Development of a Telescoped Procedure for Stages 1 and 2 of the Buprenorphine Manufacturing Process

In the established Indivior process for the manufacture of buprenorphine, Stages 1 and 2 are performed as discrete stages. In Stage 1, thebaine undergoes a Diels–Alder reaction with methyl vinyl ketone to produce 1-(4,5α-epoxy-3,6-dimethoxy-17-methyl-6α,14-etheno-14α-morphinan-7α-yl)-1-oxoethane. In Stage 2, the alkene double bond is hydrogenated using a palladium on carbon catalyst under an atmosphere of H2. This paper describes the work performed to develop an alternative telescoped process, as follows: Iso-propanol is used as the solvent for Stage 1. Once the Stage 1 reaction is complete, tetrahydrofuran is added as a cosolvent and the hydrogenation of the alkene double bond is performed. Following the catalyst removal and a solvent swap to iso-propanol by distillation, the desired product 1-(4,5α-epoxy-3,6-dimethoxy-17-methyl-6α,14-ethano-14α-morphinan-7α-yl)-1-oxoethane is isolated by crystallization. The overall yield is increased from the range 85–90 to 93%, the quality, as determined by high-performance liquid chromatography, meets specification, and many other metrics are improved.