Use of a Modified Leimgruber–Batcho Reaction to Prepare 6‐Chloro‐5‐fluoroindole

Abstract

An efficient synthesis of the title indole, the heterocyclic core of the standard 5‐HT_2C receptor agonist Ro 60‐0175, via a modified Leimgruber–Batcho indole synthesis is presented. The process can be used to make >100 g quantities of the target indole.

Keywords:

• Indole
• Ro 60‐0175
• Leimgruber–Batcho
• 5‐HT_2C receptor

Acknowledgments

We thank Drs Ken Heatherington, Graeme Harden, Peter Clayton, and Mr. Tim Haymes for performing the analysis on compounds 4–8.

Notes

^aIf the mixture is allowed to rise above 0°C then a mixture of regioisomeric products forms.

^bIn an unrelated study, it was noted that fluoride could be displaced from 5‐fluoro‐2‐nitrotoluene by reaction with sodium methoxide. However, fluoride was not displaced when 5‐fluoro‐2‐nitrotoluene was reacted with sodium‐iso‐propoxide.

^cSometimes the presence of an intermediate (assumed to be the N‐hydroxyindole) was noted at this stage by thin layer chromatography. If such an intermediate was noted, addition of further hydrazine hydrate and reaction for 30 min ensured complete formation of the indole 2.