FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
INDUSTRIAL PROCESS FOR PREPARATION OF IOVERSOL
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides industrial process for preparation of loversol.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The invention provides industrial process of preparation of loversol from 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide. The invention further provides the process in which reaction proceeds faster and product obtained is having better purity.
loversol of formula I is chemically known as N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamido]-2,4,6-triiodo isophthalamide. It is commercially available under the trade name OPTIRAY®. 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.
Several other processes are known in the art for preparation of loversol such as U.S. Patent No. 4,997,983; U.S. Patent No. 5,489,708; U.S. Patent No.


5,177,261; U.S. Patent No. 5,371,278; U.S. Patent No. 5,396,003; U.S. Patent No. 5,648,536 and U.S. Patent No. 7,244,864
There are some processes reported for the purification of loversol known in the art through 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 and U.S. Patent No. 6,500,341.
The inventors while developing a process for the preparation of loversol have found that the reaction time is reduced when sodium chloride is used in the synthesis of loversol (Formula I) from 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (Formula II). The inventors also found that purity of loversol is improved.

In one of the aspect of invention there is provided a process for preparation of loversol wherein the process includes steps of:
a) treating 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide with 2-chloroethanol in presence of sodium chloride and base.
b) Isolating pure loversol from the reaction mass thereof.


The process of invention involves addition of sodium chloride in suspension of 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide in water. The reaction mixture obtained thereof is then added with sodium hydroxide at 40-60 °C. To this clear reaction mixture 2-chloroethanol is added immediately and heated at 40-60 °C. After the reaction is over, the pH of reaction mixture was adjusted to 6.5 with hydrochloric acid. The crude loversol is purified by passing the reaction mixture over adsorbent resin. The column was eluted with aqueous methanol. Solvent is distilled off and product is recrystallized by alcoholic solvent. Alcoholic solvents includes methanol, ethanol, n-propanol, isopropanol, n-Butanol, 2-methylcellosolve and the like or mixture thereof.
In another aspect of invention there is provided loversol having the purity of >99 % when measured by HPLC.
The invention is further illustrated by the following example which is 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 invention.
Example Process for preparation of loversol-
To a suspension of 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (20 gm) in water (60 mL) was added sodium chloride (9.3 gm). The suspension was heated to 50 °C. To this mixture was added a 10 N solution of sodium hydroxide (7.86 mL) and 2-chloroethanol (12.7 gm) in one lot and the reaction mixture heated at 48 to 52 °C. The starting material remaining after 5 hours was less than 0.3%. The reaction mixture was cooled and the pH was adjusted to 6.5 with hydrochloric acid. The purity of loversol at this stage was 93%. The crude loversol was purified by passing the reaction mixture over adsorbent resin (Amberlite XAD-16 or its equivalent). The


column was eluted with aqueous methanol. Concentrated the eluted fractions. The loversol, which has purity of 98.5% was further purified by recrystallization from n-Butanol. Yield = 12.0 g Purity = 99.1%


We Claim:
1. A process for preparation of loversol wherein the process comprises steps of:
a) treating 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide with 2-chloroethanol in presence of sodium chloride and base.
b) Isolating pure loversol from the reaction mass thereof.

2. The process of claim 1, wherein base includes sodium hydroxide.
3. The process of claim 1, wherein the pure loversol is obtained by passing the reaction mixture over adsorbent resin followed by recrystallisation.
4. The process of claim 3, wherein adsorbent resin used is Amberlite XAD-16.
5. The process of claim 3, wherein eluent is aqueous methanol.
6. The process of claim 3, wherein recrystallisation is carried out in alcoholic solvent.
7. The process of claim 6, wherein alcoholic solvent includes methanol, ethanol, n-propanol, isopropanol, n-Butanol or mixture thereof.
8. The process of claim 1, wherein loversol is having a purity of >99 % when measured by HPLC.



Abstract
The invention provides industrial process of preparation of loversol from 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide. The invention further provides the process in which reaction proceeds faster and product obtained is having better purity.