Flow Synthesis Online - March 2010
Welcome to the Flow Synthesis Online newsletter.
This publication is released bi-monthly and will showcase new applications, events, and equipment in the Flow Synthesis world.
Product News |
| R Series Now supports 2 High Temperature Reactors
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| Gilson 215 Liquid Handler Now Supported
Existing users can get a free upgrade for their Flow CommanderTM software to add this feature |
| Bigger Sample Injection Loop Loading Ports
One feedback request that a few users sent us was for bigger ports so that the sample loops could be loaded faster. So for R Series systems ordered from April 2010, the ports have been upgraded to 1mm. Sample loops can be loaded either manually or using a liquid handler (see article above). |
Vapourtec News
The new building will have a dedicated clean manufacturing area, purpose built lab facilities, and product demonstration and training area. The move should be completed by the end of Q2. |
Is it your first time ? If this is the first issue of the newsletter that you've looked at, you might like to take a look at what you've missed in some previous issues. |
Events Attendees of the following events will be able to see the latest Vapourtec Flow Chemistry equipment in action, and no doubt talk to other users. |
| RSC/SCI Symposium on Continuous Processing and Flow Chemistry. 3-4 November
This is a new event, and is surely set to become a major annual fixture on the Flow Chemistry calendar. |
| UKASF Meeting 16-17 November 2010
The U.K. Automated Synthesis Forum will hold their annual meeting at the Merck Sharpe Dohme site in Newhouse, Scotland. |
Publications These links below lead to publication host sites where subscription may be necessary for some publications. |
| A flow-based synthesis of Imatinib: the API of Gleevec
Innovative Technology Centre, Department of Chemistry, University of Cambridge, U.K A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation. An in-line solvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates. |
| A highly efficient flow reactor process for the synthesis of N-Boc-3,4-dehydro-l-proline methyl ester
Dipartimento di Scienze Farmaceutiche ‘Pietro Pratesi’, Università degli Studi di Milano, Italy The multi-step preparation of N-Boc-3,4-dehydro-l-proline methyl ester using a modular flow reactor is reported. The use of immobilised reagents and scavengers in pre-packed glass tubes allows us to obtain the pure product in 87% overall yield, 97% purity, and >98% enantiomeric excess without any additional purification step. Our flow-based protocol enables the rapid multi-gram synthesis (about 9 g/12 h) of the desired product. |
| Photodimerization of Maleic Anhydride in a Microreactor Without Clogging
The Research Association of Micro Chemical Process Technology (MCPT), Kyoto, Japan Photodimerization of maleic anhydride (MA) gives insoluble precipitated products that can be a trigger to clog a conventional microreactor. To avoid this problem, we devised a microreactor that uses liquid/gas slug flow and ultrasonication. |
| Reaction Discovery Using Microfluidic-Based Multidimensional Screening of Polycyclic Iminium Ethers
† Department of Medicinal Chemistry, and KU Center for Chemical Methodology and Library Development (KU-CMLD), The University of Kansas, USA Polycyclic iminium ethers are ambident electrophilic intermediates that react with a range of nucleophiles in a highly condition-dependent manner to afford densely functionalized lactams. In an effort to expand the scope of reactivity and assist in the generation of new chemotypes from these intermediates, several iminium ethers were subjected to reaction screening using an automated microfluidics reaction platform. Application of this approach led to the discovery of several interesting reaction pathways involving the iminium ether intermediates that will be described. |
| Phase-Transfer Catalysis in Segmented Flow in a Microchannel: Fluidic Control of Selectivity and Productivity
