Phosphoramidate alkylator prodrugs
Phosphoramidate alkylator prodrugs can be used to treat cancer when administered alone or in combination with one or more anti-neoplastic agents.
1. A method to synthesize a compound having formula I:
or a pharmaceutically acceptable salt thereof; wherein each X 4 is halo; and T is:
comprising reacting a compound having the formula T-OH, a tri-substituted phosphine, a compound of the formula
and a dialkyl azodicarboxylate to yield the compound of formula I.
2. The method of claim 1 , wherein X 4 is chloro.
3. The method of claim 2 , wherein X 4 is bromo.
4. The method of claim 3 , wherein the compound of the formula:
is made by reacting bromoethylammonium bromide, phosphoryl chloride and triethyl amine.
5. The method of any one of the preceding claims, wherein each substituent in 2 the trisubstituted phosphine is independently selected from [H], C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and C 1 -C 6 alkoxy.
6. The method of claim 5 , wherein the trisubstituted phosphine is selected from the group consisting of triphenylphosphine, tributylphosphine, tripropylphosphine, triethylphosphine, trimethylphosphine and tributylphosphite.
7. The method of claim 5 , wherein the trisubstituted phosphine is triphenylphosphine.
8. The method of claim 1 , wherein the dialkyl azodicarboxylate is diethyl or diisopropyl azodicarboxylate.
9. The method of claim 8 , wherein the dialkyl azodicarboxylate is diisopropyl azodicarboxylate.