A key pharmaceutical intermediate (1) for production of edivoxetine•HCl was prepared in >99% ee via a continuous Barbier reaction, which improves the greenness of the process relative to a traditional Grignard batch process. The Barbier flow process was run optimally by Eli Lilly and Company in a series of continuous stirred tank reactors (CSTR) where residence times, solvent composition, stoichiometry, and operations temperature were optimized to produce 12 g h −1 crude ketone 6 with 98% ee and 88% in situ yield for 47 hours total flow time. Continuous salt formation and isolation of intermediate 1 from the ketone solution was demonstrated at 89% yield, >99% purity, and 22 g h −1 production rates using MSMPRs in series for 18 hours total flow time. Key benefits to this continuous approach include greater than 30% reduced process mass intensity and magnesium usage relative to a traditional batch process. In addition, the flow process imparts significant process safety benefits for Barbier/Grignard processes including >100× less excess magnesium to quench, >100× less diisobutylaluminum hydride to initiate, and in this system, maximum long-term scale is expected to be 50 L which replaces 4000-6000 L batch reactors.
This work describes the synthesis and characterisation of a new series of polyphenylenes with up to four ferrocenyl moieties. The synthetic route involves the preparation of a number of novel precursors. Cyclopentadienones, generated from the two-fold Knoevenagel condensation of di-ferrocenyl propanones and diketones, are used in [2 + 4] Diels-Alder cycloadditions with appropriately substituted acetylenes. 13 is amongst the compounds isolated. It is the largest ferrocenyl-supported polyaromatic hydrocarbon (PAH) to date. Prepared via a Sonogashira cross-coupling reaction between ethynyl-Fc and iodo-HBC, it comprises a hexa-peri-hexabenzocoronene (HBC) core linked via acetylene to a ferrocenyl unit (Fc). The electrochemical and absorption properties of the ferrocenyl-polyphenylenes and the fully conjugated 13 are discussed. The NLO data for 13, determined by hyper Rayleigh scattering techniques, are compared to those of similar fulleryl-based compounds in the literature.
This work continues our investigations into substituted polyaromatic hydrocarbons (PAHs). Presented is a new series of ferrocenyl-substituted polyphenylenes and the successful Lewis acidcatalyzed cyclodehydrogenation of one of these to form an eight-ring fused PAH supporting a ferrocene moiety (16-ferrocenyl(tribenzo[e;g,h,i;k])perylene ( 6)), the largest of its kind. The failure to generate further metallo-organic superaromatics is discussed in relation to the structure of the precursors and the oxidation of the ferrocene metal center. The synthesis of the polyphenylenes involves the [2þ4] Diels-Alder reaction of phenyl, ferrocenyl, and hydrogen-terminated ferrocenyl acetylenes and tetraphenylcyclopentadienone. The full spectroscopic characterization and the electronic and redox properties of all the systems are described and compared. The single-crystal X-ray structure of tetraphenyl ferrocenyl benzene (1), the precursor to 6, is also discussed.
Routes to (2-chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]metha-none, 1, an intermediate in the manufacture of NK1-II inhibitor LY686017 are described which produce 1 in >75% yield and 95% purity. A highly selective telescoped ortho lithation/condensation/ oxidation process was developed and successfully scaled to the clinical pilot plant to produce 25 kg of 1. For the pilot-plant campaign, the lithiation step was developed to operate at -50 °C using commercial lithium diisopropylamide (LDA), and the oxidation step employed catalytic TEMPO as the primary and NaOCl as the terminal oxidant. After completion of the pilot-plant campaign second-generation approaches to 1 were developed to improve process greenness where the lithiation and condensation step were operated as warm as -10 °C, the highly efficient AZADO catalyst was used as a substitute for TEMPO in the Anelli-Montanari oxidation, and process mass intensity was reduced 25%.
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