1,4,7,10-Tetraaza-cyclododecane production, e.g. for use in production of medical imaging contrast agents, from triethylene tetramine or ethylene diamine via new or known tetracyclic bis-aminal intermediates

摘要

Production of 1,4,7,10-tetraaza-cyclododecane (cyclen) (I) from triethylene tetramine (VIII) or ethylene diamine (VIII') involves one-pot preparation of dodecahydro-2a,4a,6a,8a-tetraaza-cyclopenta-(fg)-acenapthylene (IIa) from (VIII) or (VIII'), followed by conversion of (IIa) into (I); or preparation of 8b-methyl-dodecahydro-2a,4a,6a,8a-tetraaza-cyclopenta-(fg)-acenapthylene (IIb) from (VIII) and conversion of (IIb) into (I). Production of 1,4,7,10-tetraaza-cyclododecane (cyclen) of formula (I) from triethylene tetramine of formula NH 2-(CH 2) 2-NH-(CH 2) 2-NH-(CH 2) 2-NH 2(VIII) or ethylene diamine of formula NH 2-(CH 2) 2-NH 2(VIII') involves: (a) one-pot preparation of dodecahydro-2a,4a,6a,8a-tetraaza-cyclopenta-(fg)-acenapthylene of formula (IIa) from (VIII), followed by conversion of (IIa) into (I); (b) preparation of 8b-methyl-dodecahydro-2a,4a,6a,8a-tetraaza-cyclopenta-(fg)-acenapthylene of formula (IIb) from (VIII), followed by conversion of (IIb) into (I); or (c) one-pot preparation of (IIa) from (VIII'), followed by conversion of (IIa) into (I). [Image] Independent claims are included for: (1) the intermediate (IIb) as a new compound; (2) preparation of N-mono-functionalized or N 1,N 7-difunctionalized cyclen derivatives of formula (Va) or (Vb) respectively, by reacting (IIb) with a halo compound of formula R'X (IX) to give (depending on the stoichiometry of the reaction) a mixture of mono-substituted derivatives of formulae (IVa) and (IV'a) or a disubstituted compound of formula (IVb), then subjecting the (IVa)/(IV'a) mixture or (IVb) to alkaline hydrolysis to give (Va) or (Vb) respectively; (3) preparation of bridged cyclen derivatives of formula (VI) by reduction of (IVb); (4) preparation of bridged cyclen derivatives of formula (VII) by hydrogenolysis of (VI); and (5) (IVa), (IV'a), (IVb), (VI) and (VII) as new compounds. [Image] [Image] R' : 1-15C alkyl or -(CH 2) w-Y; w : 1-6 (preferably 1-3); Y : 6-14C aryl (optionally substituted by one or more of halo, 1-4C alkyl, OH, OR 1>, NO 2, NH 2, CONH 2, NHR 2>, CONHR 2>, NR 2>R 3>or CONR 2>R 3>); heteroaryl (preferably containing 1-3 N and 4-12C; and optionally substituted as for aryl); or CN, PO 3H 2, SO 3H, NH 2, CONH 2, NHR 2>1>, CONHR 2>1>, NR 2>1>R 3>1>or CONR 2>1>R 3>1>; R 1>1-4C alkyl, aryl or heteroaryl; R 2>, R 3>1-4C alkyl; R 2>1>, R 3>1>1-4C alkyl or COOR 4>; R 4>H, 1-4C alkyl or aryl (specifically phenyl); X : halogen.