Preparation of an intermediate compound of ioforminol

Abstract

The present invention relates to a process for the preparation of iodinated X-ray contrast agents and in particular to key intermediates thereof. More particularly, the invention relates to a work-up process for preparation of a compound mixture comprising 1-formylamino-3,5-bis(2,3-bis(formyloxy)propan-1-ylcarbamoyl)-2,4,6-trioodobenzene, a key intermediate in the process for preparing Ioforminol. Further, the invention relates to a process for preparing Ioforminol, a contrast agent useful in X-ray imaging.

Claims

1. A process for the preparation of a compound mixture (3) as a powder, wherein the compound mixture (3) comprises two or more compounds of formula (3) ##STR00004## wherein each X individually denotes hydrogen, a formyl group (COH) or an acetyl group (COCH.sub.3), said process comprising: i) formylating the amino function of 5-amino-N.sup.1,N.sup.3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (compound (4)) in the presence of a mixed anhydride comprising an acetyl group to form a product solution; ii) adding isopropanol in situ to the product solution of step i) to form a slurry comprising precipitated compound mixture (3), wherein the concentration of isopropanol is about 0.5 to 1.0 mL per gram of compound (4) and the slurry of step (ii) is stirred for 5-25 hours; and iii) collecting the precipitated compound mixture (3) by filtration.

2. The process of claim 1, further comprising seeding the product solution of step i) with compound mixture (3) before adding isopropanol.

3. The process of claim 1, wherein the concentration of the isopropanol is about 0.6 to about 0.7 ml per gram of compound (4).

4. The process of claim 1, wherein the amount of isopropanol used in step ii) is added in one portion and the process further comprises a step of washing the compound mixture (3) collected in step iii) with one or more portions of isopropanol.

5. The process of claim 1, wherein the compound mixture (3) prepared by the process has a purity of >99%.

6. A process for preparing Ioforminol from a compound mixture (3), the process comprising preparing compound mixture (3) according to the process of claim 1, hydrolyzing compound mixture (3) to form a compound (2), wherein all X in formula (3) are H, and dimerizing compound (2) to form Ioforminol.

7. The process of claim 1, wherein the slurry of step ii) is stirred for 10-20 hours.

8. The process of claim 1, wherein the compound mixture (3) comprises 0-7 wt % isopropanol.

9. A process for the preparation of a compound mixture (3) as a powder, wherein the compound mixture (3) comprises two or more compounds of formula (3) ##STR00005## wherein each X individually denotes hydrogen, a formyl group (COH) or an acetyl group (COCH.sub.3), said process comprising: i) formylating the amino function of 5-amino-N.sup.1,N.sup.3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (compound (4)) in the presence of a mixed anhydride comprising an acetyl group to form a product solution; ii) adding a short chain alcohol in situ to the product solution of step i) to form a slurry comprising precipitated compound mixture (3), wherein the concentration of the short chain alcohol is about 0.3 to 2.0 mL per gram of compound (4) and the slurry of step (ii) is stirred for 5-25 hours; and iii) collecting the precipitated compound mixture (3) by filtration; wherein the short chain alcohol is C1-C6 straight or branched, mono hydroxylated or di hydroxylated, or a mixture thereof.

10. The process of claim 9, further comprising seeding the product solution of step i) with compound mixture (3) before adding the short chain alcohol.

11. The process of claim 9, wherein the concentration of the short chain alcohol is about 0.5 to about 1.0 ml per gram of compound (4).

12. The process of claim 9, wherein the amount of short chain alcohol used in step ii) is added in one portion and the process further comprises a step of washing the compound mixture (3) collected in step iii) with one or more portions of the short chain alcohol.

13. The process of claim 9, wherein the compound mixture (3) in powder form as prepared by the process has a purity of >99%.

14. A process for preparing Ioforminol from a compound mixture (3), the process comprising preparing compound mixture (3) according to the process of claim 9, hydrolyzing compound mixture (3) to form a compound (2), wherein all X in formula (3) are H, and dimerizing compound (2) to form Ioforminol.

15. The process of claim 9, wherein the slurry of step ii) is stirred for 10-20 hours.

16. The process of claim 9, wherein the compound mixture (3) comprises 0-7 wt % short chain alcohol.

17. The process of claim 9, wherein the short chain alcohol is methanol.

18. The process of claim 9, wherein the short chain alcohol is ethanol.

19. The process of claim 9, wherein the short chain alcohol is 1-propanol.

Description

EXAMPLES

Example 1: Preparation of compound mixture (3) comprising 1-formylamino-3,5-bis(2,3-bis(formyloxy)propan-1-ylcarbamoyl)-2,4,6-trioodobenzene

(1) 5-amino-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (compound (4)) (7.5 kg, 10.6 moles) was dissolved in formic acid (4.9 l) and heated to 45? C. until a clear solution was obtained (?4 hours), then the thick amber solution was cooled to 10? C.

(2) Formic acid (9.4 l) was charged into a different reactor and cooled to 10? C., after reaching the target temperature acetic anhydride was added at such a rate that the temperature did not exceeded 15? C.

(3) After 2.5 hours all acetic anhydride was added to the formic acid and the mixed anhydride solution was added drop wise to the compound (4) solution. The rate of addition was adjusted so that the temperature never exceeded 20? C. After 2 hours all mixed anhydride had been added and the reaction was left stirring at 15? C. for additional 1 hour. Isopropanol (4.9 l) was added carefully and the suspension became noticeable thicker and was left stirring at ambient temperature. After 16 hours the reaction slurry was filtered on a vacuum nutch and washed with isopropanol (3*1.5 l) to give compound mixture (3) comprising 1-formylamino-3,5-bis(2,3-bis(formyloxy)propan-1-ylcarbamoyl)-2,4,6-trioodobenzene as a dense white powder (7.98 kg). The quantitative yield with regards to N-formylation was >99%.