An improved synthesis of pyran-3,5-dione: application to the synthesis of ABT-598, a potassium channel opener, via Hantzsch reaction.
Ketoester 1 is cyclized to give pyran-3,5-dione 2 in 78% yield using a parallel addition of ketoester 1 and base NaO(t)Bu in refluxing THF. Compared to the previously reported procedures, these optimized conditions have significantly increased the yield of this transformation and the quality of pyran 2 and prove to be suitable for large-scale preparation. An application of 2 to the synthesis of ABT-598, a potassium channel opener, is demonstrated.
Li
Wenke
W
Process Chemistry, Global Pharmaceutical Research and Development, Abbott Laboratories, North Chicago, Illinois 60064-6285, USA. wenke.li@abbott.com
Wayne
Gregory S
GS
Lallaman
John E
JE
Chang
Sou-Jen
SJ
Wittenberger
Steven J
SJ
D003500:Cyclization; D004952:Esters / Q000737:chemistry; D015221:Potassium Channels / Q000819:agonists*; D011714:Pyrans / Q000138:chemical synthesis*; D011753:Pyrones / Q000138:chemical synthesis*; D020002:tert-Butyl Alcohol
D004952:Esters; D015221:Potassium Channels; D011714:Pyrans; D011753:Pyrones; D020002:tert-Butyl Alcohol