Abstract: This invention relates generally to non-ionic X-ray contrast agents. It further relates to the preparation of iodine chloride, a key reagent in the synthesis of non-ionic X-ray contrast agents such as iodixanol and iohexol. In particular, the iodine chloride is produced in a reaction involving iodine, sodium chlorate, and hydrochloric acid as the starting materials. The instant invention relates to a method of stabilizing aqueous iodine chloride solutions by adding about one to about four molar equivalents of sodium chloride relative to sodium chlorate to an aqueous reaction mixture of sodium chlorate, hydrochloric acid, and iodine.

Abstract: This invention relates generally to industrial preparation of iodixanol (1,3-bis(acetamido)-N,N?-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane), a non-ionic X-ray contrasting agent. It further relates to a method of recovering intermediate 5-acetamido-N,N-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”) from the desalinated and desolventized dimerisation reaction mixture. In particular, the present invention employs ultrafiltration to recover non-crystalline Compound A to reduce the overall cost of iodixanol manufacture, increase the yield of iodixanol, and facilitate the subsequent purification procedures to meet the regulatory purity requirement of iodixanol.

Abstract: This invention relates generally to industrial preparation of iodixanol (1,3-bis(acetamido)-N,N?-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane), a non-ionic X-ray contrasting agent. It further relates to a method for preparing a crude mixture of the dimerisation reaction from 5-acetamido-N,N-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”) to iodixanol for the crystallization of iodixanol. In particular, it relates to an industrial procedure of simultaneously reducing the salt content and the alcoholic dimerisation solvent using a nanofiltration system prior to the crystallization of iodixanol.

Abstract: This invention relates generally to the crystallization process of 5-amino-N,N?-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (“Compound B”), an iodinated intermediate in the preparation of non-ionic X-ray contrast agents. The instant process utilizes a nanofiltration system to pass through low molecular weight salt, thereby reducing the solubility of Compound B in the retentate. This process increases supersaturation of the mother liquor and improves crystal growth in the crystallization following the initial one. The process of the present invention is useful in increasing the overall crystallization yield of Compound B in an industrial manufacturing process.

Abstract: Process for the preparation of contrast agents The invention provides a process for the preparation of an N-alkyl-acylamino-phenyl-carboxylic acid or carboxylic acid derivative by liquid phase acylation and subsequent N-alkylation of a corresponding amino-phenyl-carboxylic acid (or carboxylic acid derivative), the improvement comprising the addition of an alkylating agent to a solution containing the reaction products of said acylation, to effect said N-alkylation.

Abstract: The invention provides a process for the production of iohexol comprising reacting 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodophthalamide with a 2,3-dihydroxypropylating agent, the improvement comprising effecting that said process in the presence of a solvent comprising 2-methoxy-ethanol and, optionally, isopropanol.

Abstract: The invention provides a process for the production of iohexol comprising reacting 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodophthalamide with a 2,3-dihydroxypropylating agent, the improvement comprising effecting that said process in the presence of a solvent comprising 2-methoxy-ethanol and, optionally, isopropanol.

Abstract: The invention provides a process for the preparation of an N-alkyl-acylamino-phenyl-carboxylic acid or carboxylic acid derivative by liquid phase acylation and subsequent N-alkylation of a corresponding amino-phenyl-carboxylic acid (or carboxylic acid derivative), the improvement comprising the addition of an alkylating agent to a solution containing the reaction products of said acylation, to effect said N-alkylation.