No abstract

Pyridine halogenation reactions are crucial for obtaining the vast array of derivatives required for drug and agrochemical development. However, despite more than a century of synthetic endeavors, halogenation processes that selectively functionalize the carbon–hydrogen bond in the 3-position of a broad range of pyridine precursors remain largely elusive. We report a reaction sequence of pyridyl ring opening, halogenation, and ring closing whereby the acyclic Zincke imine intermediates undergo highly regioselective halogenation reactions under mild conditions. Experimental and computational mechanistic studies indicate that the nature of the halogen electrophile can modify the selectivity-determining step. Using this method, we produced a diverse set of 3-halopyridines and demonstrated late-stage halogenation of complex pharmaceuticals and agrochemicals.

Halopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C-H precursors are lacking. We designed a set of heterocyclic phosphines that are selectively installed at the 4-position of pyridines as phosphonium salts and then displaced with halide nucleophiles. A broad range of unactivated pyridines can be halogenated, and the method is viable for late-stage halogenation of complex pharmaceuticals. The study concludes that both tuning the phosphonium electrophilicity and pyridine substitution patterns influence the efficiency of the carbon-halogen bond-forming step.

The issue of sulfonate ester formation is one that has been of significant concern to regulatory authorities since the start of the millennia. These concerns, focused primarily on the risk of ester formation where sulfonic acid salts are formed in alcoholic solvents, has led to the need for specific analysis for such species in the final API in any product containing a sulfonic acid counterion. This concept article examines the growing experimental data that exist showing how this risk can be negated through the application of simple process controls that effectively eliminate this risk. These data are also compared to specific product data, illustrating the practical experience of organizations. The article also reflects on the Viracept incident and how the mechanistic understanding of the reaction between sulfonic acids and alcohols readily predicts the observed outcome. It is the conclusion of the authors that the continued need for exhaustive analytical testing should be replaced instead by a scientific riskbased approach, taking into full consideration the specific process conditions.

Twenty-three pyrophosphate analogues were screened as inhibitors of proliferating cell nuclear antigen independent DNA polymerase delta (pol delta) derived from calf thymus. Carbonyldiphosphonate (COMDP), also known as alpha-oxomethylenediphosphonate, inhibited pol delta with a potency (Ki = 1.8 microM) 20 times greater than that displayed for DNA polymerase alpha (pol alpha) derived from the same tissue. Characterization of the mechanism of inhibition of pol delta indicated that COMDP competed with the dNTP specified by the template and was not competitive with the template-primer. In the case of pol alpha, COMDP did not compete with either the dNTP or the polynucleotide substrate. COMDP inhibited the 3'----5' exonuclease activity of pol delta weakly, displaying an IC50 greater than 1 mM.

Virus-specific enzymes essential for viral nucleic acid replication or related functions are targets for inhibition by substrate or product nucleotide analogues in which one or more P-O bonds are replaced by a P-C bond. The simplest examples of these are PFA (phosphonoformic acid ) and PAA (phosphonoacetic acid), representing analogues of 'pyrophosphate' moieties in nucleotides. The synthesis of a series of α-halogenated and α-οxο PAA and MDP (methanediphosphonate) derivatives is described and structure/activity relationships in their inhibition of several human (α,β,γ) and viral (HSV, EBV, HIV) DNA polymerases are present ed. Inhibition of HIV RNA-directed DNA polymerase (reverse transcriptase) by PFA, α-oxophosphonoacetate and α-oxomethanediphosphonate is shown to be pH-and template-dependent. Combination of phosphonoacetate derivatives and anti-viral nucleo sides into 'hybrid' nucleotide analogues is brief ly discussed.Viruses, infecting and reproducing within host cells, have long been an elusive target for chemotherapy. However, recent advances in 3

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Oxophosphonoacetate (l), a novel biophosphate analogue containing a highly reactive a-ketone function at pH <7, proved inaccessible by direct hydrolysis of its previously unsynthesised triethyl ester (2), but can be made by oxygen transfer to the a-carbene of ethyl P,P-bis(trimethylsi1yl) phosphonoacetate followed by heating in H20.