(701f) Process Development of a Piperidine Fragment for a Pipeline Asset: A Story Centered at the Interface of Carboxylation and Hydrogenation Chemistries

A multi-disciplinary group of Abbvie scientist share the development of a robust process for a piperidine fragment by transforming methylpyridine through a lithiation and contiguous non-cryogenic carboxylation, esterification, and hydrogenation chemistries with >90% yields for each individual stage.

While organometallic reagents are synthetically useful to generate new carbon-carbon bonds, their formation can pose practical concerns. For example, their pyrophoric nature mandates a high-level of rigoristic handling while the generation of high exotherms represent a higher risk during scale-up due to reduced specific surface areas. Flow chemistry examples are leveraged to improve safety and obtain more robust processing conditions.

Quenching organolithiates intermediates with CO₂ is a rapid and highly exothermic process. Based upon the measured adiabatic temperature rise (ATR) of 80⁰C and heat of reaction (∆H_rxn) of 84.7 kJ, an uncontrolled temperature profile would pose a serious risk of thermal runaway and contribute to selectivity issues. To address these areas several reaction modalities were evaluated, including impinging jets and super critical CO­₂ to improve CO₂ availability. While the latter modality was a successful proof-of-concept, current scale-up capabilities favored reverse quenching of organolithiate intermediate with CO₂ which produce excellent yields and purity for a wide operational range at a pilot plant scale.

The esterification of the carboxylate salt was a low-risk reaction that leads to our regulatory starting material (RSM), a pyridinium salt, which must meet 99.9 PA% purity by HPLC. The RSM was hydrogenated in a flow configuration with a Trickled Packed Bed (TPB) reactor achieving excellent purity and yields. A robust process was achieved by optimizing metal-support, metal loadings, pressure, and temperature.

Overall, the formation of the organolithiate starting material and subsequent reactions and respective isolations helped achieve a piperidine product purity of 99.5% that was used with other fragments to produce our pipeline asset.