Method of Preparing Carboxylic Acid Functionalized Polymers

Abstract

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.

What is claimed is: 
     
         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.