MXPA01008615A - Process for the preparation of iopamidol - Google Patents

Abstract

The present invention discloses a process for the preparation of pure non-ionic contrast agents. The invention also includes a method for purifying the non-ionic contrast agents.

Description

PROCESS FOR THE PREPARATION OF IOPAMIDOL Technical Field The present invention relates to a process for the preparation of water-soluble, non-ionic compounds, which are useful as contrast agents.

BACKGROUND OF THE INVENTION The introduction in the diagnosis of X-rays of a contrast medium containing iodinated nonionic compounds as opacifying agents, represented a remarkable progress in the state of the art, so much so that these media will eventually replace the traditional iodized ionic products. (see Grainger and Dawson, Clinical Radiology, 1990, 42, 1-5). These non-ionic compounds, such as (S) -N, N'-bis [2-hydroxy-1- (hydroxy (methyl) ethyl-5 - [(2-hydroxy-1-oxipropylamino) -2,4,6 -triyodo-1, 3-benzenedicarboxamide (iopamidol) and 5- [acetyl (2,3-dihydroxypropyl) amino] -N, N'-bis [2,3-dihydroxypropyl] -2,4,6-triiodo-1, 3-benzenodicarboxamide (iohexol), are useful as contrast enhancers for X-rays, magnetic resonance imaging (MRI) and angiography.Intravenous injection, these compounds have a frequency of adverse reactions in patients lower than many agents However, the synthetic processes and, particularly, the final purification of these products, are complex and expensive.The neutral iodized opacifying agents differ from the ionic because they can not be isolated and purified by precipitation of the water due to their high solubility Therefore, the following problems must be solved: the removal of ionic species, normally and inorganic salts, of the final reaction mixture, the recovery of valuable excess reagents and of water-soluble reaction medium. A preferred technique to be carried out (see, for example, US Patents Nos. 4,352,788 and 4,001, 323) is that which is based on the subject of operations such as: - preliminary removal of the solvent, - extraction of the reaction medium residual, preferably with a chlorinated solvent, - levigation of the aqueous phase in a system of columns of ion exchange resins, cationic and anionic, - concentration of the levigado by evaporation, - crystallization of the crude residue. The disadvantages related to this type of process include: a) a requirement of large, complex and expensive purification plants for ion exchange resins; b) a large amount of thermal energy is required for the concentration of water used; c) the concentration of extremely dilute solutions results in the corresponding concentration of residual impurities; and d) the final product is exposed to a long-term heat treatment. The U.S. Patent No. 4,001, 323 (the '323 patent) describes a process for preparing iopamidol, which involves a) the reaction of 5-amino-2,4,6-triiodoisophthalyl dichloride (ATIPA-CI) with 2 (S) chloride ) - acetoxypropionyl to form an acetyl amide intermediate; b) the reaction of the intermediate acetyl amide with serinol in order to provide acetyliopamidol; c) the reaction of acetylpamidol with an aqueous base, such as sodium hydroxide in order to hydrolyze the ester and provide iopamidol. The product is then purified by ion exchange treatment, followed by recrystallization from ethanol. U.S. Patent No. 4,352,788 (the '788 Patent) describes a process for preparing compounds similar to the compounds of the' 323 patent. The main difference is that the compounds of the '788 patent are alkylated on the aromatic nitrogen atom. The products are isolated by countercurrent extraction or by the use of exchange resins. However, the problems that exist with the processes set forth in the '323 and' 788 patents include a) the use of a hazardous solvent; b) the basic hydrolysis can induce racemization of the optically active compound and can result in the material not meeting the optical rotation specification of U.S.P. for iopamidol. The U.S. Patent 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 exposes the preparation that begins with ATIPA-CI. However, in the '598 patent, the polyhydroxy product is purified by preparative liquid chromatography. The U.S. Patent No. 5,550,287 discloses a method for the purification of contrast agents by again using a column with a strong anionic resin followed by a column with a weak anionic resin. U.S. Patent No. 5,204,005 discloses the use of a reverse phase chromatographic process for the purification of water-soluble, non-ionic contrast compounds. An object of the present invention is to provide a process for preparing contrast agents that do not racemize the product. An object of the present invention is to provide a process that procures the product contrast agent having a specific rotation that meets the requirements of the U.S. specification. P. An object of the present invention is to provide an efficient method for the purification of water-soluble, non-ionic contrast agents.