Process Development of a Novel Route to Rilpivirine Hydrochloride

An efficient synthetic route to access rilpivirine hydrochloride was designed and demonstrated on a multikilogram scale. The synthetic route uses two subsequent aromatic nucleophilic substitutions, conducted under carefully optimized conditions to access the target in a 39% overall yield over four steps from (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride 5. The procedures developed were demonstrated on multikilogram scale in our pilot plant, and the product was obtained with a purity of 99.6% by HPLC with no single impurity above 0.10%. The challenges associated with polymorph control and impurity control in an active pharmaceutical ingredient (API) are also discussed. Overall, our process toward Rilpivirine is shorter than most processes described and displays smooth reaction conditions. This work showcases the use of a Boc protecting group as a handle to achieve a more selective nucleophilic aromatic substitution process. It also illustrates the importance of solvent choice in process development to make the chemistry applicable on a large scale under safe conditions.