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Support structures of various materials are used to enhance the performance of catalytic process chemistry. Typically, fixed bed supports contain regular channels enabling high throughput because of the low pressure drop that accompanies high flow rates. However, many fixed bed supports have a low surface-area-to-volume ratio resulting in poor contact between the substrates and catalyst. Three dimensional polymer printing (3dP) can be used to overcome these disadvantages by offering precise control over key design parameters of the fixed bed, including total bed surface area, as well as accommodating system integration features that are compatible with continuous flow chemistry. Additionally, 3dP allows for optimization of the catalytic process based on extrinsic constraints (e.g. operating pressure) and digital design features. These design parameters together with the physicochemical characterization and optimization of catalyst loading can be tuned to prepare customizable reactors based on objectives for substrate conversion and desired throughput. Using a Suzuki (carbon–carbon) cross-coupling reaction catalyzed by palladium, we demonstrate our integrated approach. We discuss key elements of our strategy including the rational design of hydrodynamics, immobilization of the heterogeneous catalyst, and substrate conversion. This hybrid digital-physical approach enables a range of pharmaceutical process chemistries spanning discovery to manufacturing scale.

Pyrrolo[2,1-f][1,2,4]triazine (1) is an important regulatory starting material in the production of the antiviral drug remdesivir. Compound 1 was produced through a newly developed synthetic methodology utilizing simple building blocks such as pyrrole, chloramine, and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-vessel-operated process. This work describes the safety of the process, impurity profiles and control, and efforts toward the scale-up of triazine for the preparation of kilogram quantity.

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 study as all intermediates can be isolated via recrystallization. The key steps in the synthesis, namely, ester formation, hydroxyamination, and deprotection were carried out on a multigram scale to afford molnupiravir in 36-41% yield with an average purity of 98 wt % by qNMR and 99 area% by HPLC.

We report the influence of substituents and physical conditions on activation energies for the noncatalyzed amination (C-N cross-coupling reactions) of aryl halides. We uncover a significant correlation between the barrier heights of the C-N bond formation and Hammett σ parameters-a formal measure of the electron-withdrawing or -donating ability of substituents on the aryl halides. Our results indicate that such correlations are useful predictive tools for the amination of aryl halides over a wide range of substituent types. From 54 cases studied (six substituents occupying specific positions relative to halogen atoms), the 2-COOHPhI + NH2n Pr amination reaction is predicted to possess the lowest noncatalyzed activation free energy (135.6 kJ mol-1) using the B3LYP method. The lower barriers for the 2-COOHPhX (for X = Cl, Br, and I) compounds are shown to originate from collusion between steric and electronic effects-specifically, the momentary formation of a hydrogen bond between an oxygen site on the ortho-COOH and the lone pair of the entering amine. Internal reaction coordinate (IRC) path calculations afforded us these and other key insights into the nature of the reactions. The control exerted by substituents on the arrangement of the transition state structure, as well as the sensitivity of the reaction barriers to temperature and solvent polarity, are discussed. These results offer new perspectives from which to assess the nature of the C-N bond formation and suggest new avenues for future exploration, especially in progress toward the metal-free amination of aryl compounds.

An efficient, inexpensive, and reliable synthesis of diaminomaleonitrile (DAMN, 1) is described starting from readily available acetone cyanohydrin as the source of hydrogen cyanide (HCN). Diaminomaleonitrile (DAMN) is known to be an important intermediate in heterocyclic and medicinal chemistry as well as being a possible precursor for the origin of life's hypothesis within prebiotic chemistry. The mechanism of its formation through organosulfur catalysis has been investigated by electrospray ionization mass spectrometry (ESI-MS) using two newly synthesized cationic "marker" molecules as a tool that allows for sensitive detection. As a result, the proposed mechanism of a thiocyanate-mediated synthesis of the HCN tetramer DAMN starting from organic disulfides was confirmed.

This is the accepted manuscript version of the work published in its final form as Dietz, Jule-Philipp;Lucas, Tobias;Groß, Jonathan;Seitel, Sebastian;Brauer, Jan;Ferenc, Dorota;Gupton, B. Frank;Opatz, Till. Organic Process Research & Development; Volume: 25; Issue: 11; Pages: 1898-1910; https://doi.org/10.1021/acs.oprd.1c00139. Deposited byshareyourpaper.organdopenaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailinghelp@openaccessbutton.org.

