Process development of 5-methoxy-1H-indole-2-carboxylic acid from ethyl 2-methylmalonate

Development is described of a new process for the preparation from malonates of 5-methoxy-1H-indole-2-carboxylic acid esters, useful intermediates in the synthesis of pharmaceutical compounds. The process uses readily available starting materials, produces little waste, can be operated safely on at least 1 molar scale, and gives high yields. The main areas of optimization included the azo coupling of a diazonium salt with malonate derivatives, the Japp-Klingemann rearrangement, and the Fischer indole synthesis.