Synthesis of 1-Chloronaloxone and 2-Chloronaloxone

This paper describes the unambiguous synthesis of authentic samples of 1-chloronaloxone and 2-chloronaloxone to support the unequivocal assignment of impurities observed in a drug product containing a combination of buprenorphine hydrochloride and naloxone hydrochloride. The key step in the synthesis of 1-chloronaloxone was the C-1-selective chlorination of (5α)-6-(1,3-dioxolan-2-yl)-4,5-epoxy-14-hydroxy-3-methoxy-17-(2-propenyl)morphinan using the Palau'Chlor reagent. The key step in the synthesis of 2-chloronaloxone was the C-2-selective chlorination of (5α)-3-diethylcarbamate-6-(1,3-dioxolan-2-yl)-4,5-epoxy-14-hydroxy-17-(2-propenyl)morphinan using a directed ortho metalation approach.