Process for producing ioversol

The present invention discloses a new process for producing ioversol (marketed as OPTIRAY.RTM.) comprising: PA1 (a) reacting 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with chloroacetyl chloride in a polar aprotic solvent, or combinations thereof, to produce N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiod oisophthalamide; PA1 (b) reacting the product of (a) with sodium hydroxide to produce N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisopthala mide; PA1 (c) reacting the product of (b) in water and sodium acetate to produce N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisopthalamide; and PA1 (d) reacting the product of (c) with an alkylating agent capable of producing hydroxylhylated product in the presence of a base and water to produce ioversol.

FIELD OF THE INVENTION 
This invention is in the field of imaging. In particular, the invention 
relates to X-ray imaging. And most particularly, the invention relates to 
a new process for obtaining ioversol. 
BACKGROUND OF THE INVENTION 
This invention relates to 
N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiod 
oisopthalamide (ioversol). 
Ioversol is commonly used as an X-ray contrast agent. The agent may be used 
in various radiographic procedures including those involving cardiography, 
coronary arteriography, aortography, cerebral and peripheral angiography, 
arthrography, intravenous pyelography and urography as well as 
myelography. 
The present commercial manufacture of ioversol proceeds in four steps from 
bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-aminoisophthalamide to crude 
ioversol product, which product is subsequently purified. This conversion 
utilizes two expensive raw materials, acetoxyacetyl chloride (AAC) and 
bromoethylacetate (BEA), which together contribute to greater than 25% of 
the final product material cost. Additionally, the present commercial 
manufacturing process requires the use of several expensive, 
environmentally undesirable and/or reactive solvents such as 
1,1,2-trichloroethane (TCE), dimethylsulfoxide (DMSO) and amylacetate. 
Each of these solvents have been particularly troublesome in manufacturing 
due to difficulties in recovery and other operational difficulties. TCE, 
in particular, is a chlorinated solvent of considerable concern in 
manufacturing. Thus, there exists a need for an improved process for the 
manufacture of ioversol which incorporates less expensive and more 
environmentally suitable raw materials. 
SUMMARY OF THE INVENTION 
The present invention provides a new process for producing ioversol 
(marketed as OPTIRAY.RTM.) comprising: 
(a) reacting 
5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with 
chloroacetyl chloride in a polar aprotic solvent or combinations thereof 
to produce 
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiod 
oisophthalamide; 
(b) reacting the product of (a) with sodium hydroxide to produce 
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisopthala 
mide; 
(c) reacting the product of (b) in water and sodium acetate to produce 
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisopthalamide; 
and 
(d) reacting the product of (c) with an alkylating agent capable of 
producing a hydroxyethylated product in the presence of a base and water 
to produce ioversol. 
The new synthetic route replaces the high cost AAC and BEA components with 
chloroacetylchloride (CAC) and an alkylating agent which is capable of 
producing a hydroxyethylated product, respectively, thus reducing the 
introduction of these components to a more elementary and far less 
expensive archetype. Further, except for a small quantity of the polar 
aprotic solvent dimethylacetamide (DMAC) utilized in the initial step, the 
remaining reactions are conducted in an aqueous reaction medium, 
eliminating TCE, DMSO and amyl acetate and their corresponding costs and 
environmental difficulties. 
DETAILED DESCRIPTION 
The current process for producing ioversol is generally depicted in Table 
1. 
TABLE I 
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The current general procedure for producing ioversol is as follows: 
STEP 1. 
Preparation of 
5-Amino-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide 
5-Amino-N,N'-bis(2,3-dihydroxpropyl)-2,4,6-triiodoisophthalamide is 
dissolved in N,N-diomethylacetamide and acetylated with acetic anhydride, 
using 4-dimethylaminopyridine as a catalyst, to produce 
5-amino-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide. Upon 
completion of the reaction, the mixture is diluted with 
1,1,2-trichloroethane and washed with aqueous sodium carbonate and aqueous 
sodium chloride solutions to remove acetic acid, which is the by-product 
of the reaction. The resulting 1,1,2-trichloroethane solution of the 
product is used in STEP #2. 
