Methods for preparing polymeric reagents and compositions of polymeric reagents

1. 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.

2. The method as in claim 1 , wherein the reactive molecule is water.

3. The method as in claim 1 , wherein the reactive molecule is selected from hydroxyalkyl attached to a solid support, mercaptoalkyl attached to a solid support, primary amine attached to a solid support, and secondary amine attached to a secondary support.

4. The method as in claim 1 , wherein the aprotic solvent is acetonitrile.