This paper describes the development of a continuous, high yielding, and scalable enolization, oxidation, and quench process for the hydroxylation of the azapirone psychtropic agent buspirone to afford 6-hydroxybuspirone (6-hydroxy-8-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl]-8-aza-spiro[4.5]decane-7,9-dione). Two feed streams were reacted continuously using an in-line static mixer followed by oxidation in a continuous flow trickle-bed reactor. The laboratory reactor operation was demonstrated at steady state for over 40 h. The process was scaled up using both volumetric (enolization) and numbering-up (oxidation) scale-up strategies. A pilot-plant reactor was developed and successfully implemented in a three-batch campaign (47 kg input per batch).

A general procedure has been developed to predict the vapor−liquid equilibria (VLE) of solvent/copolymer systems with the Panayiotou and Vera equation of state (PV-EOS), using binary interaction parameters deduced from homopolymer VLE data. Mixing rules are proposed for the PV-EOS pure-component parameters and homopolymer−solvent binary interaction parameters in order to predict solvent solubilities in copolymer systems. This methodology has been evaluated with VLE data acquired in this study for water, methanol, and methyl acetate in poly(vinyl acetate), poly(vinyl alcohol), and a copolymer comprised of these two homopolymers containing 88% (molar) poly(vinyl alcohol) repeat units. The predictions from the PV-EOS of the copolymer VLE are in excellent agreement with our experimental data.

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A thermal runaway potential was identified for the conversion of a tertiary alcohol to a hydroxypyrrolotriazine intermediate in the synthesis of brivanib alaninate. A continuous process was developed to mitigate the potential thermal runaway and allow for safer scale-up. This paper describes the hazard analysis, process development, reactor development, reaction engineering model development, and scale-up of the continuous process. The process includes three separate and stable feed streams that are mixed in distinct order using in-line static mixers. Heat exchangers are arranged and connected to facilitate a "plug flow" reactor scheme allowing sufficient residence time for reaction completion. The process has been scaled-up to the pilot plant and to manufacturing.

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