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
EFFICIENT PROCESS FOR PREPARATION OF 5-CHLOROACETAMIDO-N,N'-BIS(2,3-DIHYDROXYPROPYL)-2,4,6-TRIIODO-1,3-
BENZENEDICARBOXAMIDE
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 efficient process for preparation of 5-
Chloroacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-
benzenedicarboxamide.
The following specification particularly describes the invention and the manner in
which it is to be performed.


4. DESCRIPTION
The invention provides efficient process of preparation of 5-Chloroacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide from 5-Amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide.

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, arthroglraphy, intravenous pyelography and urography as well as myelograpihy.

U.S. Patent No. 4,396,598 provides process for preparation of loversol.
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 5-Chloroacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (Formula III) from 5-Amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (Formula II) have found that, hydrolysis can be carried out efficiently with alcohol instead of water. The inventor also noted that N-Methylpyrolidone can be recycled easily when methanol is used in the reaction.

In one of the aspect of invention there is provided a process for preparation of 5-Chloroacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide wherein the process includes steps of:
a) treating 5-Amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzene dicarboxamide with chloroacetyl chloride in presence of catalyst.
b) hydrolysis of chloroacetylated compound of step a) with alcohol.
c) isolating the 5-Chloroacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide from the reaction mass thereof.


The process of invention involves addition of 5-amino-2,4,6-triiodo-N,N'-bis (2,3-dihydroxy propyl) isophthalamide (Formula II) to N-Methyl pyrrolidone followed by dropwise addition of chloroacetyl chloride to the reaction mixture at 20-30 °C. The reaction mixture is heated to 50-60 °C. The reaction mixture is cooled and then alcoholic solvent such as methanol ethanol, n-propanol, isopropanol, n-Butanol or mixture thereof added slowly. The mass is then heated to reflux. The reaction mixture is cooled to room temperature and product is isolated from the reaction mass thereof.
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 5-Chloroacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide -
To a suspension of 5-Amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (40 gm) in N-Methylpyrolidone (40 mL) was added chloroacetyl chloride (40 mL) at 20-30 °C. The reaction mixture was heated to 50-53 °C for three hours. The reaction mixture was cooled to 20 °C and methanol (400 mL) was added slowly. The reaction was then heated and refluxed for nine hours. A white solid separated during the course of hydrolysis. When TLC indicated completion of hydrolysis, the reaction mixture was cooled to 25 °C and the product was filtered under suction and was washed with methanol. After drying under vacuum the title product was obtained as a white solid Yield = 38.0 g Purity by HPLC = 97.6 %


We Claim:
1. A process for preparation of 5-Chloroacetamido-N,N'-bis(2,3-dihydroxypropyl)-
2,4,6-triiodo-1,3-benzenedicarboxamide wherein the process comprises steps of:
a) treating 5-Amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzene dicarboxamide with chloroacetyl chloride in presence of catalyst.
b) hydrolysis of chloroacetylated compound of step a) with alcohol.
c) isolating the 5-Chloroacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide from the reaction mass thereof.

2. The process of claim 1, wherein catalyst is N-Methylpyrolidone.
3. The process of claim 1, wherein alcohol comprises methanol ethanol, n-propanol, isopropanol, n-Butanol or mixture thereof.

Abstract
The invention provides efficient process of preparation of 5-Chloroacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide from 5-Amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide.