Abstract
Laboratory Automation and High-Throughput Chemistry
Solution-Phase Parallel Synthesis of S-DABO Analogues
A simple and straightforward methodology for the parallel, solution-phase synthesis of a new series of S-DABO derivatives, bearing aromatic substitu-ents at the C2 and C6 positions, is shared by Andrea Togninelli et al. (Tetrahedron Letters 1,
Starting from potassium ethyl malonates, thio-uracil intermediates are prepared through parallel synthesis and isolated as pure products by simple extraction with ethyl acetate. Selective S-benzylation of the thiouracil intermediates is achieved in a few minutes under microwave irradiation to give the title compounds 6-arylmethyl-2-(arylme-thylthio)-5-methylpyrimidin-4(3H)-ones, which are oxidized in parallel to the corresponding sulfones.
Some of the new compounds show potent inhibitory activity against wild type enzyme HIV-1 RT without showing cytotoxicity. The entire methodology illustrates the combinatorial potential for synthesis of large compound libraries.
Ionic Liquid-Phase Technology Supported the Three-Component Synthesis of Hantzsch 1,4-Dihydropyridines and Biginelli 3,4-Dihydropyrimidin-2(l H)-Ones Under Microwave Dielectric Heating
A microwave dielectric heating-assisted liquid-phase synthesis of 1,4-dihydropyridines, 3,4-dihydropyrimi-din-2(l H)-ones, pyridines, and polyhydroquinolines using task-specific ionic liquid as a soluble support is described by Jean-Christophe Legeay et al. (Tetrahedron,
The efficiency of the ionic liquid-phase organic synthesis methodology is demonstrated by using a one-pot three-component condensation. The structure of the intermediates in each step can be verified routinely by spectroscopic analysis, and after cleavage, the target compounds were obtained in good yields and high purities.
The specific advantages of the ionic liquid-phase organic synthesis (IoLiPOS) methodology for performing reactions under microwave irradiation in homogeneous solution without solvent are higher loading capacity of the ionic liquid phase (ILP) (because only a molar equivalent of the low-molecular weight ionic liquid phase is used); simple purification of the stable intermediates in the sequence by washings with the appropriate solvent; and easy verification of structure by routine spectroscopic methods at each step. The final cleavage is possible by transesterification, saponification/acidification, or ester aminolysis.
Michael Reactions Carried Out Using a Bench-Top Flow System
The Michael reaction between methyl 1-oxoin-dan-2-carboxylate and methyl vinyl ketone is achieved successfully by P. Hodge et al. by pumping solutions of the reactants in toluene through a fluid bed of Amberlyst A21 at 50 °C. The use of a fluid bed reactor is attractive as it allows gel-type beads (i.e. the type of bead used in most studies of polymer-supported organic reactions) to be used satisfactorily in a flow system. When polymer-supported cinchonidine is used in place of Amberlyst A21, the Michael product is obtained in high yield with a moderate enantiomeric excess of 51%, which is comparable to that achieved when the reaction is catalyzed by cinchonidine itself (Org. Biomol. Chem.
A Simple and Inexpensive Device for Removal of Solvent from a Large Collection of Sample Tubes
In most high-throughput chemical syntheses, it is necessary to remove solvent from a large number of containers, such as glass tubes or vials. Solvent removal from a collection of containers is typically carried out with a vacuum centrifuge in which centrifugal force is used to prevent mechanical sample loss due to violent solvent boiling. M. H. Gelb and B. P. Holm describe a simple alternative to a vacuum centrifuge that can be assembled for less than a few thousand dollars, and is capable of removing solvent from several hundred tubes. The new device consists of a stainless steel chamber with an O-ring-sealed acrylic lid. The side of the box is fitted with a vacuum port and a four-electrode feed-through. Inside the box, at its base, is an acrylic heat insulator sheet and a layer of aluminum honeycomb, which serves as a heat-conducting rack for hundreds of test tubes. The key innovation of this vacuum box device is the use of a chemically inert, microporous cap that provides a barrier to mechanical loss of solvent due to bumping, but allows evaporative loss of gaseous solvent (J. Comb. Chem.