Jovan Jovanovi, Evgeny V. Rebrov, T. A. (Xander) Nijhuis, Volker Hessel and Jaap C. Schouten Laboratory of Chemical Reactor Engineering, Department of Chemical Engineering and Chemistry, and Institute for Complex Molecular Systems, Eindhoven University of Technology, The Netherlands Precise control over the interfacial area of aqueous and organic slugs in segmented flow in a microchannel reactor provides an attractive means to optimize the yield and productivity of a phase-transfer-catalyzed reaction. Herein, we report the selective alkylation of phenylacetonitrile to the monoalkylated product in a microchannel of 250-μm internal diameter operated in a continuous and solvent-free manner in the slug-flow regime. The conversion of phenylacetonitrile increased from 40% to 99% as a result of a 97% larger slug surface-to-volume ratio when the volumetric aqueous-to-organic phase flow ratio was raised from 1.0 to 6.1 at the same residence time. The larger surface-to-volume ratio significantly promoted catalyst phase transfer but decreased selectivity because of the simultaneous increase of the rate of the consecutive reaction to the dialkylated product. There exists an optimum flow ratio with a maximum productivity. Conversion and selectivity in the microchannel reactor were both found to be significantly larger than in a stirred reactor. |
| A Flow Process Using Microreactors for the Preparation of a Quinolone Derivative as a Potent 5HT1B Antagonist
Zizheng Qian, Ian R. Baxendale, Steven V. Ley Innovative Technology Centre, Department of Chemistry, University of Cambridge, UK This article describes the continuous flow synthesis of 6-methoxy-8-(4-methyl-1,4-diazepan-1-yl)-N-(4-morpholinophen-yl)-4-oxo-1,4-dihydroquinoline-2-carboxamide, a potent 5HT1B antagonist developed by AstraZeneca. |
| Aminolysis of Epoxides in a Microreactor System: A Continuous Flow Approach to ß-Amino Alcohols
Matthew W. Bedore, Nikolay Zaborenko, Klavs F. Jensen and Timothy F. Jamison Departments of Chemistry and Chemical Engineering, MIT The use of a continuous flow microreactor for β-amino alcohol formation by epoxide aminolysis is evaluated. Comparison to microwave batch reactions reveals that conditions obtainable in the microreactor can match or improve yields in many cases. By increasing the pressure of the system, maximum temperatures can also exceed those accessible using a microwave unit. The use of a microreactor for epoxide aminolysis reactions in the synthesis of two pharmaceutical relevant compounds is described. |
| The application of flow microreactors to the preparation of a family of casein kinase I inhibitors
Innovative Technology Centre, Department of Chemistry, University of Cambridge, UK In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors. |
| Enzyme Catalysis in an Aqueous/Organic Segment Flow Microreactor: Ways to Stabilize Enzyme Activity
† Laboratory of Chemical Biotechnology, Department of Biochemical and Chemical Engineering, Dortmund, Germany Multiphase flow microreactors benefit from rapid mixing and high mass transfer rates, yet their application in enzymatic catalysis is limited due to the fast inactivation of enzymes used as biocatalysts. Enzyme inactivation during segment flow is due to the large interfacial area between aqueous and organic phases. The Peclet number of the system points to strong convective forces within the segments, and this results in rapid deactivation of the enzyme depending on segment length and flow rate. Addition of surfactant to the aqueous phase or enzyme immobilization prevents the biocatalyst from direct contact with the interface and thus stabilizes the enzyme activity. Almost 100% enzyme activity can be recovered compared to 45% without any enzyme or medium modification. Drop tensiometry measurements point to a mixed enzyme−surfactant interfacial adsorption, and above a certain concentration, the surfactant forms a protective layer between the interface and the biocatalyst in the aqueous compartments. Theoretical models were used to compare adsorption kinetics of the protein to the interface in the segment flow microreactor and in the drop tensiometry measurements. This study is the basis for the development of segment flow microreactors as a tool to perform productive enzymatic catalysis. |
| ReactIR Flow Cell: A New Analytical Tool for Continuous Flow Chemical Processing
†Innovative Technology Centre, Department of Chemistry, University of Cambridge, U.K. A newly developed ReactIR flow cell is reported as a convenient and versatile inline analytical tool for continuous flow chemical processing. The flow cell, operated with ATR technology, is attached directly into a reaction flow stream using standard OmniFit (HPLC) connections and can be used in combination with both meso- and microscale flow chemistry equipment. The iC IR analysis software (version 4.0) enables the monitoring of reagent consumption and product formation, aiding the rapid optimisation of procedures. Short-lived reactive intermediates can also be observed in situ, giving further mechanistic insight into complex transformations. |
