title: Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine.
abstract: Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Bédard
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Longstreet
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Britton
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Yuran
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Moriguchi
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Hicklin
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Green
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: tfj@mit.edu.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Jamison
mesh_terms: D001285:Atropine / Q000138:chemical synthesis / Q000737:chemistry*; D003975:Diazepam / Q000138:chemical synthesis / Q000737:chemistry*; D055772:Green Chemistry Technology; D006863:Hydrogen-Ion Concentration; D012997:Solvents / Q000737:chemistry
chemical_list: D012997:Solvents; D001285:Atropine; D003975:Diazepam
keywords: Atropine; Continuous-flow chemistry; Diazepam; E-factor; Green chemistry