Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 14, Issue 3, Pages 657-660Publisher
AMER CHEMICAL SOC
DOI: 10.1021/op9003289
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- Emcure Pharmaceuticals Ltd.
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Etravirine (1) is a novel diarylpyrimidine non-nucleoside reverse transcriptase inhibitor and has recently been approved by the U.S. Federal Drug Administsration for the treatment of AIDS. Its reported synthesis is fraught with many difficulties, the foremost being the poor yield and long reaction time required at the aminolysis stage. We attributed this problem to the presence of a bromide group adjacent to the reaction site of the advance intermediate (6). In order to circumvent this issue, we proposed to defer the installation of the bromide group at a later stage, preferably after aminolysis. Indeed, this protocol has worked well. However, in the process of installation of diarylether and diary-amine functionalities at appropriate positions, we had to reverse the sequence of displacement reactions of the dichloride intermediate (9) with 3,5-dimethyl-4-hydroxybenzonitrile (5) and 4-aminobenzonitrile (3). The classical bromination led to the completion of etravirine synthesis.
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