The Micron-Droplet-Confined Continuous-Flow Synthesis of Freestanding High-Entropy-Alloy Nanoparticles by Flame Spray Pyrolysis.

Alloying multiple immiscible elements into a nanoparticle with single-phase solid solution structure (high-entropy-alloy nanoparticles, HEA-NPs) merits great potential. To date, various kinds of synthesis techniques of HEA-NPs are developed; however, a continuous-flow synthesis of freestanding HEA-NPs remains a challenge. Here a micron-droplet-confined strategy by flame spray pyrolysis (FSP) to achieve the continuous-flow synthesis of freestanding HEA-NPs, is proposed. The continuous precursor solution undergoes gas shearing and micro-explosion to form nano droplets which act as the micron-droplet-confined reactors. The ultrafast evolution (<5 ms) from droplets to <10 nm nanoparticles of binary to septenary alloys is achieved through thermodynamic and kinetic control (high temperature and ultrafast colling). Among them, the AuPtPdRuIr HEA-NPs exhibit excellent electrocatalytic performance for alkaline hydrogen evolution reaction with 23 mV overpotential to achieve 10 mA cm-2, which is twofold better than that of the commercial Pt/C. It is anticipated that the continuous-flow synthesis by FSP can introduce a new way for the continuous synthesis of freestanding HEA-NP with a high productivity rate.

Solid-Acid Catalyzed Continuous-Flow Aminolysis of Epoxides.

We report a solid-acid catalyzed aminolysis of epoxides under continuous-flow conditions. A titania-zirconia supported molybdenum oxide catalyst demonstrated exceptional substrate compatibility, enabling the synthesis of ß-amino alcohols in excellent yields with high catalyst durability. Characterization of the catalyst revealed the crucial role of the titania-zirconia ratio in optimizing its performance. Furthermore, this method was applied to the efficient, sequential-flow synthesis of a rivaroxaban intermediate (an oral anticoagulant and the first direct factor Xa inhibitor), combining a hydrogenation step with the aminolysis reaction without the need for intermediate isolation.

Continuous-Flow Synthesis of (R)-Tamsulosin Utilizing Sequential Heterogeneous Catalysis.

We describe the continuous-flow synthesis of (R)-tamsulosin, a blockbuster therapeutic drug employed for dysuria associated with urinary stones and benign prostatic hyperplasia, by utilizing sequential heterogeneous catalysis. Two heterogeneous catalysts have been developed for the synthesis, and the key step involves reductive amination of nitriles using dimethylpolysilane-modified Pd on activated carbon/calcium phosphate. Overall, (R)-tamsulosin was obtained in 60 % yield and 64 % ee (99 % ee after recrystallization) in a flow stream through four catalytic transformations without the need for the isolation or purification of any intermediates or byproduct.

Multi-Step Continuous-Flow Organic Synthesis: Opportunities and Challenges.

Continuous-flow multi-step synthesis takes the advantages of microchannel flow chemistry and may transform the conventional multi-step organic synthesis by using integrated synthetic systems. To realize the goal, however, innovative chemical methods and techniques are urgently required to meet the significant remaining challenges. In the past few years, by using green reactions, telescoped chemical design, and/or novel in-line separation techniques, major and rapid advancement has been made in this direction. This minireview summarizes the most recent reports (2017-2020) on continuous-flow synthesis of functional molecules. Notably, several complex active pharmaceutical ingredients (APIs) have been prepared by the continuous-flow approach. Key technologies to the successes and remaining challenges are discussed. These results exemplified the feasibility of using modern continuous-flow chemistry for complex synthetic targets, and bode well for the future development of integrated, automated artificial synthetic systems.

Stereoretentive N-Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous-Flow System.

The N-arylation of chiral amino acid esters with minimal racemization is a challenging transformation because of the sensitivity of the α-stereocenter. A versatile synthetic method was developed to prepare N-arylated amino acid esters using cyclohexanones as aryl sources under continuous-flow conditions. The designed flow system, which consists of a coil reactor and a packed-bed reactor containing a Pd(OH)2 /C catalyst, efficiently afforded the desired N-arylated amino acids without significant racemization, accompanied by only small amounts of easily removable co-products (i. e., H2 O and alkanes). The efficiency and robustness of this method allowed for the continuous synthesis of the desired product in very high yield and enantiopurity with high space-time yield (74.1 g L-1 h-1 ) and turnover frequency (5.9 h-1 ) for at least 3 days.

