JP2009513545A - Method for producing triiodotrimesic acid - Google Patents

Abstract

  A novel process for the preparation of triiodotrimesic acid used as an intermediate product for the synthesis of X-ray contrast agents is described.

Description

  Triiodotrimesic acid (Formula I) is an important intermediate product for the production of non-ionic triiodinated radiographic contrast agents. Thus, for example, DE 3001292 (Schering) describes the preparation of trisamide of triiodotrimesic acid. Such compounds are particularly important because of their advantageous pharmacological properties. The economical use of the trisamide has failed because no commercially available approach to the original starting compound of triiodotrimesic acid has yet been found. A particularly good contrast agent, Iosimide (which is already in phase 3 of clinical trials) has failed to be further developed due to the too high production cost of triiodotrimesic acid. Yes.

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

In the process, nitroisophthalic acid is hydrogenated to an amino compound and subsequently iodinated with Chlorjod. The introduction of the missing carboxyl group is made via the Sandmeyer reaction (HNO ₂ / KCN / CuCN). The reaction process proves to be very critical as the batch is increased because, on the one hand, hydrocyanic acid is produced and more copper ions must be used. The removal of copper waste from the reaction water is deemed particularly critical on a large scale. Complete saponification of nitriles to carboxylic acids is also a critical process. In the middle, an amide that is very difficult to hydrolyze is produced.

  A further patent document (NYCOMED: US 5,882,628) describes an intermediate step that is considered as a starting product for the synthesis of triiodotrimesic acid:

  Triiodomesitylene is converted to triacetate during the oxidation reaction using potassium permanganate / acetic anhydride / acetic acid / sulfuric acid under acetylation conditions (yield: 35%). The triacetate is isolated and saponified with potassium carbonate to trisalcohol in methanol (yield: 94%). The tris alcohol is then converted to trisaldehyde in a solvent of dimethyl sulfoxide by a Swern oxidation in a yield of 67%. Further oxidation to tricarboxylic acids is not described in the patent and nothing is reported in the literature for this process.

  Therefore, there is a need for a process that provides triiodotrimesic acid in high overall yields and also has the potential for batch growth under advantageous environmental and safety aspects. The above requirements are surprisingly met by the novel two-step synthesis of the present invention. The following synthetic scheme shows a new synthetic route starting from triiodomesitylene:

  In this case, starting from triiodomesitylene, potassium permanganate or sodium permanganate and a volume of 15-30: 10-20: 1.25-3.5, preferably 20: 15: 2.5 React in a mixture of acetic anhydride, acetic acid and sulfuric acid in ratio. The sulfuric acid is used in a concentration of 70% to 100%, preferably 95 to 100%. The reaction is carried out at a temperature of 10 to 120 ° C., preferably 20 to 100 ° C., particularly preferably 40 to 80 ° C. The reaction time is 12 to 36 hours, preferably 15 to 25 hours.

  Then it is distilled off. This may be done directly from the batch, possibly reducing the pressure. At this time, a mixture of acetic acid and acetic anhydride is obtained. However, water may be added first to destroy excess acetic anhydride and then pure acetic acid is distilled off. The recovered acetic acid may be used again. The residue is then neutralized with sulfuric acid by addition of an inorganic base, such as caustic soda, caustic potash or calcium hydroxide, which is solid or preferably in aqueous solution, and the concentration is continued. After the completion of evaporation, water is added at a temperature of 60-100 ° C., followed by stirring, and the resulting 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene (II) is filtered off. This is washed with water and methanol and subsequently dried.

