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. A method of preparing a carboxylic-acid functionalized methoxypolyethylene glycol (m PEG), comprising:
(i) reacting, in an organic solvent, a two-fold up to a 30-fold molar excess of a tertiary ester reagent having a structure,
where X is a halo group, and each of R 3 , R 4 and R 5 is phenyl, with a methoxyPEG-OH (mPEG-OH) having a molecular weight selected from 10,000 Da, 15,000 Da, 20,000 Da, 25,000 Da, 30,000 Da and 40,000 Da, in the presence of base at a temperature of about 25-50° C., to thereby form a reaction mixture comprising a mPEG-tertiary ester having a structure,
(ii) removing the organic solvent from the reaction mixture by distillation to provide a residue comprising the mPEG-tertiary ester,
(iii) hydrolyzing the mPEG-tertiary ester by addition of a strong base in aqueous solution to the residue from (ii) to thereby form a mPEG-carboxylate salt,
(iv) directly treating, without further isolation, the mPEG carboxylate salt from (iii) with aqueous inorganic acid to thereby provide a reaction mixture comprising a carboxylic acid-functionalized mPEG having a structure, mPEG-OCH 2 C(O)OH, and
(v) isolating the carboxylic acid-functionalized mPEG from the reaction mixture, wherein the isolated carboxylic acid-functionalized mPEG contains less than 5% by weight of mPEG-OH, wherein no trifluoroacetic acid is used in the process and the methoxyPEG-OH is branched.
2. The method of claim 1 , wherein X is selected from bromo, chloro and iodo.
3. The method of claim 1 , wherein the organic solvent is selected from t-butanol, benzene, toluene, xylenes, tetrahydrofuran (THF), dimethylformamide (DMF), and dimethylsulfoxide (DMSO).
4. The method of claim 1 , wherein the base in step (i) is selected from the group consisting of potassium t-butoxide, butyl lithium, sodium amide, and sodium hydride.
5. The method of claim 1 , wherein the reacting step is carried out for from about 0.5 hours to about 24 hours.
6. The method of claim 1 , wherein the hydrolyzing step is carried out at a pH of about 9 or above.
7. The method of claim 6 , wherein the hydrolyzing step is carried out at a pH of about 11 to about 13.
8. The method of claim 6 , wherein the strong base in the hydrolyzing step is an alkali metal hydroxide.
9. The method of claim 8 , wherein the alkali metal hydroxide is either sodium hydroxide or potassium hydroxide.
10. The method of claim 1 , wherein the hydrolyzing step is carried out at a temperature of about 10-30° C.
11. The method of claim 1 , wherein the treating step (iv) is effective to produce a reaction mixture with a pH of about 2 to 3.
12. The method of claim 11 , wherein the aqueous inorganic acid from step (iv) is selected from sulfuric acid, nitric acid, phosphoric acid and hydrochloric acid.
13. The method of claim 1 , wherein treating step (iv) is carried out at a temperature from about 10° C. to about 30° C.
14. The method of claim 1 , wherein the isolated carboxylic acid-functionalized mPEG contains less than 2% by weight of mPEG-OH.
15. The method of claim 1 , wherein the methoxyPEG-OH has a molecular weight of 20,000 Da or 40,000 Da.
16. The method of claim 1 , wherein the aqueous inorganic acid is phosphoric acid.