Evolution of hydrogen cyanide (HCN) during amino acid activation using the reagent combination ethyl cyano(hydroxyimino)acetate (Oxyma)/diisopropylcarbodiimide (DIC) is observed under ambient conditions (20 °C) in N,N-dimethylformamide (DMF). Concentration versus time profiles obtained by 1 H NMR spectroscopy in the presence and absence of amino acids indicate that HCN is formed upon addition of DIC to the reaction mixture and that HCN evolution continues to occur even after amino acid activation is complete when Oxyma and DIC are used in excess amounts relative to the amino acid. A mechanism for the reaction between Oxyma and DIC is proposed, and evidence for its validity was gathered by NMR spectroscopy.
On-flow ReactIR and (1)H NMR reaction monitoring, coupled with in situ intermediate characterization, was used to aid in the mechanistic elucidation of the N-chlorosuccinimide mediated transformation of an α-thioamide. Multiple intermediates in this reaction cascade are identified and characterized, and in particular, spectroscopic evidence for the intermediacy of the chlorosulfonium ion in the chlorination of α-thioamides is provided. Further to this, solvent effects on the outcome of the transformation are discussed. This work also demonstrates the utility of using a combination of ReactIR and flow NMR reaction monitoring (ReactNMR) for characterizing complex multicomponent reaction mixtures.
The design, development,
and scale up of a continuous iridium-catalyzed
homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor
evacetrapib, is described. The scope of this report involves initial
batch chemistry screening at milligram scale through the development
process leading to full-scale production in manufacturing under GMP
conditions. Key aspects in this process include a description of drivers
for developing a continuous process over existing well-defined batch
approaches, manufacturing setup, and approaches toward key quality
and regulatory questions such as batch definition, the use of process
analytics, start up and shutdown waste, “in control”
versus “at steady state”, lot genealogy and deviation
boundaries, fluctuations, and diverting. The fully developed continuous
reaction operated for 24 days during a primary stability campaign
and produced over 2 MT of the penultimate intermediate in 95% yield
after batch workup, crystallization, and isolation.
This communication describes an in situ method for direct observation and quantitation of dissolved H2 at high pressure with concurrent monitoring and characterization of organic reactions. This capability also allows for direct measurement of k(L)a values and provides insight into reactions that was not previously attainable.
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