  In the next reaction step, the 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene (II) is heated at a temperature of 60-100 ° C., preferably 80-100 ° C. (reflux). It is fed into water and mixed with an aqueous solution of an inorganic base, preferably caustic soda, caustic potash, calcium hydroxide, sodium carbonate or potassium carbonate, but particularly preferably an aqueous solution of NaOH or KOH. The dropwise addition time of the base is 30 minutes to 10 hours, preferably 30 minutes to 3 hours. Subsequently, the mixture is stirred for 1 to 24 hours, preferably 3 to 12 hours, particularly preferably 4 to 8 hours, at a temperature of 60 to 100 ° C., particularly preferably 80 to 100 ° C. Subsequently, it is neutralized with an inorganic acid (pH = 6-7), preferably hydrochloric acid, hydrobromic acid or sulfuric acid, but particularly preferably concentrated hydrochloric acid, magnesium sulfate is added to the hot reaction solution, An aqueous potassium manganate or sodium permanganate solution is added dropwise, followed by 1-24 hours, preferably 1-12 hours, particularly preferably 2-4 hours, 60-100 ° C., preferably 80-100. Stir at a temperature of ° C.

Subsequent post-processing may be done in various ways:
1. Excess oxidant may be destroyed by the addition of a reducing agent in solid or dissolved state (aqueous solution). For this purpose, in particular inorganic sulfites or bisulfites, such as sodium sulfite / bisulfite, or potassium sulfite / bisulfite, particularly preferably sodium sulfite or lower alcohols such as methanol, Ethanol, isopropanol and glycol are suitable. This takes place at a temperature of 10 to 100 ° C., preferably 20 to 80 ° C. Subsequently, the pH is adjusted to 0.1 to 3, preferably 0.5 to 1, by addition of sulfuric acid, and organic solvents such as ethyl acetate, propyl acetate, methyl-butyl ether (MTB), tetrahydrofuran (THF). ), N-butanol, methyl-THF, dichloromethane, toluene, to extract the product. Preference is given to ethyl acetate and MTB. The organic phase is optionally washed with water, sol or acidified water and evaporated to dryness. It has proven particularly advantageous to redistill directly with the solvent used for the crystallization. Here, the first solvent is replaced by the second solvent by the continuous addition of the second solvent during the distillation. Preference is given in particular to solvents for crystallization, such as cyclohexane and n-heptane and mixtures thereof with ethyl acetate, toluene and MTB.

In some cases, the above extraction using an organic solvent may be omitted. To this end, it is further concentrated to dryness under reduced pressure, followed by addition of water to a solvent that forms an azeotrope, such as methanol, ethanol, isopropanol, dichloromethane, MTB, ethyl acetate, butyl acetate, butanol, toluene or THF. Further removal by The amount of residual water is determined by Karl Fischer (KF) titration. The remaining residue is then stirred with an organic solvent such as methanol, ethanol, isopropanol, dichloromethane, MTB, ethyl acetate, butyl acetate, butanol, toluene or THF at a temperature of 20-100 ° C. and salted. Is filtered off. The filtrate is evaporated to dryness or redistilled with a solvent suitable for crystallization as described above.
2. Optionally, no reducing agent is added, the pH value is adjusted to 0.1-3, preferably 0.1-1, by addition of sulfuric acid, then evaporated to dryness under reduced pressure as described above, It has proved advantageous to stir the residue with an organic solvent (same treatment method as 1).

The synthetic method described here is superior to the methods of the prior art in several important advantages:
As the only oxidant, cheap and non-toxic potassium permanganate or sodium permanganate is used. The resulting manganese waste can be reused in a recycling process with complete oxidation. The method is stable and can be easily implemented on a scale of several tons. This is superior in environmentally friendly solvents. The process is inexpensive to implement, consists of only two steps and provides a high overall yield of 80-85% of theory. The method thus makes a valuable contribution to the production of an intermediate process of triiodide triiodide which is important for medical diagnosis.

The following examples are used to illustrate the novel method described above:
Production of triiodotrimesitylene
Synthesis 6, 486 (1980); WO96 / 09282, J. Med. Chem. (2000) 43 (10), 1940 or Synlett (2002), (4), 598.

