A Three‐Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous‐Flow Processing

Abstract

In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield of above 90 % for each step. A scale‐up of this five‐stage process (3 bond‐forming steps, one work‐up, and one in‐line liquid–liquid separation) provided ibuprofen at a rate of 8.09 g h−1 (equivalent to 70.8 kg y−1) using a system with an overall footprint of half the size of a standard laboratory fume hood. Aside from the high throughput, several other aspects of this synthesis expand the capabilities of continuous‐flow processing, including a Friedel–Crafts acylation run under neat conditions and promoted by AlCl3, an exothermic in‐line quench of high concentrations of precipitation‐prone AlCl3, liquid–liquid separations run at or above 200 psi to provide solvent‐free product, and the use of highly aggressive oxidants, such as iodine monochloride. The use of simple, inexpensive, and readily available reagents thus affords a practical synthesis of this important generic pharmaceutical.

The Molecular Industrial Revolution: Automated Synthesis of Small Molecules

“…Specifically,the first step is aFriedel-Crafts acylationperformed neat at 90 8 8Cwith AlCl 3 as Lewis acid and quenched with HCl, resulting in neat product separating from an aqueous solution containing aluminum byproducts.T he risks normally associated with running this type of exothermic reaction and quench in batch mode were circumvented by using automated flow chemistry, since only asmall amount of material is utilized at any given time.The same advantages were observed for the second step in which neat, melted ICl induced an oxidative 1,2-aryl rearrangement to form the targeted methyl ester,w hich was then saponified in the last chemical transformation of this sequence.U tilizing this process,u pt o7 0kgo fi buprofen (5) could be safely synthesized per year with equipment that fits in as tandard laboratory fume hood. [37] 2.3 Speed Automated synthesis platforms can also increase the speed of achemical process,aswas recently demonstrated by Jamison and co-workers with an automated flow-based platform. Specifically,t he total synthesis of ciprofloxacin hydrochloride (11)w as achieved in nine minutes under continuous flow conditions through al inear reaction sequence of six chemical reactions in five flow reactors, followed by offline acidification and filtration (Scheme 5).…”

Die molekulare industrielle Revolution: zur automatisierten Synthese organischer Verbindungen

“…¾hnliche Vorteile wurden auch fürd en zweiten Schritt gefunden, in dem unverdünntes,g eschmolzenes ICl eine oxidative 1,2-Arylumlagerung zum gewünschten Methylester induzierte,d er in der letzten chemischen Tr ansformation dieser Sequenz verseift wurde.M ithilfe dieses Prozesses konnten bis zu 70 kg Ibuprofen (10)p ro Jahr unter Einhal-tung hoher Sicherheitsstandards synthetisiert werden, und das mit einer Ausstattung,d ie in einem Standardabzug Platz fand. [37] 2.3. Geschwindigkeit isoliert werden, was diese Synthese von Ciprofloxacin-Hydrochlorid (11)s ehr zeiteffizient macht.…”

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

“…The concentration or the yield of the desired process are always reported, however, the yield of the side product is generally never reported. It is also desired to measure the concentration of the process stream after the separation stage to check its efficiency [3,21,30,60]. If the desired separation is not achieved then temperature, pressure or scavenger loading should be adjusted to optimize the separation process.…”