Enhanced mixing of biphasic liquid-liquid systems for the synthesis of gem-dihalocyclopropanes using packed bed reactors

Abstract

A continuous flow procedure for the gem-dichlorocyclopropanation of alkenes has been developed. The method is based on the generation of dichlorocarbene utilizing the classical biphasic aqueous sodium hydroxide/chloroform system. This reaction typically requires vigorous stirring for several hours in batch for completion. Tarry materials precipitate due to partial polymerization of dichlorocarbene and the process is difficult to scale. To overcome these problems and achieve very efficient mixing during the flow process a column reactor packed with PTFE beads as inert filling material has been used. PTFE beads have been found to be the optimal material to obtain fine dispersions of the aqueous phase in the organic solution. By heating the packedbed reactor at 80°C excellent conversions have been achieved after a residence time of only 4 min. The process has been applied for the synthesis of Ciprofibrate, a dichlorocyclopropane-containing drug used as treatment for several diseases associated with high lipid content in blood.

Synthesis of gem‐Dichlorocyclopropanes Using Liquid–Liquid Slug Flow

“…NaOH solution were passed through a T‐junction to form a slug flow, and the mixture was flowed into an oil bath at 60 °C (Figure 1). Both TEA and TBAB efficiently increased mass transfer and showed high yields of 97 and 95%, respectively, in 20 min 16 . However, when TEA was used, the color of the slugs changed to brown starting from the middle of the reaction tube, and black precipitates were detected in the organic slugs.…”

“…Phase transfer catalysts (PTCs), which are generally used in biphasic systems, make it quick and easy for reactants to transfer from one phase to the other, enabling simple operation, mild reaction conditions, and the use of inexpensive and eco‐friendly reagents and solvents 14–17 . However, the choice of PTC is a crucial factor in the successful operation of biphasic reactions.…”

“…Keutz et al . proposed packed bed‐based continuous‐flow dichlorocyclopropanation using tertiary amines as PTCs 16 . They argued that a slug‐flow‐based method was not suitable because the tar generated during the reaction precipitated, leading to clogging of the microchannels.…”

Interfacial Processes—The Key Steps of Phase Transfer Catalyzed Reactions

“…Turbulent flow assures particularly large interfacial surface. This technique was successfully applied for a few reactions that proceed without a PT catalyst, and also PT catalyzed reactions, particularly for generation and reactions of dibromo- [45,46] and dichlorocarbenes [47] In these papers specific features of two phase reactions in flow systems are thoroughly discussed.…”

Mini-Monoplant Technology for Pharmaceutical Manufacturing

“…For perfectly mixed reactions, one CSTR can be implemented for reactions with a specific network or a cascade of CSTRs to handle a wide range of reactions, kinetics, and phases. Some specific continuous and intensified examples (shown in Figure ) and applications of these (and related) reactor categories include plate microreactors, − oscillatory flow reactors, − coiled flow inverters, − micro packed bed reactors, , plug flow reactors with static mixer inserts, − mixed-suspension mixed-product-removal (MSMPR) crystallizers, , and miniaturized CSTRs . Thus, pharmaceutical processes may be intensified through these three targets: intensification of the synthesis route via more direct and higher-yield pathways; reactor technologies , often miniaturized, with high surface-to-volume ratios and reduced transport lengths that facilitate the use of the intensified reactions in target 1; increased productivity through continuous processing with a high degree of automation and RTRT. When all three targets are incorporated into the design of a pharmaceutical process, the result is a higher-yield, higher-productivity continuous process that can run relatively autonomously and with a smaller footprint than typical batch or semibatch processes.…”