EP1648850A1

EP1648850A1 - Method for producing triiodine trimesine acid

Info

Publication number: EP1648850A1
Application number: EP04740966A
Authority: EP
Inventors: Heiko Schirmer; Johannes Platzek; Jose Luis Martin; Juan R. Harto; Jose Carretero; Ulrich Niedballa
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 2003-07-14
Filing date: 2004-07-13
Publication date: 2006-04-26
Also published as: WO2005005362A1; JP2009513545A; DE10332552B3

Abstract

The invention relates to a novel method for producing triiodine trimesine acid used as an intermediate product for the synthesis of X-ray contrast agents.

Description

Process for the preparation of triiodotrimesic acid

Triiodotrimesic acid (Formula I) is an important intermediate for the production of nonionic triiodinated X-ray contrast media. For example, DE 3001292 (Schering) describes the preparation of trisamides of triiodotrimesic acid. Such compounds are particularly interesting because of their favorable pharmacological properties. The economic use of these trisamides failed because so far no commercially usable access to the actual starting compound, triiodotrimesic acid, has been found. A contrast medium with particularly good properties, the losimid, which was already in phase III of the clinical trials, failed in its further development due to the high production costs of triiodotrimesic acid.

DE 2831496 describes the preparation of triiodotrimesic acid starting from nitroisophthalic acid:

In this process, nitroisophthalic acid is hydrogenated to the amino compound and then iodinated with chlorine iodine. The missing carboxyl group is introduced via a Sandmeyer reaction (HN0 ₂ / KCN / CuCN). This reaction step proved to be very critical, especially when the batch was enlarged, since on the one hand hydrocyanic acid is formed and, moreover, the copper ions have to be used in excess. The removal of copper waste from the reaction waters is particularly critical on a large scale. A critical step is also the complete saponification of the nitrile to the carboxylic acid. The amide, which proved to be very difficult to hydrolyze, is run through as an intermediate.

Another patent (NYCOMED: US 5,882,628) describes intermediates which could be considered as starting materials for the synthesis of triiodotrimesic acid:

Triiodmesitylene is produced under acetylating conditions in a

Oxidation reaction with potassium permanganate / acetic anhydride / acetic acid / sulfuric acid in the

Triacetate transferred (yield: 35%). The triacetate is isolated and with

Potassium carbonate saponified in trisalcohol in methanol (yield: 94%). The

Tris alcohol is then converted into dimethyl sulfoxide by Swem oxidation

Solvent converted to trisaldehyde in 67% yield.

The further oxidation to tricarboxylic acid has not been described in this patent, and this step is also not reported in the literature.

There was therefore a need for a new synthesis which delivers triiodotrimesic acid in high overall yield with favorable environmental and safety aspects and which also has the ability to enlarge the batch. Surprisingly, these requirements are met with the new two-stage synthesis present here. The following synthesis scheme shows the new synthetic route starting from triiodmesitylene: (ll) (I)

Here, starting from triiodmesitylene with potassium or sodium permanganate in a mixture of acetic anhydride, acetic acid and sulfuric acid in a volume ratio of 15-30: 10-20: 1, 25-3.5, preferably 20: 15: 2.5. The concentration of sulfuric acid is 70% - 100%, preferably 95 - 100%. The reaction takes place at temperatures from 10 to 120 ° C., preferably 20-100 ° C., particularly preferably 40-80 ° C. The reaction time is 12-36 hours, preferably 15-25 hours.

Then it is distilled off. This can be done directly from the batch, the pressure being reduced if necessary. A mixture of acetic acid and acetic anhydride is obtained. But you can also add water to destroy the excess acetic anhydride and then distill off pure acetic acid. The recovered acetic acid can be reused. Then the residue is neutralized by adding an inorganic base such as sodium hydroxide solution, potassium hydroxide solution or calcium hydroxide in solid form or, preferably, the sulfuric acid as an aqueous solution and the concentration is continued. After evaporation is complete, water is added at temperatures between 60-100 ° C., then stirred and the precipitated 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene (II) is filtered off, which is washed with water and methanol and then is dried.

