Improved Syntheses of the Mglu₅ Antagonists MMPEP and MTEP Using Sonogashira Cross-Coupling

Boshuai Mu; Linjing Mu; Roger Schibli; Simon M Ametamey; Selena Milicevic Sephton

doi:10.3390/ph11010024

Improved Syntheses of the Mglu₅ Antagonists MMPEP and MTEP Using Sonogashira Cross-Coupling

Pharmaceuticals (Basel). 2018 Feb 20;11(1):24. doi: 10.3390/ph11010024.

Authors

Boshuai Mu¹, Linjing Mu^{2

3}, Roger Schibli^{4

5}, Simon M Ametamey⁶, Selena Milicevic Sephton^{7

8

9}

Affiliations

¹ Center of Radiopharmaceutical Sciences of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland. boshuai_mu@163.com.
² Center of Radiopharmaceutical Sciences of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland. linjing.mu@pharma.ethz.ch.
³ Department of Nuclear Medicine, University Hospital Zurich, Ramistrasse 101, 8003 Zurich, Switzerland. linjing.mu@pharma.ethz.ch.
⁴ Center of Radiopharmaceutical Sciences of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland. roger.schibli@psi.ch.
⁵ Department of Nuclear Medicine, University Hospital Zurich, Ramistrasse 101, 8003 Zurich, Switzerland. roger.schibli@psi.ch.
⁶ Center of Radiopharmaceutical Sciences of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland. simon.ametamey@pharma.ethz.ch.
⁷ Center of Radiopharmaceutical Sciences of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland. sms96@wbic.cam.ac.uk.
⁸ Department of Nuclear Medicine, University Hospital Zurich, Ramistrasse 101, 8003 Zurich, Switzerland. sms96@wbic.cam.ac.uk.
⁹ Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Box 65 Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.. sms96@wbic.cam.ac.uk.

Abstract

The Sonogashira cross-coupling, a key step in the syntheses of the mGlu₅ antagonists MMPEP and MTEP, provided an improved three-step method for the preparation of MMPEP in 62% overall yield. Using Spartan molecular modeling kit an explanation for the failure to employ analogues method in the synthesis of MTEP was sought. The DFT calculations indicated that meaningful isolated yields were obtained when the HOMO energy of the aryl halide was lower than the HOMO energy of the respective alkyne.

Keywords: MMPEP; MTEP; Sonogashira cross-coupling; mGlu5 antagonist.