Process for the preparation of intermediates useful in the preparation of non-ionic contrast agents

A process for the preparation of two or more intermediate chemical compounds useful in the preparation of one or more non-ionic contrast agents, comprising

• conducting a multi-step chemical synthesis comprising two or more sequential chemical reactions,
• each sequential chemical reaction leading to the production of at least one of the two or more intermediate chemical compounds;
• the two or more sequential reactions being carried out in one or more continuous flow reactors, wherein at least two of the two or more sequential reactions are carried out consecutively without interruption;
• wherein the two or more sequential chemical reactions are selected from either set (i) of sequential steps, or set (ii) of sequential steps, as follows:
• (i) sequential steps:
• i-a) amidation,
• i-b) reduction of a nitro group via hydrogenation,
• i-c) iodination,
• i-d) acylation, and
• i-e) selective hydrolysis;
• or
• (ii) sequential steps:
• ii-a) reduction of a nitro group via hydrogenation,
• ii-b) iodination,
• ii-c) nucleophilic acyl substitution, and
• ii-d) acylation;
• wherein the non-ionic contrast agent comprises one or more of iohexol and iodixanol, and said intermediate chemical compounds useful in the preparation of the non-ionic contrast agents are one or more of the compounds of formula II, III, IV, V and VI:
• or
• wherein the non-ionic contrast agent is iopamidol, and said intermediate chemical compounds useful in the preparation of the non-ionic contrast agent are one or more of the compounds of formula VIII, IX, X, XI and XII: