Synthesis of isotopically labelled compounds at Schering‐Plough, an historical perspective

Abstract

The use of isotopically labelled compounds at Schering-Plough (S-P) has substantially increased over the past 30 years. Since the formation of the S-P Radiochemistry section in the early 1970s, the group has expanded its role from supplying 14 C-and 3 H-labelled compounds for ADME studies for compounds in development, to providing 3 H-labelled compounds for drug discovery and also to provide stable isotope-labelled compounds that are used as LC/MS internal standards. Other isotopes used by the group have included 125 I and 35 S, which have been used to label both small molecules and proteins.

Deuterium‐ and Tritium‐Labelled Compounds: Applications in the Life Sciences

“…[279] Tr aditional approaches,s uch as double bond reduction, hydride reduction, and tritium-halogen exchange,r equire upfront precursor syntheses. [280] Alternatively,h ydrogen exchange labelling can provide ah ighly cost-and timeefficient method if carried out directly on the target molecule itself. [9] Today,H /T exchange is extensively applied, and the very high selectivity and efficiency of new homogeneous metalcatalysed exchange methods (see Section 6) enable specific tritium introduction into biologically and chemically stable positions.C onsequently,n ew hydrogen exchange methods have delivered processes that overcome the stability issues associated with earlier processes,w hich had previously often created ar ather conservative attitude towards the use of tritium-labelled compounds.…”

Iridium-Catalysed ortho-Directed Deuterium Labelling of Aromatic Esters—An Experimental and Theoretical Study on Directing Group Chemoselectivity

“…The reaction mixture was then stirred for the allotted reaction time. An aliquot (1 mL) of the reaction mixture was removed at intervals throughout the reaction (10,20,30,40,50, 60 min, 2 h, and 18 h). Each aliquot was transferred to a vial containing diethyl ether.…”

“…Research into deuterium ( 2 H or D) and tritium ( 3 H or T) labelling is more substantial than for other isotopes, and has been developed on a number of fronts over the past 60 years [1][2][3][4][5][6][7][8][9][10]. Further to this, key developments in synthetic strategies and analytical techniques for tritium labelling over the past three decades now makes this the preferred technique for many ADMET studies [5].…”

Deuterium‐ und tritiummarkierte Verbindungen: Anwendungen in den modernen Biowissenschaften

“…Besonders der standardmäßig sehr kleine Versuchsmaßstab erfordert besondere präparative Te chniken und Verfahrensweisen sowie speziell ausgebildete Fachkräfte. [280] Alternativ kann die Wasserstoffaustauschmarkierung eine sehr kosten-und zeiteffiziente Methode sein, wenn sie direkt am Zielmolekülausgeführt wird. [279] Herkçmmlich verwendete Methoden, wie Doppelbindungsreduktion, Hydridreduktion und Tr itium-Halogen-Austausch, erfordern eine vorherige Vorstufensynthese.…”