Our company has developed a robust and scalable process to synthesize an amino alcohol tosylate salt, a penultimate intermediate in the synthesis of nemtabrutinib. A key reaction in this synthetic sequence is a reductive acetal ring opening using boron trifluoride diethyl etherate as a Lewis acid and triethylsilane as the reducing agent. Detailed mechanistic inquisition revealed that in the presence of sulfolane, boron trifluoride is reduced by triethylsilane to generate diborane as the active reductant. Diborane poses many process safety hazards; it is highly reactive, flammable, and acutely toxic. The reaction headspace was studied using infrared spectroscopy and gas chromatography, while the reaction stream was studied using heat flow and adiabatic calorimetry to ensure safe scale-up of the process. Process understanding demonstrated that containing diborane within the reactor was essential to control key impurities. Extensive development efforts were directed to design a process that could safely sequester the hazardous gas. Herein, we describe the process safety analysis, the optimization, and the scale-up of the reduction reaction and the isolation, producing two batches of the amino alcohol tosylate salt with high purity at a pilot scale.
Water-free reflux condensers, which use convective cooling from the surrounding air to condense vapors, avoid the need for cooling water, which is more sustainable than water-cooled condensers, and eliminates the risk of flooding, but these devices are newer and less familiar to many chemists, who may never have used them before. To facilitate the shift to water-free condensers, several types of water-free condensers (simple glass tube, Vigreux column, Condensyn, Findenser, and air-cooled Dimroth) were characterized using three different solvents (ethyl acetate, acetone, and tetrahydrofuran) under both gentle and vigorous refluxing conditions to compare their relative performance and determine the condensing capacity/failure point. In addition to experimentally quantifying the performance of each condenser both gravimetrically and via infrared thermal imaging, energy-balance models were developed to gain insight into which factors were most important in driving their performance. Several of the water-free condensers, including the Findenser, Condensyn, and air-cooled Dimroth condenser, were shown to provide suitable performance for most refluxing operations.
Sustainable small molecule Active Pharmaceutical Ingredient (API) manufacturing starts at the onset of route development by employing a Green-by-Design strategy. Reliable metrics are imperative for setting targets and measuring process improvements throughout the development cycle. This article reviews some of the many tools and methods established to analyze and assess the greenness and sustainability of a process, each of which highlights different aspects of process efficiency, waste formation or overall environmental impact reduction. Most calculations, such as process mass intensity (PMI), are mass-based and do not consider the types of raw materials used. In contrast, a full life cycle assessment (LCA) offers detailed information about the "cradle to grave" environmental impact of a manufacturing route and its specific resources, but the high data requirements and long timelines are not conducive for multiple processes or repeated assessments during process optimization. To address these challenges, we introduce a Streamlined PMI-LCA Tool, developed in collaboration with the ACS Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR), that combines PMI with a "cradle to gate" approach to include the environmental footprint of the synthesis' raw materials. The frequent re-evaluation of a process continuously highlights areas for improvement and guides the prioritization of process development activities to effectively and rapidly achieve a Green-by-Design commercial synthetic route. The utility of this approach to Green-by-Design is demonstrated with the reduction of PMI for MK-7264 from 366 to 88 over the course of process development.
Herein, we describe an enantioselective Cu(II)-catalyzed spiroannulation of N-Boc-iminooxindoles with allylsilanes where a significant positive nonlinear effect (NLE) is observed. EPR spectroscopic studies of the copper(II) species present under synthetically relevant conditions reveal explicit spectroscopic evidence based on analysis of the metal center for the species responsible for the positive NLE in a metal-catalyzed system. EPR spectroscopy indicates that formation of a heterochiral ML2 species under scalemic conditions enriches the effective enantiopurity of the catalytically active species, leading to the asymmetric amplification observed in the spiroannulation. Mathematical analysis of the positive NLE reveals a high thermodynamic preference toward formation of the heterochiral ML2, which has a low relative reactivity when compared to the homochiral ML2.
Organic electrosynthesis is a rapidly evolving field, providing powerful methods to assemble targets of interest in organic synthesis. Concerns around the scalability of electrochemical methods remain the biggest reason behind their scarce implementation in manufacturing routes for the pharmaceutical industry. To fill this gap, we report a workflow describing the key reaction parameters toward the successful scale-up of an organic electrosynthetic method from milligram to kilogram scale. The reaction used to demonstrate our workflow and scale-up in a flow setting was the oxidation of a thioether to its corresponding sulfone, a fragment of interest in an active pharmaceutical ingredient under development. The use of online flow nuclear magnetic resonance spectroscopy, offline ion chromatography, cyclic voltammetry, and density functional theory calculations provided insight into the reaction mechanism and side reactions.
Results from a survey that was distributed to the graduate students in the Department of Chemistry at UC Davis are presented and discussed. The survey sought to gauge graduate student perception of safety culture in their department and individual labs following the 2012 UC settlement agreement. Most of the respondents indicated that they felt their lab had a positive safety culture. A clear correlation between research discipline and perceived hazard level was identified. Respondents indicated that a lack of clear expectations and safety knowledge were the biggest barriers to improving safety culture. Informal lab-wide safety discussion was identified as one of the best ways to improve safety culture, however, one-third of respondents indicated that they had relatively infrequent safety discussions and one-half of respondents indicated that they never discuss incidents or near-misses in a group-wide setting. This survey indicates that while the settlement agreement has had a positive impact on safety in the Department of Chemistry at UC Davis, key improvements could be made to further strengthen safety culture.
