# US 8,784,791 B2 · Method for preparing water-soluble polymer derivatives bearing an N-succinimidyl ester

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,784,791 B2
- Document ID: US8784791B2
- Status: Granted
- Kind: B2
- Application number: 13/856,704
- Filed: 2013-04-04
- Published: 2013-09-05
- Granted: 2014-07-22
- Earliest claimed: 2002-09-09
- Assignees: Nektar Therapeutics
- Applicants: Nektar Therapeutics
- Inventors: Antoni Kozlowski
- Web page: https://patentgrep.com/patent/US8784791B2

## CPC

- C07D 493/08: Bridged systems
- A61K 9/1611: {Inorganic compounds}
- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/209: {containing drug in at least two layers or in the core and in at least one outer layer}
- A61K 31/74: Synthetic polymeric materials
- C08G 65/002: {from unsaturated compounds (unsaturated oxiranes C08G65/14)}
- C08G 65/331: containing oxygen {(cyclic ether compounds C08G65/26)}
- C08G 65/332: containing carboxyl groups, or halides, or esters thereof
- C08G 65/33317: {heterocyclic}
- C08G 2650/42: containing orthoester groups
- C08L 2203/02: for biomedical use
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

A method is provided for preparing water-soluble polymer derivatives bearing a terminal N-succinimidyl ester. The method involves the hydrolyzing an ortho ester of a water-soluble polymer so as provide the corresponding acid and subsequently esterifying the acid.

## Claims

### Claim 1

A method for forming an N-succinimidyl ester of a water-soluble polymer from an ortho ester of the water-soluble polymer, the method comprising the steps of:
(i) conducting acid-catalyzed hydrolysis of the ortho ester of the water-soluble polymer to provide an intermediate ester of a water-soluble polymer;
(ii) conducting base-promoted hydrolysis on the intermediate ester of the water-soluble polymer to provide the water-soluble polymer bearing a terminal carboxylic acid; and
(iii) esterifying the water-soluble polymer bearing a terminal carboxylic acid using N-hydroxysuccinimide to form the N-succinimidyl ester of a water-soluble polymer,
wherein the ortho ester of the water-soluble polymer has the following structure:
the water-soluble polymer bearing a terminal carboxylic has the following structure:
and further wherein, for each of these structures,
POLY is a water-soluble polymer;
(a) is either zero or one;
X, when present, is a spacer moiety;
(z) is an integer from 1 to 24;
R1, in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl;
R2, in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl; and
each R4 is a either (i) an organic radical independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl, or (ii) one or more atoms that combine with another R4 or the remaining R4 moieties to form a cyclic ortho ester structure.

### Claim 2 (depends on 1)

The method of claim 1, wherein the water-soluble polymer is branched.

### Claim 3 (depends on 1)

The method of claim 1, wherein the water-soluble polymer is linear.

### Claim 4 (depends on 1)

The method of claim 1, wherein (z) equals three.

### Claim 5 (depends on 1)

The method of claim 1, wherein each occurrence of R1 and R2 is H.

### Claim 6 (depends on 1)

The method of claim 1, wherein each R4 combines with another R4 or the remaining R4 moieties to form an ortho ester cyclic structure.

### Claim 7 (depends on 6)

The method of claim 6, wherein each R4 combines with another R4 or the remaining R4 moieties to form an ortho ester cyclic structure selected from the group consisting of

### Claim 8 (depends on 1)

The method of claim 1, wherein the water-soluble polymer is selected from the group consisting of a poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), and poly(oxyethylated polyol).

### Claim 9 (depends on 8)

The method of claim 8, wherein the water-soluble polymer is a poly(alkylene oxide).

### Claim 10 (depends on 9)

The method of claim 9, wherein the poly(alkylene oxide) is a poly(ethylene glycol).

### Claim 11 (depends on 10)

The method of claim 10, wherein the poly(ethylene glycol) has a molecular weight of from about 5,000 Daltons to about 100,000 Daltons.

### Claim 12 (depends on 11)

The method of claim 11, wherein the poly(ethylene glycol) has a molecular weight of from about 5,000 Daltons to about 25,000 Daltons.

### Claim 13 (depends on 1)

The method of claim 1, wherein the ortho ester of the water-soluble polymer is selected from the group consisting of
wherein X, when present, is a spacer moiety, (a) is either zero or one, (m) is defined such as to provide —(CH2CH2O)— with a molecular weight of from about 1,000 Daltons to about 50,000 Daltons.

### Claim 14 (depends on 1)

The method of claim 1, wherein conducting acid-catalyzed hydrolysis includes the use of an acid selected from the group consisting of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, acetic acid, carbonic acid, phosphoric acid, oxalic acid and formic acid.

### Claim 15 (depends on 1)

The method of claim 1, wherein conducting acid catalyzed-hydrolysis includes the use of p-toluenesulfonic acid and pyridine in water.

### Claim 16 (depends on 1)

The method of claim 1, wherein conducting acid catalyzed-hydrolysis includes the use of NaHSO4 and 1,2-dimethoxyethane in water.

### Claim 17 (depends on 1)

The method of claim 1, wherein conducting base-promoted hydrolysis includes the use of a base selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, strontium hydroxide, barium hydroxide, ammonium hydroxide, magnesium hydroxide, calcium hydroxide, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, lithium carbonate, sodium phosphate, potassium phosphate, sodium borate and potassium borate.

### Claim 18 (depends on 1)

The method of claim 1, wherein both steps of conducting acid-catalyzed hydrolysis and base-promoted hydrolysis are carried out in a nonpolar solvent.

### Claim 19 (depends on 1)

The method of claim 1, wherein both steps of conducting acid-catalyzed hydrolysis and base-promoted hydrolysis are carried out in a polar aprotic solvent.

### Claim 20 (depends on 1)

The method of claim 1, wherein the esterification step is carried out with dicyclohexyl carbodiimide or diisopropyl carbodiimide in the presence of a base.