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 route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…Neat or molten reagents led to higher reactivity and throughput in the multistep flow chemical preparation of Ibuprofen, 20,21 Rufinamide, 22 Aliskiren, 23,24 Lidocaine and Diazepam. 25 Complete removal of the solvent and introduction of a different one may be necessary in some cases, although only few continuous examples were described for such processes.…”

“…Corrosivity and clogging issues could be mitigated by carefully choosing pumping and quenching methods. 21 Another example of improved throughput was provided in the case of Imatinib. The first flow approach marked a milestone in multistep flow synthesis.…”

“…12), corrosion of the back pressure regulator (BPR) unit was avoided by careful quenching of the ICl reagent. 21 Hazardous leaks were encountered during an earlier study regarding the same API, which could be avoided by using high performance polymeric materials, which are resistant towards triflic acid. 20 Clogging (apart from the choice of solvent) can be prevented by careful choice of reagents (Fig.…”

“…15), when the product remains in the mother liquor, while the solid impurities are retained on the filter material (and then discarded by an appropriate mechanism). 27 There are several examples of extraction methods using liquidliquid phase separation 96,97 to eliminate the excess of the reagents, 21,65 co-products, 65 traces of solvents 39,80 or cosolvents, 29 which have been used in a previous step. Complete removal of water may require a column filled with solid MgSO 4 desiccant after the phase separation, as exemplified in the flow preparation of Milnacipran analogs.…”

Beyond Organometallic Flow Chemistry: The Principles Behind the Use of Continuous-Flow Reactors for Synthesis

“…The fast heat transfer even allows to carry out reactions in the absence of any solvent, highlighting the green aspect of continuous-flow processing in microreactors. [91][92][93] An even faster heat transfer can be achieved by using microwave 94 or induction heaters. 95 Microwave heating is enabled by absorbance of the energy due to interaction of dipoles with the microwaves.…”