The Development of An Effective Synthetic Route of Rilpivirine

Abstract

Background: Rilpivirine (RPV) is a potent and selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of the diarylpyrimidine family with unique antiviral activity, low toxicity and high specificity. It is approved by the U.S. FDA (Food and Drug Administration) in 2011 to treat individuals infected with human immunodeficiency virus 1 (HIV-1). Significantly, rilpivirine is 3-fold more potent than etravirine. Once-daily, it is used with a low oral dose (25mg/tablet), decreasing the drug administration and bringing the better choice to the patients. However, there are many shortcomings in the existing synthesis route of RPV, such as the high cost, prolonged reaction time and low yield (18.5%).Results: This article describes our efforts to develop an efficient and practical microwave-promoted method to synthesize rilpivirine using less toxic organic reagents and low boiling solvents. The last step's reaction time decreased from 69 h to 90 min through this optimized synthetic procedure, and the overall yield improved from 18.5% to 21%. In addition, the yield of intermediate 3 increased from 52% to 62% compared to the original patent.Conclusion: Overall, through a series of process optimization, we have developed a practical synthesis method of rilpivirine, which is easy to scale with higher yield and shorter reaction time.