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).
The development of a safe and scalable oxidation process for the hydroxylation of the azapirone psychotropic agent buspirone (1) to furnish 6-hydroxybuspirone (2) is described. A mechanistic understanding of how key process factors affected product quality led to the successful application of FTIR as a process analytical technology (PAT) tool. This enabled real time quality assurance and the development of an effective and efficient manufacturing process. The identification of impurities and the development of recrystallization methods to provide active pharmaceutical ingredients (API) with optimal purity will also be addressed.
A reliable synthesis of 14 C labeled 6-hydroxy-buspirone is described. The molecule belongs to a unique class of compounds with the potential for anxiolytic activity. A radiolabeled analog was prepared to support the development of 6-hydroxy-buspirone. Specifically, a labeled variant was designed to meet the requirements of a human adsorption-distribution-metabolism-elimination (ADME) study. Multiple 14 C labels were needed to fully track the potential metabolic transformation of the molecule. Labeled 6-hydroxy-buspirone was prepared by oxidation of separately labeled versions of [ 14 C]buspirone. The final product was isolated in reasonable yield with a radiochemical purity of 99.8%.
Catalytic Epoxidation of Alkenes with Oxone. -Optimal conditions are established for the epoxidation of alkenes (9 examples) with conversions of 96-100% by in situ generated dioxiranes with OPTF acting as phase transfer catalyst and potassium monoperoxosulfate (Oxone) as oxidant. Slow addition rate, pH 7.5-8.0, the N-dodecyl chain in OPTF, and the triflate counterion are identified as the key experimental and structural variables. -(DENMARK, S. E.; FORBES, D. C.; HAYS, D. S.; DEPUE, J. S.; WILDE, R. G.; J. Org.
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