Merck-DuPont synthesis

The battle is not yet won, of course, but the HIV protease inhibitors are being followed by a new generation of nonnucleoside reverse transcriptase inhibitors, which promise to be less toxic to humans. An example is the DuPont-Merck compound DMP-266, made as a single enantiomer and now under clinical trials. This compound, though it contains a most unusual cyclopropane and alkyne combination, is nevertheless a much simpler compound than Crixivan. We shall devote most of this final chapter to the synthesis of the established and chemically more interesting drug Crixivan. 

Materials and Particle Preparation. Methanol (Baker), ethanol (Merck), and 1-propanol (Baker) were of analytic reagent quality. Absolute technical grade ethanol (Nedalco) was used only for the large-scale (9 L) synthesis of Al. Solvents, tetraethoxysilane (Fluka, purum grade) and 7-aminopropyltriethoxysilane (Janssen) were freshly distilled before each synthesis. Ammonium hydroxide (Merck, 25%) was of analytical reagent quality and contained 14.0 mol/L NH3 as indicated by titration. The silicas Ludox AS40 and Compol were kindly provided by DuPont and Fujimi. 

A concise and efficient synthesis of the potent reverse transcriptase inhibitor Elfavirenz [Scheme 3.130] by the DuPont-Merck process development groups entailed the removal of an A, 0-acetal under basic conditions. Oxidation of the N-p-methoxybenzyl derivative 130,1 with DDQ at 0 C generated the N,0-acetal 1303 in quantitative yield. Treatment of 1303 with sodium hydroxide in... 

Finally, the integration of combinatorial chemistry with other drug discovery tools is occurring. The identification of hydroxyethylamine-based inhibitors of cathepsin D by Ellman (libraries 1.14a,b and 1.15), and the penultimate derivation of selective MMP-3 inhibitors from a library of N-carboxyalkyl amino acid by researchers at DuPont Merck (library 1.23), represent two illustrations of the successful merger of structure-based ligand design and library synthesis. The recent introduction of S AR by NMR methodology for lead discovery has also been used in conjunction with a combinatorial library (library 4.12). 

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