STEP 2. 
Preparation of 
5-Acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalami 
de 
Most of the solvent (1,1,2-trichloroethane) is distilled from the solution 
of 5-amino-N,N'bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide 
prepared in STEP #1. The reaction solvent, N,N-dimethylacetamide, is 
added. Excess acetoxyacetyl chloride is added and the reaction mixture is 
stirred at ca. 40.degree. C. until the reaction is completed. 
5-Acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalami 
de is formed. 1,1,2-trichloroethane is added to dilute the reaction mixture 
and the solution is washed with aqueous sodium bicarbonate and aqueous 
sodium chloride solutions to remove acetoxyacetic acid and other 
by-products. The resulting organic layer which contains the reaction 
product is used in the next step. 
STEP 3. 
Preparation of 
5-[N-(2-Acetoxyethyl)acetoxyacetamido]-N,N'-bis(2,3-diacetoxypropyl)-2,4,6 
-triiodoisophthalamide 
Solvent (1,1,2-trichloroethane) is distilled from the solution of 
5-acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalami 
de prepared in STEP #2. Dimethyl sulfoxide is added as the reaction 
solvent. Potassium carbonate and 2-bromoethyl acetate are added and the 
mixture is stirred for ca. 10 hours at ca. 40.degree. C. to complete the 
reaction to form 
5-[N-(2-acetoxyethyl)acetoxyacetamido]-N,N'-bis(2,3-diacetoxypropyl)-2,4,6 
-triiodoisophthalamide. After the reaction is completed 
1,1,2-trichloroethane is added to dilute the mixture. To remove the 
inorganic salts and dimethyl sulfoxide in the medium, the mixture is 
washed once with deionized water, and twice with aqueous sodium chloride 
solution. The organic layer, which contains the product, is then distilled 
to remove the solvent and the residue is dissolved in amyl acetate while 
the mixture is still hot. The mixture is then cooled and stirred 
continuously to complete the crystallization. The reaction product is 
collected and dried. After testing, it is used in STEP #4 to prepare crude 
ioversol aqueous solution. 
STEP 4. 
Preparation of N,N'-bis(2,3-dihydroxypropyl 
)-5-[N-(2-hydroxyethyl)qlycolamido]-2,4,6-triiodoisophthalamide, (crude 
ioversol aqueous solution) 
5-[N-(2-Acetoxyethyl)acetoxyacetamido]-N,N'bis(2,3-diacetoxypropy)-2,4,6-tr 
iiodoisophthalamide solids are slurried in hot water containing a catalytic 
quantity of sulfuric acid. The solid gradually dissolves as it is heated 
with the steam on the jacket. The material is hydrolyzed to produce crude 
ioversol and acetic acid as a by-product. To remove the acetic acid, clean 
steam is sparged into the reactor. The solution volume is maintained 
constant by adding deionized water during the reaction and acetic acid 
removal. The reaction is tested for completeness of hydrolysis and for the 
removal of acetic acid. 
The solution which contains ioversol, (crude ioversol aqueous solution) is 
cooled and utilized in subsequent purification steps. 
The process of the invention for producing ioversol is depicted in Table 2. 
TABLE II 
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The general procedure for the process of the invention involves reacting 
5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with 
chloroacetyl chloride in a polar aprotic solvent. 
The resulting product is hydrolyzed with sodium hydroxide. A homogeneous 
solution is obtained by adding water. Precipitation is affected to yield 
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthal 
amide. This product is mixed with water and sodium acetate and the pH 
adjusted. A base is added as the reaction proceeds in order to maintain pH 
at a constant level and produce 
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisopthalamide. 
This product from the previous step is subsequently treated in aqueous 
solution with a base and reacted with an alkylating agent capable of 
producing an hydroxyethylated product. The reaction product is crude 
ioversol. The reaction pH is maintained by addition of mineral acid. 
Finally, salt and low molecular weight impurities are removed. 
