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A general method for the continuous processing of suspensions and particulates is reported. A commercially available agitating cell reactor which uses a transverse mixing motion to maintain solids in suspension has been successfully applied to a salt-forming reaction. The flow device delivered 208 g of N-iodomorpholinium hydroiodide salt over a 9-h period (equating to 3.88 kg/week) under optimized conditions. The reactor is suitable for the medium-scale (5 kg) processing of solid-forming reactions and appears to offer the potential for a variety of more complex applications.

Type of publicationArticle ( 1 This is the pre-peer reviewed version of the following article: Deadman, B. J., Benjamin J. Deadman, [a] Stuart G. Collins [a] and Anita R. Maguire* [b] 2 This is the pre-peer reviewed version of the following article: Deadman, B. J., , Taming Hazardous Chemistry in Flow: The Continuous Processing of Diazo and Diazonium Compounds. Chem. Eur. J. which has been published in final form at http://dx.doi.org/10.1002/chem.201404348 DOI: 10.1002/chem.201404348 IntroductionDiazo and diazonium compounds are extremely versatile intermediates and reagents in organic synthesis. Diazoalkanes are important alkylating reagents, [1,2] while α-diazocarbonyls are important for their role in generating carbenes and metal carbenoids, [1,[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and also for providing access to reactive ketene and heteroanalogous intermediates via the Wolff rearrangement. [21][22][23][24][25][26] Diazo compounds are also important 1,3-dipoles for heterocycle-forming cycloaddition reactions. [27][28][29][30][31][32] The diazonium ion moiety is an important leaving group in Sandmeyer, [33][34][35] Meerwein, [36,37] Balz-Schiemann [38,39] and palladium catalysed cross coupling [40][41][42] chemistry; and is an essential reagent for the preparation of azo compounds, the backbone of the synthetic dye industry. [42,43] The versatility of the diazo and diazonium moieties is matched only by their fearsome reputation. Diazoalkanes are highly toxic due to their potent alkylation of DNA. [44] Furthermore, diazo and diazonium compounds are highly energetic by nature and explosions can be triggered by shock, heat or exposure to concentrated acids. [44,45] α-Diazocarbonyls are considerably more stable than diazoalkanes and diazoniums due to the resonance stabilisation of adjacent carbonyls but detonation is still possible under more forcing conditions. [44,46] These safety concerns necessitate caution when using diazo and diazonium intermediates in the laboratory, and have limited their use on scale in industry. The synthetic utility of these hazardous compounds has led to a recent interest in developing safer alternative methods for their preparation and use. [1,44] Continuous processing is rapidly growing in the academic, pharmaceutical and fine chemical sectors due to its favourable safety profile among other benefits such as efficient mixing, enhanced heat and mass transfer, access to extreme reaction conditions, reproducibility and scale up, in-line workups and automated operation. [47][48][49][50][51][52][53][54] The safety profile offered by continuous processing is perhaps the most compelling reason for its popularity in recent years. Sensitive and toxic reaction intermediates can be generated and consumed during a single flow process without the need for stockpiling hazardous quantities of material. Furthermore, the high surface area-tovolume ratio of tubular flow reactors also ensures rapid dissipation of heat and reduces the risk of reaction runaway.Continuou...

On-line mass spectrometry allowed the flow conditions to be quickly tuned for safe operation and optimal generation of the desired product. The validity of this approach was corroborated by off-line liquid chromatography/mass spectrometry (LC/MS) analysis of flow samples.

Here we report the direct comparison of a conventional batch mode synthesis of Meclinertant (SR48692, 1), a neurotensin receptor-1 antagonist, with its machine-assisted flow chemistry alternative. By using these enabling tools, combined with solid-supported reagents and scavengers, many process advantages were observed. Care, however, must be taken not to convert these techniques into expensive solutions to problems that do not exist.