Preparation of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene (II) 400 g (803 mmol) of triiodomesitylene were added with 0.9 l acetic anhydride, 1.4 l acetic acid and concentrated. It suspended in 121 ml of sulfuric acid, 160 g (1.01 mol) of potassium permanganate was added little by little (over 2 hours) at 40 ° C., and the mixture was stirred at 40 ° C. for 18 hours. After completion of the reaction, with careful stirring, 152 ml of water was added and stirred for 2 hours at room temperature. Next, 363.2 ml of 50% sodium hydroxide solution was added (exact amount to neutralize sulfuric acid). Subsequently, it was further distilled off under reduced pressure (concentration). 4 l of water was added dropwise with stirring, followed by stirring for 1 hour at 10 ° C. The resulting precipitate was aspirated and washed twice with 1.5 l of water and 500 ml of methanol, respectively, and dried at 50 ° C. in vacuo.
Yield: 0.456 kg (93% of theory)
Elemental analysis:
Calculated value: C 24.43 H 2.13 J 62.01
Found: C 24.26 H 2.09 J 62.31.

Production of triiodotrimesic acid (I) (Modification A)
250 g (407 mmol) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and carefully mixed with 200 ml of 50% caustic soda solution at 90 ° C. Stir at 90 ° C. for 5 h. Subsequently neutralized with concentrated hydrochloric acid (pH value = 6-7), mixed with 367 g (1.488 mol) of magnesium sulfate, a solution consisting of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise, Stir for 2 h under reflux. Cool to room temperature (RT), add 50 g of sodium sulfite and stir for 1 hour at room temperature. Next, the pH value was adjusted to 1 with 50% sulfuric acid. 2 l of ethyl acetate was added and stirred well. The organic phase was separated and the aqueous phase was extracted twice with 0.5 l of ethyl acetate. The organic phases are combined, washed once with 2.5 l of water and subsequently redistilled with cyclohexane. Upon cooling (0 ° C.), the product crystallized out.
Yield: 206g (86% of theory)
Elemental analysis:
Calculated value: 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) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and carefully mixed with 200 ml of 50% caustic soda solution at 90 ° C. Stir at 90 ° C. for 5 h. Subsequently neutralized with concentrated hydrochloric acid (pH value = 6-7), mixed with 367 g (1.488 mol) of magnesium sulfate, a solution consisting of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise, Stir for 2 h under reflux. Cool to room temperature (RT), add 50 g of sodium sulfite and stir for 1 hour at room temperature. Next, the pH value was adjusted to 1 with 50% sulfuric acid. 2 l of ethyl acetate was added and stirred well. The organic phase was separated and the aqueous phase was extracted twice with 0.5 l of ethyl acetate. The organic phases are combined and washed once with 2.5 l of water. The acetate solution was distilled to remove water azeotropically (water content <0.2% after Karl Fischer titration). The solution thus prepared was used for further reactions. (For example, production of acid chloride using SOCl ₂ ). An aliquot of evaporation determines the yield.
Yield: 211 g (88% of theory)
Elemental analysis:
Calculated value: 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 carefully mixed with 200 ml of 50% caustic soda solution at 90 ° C. Stir at 90 ° C. for 5 h. Subsequently neutralized with concentrated hydrochloric acid (pH value = 6-7), mixed with 367 g (1.488 mol) of magnesium sulfate, a solution consisting of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise, Stir for 2 h under reflux. Cool to room temperature (RT), add 50 g of sodium sulfite and stir for 1 hour at room temperature. Next, the pH value was adjusted to 1 with 50% sulfuric acid. Further evaporation in vacuo and residual water was distilled off azeotropically by addition of isopropanol. The isopropanol was added continuously. If the water content <1% (KF), an additional 10 l of isopropanol was added and stirred at 40 ° C. for 1 hour. The salt itch was filtered off and washed twice with 3 l of isopropanol. The filtrate was evaporated to dryness in vacuo.
Yield: 213 g (89% of theory)
Elemental analysis:
