Synthesis of potential related compounds of Cefdinir

The synthesis of three contaminants of Cefdinir ( 1 ), formed during the preparation of Cefdinir bulk drug, is described. The products identified as (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid-5-oxide ( 2 ), (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-8-oxo-3-vinyl- 5-thia-1-azabicyclo [4.2.0] oct-3-ene-2-carboxylicacid ( 3 ) and (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-8-oxo-3-methyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid ( 4 ).


Introduction
Cefdinir 1 is [syn-7-[2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4carboxylic acid].It is a third generation cephalosporin antibacterial drug for oral administration. 1he most remarkable future of Cefdinir is the excellent activity against staphylococcus species. 2 Several methods are reported in the literature for the preparation of Cefdinir [3][4][5][6][7] , but the related compounds were not discussed.However, the degradation kinetics of cefdinir has been cited in the literature. 8The preparation of these three contaminants has been necessary for the preparation of reference compounds for the quality control of bulk drugs and drug formulations, and pathways have been developed starting from the parent Cefdinir 1.

Results and Discussion
Cefdinir was prepared, starting from 7-amino-3-vinyl-3-cephem-4-carboxylic acid 5 by acylating with compound 6 followed by hydrolysis with base (Scheme 1).During the analysis of different batches of Cefdinir, three unknown impurities 2, 3 and 4 were detected whose area percentage ranged from 0.05 % and 0.15%.A comprehensive study has been carried out to synthesize these impurities.

Scheme 1
Sulfoxides are very common impurities in cephalosporin antibacterial compounds.The elimination of these compounds was very difficult from the finished products.Cefdinir sulfoxide 2 was observed up to 0.1% in most of the Cefdinir batches prepared in the laboratory.Therefore it was necessary to synthesize the sulfoxide in pure form for the validation of this impurity in the Cefdinir bulk drug.Cefdinir sulfoxide was prepared by the oxidation of Cefdinir in 30% yield by using per acetic acid as an oxidizing agent (Scheme 2).

Scheme 2
Treating the silylated Cefdinir 1 with triethylamine in methylene chloride provided a more selective approach for the preparation of delta-2 Cefdinir 3.During the monitoring by HPLC, 60% of delta-2 Cefdinir was formed, which was further purified by acid-base treatment to obtain compound 3 in 48 % yield.(Scheme 3).

Scheme 3
Compound 4 was formed due to presence of desacetoxycephalosporanic acid 7 as an impurity in the key raw material 7-aminio-3-vinyl-3-cephem-4-carboxylic acid 5. Compound 4 was prepared in 80% yield by the acylation of compound 7 with compound 6 followed by basic hydrolysis.(Scheme 4).

Conclusions
A procedure has been described for the preparation of three new impurities formed during the preparation of Cefdinir bulk drug in quite good yield and purity.

Experimental Section
General Procedures.All melting points were determined with a Palmon melting point apparatus. 1H-NMR and 13 C NMR analysis were recorded on a Bruker 300 MHz and 75 MHz spectrometer respectively.Chemical shifts are reported in ppm downfield from TMS as internal standard.Mass spectra were measured on Perkin Elmer PE SCIEX-API 2000 mass spectrometer.