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to an improved process for the preparation and purification of contrast enhancing agents, such as iopamidol and iohexol. The process converts 5-amino-2,4,6-triiodoisophthalyl dichloride (ATIPA-CI) into 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 the first reaction of the ATIPA-CI with 2 equivalents of a dihydroxy-amine such as, for example, serinol, (2- amino-1, 3-dihydroxypropane) or other 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), so as to form the tetraester diamide. The tetraester-diamide product is then treated with a 2 (S) -alkyloxylated 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 exclusion resin in order to remove the acid and purified by passing it through a bed of polymeric, non-ionic adsorbent resin to remove other impurities from the reaction. The final purification is carried out by recrystallization of the 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 incorporated herein by reference in their entirety. In the case of inconsistencies, the present exposition will prevail, including the definitions. The present invention relates to a process for the preparation of a polyhydroxy compound and salts and enantiomers thereof, having the formula I wherein R1 and R2 are dihydroxyalkyl groups and R3 is hydrogen, alkyl or hydroxy. The process comprises the step of deacylating and acylating the compound having the formula: in an acidic medium, to provide the polyhydroxy-free compound. R 4 and R 5 are dihydroxyalkyl groups, optionally acylated, and R 6 is lower alkyl. The polyhydroxy compound can be purified by treatment with an acid exclusion resin. The invention also contemplates compounds having the formula wherein each R7 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. Preferred acyl groups are formyl, acetyl, propionyl and butanoyl. The most preferred acyl group is acetyl. The dihydroxyalkyl groups are straight chain or branched alkyl radicals containing from 2 to 6 carbon atoms and having two hydroxy groups. The most preferred dihydroxyalkyl groups are 1,3-dihydroxypropyl, 1,2-dihydroxypropyl. 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. Preferred lower alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl and t-butyl. Most preferred are methyl or ethyl. The most preferred is methyl. The advantages of the present invention include the reduction of racemisation of the product and an improved method for the isolation of the product. This provides a product with a greater enantiomeric excess (ee) than the methods set forth in the documents set forth above. The process of the invention involves the deacylation of an iopamidol ester by the use of a catalytic amount of acid. The acid is removed by batch treatment with a small amount of an acid extraction resin. The final purification involves the passage of an aqueous solution of the product through a column of non-ionic polymer adsorbent resin, followed by the concentration in an oil and recrystallization from acetonitrile / ethanol or only ethanol. This process consistently produces material that meets all specifications of the U.S.P. , including the specification of optical rotation. Typical acid extraction resins include weak basic resins such as, for example, IRA-68, IRA-67, Dowex® WGR-2 and the like. These resins remove any acid present. Typical non-ionic polymeric adsorption resins include polyaromatic resins, such as, for example, Amberlite XAD-16, XAD-4 and the like. These resins work to remove impurities formed during the reaction process. In Scheme 1 below, a preferred embodiment is illustrated. The process converts 5-amino-2,4,6-triiodoisophthalyl dichloride (ATIPA-CI) to 5-amino-N, N'-bis (1,3-diacetoxy-2-propyl) -2,4,6- triiodoisophthalamide (tetraacetyl diamide) in a single reaction vessel, upon first reacting ATIPA-CI with 2 equivalents of serinol in the presence of triethylamine followed by treatment with acetic anhydride in the presence of a catalytic amount of dimethylaminopyridine (DMAP). The tetraacetyl diamide product is easily isolated by precipitation of water and no further purification is generally required. The tetraacetyl compound is treated with 2 (S) -acetoxypropionyl chloride to provide a pentaacetyl triamide. The acetate groups are removed by a transesterification reaction with hydrochloric acid in methanol to provide iopamidol. The acid is removed with an acid extraction resin. Other impurities are removed by the use of a polymeric absorption resin. The product can be crystallized from ethanol or, optionally, if it contains excess impurities, a mixture of acetonitrile / ethanol.