In the next reaction step, the 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene (II) is placed in water at temperatures of 60-100 ° C., preferably 80-100 ° C. (reflux) and with an aqueous Solution of an inorganic Base, preferably sodium hydroxide solution, potassium hydroxide solution, calcium hydroxide, sodium carbonate or potassium carbonate, but particularly preferably NaOH or KOH. The dropping time of the base is 30 minutes to 10 hours, preferably 30 minutes to 3 hours. The mixture is then stirred for 1 to 24 hours, preferably 3-12, particularly preferably 4-8 hours at temperatures between 60 and 100 ° C., particularly preferably 80-100 ° C. Then neutralized with an inorganic acid (pH = 6-7), preferably hydrochloric acid, hydrobromic acid or sulfuric acid, but particularly preferably concentrated hydrochloric acid, manganese sulfate is added to the hot reaction solution, and an aqueous potassium or sodium permanganate solution is added dropwise, and the mixture is then 1 to 24 Hours, preferably 1-12, particularly preferably 2-4 hours at temperatures between 60 and 100 ° C, particularly preferably 80-100 ° C, stirred. The subsequent processing can be done in different ways:

1. The excess of oxidizing agent can be destroyed by adding a reducing agent in solid or dissolved form (aqueous solution). Inorganic sulfites or hydrogen sulfites, such as sodium sulfite / hydrogen sulfite or potassium sulfite hydrogen sulfite, particularly preferably sodium sulfite or lower alcohols such as methanol, ethanol, isopropanol, glycol, are particularly suitable for this purpose. This happens at temperatures between 10 to 100 ° C, preferably 20 - 80 ° C. The pH is then adjusted to 0.1-3, preferably 0.5-1, by adding sulfuric acid, and the product is extracted by extraction with an organic solvent such as ethyl acetate, propyl acetate, methyl butyl ether (MTB), tetrahydrofuran (THF), Extracted n-butanol, methyl-THF, dichloromethane, toluene. Ethyl acetate and MTB are preferred. The organic phases can optionally be washed with water, brine or acidified water and evaporated to dryness. It has proven particularly favorable to distill directly onto the solvent used for the crystallization. During the distillation, the first is added by the continuous addition of a second solvent second solvent replaced. Cyclohexane and n-heptane, and their mixtures with ethyl acetate, toluene and MTB, have proven particularly useful as solvents for the crystallization. In some cases, an extraction with an organic solvent as described above can also be dispensed with. For this purpose, the mixture is largely evaporated to dryness under reduced pressure and then water is largely removed by adding an azeotrope-forming solvent such as methanol, ethanol, isopropanol, dichloromethane, MTB, ethyl acetate, butyl acetate, butanol, toluene or THF. The amount of residual water is determined by Karl Fischer (KF) titration. Then the remaining residue is washed with an organic solvent such as methanol, ethanol, isopropanol, dichloromethane, MTB, ethyl acetate, butyl acetate, butanol, toluene or THF at temperatures between 20 - Stirred 100 ° C and filtered off from the salts. The filtrate can be evaporated to dryness or, as described above, distilled to a solvent suitable for crystallization.

2. In some cases it has proven to be advantageous not to add a reducing agent, but to adjust the pH to 0.1-3, but preferably 0.1-1, by adding sulfuric acid and then to dryness as described above under reduced pressure evaporate and stir the residue with an organic solvent (same procedure as under 1 -)

The synthesis process described here is distinguished by several important advantages over the process of the prior art: the cheap and non-toxic potassium or sodium permanganate is used as the sole oxidant. The resulting manganese waste can be made reusable in a recycling process by means of oxidation. The process is robust and can easily be carried out on a multi-ton scale. It is characterized by environmentally friendly solvents. The Ver-. Driving is inexpensive to carry out, consists of only two stages and delivers a high overall yield of 80-85% of theory. This method thus makes a valuable contribution to the production of an intermediate stage of the triiodinated trisamides which are important for medical diagnostics.

The following examples serve to describe the new process: Production of triiodotrimesitylene

Taken from Synthesis 6, 486 (1980); WO 96/09282, J. Med. Chem. (2000) 43 (10), 1940 or after Synlett (2002), (4), 598

Preparation of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene (II)

400 g (803 mmol) of triiodmesitylene are concentrated in 0.9 I acetic anhydride, 1, 4 I acetic acid and 121 ml. Suspended sulfuric acid and at 40 ° C 160 g (1.01 mol) of potassium permanganate are added in portions (over 2 hours) and stirred at 40 ° C for 18 hours. When the reaction has ended, 152 ml of water are carefully added with stirring and stirring is continued for 2 hours at room temperature. Then add 363.2 ml of 50% sodium hydroxide solution (exactly the amount to neutralize the sulfuric acid!). The mixture is then largely distilled off (reduced) under reduced pressure. 4 l of water are added dropwise with stirring and the mixture is then stirred at 10 ° C. for one hour. The precipitate is filtered off, washed twice with 1.5 l of water and with 500 ml of methanol and dried in vacuo at 50 ° C. Yield: 0.456 kg (93% of theory)

