Abstract

An improved synthetic route of (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetic acid (2a), an important intermediate for the preparation of Ceftaroline, from N-(3-aminoisoxazol-5-yl)acetamide (8) in total yield of 47% has been developed. The key intermediate (Z)-N-(3-(2-acetamido-1-(ethoxyimino)-2-oxoethyl)-1,2,4-thiadiazol-5- yl)pivalamide (12a) was easily isolated from (Z/E)-N-(3-(2-acetamido-1-(ethoxyimino)-2-oxoethyl)-1,2,4 -thiadiazol-5- yl)pivalamide. The title compound 2a was obtained from the hydrolysis of 12a with a yield of 83%, and its structure was comfirmed by X-ray single crystal diffraction analysis. Moreover, (E)- and (Z)-N-(3-(2-acetamido-1-(ethoxyimino)-2 - oxoethyl)-1,2,4-thiadiazol-5-yl)pivalamide were prepared respectively from the etherification of oxime hydroxyl group under different conditions. This improved procedure has many appealing attributes such as convenient separation, good yields, and easy access to large scale.

Keywords: Antibiotics, Ceftaroline, etherification, isothiocyanate, oxime, 1, 2, 4-thiadiazol derivatives.

Graphical Abstract