Methods of chemical systhesis of phenolic nitrogen mustard prodrugs

A method of synthesis comprising the steps of, in order:

• glutamate conjugation (GC), in which a 4-[N,N-bis(2-silyloxyethyl)aminolphenyl haloformate, activated carbonate, or activated carbamate 5, reacts with a glutamate, 15, to give an N-{4-[N,N-bis(2-silyloxyethyl)amino]phenoxycarbonyl}-L-glutamate, 6:
• silyloxy deprotection (SD), in which said N-{4-[N,N-bis(2-silyloxyethyl)amino]phenoxy-carbonyl}-L-glutamate, 6, is converted to an N-{4-[N,N-bis(2-hydroxyethyl)amino]phenoxycarbonyl}-L-glutamate, 7:
• sulfonic esterification (SE), in which said N-{4-[N,N-bis(2-hydroxyethyl)amino]phenoxycarbonyl}-L-glutamate, 7, is converted to an N-{4-[N,N-bis(2-sulfonyloxyethyl)amino]phenoxycarbonyl}-L-glutamate, 8:
• wherein:
• X1 is a leaving group;
• n is an integer from 0 to 4;
• each RA is independently an aryl substituent;
• each RB is a silyl substituent, and is independently C1-7alkyl, C3-20heterocyclyl, or C5-20aryl, and is optionally substituted;
• each RC is a sulfonic substituent, and is independently C1-7alkyl, C3-20heterocyclyl, or C5-20aryl, and is optionally substituted;
• and,
• each Z2 is independently a carboxylic acid protecting group.