Methods for preparing polymeric reagents and compositions of polymeric reagents
Methods for preparing active carbonate esters of water-soluble polymers are provided. Also provided are other methods related to the active carbonate esters of water-soluble polymers, as well as corresponding compositions.
1. A method for preparing a polymeric reagent, the method comprising:
(a) combining a composition comprising an aprotic solvent and a hydroxy-terminated, water-soluble polyethylene glycol polymer with a composition comprising disuccinimidyl carbonate, wherein the composition comprising the disuccinimidyl carbonate is contains a molar excess of the disuccinimidyl carbonate relative to the hydroxy-terminated, water-soluble polyethylene glycol polymer, to thereby react the hydroxyl group of the water-soluble polyethylene glycol polymer with the disuccinimidyl carbonate to form a composition comprising an active succinimidyl carbonate ester of the water-soluble polyethylene glycol polymer and unreacted disuccinimidyl carbonate;
(b) adding a composition comprising a reactive molecule selected from the group consisting of water, hydrogen sulfide, and a lower alkyl monohydric alcohol to the composition comprising the active succinimidyl carbonate ester of a water-soluble polyethylene glycol polymer and unreacted disuccinimidyl carbonate, wherein the composition comprising the reactive molecule is added such that substantially all of the unreacted disuccinimidyl carbonate is substantially consumed wherein compositions resulting from step (a) are not isolated prior to conducting step (b).
2. The method of claim 1 , wherein the aprotic solvent is a polar aprotic solvent.
3. The method of claim 2 , wherein the polar aprotic solvent is selected from acetonitrile, dimethyl sulfoxide, hexamethylphosphoramide, dimethylformamide, (dimethylacetamide), and N-methylpyrrolidone.
4. The method of claim 1 , wherein the composition comprising the disuccinimidyl carbonate contains at least a two-fold molar excess of the disuccinimidyl carbonate relative to the hydroxy-terminated, water-soluble polyethylene glycol polymer.
5. The method of claim 1 , wherein step (a) is carried out in the presence of a catalyst or an acid-neutralizing base.
6. The method of claim 1 , wherein combining step (a) is carried out under substantially non-aqueous conditions.
7. The method of claim 1 , wherein the composition resulting from step (b) comprising the active succinimidyl carbonate ester of the water-soluble polyethylene glycol polymer is reacted with lysine or a hydrochloride salt of lysine to form a water-soluble polyethylene glycol lysine derivative.