US 11,834,553 B2
Alkoxylation methods
Antoni Kozlowski, Huntsville, AL (US); Samuel P. McManus, Huntsville, AL (US); Sachin Tipnis, Houston, TX (US); Greg Lavaty, Sugar Land, TX (US); David Swallow, Spring, TX (US); John R. Handley, Eveleth, MN (US); and Anthony G. Schaefer, Huntsville, AL (US)
Assigned to Nektar Therapeutics, San Francisco, CA (US)
Filed by Nektar Therapeutics, San Francisco, CA (US)
Filed on Oct. 2, 2020, as Appl. No. 17/062,457.
Application 17/062,457 is a continuation of application No. 15/075,750, filed on Mar. 21, 2016, abandoned.
Application 15/075,750 is a continuation of application No. 14/284,067, filed on May 21, 2014, granted, now 9,320,808, issued on Apr. 26, 2016.
Application 14/284,067 is a continuation of application No. 13/510,555, abandoned, previously published as PCT/US2010/057289, filed on Nov. 18, 2010.
Claims priority of provisional application 61/290,072, filed on Dec. 24, 2009.
Claims priority of provisional application 61/262,463, filed on Nov. 18, 2009.
Prior Publication US 2021/0024693 A1, Jan. 28, 2021
Int. Cl. C08G 65/331 (2006.01); C08G 65/329 (2006.01); C08G 65/333 (2006.01); A61K 47/60 (2017.01); C08G 65/48 (2006.01); C07D 491/22 (2006.01); C07C 51/41 (2006.01); C07C 53/18 (2006.01); A61K 31/4745 (2006.01)
CPC C08G 65/331 (2013.01) [A61K 31/4745 (2013.01); A61K 47/60 (2017.08); C07C 51/412 (2013.01); C07C 53/18 (2013.01); C07D 491/22 (2013.01); C08G 65/329 (2013.01); C08G 65/33396 (2013.01); C08G 65/48 (2013.01); C08L 2203/02 (2013.01)] 16 Claims
 
1. A method of preparing a highly pure reactive multi-armed polyethylene glycol reagent suitable for use in preparing a pharmaceutical conjugate, the method comprising:
(a) providing a previously isolated alkoxylatable oligomer having a structure:

OG Complex Work Unit Chemistry
and a weight average molecular weight of from 300 daltons to 5,000 daltons, wherein the value of each n is substantially the same;
(b) alkoxylating the isolated alkoxylatable oligomer from step (a) in an aprotic, substantially anhydrous organic solvent in the presence of from 0.01 to about 6.0 weight percent of a strong base by sequential addition of oxirane (ethylene oxide) under anhydrous liquid phase conditions of less than 20 ppm water and in an amount effective to form a reaction mixture comprising an alkoxylated polymeric product having a weight-average molecular weight of from about 6,000 daltons to about 80,000 daltons,
(c) recovering from the reaction mixture the alkoxylated polymeric product, wherein the recovered alkoxylated polymeric product has a purity of greater than 92 weight percent, and
(d) forming a reactive water-soluble multi-armed polyethylene glycol reagent by transforming the recovered alkoxylated polymeric product to bear reactive groups suitable for conjugation with a biologically active agent.