Click chemistry gained wide range applicability for linking small organic molecules to antibodies and other proteins. Unnatural amino acids, such as substituted tyrosine, phenyalanine, lysine with azido or alkynyl group, are extensively used in protein engineering bioprocess to introduce azido or alkynyl into antibodies. A general, effecient chemical synthesis for bromoethylation of tyrisine is needed to enable further developments in antibody-drug conjugation. However, it is notable that bromoethylation of phenol provides low cyield due to the elimination reaction of dibromoethane with inorganic bases, such as potassium carbonate, sodium hydroxide, etc.<br/>Here we report a high yield chemical synthesis to introduce bromoethyl group into phenols and also as a good precursor for azido-tyrosine synthesis. (Figure 1). There are reports of low yielding syntheses of bromoethyl-tyrosine, ranged from 5 to 20%, and we have obtained similiar results by following the literature methods. The common understanding is that dibromoethane under basic conditions eliminates HBr to generate bromoethene as a side reaction. Our solution is to directly use dibromoethane as solvent and 18-crown-6 as phase transfer catalyst to control the basic condition of potassium carbonate hence suppressing the elimination side reaction. Bromoethylation of tyrosine with this condition offers a high yield conversion and convenient route to azido-tyrosine as in Figure 2.

Bromoethylation of phenols

252nd National Meeting (2016)

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