Continuous Flow Synthesis of [Au(NHC)(Aryl)] (NHC=N-Heterocyclic Carbene) Complexes.

The use of weak and inexpensive bases has recently opened promising perspectives towards the simpler and more sustainable synthesis of Au(I)-aryl complexes with valuable applications in catalysis, medicinal chemistry, and materials science. In recent years, continuous manufacturing has shown to be a reliable partner in establishing sustainable and controlled process scalability. Herein, the first continuous flow synthesis of a range of Au(I)-aryl starting from widely available boronic acids and various [Au(NHC)Cl] (NHC=N-heterocyclic carbene) complexes in unprecedentedly short reaction times and high yields is reported. Successful synthesis of previously non- or poorly accessible complexes exposed fascinating reactivity patterns. Via a gram-scale synthesis, convenient process scalability of the developed protocol was showcased.

Continuous Synthesis of Aryl Amines from Phenols Utilizing Integrated Packed-Bed Flow Systems.

Aryl amines are important pharmaceutical intermediates among other numerous applications. Herein, an environmentally benign route and novel approach to aryl amine synthesis using dehydrative amination of phenols with amines and styrene under continuous-flow conditions was developed. Inexpensive and readily available phenols were efficiently converted into the corresponding aryl amines, with small amounts of easily removable co-products (i.e., H2 O and alkanes), in multistep continuous-flow reactors in the presence of heterogeneous Pd catalysts. The high product selectivity and functional-group tolerance of this method allowed aryl amines with diverse functional groups to be selectively obtained in high yields over a continuous operation time of one week.

Continuous Flow Synthesis of ACE Inhibitors From N-Substituted l-Alanine Derivatives.

A strategy for the continuous flow synthesis of angiotensin converting enzyme (ACE) inhibitors is described. An optimization effort guided by in situ IR analysis resulted in a general amide coupling approach facilitated by N-carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three-step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88 % yield with throughputs in the range of ≈0.5 g h-1 , all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization (WHO) essential medicine, in an industrially relevant flow platform that scaled throughput to ≈1 g h-1 .

Continuous flow synthesis of ZSM-5 zeolite on the order of seconds.

The hydrothermal synthesis of zeolites carried out in batch reactors takes a time so long (typically, on the order of days) that the crystallization of zeolites has long been believed to be very slow in nature. We herein present a synthetic process for ZSM-5, an industrially important zeolite, on the order of seconds in a continuous flow reactor using pressurized hot water as a heating medium. Direct mixing of a well-tuned precursor (90 °C) with the pressurized water preheated to extremely high temperature (370 °C) in the millimeter-sized continuous flow reactor resulted in immediate heating to high temperatures (240-300 °C); consequently, the crystallization of ZSM-5 in a seed-free system proceeded to completion within tens of or even several seconds. These results indicate that the crystallization of zeolites can complete in a period on the order of seconds. The subtle design combining a continuous flow reactor with pressurized hot water can greatly facilitate the mass production of zeolites in the future.

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology.

Tamiflu is one of the most effective anti-influenza drugs, which is currently manufactured by Hoffmann-La Roche from shikimic acid. Owing to its importance, more than 60 synthetic routes have been developed to date, however, most of the synthetic routes utilise the potentially hazardous azide chemistry making them not green, thus not amenable to easy scale up. Consequently, this study exclusively demonstrated safe and efficient handling of potentially explosive azide chemistry involved in a proposed Tamiflu route by taking advantage of the continuous-flow technology. The azide intermediates were safely synthesised in full conversions and >89% isolated yields.

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform.

The multistep flow synthesis of complex molecules has gained momentum over the last few years. A wide range of reaction types and conditions have been integrated seamlessly on a single platform including in-line separation as well as monitoring. Beyond merely getting considered as 'flow version' of conventional 'one-pot synthesis', multistep flow synthesis has become the next generation tool for creating libraries of new molecules. Here we give a more 'engineering' look at the possibility of developing a 'unified multistep flow synthesis platform'. A detailed analysis of various scenarios is presented considering 4 different classes of drugs already reported in the literature. The possible complexities that an automated and controlled platform needs to handle are also discussed in detail. Three different design approaches are proposed: (i) one molecule at a time, (ii) many molecules at a time and (iii) cybernetic approach. Each approach would lead to the effortless integration of different synthesis stages and also at different synthesis scales. While one may expect such a platform to operate like a 'driverless car' or a 'robo chemist' or a 'transformer', in reality, such an envisaged system would be much more complex than these examples.

