PEGylation by Amide Linkage Formation

PEGylation of -NH using activated carboxylic acid esters (Equation 3.3) is a well-developed strategy in bioconjugation technology. In these reactions, the polymer is connected to the activated carboxyl group by means of a linker, the nature of which can have a profound affect on the reactivity of the activated polymer and on the stability of the conjugate. 

Succinimidyl succinate 1 is typically prepared by the reaction of succinic anhydride with mPEG under different reaction conditions to give the corresponding succinic acid-terminated polymer, followed by diimide-mediated esterification with N-hydroxysuccinimide [61]. The DMAP accelerated ring-opening reaction as well as melt synthetic method have also been published [62]. 

In a related work, but employing a-methylacrylonitrile as Michael acceptor, a-methylpropionic mPEG acid derivative 20 was obtained (Equation 3.6) [75,76]. 

A related method for the synthesis of 18b, which involves the use of tert-butyl acrylate as an electrophilic acceptor, has been reported in the patent literature. It has been suggested that this method works well with high molecular weight mPEGs (20 and 30 kDa (68%)) and it was indicated that the reaction does not proceed in the absence of the quaternary ammonium salt as a phase transfer catalyst [77]. 

It has been published and patented that mPEG-propionic acid can be obtained by nucleophilic displacement reaction of mPEG-alkoxide with ethyl 3-bromopropionate or with halogenated 3-halopropionate substrates [78,79]. However, it was later indicated that the first method does not afford the required acid but the elimination product, due to the acid-base reaction of the hydrogen in the position a- to the carboxylic group [74]. 

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