Polar aprotic solvents for use with the invention include 
dimethylacetamide, acetonitrile, dimethylsulfoxide, dimethylformamide, 
tetrahydrofuran, dimethoxyethane, acetonitrile, or combinations thereof. 
Suitable bases for use with the water include sodium hydroxide, lithium 
hydroxide, ammonium hydroxide, and potassium hydroxide. Alkylating agents 
capable of producing a hydroxyethylated product suitable for use with the 
invention include 2-chloroethanol, ethylene oxide, ethylene carbonate, 
2-bromoethanol, 2-iodoethanol, and 2-tosylethanol. 
Specifically, the process of the invention is detailed in the Examples 
section of this document.

The following examples illustrate the specific embodiments of the invention 
described in this document. As would be apparent to skilled artisans, 
various changes and modifications are possible and are contemplated within 
the scope of the invention described. 
EXAMPLES 
Example 1 
Preparation of N,N'-bis[2,3-di(2-chloroacetoxy) 
propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide 
5-Amino-N,N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (84.6 g, 
0.12 moles) was dissolved in 172 mL of N,N-dimethylacetamide at 50.degree. 
C. The solution was cooled to 10.degree. C. and 62 mL (88.09g, 0.78 moles) 
of chloroacetyl chloride were added over 30 minutes. The reaction mixture 
was stirred for 3 hours at 50.degree. C. HPLC analysis of the reaction 
mixture showed that it contained 99.8% 
N,N'-bis[2,3-di-(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triio 
do-isophthalamide. The material was carried forward to Example 2 without 
further purification. 
Example 2 
Preparation of 
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthal 
amide 
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodo 
isophthalamide in N,N-dimethylacetamide, from Example 1, was hydrolyzed by 
adding 156 mL of 10N sodium hydroxide solution (1.56 moles). Water (100 
mL) was then added to the mixture to give a homogeneous solution. 1N 
Hydrochloric acid (59 mL, 0.59 moles) was added to precipitate the 
N,N'-bis (2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophtha 
lamide. The precipitate was collected and washed with water. The wet 
product was dried at 60.degree. C. in a vacuum oven to give 81.69 g of 
product, 88.4% yield. The material was 100 % pure by HPLC analysis. 
Example 3 
Preparation of N,N'-bis[2,3-di(2-chloroacetoxy) 
propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide 
5-Amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (70.5 g, 
0.1 moles) was dissolved in 71 mL of N,N-dimethylacetamide at 50.degree. 
C. Acetonitrile (71 mL) was added to the mixture. Chloroacetyl chloride 
(52 mL, 73.4 g, 0.65 moles) was added over 30 minutes. The reaction 
mixture was stirred for 3 hours at 50.degree. C. HPLC analysis of the 
reaction mixture showed that it contained 98.5% 
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiod 
oisophthalamide. The material was carried forward to Example 4, without 
further purification. 
Example 4 
Preparation of 
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthal 
amide 
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodo 
isophthalamide in N,N-dimethylacetamide and acetonitrile, from Example 3, 
was hydrolyzed by adding 130 mL of 10N sodium hydroxide solution (1.3 
moles). Water (36 mL) was then added to the mixture to give a homogeneous 
solution. 1N Hydrochloric acid (100 mL, 0.1 moles) was added to 
precipitate the 
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthal 
amide. The precipitate was collected and washed with water. The wet product 
was dried at 60.degree. C. in a vacuum oven to give 71.6 g of product, 
92.2% yield. The material was 100% pure by HPLC analysis. 
Example 5 
Preparation of 
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisophtha lamide 
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodo 
isophthalamide (39.08 g, 0.05 moles) was suspended in 150 mL of water. 
Sodium acetate (32.8 g, 0.4 moles) was added and the pH of the mixture was 
adjusted to 6.4 with 1 mL of 12N hydrochloric acid. The mixture was heated 
to reflux. The pH of the reaction mixture was maintained at 6.3 to 6.5 by 
adding 5N sodium hydroxide solution. At the end of the reaction the 
mixture contained 96.4% 
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisophtha lamide. 