SCHEME I Preferred compounds of the invention include the compounds: (S) -N, N'-bis [2-hydroxy-1- (hydroxy (methyl) ethyl] -5 - [(2-hydroxy-1-oxypropyl-amino] - 2,4,6-triiodo-1,3-benzenedicarboxamide, (S) -N, N'-bis [2,3-dihydroxypropyl] -5 - [(2-hydroxy-1-oxopropylamino) -2,4,6 -triyodo-1, 3-benzenedicarboxamide, and 5 [acetyl (2,3-dihydroxypropyl) amino] -N, N'-bis [2,3-dihydroxypropyl] -2,4,6-triiodo-1,3-benzenedicarboxamide (iohexol) The process of the invention includes a method for deacylating a compound, wherein all hydroxy groups have been acylated and a method for deacylating monoacylated compounds, such as, for example, acetylpamidol.Examples of the alkanoyloxy group include acetyloxy , propionyloxy, butanoyloxy and the like A preferred alkanoyloxy group is acetyloxy Acyl groups include groups such as, for example, acetyl, propionyl, butanoyl and the like A preferred acyl group is acetyl The invention also contemplates a method for purification of agents non-ionic contrast agents, soluble in water. As used herein, the term "acyl" refers to groups having the formula -C (= O) -R95 wherein R95 is hydrogen or a lower alkyl or aryl group. Representative examples of acyl groups include groups such as, for example, formyl, acetyl, propionyl and the like. As used herein, the term "alkyl" refers to straight or branched chain alkyl radicals containing from 1 to 12 carbon atoms. The term "lower alkyl" refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, / so-propyl, 2-methylpropyl n- butyl, 2-butyl, f-butyl n-pentyl, 1-methyl butyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. As used herein, the term "aryl" refers to a monocyclic or bicyclic carboxy cyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Similary. The aryl groups can be substituted or not substituted with one, two or three substitutes. As used herein, the term "dihydroxyalkyl" refers to straight or branched chain alkyl radicals containing from 2 to 6 carbon atoms and having two hydroxy groups. Representative examples of dihydroxyalkyl groups include groups such as, for example, 1,3-dihydroxypropyl, 1,2-dihydroxypropyl and the like. As used herein, the term "halo" refers to F, Cl, Br or I. As used herein, the term "haloalkyl" refers to a lower alkyl group in which one or more hydrogen hydrogen have been replaced with a halogen, including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl and the like. As used herein, the "S" and "R" configuration terms are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Puré Appl. Chem. (1976) 45, 13-30. The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York 14652-3512); Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz and Bauer (Waterbury, CT 06708). Compounds that are not commercially available can be prepared by using methods known from the chemical literature. Polymer resins, for example, IR-68 and Ambelite XAD-16 are available from suppliers such as Rohm and Hass Company (Philadelphia, PA 19106). The following examples illustrate the process of the invention, without limitation. Example 1 N. N'-bisf2- (acetyloxy) -1-r (acetyloxy) metinetin-5-amino-2,4,6-trivode-1,3-benzenedicarboxamide. A suitable reaction vessel was charged with 50 kg of 5-amino-2,4,6-triiodoisophthalyl dichloride (ATIPA-CI) and 75 kg of dimethylacetamide (DMA) and mixed. To the above vessel, a solution of 18.5 kg of 2-amino-1,3-propanediol (serinol) and 30 kg of triethylamine in 45 kg of DMA was added. The reaction was mixed while gradually raising the temperature to about 30 ° C. This temperature was maintained for about 1.5 hours. The reaction was cooled and 0.5 kg of 4-dimethylaminopyridine was added to the vessel, followed by the slow addition of 52 kg of acetic anhydride. The reaction was stirred for about 2 hours and quenched by slow addition in water. The solid was isolated by filtration, rinsed with water and dried (yield: 66 kg; 90%). 1 H NMR (300 MHz, DMSO-d 6) d 2.0 (S, 12 H), 4.1 (m, 8 H), 4.3 (m, 2 H), 8.4, 8.7 (2 d, 2 H). 13C NMR (75 MHz, DMSO-dβ) d 20.8, 46.9, 62.1, 73.5 79.7, 147.6, 148.5, 169.5, 170.2.

