Process for the preparation of cefixime

Details Process for the preparation of cefixime Process for the preparation of cefixime

2002-12-05

2004-10-05

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

06800755

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of an orally active cephalosporin antibiotic. The present invention more particularly relates to an improved process for the preparation of cefixime of the formula (I).
DESCRIPTION OF THE PRIOR ART
Cefixime is an orally active third-generation cephalosporin antibiotic and is more potent against gram-negative bacteria. International publication No 99/51607 and U.S. Pat. No. 4,409,214 discloses the process for the preparation of the cefixime of the formula (I), which involves condensation of 7-amino-3-vinyl-3-cephem-4-carboxylic acid with the derivative of (Z)-2-amino-&agr;-(1-alkoxycarbonylmethoxyimino)-4-thiazole acetic acid to produce ester compound of formula (II),
wherein R represents (C
1
-C
4
) alkyl group; followed by hydrolysis to produce cefixime of the formula (I).
GB 2 330 140 discloses a process for the preparation of cefixime of formula (I) which comprises treating the compound of formula (II) with Na
2
CO
3
in DMF and water, which has the following problems: (i) color and quality are poor, (ii) fails in residual solvent i.e. DMF.
GB 2 330 141 discloses a process for the preparation of the compound of formula (I) which comprises treating the compound of formula (II) in an organic solvent with aqueous solution of Na
2
CO
3
and phase transfer catalyst. The color, quality and yield of the product obtained from bi-phasic reaction are poor.
In U.S. Pat. No. 4,409,214 and WO 95/33753 discloses the process for the preparation of cefixime in which the hydrolysis step involves the use of hazardous trifluoroacetic acid and anisole. In WO 99/52913 the hydrolysis step along with deblocking the amino protective group and carboxylate protective group involves the use of phenol and protonic acid. The steps described in the above patents are more complicated and also suffer from low yield and poor quality.
J. Antibiotics (1985), 38, 1738 discloses various processes for the preparation of cefixime of formula (I). The processes involve the use of column chromatography for purification thereby suffers in poor yield. Column purification cannot be used in large-scale operations, there by making the process commercially not viable.
We have now achieved an improved process for the preparation of the cefixime of the formula (I), which has advantages over the processes, described in the above-mentioned prior art documents.
OBJECTIVES OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of cefixime of the formula (I), which has better quality such as color and solubility.
Another objective of the present invention is to provide an improved process for the preparation of cefixime of the formula (I), which avoids the use of hazardous chemicals like TFA and also easy to implement on commercial scales.
Still another objective of the present invention is to provide an improved process for the preparation of cefixime of the formula (I) in good yield and high purity.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of cefixime of formula (I), which comprises the steps of:
i. dissolving the ester compound of formula (II)
 wherein R represents (C
1
-C
4
) alkyl group; in water/water immiscible solvent using sodium bicarbonate at a temperature in the range of 0° C. to 35° C.,
(ii) hydrolysing step (i) mixture with sodium hydroxide at a temperature in the range of 0° C. to 25° C. and
(iii) acidifying the resultant mass to pH 2.3 to 3.0 with dilute acid in the presence or absence of solvent at a temperature in the range of 10° C. to 45° C., to isolate the cefixime of the formula (I).


REFERENCES:
patent: WO 200198309 (2001-12-01), None
Translation of WO 01/98309.

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