Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-02-26
2004-10-12
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C424S009452
Reexamination Certificate
active
06803485
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for the preparation of nonionic, water soluble compounds that are useful as contrast agents.
BACKGROUND OF THE INVENTION
The introduction in X-ray diagnosis of contrast media containing non-ionic iodinated compounds as opacifying agents represented a remarkable progress in the state of the technique, so far that, these media will eventually substitute the traditional iodinated ionic products (see Grainger and Dawson, Clinical Radiology, 1990, 42, 1-5). These nonionic compounds, such as, (S)-N,N′-bis[2-hydroxy-1-(hydroxy(methyl)ethyl-5-[(2-hydroxy-1-oxypropylamino]-2,4,6,-triiodo-1,3-benzenedicarboxamide (iopamidol) and 5-[acetyl(2,3-dihydroxypropyl)amino]-N,N′-bis[2,3-dihydroxypropyl]-2,4,6,-triiodo-1,3-benzenedicarboxamide (iohexol), are useful as contrast enhancing agents for X-ray, magnetic resonance imaging (MRI) and angiography. These compounds have a lower frequency of adverse reactions in patients, during intravenous injection, than many ionic contrast agents.
However, the synthetic processes and, particularly, the final purification of these products are complex and expensive. Neutral iodinated opacifying agents differ from ionic ones because they cannot be isolated and purified by precipitation from water due to their high solubility. Thus the following problems must be solved: the removal of ionic species, usually inorganic salts, from the final reaction mixture, the recovery of valuable reagents in excess and of water-soluble reaction media. A preferred technique to be performed (see for example, U.S. patents: U.S. Pat. Nos. 4,352,788 and 4,001,323) is the one based on the submission of operations such as:
preliminary removal of the solvent,
extraction of the residual reaction medium, preferably with a chlorinated solvent,
elution of the aqueous phase on a system of columns of cationic and anionic ion-exchange resins,
concentration of the elute by evaporation,
crystallization of the crude residue.
The drawbacks related to this type of process include: a) a requirement for large complex and expensive purification plants for ion-exchange resins; b) a large quantity of thermal energy is required for the concentration of the water employed; c) the concentration of extremely diluted solutions causes the corresponding concentration of trace impurities; and d) the final product is exposed to a long-lasting thermal treatment.
U.S. Pat. No. 4,001,323 (the '323 patent) describes a process for preparing iopamidol which involves a) reacting 5-amino-2,4,6-triiodoisophthalyl dichloride (ATIPA-CI) with 2(S)-acetoxypropionyl chloride to form an acetyl-amide intermediate; b) reacting the acetyl amide intermediate with serinol to provide acetyliopamidol; c) reacting the acetyliopamidol with an aqueous base, such as, sodium hydroxide to hydrolyze the ester and provide iopamidol. The product is then purified by ion exchange treatment, followed by recrystallization from ethanol.
U.S. Pat. No. 4,352,788 (the '788 patent) describes a process for preparing compounds similar to the compounds of the '323 patent. The principle difference is the compounds of the '788 patent are alkylated at the aromatic nitrogen atom. The products are isolated by counter-current extraction or by using exchange resins.
However, problems that exist with the process disclosed in the '323 and the '788 patents include a) the use of a hazardous solvent; b) the basic hydrolysis can induce racemization of the optically active compound and may produce material which does not meet the U.S.P. optical rotation specification for iopamidol.
U.S. Pat. No. 4,396,598 (the '598 patent) discloses a method for preparing N,N′-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalimide. This patent also discloses the preparation starting with ATIPA-CI. However in the '598 patent, the polyhydroxy product is purified via preparative liquid chromatography.
U.S. Pat. No. 5,550,287 discloses a method for purification of the contrast agents again using a column with a strong anionic resin followed by a column with a weak anionic resin.
U.S. Pat. No. 5,204,005 discloses the use of a reverse phase chromatographic process for purification of water soluble, non-ionic contrast medium compounds.
An object of the present invention is to provide and process to prepare contrast agents which do not racemize the product.
An object of the present invention is to provide and process which furnishes the product contrast agent having a specific rotation that meets the requirements of the U.S.P. specification.
An object of the present invention is to provide an efficient method for the purification of non-ionic water soluble contrast agents.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the manufacture and purification of contrast enhancing agents, such as, iopamidol and iohexol. The process converts 5-amino-2,4,6-triiodoisophthalyl dichloride (ATIPA-CI) to an isophthalyl-diamide, such as, for example, 5-amino-N,N′-bis(1,3-diacetoxy-2-propyl)-2,4,6-triiodoisophthalamide (tetraacetyl-diamide) in a single reaction vessel by first reacting the ATIPA-CI with 2 equivalents of a dihydroxy-amine such as, for example, serinol, (2-amino-1,3-dihydroxypropane), or another suitable dihydroxyamino compound, in the presence of triethylamine, followed by treatment with an acid anhydride in the presence of a catalytic amount of dimethylaminopyridine (DMAP), to form the tetraester-diamide. The tetraester-amide product is then treated with an 2(S)-alkanoyloxylated propionyl chloride to produce the pentaester of iopamidol. The pentaester is treated with a catalytic amount of hydrochloric acid in methanol to deacylate the ester and provide iopamidol. The crude product is treated with an acid scavenging resin to remove the acid and purified by passing through a bed of nonionic polymeric adsorbent resin to remove other impurities from the reaction. The final purification is performed by recrystallization from ethanol or a mixture of acetonitrile in ethanol to provide pure iopamidol.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
The present invention relates to a process for the preparation of a polyhydroxy compound and salts and enantiomers thereof having formula I.
wherein R
1
and R
2
are dihydroxyalkyl groups, and R
3
is hydrogen, alkyl, or hydroxy. The process comprising the step of deacylating an acylated compound having the formula:
in an acidic medium, to provide the free polyhydroxy compound. R
4
and R
5
are optionally acylated dihydroxyalkyl groups and R
6
is lower alkyl. The polyhydroxy compound can be purified by treatment with an acid scavenging resin.
The invention also contemplates compounds having the formula:
wherein each R
7
is an acyl group, and salts and enantiomers thereof.
Examples of acyl groups include groups such as, for example, formyl, acetyl, propionyl, butanoyl, pivaloyl, pentanoyl, trifluoroacetyl, trichloroacetyl, benzoyl, and the like. The preferred acyl groups are formyl, acetyl, propionyl, and butanoyl. The most preferred acyl group is acetyl.
The dihydroxyalkyl groups are straight or branched chain alkyl radicals containing from 2 to 6 carbon atoms and having two hydroxy groups. Most preferred dihydroxyalkyl groups are 1,3-dihydroxypropyl, 1,2-dihydroxypropyl.
The lower alkyl groups include straight or branched chain alkyl groups having from 1 to about 6 carbon atoms. Examples of lower alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, iso-propyl, 2-methylpropyl n-butyl, 2-butyl, t-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, and n-hexyl,. The preferred lower alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, and t-bu
Bhatia Ashok V.
Chamberlin Steven A.
Drengler Keith A.
Hufnagel John J.
Lorenzini Richard A.
Bracco Imaging S.p.A.
Kramer Levin Naftalis & Frankel LLP
Kumar Shailendra
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