Microwave-Assisted Parallel Synthesis of a 14-Helical β-Peptide Library
To facilitate the preparation of β-peptide libraries in parallel, J. K. Murray and S. H. Gellman adapt reaction conditions for the solid-phase synthesis of 14-helical β-peptides for use in a multimode microwave reactor. The low-temperature/ pressure requirements of microwave-assisted β-peptide synthesis are found to be compatible with multiwell filter plates composed of polypropylene. Microwave heating of the 96-well plate is sufficiently homogeneous to allow the rapid preparation of a β-peptide library in acceptable purity (J. Comb. Chem.
Microwave-Promoted Aminocarbonylations of Aryl Chlorides Using Mo(CO)6 as a Solid Carbon Monoxide Source
M. Larhed and O. Lagerlund present a robust and straightforward palladium-catalyzed aminocarbonylation protocol that rapidly transforms aryl chlorides into a variety of benzamides. Noteworthy features of this microwave-promoted method include the use of commercially available [(t-Bu)3PH]BF4 to activate the strong Ar-C1 bond; impressive results with sluggish aniline and tert-butylamine reactants; tolerance of air; short reaction times; and use of Mo(CO)6 as a solid carbon monoxide source. This procedure is a convenient and versatile alternative for small-scale carbonylative applications relative to existing methods starting from aryl bromides or aryl iodides (J. Comb. Chem.
A Fluorous Capping Strategy for Fmoc-Based Automated and Manual Solid-Phase Peptide Synthesis
According to a report by K. Kumar and V. Montanari, peptides synthesized via standardized Fmoc protocols with commercial automated synthesizers can be purified from deletion products by simple centrifugation of aqueous solutions. The deletion products are capped with fluorous trivalent iodonium salts. At the end of the synthesis, the crude peptide is dissolved in water and centrifuged, and the deletion products precipitate leaving only the full-length peptide in solution. Protocols for generalized use of this strategy are reported (Eur. J. Org. Chem.
Microfluidic Chip Techonology and Microreactor Techonology
Optimal Operation of Semibatch Processes with a Single Reaction
Batch and semibatch processes are important to the fine chemicals and pharmaceutical industry. Since the production volumes are low, batch plants are typically multiproduct facilities in which several different products share the same piece of equipment.
The following characteristics are typical for a large number of batch industries: most reactions are liquid-phase reactions, and while the final product is the result of several synthesis steps, each synthesis step is a new batch operation that typically requires different reactants and solvents, and has different batch operating conditions. Some of these steps are conducted with the same equipment, whereas others use different batch equipment. Normally, batch chemical reactors are operated at constant temperature and, if semibatch, with a constant feed rate for the reactant(s). The operating temperature and feed rate are determined heuristically, typically by doing a few laboratory experiments. A recipe, which consists of a series of time-related steps, is followed in an open-loop fashion for industrial scale batch processes.
Batch-to-batch variation in product yield and quality is observed in a number of batch reactors. Some measurements, such as temperature, pH, viscosity, and pressure, are captured online. In addition, periodic samples are taken for measuring concentration offline. These data are typically used for determining the proper operation of the batch. This information is not used for making online adjustments to the operating strategy.
Srinivas Palanki and Jyothy Vemur offer a methodology for determining the optimal temperature and the optimal feeding policy for a semibatch reactor. The end-point optimization problem is mathematically formulated, and a solution is presented. The methodology illustrates that the optimal operating strategy depends on the structure of the reaction kinetics, which strongly influences whether the optimal inputs should be at their constraints (upper or lower bounds) or somewhere in between. After a simplification of the analytical expressions for elementary irreversible and reversible reactions, the methodology is illustrated via simulation of three semibatch reactors (Int. J. Chem. React. Eng.
Thermal Management in Catalytic Microreactors
The assumption that a microreactor is thermally uniform simply is not correct. The experimental results reported by D. G. Norton et al. demonstrate that thermal uniformity of microreactor systems is highly dependent on, and can be controlled by, selection of reactor materials, geometry, the reaction sets involved, feed composition, and flow rate. The specific design of a microreactor can therefore be tailored according to its particular application. For mildly exothermic or endothermic reactions, it may be possible to achieve the desired level of thermal uniformity easily, but for highly exothermic or endothermic reactions, appropriate attention must be paid to the thermal bandwidth of the system to determine whether it is adequate.
