Methods of chemical systhesis of phenolic nitrogen mustard prodrugs

US6916949B2 · kind B2 · utility

Assignee

• Cancer Research Technology Limited · GB

Inventors

• Caroline Joy Springer · London, GB
• Dan Niculescu-Duvaz · Sutton, GB

Key dates

• Filing date: Jan 24, 2002
• Grant date: Jul 12, 2005
• Expiry date: Jan 24, 2022

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07F7/1804
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

Abstract

This invention pertains to novel methods for the synthesis of certain nitrogen mustard prodrugs, such as N-{4-[N,N-bis(2-haloethylamino)-phenoxycarbonyl}-L-glutamic acid: wherein: X2 is a halo group, and is —F, —Cl, —Br, or —I; n is an integer from 0 to 4; and, each RA is an aryl substituent. The methods comprise, at least, the steps of: glutamate conjugation (GC); silyloxy deprotection (SD); and, sulfonic esterification (SU). Certain preferred methods comprise the steps of: amine substitution (AS); silyloxy protection (SP); phenolic deprotection (PD); activation (AC); glutamate conjugation (GC); silyloxy deprotection (SD); sulfonic estenfication (SU); halogenation (HL); glutamate deprotection (GD); and glutamic acid protection (GP).