Gadomelitol, P-792, Vistarem

Chemical Name: Hydrogen [2,2',2'',2'''-[1,4,7,10-tetraazacyclododecane-1,4,7,10-triyl]tetrakis[5-[[2-[[4- [[4-[[2-[[3,5-bis[bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl-2,4,6-tribromo]carbamoyl]phenyl]amino]-2-oxoethyl]carbamoyl]phenyl]carbamoyl]phenyl]amino]-2-oxoethyl]amino]-5-oxopentanoato](4-)]gadolinate(1-); Hydrogen [[1,1',1'',1''',1'''',1''''',1'''''',1''''''',1'''''''',1''''''''',1'''''''''',1''''''''''',1'''''''''''',1''''''''''''',1'''''''''''''',1'''''''''''''''-[(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-kappaN1,kappaN4,kappaN7,kappaN10)tetrakis[[4-(carboxy-kappaO)-1-oxo-4,1-butanediyl]imino(1-oxo-2,1-ethanediyl)imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino(1-oxo-2,1-ethanediyl)imino(2,4,6-tribromo-5,1,3-benzenetriyl)bis(carbonylnitrilo)]]hexadecakis[1-deoxy-D-glucitolato]](4-)]gadolinate(1-)
CAS No. 227622-74-4
项目整合开发状态: Phase II
项目研究机构: Guerbet (Originator)
合成路线:Alkylation of tetraazacyclodecane (I) with ethyl 2-bromobutyrate (II) afforded the tetrasubstituted macrocycle (III) as a mixture of diastereoisomers.Subsequent hydrolysis of the ethyl ester groups of (III) using ethanolic NaOH gave the octacarboxylic acid (IV).Complexation of (IV) with either Gd2O3 or GdCl3 and NaOH generated the corresponding gadolinium chelate.The mixture of diastereoisomeric chelates was then isomerized under acidic conditions to furnish the racemic pair of R,R,R,R and S,S,S,S isomers (V).

合成路线:Coupling between 4-nitrobenzoyl chloride (VI) and 4-aminobenzoic acid (VII) afforded nitrobenzamide (VIII),which was further reduced to amine (IX) by catalytic hydrogenation over Pd/C.Acylation of (IX) with phthalimidoacetyl chloride (X) yielded diamide (XI).The carboxyl group of (XI) was then activated as the corresponding acid chloride (XII) by treatment with SOCl2.Then,condensation of the glycylamide derivative (XIII) with acid chloride (XII) furnished amide (XIV).

合成路线:Deprotection of the phthaloyl group of (XIV) by hydrazinolysis provided amine (XV).This was then coupled with the octaacid gadolinium chelate (V) in the presence of EDC and HOBt leading to the target amide.