Continuous synthesis of 4-(2-fluoro-4-nitrophenyl)morpholine in microreactors: Optimization of process conditions and scale-up to millidevices

• Published in: Chemical engineering and processing 2021-04, Vol.161, p.108316, Article 108316
• Main Authors: Pereira, H.S., Santana, H.S., Silva, J.L.
• Format: Article
• Language: English
• Subjects: Active pharmaceutical; Computational fluid dynamics; Microfluidics; Micromixers; Process intensification
• ISSN: 0255-2701; 1873-3204
• DOI: 10.1016/j.cep.2021.108316

[Display omitted] •The synthesis of ortho-4-(2-fluoro-4-nitrophenyl)morpholine was evaluated.•The synthesis was firstly approached in micro and millidevices.•The optimal conditions were assessed in microreactors.•Micro and millireactors appear as interesting alternative for continuous synthesis.•Micromixers allowed an efficient process scale-up. The continuous production of the intermediate ortho-4-(2-fluoro-4-nitrophenyl)morpholine (o-FNM) was firstly explored in Microfluidic devices. The o-FNM is a key intermediate to synthesize Linezolid, a highly effective active pharmaceutical used against a wide class of Gram-positive pathogens. It is synthesized by eight consecutive reactions, taking about 60 h. One of the most prolonged step, lasting about 11 h, is the reaction between morpholine and 2,4-difluoronitrobenzene to produce o-FNM. Despite these features, there is still a lack on researches approaching such process. The present paper evaluated for the first time the production of o-FNM in micro- and millireactors by CFD. An optimization of operating conditions (temperature, reactants molar ratio (MR) and residence time (τ)) was performed by a Central Composite Rotatable Design, evaluating its effects on the limiting reactant conversion, selectivity and production rate. The optimal production rate (157−195 mg/h in the microreactor) was noticed at 105 °C, MR = 4, τ = 50 s. The performance of different micromixer designs and scale-up effects was assessed. The devices exhibited o-FNM production rate about 1.5–7.5 g/h, equivalent to the reported in literature, keeping high levels of limiting reactant conversions (≈ 99 %) and considerable selectivities (≥ 10).