Conjugated Polymers Via Direct Arylation Polymerization in Continuous Flow: Minimizing the Cost and Batch-to-Batch Variations for High-Throughput Energy Conversion.

Continuous flow methods are utilized in conjunction with direct arylation polymerization (DArP) for the scaled synthesis of the roll-to-roll compatible polymer, poly[(2,5-bis(2-hexyldecyloxy)phenylene)-alt-(4,7-di(thiophen-2-yl)-benzo[c][1,2,5]thiadiazole)] (PPDTBT). PPDTBT is based on simple, inexpensive, and scalable monomers using thienyl-flanked benzothiadiazole as the acceptor, which is the first ß-unprotected substrate to be used in continuous flow via DArP, enabling critical evaluation of the suitability of this emerging synthetic method for minimizing defects and for the scaled synthesis of high-performance materials. To demonstrate the usefulness of the method, DArP-prepared PPDTBT via continuous flow synthesis is employed for the preparation of indium tin oxide (ITO)-free and flexible roll-coated solar cells to achieve a power conversion efficiency of 3.5% for 1 cm2 devices, which is comparable to the performance of PPDTBT polymerized through Stille cross coupling. These efforts demonstrate the distinct advantages of the continuous flow protocol with DArP avoiding use of toxic tin chemicals, reducing the associated costs of polymer upscaling, and minimizing batch-to-batch variations for high-quality material.

Synthesis and Utilization of Nitroalkyne Equivalents in Batch and Continuous Flow.

We report a method for overcoming the low stability of nitroalkynes through the development of nitrated vinyl silyltriflate equivalents. Because of their instability, nitroalkynes have only rarely been utilized in synthesis. The reactivity of these silyltriflates, which are prepared in situ, is exemplified by dipolar cycloaddition reactions with nitrones to give highly substituted 4-nitro-4-isoxazolines in high yields. This approach has proven general for several different alkyl and aryl substituted alkynes. In order to minimize the accumulation of potentially hazardous reaction intermediates, we have also developed a continuous flow variant of this method that is capable of carrying out the entire reaction sequence in a good yield and a short residence time.

A Unified Continuous Flow Assembly-Line Synthesis of Highly Substituted Pyrazoles and Pyrazolines.

A rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N-alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short order. Continuous flow synthesis enables the safe handling of diazoalkanes at elevated temperatures, and the use of aryl alkyne dipolarphiles under catalyst-free conditions. This assembly-line synthesis provides a flexible approach for the synthesis of agrochemicals and pharmaceuticals, as demonstrated by a four-step, telescoped synthesis of measles therapeutic, AS-136A, in a total residence time of 31.7 min (1.76 g h-1 ).

Flow Asymmetric Propargylation: Development of Continuous Processes for the Preparation of a Chiral ß-Amino Alcohol.

The development of a flow chemistry process for asymmetric propargylation using allene gas as a reagent is reported. The connected continuous process of allene dissolution, lithiation, Li-Zn transmetallation, and asymmetric propargylation provides homopropargyl ß-amino alcohol 1 with high regio- and diastereoselectivity in high yield. This flow process enables practical use of an unstable allenyllithium intermediate. The process uses the commercially available and recyclable (1S,2R)-N-pyrrolidinyl norephedrine as a ligand to promote the highly diastereoselective (32:1) propargylation. Judicious selection of mixers based on the chemistry requirement and real-time monitoring of the process using process analytical technology (PAT) enabled stable and scalable flow chemistry runs.

Continuous-Flow Microwave Synthesis of Metal-Organic Frameworks: A Highly Efficient Method for Large-Scale Production.

