This invention relates to a process for the preparation of an antibiotic in crystalline form. In particular, it relates to a process for the preparation of the antibiotic ceftazidime pentahydrate.
The semi-synthetic cephalosporin antibiotic ceftazidime, chemically named (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetami do]-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate, is described in U.S. Pat. No. 4,258,041. A particularly useful pharmaceutical form of ceftazidime is its crystalline pentahydrate which is described by Brody et al. in U.S. Pat. No. 4,329,453. Prior to the present invention, ceftazidime pentahydrate has been obtained with a disalt of ceftazidime, for example, the dihydrochloride salt as described by Brody et al. The dihydrochloride salt of ceftazidime is first prepared and isolated, the salt is dissolved in an aqueous medium which may contain a water-miscible organic solvent, and the pH of the mixture is adjusted to between about 3.3 and 4.0 to form the pentahydrate. The pentahydrate will generally crystallize from the acidic mixture. The disalts of ceftazidime, for example the dihydrochloride salt, are obtained by the acidic removal of an amino-protected and esterified ceftazidime. This intermediate hereinafter referred to as "diblocked ceftazidime" is an intermediate arising in the overall preparation of ceftazidime by the acylation of 7-amino-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate with the diprotected side chain moiety of ceftazidime. A preferred protecting group for the 2-amino group of the 2-aminothiazole ring in the 7-position of ceftazidime is the trityl group, while the carboxy group in the 7-position side chain of ceftazidime is preferably protected by the t-butyl group. Both of these groups are removable under acidic conditions and typically the deblocking step following the acylation comprises the use of formic acid and hydrochloric acid to remove both the trityl group and the t-butyl ester group. In the course of this deblocking, the ceftazidime dihydrochloride salt is formed. Other acid labile protecting groups for the amino group and the carboxy group may be employed instead of the preferred trityl and t-butyl groups.
According to the process of this invention, ceftazidime pentahydrate in crystalline form is obtained directly from the reaction mixture in which the deblocking of the diblocked ceftazidime is carried out. The separate preparation and isolation of a ceftazidime disalt, for example, the dihydrochloride salt, is thus avoided. The process of the invention affords crystalline ceftazidime pentahydrate in quality equal to that provided by the known procedures.