Method of Preparing Carboxylic Acid Functionalized Polymers
Methods for preparing water soluble, non-peptidic polymers carrying carboxyl functional groups, particularly carboxylic acid functionalized poly(ethylene glycol) (PEG) polymers are disclosed, as are the products of these methods. In general, an ester reagent R(C═O)OR′, wherein R′ is a tertiary group and R comprises a functional group X, is reacted with a water soluble, non-peptidic polymer POLY-Y, where Y is a functional group which reacts with X to form a covalent bond, to form a tertiary ester of the polymer, which is then treated with a strong base in aqueous solution, to form a carboxylate salt of the polymer. Typically, this carboxylate salt is then treated with an inorganic acid in aqueous solution, to convert the carboxylate salt to a carboxylic acid, thereby forming a carboxylic acid functionalized polymer.
1 . An isolated polymer product comprising a carboxylic acid functionalized polymer, made by the method comprising:
i) reacting an ester reagent R(C═O)OR′, where R′ is a tertiary group and R comprises a functional group X, with a water soluble, non-peptidic polymer POLY-Y comprising a capping group, where Y is a functional group which reacts with X to form a covalent bond, to form a tertiary ester of the polymer;
ii) treating the tertiary ester of the polymer with a strong base in aqueous solution, to form a carboxylate salt of the polymer; and
iii) treating the carboxylate salt of the polymer with an inorganic acid in aqueous solution, to convert the carboxylate salt to a carboxylic acid, thereby forming a carboxylic acid functionalized polymer,
wherein the product contains less than 5% by weight of said POLY-Y polymer, with the balance consisting essentially of said carboxylic acid functionalized polymer.
2 . The polymer product of claim 1 , containing less than 2% by weight of said POLY-Y polymer.
3 . The polymer product of claim 1 , containing less than 0.5% by weight of said POLY-Y polymer.
4 . The polymer product of claim 1 , containing substantially no amount of low molecular weight organic acid.
5 . The polymer product of claim 1 , containing substantially no amount of monomeric organic carboxylic acid.
6 . The polymer product of claim 1 , containing substantially no amount of trifluoroacetic acid.
7 . The polymer product of claim 1 , wherein said carboxylic acid functionalized polymer is a PEG carboxylic acid.
8 . The polymer product of claim 7 , wherein said carboxylic acid functionalized polymer is mPEG-CH 2 —COOH, and said polymer product contains less than 5% by weight of mPEG-OH.
9 . The polymer product of claim 8 , containing less than 2% by weight of mPEG-OH.
10 . The polymer product of claim 9 , containing less than 0.5% by weight of mPEG-OH.
11 . The polymer product of claim 10 , containing substantially no amount of trifluoroacetic acid.
12 . The polymer product of claim 7 , wherein said carboxylic acid functionalized polymer is HOOC—CH 2 —PEG-CH 2 —COOH, and said product contains less than 5% by weight of HO-PEG-OH.
13 . The polymer product of claim 12 , containing less than 0.5% by weight of HO-PEG-OH.
14 . The polymer product of claim 13 , containing substantially no amount of trifluoroacetic acid.
15 . The polymer product of claim 7 , wherein said carboxylic acid functionalized polymer is a multifunctional branched or multiarm carboxylic acid functionalized PEG represented by PEG-(CH 2 —COOH) x , where x is 3 to 8, and said product contains less than 5% by weight of PEG-(OH) x .
16 . The polymer product of claim 15 , containing substantially no amount of trifluoroacetic acid.