The authors describe a catalytic microreactor with “tunable” wall thermal resistance (conductivity and thickness). To manipulate the thermal conductivity of the walls, metallic plates (thermal spreaders) of different thermal conductivities and thicknesses can be installed on the reactor walls. Changing the thermal properties of the walls has a substantial effect on reactor thermal uniformity, but only a slight effect on conversion and extinction limits. Further experiments show that the flow rate and feed composition for a reactor have a large effect on the operating temperature, but only a moderate effect on thermal uniformity. An analysis of the overall energy balance of this system indicates that more than 50% of the generated heat is lost to the surroundings before the fluid exits the reactor, although this energy exchange becomes less efficient as the flow rate increases (Ind. Eng. Chem. Res.
Rapid Formation of Amides via Carbonylative Coupling Reactions Using a Microfluidic Device
Carbonylative cross-coupling reactions of arylhalides to form secondary amides are rapidly carried out by P. W. Miller et al. on a glass-fabricated microchip. The authors claim that this is the first time a microstructured device has been used to perform a gas-liquid carbonylation reaction. The total yields of products obtained are good considering the very short residence times (<2 min) for these conventionally slow reactions. When compared to traditional batch scale reactions, the gains in yields obtained by the microreactor in this time are significant, and demonstrate a distinct advantage in using such methods (Chem. Commun.
Continuous-Flow High-Pressure Hydrogenation Reactor for Optimization and High-Throughput Synthesis
R. V. Jones et al. report a novel continuous-flow hydrogenation reactor, and its integration with a liquid handler to generate a fully automated high-throughput hydrogenation system for library synthesis. The reactor, named the H-Cube, combines endogenous hydrogen generation from the electrolysis of water with a continuous flow-through system. The system achieves significant advances over current batch hydrogenation reactors in terms of safety, reaction validation efficiency, and rates of reaction. The hydrogenation process is described along with a detailed description of the device's main parts. The reduction of a series of functional groups, varying in difficulty up to 70 °C and 70 bar are also described. The paper concludes with the integration of the device into an automated liquid handler followed by the reduction of a nitro compound in a high-throughput manner. The system is fully automated, and can conduct five reactions in the time it takes to perform and workup one reaction manually on a standard batch reactor (J. Comb. Chem.
Solving the Clogging Problem: Precipitate-Forming Reactions in Flow
The clogging of channels that occurs upon precipitate formation is a common concern for microreactor chemistry. Fluid fields generated in microfluidic devices can control reagent mixing, and allow the formation of an emulsion upon the collision of two immiscible liquids. D. T. McQuade et al. report that a simple microfluidic device can replicate these flow phenomena. Their device is composed of syringe pumps, syringes, needles, and commercially available laboratory tubing. By using disperse-phase droplets as individual reactors, they confine the solid products to these droplets, thus keeping them away from the tubing walls and avoiding clogged channels. To demonstrate the suitability of their device for the synthesis of solid particles, the authors choose a simple system in which aqueous reagents combine to form a solid precipitate — mixing. As demonstrated by the synthesis of indigo as a precipitate, by performing these reactions in a monodisperse droplet flow, the solid particles are effectively isolated from the walls of the tubing. It is claimed that this device not only allows the practical synthesis of solids in microfluidic devices, but also retains the advantages of traditional microreactors (Angew. Chem.
Microarrays of Synthetic Heparin Oligosaccharides
Carbohydrate microarrays are a powerful platform for screening interactions involving these molecules in a high-throughput manner. The chip-based format offers important advantages over classic methods, such as the ability to screen several thousand binding events on a single glass slide, and the miniscule amounts of both analyte and ligand required for one experiment. P. H. Seeberger et al. present a new method for the preparation of microarrays displaying synthetic heparin oligosaccharides derived by solution and solid-phase assembly methods. Strategic placement of an orthogonally protected amine linker is key to the success of the array construction. The potential of the new methodology is demonstrated by probing the carbohydrate affinity of two heparin-binding proteins, FGF-1 and FGF-2, that are implicated in the development and differentiation of several tumors (J. Am. Chem. Soc.
