Process for the preparation of macrocyclic chelant 2,2′,2″-(10-(2-hydroxypropyl)-1,4,7,10-tetra azacyclododecane-1,4,7-triyl) triacetic acid and it's complexes with paramagnetic metal ions

A process for the preparation of Gadoteridol of formula (1a) having purity greater than 99.5%

• comprising:
• a. reacting 1,4,7,10-tetraazacyclododecane of formula (6)
• with tert-butyl 2-bromoacetate of formula (5)
• to obtain tert-butyl 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate hydrobromide of formula (4);
• b. hydrolyzing tert-butyl 2,2′,2″-(1,4,7,10-tetraazacyclo dodecane-1,4,7-triyl) triacetate hydrobromide of formula (4) to 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid of formula (3), optionally isolating intermediate of formula (3);
• c. alkylating 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid compound of formula (3) with propylene oxide of formula (2)
• and treating with a suitable acidic resin furnished chelating ligand 2,2′,2″-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclo dodecane-1,4,7-triyl) triacetic acid of formula (1);
• and
• d. complexing 2,2′,2″-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid of formula (1) with Gadolinium oxide to yield Gadoteridol of formula (1a). Optionally purifying formula (1a), which comprises of;
• a) providing a solution of Gadoteridol of formula (1a) in protic solvent or mixture of solvents thereof;
• b) treating with a suitable acidic resin;
• c) optionally, filtering the reaction mass;
• d) treating with a suitable basic resin;
• and
• e) isolating pure Gadoteridol of formula (1a).

A process for the purification of Gadoteridol of formula (1a) comprising;

• a. providing a solution of Gadoteridol of formula (1a) in protic solvent or mixture of solvents thereof;
• b. adjusting the pH of the solution to 3.0 to 4.0 using suitable acidic resin;
• c. optionally, filtering the reaction mass;
• d. adjusting the pH of the solution to 7.0-8.0 by adding suitable basic resin;
• and
• e. isolating pure Gadoteridol of formula (1a).