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 synthetic method comprising:
(a) combining a composition comprising an aprotic solvent and an amine-terminated or hydroxy-terminated water-soluble polymer with a composition comprising an activated carbonate reagent, optionally in the presence of a catalyst or acid-neutralizing base, wherein the composition comprising the activated carbonate reagent is added such that there is an excess of the activated carbonate reagent relative to the amine-terminated or hydroxy-terminated water-soluble polymer, to thereby result in a composition comprising an active carbonate ester of the water-soluble polymer and unreacted activated carbonate reagent; and
(b) adding a composition comprising a reactive molecule to the composition comprising the active carbonate ester of the water-soluble polymer and unreacted activated carbonate reagent, wherein the composition comprising a reactive molecule is added such that substantially all of the unreacted activated carbonate reagent is substantially consumed.
2 . The method of claim 1 , wherein the active carbonate ester of the water-soluble polymer has a structure of the following formula:
POLY-O—(C═O)—O—R
wherein:
POLY is a water-soluble polymer; and
R is an organic radical,
with the proviso that when POLY is a linear, methyl-capped poly(ethylene glycol), the linear, methyl-capped polyethylene glycol has a molecular weight of at least 103.
3 . The method of claim 1 , wherein the activated carbonate reagent has a structure of one of the following formulae: R—O(C═O)—OR; R—O(C═O)—OR′; and R—O(C═O)X, wherein R is an organic radical, R′ is an organic radical different than R, and X is Cl, Br, or I.
4 . The method of claim 1 , wherein the aprotic solvent is selected from the group consisting of acetonitrile, dimethylsulfoxide, dimethylformamide, chloroform, dichloromethane, and combinations thereof.
5 . The method of claim 1 , further comprising reacting the active carbonate ester of the water-soluble polymer in one or more reactions to form a polymeric reagent.
6 . The method of claim 1 , wherein the active carbonate ester of the water-soluble polymer is isolated by distilling off the solvent.
7 . The method of claim 1 , wherein the active carbonate ester of the water-soluble polymer is isolated by precipitation upon addition of a non-solvent.
8 . The method of claim 7 , wherein the non-solvent is selected from the group consisting of isopropyl alcohol, hexane, ethyl ether, and combinations thereof.
9 . The method of claim 1 , wherein the amine-terminated or hydroxy-terminated water-soluble polymer is a water-soluble polymer bearing a terminal amine group or hydroxy group, wherein the water-soluble polymer is selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharide), poly(a-hydroxyacetic acid), poly(acrylic acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers or terpolymers thereof.
10 . The method of claim 6 , wherein the water-soluble polymer is a poly(ethylene glycol).
11 . The method of claim 10 , wherein the poly(ethylene glycol) is a linear poly(ethylene glycol).
12 . The method of claim 10 , wherein the poly(ethylene glycol) is a branched poly(ethylene glycol).
13 . The method of claim 10 , wherein the poly(ethylene glycol) is a multi-arm poly(ethylene glycol).
14 . The method of claim 10 , wherein the poly(ethylene glycol) has a molecular weight of about 100 to about 100,000 Daltons.
15 . The method of claim 1 , wherein the amine-terminated or hydroxy-terminated water-soluble polymer is an amine-terminated, water-soluble polymer.
16 . The method of claim 1 , wherein the amine-terminated or hydroxy-terminated water-soluble polymer is a hydroxy-terminated, water-soluble polymer.
17 . The method of claim 1 , wherein the activated carbonate reagent is selected from the group consisting of di(1-benzotriazolyl) carbonate, disuccinimidyl carbonate, p-nitrophenyl chloroformate, trichlorophenyl chloroformate, p-nitrophenyl succinimidyl carbonate, p-nitrophenyl 1-benzotriazolyl carbonate, pentafluorophenyl chloroformate, and 1,1′-carbonyldiimidazole.
18 . The method of claim 1 , wherein the excess of the activated carbonate reagent relative to the amine-terminated or hydroxy-terminated, water-soluble polymer represents at least about a 5 mol % excess.
19 . The method of claim 1 , wherein the excess of the activated carbonate reagent relative to the amine-terminated or hydroxy-terminated, water-soluble polymer represents at least about a 50 mol % excess.
20 . The method of claim 1 , wherein the excess of the activated carbonate reagent relative to the amine-terminated or hydroxy-terminated, water-soluble polymer represents at least about a two-fold molar excess.
21 . The method of claim 1 , wherein the reactive molecule is selected from the group consisting of water, a lower alkyl monohydric alcohol, hydrogen sulfide, and a lower alkyl monobasic amine.
22 . The method as in claim 21 , wherein the reactive molecule is water.
23 . The method of 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 solid support.