title: Continuous-Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols.
abstract: Cinnarizine, cyclizine, buclizine, and meclizine belong to a family of antihistamines that resemble each other in terms of a 1-diphenylmethylpiperazine moiety. We present the development of a four-step continuous process to generate the final antihistamines from bulk alcohols as the starting compounds. HCl is used to synthesize the intermediate chlorides in a short reaction time and excellent yields. This methodology offers an excellent way to synthesize intermediates to be used in drug synthesis. Inline separation allows the collection of pure products and their immediate consumption in the following steps. Overall isolated yields for cinnarizine, cyclizine, and a buclizine derivative are 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h(-1) .
authors.affiliation: Department of Chemical Engineering and Chemistry, Technische Universiteit Eindhoven, Den Dolech 2, 5600 MB, Eindhoven, Netherlands.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Borukhova
authors.affiliation: Department of Chemical Engineering and Chemistry, Technische Universiteit Eindhoven, Den Dolech 2, 5600 MB, Eindhoven, Netherlands. t.noel@tue.nl.|Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S4), 9000, Ghent, Belgium. t.noel@tue.nl.
authors.forename: Timothy
authors.initials: T
authors.lastname: Noël
authors.affiliation: Department of Chemical Engineering and Chemistry, Technische Universiteit Eindhoven, Den Dolech 2, 5600 MB, Eindhoven, Netherlands. v.hessel@tue.nl.
authors.forename: Volker
authors.initials: V
authors.lastname: Hessel
mesh_terms: D000438:Alcohols / Q000737:chemistry*; D001593:Benzyl Compounds / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D002936:Cinnarizine / Q000138:chemical synthesis* / Q000737:chemistry; D003501:Cyclizine / Q000138:chemical synthesis* / Q000737:chemistry; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000438:Alcohols; D001593:Benzyl Compounds; D006633:Histamine Antagonists; D010879:Piperazines; C046894:buclizine; D002936:Cinnarizine; C021292:benzyl chloride; D003501:Cyclizine
keywords: alcohols; halogenation; hydrogen chloride; multicomponent reactions; synthesis design