title: 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.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139 (USA).
authors.forename: David R
authors.initials: DR
authors.lastname: Snead
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Jamison
mesh_terms: D000215:Acylation; D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000737:chemistry; D002384:Catalysis; D002712:Chlorides / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D007052:Ibuprofen / Q000138:chemical synthesis* / Q000302:isolation & purification
chemical_list: D017607:Aluminum Compounds; D002712:Chlorides; D000077410:Aluminum Chloride; D007052:Ibuprofen
keywords: Friedel-Crafts acylation; continuous flow; flow techniques; ibuprofen; separation techniques