Synthesis of TAK-218 using (R)-2-methylglycidyl tosylate as a chiral building block

We performed an asymmetric synthesis of (S)-2,3-dihydro-2,4,6,7-tetramethyl -2-[(4-phenyl-1-piperidinyl)-methyl]-5-benzofuranamine dihydrochloride (TAK -218, 1), a compound used for the treatment of traumatic and ischemic centr al nervous system injuries. Oxirane 6, which was synthesized from (R)-2-met hylglycidyl tosylate, was treated with aqueous trifluoroacetic acid to affo rd benzofuranmethanol 7 with inversion of stereochemistry at the stereogeni c center. Compound 7 was converted into 1 with high enantiomeric excess in four steps. (C) 1999 Elsevier Science Ltd. All rights reserved.