Continuous flow functionalization of pharmaceutically relevant synthons by activation with lithiated derivatives

Continuous flow chemistry has offered since several decades a lot of benefits concerning reaction efficiency, safety, scalability, selectivity and temperature control. It is particularly appealing for processes implying highly reactive organometallic intermediates and more specifically lithiated derivatives. Flash chemistry, which combines flow microreactor technology and very short residence time, allows efficient and selective carbon-carbon or carbon-heteroatom bonds formation. Therefore, arduous processes or even impossible chemistry with conventional batch reactors, such as external trapping of reactive and unstable species (like carbenoids) with electrophiles, can be achieved. Flow chloromethylation has shown to be an attractive way to access chloromethylketones, which are valuable synthons that can be post-functionalized for bioactive compounds preparation. In the second chapter of this work, we developed a new procedure by taking advantages of flow chemistry to trap thermally unstable chloromethyllithium intermediate with esters, challenging electrophiles, due to a limited relative reactivity. Thus, thanks to precise control of the residence time (bellow 5 s) and of the stoichiometry, the chloromethylketone products can be chemoselectively obtained with high optimized yields. This novel method has been applied on a large range of functionalized esters with good to excellent yields, up to 99%. A scale-out procedure has also been set up and carried out on a Formoterol intermediate (an asthma medication), allowing an output of more than 1 g with a high throughput of 10.63 g.h⁻¹. The third chapter is about flow iodination of a specific substituted pyridine via regioselective deprotonation and trapping with iodine and its scale-up. The process has been studied on a commercially available flow systems, developed by Corning industry, whose aim of the reactors’ design is to improve mixing capacity, a noticed advantage during this project. The reaction has been optimized on their LowFlow device, including 0.5 mL coil reactors. Stoichiometry and more specifically the amount of lithiated base compared to starting material was a key parameter to avoid by-products, leading to a very good yield of 76% with a high throughput of 4.7 g.h⁻¹. Thus, as planned, we have set up a scale-up of the process by sizing-up, using Corning G1’s reactors whose internal volume is 8.2 mL, representing a 16-fold increase in dimensions. We were pleased to notice that optimized conditions have been homothetic during large-scale transition and by applying these conditions to the new flow set-up, a particularly good yield of 82% of the desired iodinated product with an excellent throughput of 83.5 g.h⁻¹ have been selectively obtained.

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