Metal-organic frameworks are having a tremendous impact on novel strategic applications, with prospective employment in industrially relevant processes. The development of such processes is strictly dependent on the ability to generate materials with high yield efficiency and production rate. We report a versatile and highly efficient method for synthesis of metal-organic frameworks in large quantities using continuous flow processing under microwave irradiation. Benchmark materials such as UiO-66, MIL-53(Al), and HKUST-1 were obtained with remarkable mass, space-time yields, and often using stoichiometric amounts of reactants. In the case of UiO-66 and MIL-53(Al), we attained unprecedented space-time yields far greater than those reported previously. All of the syntheses were successfully extended to multi-gram high quality products in a matter of minutes, proving the effectiveness of continuous flow microwave technology for the large scale production of metal-organic frameworks.

Hydrothermal continuous flow synthesis and exfoliation of NiCo layered double hydroxide nanosheets for enhanced oxygen evolution catalysis.

We report the controlled synthesis of NiCo layered double hydroxide (LDH) nanoplates using a newly developed high temperature high pressure hydrothermal continuous flow reactor (HCFR), which enables direct growth onto conductive substrates in high yield and, most importantly, better control of the precursor supersaturation and, thus, nanostructure morphology and size. The solution coordination chemistry of metal-ammonia complexes was utilized to synthesize well-defined NiCo LDH nanoplates directly in a single step without topochemical oxidation. The as-grown NiCo LDH nanoplates exhibit a high catalytic activity toward the oxygen evolution reaction (OER). By chemically exfoliating LDH nanoplates to thinner nanosheets, the catalytic activity can be further enhanced to yield an electrocatalytic current density of 10 mA cm(-2) at an overpotential of 367 mV and a Tafel slope of 40 mV dec(-1). Such enhancement could be due to the increased surface area and more exposed active sites. X-ray photoelectron spectroscopy (XPS) suggests the exfoliation also caused some changes in electronic structure. This work presents general strategies to controllably grow nanostructures of LDH and ternary oxide/hydroxides in general and to enhance the electrocatalytic performance of layered nanostructures by exfoliation.

Continuous-Flow Synthesis and Derivatization of Aziridines through Palladium-Catalyzed C(sp(3) )-H Activation.

A continuous-flow synthesis of aziridines by palladium-catalyzed C(sp(3) )-H activation is described. The new flow reaction could be combined with an aziridine-ring-opening reaction to give highly functionalized aliphatic amines through a consecutive process. A predictive mechanistic model was developed and used to design the C-H activation flow process and illustrates an approach towards first-principles design based on novel catalytic reactions.

The continuous flow synthesis of azos.

Azo compounds find use in many areas of science, displaying crucial properties for important applications as photoconductive organic pigments, fluorescent quenchers, paints, cosmetics, inks, and in the large and valuable dye industry. Due to the unstable intermediates, and the exothermic and fast reactions used in their synthesis, high value azo compounds are excellent candidates for continuous flow manufacturing. This comprehensive review covers the progress made to date on developing continuous flow systems for azo synthesis and reflects on the main challenges still to be addressed, including scale up, conversion, product purity, and environmental impact. The further development of integrated continuous flow processes has the potential to help tackle these challenges and deliver improved methods for azo compound generation.

Improved Chemical and Radiochemical Synthesis of Neuropeptide Y Y2 Receptor Antagonist N-Methyl-JNJ-31020028 and Preclinical Positron Emission Tomography Studies.

Neuropeptide Y (NPY) is one of the most abundant peptides in the central nervous system of mammals and is involved in several physiological processes through NPY Y1, Y2, Y4 and Y5 receptors. Of those, the Y2 receptor has particular relevance for its autoreceptor role in inhibiting the release of NPY and other neurotransmitters and for its involvement in relevant mechanisms such as feeding behaviour, cognitive processes, emotion regulation, circadian rhythms and disorders such as epilepsy and cancer. PET imaging of the Y2 receptor can provide a valuable platform to understand this receptor's functional role and evaluate its potential as a therapeutic target. In this work, we set out to refine the chemical and radiochemical synthesis of the Y2 receptor antagonist N-[11C]Me-JNJ31020028 for in vivo PET imaging studies. The non-radioactive reference compound, N-Me-JNJ-31020028, was synthesised through batch synthesis and continuous flow methodology, with 43% and 92% yields, respectively. N-[11C]Me-JNJ-31020028 was obtained with a radiochemical purity > 99%, RCY of 31% and molar activity of 156 GBq/µmol. PET imaging clearly showed the tracer's biodistribution in several areas of the mouse brain and gut where Y2 receptors are known to be expressed.