Organic chemists face the ongoing challenge of developing and optimizing a synthesis for active pharmaceutical ingredients
(APIs). These challenges involve a multitude of issues designed to improve yield, purity, stereoselectivity, process conditions
(i.e., temperature and pressure), scalability, and production economics. A recent literature review reveals insight into some
of these challenges as they relate to organic chemical production overall and pharmaceutical chemical development in particular.
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O-arylation and O-alkylation
Researchers at Merck & Co. recently reported on a large-scale synthesis of a potent glucokinase inhibitor, MK-0941, through
selective O-arylation and O-alkylation. Glucokinase inhibitors are under clinical development for treating Type II diabetes. MK-0941 is a glucokinase
inhibitor that has a differentially substituted 3,5-dihydroxybenzamide structure, and an efficient synthesis that would be
suitable for large-scale preparation was required. The researchers reported on several drawbacks of the early-stage synthesis,
including multiple recrystallizations to improve enantomeric purity, yield variability, and batch-to-batch variability in
the impurity profile of the desired compound. Several factors were key to improving the synthesis: a highly selective mono-O-arylation of methyl 3,5-dihydroxybenzoate with 2-ethanesulfonyl-5-chloropyridine and the selection of a proper protective
group for the SN2 O-alkylation (1).
Patricia Van Arnum
One-pot protein synthesis
Researchers at the University of Chicago recently developed a one-pot protein synthesis involving a 204-residue covalent-dimer
vascular endothelial growth factor (VEGF). VEGF is a protein involved in vasculogenesis and angiogenesis and is studied in
reference to pharmaceutical compounds, particularly anticancer compounds. The researchers reported that they prepared a 204-residue
covalent dimmer VEGF with full mitogenic activity from three unprotected peptide segments by one-pot native chemical ligations.
The covalent structure of the synthetic VEGF was confirmed through mass measurements, and the three-dimensional structure
of the synthetic protein was determined by high-resolution X-ray crystallography (2, 3).
Chemical protein synthesis is one research area of University of Chicago professor Stephen B.H. Kent, a co-author of the recently
published research on the VEGF synthesis. One area of focus is the preparation of long polypeptide chains of protein molecules
by the chemoselective reaction (i.e. chemical ligation) of unprotected protein segments containing mutually reactive functional
groups. An example of these ligation chemistries is thioester-mediated, amide-forming ligation or native ligation. The resulting
polypeptide chains are folded with good efficiency to produce high-purity synthetic proteins. The covalent structure of the
molecule is confirmed by mass spectrometry, and the three-dimensional fold structure of the synthetic protein is determined
by X-ray crystallography. Another area of research focus is kinetically controlled ligation, a chemistry used for the full
convergent synthesis of large protein molecules. The research group is examining insertion reactions for creating molecular
diversity in preformed molecular scaffolds and the use of polymer-supported ligation.