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
PREPARATION OF 5-(ACETYLAMINO)-N,N'-BIS(2,3-DIHYDROXYPROPYL)-2,4,6-TRIIODO-1,3-BENZENDICARBOXAMIDE AND SALTS THEREOF
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 5-(acetylamino)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzendicarboxamide and salts thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.


4. DESCRIPTION
The invention provides process of preparation of 5-(acetylamino)-N,N'-bis(2)3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzendicarboxamide and salts thereof.
lohexol of Formula I is chemically known as 5-[acetyl(2,3-dihydroxy propyl) amino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide. It is commercially available under the trade name Ominipaque®. It is used as radiocontrast agent and can be adminastered orally or by injection.

FORMULA I
U.S. Patent No 4,250,113 provides process for preparation of lohexol.
Several other processes are known in the art for preparation of lohexol such as U.S. Patent No. 4,584,401; U.S. Patent No. 4,021,481; U.S. Patent No. 5,191,119; U.S. Patent No. 6,153,796; US patent No. 5,948,940; US patent No. 6,610,885; US patent No. 5,705,692; US patent No. 5,847,212; US patent No. 5,965,772; US patent No. 6,469,208; U.S. Patent No. 7,244,864. and European patent No. 0,915,835
There are some processes reported for the purification of lohexol known in the art through U.S. Patent No. 6,646,171 and European patent No. 1025067.


The inventors while developing a process for the preparation of lohexol have found that 5-(acetylamino)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzendicarboxamide (Formula III) can be prepared from 5-amino-2,4,6-triiodo-N,N'-bis (2,3-dihydroxy propyl) isophthalamide (Formula II) by actetylating compound of Formula II with acetyl halide and catalyst without using any solvent as depicted in scheme-l

In one of the aspect of invention there is provided a process for preparation of compound of Formula III wherein the process includes steps of:
a) reacting the compound of Formula II with acetylating agent in presence of catalyst.
b) hydrolysis of acetylated compound with alcohol to get compound of Formula III.
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 acetylating reagent such as acetyl chloride or acetyl bromide to the reaction mixture at 10-20°C. The reaction mixture is then heated at 40-60°C. The reaction mass is cooled to room temperature and then alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, n-Butanol is added dropwise at 20-25°C. Reaction mixture is refluxed. After completion of reaction, mixture is cooled to room temperature. The solid product filtered and washed with fresh alcohol.


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-(acetylamino)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzendicarboxamide -
5-amino-2,4,6-triiodo-N,N'-bis (2,3-dihydroxy propyl) isophthalamide (100 gm, Formula II) was added to N-Methyl pyrrolidone (100 ml) and the reaction mixture was stirred for 10 minutes.
Acetyl chloride, (90 gm) was added to the reaction mixture dropwise in 30 min. at 10-20°C and was heated at 50°C for 4 hours. The reaction mass was cooled to room temperature. To this reaction mixture methanol (800 ml) was added dropwise for 30 minutes and reaction mixture refluxed for 14 hours. After completion the reaction the reaction mass was cooled to room temperature. The solid product filtered and washed four times with fresh methanol (50 ml). Yield = 78 g Purity = 93%


We Claim:
1. A process of preparation of 5-(acetylamino)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzendicarboxamide (Formula III), wherein the process comprises steps of treatment of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzendicarboxamide (Formula II) with acetylating agent in presence of catalyst followed by hydrolysis.

2. The process of claim 1, wherein acetylating agent is acetyl chloride.

3. The process of claim 1, wherein catalyst is N-Methyl pyrrolidone.
4. The process of claim 1, wherein the hydrolysis is carried out by alcohol.
5. The process of claim 4, wherein alcohol includes methanol, ethanol, propanol, isopropanol and n-butanol.

Abstract
The invention provides process for preparation of 5-(acetylamino) -N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzendicarboxamide from 5-amino-2,4,6-triiodo-N,N'-bis (2,3-dihydroxy propyl) isophthalamide where acetyl chloride is used as a acetylating agent and N-Methyl pyrrolidone is used as a catalyst. Reaction carried out without using any solvent.