High-Throughput Bioscreening and Assay Development
Genome-Wide Analysis of Human Kinases in Clathrin- and Caveolae/Raft-Mediated Endocytosis
A high-throughput RNA interference assay with automated image analysis on two high-content screening instruments (Opera TEHS by Evotec and ArrayScan VTI by Cellomics) is offered by Lucas Pelkmans (Nature,
A Small Molecule Agonist of the Wnt Signaling Pathway
Combinatorial small molecule libraries (100.000 heterocyclic compounds) are screened for modulators of the Wnt signalling pathway by Liu Jun (Angew. Chem.
Exploiting High-Throughput Ion Channel Screening Technologies in integrated Drug Discovery
Ion channels are currently a field of major interest in drug discovery. Although existing drugs that modulate channel function already represent a key class of pharmaceutical agents, future ion channel drugs could help to treat an even wider variety of diseases. Despite their disease relevance, ion channels remain largely underexploited as drug targets, mainly due to the absence of screening technologies that provide the throughput and quality of data required to support medicinal chemistry. Currently, ion channel drug discovery is focused on the need to identify compounds that can provide tractable starting points for medicinal chemistry.
Advances in laboratory automation create significant opportunities for increasing screening throughput for ion channel assays, but careful assay configuration to model drug-target interactions in a physiological manner remains an essential consideration. Ion channel screening platforms are described in a review by J. M. Treherne, and the author provides some insight into the variety of technologies available for screening, and some of their inherent advantages and limitations (Curr. Pharm. Des.
Activity-Based High-Throughput Profiling of Metalloprotease inhibitors Using Small Molecule Microarrays
S. Q. Yao et al. describe a high-throughput nanodroplet small molecule microarray (SMM) method that enables quick and cost-efficient identification of potent inhibitors of metallo-proteases in an activity-dependent manner. Because this method is potentially extendable to other enzymes, it could become a new tool for the fingerprinting or profiling of inhibitors against certain enzymes. It enables potent and highly selective inhibitors to be directly identified without the need of time-consuming hit validation. The utility of this method is demonstrated with a 400-member hydroxamate peptide library. Before the technique can be applied for routine high-throughput screening of enzyme inhibitors, a key issue must be addressed. With the current method, inhibitor/enzyme mixtures are individually prepared before spotting, and the microarray is processed immediately postspotting. This inevitably limits the throughput of the screening, especially with multiple enzymes (Chem. Commun.
Lims and Process Informatics
The Future of Process Control Systems
“Process control systems” was the main topic of the Annual NAMUR Conference, presented November 9-11, 2005, in Lahnstein, Germany. Process control systems (PCS) are the central point in information interchange in a technical system. NAMUR speakers discussed today's requirements for PCS, based on the growing requirements of users, and the increasing complexity of technical systems. Today, users require maximized availability, reliability, scalability, and continuity.
Internet-Based SCADA
The Internet offers many new possibilities for the application field of process control and automation. Features like remote accessibility and information sharing, regardless of the operating system or programming language used, could not be implemented in a traditional control system without enormous effort and cost. The authors define limitations in terms of functionality, performance, security and reliability. Internet-based Supervisory Control and Data Acquisition (SCADA) systems are generally less secure than traditional SCADA systems because of their openness and remote connectivity. With standard Web security methods (encryption etc.), the security of an Internet-based SCADA system can be managed.
An Internet-based SCADA system typically uses Web technologies, where a Web server stores information, and a Web browser reads and writes the information. The main advantage of implementing an Internet-based SCADA system is its standards-based architecture, which uses existing computer and communication technologies to achieve optimum system functionality at a minimum cost. Internet-based SCADA systems are generally easy to operate, because the browser navigation tools are familiar to anyone who uses the Internet. Therefore, training requirements are fewer, and faster learning curves are possible.
XML is slowly finding its way into industrial automation, and is replacing many of the proprietary vendor protocols. XML is an efficient and effective way of storing and sharing information. A wide range of applications easily can share data in a controlled and consistent manner.
Web integration is another application field for Web technologies within process automation. Standard Web technologies can be used to integrate different distributed subsystems (IEE Computing and Control Engineering,