Synthesis of a Key Linezolid Intermediate via Fixed-Bed Continuous-Flow Hydrogenation: Insights into Catalyst Grade Selection and Optimum Reaction Conditions for Scale-Up

Abstract 3-Fluoro-4-morpholinoaniline 1 is a key precursor in the synthesis of the high-volume antibacterial drug Linezolid and is typically obtained via catalytic hydrogenation-mediated nitro-group reduction in 4-(2-fluoro-4-nitrophenyl)morpholine 2. Ability to carry out this transformation in a safe and scalable manner, without significant deshalo impurity formation, is of paramount importance in defining an efficient process for the titular API. Herein, we describe a detailed study into fixed-bed-mediated hydrogenation of 2 in order to delineate an easily scalable means of accessing 1 in continuous flow that incorporates elements of simplicity and efficiency. The effect of catalyst (Pd/C and Raney Ni) grade in conjunction with other parameters (such as time, temperature, solvent, and concentration) has been investigated. Further, catalyst stability and longevity were evaluated by conducting a time-on-stream study. The best reaction conditions afforded (a) >99.5% product formation, (b) near quantitative isolated yield of 1, and (c) a space–time yield of 1.65 kg/L/h, as opposed to 0.0058 kg/L/h that could be obtained in conventional batch techniques.