Synthesis of the Potassium Channel Opener (3S,4R)‐3,4‐Dihydro‐4‐(2,3‐dihydro‐2‐methyl‐3‐oxo‐pyridazin‐6‐Yl)oxy‐3‐hydroxy‐6‐(3‐hydroxyphenyl)sulphonyl‐2,2,3‐trimethyl‐2H‐benzo[b]pyran

Abstract

The preparation of the potassium channel opener (3S,4R)‐3,4‐dihydro‐4‐(2,3‐dihydro‐2‐methyl‐3‐oxo‐pyridazin‐6‐yl)oxy‐3‐hydroxy‐6‐(3‐hydroxyphenyl)sulphonyl‐2,2,3‐trimethyl‐2H‐benzo[b]pyran (1) as a single enantiomer is reported. Considerable improvements have been implemented with respect to the original synthesis that allow for the preparation of multigram quantities of the final target compound. The optimized synthesis consists of a six‐step linear sequence whose key step is an asymmetric epoxidation protocol through the use of Jacobsen's (S,S)‐(+)‐N,N′‐bis(3,5‐di‐tert‐butylsalicylidene)‐1,2‐cyclohexanediaminomanganese(III) chloride catalyst.

Keywords:

• asymmetric epoxidation
• 6‐(hydroxyphenyl)sulphonylbenzo[b]pyran
• potassium channel opener
• smooth muscle relaxant activity

Acknowledgments

The authors thank their colleagues in the Analytical Research and Development Group for their work to develop methods to determine the chemical and optical purities. Also, we thank Michael H. Chen for useful discussions during the implementation of this project, Ji Zhang for providing us with the experimental procedure for the preparation of 1‐methyl‐3,6‐(1H,2H)‐pyridazinedione, and Daniel T. Belmont, Jerry D. Clark, and D. Keith Anderson for reviewing this manuscript, all of them from the RAPI Group in Ann Arbor.