Sulfonate esters of 1-hydroxypyridin-2(1H)-one and ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma) as effective peptide coupling reagents to replace 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole

Abstract

A new family of sulfonate ester-type coupling reagents is described which differs in its leaving group. The sulfonate ester coupling reagents ethyl 2-cyano-2-(naphthalen-2-ylsulfonyloxyimino)acetate (NpsOXY), and ethyl 2-cyano-2-(tosyloxyimino)acetate (TsOXY) are more efficient alternatives to the benzotriazole sulfonate esters in terms of racemization suppression and coupling effectiveness. Both oxyma and its related sulfonate esters can be handled with a considerably lower risk than the explosive benzotriazole and its derivatives. 2-Oxopyridin-1(2H)- yl naphthalene-2-sulfonate (NpsOPy) and 2-oxopyridin-1(2H)- yl 4-methylbenzenesulfonate (TsOPy) sulfonate esters derived from 1-hydroxypyridin-2(1H)-one were also successfully used as new coupling reagents requiring a longer preactivation time during the coupling process. An improvement in yield and almost comparable optical purity to that of the 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) analogues was observed. © 2010 Pharmaceutical Society of Japan.