Synthesis of ¹⁴C‐labeled 4‐hydroxyindole as an intermediate for the preparation of (S)‐2‐[4‐[2‐[3‐(indol‐2‐[¹⁴C]‐4‐yloxy)‐2‐hydroxypropylamino]‐2‐methylpropyl]‐phenoxy]pyridine‐5‐carboxamide (LY368842‐[indole‐¹⁴C]) glycolate

Abstract

Synthesis of 4‐hydroxyindole labeled with 14C at the 2‐position was accomplished based on the vicarious nucleophilic substitution reaction of benzyl‐protected 3‐nitrophenol with p‐chlorophenoxyacetonitrile‐[1‐14C]. This was followed by the reductive cyclization of o‐nitrocyanomethyl derivative by palladium catalyzed hydrogenation. p‐Chlorophenoxyacetonitrile‐[1‐14C] was prepared from commercially available p‐chlorophenoxymethyl chloride and sodium cyanide‐[14C]. 4‐Hydroxyindole‐[2‐14C] was used for the synthesis of 14C‐labeled β3 adrenergic agonist LY368842. Copyright © 2002 John Wiley & Sons, Ltd.

Nucleophilic Substitution of Hydrogen in Heterocyclic Chemistry

“…This protocol was recently applied to the synthesis of 4-hydroxyindole labeled with 14 C at the 2-position, the key intermediate for the synthesis of 14 C-labeled β 3 adrenergic agonist LY368842 (Scheme 102) . The required chlorophenoxyacetonitrile was prepared from commercially available 4-chlorophenoxymethyl chloride and K 14 CN.…”

Reductive Monoalkylation of Aromatic and Aliphatic Nitro Compounds and the Corresponding Amines with Nitriles

“…The use of a transfer hydrogenation procedure appeared to be much faster compared to direct reduction with hydrogen over palladium or other types of catalysts. Indeed, there were a number of reports of intramolecular nitrile-mediated reductive alkylations that have been conducted with hydrogen as a reductant at various pressures and over various types of catalysts. − Also, using active rhodium catalysts, Galan et al have demonstrated direct reductive coupling of aliphatic nitriles to form the corresponding secondary amines in high yield. In these instances, direct reduction of nitrile led to the corresponding amine, which then reacted with nitrile leading to a secondary amine product in a process likely identical to that reported here.…”

An efficient and practical synthesis of [2-11C]indole via superfast nucleophilic [11C]cyanation and RANEY® Nickel catalyzed reductive cyclization

“…It was also evident that conditions that favored a high ratio of We next set out to investigate the effect of basicity on ORCY and radiolabeled product distribution. The results listed in Table 1, entries 5 and 6 showed that no [ 11 Increasing the pH to 8.7 increased the ORCY to 60% but only We initially tested several reducing agents for the reductive cyclization of [ 11 C]-2 to [2-11 C]indole including: Pd-C/H 2 in ethyl acetate 22,23 and in alcoholic solvents; 24,25 Pd-C/H 2 in ethanol/acetic acid; 9,26,27 Pd-C in the presence of in situ H 2 ; 28,29 RANEY® Nickel or Pd-C in the presence of NH 4 CO 2 H/ HCO 2 H; 30 Al-NiCl 2 •6H 2 O; 31 Zn/acetic acid. 32 Results were generally disappointing: although most worked under carrieradded conditions with or without carbon-11, they either provided only a trace of desired [2-11 C]indole or none at all under no-carrier-added (NCA) conditions.…”

“…In 2002, Czeskis and colleagues reported an elegant method for synthesis of 4-hydroxy [2-14 C]indole. 9 Starting from Na 14 CN, they first synthesized p-chlorophenoxy [1- 14 C]acetonitrile which was reacted with benzyl-protected 3-nitrophenol via a vicarious nucleophilic substitution reaction to afford a 2-(2-nitrophenyl) acetonitrile derivative, which was reduced and cyclized to form 14 C-labeled 4-hydroxyindole. Four years later, Pedras and Okinyo reported a synthesis of stable isotope deuterium labeled [5,6,7,8-2 H 4 ]indole using chloroacetonitrile direct alkylation and reductive cyclization reactions.…”