Improved Synthesis of 1-Chloro-6-methoxy-isoquinolin-3-ol and Its Derivatives

Abstract

A convenient and efficient synthetic route to 1-chloro-6-methoxy-isoquinolin-3-ol and its derivatives is reported. This new method involves carboxylation of 4-methoxy-2-methylbenzonitrile, subsequent conversion of the resulting 2-cyano-5-methoxy-phenylacetic acid to its acid chloride, and acid-promoted cyclization of the 2-cyano-5-methoxy-phenyl-acetyl chloride. This procedure offers a better overall yield than the previously reported route and is also less hazardous and more reproducible.

Keywords:

• Carboxylation
• cyclization
• 1-chloro-6-methoxy-isoquinolin-3-ol
• 4-methoxy-2-methylbenzonitrile

ACKNOWLEDGMENTS

The authors thank Dr. Nick Meanwell for providing helpful comments. The authors also thank the Department of Analytical Services at Bristol-Myers Squibb for their assistance with compound characterization.