Synthesis of deuterated optically active verapamil and gallopamil, and of N ‐ 13 C‐methyl‐verapamil

Deuterated (‐)‐verapamil, (2S)‐(‐)‐2‐(2,5,6‐ 2 H 3 ‐3,4‐dimethoxyphenyl)‐2‐isopropyl‐5‐[(2,5,6‐ 2 H 3 ‐3,4‐dimethoxyphenethyl)methylamino]valeronitrile, and its analog (‐)‐ 2 H 5 ‐gallopamil, (2S)‐(‐)‐2‐(2,6‐ 2 H 2 ‐3,4,5‐trimethoxyphenyl)‐2‐isopropyl‐5‐[(2,5,6‐ 2 H 3 ‐3,4‐dimethoxyphenethyl)methylamino]valeronitrile, were prepared. (‐)‐Gallopamil readily incorporated five atoms of deuterium into the available positions in the aromatic rings. (‐)‐ 2 H 6 ‐Verapamil was prepared from ring trideuterated 3,4‐dimethoxyphenylacetic acid and (2S)‐(+)‐triphenyl‐methoxy‐2‐[(methanesulfonyl)oxy]propane. Three additional atoms of deuterium were incorporated into the aromatic ring of the N ‐methyl‐3,4‐dimethoxyphenethylamine moiety incorporated as the the short N ‐alkyl side chain. N ‐ 13 C‐Methylverapamil was prepared from N ‐ 13 C‐methyl‐3,4‐dimethoxyphenethylamine.