Method of preparing carboxylic acid functionalized polymers

Patent metadata

Field	Value
Publication number	US-11111335-B2
Application number	US-201816000561-A
Country	US
Kind code	B2
Filing date	Jun 5, 2018
Priority date	Nov 6, 2003
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

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.

First claim

It is claimed:

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.

Assignees

• Nektar Therapeutics

Inventors

• Harris J Milton
• Kozlowski Antoni
• Guo Lihong

Classifications

• C08F271/00

  Macromolecular compounds obtained by polymerising monomers on to polymers of nitrogen-containing monomers as defined in group C08F26/00 · CPC title

• C08G65/00

  Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule · CPC title

• A61K31/765 Primary

  Polymers containing oxygen · CPC title

• C08G65/332 Primary

  containing carboxyl groups, or halides, or esters thereof · CPC title

• C08F261/04

  on to polymers of vinyl alcohol · CPC title