FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
INDUSTRIAL PROCESS FOR THE PREPARATION OF
IOVERSOL.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation of iodinated X-ray contrast agent, loversol. More particularly this invention provides a industrial process for the preparation of N, N'-Bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-2-chloroacetamido]-2,4,6-triiodoisophthalamide intermediate with reduced reaction time.
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 agent, loversol. More particularly this invention provides a industrial process for the preparation of N, N'-Bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-2-chloroacetamido]-2,4,6-triiodoisophthalamide intermediate with reduced reaction time.
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, arthroglraphy, 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 )acetoxyacetam ido]-N, N'-bis(2,3-d iacetoxypropyl )-2,4,6—triiodo -isophthalamide.
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U.S. Patent No. 5,489,708 process for the production of ioversol from 5-[N-(2-acetoxyethyl) 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.
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 using N, N'-Bis(2,3-dihydroxypropyl)-5-[M-(2-hydroxyethyl)-2-chloroacetamido]-2,4,6-triiodoisophthalamide.
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 loversol.
As disclosed in '904 patent, the manufacture of ioversol proceeds in four steps i.e. by a) reacting 5-amino-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoiso phthalamide 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-triiodoiso phthalamide, (b) reacting the product of (a) with a base to produce N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoiso pthalamide, (c) reacting the product of (b) with an alkylating agent capable of producing a hydroxyethylated product in the presence of a base and water to produce N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chlloroacetamido)] -2,4,6-triiodo isopthalamide, and (d) reacting the product of (c) in water and acetate ions to produce ioversol. There exists a need for an improved cost effective process for
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the manufacture of ioversol, using N, N'-Bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-2-chloroacetamido]-2,4,6-triiodoisophthalamide as an intermediate.
The primary object of the present invention is to develop a cost effective industrial process, which is simplified and requires reduced reaction time.
The present inventors have developed a process for the preparation of ioversol. This involves the reaction of N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide of formula II with a alkylating agent in absence of base, to produce N,N'-Bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-2-chloroacetamido]-2,4,6-triiodoisophthalamide of formula III, which is then converted to Ioversol.


HO N
HO
CI
Formula II

Formula

Unlike the conventional processes for making N, N’-Bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-2-chloroacetamido]-2,4,6-triiodoisophthalamide which require multiple steps, the process disclosed in the present invention does not require any base; it involves fewer manufacturing steps and incurs reduced reaction time by about 30% over the prior art processes. Furthermore, there is no work up required once the compound of formula III is formed. Thus the cost of producing ioversol can be substantially reduced.
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In one of the aspect of the present invention there is provided a process for preparation of ioversol. The process includes steps of,
a) Reacting N, N’-bis (2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide with alkylating agent in absence of base
b) converting the product of step a) to ioveirsol by the methods known in the art.
N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamiclo)-2,4,6-triiodoisophthalamide is
obtained by any method known to the skilled artisan. N,N'-bis(2,3-
dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide so obtained is
treated with alkylating agent in water at 50°C, in absence of a base . Initially, when
the reaction mixture is a slurry, the pH is maintained at 10 -10.3. After 2 hours,
when all the solids get dissolved, the pH is maintained at 9-9.4. HPLC analysis of
the reaction mixture after 8 hours showed that it contained about 96 % of N,N'-
bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-2-chloroacetamido]-2,4 ,6-
triiodoisophthalamide. The reaction mixture is carried forward without further processing and converted to ioversol by the method known in the art.
The alkylating agent in is selected from the group consisting of chloroethanol, ethylene oxide, ethylene carbonate, 2-bromoethanol, 2-iodbethanol and 2-tosylethanol.
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-dihvdroxypropvl)-5-[N-(2-hvdroxvethvl)(2-chloro acetamido)]-2,4,6-triiodoisopthalamide.
Chloroethanol (334 ml) was added to stirred solution of N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide (500 g) and water at 50 °C. Initially, when the reaction mixture was a slurry, the pH was maintained at 10.3. After 2 hours, when all the solids have dissolved, the pH was maintained at about 9.4. HPLC analysis of the reaction mixture after 10 hours showed that it contained about 97 % of N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-2-chloroacetamido]-2,4 ,6-triiodoisophthalamide. The reaction mixture was carried forward without further processing. Purity: 97 % (by HPLC)
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WE CLAIM:
1. A process for preparation of ioversol. The process includes steps of,
a) reacting N,N,-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide with alkylating agent in absence of base,
b) converting the product of step a) to ioversol.

2. A process of claim 1, wherein alkylating agent in is selected from the group consisting of chloroethanol, ethylene oxide, ethylene carbonate, 2-bromoethanol, 2-iodbethanol and 2-tosylethanol.
3. The process of claim 2, wherein the alkylating agent is chloroethanol.
4. N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisopthalamide of claim 1, having the purity of 96% or more.

Dated this &0_™ day of April 2007.