammonium salt phase transfer catalyst, e.g., tetrabutylammonium hydrogensulfate in an amount ranging from 35 to 120 mole % based on cefpodoxime. The method can effectively inhibit the formation of the &Dgr;
2
-isomer, but has problems in that the yield of the desired products is very low in the range of 50 to 60%, and the use of expensive quaternary ammonium salts is required.
In addition, according to the method disclosed in Korean Publication No. 99-54751, cefpodoxime proxetil is prepared by reacting a cephem compound of cefpodoxime with an alkylcarbonate to obtain an ester and then acylating the ester with an active ester form of arinothiazolyl acetic acid in the presence of a large amount of a quaternary ammonium salt. This method also requires the use of expensive quaternary ammonium salts and suffers from low productivity due to a long process time of about 3 days.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide an improved process for preparing cefpodoxime proxetil of high purity.
In accordance with one aspect of the present invention, there is provided a method of preparing cefpodoxime proxetil of formula (I) which comprises reacting a cefpodoxime salt of formula (III) with 1-iodoethylisopropylcarbonate of formula (IV) in an organic solvent in the presence of a crown ether of formula (V):
wherein, n is 1 or 2; M is an alkali metal or alkaline earth metal; and m is 4, 5 or 6.


REFERENCES:
patent: 4486425 (1984-12-01), Nakao et al.
patent: 5498787 (1996-03-01), Wang et al.
patent: 5789585 (1998-08-01), Lee et al.
patent: 0 620 225 (1994-03-01), None
patent: 1598 568 (1978-04-01), None
The Journal of Antibiotics, vol. 40, Mar. 1987, 370-384 , Koichi Fujimoto, et al.

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