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We converted diverse commercial meta-substituted phenols to the allyl-substituted precursors via nucleophilic substitution using batch technology to allow processing these in microflow by means of the photo-Claisen rearrangement. The latter process is researched on its own, as detailed below, and also prepares the ground for a fully continuous two-step microflow synthesis, as outlined above. It is known that batch processing of electronically deactivated phenols (e.g., bearing a cyano or nitro group) has several orders of magnitude lower reactivity than their parental counterparts [1]. Thus, we here explore if the high quantum yield of microflow, yet at very short residence time, is sufficient to activate the deactivated molecules. In addition, the realization of a true orthogonal two-step flow synthesis can open the door to a large synthetic scope of our approach and possibly overcome limitations due to missing orthogonality of our previously reported thermal approach of combined nucleophilic substitution-Claisen rearrangement in microflow. Consequently, we make for our photo microflow approach an orthogonality check, as previously reported for the thermal approach, and compare both.

To get a broader picture, we have investigated some major parametric sensitivities such as the irradiation intensity, the choice of solvent, the reactant concentration, and, most notably, the influence of the substitution pattern. The irradiation intensity was varied by increasing distance between a lamp and the microflow capillary. In addition, the normal photo-Claisen microflow process (at room temperature) is compared to a high-temperature photo-Claisen microflow process, to check the potential of such novel process window [2]. This is difficult to realize in batch, as the combination of strong ultraviolet (UV) irradiation and high temperature causes a high hazard potential. Yet, under microflow, this can be safely handled.

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Journal of Flow Chemistry
Authors: F. Benaskar, A. Ben-Abdelmoumen, N. G. Patil, E. V. Rebrov, J. Meuldijk, L. A. Hulshof, V. Hessel, U. Krtschil and J. C. Schouten

Abstract

An extended cost study consisting of 14 process scenarios was carried out to envisage the cost impact of microprocessing and microwaves separately or in combination for two liquid-phase model reactions in fine-chemicals synthesis: (1) Ullmann C–O cross-coupling reaction and (2) the aspirin synthesis. The former, a Cu-catalyzed substitution reaction, was based on an experimental investigation, whereas the latter, a noncatalyzed aromatic esterification reaction, was based on literature data. The cost of 4-phenoxypyridine production, as a pharmaceutical intermediate in the synthesis of vancomycin or vancocin, was compared with that of the synthesis of aspirin, a key example of large-scale fine-chemical production plants. The operating costs in the Ullmann synthesis were found to be related to material-based process (reactant excess, pretreatment, and catalyst synthesis), whereas those in the aspirin synthesis appeared to be related to downstream-based process (workup, waste treatment). The impact of an integrated microwave heating and microprocessing system on profitability was demonstrated with respect to operational cost and chemical productivity. Different modes of microwave heating and catalyst supply were studied and compared with conventional oil-bath-heated systems in batch and continuous processes. The overall costs including profitability breakthrough for a competitive market price of product were obtained from various combinations of heating and processing. In case of the Ullmann synthesis, the CAPEX (capital expenditure) was negligible compared to the OPEX (operational expenditure), whereas in the aspirin synthesis, the CAPEX was found around 40%, both at a production scales of 1–10 kg/day using proposed upscale methods. The source of the catalyst strongly determined the profitability of a continuously operated Ullmann process due to its effect on the chemical performance. Higher energy efficiencies could be attained using single-mode microwave irradiation; however, the energy contribution to the overall cost was found to be negligible. Different scenarios provided a cost-feasible and profitable process; nevertheless, an integrated microwave heating and microflow processing led to a cost-efficient system using a micropacked-bed reactor in comparison to wall-coated microreactor, showing a profit margin of 20%.

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