title: Synthesis of enantiomerically pure [14C]-labelled morpholine derivatives for a class of trace amine-associate receptor 1 agonists.
abstract: Various agonists of the trace amine-associate receptor 1, under consideration as potential clinical development candidates, were labelled with carbon-14 for use in preclinical in vitro and in vivo drug metabolism studies. Herein, the [14C]-radiosynthesis of 2-phenyl-substituted morpholines 1 is described. After evaluating and optimizing different synthetic routes, 4-iodonitrobenzene 3 was selected as starting material for the 14-step synthesis. Incorporation of carbon-14 into the acetyl moiety allowed a safe and efficient synthesis of [14C]-labelled 4-nitroacetophenone 2 in five steps and 38% yield. Further transformation of 2 to the target compounds 1 was achieved in a 9-step synthesis. In a representative example, [14C]-labelled 1 was obtained in an overall yield of 11% and was isolated in >99% radiochemical purity and a specific activity of 47 mCi/mmol.
authors.affiliation: Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Edelmann
authors.affiliation: Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.affiliation: Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: René
authors.initials: R
authors.lastname: Trussardi
authors.affiliation: Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Iding
authors.affiliation: Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Guido
authors.initials: G
authors.lastname: Galley
authors.affiliation: Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pflieger
authors.affiliation: Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Norcross
mesh_terms: D002250:Carbon Radioisotopes / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D007553:Isotope Labeling; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D000095383:Trace Amine-Associated Receptors
chemical_list: D002250:Carbon Radioisotopes; D009025:Morpholines; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors
keywords: TAAR1; biocatalysis; carbon-14; cyanation; enantioselective reduction; radiosynthesis