Nirmatrelvir, the novel antiviral component of Pfizer’s orally available combination therapy Paxlovid, used to treat COVID-19, presents a significant synthetic challenge. Herein, we report process optimization insights that could enable a scalable and cost-effective manufacturing process to make nirmatrelvir. The disclosed development opens up a path to three new complete routes, offering options to eliminate some of the major cost-drivers for nirmatrelvir and deliver the final API in higher yield and lower overall cost while maintaining quality requirements.

Di-tert-butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di-tert-butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(OtBu)2 as the base for the alkylation of (R)-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di-tert-butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The developed protocol could also be applied for the preparation of the hepatitis B drug adefovir (64% yield/1 g scale).

Copper supported on KIT-6 mesoporous silica was prepared via ammonia evaporation (AE) method and applied for the catalytic hydrogenation of dimethyl oxalate (DMO) to ethylene glycol (EG). The high specific surface area and interconnected mesoporous channels of the support facilitated the dispersion of copper species. The effect of AE temperature and copper loading on the structure of catalysts and induced change in hydrogenation performance were studied in detail. The results showed that both parameters influenced the overall and/or intrinsic activity. The hydrogenation of DMO to EG was proposed to proceed via the synergy between Cu0 and Cu+ sites and catalysts with high surface Cu0/Cu+ ratio exhibited high intrinsic activity in the investigated range.

Pyrrolotriazine 1 is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. These efforts help to secure the remdesivir supply chain.

A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low-cost, widely available starting materials-we refer to this as supply-centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precursors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate, and water to produce the oxathiolane.

An economical synthesis of lamivudine was developed by employing a new method to establish the stereochemistry about the heterocyclic oxathiolane ring. Toward this end, an inexpensive and readily accessible lactic acid derivative served the dual purpose of activating the carbohydrate's anomeric center for N-glycosylation and transferring stereochemical information to the substrate simultaneously. Both enantiomers of the lactic acid derivative are available, and either β-enantiomer in this challenging class of 2'-deoxynucleoside active pharmaceutical ingredients can be formed.

A concise and practical synthesis has been developed to provide the 8-fluoro-5-hydroxy-3,4-diydrocarbostyril (

Pyrrolo[2,1-f][1,2,4]triazine (1) is an important regulatory starting material in the production of Remdesivir (Veklury®). Compound 1 was produced through a newly developed synthetic methodology utilizing the simple building blocks pyrrole, chloramine and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-reactor operated process. This work describes the safety of the process, impurity profiles and control, and efforts towards the scale-up of triazine for the preparation of kilogram quantity.

The present manuscript describes a simple, two step synthesis of tenofovir from HPA through phosphonomethalation with a novel doubly protected oxymethylphosphonate electrophile. The crystalline electrophile can be prepared in a simple reaction sequence and can be deblocked more easily than its ditehyl analogue involved in the current commercial process for making the drug.The approach is general and can also be used for the preparation of related antivirals and the synthesis of adefovir is described as well.

A new route to MK-4482 was developed. The route replaces uridine with the more available and less expensive cytidine. Low-cost, simple reagents are used for the chemical transformations, and the yield is improved from 17% to 44%. A step is removed from the longest linear sequence, and these advancements are expected to expand access to MK-4482 should it become a viable drug substance.

A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The reactions can be conducted in either order with overall yields of 67% (first step—esterification) and 37% (first step—hydroxamination). Selective esterification of the nucleoside’s primary alcohol by enzymatic means eliminated the need for diol protection/deprotection, and direct transamination with hydroxylamine precluded the necessity of activating the nucleobase for amine coupling. This results in a significant advancement over the reported synthesis which is formed in at best 17% yield. The step count is reduced from five transformation to two, and the more expensive uridine is replaced with the more available cytidine.