Elemental analysis: Calc .: C 24.43 H 2.13 J 62.01 Found: C 24.26 H 2.09 J 62.31

Production of triiodotrimesic acid (I) (variant A) 250 g (407 mmol) 1, 3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and 200 ml of 50% sodium hydroxide solution are carefully added at 90 ° C and 5 hours at 90 ° C stirred. Then with conc. Hydrochloric acid neutralized (pH = 6-7), 367 g (1, 488 mol) of magnesium sulfate added, a solution of 411 g (2.604 mol)

Potassium permanganate added dropwise in 4 l of water and stirred under reflux for 2 h. The mixture is cooled to room temperature (RT), 50 g of sodium sulfite are added and the mixture is stirred at room temperature for one hour. The pH is then adjusted to 1 using 50% sulfuric acid. 2 l of ethyl acetate are added and the mixture is stirred well. The organic phase is separated off and the water phase is extracted twice with 0.5 l of ethyl acetate. The organic phases are combined, washed once with 2.5 l of water and then distilled to cyclohexane. The product crystallizes out on cooling (0 ° C). Yield: 206 g (86% of theory)

Elemental analysis: Calc .: C 18.39 H 0.51 J 64.77 Found: C 18.47 H 0.56 J 64.65

Production of triiodotrimesic acid (I) (variant B)

250 g (407 mmol) 1, 3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and 200 ml of 50% sodium hydroxide solution are carefully added at 90 ° C and 5 hours at 90 ° C stirred. Then with conc. Hydrochloric acid neutralized (pH = 6-7), 367 g (1, 488 mol) of magnesium sulfate were added, a solution of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise and the mixture was stirred under reflux for 2 h. The mixture is cooled to room temperature (RT), 50 g of sodium sulfite are added and the mixture is stirred at room temperature for one hour. The pH is then adjusted to 1 using 50% sulfuric acid. 2 l of ethyl acetate are added and the mixture is stirred well. The organic phase is separated off and the water phase is extracted twice with 0.5 l Ethyl acetate after. The organic phases are combined, washed once with 2.5 l of water. The ethyl acetate solution is distilled to remove azeotropic water (water content after Karl Fischer titration <0.2%). A solution prepared in this way can be used for further reaction (eg preparation of the acid chloride with SOCI ₂ ). The yield was determined by evaporating an aliquot.

Yield: 211 g (88% of theory)

Elemental analysis:

Calc .: C 18.39 H 0.51 J 64.77

Found: C 18.50 H 0.62 J 64.54

Production of triiodotrimesic acid (I) (variant C)

250 g (407 mmol) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and 200 ml of 50% sodium hydroxide solution are carefully added at 90 ° C. and 5 hours at 90 ° C stirred. Then with conc. Hydrochloric acid neutralized (pH = 6-7), 367 g (1, 488 mol) of magnesium sulfate were added, a solution of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise and the mixture was stirred under reflux for 2 h. The mixture is cooled to room temperature (RT), 50 g of sodium sulfite are added and the mixture is stirred at room temperature for one hour. The pH is then adjusted to 1 using 50% sulfuric acid. It is largely evaporated in vacuo and residual water is distilled by adding isopropanol. azeotope. The isopropanol is added continuously. If the water content is <1% (KF), a further 10 l of isopropanol are added and the mixture is stirred at 40 ° C. for one hour. The salt pulp is filtered off and rinsed twice with 3 l of isopropanol. The filtrate is evaporated to dryness in vacuo.

Yield: 213 g (89% of theory) Elemental analysis:

Calc .: C 18.39 H 0.51 J 64.77

Found: C 18.46 H 0.59 J 64.64

Production of triiodotrimesic acid (I) (variant D)

250 g (407 mmol) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and 200 ml of 50% sodium hydroxide solution are carefully added at 90 ° C. and 5 hours at 90 ° C stirred. Then with conc. Hydrochloric acid neutralized (pH = 6-7), 367 g (1, 488 mol) of magnesium sulfate were added, a solution of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise and the mixture was stirred under reflux for 2 h. The mixture is cooled to room temperature (RT), 50 g of sodium sulfite are added and the mixture is stirred at room temperature for one hour. The pH is then adjusted to 1 using 50% sulfuric acid. It is largely evaporated in vacuo and residual water is distilled out azeotropically by adding ethanol (continuous addition of ethanol). If the water content is <1% (KF), a further 10 l of ethanol are added and the mixture is stirred at 40 ° C. for one hour. The salt pulp is filtered off and rinsed twice with 5 l of isopropanol. The filtrate is evaporated to dryness in vacuo.

