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:
IMPROVED 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 improved process for the preparation of iohexol from 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 improved process for the preparation of iohexol from 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. 5,204,005, U.S. Patent No. 5,663,432, 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 lohexol and its intermediates.
The final step in the synthesis of iohexol is a N-alkylation step in which 5-acetamido-N.N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodoisophthalmide is reacted in the liquid phase with an alkylating agent to introduce the 2,3-dihydroxypropyl group at the nitrogen of the 5-acetamido group. Following this reaction, iohexol is isolated from the reaction mixture and purified by crystallisation and treatment with ion exchange resins.
U.S. Patent No. 5,847,212 discloses a process combining 5-acetamino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-1,3-benzene-dicarboxamide, a solvent, glycidol, and a base, and isolating the iohexol after completion of reaction.
U.S. Patent No. 6,153,796 discloses production of iohexol comprising reacting 5-acetamido-N.N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodoisophthalmide with a 2,3-dihydroxypropylating agent, in the presence of a solvent comprising 2-methoxy-ethanol and isopropanol.
The manufacture of iohexol is disclosed for example in U.S. Pat. No. 4,250,113, which is hereby incorporated by reference. In the last step of the multistep chemical synthesis crude iohexol is obtained from the reaction between 5-Acetamide and 1-chloro-2,3-propandiol at ambient temperature in propylene glycol and in the presence of sodium methoxide. The solvent is then evaporated and crude iohexol is obtained. The crude product is evaporated to dryness and recrystallised twice from butanol.
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Several suggestions to improve the N-alkylation and the purification steps have been published. U.S.Application 20060178533 and PCT Application WO-A-02/083623 discloses the purification of crude iohexol using 1-methoxy-2-propanol as the solvent optionally in a mixture with other solvents.
The N-alkylation step is challenging because O-alkylated by-products can also be formed when the alkylation occurs at the oxygen atoms of the hydroxy groups. It is therefore a desire to limit the formation of these O-alkylated by-products and thereby to limit their presence in the final purified iohexol. The upper limit for values for O-alkylated by-products in the end product is fixed by the European Pharmacopea to 0.6% (HPLC by area).
The O-alkylated by-products are removed to the degree desired or necessary by recrystallisation steps. Further unidentified by-products also referred to as impurities are also formed during the alkylation reaction and must be reduced to a tolerable level. In addition the solvents used should be easily available, be environmentally friendly and be of low toxicity.
There is therefore a need to identify a solvent that can be used in the N-alkylation reaction and that fulfill the requirements mentioned above.
The present inventors have developed a simple process for the preparation of iohexol. This involves the reaction of 5-acetamido-N,N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodoisophthalmide of formula II with a propylating agent using a solvent 2-ethoxyethanol, to produce crude iohexol, which is recrystallized using hot butanol and percolated over adsorbent resins by any process known to the skilled artisan.
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Formula II
In one of the aspect of the present invention there is provided a process for preparation of iohexol. The process includes steps of, reacting 5-acetamido-N,N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodoisophthalmide with a propylating agent, in presence of 2-ethoxyethanol.
The propylating agent is selected from 1-halo-2,3-propanediol or glycidol. eg. 1-chloro-2,3-propanediol, 1-bromo-2,3-propanediol, glycidol and the like.
The N-alkylation step takes place in the presence of a base. The base used in the N-alkylation process according to the invention must be soluble in the reaction solvent, eg. Sodium hydroxide and the like.
The N-alkylation step is effected at a temperature between 20-50° C. The N-alkylation step will be allowed to proceed for several hours with a preferred reaction time of 15 to 45 hours and particularly preferred from 30 to 40 hours. The reaction may be terminated by quenching with an acid. Inorganic or organic acids may be used and inorganic acids such as HCI are preferred. The reaction may be monitored, e.g. by HPLC, to determine the appropriate stage at which quenching should take place. Following termination of the reaction, the crude iohexol reaction
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product may be separated from the solvent e.g. by cooling and/or solvent evaporation. The evaporation should preferably be performed under reduced pressure.
The solution of crude iohexol is percolated over cation and anion exchange resin, subjected to recrystallization to get pure iohexol, which can optionally be subjected to adsorbent resin.
The iohexol may have, for example, a purity of 99% or more when measured by HPLC and O-alkylated impurity content of about 0.51 %w/w or less.
The iohexol may have, for example, a purity of 99% or more when measured by HPLC and other impurity content of about 0.19 %w/w or less.
The other impurity may include for eg. 5-acetamido-N,N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodoisophthalmide and other related substance.
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 lohexol.
To a four-necked flask was charged 2-ethoxyethanol (750 ml_) and water (750 ml_). Then 5-Acetylamino-N,N'-Bis(2,3-dihydroxypropyl) - 2,4,6- Triiodoisophthalamide (250 gm) was charged under stirring followed by 1-Chloro-2,3-propanediol (37 gm). Caustic lye was added to the reaction mixture to obtain a pH 11.8. The reaction mixture was heated and the temperature was maintained between 45 to 50 °C. The pH of the reaction mixture was maintained between 11.5 to 12.0 by addition of caustic lye. After four hours a clear solution was obtained. Again 1-Chloro-2,3-propanediol (18.5 gm) was added and stirring was continued at 45-50 °C. After stirring for 40 hours the reaction mixture was analysed by HPLC to find that the starting material remaining was less than 2%.. The reaction was quenched by addition of HCI to bring pH to 7.0. The reaction mixture was then concentrated under reduced pressure. Methanol (1.0 Lit) was added to the residue and undissolved matter was filtered off. The methanolic solution was concentrated to dryness and the residue dissolved in water (500 mL). The solution containing crude lohexol was percolated over cation and anion exchange resins and the eluate was concentrated to dryness to obtain the crude product.The product was further purified by recrystallization from hot butanol and percolation over adsorbent resins like Amberlite XAD-16.
Yield: 69%
Purity: 99.3 % (by HPLC)
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WE CLAIM:
1. A process for preparation of iohexol comprises the steps of, reacting 5-acetamido-N.N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodoisophthalmide with a propylating agent, in presence of 2-ethoxyethanol.
2. The process of claim 1, wherein the propylating agent is selected from 1-chloro-2,3-propanediol, 1-bromo-2,3-propanediol, glycidol and the like.
3. The process of claim 2, wherein the propylating agent is 1-chloro-2, 3-propanediol
4. The process of claim 1, wherein the iohexol have a purity of 99% or more when measured by HPLC and O-alkylated impurity content of about 0.51 %w/w or less.
5. The process of claim 1, wherein the iohexol have a purity of 99% or more when measured by HPLC and other impurity content of about 0.19 %w/w or less.
6. The process of claim 5, wherein the other impurity include 5-acetamido-N,N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodoisophthalmide and other related substance
Dated this27TH day of April, 2007.

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