Pyrrolotriazine 1 is an important precursor to Remdesivir, and an efficient synthesis is disclosed. This route features atom economy and reduced derivatization of starting materials, by making use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. A one-pot cascade sequence was developed for direct cyanation of pyrrole. Amination and cyclization with formamidine acetate complete the synthesis. The problematic nature of typically dilute electrophilic aminations was solved with semi-continuous processing. Moreover, development of a continuous platform afforded access to the ideal yet non-commercial aminating reagent, monochloramine. These efforts help to secure the Remdesivir supply chain.

A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low cost, widely available starting materials – we refer to this as supply centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precurors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate and water to produce the oxathiolane.

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.

Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available materials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one‐step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.

While the primary role of supports in catalysis has been to anchor metal particles to prevent sintering, supports can also activate catalytic processes. We report computational and experimental results that provide a fundamental understanding of how a graphene support may activate both oxidative and reductive reaction steps in the catalytic cycle of Suzuki-Miyaura palladium-catalyzed cross-coupling reactions. Theoretical investigations reveal that the high catalytic activity is linked to the ability of a graphene support to act as both an efficient charge donor and acceptor in oxidation and reduction reaction steps. We compare the activation energy and turn over frequency for a series of supported and homogeneous catalysts and find that exposing palladium-graphene to defect inducing microwave radiation results in dramatically lower activation energies and higher turnover frequencies. These results explain why a defected graphene support may catalyze reaction steps that require both charge donation, and charge acceptance.

We report the synthesis of uncapped ‘naked’ palladium nanoparticles (PdNPs) through the facile and green route of femtosecond laser reduction in liquid using two different precursors: potassium tetrachloropalladate (K2PdCl4) and palladium nitrate (Pd(NO3)2). Stabilization of the Pd precursor by lowering the pH enabled the synthesis of PdNPs in the sub-5 nm range. Laser synthesis using both precursors generated ultrasmall spherical NPs with average diameters of 1.2 nm and 3.1 nm for the nitrate and chloride precursors, respectively. An additional population of anisotropic large particles with nanopopcorn and nanoflower morphologies observed in electron microscopy images appears to result from the aggregation of the ultrasmall PdNPs. The PdNPs are efficient catalysts for Suzuki cross-coupling reactions and for the reduction of para-nitrophenol by sodium borohydride in water. The excellent catalytic activity of our laser-generated PdNPs is attributed to the ligand-free structure and small particle sizes generated through laser reduction in liquid.

The application of continuous methods in the synthesis of active pharmaceutical ingredients continues to receive significant attention in the academic as well as the industrial research communities. One of the major advantages of continuous methods is the ability to safely access kinetic synthons as well as highly reactive reagents that are typically unavailable through traditional batch methods. In this work, we report the high-yielding, clean formation of an aryl-turbo Grignard and its selective addition to a highly-enolizable 1,3-dichloroacetone, for the continuous synthesis of a key intermediate for fluconazole, a widely-prescribed anti-fungal agent. In addition, process optimization of the final API was also carried out to arrive at a semi-continuous method to this essential medicine.

In this research, we report a scientific investigation of an efficient method used for the synthesis of highly active Palladium Nanoparticles decorated with Fe3O4, Co3O4, and Ni (OH)2 Supported on Graphene as Potential Efficient Catalysts for Suzuki Cross—Coupling. Pd/Fe3O4 nanoparticles supported on graphene nanosheets (Pd/Fe3O4/G) showed an excellent catalytic activity for Suzuki coupling reactions and recycled for up to four times without loss of catalytic activity. An efficient magnetic catalyst has been successfully synthesized using a simple, reproducible fast and reliable method using microwave irradiation conditions. The prepared catalysts are magnetic as in case of iron and cobalt oxides which is an advantage in the separation process of catalyst from the reaction medium via applying a strong external magnetic field. The synthesis approach is based on the Microwave (MW)-assisted simultaneous reduction of palladium and ferric nitrates in the presence of graphene oxide (GO) nanosheets using hydrazine hydrate as the reducing agent. The results provide a fundamental understanding of the system variables by comparing the catalytic activity and recyclability of different catalysts with different properties. The most active and recyclable catalyst was Pd–Fe3O4—supported on graphene which offers several added advantages including recyclability of up to seven times, mild reaction conditions, and short reaction times in an environmentally benign solvent system. Furthermore, the magnetic properties imparted by the Fe3O4 component of the catalyst enables the catalyst to be easily isolated and recycled, thus greatly simplifying the ability to purify the reaction products and increasing the economic value of the catalyst. The utility of these magnetic catalysts towards Suzuki cross coupling reaction was also demonstrated. The high activity and recyclability of these catalysts are attributed to a strong catalyst-support interaction where the defect sites in the reduced GO nanosheets act as nucleation centers for anchoring the Pd and Fe3O4 nanoparticles thus minimizing the potential of their agglomeration and the subsequent decrease in the catalytic activity.

