RILPIVIRINE HCL

Rilpivirine Hydrochloride was shown to be able to treat and or prevent immunodeficiency virus-1. It also has uses for anti-viral therapy

ChEBI: A hydrochloride obtained by reaction of rilpivirine with one equivalent of hydrochloric acid. Used for treatment of HIV.

Rilpivirine hydrochloride (Edurant), a non-nucleoside reverse transcriptase inhibitor (NNRTI), received its approval both from the U.S. FDA and E.U. EMA in 2011 for the treatment of HIV-1 infection in treatment-na?ve adult patients. It was discovered and developed by Janssen Pharmaceuticals and its subsidiary Tibotec Pharmaceuticals. As a second generation NNRTI, rilpivirine hydrochloride displayed higher potency and longer half-life with a 25 mg once a day dose, compared to existing NNRTIs, such as the 200 mg BID of efavirenze (Sustiva). In late 2011, the fixed-dose combination products of rilpivirine hydrochloride with two nucleoside reverse transcriptase inhibitor (RTIs) emtricitabine and tenofovir disoproxil fumarate, co-developed by Gilead Science and Tibotec, were also approved both by the FDA and EMA under brand names Complera® and Eviplera®, respectively.

Similar to efavirenze, rilpivirine hydrochloride is a diarylpyrimidine (DAPY) compound, and the large-scale process synthesis begins with commercially available 2-methylthio-4-pyrimidinone (193) shown in the scheme.

Thioether 193 was condensed with neat 4-cyanoaniline (194) at elevated temperature to afford diarylamine 195 in 77% yield. Subsequent treatment of pyrimidone 195 with refluxing POCl3 provided the corresponding chloride 196 in 77% yield.160,161 In the presence of K2CO3, chloride 196 was treated with the (E)-cinnamonitrile aniline 200 to give rilpivirine hydrochloride (XIX) in good yield.158 Aniline 200 was prepared via a Heck reaction of commercially available 4-iodo-2,6-dimethyl-benzeneamine (197) and acrylonitrile (198) affording compound 199 as a 4:1 mixture of E/Z isomers. The distribution of E/Z olefins was increased to 98:2 by salt formation and recrystallization to ultimately provide pure (E)-200 in 64% yield for two steps.