Efficient One-Pot Synthesis of the GABA_B Positive Allosteric Modulator (R,S)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one

Abstract

The GABA_B positive allosteric modulator (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (1) was synthesized in one pot from the anhydrous lithium salt of 2,4-di-tert-butylphenol and methyl trifluoropyruvate mediated by a stoichiometric amount of anhydrous gallium(III) chloride in 64% overall yield. The enantiomers of 1 were separated by chiral-phase HPLC (Chiralpak AD®), and the absolute configuration was determined by X-ray crystallography.

Keywords:

• (R,S)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one
• GABA_B positive allosteric modulator
• gallium(III) chloride
• one-pot synthesis

ACKNOWLEDGMENTS

We thank Daniel Zimmerli for separation of the enantiomers of 1 and the analytical department PRBD-E for measuring and interpreting ¹HNMR and MS spectra.