A concise and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, a key building block for several clinical and experimental HIV protease inhibitors including the highly important drug darunavir, was achieved via a one-pot procedure using furan and Cbz-protected glycol aldehyde as starting materials. A [2+2]-photocycloaddition between both reactants which can be prepared from wood-based starting materials according to the principles of xylochemistry, followed by hydrogenation and lipase-catalyzed kinetic resolution afforded the target compound in high yield and up to 99% ee.

Access to affordable medications continues to be one of the most pressing issues for the treatment of disease in developing countries. For many drugs, synthesis of the active pharmaceutical ingredient (API) represents the most financially important and technically demanding element of pharmaceutical operations. Furthermore, the environmental impact of API processing has been well documented and is an area of continuing interest in green chemical operations. To improve drug access and affordability, we have developed a series of core principles that can be applied to a specific API, yielding dramatic improvements in chemical efficiency. We applied these principles to nevirapine, the first non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV. The resulting ultra-efficient (91% isolated yield) and highly-consolidated (4 unit operations) route has been successfully developed and implemented through partnerships with philanthropic entities, increasing access to this essential medication. We anticipate an even broader global health impact when applying this model to other active ingredients.

Wacker-type reaction has been considered as an effective industrially viable route for oxidation of various organic compounds since 1970s [1]. Products of these processes, such as aldehydes and ketones are extremely valuable in fine chemicals industry [2]. Despite the historical success of these reactions, there hasn’t been many studies in terms improving their processes throughput, and particularly the attributed Palladium catalyst efficiency. During the past decade, oxidation of organic compounds via electrocatalytic oxidation has provided a valuable opportunity to increase the reaction efficiency as well as tuning the metallic catalyst specifically designed for these processes [3]. Electrochemistry is a well-known method used for a multitude of purposes ranging from renewable energy production [4], corrosion protection [5], and organic syntheses [3]. This method has been used in large scale production of different metal oxides, commodity chemicals and active pharmaceutical ingredients (e.g. acetone, and cephalosporin, respectively) [6]. However, the true potential of this configuration for organic synthesis is yet to be discovered. The recent reports on electrochemical Wacker oxidation of olefins as model organic substrates has shown that through this process modification, a higher yield compared to traditional batch configuration can be achieved [3]. Nonetheless, the effect of catalyst tuning and property optimization on electrochemical Wacker oxidation is a critical component towards process intensification. Solid-supported catalysis has been found to be one of the most successful methods to improve upon traditional homogeneously catalyzed reactions [7]. During this catalyst-preparation method, metallic particles of catalyst are immobilized on the surface of a support capable of high charge transfer (e.g. graphene [8]). Hence, the redox reactions occurring during the catalytic cycle of the metal particles are improved by faster and more efficient electrical charge transfer through the support. One of the major drawbacks of the electrochemical approach for Wacker-type reactions is the lack of control over regioselectivity of olefin oxidation. Therefore, a mixture of two different products (aldehyde and ketone) (Figure 1) is often obtained. It has been shown that by promoting an anodic oxidation or cathodic reduction of catalyst, a certain regioselectivity can be promoted [9]. Thus, the type of product (aldehyde or ketone) can be controlled. Figure 1 Regioselective Wacker-type electrocatalytic oxidation of terminal olefins to ketone (top) and aldehyde (bottom) In this