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:
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.
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