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 IOHEXOL.
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, lohexol. More particularly this invention provides a industrial process for the preparation of 5-Acetylamino-N,N'-Bis(2,3-dihydroxypropyl) - 2,4,6- Triiodoisophthalamide intermediate .
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, lohexol. More particularly this invention provides a industrial process for the preparation of 5-Acetylamino-N,N'-Bis(2,3-dihydroxypropyl) - 2,4,6-Triiodoisophthalamide intermediate.
Chemically, lohexol is 5-[Acetyl(2,3-dihydroxypropyl)amino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide having the structure as per formula I. lohexol is commonly used as an X-ray contrast agent. The agent may be used in various radiographic procedures including those involving Cerebral Arteriography, Peripheral Arteriography, Peripheral Venography, Excretory Urography, IV DSA, IA DSA, CT-Head, CT-Body, Angiocardiography, Visceral Angiography and myelograpihy.
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Formula I
U.S. Patent No. 4,250,113 disclosed the lohexol, as a useful nonionic x-ray contrast agent.
U.S. Patent No. 4,021,481 provides the process for the production of lohexol.
U.S. Patent No.4, 584,401 process for the production of lohexol from olefinic intermediates as precursors to non-ionic polyiodo contrast media.
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U.S. Patent No. 5,840,967 and U.S. Patent No. 6,610,885 provides process for the production of Iohexol involving the acylation, which is conveniently acid catalysed, the product is base hydrolysed.
U.S. Patent No. 6,337,422, discloses yellow polymorph of 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide.
U.S. Patent No. 5,204,005, U.S. Patent No. 5,663,432, U.S. Patent No. 6,153,796, U.S. Patent No. 5,948,940, U.S. Patent No. 5,191,119, U.S. Patent No. 6,232,499, U.S. Patent No. 5,698,739, U.S. Patent No. 5,705,692, U.S. Patent No. 5,824,821, U.S. Patent No. 5,965,772, U.S. Patent No. 5,866,100, U.S. Patent No. 6,646,171, U.S. Patent No. 6,469,208, U.S. Patent No. 6,897,339, U.S. Patent No. 6,500,341 provides several other processes related to preparation and purification of Iohexol and its intermediates.
As disclosed in the '967 & '885 patent, the manufacture of iohexol involves following steps i.e. acid catalysed acylation of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodophthalamide compound of formula II with acetic anhydride, to get penta acetyl compound of formula III. Thereafter penta acetyl compound of formula III is base hydrolysis (to remove O-acyl groups) to get mono acetyl compound of formula IV.
The present inventors have found that the product obtained after base hydrolysis is sticky and difficult to filter, hence they have come up with a simple acid hydrolysis process, wherein the product is easy to filter and have high purity.
The present inventors have developed a process for the preparation of iohexol. This involves acid catalysed acylation of 5-Amino-N,N'-Bis(2,3-Dihydroxypropyl)-2,4,6-Triiodoisophthalamide of formula II, characterized by the fact that the penta acetyl product of formula III is acid hydrolysed to get the mono acetyl compound of formula IV. The compound of formula IV is converted to iohexol by any method known in the art.
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In one of the aspect of the present invention there is provided a process for preparation of iohexol. The process includes steps of,
a) acid catalysed acylation of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-
triiodophthalamide compound of formula II to get penta acetyl compound of
formula III,
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b) penta acetyl compound of formula III is acid hydrolysed to get mono acetyl compound of formula IV.
The penta acetyl compound of formula III is optionally isolated or in-situ converted to its mono acetyl hydrolysed product of formula IV.
5-amino-N,N,-bis(2,3-dihydroxypropyl)-2,4,6-triiodophthalamide is obtained by any method known to the skilled artisan. The 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodophthalamide so obtained is treated with acylating agent. To this catalytic amount of sulphuric acid was added drop wise, and refluxed. Following the acylation, the product is acid hydrolysed, eg. Sulphuric acid was added drop wise to remove unwanted O-acyl groups without displacing the desired N-acyl groups. The reaction mass is subjected to treatment of acetone and 25% ammonia solution. Cooled to ambient temperature and stirred for two hours. The Acetylamino-N,N'-Bis(2,3-dihydroxypropyl) -2,4,6-Triiodoisophthalamide was filtered and washes with acetone, dries over vaccum.