Example 2 Preparation of Pentaacetylpamidol The product, 55 kg, prepared in Example 1, was dissolved in 60 kg of DMA. 2 (S) -acetoxypropionyl chloride was added slowly. the reaction was stirred at room temperature for about 2 hours and warmed by the slow addition of isopropanol. The mixture was neutralized with tributylamine. The pentaacetylpamidol was collected by filtration, rinsed with isopropanol and dried (yield: 56 kg, 90%). 1 H NMR (300 MHz, DMSO-d 6) d 1.5 (d, 3 H), 2.0 (S, 12 H), 2.1 (2 S, 3 H), 4.1 (m, 8 H), 4.3 (m, 2 H), 5.2 (q, 1 H), 8.8 (d, 1 H), 8.9 (t, 1 H), 10.1 (S, 1 H). 13C NMR (75 MHz, DMSO-d6) d 17.6, 20.8, 47.0, 62.1, 69.4, 90.1, 99.0, 142.4, 149.6, 168.0, 169.1, 169.5, 170.3. Example 3 Preparation of lopamidol A solution of 58 kg of pentaacetyliopamidol in 400 L of methanol containing a catalytic amount, 400 g, of aqueous hydrochloric acid was heated to reflux for about 30 hours. The methanol was removed by distillation and the residue was dissolved in water. The acid was neutralized by stirring the solution with an acid extraction resin (IRA-68). The resin was removed by filtration and the resulting aqueous solution was passed through a 50 kg column of Amberlite XAD-16 resin. The levigant was concentrated in order to provide an oil and the residue was crystallized by heating the oil in a mixture comprising 40 kg of acetonitrile and 150 L of ethanol, followed by cooling. The iopamidol was collected by filtration, rinsed with ethanol and dried (yield: 34 kg, 74%). Specific Rotation [a] D20 = -5.0 in methanol. 1 H NMR (300 MHz, D 2 O) d 1 .6 (d, 3 H), 3.8 (d, 8 H), 4.2 (m, 2 H), 4.5 (q, 1 H). 1 3C NMR (75 MHz, D2O) d 21.5, 55.1, 61.8, 70.2, 91.0, 99.8, 144.2, 151.2, 173.8, 178.6. Comparative Example 1 L-5- (α-Acetoxypropionylamino) 2,4,6-triiodo-isophthalyl chloride A solution of 100 g (168 mmol) of 5-amino-2,4,6-triiodo-isophthalyl chloride was prepared in 100 ml of dimethylacetamide. L-2-acetoxypropionyl chloride was added dropwise to the solution at room temperature. The mixture was stirred for 16 hours at room temperature.

The reaction mixture was diluted with 200 mL of acetone and spent drop was added to 500 mL of cold water. The solid product was collected, rinsed with water and dried under vacuum at 65 ° C (Production: 10 g, 93%). Comparative Example 2 L-5-α-acetoxypropionylamino-2,4,6-trivodo-isophthalic acid di (1,3-dihydroxyisoisopropylamide (acetylpamidol)) The intermediate compound prepared in Example 1, (27.0 g, 38. 0 mmol), was dissolved in 140 ml of dimethylacetamide. Tributylamine (14.2 g, 76.6 mmol) was added, followed by a solution of 1,3-dihydroxy (8.6 g, 94.4 mmol) in 80 mL of dimethylacetamide. The mixture was stirred and heated at 50 ° C for 22 hours. The reaction mixture was added dropwise to 1.0 L of methylene chloride with vigorous stirring and the resulting precipitate was filtered off and rinsed to provide 25.8 g of the main compound.

