Improved synthesis of ¹³C,²H₃- and ²H₃-salmeterol by Cs₂CO₃-mediated monoalkylation of a primary amine

An abbreviated synthesis of isotopically labelled salmeterol has been achieved. The key improvement utilizes a highly selective Cs₂CO₃-mediated one-pot alkylation of benzylamine by 6-bromo-1-(4′-phenylbutoxy)hexane to prepare the limiting reagent, 6-N-benzylamino-1-(4′-phenylbutoxy)hexane without overalkylation. The method was applied to synthesis of the title compounds in >97 at% isotopic purity.