# US 7,608,663 B2 · Method of preparing propionic acid-terminated polymers

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- Number: US 7,608,663 B2
- Document ID: US7608663B2
- Status: Granted
- Kind: B2
- Application number: 11/040,142
- Filed: 2005-01-21
- Published: 2005-08-04
- Granted: 2009-10-27
- Earliest claimed: 2004-01-21
- Assignees: Nektar Therapeutics
- Inventors: Antoni Kozlowski; Samuel P. McManus
- Web page: https://patentgrep.com/patent/US7608663B2

## CPC

- C08F 8/14: Esterification
- C08G 65/3322: {acyclic}
- C08F: MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS

## Abstract

The invention provides methods for preparing polymers bearing a terminal propionic acid. The method involves first reacting a water soluble and non-peptidic polymer comprising at least one hydroxyl group with a tertiary alkyl acrylate in the presence of a catalyst to form a propionic acid ester of the polymer, wherein the polymer has a weight average molecular weight of at least about 10,000 Da; and then treating the propionic acid ester of the polymer with a strong acid to form a propionic acid of the polymer.

## Claims

### Claim 1

A method for preparing a water soluble and non-peptidic polymer functionalized with at least one propionic acid group, the method comprising:
i) reacting a water soluble and non-peptidic polymer comprising at least one hydroxyl group with a tertiary alkyl acrylate in the presence of a catalyst comprising a quaternary ammonium salt to form a propionic acid ester of the polymer, wherein the polymer has a weight average molecular weight of at least about 10,000 Da; and
ii) treating the propionic acid ester of the polymer with a strong acid to form a propionic acid-functionalized polymer;
with the proviso that the water soluble and non-peptidic polymer functionalized with at least one propionic acid group is neither methoxy PEG propionic acid having a weight average molecular weight of about 20,000 Da, nor methoxy PEG propionic acid having a weight average molecular weight of about 30,000 Da.

### Claim 2 (depends on 1)

The method of claim 1, wherein the tertiary alkyl acrylate is α- or β-substituted.

### Claim 3 (depends on 2)

The method of claim 2, wherein the substituting group is selected from the group consisting of halo, hydroxyl, thiol, alkylthio, acyl, acyloxy, nitro, cyano, azido, trihalomethyl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl.

### Claim 4 (depends on 3)

The method of claim 3, wherein the substituting group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and benzyl.

### Claim 5 (depends on 1)

The method of claim 1, wherein the tertiary alkyl group of the tertiary alkyl acrylate is tert-butyl, tert-amyl, α,α′-dimethylbenzyl, trityl, 1-adamantyl, or 2-methyl-2-adamantyl.

### Claim 6 (depends on 1)

The method of claim 1, wherein the tertiary alkyl acrylate has the structure:
wherein:
R1 and R2 are each independently selected from the group consisting of hydrogen, halo, hydroxyl, thiol, alkylthio, acyl, acyloxy, nitro, cyano, azido, trihalomethyl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; and
R3-R5 are each independently alkyl, substituted alkyl, aryl or substituted aryl.

### Claim 7 (depends on 6)

The method of claim 6, wherein R3, R4, and R5, are each methyl, ethyl, or phenyl.

### Claim 8 (depends on 6)

The method of claim 6, wherein R1 and R2 are hydrogen.

### Claim 9 (depends on 6)

The method of claim 6, wherein R1 is hydrogen and R2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and benzyl.

### Claim 10 (depends on 1)

The method of claim 1, wherein the strong acid is trifluoroacetic acid, trifluoromethanesulfonic acid, formic acid, hydrochloric acid, or toluenesulfonic acid.

### Claim 11 (depends on 1)

The method of claim 1, wherein the catalyst comprising the quaternary ammonium salt is selected from the group consisting of tetramethyl ammonium halide, tetraethyl ammonium halide, tetrapropyl ammonium halide, tetrabutyl ammonium halide, tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide, tetrapropyl ammonium hydroxide, and tetrabutyl ammonium hydroxide.

### Claim 12 (depends on 1)

The method of claim 1, wherein the catalyst comprising the quaternary ammonium salt has the structure:
wherein each R is independently alkyl or substituted alkyl and X is a counter ion.

### Claim 13 (depends on 12)

The method of claim 12, wherein each R is C1-C8 alkyl and X is halo or hydroxide.

### Claim 14 (depends on 1)

The method of claim 1, wherein said reacting step and said treating step are conducted in the presence of an organic solvent.

### Claim 15 (depends on 14)

The method of claim 14, wherein the organic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile, toluene, xylene, phenylacetonitrile, nitrobenzene, tetrachloroethylene, anisole, and chlorobenzene.

### Claim 16 (depends on 1)

The method of claim 1, wherein the polymer has a weight average molecular weight of about 10,000 to about 100,000 Da.

### Claim 17 (depends on 16)

The method of claim 16, wherein the polymer has a weight average molecular weight of about 20,000 to about 60,000 Da.

### Claim 18 (depends on 1)

The method of claim 1, wherein the water soluble and non-peptidic polymer is selected from the group consisting of poly(alkylene glycols), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxyacetic acid), poly(acrylic acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines, poly(N-acryloylmorpholine), and copolymers or terpolymers thereof.

### Claim 19 (depends on 1)

The method of claim 1, wherein the water soluble and non-peptidic polymer is poly(ethylene glycol).

### Claim 20 (depends on 19)

The method of claim 19, wherein the poly(ethylene glycol) is selected from the group consisting of monofunctional PEG, difunctional PEG, and branched PEG.

### Claim 21 (depends on 19)

The method of claim 19, wherein the poly(ethylene glycol) has a weight average molecular weight of about 10,000 to about 100,000 Da.

### Claim 22 (depends on 21)

The method of claim 21, wherein the poly(ethylene glycol) has a weight average molecular weight of about 20,000 to about 60,000 Da.

### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

The method of any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22, further comprising the step of chromatographically purifying the propionic acid of the polymer to separate the propionic acid of the polymer from impurities bearing a hydroxyl end-cap.

### Claim 24 (depends on 23)

The method of claim 23, further comprising derivatizing the propionic acid-functionalized polymer to form a reactive derivative.

### Claim 25 (depends on 1)

The method of claim 1, further comprising derivatizing the propionic acid-functionalized polymer to form an acid derivative selected from the group consisting of acyl halide, acyl pseudohalide, ester, anhydride, amide, imide, and hydrazide.

### Claim 26 (depends on 1)

The method of claim 1, further comprising derivatizing the propionic acid-functionalized polymer to form an active ester.

### Claim 27 (depends on 26)

The method of claim 26, wherein the active ester is selected from the group consisting of N-succinimidyl ester, o-, m-, or p-nitrophenyl ester, 1-benzotriazolyl ester, imidazolyl ester, and N-sulfosuccinimidyl ester.

### Claim 28

A method for preparing a branched water soluble and non-peptidic polymer functionalized with at least one propionic acid group, the method comprising:
i) reacting a branched water soluble and non-peptidic polymer comprising at least one hydroxyl group with a tertiary alkyl acrylate in the presence of a catalyst to form a propionic acid ester of the polymer, wherein the polymer has a weight average molecular weight of at least about 10,000 Da; and
ii) treating the propionic acid ester of the polymer with a strong acid to form a propionic acid of the polymer.