Method of preparing carboxylic acid functionalized polymers
View Patent ↗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═0)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. A method comprising
i) reacting, in an organic solvent, a molar excess of an ester reagent of the following structure
wherein:
X is a leaving group;
each of R 1 and R 2 is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, aryl, aralkyl, and heterocycle;
each of R 3 -R 5 is independently selected from lower alkyl, aryl, aralkyl, and cycloalkyl, where any of R 3 -R 5 may be linked to form a ring or ring system;
where any of R 1 to R 5 , excepting hydrogen, may be substituted with a group selected from lower alkyl, lower alkoxy, C3-C6 cycloalkyl, halo, cyano, oxo (keto), nitro, and phenyl; and
n is 1 to about 24,
with a 4-arm PEG-OH to form a 4-arm PEG-tertiary ester,
ii) removing the organic solvent;
iii) combining the 4-arm PEG-tertiary ester with water;
iv) treating the 4-arm PEG-tertiary ester with a strong base in aqueous solution, to form a 4-arm PEG-carboxylate salt; and
v) treating the 4-arm PEG-carboxylate salt with an inorganic acid in aqueous solution, to convert the carboxylate salt to a carboxylic acid, thereby forming a 4-arm PEG-carboxylic acid.
2. The method of claim 1 , wherein said strong base is an alkali metal hydroxide.
3. The method of claim 1 , wherein said treating with strong base is effective to produce a reaction pH of about 11 to 13.
4. The method of claim 1 , wherein said inorganic acid is an acid that produces non-nucleophilic anions in aqueous solution.
5. The method of claim 4 , wherein the acid is selected from the group consisting of sulfuric acid, nitric acid, phosphoric acid, and hydrochloric acid.
6. The method of claim 1 , wherein n is 1 to 6.
7. The method of claim 6 , wherein n is 1 or 2.
8. The method of claim 7 , wherein each of R 1 and R 2 is independently hydrogen or unsubstituted lower alkyl, and each of R 3 to R 5 is independently unsubstituted lower alkyl or phenyl.
9. The method of claim 8 , wherein each of R 1 and R 2 is independently hydrogen or methyl, and each of R 3 to R 5 is independently methyl, ethyl, or phenyl.
10. The method of claim 9 , wherein each of R 1 and R 2 is H and n is 1.
11. The method of claim 10 , wherein the tertiary ester reagent is a t-butyl haloacetate.
12. The method of claim 1 , further comprising converting the carboxylic acid to an activated carboxylic acid derivative.
13. The method of claim 12 , wherein said activated carboxylic acid derivative is an activated ester.
14. The method of claim 13 , further comprising conjugating said activated ester with a molecule, by reacting said activated ester with a functional group on said molecule.
15. The method of claim 14 , wherein said functional group is selected from the group consisting of an amino group, a hydroxyl group, or a thiol group.
16. The method of claim 1 , wherein no step uses trifluoroacetic acid.