Metal complexes of tetraazamacrocycle derivatives
View Patent ↗Improved methods for synthesizing bifunctional chelates of tetraazamacrocycle derivatives and intermediates thereof are disclosed as well as novel tetraazamacrocycle derivatives and intermediates thereof.
1. A process for alkylating the free macrocyclic nitrogen of a trisalkylated tetraazamacrocycle of Formula 1 to yield a compound of Formula 2, the process comprising alkylating the free macrocyclic nitrogen with an alkylating agent, R 4 Y, in an organic solvent in the presence of a weak base
wherein the weak base comprises a metal ion M, R 1 , R 2 and R 3 are independently hydrocarbyl, substituted hydrocarbyl or heterocyclo; R 4 is optionally substituted, alkyl or aryl, X is a counterion; and Y is a leaving group.
2. The process according to claim 1 wherein M is selected from alkali metals, alkaline earth metals, transition metals and the lanthanides; R 1 , R 2 and R 3 are independently hydrocarbyl, substituted hydrocarbyl or heterocyclo; R 4 is an optionally substituted alkyl, aryl or acyl; X comprises halides, nitrates, sulfates or phosphates; and Y comprises the halides, methanesulfonate, trifluoroacetate, trifluormethanesulfonate or p-toluene-sulfonate.
3. The process according to claim 1 wherein R 1 , R 2 and R 3 are independently selected from the group consisting of —CH 2 CO 2 R 5 , —CH 2 ArOR 5 , —CH 2 SR 5 , —CH 2 PO 3 H 2 , —CH 2 SO 3 H, —CH 2 Ar(OR 5 ) 2 , —CH 2 Ar(OR 5 )R 6 and —CH 2 Ar(OR 5 ) 2 R 6 ; wherein R 5 and R 6 are independently H, t-Bu, Et, Me, benzyl or methoxybenzyl.
4. The process according to claim 1 wherein R 4 is —CH 2 ArOR 7 , —CH(R 8 )CO 2 R 7 , —CH 2 Ar(OR 7 ) 2 , —CH 2 Ar(OR 7 )R 8 , or —CH 2 Ar(OR 7 ) 2 R 8 ; R 7 is H, t-Bu, Et or Me; R 8 is selected from the group consisting of optionally substituted acyl, aryl and heteroaryl, alkoxy, hydroxy, halo, amino, nitro, thiols, disulfides, carbohydrates, vitamins, and combinations and derivatives thereof; and Ar is an optionally substituted phenyl, pyrimidinyl or pyridinyl.
5. The process according to claim 1 , wherein
R 1 , R 2 and R 3 are independently selected from the group consisting of —CH 2 CO 2 R 5 , —CH 2 ArOR 5 , —CH 2 SR 5 , —CH 2 PO 3 H 2 , —CH 2 SO 3 H, —CH 2 Ar(OR 5 ) 2 , —CH 2 Ar(OR 5 )R 6 and —CH 2 Ar(OR 5 ) 2 R 6 ;
R 4 is —CH 2 ArOR 7 , —CH(R 8 )CO 2 R 7 , —CH 2 Ar(OR 7 ) 2 , —CH 2 Ar(OR 7 )R 8 , or —CH 2 Ar(OR 7 ) 2 R 8 ;
R 5 , R 6 and R 7 are independently hydrogen, alkyl or substituted alkyl;
R 8 is selected from a group consisting of optionally substituted acyl, aryl and heteroaryl, alkoxy, hydroxy, halo, amino, nitro, thiols, disulfides, carbohydrates, vitamins, combinations and derivatives;
Ar is an optionally substituted phenyl, pyrimidinyl or pyridinyl; and
Y is a leaving group selected from the group consisting of bromide, chloride, iodide, methanesulfonate, trifluoroacetate, trifluormethanesulfonate and p-toluenesulfonate.
6. The process according to claim 5 wherein R 1 , R 2 and R 3 are independently —CH 2 CO 2 R 5 ; and R 5 is H, t-Bu, Et, Me, benzyl or benzylmethoxy.
7. The process according to claim 5 wherein R 4 is —CH 2 Ar(OR 5 )NO 2 or —CH(CO 2 R 5 )—(CH 2 ) 4 NHCO 2 CH 2 Ar.
8. The process according to claim 7 wherein Ar is phenyl, M is sodium and Y is bromide.