Patent EA-003253-B1 (EA)
Title: A process for preparation of n,n'-bis[2,3-dihydroxypropyl]-5-[(hydroxyacetyl)metilamino]-2,4,6-triodo-1,3-benzenedi carboxamide
Inventor: ALLESANDRONI LAURA
IPC: C07B61/00
Filed: 1999-11-25
Abstract: 1. A process for the preparation of N,N'-bis[2,3-dihydroxupropyl]-5[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzendicarboxylic comprising the following steps: a) esterification of 5-hydroxy-1,3-benzenedicarboxylic acid n-butyl and acidic catalysis to give 5-hydroxy-1,3-benzenedicarboxylic acid n-butyl diester(VIII); b) amidation of compond (VIII) with an isoserinol excess, to give an aqueous solution of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzene-dicarboxamide, which is optionally transformed in the sodium salt (III); c) iodination of compound (III) with ICl, in stoichiometric amount of in a 1% excess, to give N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triodo-1,3-benzene-dicarboxamide (IV); d) alkylation of compound (IV) with compound (IX), 2-chloro-N-methyl-acetamidc, in aqueous solution, to give N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[2-methylamino)-2oxocthoxy]-1,3-benzene-dicarboxamide (VII), which is used as humid product; finally, e) Smiles' rearrangement of compound (VII) in basic conditions and subsequent purification to give Iomeprol (I), according to the following scheme: 2. A process as claimed in claim 2, in which a catalytic amount of H2SO4 or p-toluenesulfonic acid, equivalent to 6% by mol, is used. 3. A process according to claim 1-2, in which compound (VIII) is recovered by direct crystallization from the final reaction mixture, which has previously been concentrated, by cooling. 4. A process according to claim 1-2, in which compound (VIII) is recovered by precipitation from an alkali aqueous solution, previously removing the organic solvent to a melted residue, which is subsequently treated with an inorganic base or ammonia aqueous solution, then subjected to controlled cooling to obtain compound (VIII) as partially crystalline solid. 5. A process as claimed in claim 4, in which compound (VIII) recovered as solid is redissolved in n-butanol to give a solution which is used as such in the subsuquent step. 6. A process as claimed in claim 1-2, in which, instead of recovering of n-butalic diester(VIII),getting after the step (a), at the end of amidating of compound by isoserinol the reaction mixture is diluted with water, then purified from the isoserinol excess through a first column containing a strongly acidic cation exchange resin and from the ionic impurities through a second weakly basic anion exchange resin, connected in series with the first column. 7. A process as claimed in claim 1-4, in which step b) is carried out in mass in a 120% isoserinol excess, at a temperature of 90-95 degree C., for a time of about 12 hours, distilling off under vacuum the n-butanol formed in the reaction, treating the mass with water after completion of the reaction, to obtain an aqueous solution which is purified through a cation exchange resin and adjusted to pH 9-10 with NaOH to give the aqueous solution of the sodium salt corresponding to the compound (III). 8. A process as claimed in claim 5, in which before the reaction step (b) the solvent is removed to obtain compound (VIII) as a melted residue, which is finally treated under the conditions of claim 7. 9. A process as claimed in claim 7-8, in which the excess isoserinol is recovered and recycled in the process by elution from the resin with a diluted ammonia solution, the solution is concentrated to a residue and then purified by formation of isoserinol oxalate in ethanol solution and subsequent purification through a strongly acidic polystyrene matrix ion exchange cationic resin, isoserinol being recovered by elution with a diluted ammonia solution. 10. A process as claimed in claim 1-9, in which iodination is effected using ICl in neutral aqueous solution as iodinating agent, at pH ranging from 6 to 7, at room temperature, controlling by means of a potentiometer that the addition of iodinating agent is equivalent to the stoichiometric amount or to a slight excess (about 1%), to give a solution which is directly subjected to the subsequent alkylation step. 11. A process as claimed in claim 1, in which alkylation of compound (IV) with compound (IX) is carried out at neutral pH and at a temperature of 95 degree C, the alkylating agent being added in amounts of 1.8-2.2 mol per mol of substrate, at the end of the reaction the resulting suspension being cooled and fed to the recovery step of compound (VII).