Preparation of ioforminol, an x-ray contrast agent

Abstract

The present invention relates to a process for the preparation of Ioforminol, a contrast agent useful in X-ray imaging. More particularly, the invention relates to preparation of Ioforminol from a compound mixture comprising 1-formylamino-3,5-bis(2,3-bis(formyloxy)propan-1-ylcarbamoyl)-2,4,6-trioodobenzene by a process comprising in situ hydrolysis and a bis-alkylation.

Claims

1. A process for preparation of Compound (1) ##STR00005## from a composition comprising compound (3) in situ, ##STR00006## wherein each X of compound (3) individually denotes hydrogen, a formyl group (—CO—H) or an acetyl group (—CO—CH3) and the composition of compound (3) comprises 0-15% C.sub.1-C.sub.6 straight or branched alcohol that is mono- or di- hydroxylated; said process comprising, suspending the composition of compound (3) in water such that the amount of water is about 0.25-2.0 litre water/kg compound (3), adjusting and maintaining the pH and temperature of the suspension between 10.0 -12.5 and below room temperature, respectively to allow compound (3) to hydrolyze to compound (2) in water without additives or organic solvent(s), and ##STR00007## adding a dialkylating agent to carry out bis-alkylation of compound (2) to form compound (1) in situ, wherein the process is performed in less than 24 hours and provides a conversion of compound (3) to compound (1) with a yield of 90% or higher.

2. The process of claim 1, wherein the C.sub.1-C.sub.6 straight or branched alcohol is methanol, ethanol, propanol, or iso-propanol.

3. The process of claim 1 wherein the composition comprising compound (3) is a fine powder with low acid content.

4. The process of claim 1 wherein the composition of compound (3) comprises 2-5% alcohol.

5. The process of claim 1, wherein the dialkylating agent is a dihalo-substituted alkanol or halo-substituted heterocycloalkyl.

6. The process of claim 5 wherein the dialkylating agent is epichlorohydrin.

7. The process of claim 1, wherein the temperature of the hydrolysis step is maintained between 12-16 ° C.

8. The process of claim 1, wherein the pH of the hydrolysis step is adjusted by a strong water soluble base and the base is selected from sodium hydroxide and potassium hydroxide.

9. The process of claim 1, wherein the dialkylation agent is selected from 1,3-dichloro-2-propanol, 1-chloro-2,3-propanol, and 1,3-dibromo-2-hydroxypropane.

10. A process for preparation of Compound (1) ##STR00008## from a composition comprising compound (3) in situ, ##STR00009## wherein each X of compound (3) individually denotes hydrogen, a formyl group (—CO—H) or an acetyl group (—CO—CH.sub.3) and the composition of compound (3) comprises 2-5% alcohol; said process comprising, suspending the composition of compound (3) in water such that the amount of water is about 0.25 -2.0 litre water/kg compound (3), adjusting and maintaining the pH and temperature of the suspension between 10.0-12.5 and 12-16 ° C., respectively using a strong water soluble base to allow compound (3) to hydrolyze to compound (2), and ##STR00010## adding a dialkylating agent to carry out bis-alkylation of compound (2) to form compound (1) in situ, wherein the alcohol is methanol, ethanol, propanol, or iso-propanol, wherein the dialkylation agent is selected from 1,3-dichloro-2-propanol, 1-chloro-2,3-propanol, 1,3-dibromo-2-hydroxypropane, and epichlorohydrin, and wherein the process is performed in less than 24 hours and provides a conversion of compound (3) to compound (1) with a yield of 90% or higher.

11. The process of claim 10, wherein the strong water soluble base is sodium hydroxide, potassium hydroxide, or aqueous solution thereof.

12. The process of claim 10, wherein the alcohol is iso-propanol.

13. The process of claim 10, wherein the dialkylation agent is epichlorohydrin.

14. The process of claim 10, wherein the strong water soluble base is aqueous sodium hydroxide.

15. The process of claim 10, wherein the process is carried out in water without additives or organic solvents.

16. The process of claim 10, wherein the process provides a conversion of compound (3) to compound (1) with a yield of 93% or higher.

17. A process for preparation of Compound (1) ##STR00011## from a composition comprising compound (3) in situ, ##STR00012## wherein each X of compound (3) individually denotes hydrogen, a formyl group (—CO—H) or an acetyl group (—CO—CH.sub.3) and the composition of compound (3) comprises 2-5% alcohol; said process comprising, suspending the composition of compound (3) in water such that the amount of water is about 0.25 -2.0 litre water/kg compound (3), adjusting and maintaining the pH and temperature of the suspension between 10.0 -12.5 and 12-16 ° C., respectively using aqueous sodium hydroxide to allow compound (3) to hydrolyze to compound (2), and ##STR00013## adding epichlorohydrin to carry out bis-alkylation of compound (2) to form compound (1) in situ, wherein the alcohol iso-propanol, and wherein the process is performed in less than 24 hours and provides a conversion of compound (3) to compound (1) with a yield of 90% or higher.

18. The process of claim 17, wherein the process is carried out in water without additives or organic solvents.

19. The process of claim 17, wherein the process provides a conversion of compound (3) to compound (1) with a yield of 93% or higher.

Description

EXAMPLES

Example 1

Preparation of Compound (1) from Compound (3)

(1) Compound (3) (1103 kg, 890 mol) was suspended in water (1213 L) using a reactor with overhead mechanical stirring. The suspension was cooled to 10 degrees and aqueous NaOH (50%) was added for 12 h keeping the pH and temperature below 12.5 and 20 degrees, respectively. The solution was cooled to 16 degrees and the pH was set to 11.1 using a pH stat system charged with HCl (30%) and NaOH (50%). The system was left running as long as the temperature was <18 degrees. EPI (41 kg, 445 mol) was added continuously over a period of 2.5 h keeping the temperature between 15-18 degrees. After stirring for 38 h the reaction mixture was quenched by adjusting the pH to 7 using HCl (30%). HPLC showed ˜95.5% UV yield of compound (1).

(2) The dialkylation reaction time was prolonged in this example to ensure completion and maximize the yield. The reaction can be quenched considerably earlier, such as 10-12 hours, without significant loss of yield.