study, a palladium on graphene nanoplatelet solid-supported catalyst was prepared via an all-aqueous ascorbic acid-mediated chemical reduction process for Wacker-type electrochemical oxidation of 1-octene as a model substrate. During the process optimization turn over frequency (TOF) of the prepared electrocatalyst compared to conventional homogeneous PdCl­2 [9] and solid-supported Pd on carbon nanotube [3] catalysts was improved by approximately 110 and 50 time fold, respectively. Nevertheless, through controlling the promoted half-cell reaction, oxidation or reduction, the regioselectivity of the reaction was controlled where aldehyde and ketone products were successfully prepared with optimal selectivity. Higher activity of prepared catalysts due to improved charge transfer via graphene as well as improved control over anodic oxidation through cell-type alternation are thought to be the governing factors in such improved yield and regioselectivity. References Michel, B.W., L.D. Steffens, and M.S. Sigman, The Wacker Oxidation. 2014, Wiley. Calter, M., Palladium Reagents and Catalysts: Innovations in Organic Synthesis By Jiro Tsuji (Okayama University of Science). John Wiley and Sons, New York, NY. 1995. xiv + 560 pp. 15 × 22.5 cm. ISBN 0-471-95483-7. Journal of Natural Products, 1996. 59(12): p. 1215-1215. Donck, S., et al., Tsuji–Wacker Oxidation of Terminal Olefins using a Palladium–Carbon Nanotube Nanohybrid. ChemCatChem, 2015. 7(15): p. 2318-2322. Ghobadi, S., et al., Green Composite Papers via Use of Natural Binders and Graphene for PEM Fuel Cell Electrodes. ACS Sustainable Chemistry & Engineering, 2017. 5(9): p. 8407-8415. Zhang, H., et al., Simultaneously Harvesting Thermal and Mechanical Energies based on Flexible Hybrid Nanogenerator for Self-Powered Cathodic Protection. ACS Applied Materials & Interfaces, 2015. 7(51): p. 28142-28147. Cardoso, D.S.P., et al., Organic Electrosynthesis: From Laboratorial Practice to Industrial Applications. Organic Process Research & Development, 2017. 21(9): p. 1213-1226. Yang, Y., et al., Three dimensional composites of graphene as supports in Pd-catalyzed synthetic applications. Reaction Chemistry & Engineering, 2018. Siamaki, A.R., et al., Microwave-assisted synthesis of palladium nanoparticles supported on graphene: A highly active and recyclable catalyst for carbon–carbon cross-coupling reactions. Journal of Catalysis, 2011. 279(1): p. 1-11. Mitsudo, K., et al., Electrochemical Generation of Cationic Pd Catalysts and Application to Pd/TEMPO Double-Mediatory Electrooxidative Wacker-Type Reactions. Journal of the American Chemical Society, 2007. 129(8): p. 2246-2247. Figure 1

Ciprofloxacin is a broad-spectrum antibiotic that is recognized as one of the World Health Organization’s Essential Medicines. It is particularly effective in the treatment of Gram-negative bacterial infections associated with urinary, respiratory, and gastrointestinal tract infections. A streamlined and high yielding continuous synthesis of ciprofloxacin has been developed, which employs a chemoselective C-acylation step that precludes the need for intermediate isolations, extractions, or purifications. The end-to-end process has a residence time of 4.7 min with a 15.8 g/h throughput at laboratory scale and an overall isolated yield of 83%.

The application of flow reactors in multiphase catalytic reactions represents a promising approach for enhancing the efficiency of this important class of chemical reactions. We developed a simple approach to improve the reactor productivity of multiphase catalytic reactions performed using a flow chemistry unit with a packed bed reactor. Specifically, a tube-in-tube membrane contactor (sparger) integrated in-line with the flow reactor has been successfully applied to the aerobic oxidation of benzyl alcohol to benzaldehyde utilizing a heterogeneous palladium catalyst in the packed bed. We examined the effect of sparger hydrodynamics on reactor productivity quantified by space time yield (STY). Implementation of the sparger, versus segmented flow achieved with the built in gas dosing module (1) increased reactor productivity 4-fold quantified by space time yield while maintaining high selectivity and (2) improved process safety as demonstrated by lower effective operating pressures.

