FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rulel3)
1. TITLE OF THE INVENTION:PROCESS FOR THE PREPARATION OF IOVERSOL.
2. APPLICANT (S)(a) NAME: WOCKHARDT LTD.(b) NATIONALITY: INDIAN(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Sandra (East),Mumbai-400051.
3. PREAMBLE TO THE DESCRIPTIONThe present invention provides a process for the preparation of iodinated X-ray contrast agents. More particularly this invention provides a process for the preparation of loversol.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides a process for the preparation of iodinated X-ray contrast agents. More particularly this invention provides a process for the preparation of loversol.
Chemically, ioversol is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamido]-2,4,6-triiodo isophthalamide having the structure as per formula I. loversol 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 myelograpihy.

U.S. Patent No. 4,396,598 disclosed the loversol, as a useful nonionic x-ray contrast agent.
U.S. Patent No. 4,997,983 provides the process for the production of ioversol from 5-[N-(2-acetoxyethyl)acetoxyacetamido]-N,N,-bis(2,3-diacetoxypropyl)-2,4,6-triiodo -isophthalamide.
U.S. Patent No. 5,489,708 process for the production of ioversol from 5-[N-(2-acetoxyethyi) acetoxyacetamido] - N.N'-bis (2,3-diacetoxypropyl) - 2,4,6-triiodoiso phthalamide and an O-alkyl isomer of 5-[N-(2-acetoxyethyl) acetoxy acetamidol]-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide.
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U.S. Patent No. 5,177,261 and U.S. Patent No. 5,371,278 provides process for the production of ioversol from 5-amino-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide.
U.S. Patent No. 6,596,904 ('904 patent) provides process for the production of ioversol by reaction of the N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodo isopthalamide in water with acetate ions to produce ioversol.
U.S. Patent No. 5,204,005, U.S. Patent No. 5,160,437, U.S. Patent No. 5,221,485, U.S. Patent No. 5,210,300, U.S. Patent No. 5,396,003, U.S. Patent No. 5,663,432, U.S. Patent No. 5,648,536, U.S. Patent No. 5,840,967, U.S. Patent No. 6,232,499, U.S. Patent No. 6,337,422, U.S. Patent No. 5,866,100, U.S. Patent No. 6,500,341, US patent application 2004-082811, US patent application 2005-036946 provides several other processes of preparation and purification of Ioversol.
The present inventors have developed a process for the preparation of ioversol. This involves the reaction of 5-amino-N,N,-bis(2,3-dihydroxypropyl)-2,4,6-triiodoiso phthalamide with chloroacetyl chloride in N-methyl pyrrolidone solvent to produce N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodoiso phthalamide. This on hydrolysis in acidic media produces N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisopthal-amide in high yield with good purity. N,N'-bis (2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)] -2,4,6-triiodo isopthalamide is then converted to ioversol.
In one of the aspect of the present invention there is provided a process for preparation of ioversol wherein the said process includes steps of,
a) reacting 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoiso phthalamide with chloroacetyl chloride in polar aprotic solvent
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b) converting the product of step a) to ioversol by the methods known in the art.
In yet another aspect of the present invention there is provided a process for preparation of ioversol wherein the said process includes steps of,
a) reacting 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoiso phthalamide with chloroacetyl chloride in polar aprotic solvent
b) hydrdysing the product of step a) in acidic media to obtain N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4I6-triiodoisopthal- amide.
c) converting the product of step b) to ioversol by the methods known in the art.
The process of present invention is related to a process of preparation of ioversol. This involves the reaction of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoiso phthalamide with chloroacetyl chloride in polar aprotic solvent such as N-methyl pyrrolidone or its mixture with other polar aprotic solvent to produce N,N'-bis[2,3-di(2-chloroacetoxy) propyl]-5-(2-chloroacetamido)-2,4,6-triiodoiso phthalamide by stirring for three hours at below 80 °C. Followed by water was added and the reaction mass was stirred for an hour at 70°C to get N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisopthalamide in high yield with good purity. The N,N'-bis (2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloro acetamido)] -2,4,6-triiodoisopthalamide is then converted to ioversol by the method known in the art.
Other polar aprotic solvent includes dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide or the like.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the
invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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Example-1
Preparation of N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloro acetamido)]-2,4,6-triiodoisopthalamide.
5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoiso phthalamide (500 g) was taken in N-methyl-Pyrrolidone (500 ml). Chloroacetyl chloride (500 ml) was then added over three hours maintaining the temperature below 35°C. After addition, the reaction mixture was stirred for three hours at 50 °C to reach on completion. The 1.3 L water was added to the reaction mass to isolate the product. The precipitated product was filtered, washed and dried. Yield : 97% Purity: 96% (by HPLC)
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WE CLAIM:
1. A process for preparation of ioversol wherein the said process comprising,
a) reacting 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoiso phthalamide with chloroacetyl chloride in polar aprotic solvent
b) converting the product of step a) to ioversol

2. A process of claim 1 wherein the polar aprotic solvent is N-methyl pyrrolidone or its mixture with other polar aprotic solvent.
3. A process of claim 2 wherein the other polar aprotic solvent includes dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide or the like.
4. A process for preparation of ioversol wherein the said process comprising,

a) reacting 5-amino-NlN'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoiso phthalamide with chloroacetyl chloride in polar aprotic solvent
b) hydrdysing the product of step a) in acidic media to obtain N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisopthalamide.
c) converting N,N,-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloro acetamido)]-2,4,6-triiodoisopthalamide to ioversol

5. A process of claim 4 wherein the polar aprotic solvent is N-methyl pyrrolidone or its mixture with other polar aprotic solvent.
6. A process of claim 5 wherein the other polar aprotic solvent includes dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide or the like.
7. N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-
triiodoisopthalamide having the purity of 96 % or more.
Dated this^™ day of Feb, 2007. For Wockhardt Umited
(Mandar Kodgule) Authorized signatory
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