Electrochemical iodination of N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide

Patent metadata

Field	Value
Publication number	US-12129563-B2
Application number	US-202218694306-A
Country	US
Kind code	B2
Filing date	Sep 22, 2022
Priority date	Sep 24, 2021
Publication date	Oct 29, 2024
Grant date	Oct 29, 2024

Abstract

The invention is related to a process for preparing a iodinating X-rays contrast agent. More specifically, it relates to a process for the preparation of N,N′-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxaniide (I) by electrochemical iodination of N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with molecular iodine (I2) which is in situ electrochemically generated from a source of iodide ions (I−). The iodide ions (I−) are obtained by the dissolution of hydrogen iodide (HI) or an alkali metal iodide in the reaction medium or produced during the reaction of N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide with I2. The invention also relates to the use of the intermediate compound of formula (I), obtained through the above electrochemical iodination of compound (II), in the preparation of N,N′-bis[2,3-dihydroxypropyl]-5(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide (iomeprol).

First claim

The invention claimed is:

1. A process for the preparation of N,N′-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I), comprising the steps of:
a) dissolving N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) in a reaction medium in the presence of molecular iodine (I 2 ) and
b) iodinating said compound (II) with the molecular iodine (I 2 ) to obtain said compound (I), wherein the reaction medium is an aqueous solution and the molecular iodine (I 2 ) is in situ electrochemically generated from a source of iodide ions (I − ) and wherein steps a) and b) are carried out in

galvanostatic mode using an undivided electrolytic cell or
in potentiostatic mode using an electrolytic cell formed by two-compartments divided by a porous septum or by a ionic exchange membrane.

2. The process according to claim 1 wherein the aqueous solution is water.

3. The process according to claim 1 , wherein the molecular iodine (I 2 ) is electrochemically generated from the source of iodide ions (I − ) by applying a constant electric current, and wherein the source of iodide ions (I − ) is selected from HI and an alkali metal iodide.

4. The process according to claim 3 , wherein the applied electric current is comprised in the range from 5 to 100 mA/cm 2 .

5. The process according to claim 3 , wherein the alkali metal iodide is NaI or KI.

6. The process according to claim 1 , wherein in galvanostatic mode said molecular iodine (I 2 ) is electrochemically re-generated from iodide ions (I − ) produced by the reaction of N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with I 2 by applying a constant electric current which is switched on after a time ranging from 1 hour to 6 hours.

7. The process according to claim 6 , wherein the reaction medium is kept at a pH comprised in the range from 5 to 7.5 by addition of a protic acid and at a temperature comprised between 40°° C. and 60° C.

8. The process according to claim 1 , wherein in potentiostatic mode said molecular iodine (I 2 ) is electrochemically re-generated from iodide ions (I − ) produced by the reaction of N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with I 2 by applying a constant voltage producing an anode potential from 0.5 to 0.9 V vs SCE (saturated calomel electrode).

9. The process according to claim 8 , wherein the reaction medium is kept at a pH from 10 to 12 by addition of a strong base and at a temperature comprised between 50° C. and 70° C.

10. The process according to claim 1 , wherein the two compartments of the cell are separated by said ionic exchange membrane selected from a cationic membrane.

11. The process according to claim 1 , wherein the two-compartments electrolytic cell comprises an anodic compartment filled with an aqueous solution of compound (II) and I 2 according to step a) of claim 1 (anolyte) and a cathodic compartment filled with a 0.1-0.5 M NaOH solution (catholyte).

12. The process according to claim 11 which is carried out in flux conditions by recirculating the aqueous solution of compound (II) and I 2 (anolyte) and the 0.1-0.5 M NaOH solution (catholyte).

13. The process according to claim 1 further comprising the following step:
c) isolating the N,N′-bis-(2,3-dihydroxypropyl)-5-hydroxy-2 4,6-triiodo-1,3-benzenedicarboxamide (I) obtained through the electrochemical iodination of N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II).

14. The process according to claim 1 , wherein said molecular iodine (I 2 ) is electrochemically re-generated from iodide ions (I − ) produced by the reaction of N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with I 2 by applying a constant voltage producing an anode potential from 0.65 to 0.7 V vs SCE (saturated calomel electrode).

15. A process for preparing N,N′-bis-[2,3-dihydroxypropyl]-5-(hydroxyacetyl) methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide (IV) comprising the steps of:
a) dissolving N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) in a reaction medium in the presence of molecular iodine (I 2 );
b) iodinating said compound (II) with the molecular iodine (I 2 ) to obtain N,N′-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I);
c) isolating said compound (I);
d) reacting said compound (I) with CICH 2 (CO) NHCH 3 to obtain the intermediate (III)

e) subjecting said intermediate (III) to Smile's rearrangement in the presence of a base, so as to obtain N,N′-bis [2,3-dihydroxypropyl]-5-(hydroxyacetyl) methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide (IV)

wherein the reaction medium of step a) is an aqueous solution, and the molecular iodine (I 2 ) in step b) is in situ electrochemically generated from a source of iodide ions (I − ) and wherein steps a) and b) are carried out in
galvanostatic mode using an undivided electrolytic cell or
in potentiostatic mode using an electrolytic cell formed by two-compartments divided by a porous septum or by a ionic exchange membrane.

Assignees

• Bracco Imaging Spa

Inventors

• Lattuada Luciano
• Cavallotti Camilla
• Giovenzana Giovanni Battista
• Uggeri Fulvio
• Minguzzi Alessandro
• Vertova Alberto
• Sorti Letizia
• Morelli Carlo

Classifications

• C07C237/46

  having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring · CPC title

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title

• C25B3/11

  Halogen containing compounds · CPC title

• C25B3/09

  Nitrogen containing compounds · CPC title

• C25B15/087

  Recycling of electrolyte to electrochemical cell · CPC title