A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones

Three different continuous flow strategies for the generation of important 4-aryl-2-butanone derivatives including the anti-inflammatory drug nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone] and the aroma compounds raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] and its methyl ether [4-(4-methoxyphenyl)-2-butanone] were evaluated. All three protocols involve the initial preparation of the corresponding 4-aryl-3-buten-2-ones via Mizoroki-Heck, Wittig, or aldol strategies, which is then followed by selective hydrogenation of the C=C double bond to the desired 4-aryl-2-butanones. The synthetic routes to 4--aryl-3-buten-2-ones were first optimized/intensified on small scale to reaction times of 1-10 min using batch microwave heating technology and then translated to a scalable continuous flow process employing commercially available stainless steel capillary tube reactors. For the synthesis of 4-(4-methoxyphenyl)-3-buten-2-one a further scale-up using a custom-built mesofluidic mini-plant flow system capable of processing several liters per hour was designed to further expand the scale of the process. The final hydrogenation step was performed using a fixed-bed continuous flow hydrogenator employing Ra/Ni as a catalyst.