Synthesis of (18) F-Difluoromethylarenes from Aryl (Pseudo) Halides

Hang Shi; Augustin Braun; Lu Wang; Steven H Liang; Neil Vasdev; Tobias Ritter

doi:10.1002/anie.201604106

Synthesis of (18) F-Difluoromethylarenes from Aryl (Pseudo) Halides

Angew Chem Int Ed Engl. 2016 Aug 26;55(36):10786-90. doi: 10.1002/anie.201604106. Epub 2016 Aug 5.

Authors

Hang Shi^{1

2}, Augustin Braun¹, Lu Wang², Steven H Liang^{3

4}, Neil Vasdev^{5

6}, Tobias Ritter^{7

8

9}

Affiliations

¹ Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
² Division of Nuclear Medicine and Molecular Imaging & Gordon Center for Medical Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
³ Division of Nuclear Medicine and Molecular Imaging & Gordon Center for Medical Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. liang.steven@mgh.harvard.edu.
⁴ Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. liang.steven@mgh.harvard.edu.
⁵ Division of Nuclear Medicine and Molecular Imaging & Gordon Center for Medical Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. vasdev.neil@mgh.harvard.edu.
⁶ Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. vasdev.neil@mgh.harvard.edu.
⁷ Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA. ritter@chemistry.harvard.edu.
⁸ Division of Nuclear Medicine and Molecular Imaging & Gordon Center for Medical Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. ritter@chemistry.harvard.edu.
⁹ Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470, Mülheim an der Ruhr, Germany. ritter@chemistry.harvard.edu.

Abstract

A general method for the synthesis of [(18) F]difluoromethylarenes from [(18) F]fluoride for radiopharmaceutical discovery is reported. The method is practical, operationally simple, tolerates a wide scope of functional groups, and enables the labeling of a variety of arenes and heteroarenes with radiochemical yields (RCYs, not decay-corrected) from 10 to 60 %. The (18) F-fluorination precursors are readily prepared from aryl chlorides, bromides, iodides, and triflates. Seven (18) F-difluoromethylarene drug analogues and radiopharmaceuticals including Claritin, fluoxetine (Prozac), and [(18) F]DAA1106 were synthesized to show the potential of the method for applications in PET radiopharmaceutical design.

Keywords: aryl (pseudo) halides; difluoromethylarenes; fluorine-18; positron emission tomography; radiopharmaceuticals.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry
Fluorine Radioisotopes / chemistry
Fluoxetine / chemical synthesis
Fluoxetine / chemistry
Halogenation
Isotope Labeling
Loratadine / chemical synthesis
Loratadine / chemistry
Phenyl Ethers / chemical synthesis
Phenyl Ethers / chemistry
Positron-Emission Tomography
Radiopharmaceuticals / chemical synthesis
Radiopharmaceuticals / chemistry*

Substances

Acetamides
DAA 1106
Fluorine Radioisotopes
Phenyl Ethers
Radiopharmaceuticals
Fluoxetine
Loratadine
Fluorine-18

Abstract

Publication types

MeSH terms

Substances

Grants and funding