The reaction mixture was cooled to room temperature and the product 
precipitated from the reaction mixture. The precipitate was isolated and 
washed with water. The solid was dried at 60.degree. C. in a vacuum oven 
to give 33 g of product, 94% yield. The material was 97.75% pure by HPLC 
analysis. 
Example 6 
Preparation of 
N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiod 
oisophthalamide 
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisophtha lamide 
(30.0g, 0.039 moles), aqueous sodium hydroxide (50% w/w solution; 7.28 g, 
0.091 moles), and deionized water (85 mL) were combined in a 500 mL, 
3-necked round bottomed flask equipped with thermometer, overhead stirrer, 
and a reflux condenser connected to a 10% aqueous sodium hydroxide trap. 
The mixture was heated to 50.degree. C., and the 2-chloroethanol was added 
all at once by syringe. Heating was continued for 7 hours. The mixture was 
cooled to 10.degree.-15.degree. C., and the reaction was quenched with 5 
mL of concentrated hydrochloric acid. By HPLC the reaction mixture 
contained 93% 
N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiod 
oisophthalamide. The reaction mixture was carried forward without further 
processing. 
Example 7 
Preparation of 
N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiod 
oisophthalamide 
N,N'-bis(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisophtha lamide 
(17.65 g, 0.023 moles), NaCl (1.3 g, 0.023 moles), NaOAc (15.1 g, 0,184 
moles), and deionized water (165 mL) were combined in a 500 mL 4-necked 
round bottomed flask equipped with thermometer, overhead stirrer, 
air-cooled reflux condenser, and a glass tube attached to an ethylene 
oxide gas cylinder. The mixture was cooled to 2.degree. C. with an ice 
bath, and ethylene oxide (18.11 g, 0.411 moles) was bubbled subsurface at 
a rate of ca. 190 mL/min. The air-cooled condenser and ethylene oxide 
inlet tube were removed and replaced with a dry ice condenser attached to 
a 10% aqueous NaOH trap. The mixture was heated to 50.degree. C. The pH 
was maintained at 10.0 with 1N hydrochloric acid while the mixture was 
heterogeneous. When the solids dissolved, the pH was maintained at 
9.6-9.8. After 4 hours, the mixture was cooled to room temperature and 
quenched first with 1.0N hydrochloric acid (40 mL) and then with 
concentrated hydrochloric acid (20 mL) to pH 4.5. The reaction mixture 
contained 93% ioversol by HPLC. Assay of the product gave a yield of 17.6 
g (94.3%). The reaction mixture was carried forward without further 
processing. 
Example 8 
Removal of salts and other lower molecular weigh impurities from crude 
ioversol 
A column (2.5 cm diameter, 29 cm height) was packed, using the procedure 
recommended by the manufacturer, with Amberlite XAD-16 resin. Crude 
ioversol (4.5 g) containing ioversol (45.3%), sodium acetate (40.9%), NaCl 
(3.2%), ethylene glycol (10.2%) and other organic impurities was dissolved 
in water (12 mL) and loaded into the XAD-16 column. The column was eluted 
with water at a flow rate of 3.0 mL per minute. The elution profile was 
monitored with a conductivity meter for ionic substances and an UV 
detector at 254 nm for ioversol. When the conductivity started to 
increase, fractions were collected (30 mL each). The salts and other lower 
molecular weight impurities were eluted from the column. The column was 
then eluted with a mixture of methanol and water (50/50) which cleanly 
effected deadsorption of ioversol from the column in 95-99% yield. The 
XAD-16 column may be re-equilibrated with water for reuse. The isolated 
ioversol fraction contained less than 5 ppm of ethylene glycol (by HPLC) 
and were devoid of ionic impurities (by conductivity analyses). 
Although the invention has been described with respect to specific 
modifications, the details thereof are not to be construed as limitations, 
for it will be apparent that various equivalents, changes and 
modifications may be resorted to without departing from the spirit and 
scope thereof, and it is understood that such equivalent embodiments are 
to be included therein.