Ultrasound‐Assisted Microcontinuous Process Facilitates the Selective Deuteration of Steroid Hormones

Constructing deuterated molecules efficiently and practically has been a long-standing challenge. Deuterated steroid hormones are essential for medical research and drug metabolism studies and are thus in high demand; mild and selective methods for the deuteration of steroid hormones have remained unexplored. Herein, we demonstrate a practical and efficient approach to synthesize 12 deuterated steroid hormones with up to 98% selectivity and 99% d-incorporation under an ultrasound-assisted microcontinuous process. Optical rotation experiments confirm that steroid hormones configurations are preserved during the H/D exchange reaction. Our protocol enables rapid, inexpensive, and sustainable gram-scale synthesis, facilitated by the reuse of deuterated solvents via molecular distillation technology. Applying synthetic deuterated steroid hormones as mass spectrometry standards, six steroid hormones in metabolites are accurately analyzed from Frozen Human Plasma-1950 sample. Overall, this work has successfully demonstrated the application of ultrasound assisted microcontinuous processing in enhancing H/D exchange reactions.