Objective: Stable and non-radioactive isotope labeled compounds gained significance in recent
drug discovery and other various applications such as bio-analytical studies. The modern bioanalytical
techniques can study the adverse therapeutic effects of drugs by comparing isotopically labeled
internal standards. A well-designed labeled compound can provide high-quality information about
the identity and quantification of drug-related compounds in biological samples. This information can
be very useful at key decision points in drug development. In this study, we tried to synthesize Nilutamide-
d6 which can be useful to study the adverse effects of Nilutamide, and based on these can modify
or widen the new drug derivatives. Nilutamide is a nonsteroidal antiandrogen which is used in the
treatment of prostate cancer. The aim of this study was to develop a synthetic approach to prepare deuterium
labeled [2H6]-5, 5-dimethylimidazolidine-2, 4-dione and [2H6]-nilutamide.
Methods: Since nilutamide is a derivative of hydantoin, it involves the synthesis of Dimethylhydantoin
via Bucherer-Bergs hydantoin synthesis, followed by oxidative N-arylation with 4-iodo-1-nitro-2-
Conclusion: We successfully synthesized [2H6]-nilutamide and [2H6]-dimethylhydantoin with good
isotopic purity, measured to be of adequate quality for use as internal standards in bio-analytical studies.
A brief mechanistic study of Bucherer-Bergs hydantoin reaction was carried and the reason for possible
H/D exchange was explained.
Keywords: Bucherer-Bergs hydantoin synthesis, [2H6]- 5, 5-dimethyl imidazolidine-2, 4-dione, [2H6]-nilutamide, antineoplastic,
non-steroidal antiandrogen, prostate cancer, deuterium labeling.
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