The synthesis of tritium, carbon-14 and stable isotope labelled selective estrogen receptor degraders

Abstract

As part of a Medicinal Chemistry program aimed at developing an orally bioavailable selective estrogen receptor degrader, a number of tritium, carbon-14, and stable isotope labelled (E)-3-[4-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl]prop-2-enoic acids were required. This paper discusses 5 synthetic approaches to this compound class.

Synthesis of 2 C‐14 labeled cathepsin C inhibitors: The use of a cyanide to displace a Benzotriazole

“…Building on our past experience in labeling AZD5248 with C‐14, we proposed to conduct the synthesis is an analogous manner . Nitrile 3 had previously been prepared from 4‐iodobromobenzene via a CuI catalyzed reaction with K 14 CN to give a 9:1 mixture of 4‐bromobenzo‐[ 14 C]‐nitrile and 4‐iodobenzo‐[ 14 C]‐nitrile .…”

“…The preparation of the 9:1 mixture of iodobenzo‐[ 14 C]‐nitrile and bromobenzo‐[ 14 C]‐nitrile from K 14 CN was described previously . ( S )‐ tert‐ butyl 2‐(((S)‐1‐amino‐1‐oxo‐3‐(4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)phenyl)propan‐2‐yl)carbamoyl)‐1,4‐oxazepane‐4‐carboxylate, and 2‐(4‐(3‐methyl‐2‐oxo‐2,3‐dihydrobenzo[d]oxazol‐5‐yl)phenyl)acetaldehyde were obtained from RIA medicinal chemistry, Mölndal, Sweden.…”

“…Building on our past experience in labeling AZD5248 with C‐14, we proposed to conduct the synthesis is an analogous manner . Nitrile 3 had previously been prepared from 4‐iodobromobenzene via a CuI catalyzed reaction with K 14 CN to give a 9:1 mixture of 4‐bromobenzo‐[ 14 C]‐nitrile and 4‐iodobenzo‐[ 14 C]‐nitrile . This mixture was reacted with boronate 4 to give amide 5 in 80% radiochemical yield and amide 5 was dehydrated with Burgess reagent to give the penultimate compound, 6 , in 95% yield (Scheme ).…”

“…The preparation of the 9:1 mixture of iodobenzo-[ 14 C]-nitrile and bromobenzo-[ 14 C]-nitrile from K 14 CN was described previously. 6 (S)-tert-butyl 2-(((S)-1-amino-1-oxo-3-(4-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl) carbamoyl)-1,4-oxazepane-4-carboxylate, and 2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)acetaldehyde SCHEME 6 Proposed diastereoselective synthesis of (S,S)-12 from 10 based on the work of Yan and coworkers 16 were obtained from RIA medicinal chemistry, Mölndal, Sweden. K 14 CN was obtained from Institute of Isotopes Co., Ltd. (IZOTOP).…”

The synthesis of a tritium, carbon-14, and stable isotope-labeled cathepsin C inhibitors

“…Carbon‐14‐labeled AZD5248 was required to support a quantitative whole body autoradiography study . Retrosynthetic analysis revealed the possibility of using 4‐bromo[ 14 C]benzonitrile, a compound that we have prepared previously . Thus, in a modification to the medicinal chemistry route, 6 BOC‐protected boronic ester 1 was coupled with [ 14 C] 9 to give [ 14 C] 10 in moderate yield (Scheme ).…”