# US 5,705,692 A · Process for the preparation of iohexol

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- Number: US 5,705,692 A
- Document ID: US5705692A
- Status: Granted
- Kind: A
- Application number: 08/721,431
- Filed: 1996-09-27
- Granted: 1998-01-06
- Earliest claimed: 1996-09-27
- Assignees: Abbott Laboratories
- Inventors: Xiu C. Wang; Steve A. Chamberlin; Ashok V. Bhatia; Gregg E. Robinson; John Hufnagel
- Web page: https://patentgrep.com/patent/US5705692A

## CPC

- C07C 213/02: by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Provided is a novel process for the preparation of iohexol having improved yields and purity, reduced number of isolated intermediates, and significantly reduced volume of ion-exchange resins required to desalinate the final product.

## Claims

### Claim 1

A process for making iohexol comprising the steps of:
a. combining 5-amino-2,4,6-triiodoisophthalic acid dichloride, acetyl halide, and a solvent selected from N,N-dimethylacetamide, dimethylformamide, or 1-methyl-2-pyrrolidone to form a first reaction mixture;
b. maintaining the first reaction mixture for a period of time sufficient to allow the reaction to proceed to completion;
c. combining 3-amino-1,2-propanediol, N,N-dimethylacetamide, and a base with the first reaction mixture to form a second reaction mixture;
d. maintaining the second reaction mixture for a period of time sufficient for 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide formation;
e. converting 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide to iohexol in the presence of 3-chloro-1,2-propanediol or 3-bromo-1,2-propanediol, base and alcohol; and
f. isolating the iohexol.

### Claim 2 (depends on 1)

The process of claim 1 wherein step (a) uses N,N-dimethylacetamide.

### Claim 3 (depends on 1)

The process of claim 1 wherein the acetyl halide is acetyl chloride or acetyl bromide.

### Claim 4 (depends on 3)

The process of claim 3 wherein the acetyl halide is acetyl chloride.

### Claim 5 (depends on 1)

The process of claim 1 wherein the base of step (c) is lithium hydroxide, lithium alkoxide, lithium carbonate, triethylamine, sodium carbonate, potassium carbonate, and 3-amino-1,2-propanediol.

### Claim 6 (depends on 1)

The process of claim 1 wherein the lithium base of step (e) is lithium hydroxide or lithium alkoxide.

### Claim 7 (depends on 1)

The process of claim 1 wherein the alcohol of step (e) is methanol or ethanol.

### Claim 8 (depends on 7)

The process of claim 7 wherein the alcohol is methanol and the iohexol is precipitated in the presence of isopropyl alcohol, butanol, ethyl acetate, acetonitrile, acetone, or an alcohol of 3-8 carbon atoms.

### Claim 9 (depends on 7)

The process of claim 7 wherein the alcohol is ethanol.

### Claim 10 (depends on 1)

The process of claim 1 further comprising the step of collecting the 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide.

### Claim 11 (depends on 10)

The process of claim 10 wherein the collecting includes precipitating the 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide in ethyl acetate, butanol, acetonitrile, isopropanol, or mixtures thereof.

### Claim 12 (depends on 11)

The process of claim 11 further comprising recrystallization of 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide.

### Claim 13 (depends on 12)

The process of claim 12 wherein the recrystallization of 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide comprises solubilizing the precipitate in water followed by the addition of alcohol sufficient to cause the 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide to precipitate.

### Claim 14 (depends on 8)

The process of claim 8 wherein the iohexol is precipitated in the presence of isopropyl alcohol.

### Claim 15

A process for making iohexol comprising the steps of:
a. combining 5-amino-2,4,6-triiodoisophthalic acid dichloride, acetyl chloride and N,N-dimethylacetamide to form a first reaction mixture;
b. maintaining the first reaction mixture for four to eighteen hours to allow the reaction to proceed to completion;
c. combining 3-amino-1,2-propanediol, N,N-dimethylacetamide, and lithium hydroxide with the first reaction mixture to form a second reaction mixture;
d. maintaining the second reaction mixture for six to eighteen hours to form 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide;
e. adding the reaction mixture to ethyl acetate and isopropanol to precipitate the 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide;
f. converting the 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide to iohexol in the presence of lithium hydroxide and methanol; and
g. isolating the iohexol.

### Claim 16

A process for making 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide comprising the steps of:
a. combining 5-amino-2,4,6-triiodoisophthalic acid dichloride, acetyl halide, and a solvent selected from N,N-dimethylacetamide, dimethylformamide, or 1-methyl-2-pyrrolidone to form a first reaction mixture;
b. maintaining the first reaction mixture for a period of time sufficient to allow the reaction to proceed to completion;
c. combining 3-amino-1,2-propanediol, N,N-dimethylacetamide, and a base with the first reaction mixture to form a second reaction mixture;
d. maintaining the second reaction mixture for a period of time sufficient for 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide formation;
e. isolating the 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodobenzene dicarboxamide so formed.