Patent Watch

October 24, 2011

Make a better cephalosporin antibiotic. O. D. Tyagi and co-inventors describe a method for preparing cefixime (2), a cephalosporin antibiotic that is used to treat gonorrhea, tonsillitis, and pharyngitis. The objective is to improve the color and solubility of cefixime, but the patent’s claims concentrate on the process, not on product quality. The inventors discuss several alternative processes for preparing 2 that give low yields and poor quality product or require chromatographic methods to purify the product.

The method shown in Figure 1 involves the condensation of intermediate 1 with thiourea in water adjusted to pH 5.7 by adding NaHCO3. After the reaction is complete, the mixture is treated with active carbon and Na2S2O4. After filtration, the solution is acidified to form the methyl ester of 2, which is isolated and hydrolyzed with NaOH to give crude 2. The crude product is redissolved in base, purified with active carbon and EDTA, filtered, and precipitated by adding acetone. Cefixime is obtained in 28.4% yield and 99.76% purity.

The purity and color of the isolated product depend on the temperature used in the acidification step. When this step is carried out at 25–30 °C, 2 is 98.81% pure, and its 3% solution in MeOH is hazy. As the acidification temperature is increased, the product quality improves; at 65–67 °C, the product purity is ≈100%, its MeOH solution is clear, and the solution transmittance at 650 nm is 97.5–98.5%.

The inventors also report a synthesis of intermediate 1 (Figure 2), but no experimental details are given. The process to make 2 gives high-purity product, but the yield is quite poor.

(Lupin Ltd. [Mumbai, India]. US Patent 8,008,478, Aug. 30, 2011; Keith Turner)

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