Methods of making cross-bridged macropolycycles

A method for preparing a cross-bridged macropolycycle, said method comprising derivatizing N,N′-bis-(2-aminoethyl)-1,3-propanediamine by a series of steps including:

• quaternizing an intermediate using a quaternizing agent, wherein said step is carried out using less than fifteen-fold of said quaternizing agent;
• and
• reducing a diquaternized intermediate, wherein said step is carried out using an amount less than fifteen-fold of reducing agent;
• and wherein further said series of steps is carried out using one solvent system and in the absence of any step of vacuum distilling an intermediate.