Synthesis of a NO-releasing prodrug of rofecoxib.
[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.
Engelhardt
F Conrad
FC
Department of Process Research, Merck & Company, Inc., P.O. Box 2000, Rahway, New Jersey 07065-0900, USA.
Shi
Yao-Jun
YJ
Cowden
Cameron J
CJ
Conlon
David A
DA
Pipik
Brenda
B
Zhou
George
G
McNamara
James M
JM
Dolling
Ulf-H
UH
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
D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D007783:Lactones; D011355:Prodrugs; D013450:Sulfones; C116926:rofecoxib; D002245:Carbon Dioxide; D009569:Nitric Oxide