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%.
Catalytic Bu4NOAc as silicon activator of ethyl 2-(trimethylsilyl)acetate, in THF, was utilized for the synthesis of β-hydroxy esters, whereas employing catalytic Bu4NOTMS gave α,β-unsaturated esters. The established reaction conditions were applicable to a diverse range of aromatic, heteroaromatic, aliphatic aldehydes and ketones. Reactions were achieved at room temperature without taking any of the specialized precautions that are in place for other organometallics. A stepwise olefination pathway via silylated β-hydroxy esters with subsequent elimination to form the α,β-unsaturated ester has been demonstrated. The key to selective product formation lies in use of the weaker acetate activator which suppresses subsequent elimination whereas stronger TMSO– activator (and base) facilitates both addition and elimination steps. The use of tetrabutyl ammonium salts for both acetate and trimethylsilyloxide activators provide enhanced silicon activation when compared to their inorganic cation counterparts.
Dihydroxamic acids contain two bidentate ligand groups and are very powerful chelating agents for metal ions. Five water-soluble acids of the general formula HONHCO(CH2),-CONHOH were examined by differential-pulse voltammetry (DPV), cyclic voltammetry (CV) and microcoulometry (MC).The acids were prepared by J. Glennon at Cork University using procedures of Brown and co workers.1.2 The acids listed in Table 1 were investigated.A series of Prideaux buffers were used as supporting electrolytes, with suitable amounts of potassium nitrate added,
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