Patent ID: 8809489

Claim:
A synthetic method comprising: (a) combining a composition comprising an aprotic solvent and mPEG (20,000 Da)-OH, with a composition comprising di(1-benzotriazolyl)carbonate, wherein the composition comprising the di(1-benzotriazolyl)carbonate is added such that there is an excess of the di(1-benzotriazolyl)carbonate relative to mPEG (20,000 Da)-OH, to thereby result in a composition comprising an active carbonate ester of the water-soluble polymer having the following structure: and unreacted di(1-benzotriazolyl)carbonate; (b) adding a composition comprising a reactive molecule selected from the group consisting of water, a lower alkyl monohydric alcohol, hydrogen sulfide and a lower alkyl monobasic amine to the composition comprising the active carbonate ester of a water-soluble polymer and unreacted di(1-benzotriazolyl)carbonate, wherein the composition comprising the reactive compound is added such that substantially all of the unreacted di(1-benzotriazolyl)carbonate is substantially consumed; (c) reacting the active carbonate ester of a water-soluble polymer with lysine to form a polymeric lysine derivative; (d) reacting the polymeric lysine derivative in one or more reactions to form a polymeric reagent; and (e) reacting the polymeric reagent with an active agent under conjugation conditions to thereby result in a water-soluble polymer-active agent conjugate.