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A Method to Identify Best Available Technologies (BAT) for Hydrogenation Reactors in the Pharmaceutical Industry
J. Flow Chem. 2012, 2(3), 77–82
http://www.akademiai.com/content/8652651g3378x686/?p=ab7c1bc4cd7740e1855623297649f542&pi=3
http://www.akademiai.com/content/8652651g3378x686/fulltext.pdf
| Journal of Flow Chemistry | |
| Publisher | Akadémiai Kiadó |
| ISSN | 2062-249X (Print) 2063-0212 (Online) |
| Subject | Flow Chemistry |
| Issue | Volume 2, Number 3/September 2012 |
| Pages | 77-82 |
| DOI | 10.1556/JFC-D-12-00014 |
Authors
* Author for correspondence: claude.debellefon@lgpc.cpe.fr1CNRS, CPE Lyon University of Lyon Villeurbanne France
Abstract
A methodology that may be applied to help in the choice of a continuous reactor is proposed. In this methodology, the chemistry is first described through the use of eight simple criteria (rate, thermicity, deactivation, solubility, conversion, selectivity, viscosity, and catalyst). Then, each reactor type is also analyzed from their capability to answer each of these criteria. A final score is presented using “spider diagrams.” Lower surfaces indicate the best reactor choice. The methodology is exemplified with a model substrate nitrobenzene and a target pharmaceutical intermediate, N-methyl-4-nitrobenzenemethanesulphonamide, and for three different continuous reactors, i.e., stirred tank, fixed bed, and an advanced microstructured reactor. Comparison with the traditional batch reactor is also provided.
The application of flow microreactors to the preparation of a family of casein kinase I inhibitors
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The Application of Flow Microreactors to the Preparation of a Family of Casein Kinase I Inhibitors.
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Org. Biomol. Chem. 2010, 8, 1798-1806.
Link: 10.1039/b925327k
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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.
DOI: 10.1039/B925327K
Continuous Flow Synthesis of alpha-Halo Ketones: Building Blocks for Anti-retroviral Agents
Chiral alpha-halo ketones derived from N-protected amino acids are key building blocks for the synthesis of HIV protease inhibitors such as atazanavir used in HAART combination therapy.
Kappe and De Souza have reported a continuous flow through route to these intermediates which utilises a tube-in-tube reactor to introduce diazomethane generated on demand into the reaction stream containing mixed anhydride derivatives of N-protected amino acids. The resulting alpha-diazo ketones are then decomposed with HCl or HBr to afford the corresponding alpha-halo ketones.
This process allows the safe generation, separation and use of diazomethane in a continuous integrated multi-step synthesis of important API intermediates.
The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor.
The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber.
The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide.
This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ∼4.5 h (87% yield).
Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor.
Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor.
B. Gutmann, J.-P. Roduit, D. Roberge, C. O. Kappe, J. Flow Chem. 2012, 2,8-19.
http://www.akademiai.com/content/l622j82k3171t080/?p=0213e26b691f494d8eb782308d34fe77&pi=2
Authors
, C. Oliver Kappe2 1Christian Doppler Laboratory for Microwave Chemistry and Institute of Chemistry, Karl-Franzens-University Graz A-8010 Heinrichstrasse 28 Graz Austria
2Microreactor Technology, Lonza AG CH-3930 Visp Switzerland
Abstract
Hydrazoic acid (HN3) was used in a safe and reliable way for the synthesis of 5-substitued-1H-tetrazoles and for the preparation of N-(2-azidoethyl)acylamides in a continuous flow format. Hydrazoic acid was generated in situ either from an aqueous feed of sodium azide upon mixing with acetic acid, or from neat trimethylsilyl azide upon mixing with methanol.
For both processes, subsequent reaction of the in situ generated hydrazoic acid with either organic nitriles (tetrazole formation) or 2-oxazolines (ring opening to β-azido-carboxamides) was performed in a coil reactor in an elevated temperature/pressure regime. Despite the explosive properties of HN3, the reactions could be performed safely at very high temperatures to yield the desired products in short reaction times and in excellent product yields.
The scalability of both protocols was demonstrated for selected examples. Employing a commercially available benchtop flow reactor, productivities of 18.9 g/h of 5-phenyltetrazole and 23.0 g/h of N-(1-azido-2-methylpropan- 2-yl)acetamide were achieved.
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