Continuous flow synthesis concatenated with continuous flow liquid–liquid extraction for work-up and purification: selective mono- and di-iodination of the imidazole backbone

Abstract

Flow processes for mono- and di-iodination of the imidazole backbone were devised, developed, and implemented on the multi-jet oscillating disk (MJOD) flow reactor platform. The flow processes were based on batch protocols previously developed in our research group and involved N,N′-1,3-diiodo-5,5-dimethylhydantoin as the iodination reagent. The flow processes demanded short reactor residence times, and afforded the mono- or di-iodinated imidazoles at a high mass × time yield [g min⁻¹]. The continuous flow processes leading to 4(5)-iodo-1H-imidazole HCl salt was concatenated with a continuous flow work-up section that was assembled by a series of hold-up tanks and two additional MJOD flow reactors that both were utilized as liquid–liquid extractors. The overall mass throughput allowed a production of 4(5)-iodo-1H-imidazole HCl salt at a capacity of 95 g day⁻¹. The continuous flow reaction unit utilized for the preparation of 4,5-diiodo-1H-imidazole was concatenated with a double set of hold-up tanks/stirred tank-batch reactors and semi-continuous vacuum filtration units for the isolation of precipitated/crystallized 4,5-diiodo-1H-imidazole at a production capacity of 295 g day⁻¹.