Industrial Syntheses of the Central Core Molecules of HIV Protease Inhibitors

One-Pot Synthesis of α-Haloketones Employing a Membrane-Based Semibatch Diazomethane Generator

“…NaHCO 3 -Et 2 O, the organic phase dried over MgSO 4 , and the solvent was then removed under vacuum to give 843 mg (91%) of phenacyl chloride as a yellowish solid. 1 4.4. Procedure for the Synthesis of α-Chloroketone Starting from N-Boc-L-phenylalanine.…”

“…Within 2 years of their introduction, annual death rates from AIDS in the developed world reduced dramatically [1]. As a consequence, viral protease inhibitors, such as saquinavir and atazanavir, have become listed by the World Health Organization (WHO) as Essential Medicines for a basic health care system (Scheme 1).…”

“…The key structural unit in these protease inhibitors is a chiral aminoalcohol structure, formally derived from L-phenylalanine. A large body of research has been directed towards the synthesis of this chiral building block [1]. The most direct route involves halomethylation of N-protected-L-phenylalanine, followed by reduction of the haloketone to the N-protected aminoepoxide [1].…”

“…A large body of research has been directed towards the synthesis of this chiral building block [1]. The most direct route involves halomethylation of N-protected-L-phenylalanine, followed by reduction of the haloketone to the N-protected aminoepoxide [1]. The protease inhibitor is then further assembled by a nucleophilic ring opening of the epoxide with the nitrogen of the C-terminal building block.…”

“…Even though a wide range of reagents and reaction conditions has been developed to accomplish the halomethylation, the most effective method remains the condensation of an activated amino acid with anhydrous diazomethane (CH 2 N 2 ) to the α-diazoketone, followed by an α,α-substitution reaction with a hydrogen halide (Scheme 1) [1]. Diazomethane (CH 2 N 2 ) is an exceptionally potent and versatile C1-building block in organic synthesis [2].…”