Development of efficient and cost-effective manufacturing routes towards HIV active pharmaceutical ingredients (APIs) is essential to ensure their global, affordable access. Continuous pharmaceutical manufacturing (CPM) is a new production paradigm for the pharmaceutical industry, whose potential for enhanced efficiency and economic viability over currently implemented batch protocols offers promise for improving HIV API production. Nevirapine is a widely-prescribed HIV API, whose continuous flow synthesis was recently demonstrated. This paper presents technoeconomic optimisation of nevirapine CPM, including the continuous flow synthesis and a conceptual continuous crystallisation. Arrhenius law parameter estimation from published reaction kinetic data allows explicit modelling of the temperature-dependence of reaction performance and an experimentally validated aqueous API solubility computation method is used to model crystallisation processes. A nonlinear optimisation problem for cost minimisation is formulated for comparative evaluation of different plant designs. Higher reactor temperatures are favoured for CPM total cost minimisation, while lower pH (less neutralising agent) is required to attain the desired plant capacities for cost optimal configurations compared to batch crystallisation designs. Suitable E-factors for pharmaceutical manufacturing are attained when higher solvent recoveries are assumed. Implementing CPM designs significantly lowers the nevirapine cost of goods towards reducing the price of societally- mportant HIV medicines.

A molecular rotational resonance (MRR) spectrometer designed to monitor the product composition of an asymmetric continuous flow reaction online is presented. The MRR technique is highly sensitive to small changes in molecular structure and, as such, is capable of rapidly quantifying isomers as well as other impurities in a complex mixture, without chromatographic separation or chemometrics. The spectrometer in this study operates by automatically drawing a portion of the reaction solution into a reservoir, volatizing it by heating, and measuring the highly resolved MRR spectra of each of the components of interest in order to determine their relative quantity in the mixture. The reaction under study was the hydrogenation of artemisinic acid, an intermediate step in the semisynthesis of the antimalarial drug artemisinin. Four analytes were characterized in each measurement: the starting material, the product, a diastereomer of the product, and an overreduction byproduct that was not directly quantifiable by either HPLC or NMR methods. The MRR instrument has a measurement cycle time of approximately 17 min for this analysis and can run for several hours without any user interaction.

[Image: see text] Nearly 10 years ago, Frank Gupton and I had a chance encounter where we learned that we both had interest in creating efficient routes to generic medicines. Lucky for me, Frank and I began mentoring each other—Frank teaching me wisdom gained from 30 years in industry and I sharing what I knew about the academic world. As some who know Frank will understand, his lessons in some cases seem devilishly obvious and should be chanted daily like a zen koan while others are subtle and complex, requiring many years of reflection. Frank was asked by OPR&D to offer these lessons in a condensed form so that others might learn what I have. Frank and I decided that a transcript of our many conversations condensed into one document might do the trick.

A Rh-catalysed asymmetric conjugate addition of aryl boronic acids to β-substituted nitroalkenes was developed employing a P-chiral P-alkene hybrid bidentate ligand with enantioselectivities of up to 94:6 er. DFT modelling of the transition state for the addition reaction was consistent with our previous model for stereocontrol employing this family of chiral ligands. Application of the β-chiral nitroalkanes was demonstrated in the intramolecular Buchwald–Hartwig amination and aminocarbonylation to provide 5- and 6-membered chiral heterocycles.

Continuous flow synthesis is an essential route towards high throughput manufacturing of fine chemical and pharmaceutical products. The mentioned chemistries are often catalyzed by solid-supported catalysts via packed beds which are characterized by multiple issues such as high pressure-drops, micro channeling through the bed, and leaching of the metallic catalyst into the product stream. These issues lower the overall process efficiency. Three dimensional (3D) structures, known as monoliths, with high porosity and mechanical robustness, offer the ideal properties to be used macroscopic supports for metallic catalyst particles. This approach has shown to alleviate several known issues with catalyst packed beds effectively. Herein centimeter-scale monolithic catalysts of palladium (Pd)-decorated, covalently-bonded graphene oxide (GO) layers have been prepared via a completely aqueous, one-pot system. These monolithic composite structures were designed for Suzuki cross-coupling reactions in flow. As highly engineered materials, monoliths’ properties such as oxygen content and Pd catalyst ionic species were tuned via microwave irradiation and ethanol vapor reduction treatments. The optimal monolithic catalysts showed over 5 h of operational longevity in flow, which was 300% higher than the conventional Pd on GO catalyst packed beds. As a proof of concept, the monolithic catalyst was successfully used as a model structure for nondestructive X-ray CT-scan elemental and porosity mapping in the centimeter scale.

