Generation of tosyl azide in continuous flow using an azide resin, and telescoping with diazo transfer and rhodium acetate-catalyzed O-H insertion.

Generation of tosyl azide 12 in acetonitrile in flow under water-free conditions using an azide resin and its use in diazo transfer to a series of aryl acetates are described. Successful telescoping with a rhodium acetate-catalyzed O-H insertion has been achieved, thereby transforming the aryl acetate 8 to a-hydroxy ester 10, a key intermediate in the synthesis of clopidogrel 11, without requiring isolation or handling of either tosyl azide 12 or a-aryl-a-diazoacetate 9, or indeed having significant amounts of either present at any point. Significantly, the solution of a-diazo ester 9 was sufficiently clean to progress directly to the rhodium acetate-catalyzed step without any detrimental impact on the efficiency of the O-H insertion. In addition, the rhodium acetate-catalyzed O-H insertion process is cleaner in flow than under traditional batch conditions. Use of the azide resin offers clear safety advantages and, in addition, this approach complements earlier protocols for the generation of tosyl azide 12 in flow; this protocol is especially useful with less acidic substrates

Taming tosyl azide: the development of a scalable continuous diazo transfer process

Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a 'one pot' batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo transfer to a range of acceptors, including beta-ketoesters, beta-ketoamides, malonate esters and beta-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an alpha-diazocarbonyl in > 98% purity without any column chromatography

Exploiting the continuous in situ generation of mesyl azide for use in a telescoped process

The hazardous diazo transfer reagent mesyl azide has been safely generated and used in situ for continuous diazo transfer as part of an integrated synthetic process with an embedded safety quench. Diazo transfer to β‐keto esters and a β‐ketosulfone was successful. In‐line phase separation, by means of a continuous liquid–liquid separator enabled direct telescoping with a thermal Wolff rearrangement. 1

Enabling the synthesis and reactivity of α-diazocarbonyl compounds using continuous flow chemistry

Use of diazo compounds for large scale synthesis has been limited due to the challenges associated with these hazardous reagents; this thesis explores how continuous flow processing can be employed to enable safe generation, handling and use of diazo compounds and their precursors, specifically sulfonyl azides, to overcome these challenges and thereby enable the consideration of the use of diazo chemistry in future synthetic processes. The first chapter is a literature review of recent advances in the available approaches for the generation of diazo compounds with a particular emphasis on telescoping in situ generation with subsequent transformations; use of batch and/or continuous flow processing conditions are discussed. The second chapter shows for the first time that tosyl azide can be efficiently generated and used for diazo transfer, to a range of substrates, under continuous flow conditions, obviating the requirement to prepare, store or handle this hazardous reagent. Successful application to a broad of substrates was demonstrated including β-ketoesters, diethyl malonate, a β-ketoamide and β-oxo-sulfones. Extensive studies were carried out to find the optimum conditions for in situ sulfonyl azide formation and diazo transfer. A novel quench was designed and successfully implemented, to safely address unreacted or excess tosyl azide. The third chapter describes the extension of the continuous flow diazo transfer methodology to synthesis and use of mesyl azide as the diazo transfer reagent, with the advantage of facile removal of the water soluble byproducts by phase separation in continuous flow. While the hazards associated with use of mesyl azide are greater than those of tosyl azide, under traditional batch conditions, use of flow technology overcomes these barriers. Use of the “salt assisted liquid-liquid extraction” (SALLE) separation technique in conjunction with a designed in-line liquid–liquid separator, provided a clean outflow of α-diazo-β-keto ester in acetonitrile of sufficient quality to enable telescoping of the sulfonyl azide formation and the diazo transfer step with a subsequent thermal Wolff rearrangement. An interesting application of FlowNMR is described which enabled investigation of the mechanism of mesyl azide formation. Use of an alternative water soluble diazo transfer reagent, m-carboxybenzenesulfonyl azide, in both organic and aqueous media was explored. The fourth chapter builds on the diazo transfer in flow methodology successfully developed in Chapters 2 and 3, and specifically explores its incorporation in the synthesis of the key API intermediate, methyl 2-hydroxyl-2-chlorophenylacetate, used in the synthesis of the anti-platelet drug, Plavix®. As the original diazo transfer process, in aqueous acetonitrile, was not compatible for the formation of aryl diazo acetates, an alternative flow protocol for generation of tosyl azide was developed in an aqueous-free medium. Telescoping the formation of tosyl azide, diazo transfer and subsequent transition metal catalysed OH insertion of the α-aryl-α-diazoacetate product in flow was achieved; notably the rhodium catalysed OH insertion was cleaner in flow than under batch conditions. Full experimental details, including spectroscopic and analytical data for all compounds prepared, are reported at the end of each chapter

Mechanistic study of in situ generation and use of methanesulfonyl azide as a diazo transfer reagent with real-time monitoring by FlowNMR

The mechanistic pathway by which the hazardous diazo transfer reagent methanesulfonyl azide can be formed in situ, from methanesulfonyl chloride and aqueous sodium azide, has been investigated using real-time reaction monitoring by FlowNMR. In the presence of triethylamine, rapid generation of methanesufonyl azide is observed, via a mechanistic pathway consistent with involvement of a sulfene or methanesulfonyl triethylammonium intermediate. Accordingly, it is possible to generate and use methanesulfonyl azide in a single synthetic step for a diazo transfer process