title: Synthesis of a NO-releasing prodrug of rofecoxib.
abstract: [reaction: see text] A newly developed synthesis of a NO-releasing prodrug of rofecoxib is described. The highly productive process consists of five chemical steps and produces prodrug 1 in an overall 64% yield from commercially available 3-phenyl-2-propyn-1-ol (4). The synthesis is highlighted by the carbometalation reaction of propargyl alcohol 4 to generate the tetrasubstituted olefin core, sulfone acid 2. Additionally, two alternate end-game strategies to prepare NO-COXIB 1 from this intermediate were explored and developed: (1) a convergent synthesis where a bromonitrate side chain is introduced in one step and (2) a two-step sequence that first installs the requisite six-carbon ester side chain followed by chemoselective nitration.
authors.affiliation: Department of Process Research, Merck & Company, Inc., P.O. Box 2000, Rahway, New Jersey 07065-0900, USA.
authors.forename: F Conrad
authors.initials: FC
authors.lastname: Engelhardt
authors.forename: Yao-Jun
authors.initials: YJ
authors.lastname: Shi
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Cowden
authors.forename: David A
authors.initials: DA
authors.lastname: Conlon
authors.forename: Brenda
authors.initials: B
authors.lastname: Pipik
authors.forename: George
authors.initials: G
authors.lastname: Zhou
authors.forename: James M
authors.initials: JM
authors.lastname: McNamara
authors.forename: Ulf-H
authors.initials: UH
authors.lastname: Dolling
mesh_terms: D002245:Carbon Dioxide; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007202:Indicators and Reagents; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D009569:Nitric Oxide / Q000032:analysis*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D007783:Lactones; D011355:Prodrugs; D013450:Sulfones; C116926:rofecoxib; D002245:Carbon Dioxide; D009569:Nitric Oxide