Methods of preparing a monodisperse oligo(ethylene glycol) reagent composition

Patent metadata

Field	Value
Publication number	US-12016952-B2
Application number	US-202117409653-A
Country	US
Kind code	B2
Filing date	Aug 23, 2021
Priority date	Dec 16, 2003
Publication date	Jun 25, 2024
Grant date	Jun 25, 2024

Abstract

Methods of preparing monodisperse oligomer reagent compositions such as oligo(ethylene glycol) reagent compositions are described herein. The methods involve reacting a halo-terminated oligomer such as an oligo(ethylene oxide) having (m) monomers with a hydroxyl-terminated oligomer such as a hydroxyl-terminated oligo(ethylene oxide) having (n) monomers.

First claim

What is claimed is:

1. A method of preparing a monodisperse oligo(ethylene glycol) reagent composition, comprising:
(i) reacting a halo-terminated oligo(ethylene glycol) having (m) monomer subunits and a C1-C2 alkoxy (methoxy or ethoxy) end-capping group with a first hydroxyl-terminated oligo(ethylene glycol), HO—(CH 2 CH 2 O) n —H, having (n) monomer subunits, under conditions effective to displace the halo group from the halo-terminated oligo(ethylene glycol) to thereby form an oligo(ethylene glycol) having (m)+(n) monomer subunits (OEG m+n ), wherein reacting the halo-terminated oligo(ethylene glycol) with the first hydroxyl-terminated oligo (ethylene glycol) comprises adding a 1:1 molar ratio of the halo-terminated oligo(ethylene glycol) to the first hydroxyl-terminated oligo (ethylene glycol) in a solution, where halo is selected from chloro, bromo, and iodo;
(ii) converting the terminal hydroxyl group of OEG m+n into a halo group, —X, to form OEG m+n− X; and
(iii) reacting OEG m+n− X with a second hydroxyl-terminated oligo(ethylene glycol) having (n) monomer subunits under conditions effective to displace the halo group of OEG m+n− X to thereby form an oligo(ethylene glycol) having (m)+2(n) monomer subunits (OEG m+2n ), wherein reacting the OEG m+n− X with the second hydroxyl-terminated oligo (ethylene glycol) comprises adding a 1:1 molar ratio of OEG m+n− X to the second hydroxyl-terminated oligo (ethylene glycol) in a solution;
where (m) and (n) each independently range from 1-6 in each occurrence, and (OEG m+2n ) corresponds to a structure CH 3 (CH 2 ) 0,1 O(CH 2 CH 2 O) m+2n H, and is present as part of a monodisperse composition of CH 3 (CH 2 ) 0,1 O(CH 2 CH 2 O) m+2n H.

2. The method of claim 1 , where (m) is 1, 2, or 3 and (n) in each occurrence ranges from 2-6.

3. The method of claim 1 , wherein reacting steps (i) and (iii) are carried out in the presence of a strong base.

4. The method of claim 3 , wherein the strong base is selected from sodium, potassium, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium tert-butoxide, and potassium tert-butoxide.

5. The method of claim 1 , wherein the C1-C2 alkoxy end-capping group of the halo-terminated oligo(ethylene glycol) having (m) monomer subunits is methoxy.

6. The method of claim 1 , wherein reacting steps (i) and (iii) are carried out in an organic solvent at a temperature ranging from about 0° C. to about 80° C.

7. The method of claim 1 , wherein halo is bromo.

8. The method of claim 1 , further comprising purifying the monodisperse composition of CH 3 (CH 2 ) 0,1 O(CH 2 CH 2 O) m+2n H formed in step (iii) to form a purified composition.

9. The method of claim 8 , wherein the purifying comprises chromatography.

10. The method of claim 8 , further comprising converting the hydroxyl terminus of CH 3 (CH 2 ) 0,1 O(CH 2 CH 2 O) m+2n H to an active group suitable for coupling to a small molecule.

11. The method of claim 10 , wherein the active group is selected from an aldehyde and an activated carboxylic ester.

Assignees

• Nektar Therapeutics

Inventors

• Bentley Michael D
• Viegas Tacey X
• Goodin Richard R
• Cheng Lin
• Zhao Xuan

Classifications

• A61K31/485

  Morphinan derivatives, e.g. morphine, codeine · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title

• C07C41/24

  by elimination of halogens, e.g. elimination of HCl · CPC title

• A61K47/60 Primary

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61P25/36

  Opioid-abuse · CPC title