# US 11,111,335 B2 · Method of preparing carboxylic acid functionalized polymers

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- Number: US 11,111,335 B2
- Document ID: US11111335B2
- Status: Granted
- Kind: B2
- Application number: 16/000,561
- Filed: 2018-06-05
- Published: 2018-10-04
- Granted: 2021-09-07
- Earliest claimed: 2003-11-06
- Assignees: Nektar Therapeutics
- Applicants: Nektar Therapeutics
- Inventors: J. Milton Harris; Antoni Kozlowski; Lihong Guo
- Web page: https://patentgrep.com/patent/US11111335B2

## CPC

- C08G 63/91: Polymers modified by chemical after-treatment
- A61K 31/765: Polymers containing oxygen
- C08F 251/00: Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
- C08F 261/04: on to polymers of vinyl alcohol
- C08F 265/00: Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00
- C08F 271/00: Macromolecular compounds obtained by polymerising monomers on to polymers of nitrogen-containing monomers as defined in group C08F26/00
- C08F 283/06: on to polyethers, polyoxymethylenes or polyacetals {(C08F283/004 takes precedence)}
- C08F 289/00: Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds not provided for in groups C08F251/00 - C08F287/00
- C08F 291/00: Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00
- C08G 65/30: Post-polymerisation treatment, e.g. recovery, purification, drying
- C08G 65/332: containing carboxyl groups, or halides, or esters thereof
- C08G 65/3322: {acyclic}
- C08G 65/3346: {having sulfur bound to carbon and oxygen}
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C08F: MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS

## 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.

## Claims

### Claim 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 R3, R4 and R5 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-OCH2C(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.

### Claim 2 (depends on 1)

The method of claim 1, wherein X is selected from bromo, chloro and iodo.

### Claim 3 (depends on 1)

The method of claim 1, wherein the organic solvent is selected from t-butanol, benzene, toluene, xylenes, tetrahydrofuran (THF), dimethylformamide (DMF), and dimethylsulfoxide (DMSO).

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 1)

The method of claim 1, wherein the reacting step is carried out for from about 0.5 hours to about 24 hours.

### Claim 6 (depends on 1)

The method of claim 1, wherein the hydrolyzing step is carried out at a pH of about 9 or above.

### Claim 7 (depends on 6)

The method of claim 6, wherein the hydrolyzing step is carried out at a pH of about 11 to about 13.

### Claim 8 (depends on 6)

The method of claim 6, wherein the strong base in the hydrolyzing step is an alkali metal hydroxide.

### Claim 9 (depends on 8)

The method of claim 8, wherein the alkali metal hydroxide is either sodium hydroxide or potassium hydroxide.

### Claim 10 (depends on 1)

The method of claim 1, wherein the hydrolyzing step is carried out at a temperature of about 10-30° C.

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 11)

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.

### Claim 13 (depends on 1)

The method of claim 1, wherein treating step (iv) is carried out at a temperature from about 10° C. to about 30° C.

### Claim 14 (depends on 1)

The method of claim 1, wherein the isolated carboxylic acid-functionalized mPEG contains less than 2% by weight of mPEG-OH.

### Claim 15 (depends on 1)

The method of claim 1, wherein the methoxyPEG-OH has a molecular weight of 20,000 Da or 40,000 Da.

### Claim 16 (depends on 1)

The method of claim 1, wherein the aqueous inorganic acid is phosphoric acid.