ChemicalBook CAS DataBase List Cefotaxime

Cefotaxime synthesis

8synthesis methods

Product Name:Cefotaxime
CAS Number:63527-52-6
Molecular formula:C16H17N5O7S2
Molecular Weight:455.47

Cefotaxime, α-O-methyloxime acetate (6R, 7R)-7-[2-(2-amino-4-thiazolyl)- glyoxylamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.56), is synthesized by acylating of 7-aminocephalosporanic acid with 2-(2-amino- 4-thiazolyl)-2-methoxyiminoacetic acid, which is protected at the amino group by a trityl protection (32.1.2.54). After removing the trityl protection from the resulting product (32.1.2.55) with dilute formic acid, the desired cefotaxime (32.1.2.56) is formed. The ethyl ester of 2-(2- amino-4-thiazolyl)-2-methoxyminoacetic acid necessary for this synthesis, as well as for the synthesis of a number of other antibiotics of the cephalosporin series, is synthesized from acetoacetic ester. Nitrosation of acetoacetic ester with nitrous acid gives isonitrosoacetoacetic ester (32.1.2.49). O-Methylation of the hydroxyl group of obtained product with dimethylsulfate in the presence of potassium carbonate gives ethyl 2-(methoxyimino)acetoacetate (32.1.2.50).
Brominating the resulting product with bromine in methylene chloride in the presence of p-toluenesulfonic acid gives 4-bromo-2-methoxyiminoacetoacetic ester (32.1.2.51). Reacting this with thiourea according to the classic scheme of preparing of thiazoles from α- bromocarbonyl compounds and thioamides gives the ethyl ester of 2-(2-amino-4-thiazolyl)-2- methoxyiminoacetic acid (32.1.2.52). Reacting this with triphenylchloromethane in the presence of triethylamine results in a trityl protection of the amino group, forming the ethyl ester of 2-(2-tritylamino-4-thiazolyl)-2-methoxyminoacetic acid (32.1.2.52), which is hydrolyzed to the acid (32.1.2.54) using sodium hydroxide. The resulting acid (32.1.2.54), as was already stated, is used for acylating of 7-aminocephalosporanide acid in the presence of dicyclohexylcarbodiimide, giving tritylated cefotaxime, α-O-methyloxime acetate 7-[2-(2- tritylamino)-4-thiazolyl-glycoxylamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-en-2-carboxylic acid (32.1.2.55). Finally, removing the trityl protection from the synthesized product (32.1.2.55) using dilute formic acid gives cefotaxime (32.1.2.56).