Efavirenz Merck, DuPont

Efavirenz (DMP 266) (1) is an effective non-nucleoside inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV) recently registered by the US Food Drug Administration (FDA) for treatment of the acquired immunodeficiency syndrome (AIDS).1 2 3 Inhibition of HIV reverse transcriptase by nucleosides like azidothymidine (AZT) (2) is a proven therapy for delaying the progression to AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents. The recent development of both protease inhibitors and non-nucleoside reverse transcriptase inhibitors offers hope of effective treatment especially when coadministered. 

Structural features of 1 are an oxazinone moiety and a cyclopropyl acetylene unit connected to a chiral quaternary carbon center. 

The importance of this compound gave rise to the development of a short and efficient synthesis, allowing large scale processes, which is presented in this problem. 

The reaction is carried out in a two phase system with 30 % aqueous NaOH and MTBE, which allows trapping as well as removal of the HC1 evolved. Anilide 4 is obtained directly by crystallization from the reaction mixture. This reaction was carried out on a 1,000 g scale.2 

Metx/ Methyl tert-butyl ether (MTBE) (14) was used as solvent because it is 

Pivaloyl chloride (13) reacts with aniline (3) to amide 4 by nucleophilic attack of Ihe nitrogen to the carbonyl group under loss of HCl. 

The reaction is earned out in a two phase system w ith 30 % aqueous NaOH and MTBE. which allows trapping as well as removal of the HCl evolved. Anilide 4 is obtained directly by ciystallization from the reaction mixture, This reaction was carried out on a 1,000 g scale. Methyl erf-buty) ether (MTBE) (14) was used as solvent because it i.s not halogcnatcd (at industrial plant scale, the use of halogenated solvents is avoided because of their noxiousness) and its handling compared to that of diethyl ether is safer because of its low er volatility and lack of peroxide formation. 

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There are a few key enzymes for the proliferation of human immunodeficiency virus (HIV). Reverse transcriptase is one of them since HIV is a member of the DNA viruses. Efavirenz (1) is an orally active non-nucleoside reverse transcriptase inhibitor (NNRTI) and was discovered at Merck Research Laboratories [1] for treatment of HIV infections. Efavirenz was originally licensed to DuPont Merck Pharmaceuticals which was later acquired by Bristol-Myers Squibb.11 The typical adult dose is 600 mg once a day and 1 is one of three key ingredients of the once-a-day oral HIV drug, Atripla (Figure 1.1). 

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