Methods for preparing functionalized polymers from polymer alcohols

A method for forming an alkylated functionalized polymer, said method comprising:

• (a) providing a water-soluble and non-peptidic polymer comprising two hydroxyl groups;
• (b) alkylating the water-soluble and non-peptidic polymer to form a mixture comprising (i) unalkylated water-soluble and non-peptidic polymer from step (a), (ii) a monoalkylated polymer comprising a single alkoxy group, and (iii) a dialkylated polymer comprising two alkoxy groups, under conditions effective to form at least about 25 mol percent of the dialkylated polymer;
• (c) reacting the mixture from step (b), in one or more reaction steps, with one or more functionalizing reagents to effect the introduction of a functional group, Y, to form a mixture comprising (i) unalkylated polymer comprising two Y groups, a monoalkylated polymer comprising a single Y group, and a dialkylated polymer comprising no Y groups;
• and
• (d) purifying the mixture from step (c) to provide a monoalkylated polymer substantially free from the unalkylated and dialkylated polymer species.

A method of forming a functionalized polymer, comprising:

• (a) providing a polymer comprising a formula HO-POLY-OH, wherein POLY is a water-soluble and non-peptidic polymer;
• (b) optionally, converting HO-POLY-OH to a mixture comprising HO-POLY-OH, HO-POLY-Z and Z-POLY-Z, wherein Z is a leaving group, under conditions effective to form no more than about 45 percent of Z-POLY-Z;
• (c) reacting HO-POLY-OH of step (a) or the mixture of step (b) with a functionalizing reagent comprising the structure X-L0,1-Y, wherein X is a group that reacts with a hydroxyl, optionally in anionic form, or with a carbon atom to which the hydroxyl or leaving group is attached, L0,1 is an optional linker, and Y is an ionizable group, optionally as a protected ionizable group, to form a mixture comprising HO-POLY-OH, HO-POLY-L0,1-Y, and Y-L0,1-POLY-L0,1-Y, under conditions effective to form preferably no more than about 45 percent of Y-L0,1-POLY-L0,1-Y;
• (d) optionally, alkylating the mixture from step (b) or step (c);
• and
• (e) after deprotection of the functional group Y, if necessary, purifying the mixture from step (c) or step (d) by ion exchange chromatography to provide substantially pure polymer comprising a single -L0,1-Y group.

A method of separating a mixture of polymer species by ion exchange chromatography, comprising:

• (a) providing a mixture of water-soluble and non-peptidic polymers, said mixture comprising a neutral polymer absent an ionizable functional group, a monofunctional polymer comprising a single ionizable functional group, and a difunctional polymer comprising two ionizable functional groups;
• (b) passing the mixture through a first ion exchange column to provide an eluate, wherein said passing the mixture step is carried out under conditions effective to adsorb substantially all of the difunctional polymer onto the first column;
• (c) passing the eluate through a second ion exchange column under conditions effective to adsorb substantially all of the monofunctional polymer onto said second column;
• (e) washing the second column with water or a low ionic solution to remove neutral polymer absent an ionizable functional group in a wash solution;
• and
• (f) passing a solution having high ionic strength through the second column to desorb the monofunctional polymer.

An ion exchange chromatography apparatus, comprising:

• a supply of solution of a water-soluble and non-peptidic polymer mixture comprising a neutral polymer absent ionizable functional groups, a monofunctional polymer comprising a single ionizable functional group, and a difunctional polymer comprising two ionizable functional groups;
• a first ion exchange column comprising a first inlet, a first outlet, and a first ion exchange media, said first inlet being in fluid communication with said supply;
• a second ion exchange column comprising a second inlet, a second outlet, and a second ion exchange media, said second inlet being in fluid communication with said first outlet;
• and
• at least one product recovery vessel in fluid communication with said second outlet, adapted to receive eluent exiting from said second ion exchange column.