The acylating agent in is selected from acid halide or acetic anhydride.
The acid catalyst in the acylation step is selected from sulphuric acid, p-toluene sulfonic acid and the like.
Acid hydrolysis may be with any mineral acid, eg. Hydrochloric acid, nitric acid, phosphoric acid, sulphuric acid, boric acid and the like.
Product isolation may involve removing the solvents, which may include, for example, one or more of filtration, filtration under vacuum, distillation, distillation under vacuum, evaporation, decantation, drying under vacuum and centrifugation.
In yet another aspect of present invention, the Acetylamino-N,N'-Bis(2,3-dihydroxypropyl) -2,4,6-Triiodoisophthalamide intermediate so formed is having purity of 96% or more.
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The compound of formula IV can be converted to iohexol by the methods known in the art. For eg it can be N-alkylated with suitable propylating agent and purified to get lohexol.
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.
Example-1: Preparation of Acetylamino-N,N'-Bis(2.3-dihvdroxypropvl) -2,4,6-Triiodoisophthalamide.
To a four-necked flask equipped with a mechanical stirrer was charged acetic anhydride (375 ml_) followed by 5-Amino-N,N,-Bis(2,3-Dihydroxypropyl)-2,4,6-Triiodoisophthalamide (250 gm). To the stirred mixture was added sulfuric acid (15 gm), dropwise over half an hour. The reaction mixture was then heated to 60 °C and stirred for four hours. The reaction was monitored by TLC. Methanol (750 ml_) was then added dropwise to the reaction mixture followed by water (375 ml_). Again sulfuric acid (15 gm) was added dropwise and stirring continued. A clear solution was obtained. Reflux (64 °C) was maintained for 15 hours. Solid separation was observed six hours after start of reflux. The reflux condenser was replaced with a distillation condenser and methanol was distilled out (600 mL) at atmospheric pressure. Acetone (750 mL) was then charged to the reaction mixture folowed by 25% ammonia solution (50 ml_).The reaction mixture was cooled to ambient temperature and stirred for two hours. The solid product was thereafter filtered in buchner funnel, washed with aceton (250 mL) and dried in a vacuum oven to isolate the product. Yield: 87% Purity: 96 % (by HPLC)
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WE CLAIM:
1. A process for preparation of 5-Acetylamino-N,N'-Bis(2,3-dihydroxypropyl) -
2,4,6- Triiodoisophthalamide intermediate. The process comprising,
a) acid catalysed acylation of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodophthalamide compound of formula II to get penta acetyl compound of formula III,
b) penta acetyl compound of formula III is acid hydrolysed to get mono acetyl compound of formula IV.

2. A process of claim 1, wherein acylating agent in is selected from acid halide or acetic anhydride.
3. The process of claim 2, wherein the acylating agent is acetic anhydride.
4. The process of claim 1, wherein the acid catalyst in the acylation steps is selected from sulphuric acid, p-toluene sulfonic acid and the like.
5. The process of claim 4, wherein the acid catalyst is sulphuric acid.
6. The process of claim 1, wherein the product of step b) is acid hydrolysed using a mineral acid.
7. The process of claim 6, wherein the mineral acid is selected from hydrochloric acid, nitric acid, phosphoric acid, sulphuric acid, boric acid and the like.
8. The process of claim 7, wherein the mineral acid is sulphuric acid.
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9. 5-Acetylamino-N,N'-Bis(2,3-dihydroxypropyl) - 2,4,6- Triiodoisophthalamide having purity of 96% or more.
Dated this 27TH day of April, 2007. For Wockhardt Limited

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