Yield: 215 g (90% of theory)

Elemental analysis: Calc .: C 18.39 H 0.51 J 64.77 Found: C 18.41 H 0.54 J 64.59

Production of triiodotrimesic acid (I) (variant E) 250 g (407 mmol) 1, 3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and 200 ml of 50% sodium hydroxide solution are carefully added at 90 ° C and 5 hours at 90 ° C stirred. Then with conc. Hydrochloric acid neutralized (pH = 6-7), 367 g (1, 488 mol) of magnesium sulfate added, a solution of 411 g (2.604 mol)

Potassium permanganate added dropwise in 4 l of water and stirred under reflux for 2 h. The mixture is cooled to room temperature (RT), 50 g of sodium sulfite are added and the mixture is stirred at room temperature for one hour. The pH is then adjusted to 1 using 50% sulfuric acid. It is largely evaporated in vacuo and residual water is distilled out azeotropically by adding isopropanol (continuous addition of isopropanol). If the water content is <1% (KF), a further 10 l of isopropanol are added and the mixture is stirred at 40 ° C. for one hour. The salt pulp is filtered off and rinsed twice with 5 l of isopropanol. The filtrate is evaporated to dryness in vacuo.

Yield: 214 g (90% of theory)

Elemental analysis: Calc .: C 18.39 H 0.51 J 64.77 Found: C 18.47 H 0.55 J 64.71

Production of triiodotrimesic acid (I) (variant F)

250 g (407 mmol) 1, 3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and 200 ml of 50% sodium hydroxide solution are added carefully at 90 ° C and 5 hours at 90 ° C stirred. Then with conc. Hydrochloric acid neutralized (pH = 6-7), 367 g (1, 488 mol) of magnesium sulfate were added, a solution of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise and the mixture was stirred under reflux for 2 h. The mixture is cooled to room temperature (RT), 50 g of sodium sulfite are added and the mixture is stirred at room temperature for one hour. Then with 50% sulfuric acid to a pH Value of 1 set. It is largely evaporated in vacuo and the remaining water is distilled off azeotropically by adding ethanol (continuous addition of ethanol). If the water content is <1% (KF titration), another 10 l of ethanol are added and the mixture is stirred at 40 ° C. for one hour. The salt paste is filtered off and rinsed twice with 5 l of ethanol. The filtrate is evaporated to dryness in vacuo.

Yield: 213 g (89% of theory)

Elemental analysis: Calc .: C 18.39 H 0.51 J 64.77

Found: C 18.44 H 0.54 J 64.66

Production of triiodotrimesic acid (I) (variant G)

250 g (407 mmol) 1, 3,5-triiodo-2,4-diacetoxymethyIen-6-methylbenzene are suspended in 2.5 l of water and 200 ml of 50% sodium hydroxide solution are added carefully at 90 ° C and 5 hours at 90 ° C stirred. Then with conc. Hydrochloric acid neutralized (pH = 6-7), 367 g (1, 488 mol) of magnesium sulfate were added, a solution of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise and the mixture was stirred under reflux for 2 h. The mixture is cooled to room temperature (RT), 50 g of sodium sulfite are added and the mixture is stirred at room temperature for one hour. The pH is then adjusted to 1 using 50% sulfuric acid. It is largely evaporated in vacuo and residual water is distilled out azeotropically by adding methanol (continuous addition of methanol). If the water content is <2% (KF titration), another 10 l of methanol are added and the mixture is stirred at 40 ° C. for one hour. The salt paste is filtered off and rinsed twice with 5 l of methanol. The filtrate is evaporated to dryness in vacuo.

Yield: 213 g (89% of theory) Elemental analysis:

Calc .: C 18.39 H 0.51 J 64.77

Found: C 18.36 H 0.62 J 64.72

Claims

claims

Process for the preparation of triiodotrimesic acid, characterized in that in an oxidation process triiodmesitylene is reacted with potassium or sodium permanganate in a mixture of acetic anhydride, acetic acid and sulfuric acid at temperatures of 10 to 120 ° C within 12 to 36 hours, then the resultant is obtained Intermediate 1, 3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene isolated, this then treated with base 1, 5 to 34 hours at temperatures between 60 and 100 ° C, then neutralized the reaction solution and then with an aqueous potassium - or sodium permaganate solution treated at temperatures from 60 to 100 ° C within 1 to 24 hours.

2. The method according to claim 1, characterized in that the reaction to the intermediate product is carried out at 40 to 80 ° C.

3. The method according to claim 1, characterized in that the reaction to the intermediate product is carried out within 15 to 25 hours.

4. The method according to claim 1, characterized in that the basic treatment of the intermediate is carried out at 80 to 100 ° C.

5. The method according to claim 1, characterized in that the basic treatment of the intermediate is carried out within 3 to 12 hours.

6. The method according to claim 1, characterized in that the oxidation of the intermediate product is carried out at 80 to 100 ° C.

7. The method according to claim 1, characterized in that the oxidation of the intermediate product is carried out within 2 to 4 hours.

8. 1, 3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene.