The Synthesis of a Naloxone-Related Oxidative Drug Product Degradant

Naloxone is a nonselective opioid receptor antagonist used to reverse the effects of opiate-related overdose. Studies aimed toward identifying naloxone degradants present in a buprenorphine/naloxone combination drug product revealed several compounds whose structures could not be confirmed by comparison to authentic samples. We report herein the confirmation of the structural assignment of one of these compounds (so-called, "Degradant E") by chemical synthesis starting from naloxone. Key features of the developed route include the conversion of the <i>N</i>-allyl group to the corresponding Boc carbamate as a means of facilitating the chemoselective oxidative cleavage of the C6-C7 bond. In addition, the use of a pivalate ester derivative of naloxone's phenol group offered a convenient means of isolating Degradant E as the corresponding HCl salt using an acid-promoted global ester hydrolysis in the final step.