Preparation of iodixanol

Abstract

A process for the preparation of iodixanol by dimerisation of 5-acetamido-N,N′-bis (2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (“Compound A”) in which, after the dimerisation step, unreacted Compound A is precipitated from the reaction mixture and recovered for re-use. The process substantially increases the net yield of iodixanol and simplifies its purification.

1 . A process in which iodixanol is prepared in a series of successive processes by dimerisation of 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (“Compound A”) in which, after the dimerisation step, unreacted Compound A is precipitated from the reaction mixture and recovered, optionally crystallised, and then re-used in a subsequent process in the series. 
     
     
         2 . A process according to  claim 1  in which the dimerisation step is carried out using epichlorohydrin, 1,3-dichloro-2-hydroxypropane or 1,3-dibromo-2-hydroxypropane as the dimerisation agent in a non-aqueous solvent or in water or a mixture of water and one or more alcohols. 
     
     
         3 . A process according to  claim 2  in which the dimerisation agent is epichlorohydrin and the solvent is 2-methoxyethanol or methanol. 
     
     
         4 . A process according to  claim 1  in which precipitation of Compound A is effected with water, optionally together with an alcoholic co-solvent. 
     
     
         5 . A process according to  claim 4  in which the pH of the mixture is adjusted to 10-11 with acid to provoke precipitation, the temperature adjusted if necessary to 15-40 C and the solution optionally seeded with crystals of Compound A. 
     
     
         6 . A process according to  claim 5  in which further acid is added to a pH of 2-5. 
     
     
         7 . A process according to  claim 1  in which the Compound A recovered is recrystallised. 
     
     
         8 . A process according to  claim 1  in which, after separation of Compound A, the iodixanol-containing mixture is purified without the use of chromatographic methods. 
     
     
         9 . A process according to  claim 1  in which the recovered Compound A is re-used in a subsequent process for the preparation of iodixanol.