Synthesis of the tritiated isotopomers of enzastaurin and its N-des-pyridylmethyl metabolite for use in ADME studies

✍ Scribed by William J. Wheeler; Dean K. Clodfelter

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: French
• Weight: 165 KB
• Volume: 51
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.1497

✦ Synopsis

Abstract

Enzastaurin (3‐(1‐methyl‐1__H__‐indol‐3‐yl)‐4‐[1‐[1‐(2‐pyridinylmethyl)‐4‐piperidinyl]‐1__H__‐indol‐3‐yl]‐1__H__‐pyrrole‐2,5‐dione, 1), an agent with potential utility in the treatment of solid tumors, is currently in phase II clinical trials. Enzastaurin undergoes metabolism in vitro and in vivo to several products of oxidative metabolism, the major one of which is 3‐(1‐methyl‐1__H__‐indol‐3‐yl)‐4‐(1‐piperidin‐4‐yl‐1__H__‐indol‐3‐yl)‐1__H__‐pyrrole‐2,5‐dione (2). In a model study, the attempted synthesis 1‐[^2^H] by reaction of 1 with deuterium gas in the presence of Ir[(COD)(Cy~3~P)pyr]PF~6~ (Crabtree's catalyst) was unsuccessful. Alternatively, it was decided to prepare tritiated 2 as both a final product and the starting material for the tritiation of 1. We have reported herein a route that was developed for use in the preparation of tritium‐labeled 2‐[^3^H] and its successful conversion to 1‐[^3^H]. Copyright © 2008 John Wiley & Sons, Ltd.