Comparative Example 3 L-5-a-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid di (1,3-dihydroxyiso-propylamide (acetylpamidol) L-5-a-acetoxypropionylamino-2,4,6-triiodo-isophthalic acid di (1,3-dihydroxyisopropylamide (20 g, 24.4 mmol) was dissolved in water, the pH was adjusted to 1 l with a concentrated sodium hydroxide solution and heated to 40 ° C. An additional NaOH solution was added until The pH was stabilized, indicating the complete saponification of the acetoxy groups The reaction mixture was acidified to pH 7 with 3N hydrochloric acid The resulting solution was passed over a column of IR 120 resin (25 g) and was followed by Pass over a column of resin A-21 (35 g) to desalt the solution (Resins available from Rohm &Haas Co.) The product was purified by passing over an XAD-16 column. by removing the solvent in vacuo, followed by crystallization from acetonitrile / water (1: 3) (production: 9.2 g; 48%). Elemental analysis, calculated for C17H22l13N3On: C, 26.27% and I, 47.79%. It was found: C, 26.27% and I, 48.79%. Specific Rotation [a] D20 = -4.5 in methanol. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the processes set forth and to the reaction conditions. It is intended that variations that are obv to someone of ordinary skill in the art be included within the scope and nature of the invention, which is defined in the appended claims.

Claims (10)

CLAIMS 1. A process for the preparation of a polyhydroxy compound and salts and enantiomers thereof, characterized in that it has the formula] _:
1. I wherein R1 and R2 are dihydroxyalkyl and R3 is hydrogen, alkyl or hydroxy; said process comprising the step of deacylating and acylating the compound having the formula: in an acidic medium,? 4 .. D5 wherein R and R are acylated dihydroxyalkyl groups, and R is lower alkyl.
2. 2. The process according to claim 1, characterized in that R1 and R2 are independently selected from the group consisting of 1,3-dihydroxypropyl and 2,3-dihydroxypropyl.
3. 3. The process according to claim 2, characterized in that R1 and R2 are 1,3-dihydroxypropyl.
4. 4. The process according to claim 2, characterized in that R1 and R2 are 2,3-dihydroxypropyl. The process according to claim 1, characterized in that the acylated dihydroxyalkyl group is acylated with an acyl group selected from the group consisting of formyl, acetyl, propionyl and butanoyl. 6. The process according to claim 6, characterized in that the acylated dihydroxyalkyl group is acylated with an acyl group selected from the group consisting of acetyl, propionyl and butanoyl. 7. The process according to claim 1, characterized in that R4 and R5 are 1,3-diacetyloxypropyl. 8. The process according to claim 1, characterized in that R4 and R5 are 2,3-diacetyloxypropyl. The process according to claim 1, characterized in that R3 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl and / -butyl. 10. The process according to claim 9, characterized in that R3 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and / so-propyl. eleven . The process according to claim 10, characterized in that R3 is methyl. The process according to claim 10, characterized in that R3 is hydrogen. 3. The process according to claim 1, characterized in that R6 is selected from the group consisting of methyl, ethyl, propyl and butyl. The process according to claim 13, characterized in that R6 is selected from the group consisting of methyl, ethyl, n-propyl, / so-propyl, n-butyl and f-butyl. 1
5. 5. The process according to claim 14, characterized in that R6 is selected from the group consisting of methyl and ethyl. 1
6. 6. The process according to claim 15, characterized in that R6 is methyl. 1
7. 7. A compound and salts and enantiomers thereof, characterized in that it has the formula: wherein R7 is an acyl group. 1
8. 8. The compound according to claim 17, characterized in that each R7 is independently selected from the group consisting of formyl, acetyl, propionyl, butanoyl, pivaloyl, pentanoyl, trifluoroacetyl, trichloroacetyl and benzoyl. 1
9. 9. The compound according to claim 18, characterized in that each R7 is independently selected from the group consisting of formyl, acetyl, propionyl and butanoyl. 20. The compound according to claim 19, characterized in that each R7 is acetyl.