Efficient and robust synthetic processes of active pharmaceutical ingredients (APIs) are highly desirable, and continuous flow chemistry is a critical component of this endeavor. The clinical importance of ondansetron, a World Health Organization essential medicine, prompted us to investigate continuous synthetic approaches to this API. Our efforts to improve the synthetic processes led to a continuous condensation step and a continuous Mannich reaction. A continuous work-up and purification process was also established for the former. A batch process was employed for an elimination and Michael addition step, as it not only accommodated the physical properties of the reaction mixtures, but also provided a high productivity of the desired product. Taken together, these findings demonstrate the complementary advantages of flow and batch chemistry in API synthesis.
Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.
Computer-aided synthesis planning (CASP) tools can propose retrosynthetic pathways and forward reaction conditions for the synthesis of organic compounds, but the limited availability of context-specific data currently necessitates experimental development to fully specify process details. We plan and optimize a CASP-proposed and human-refined multistep synthesis route toward an exemplary small molecule, sonidegib, on a modular, robotic flow synthesis platform with integrated process analytical technology (PAT) for data-rich experimentation. Human insights address catalyst deactivation and improve yield by strategic choices of order of addition. Multi-objective Bayesian optimization identifies optimal values for categorical and continuous process variables in the multistep route involving 3 reactions (including heterogeneous hydrogenation) and 1 separation. The platform’s modularity, robotic reconfigurability, and flexibility for convergent synthesis are shown to be essential for allowing variation of downstream residence time in multistep flow processes and controlling the order of addition to minimize undesired reactivity. Overall, the work demonstrates how automation, machine learning, and robotics enhance manual experimentation through assistance with idea generation, experimental design, execution, and optimization.
By simple combination of water and sodium iodide (NaI) with chlorotrimethylsilane (TMSCl), promotion of a Vorbrüggen glycosylation en route to essential HIV drugs emtricitabine (FTC) and lamivudine (3TC) is achieved. TMSCl–NaI in wet solvent (0.1 M water) activates a 1,3-oxathiolanyl acetate donor for N-glycosylation of silylated cytosine derivatives, leading to cis-oxathiolane products with up to 95% yield and 20:1 dr. This telescoped sequence is followed by recrystallization and borohydride reduction, resulting in rapid synthesis of (±)-FTC/3TC from a tartrate diester.
Batch and continuous reactors both enable exploration of a chemical design space. The former rely on transient experiments, thus experiencing a wide variety of operating conditions over time, whereas the latter are usually operated at steady state and are representative of only one set of conditions. Operating a continuous reactor under dynamic conditions allows more efficient exploration of the underlying reaction space for extraction of kinetics and optimization of performance. We present a methodology to efficiently explore a design space using a tubular flow reactor installed on an automatic platform (equipped with FTIR and HPLC analysis) operated in a transient regime using sinusoidal variations of the parameters. This data-dense method proves to be quicker with respect to steady-state operations because of the larger amount of information collected during a single experiment. A computational analysis provides a simple criterion for the design of dynamic experiments in order for them to be representative of steady-state conditions. The methodology is applied experimentally to the synthesis of a pharmaceutical intermediate via an esterification reaction in the presence of base. In the experiments, up to three parameters (reaction time, base equivalents, and temperature) are changed simultaneously. Proper design of the trajectories in the design space allows verification of the consistency of the results by exploiting the self-crossings within each trajectory and crossings between different trajectories. The experiments further validate the developed criterion for dynamic operations.
The approach to reproductive health and safety in academic laboratories requires increased focus and a shift in paradigm. Our analysis of the current guidance from more than 100 academic institutions’ Chemical Hygiene Plans (CHPs) indicates that the burden to implement laboratory reproductive health and safety practices is often placed on those already pregnant or planning conception. We also found inconsistencies in the classification of potential reproductive toxins by resources generally considered to be authoritative, adding further confusion. In the interest of human health and safe laboratory practice, we suggest straightforward changes that institutions and individual laboratories can make to address these present deficiencies: Provide consistent and clear information to laboratory researchers about reproductive health and normalize the discussion of reproductive health among all researchers. Doing so will promote safer and more inclusive laboratory environments.
A scalable four step synthesis of molnupiravir from cytidine is described herein. The attractiveness of this approach is its fully chemical nature involving inexpensive reagents and more environmentally friendly solvents such as water, isopropanol, acetonitrile and acetone. Isolation and purification procedures are improved in comparison to our earlier report, as all intermediates can be isolated via aqueous acid treatment and recrystallization. The key steps in the synthesis, namely ester formation, hydroxamination and deprotection were done on multigram scale to afford molnupiravir in 36-41% yield with average purity of 98 wt% by q-NMR and 99 area % by HPLC.
Synthetic chemistry provides access to advanced materials that facilitate innovation in key industries such as medicine, energy, and agriculture. Automation is poised to challenge the traditional process of chemical synthesis and development. Continuous flow chemistry has recently come into maturity and provides a flexible platform amenable to automation. The merger of synthesis and automation promises to democratize access to custom complex small molecules for non-experts as well as accelerate the development of new synthetic protocols by relieving expert chemists of routine tasks. In this contribution, we discuss recent case studies that present strategies towards realizing automated synthesis with a further focus on works that leverage continuous flow chemistry as an enabling technology.
Large quantities of fluorinated gases are generated as intermediates or byproducts from fluorinated polymer production annually, and they are effective ozone depleting substances or greenhouse gases. On the other hand, the incorporation of fluoroalkyl groups into drug molecules or bioactive compounds has been shown to enhance biological properties such as the bioavailability, binding selectivity, and metabolic stability. Extraction of fluoroalkyl sources, including trifluoromethyl and difluoromethyl groups, from the fluorinated gases is highly desirable, yet challenging under regular batch reaction conditions. Flow chemistry is an emerging and promising technique to address long-standing challenges in gas–liquid batch reactions such as insufficient interfacial contact and scalability issues. In this review, we highlight recent advances in continuous flow strategies toward enabling the use of fluorinated greenhouse gases in organic synthesis.
Large quantities of fluorinated gases are generated as intermediates or byproducts from fluorinated polymer production annually, and they are effective ozone depleting substances or greenhouse gases. On the other hand, the incorporation of fluoroalkyl groups into drug molecules or bioactive compounds has been shown to enhance biological properties such as the bioavailability, binding selectivity, and metabolic stability. Extraction of fluoroalkyl sources, including trifluoromethyl and difluoromethyl groups, from the fluorinated gases is highly desirable, yet challenging under regular batch reaction conditions. Flow chemistry is an emerging and promising technique to address long-standing challenges in gas–liquid batch reactions such as insufficient interfacial contact and scalability issues. In this review, we highlight recent advances in continuous flow strategies toward enabling the use of fluorinated greenhouse gases in organic synthesis.