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.

Herein we report the development of the first graphene-supported platinum catalyst that has demonstrated exceptional catalytic activity and stability for hydrosilylation reactions of olefins (TOF 4.8 × 106 h−1, TON = 9.4 × 106). The catalyst also exhibited functional group tolerance over a broad range of industrially relevant substrates with minimal metal leaching. In addition, the catalyst system was successfully translated into a packed bed platform for continuous hydrosilylation reactions.

There are several crucial issues that need to be addressed in the field of applied catalysis. These issues are not only related to harmful environmental impact but also include process safety concerns, mass and heat transfer limitations, selectivity, high pressure, optimizing reaction conditions, scale-up issues, reproducibility, process reliability, and catalyst deactivation and recovery. Many of these issues could be solved by adopting the concept of micro-reaction technology and flow chemistry in the applied catalysis field. A microwave assisted reduction technique has been used to prepare well dispersed, highly active Pd/Fe3O4 nanoparticles supported on reduced graphene oxide nanosheets (Pd-Fe3O4/RGO), which act as a unique catalyst for Suzuki cross coupling reactions due to the uniform dispersion of palladium nanoparticles throughout the surface of the magnetite - RGO support. The Pd-Fe3O4/RGO nanoparticles have been shown to exhibit extremely high catalytic activity for Suzuki cross coupling reactions under both batch and continuous reaction conditions. This paper reported a reliable method for Suzuki cross-coupling reaction of 4-bromobenzaldehyde using magnetically recyclable Pd/Fe3O4 nanoparticles supported on RGO nanosheets in a microfluidic-based high throughput flow reactor. Organic synthesis can be performed under high pressure and temperature by using a stainless steel micro tubular flow reactor under continuous flow reaction conditions. Optimizing the reaction conditions was performed via changing several parameters including temperature, pressure, and flow rate. Generally, a scalable flow technique by optimizing the reaction parameters under high-temperature and continuous reaction conditions could be successfully developed.

An efficient, sustainable, and continuous method for the preparation of graphene supported palladium nanoparticles (Pd/G) has been developed using microwave irradiation as a heating source for the metal deposition process. The Pd/G produced from this method was effective in Suzuki-Miyaura cross-coupling reactions with a broad range of substrates. When incorporated into a packed bed flow reactor, this ligand free catalyst system continued to demonstrate high reaction conversions with limited catalyst leaching in the reaction mixture (347 ppb palladium).

Herein, we report a facile and efficient one-step method for the synthesis of highly active, Pd/Fe3O4 nanoparticles supported on graphene nanosheets (Pd/Fe3O4/G) that exhibit excellent catalytic activity for Suzuki and Heck coupling reactions and that can be magnetically separated from the reaction mixture and recycled multiple times without loss of catalytic activity. The synthesis approach is based on the Microwave (MW)-assisted reduction of palladium and ferric nitrates in the presence of graphene oxide (GO) nanosheets using hydrazine hydrate as the reducing agent. The results provide a fundamental understanding of the system variables by comparing the catalytic activity and recyclability of four different catalysts with different properties. The most active and recyclable catalyst contains 7.6 wt% Pd nanoparticles with 4-6 nm diameters in Pd(0) oxidation state well-dispersed with 30 wt% Fe3O4 nanoparticles with 12–16 nm diameters on highly reduced GO containing a C/O ratio of 8.1. These combined properties produce remarkable catalytic activity for Suzuki cross coupling reactions under MW reaction conditions with an extremely high turnover number (TON) of 9250 and turn over frequency (TOF) of 111,000 h−1 at 80 °C. The magnetic properties imparted by the Fe3O4 component of the catalyst enables the catalyst to be easily isolated and recycled, thus greatly simplifying the ability to purify the reaction products and increasing the economic value of the catalyst. The utility of these magnetic catalysts towards Suzuki and Heck cross coupling reactions with a variety of functionalized substrates was also demonstrated.