US 12,016,952 B2
Methods of preparing a monodisperse oligo(ethylene glycol) reagent composition
Michael D. Bentley, Huntsville, AL (US); Tacey X. Viegas, Madison, AL (US); Richard R. Goodin, Rising Sun, IN (US); Lin Cheng, Sunnyvale, CA (US); and Xuan Zhao, Beijing (CN)
Assigned to Nektar Therapeutics, San Francisco, CA (US)
Filed by Nektar Therapeutics, San Francisco, CA (US)
Filed on Aug. 23, 2021, as Appl. No. 17/409,653.
Application 17/409,653 is a continuation of application No. 16/020,773, filed on Jun. 27, 2018, granted, now 11,129,794.
Application 16/020,773 is a continuation of application No. 15/178,465, filed on Jun. 9, 2016, abandoned.
Application 15/178,465 is a continuation of application No. 14/248,245, filed on Apr. 8, 2014, granted, now 9,388,104, issued on Jul. 12, 2016.
Application 14/248,245 is a continuation of application No. 13/271,158, filed on Oct. 11, 2011, abandoned.
Application 13/271,158 is a continuation of application No. 12/710,167, filed on Feb. 22, 2010, granted, now 8,067,431, issued on Nov. 29, 2011.
Application 12/710,167 is a continuation of application No. 11/344,404, filed on Jan. 30, 2006, abandoned.
Application 11/344,404 is a continuation in part of application No. 11/015,196, filed on Dec. 16, 2004, granted, now 7,786,133, issued on Aug. 31, 2010.
Claims priority of provisional application 60/530,122, filed on Dec. 16, 2003.
Prior Publication US 2021/0393513 A1, Dec. 23, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. C07C 41/24 (2006.01); A61K 9/00 (2006.01); A61K 31/167 (2006.01); A61K 31/485 (2006.01); A61K 47/60 (2017.01)
CPC A61K 9/007 (2013.01) [A61K 31/167 (2013.01); A61K 31/485 (2013.01); A61K 47/60 (2017.08); C07C 41/24 (2013.01)] 11 Claims
 
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—(CH2CH2O)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 (OEGm+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 OEGm+n into a halo group, —X, to form OEGm+n−X; and
(iii) reacting OEGm+n−X with a second hydroxyl-terminated oligo(ethylene glycol) having (n) monomer subunits under conditions effective to displace the halo group of OEGm+n−X to thereby form an oligo(ethylene glycol) having (m)+2(n) monomer subunits (OEGm+2n), wherein reacting the OEGm+n−X with the second hydroxyl-terminated oligo (ethylene glycol) comprises adding a 1:1 molar ratio of OEGm+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 (OEGm+2n) corresponds to a structure CH3(CH2)0,1O(CH2CH2O)m+2nH, and is present as part of a monodisperse composition of CH3(CH2)0,1O(CH2CH2O)m+2nH.