Optimisation and Scale-up of α-Bromination of Acetophenone in a Continuous Flow Microreactor

Abstract

To expand the knowledge base for fundamental organic reactions in continuous flow, the α-bromination of acetophenone was successfully transformed from a known batch procedure to a continuous flow process in 99 % yield through D-optimal optimisation and subsequent scale-up of the validated optimum. Using a preparative scale system, a space-time yield of 0.26 kg/m 3 /s (comparable literature batch reaction 0.24 kg/m 3 /s) was achieved under conditions suitable for laboratory and small-scale industrial application where high yield or purity is required, e.g., when expensive substrates are used.

The evolution of Tamiflu synthesis, 20 years on: Advent of enabling technologies the last piece of the puzzle?

“…This 12 steps route has advantages over the previous routes because it utilises commercially available starting materials and requires minimal protection group manipulations. It however still employs potentially hazardous azide chemistry as a means to prepare the substrate for a Curtius rearrangement, which would most likely make this approach be ruled out on scale for safety reasons, unless other processing techniques such as flow chemistry are utilised to address these safety concerns [ 2 , 79 ] The resolution of (±)- 75 via chiral HPLC was a major contributing factor to the very low overall yield (2.8%). Just as the commercial route, the hazardous azide chemistry is employed, which was unfortunately accompanied by very low yield.…”

“…Oseltamivir 28 was isolated using an acid-base extraction and purified by column chromatography to afford (−)-oseltamivir 28 in 13% overall yield which is comparable to the batch approach (15%). Noteworthy, continuous flow synthesis can easily be scaled-up compared to batch making the flow procedure more attractive [ 57 , 65 , 67 , 79 , [96] , [97] , [98] , [99] , [100] ] The authors easily increased continuous flow productivity by long-time operation or directly scaling-up to a larger scale after optimisation on a small scale. However, batch scale-up is flawed at each stage of the scale-up, modifications made to the reactor vessel result in changes to the surface to volume ratio, process will need process re-optimisation at every stage of scale up due change is mass transfer ratios, which in turn have a profound effect on the thermal and mass-transport properties of the reaction.…”

Mild Homologation of Esters through Continuous Flow Chloroacetate Claisen Reactions

“…Theh alogenation of ketones [4] requires dealing with challenging waste streams, toxic reagents,a nd corrosivity,e specially when the reactions are carried out on al arge scale (Route A, Scheme 1). [5] Furthermore,s uch halogenations are known to suffer from low regioselectivity,multiple halogenation, and incompatibilities with several common functionalities. [4,6] In contrast, the acylation of lithium carbenoids of type 3 avoids the issues of site-selectivity and mono-or bis-chlorination (Route B).…”

“…Recent research in lithium carbenoid chemistry by Pace and others has underlined the possibilities of such an approach. [10] In this Claisen-type homologation, chloroacid lithium dianions (4)u ndergo acylation with esters (5). [8] However,s everal drawbacks of Route Br emain:1 )halomethyl lithium reagents are incompatible with an umber of electrophilic functionalities;2 )the availability of pro-nucleophiles like CH 2 ClBr is increasingly restricted due to environmental legislation; [9] 3) monohalo-homologation leading to chloroketones 1 usually requires the use of special acylating agents to avoid over-addition.…”

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

“…In 2012, the same authors described the multivariate D-optimal optimization of a microreactor-based flow method for the methoxyisopropyl (MIP) protection of cyanohydrin [19] and a new flow protocol for the selective α-monobromination of acetophenone [20].…”