Cefoxitin synthesis

Cefoxitin, 3-(hydroxymethyl)-8-oxo-7-methoxy-7-[(2-thienylacetyl)amino]- 5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid carbamate (32.1.2.30), is synthesized in various ways starting from cefamicin C-7β-(D-5-amino-5-carboxyvaleramido)- 3-aminocarbonylhydroxymethyl-7-methoxy-3-cefem-4-carboxylic acid, in which a methoxy group is initially present at C7, and the task of making the desired drug essentially consists of a transamidation reaction.
The other way is to start synthesis from 7-aminocephalosporanic acid, to which it is necessary to insert a methoxy group at C7. In one of the examples of the synthesis of cefoxitin starting from cefamicin C, the free amino group is initially protected via tosylation, and the product in the form of a well-crystallizing dicyclohexylamine salt is isolated (32.1.2.28). Next, the carbonyl group at position 2 of the cephalosporanic system is esterified using methylchloromethyl ether. The resulting compound (32.1.2.29) is reacted with 2-(2-thienyl)acetylchloride, then the ester protection is removed from the carboxylic group with hydrogen chloride in methanol, producing the desired cefoxitin (32.1.2.30).

Another way for the synthesis of cefoxitin is started from 7-aminocephalosporanic acid, more correct, from its benzhydryl ester (32.1.2.31), which is synthesized by previous tosylation of the amino group of the initial 7-aminocephalosporanic acid, esterification of the carboxyl group by diphenyldiazomethane, and subsequent removal of the tosyl protection.
When reacted with nitrous acid, the product is diazotized, giving the diphenyl methyl ester of 7-diazocephalosporanic acid (32.1.2.32). A subsequent reaction of the resulting compound with triethylammonium azide in dichloromethane and then with bromine azide gives the diphenyl methyl ester of 7-bromo-7-azidocephalosporanic acid (32.1.2.33). Treating this with methanol in the presence of silver borofluoride results in the replacement of the bromine atom, giving the diphenylmethyl ester of 7-methoxy-7-azidocephalosporanic acid (32.1.2.34). The resulting azide is reduced by hydrogen in the presence of a platinum oxide catalyst, forming the diphenyl methyl ester of 7-methoxy-7-aminocephalosporanic acid (32.1.2.35). Acylation of this compound with 2-(2-thienyl)acetylchloride gives the benzhydryl ester of 7-methoxy-7-[2-(2-thienyl)-acetamido]cephalosporanic acid (32.1.2.36), the ester protecting group of which is hydrolyzed using trifluoroacetic acid and then upon reacting the resulting acid with sodium bicarbonate, it is transformed to the potassium salt (32.1.2.37). The resulting product is then hydrolyzed by the enzyme Citrusi acetylesterase to the potassium salt of 3-hydroxymethyl-7-methoxy-7-[2-(2-thienyl)acetamido]-3-cefem- 4-carboxylic acid (32.1.2.38). Using the method described above, i.e. the initial reaction with chlorosulfonyl isocyanate followed by hydrolysis with water, the resulting compound, (32.1.2.38), is transformed to the desired cefoxitin (32.1.2.20).