Calculated value: 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 carefully mixed with 200 ml of 50% caustic soda solution at 90 ° C. Stir at 90 ° C. for 5 h. Subsequently neutralized with concentrated hydrochloric acid (pH value = 6-7), mixed with 367 g (1.488 mol) of magnesium sulfate, a solution consisting of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise, Stir for 2 h under reflux. Cool to room temperature (RT), add 50 g of sodium sulfite and stir for 1 hour at room temperature. Next, the pH value was adjusted to 1 with 50% sulfuric acid. Further evaporation in vacuo and residual water was distilled off azeotropically by addition of ethanol (continuous addition of ethanol). If the water content <1% (KF), an additional 10 l of ethanol was added and stirred for 1 hour at 40 ° C. The salt itch was filtered off and washed twice with 5 l of isopropanol. The filtrate was evaporated to dryness in vacuo.
Yield: 215 g (90% of theory)
Elemental analysis:
Calculated value: 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) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and carefully mixed with 200 ml of 50% caustic soda solution at 90 ° C. Stir at 90 ° C. for 5 h. Subsequently neutralized with concentrated hydrochloric acid (pH value = 6-7), mixed with 367 g (1.488 mol) of magnesium sulfate, a solution consisting of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise, Stir for 2 h under reflux. Cool to room temperature (RT), add 50 g of sodium sulfite and stir for 1 hour at room temperature. Next, the pH value was adjusted to 1 with 50% sulfuric acid. Further evaporation in vacuo and the remaining water was distilled off azeotropically by addition of isopropanol (continuous addition of isopropanol). If the water content <1% (KF), an additional 10 l of isopropanol was added and stirred at 40 ° C. for 1 hour. The salt itch was filtered off and washed twice with 5 l of isopropanol. The filtrate was evaporated to dryness in vacuo.
Yield: 214 g (90% of theory)
Elemental analysis:
Calculated value: 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) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and carefully mixed with 200 ml of 50% caustic soda solution at 90 ° C. Stir at 90 ° C. for 5 h. Subsequently neutralized with concentrated hydrochloric acid (pH value = 6-7), mixed with 367 g (1.488 mol) of magnesium sulfate, a solution consisting of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise, Stir for 2 h under reflux. Cool to room temperature (RT), add 50 g of sodium sulfite and stir for 1 hour at room temperature. Next, the pH value was adjusted to 1 with 50% sulfuric acid. Further evaporation in vacuo and residual water was distilled off azeotropically by addition of ethanol (continuous addition of ethanol). If the water content <1% (KF titration), an additional 10 l of ethanol was added and stirred at 40 ° C. for 1 hour. The salt itch was filtered off and washed twice with 5 l of ethanol. The filtrate was evaporated to dryness in vacuo.
Yield: 213 g (89% of theory)
Elemental analysis:
Calculated value: 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) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene are suspended in 2.5 l of water and carefully mixed with 200 ml of 50% caustic soda solution at 90 ° C. Stir at 90 ° C. for 5 h. Subsequently neutralized with concentrated hydrochloric acid (pH value = 6-7), mixed with 367 g (1.488 mol) of magnesium sulfate, a solution consisting of 411 g (2.604 mol) of potassium permanganate in 4 l of water was added dropwise, Stir for 2 h under reflux. Cool to room temperature (RT), add 50 g of sodium sulfite and stir for 1 hour at room temperature. Next, the pH value was adjusted to 1 with 50% sulfuric acid. Further evaporation in vacuo and residual water was distilled off azeotropically by addition of methanol (continuous addition of methanol). If the water content <2% (KF titration), an additional 10 l of methanol was added and stirred for 1 hour at 40 ° C. The salt itch was filtered off and washed twice with 5 l of methanol. The filtrate was evaporated to dryness in vacuo.
Yield: 213 g (89% of theory)
Elemental analysis:
Calculated value: C 18.39 H 0.51 J 64.77
Found: C 18.36 H 0.62 J 64.72.

Claims (8)

  In the oxidation process, triiodomesitylene is reacted with potassium permanganate or sodium permanganate in a mixture of acetic anhydride, acetic acid and sulfuric acid at a temperature of 10 to 120 ° C. for 12 to 36 hours. The resulting intermediate product, 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene, is subsequently isolated, which is then heated for 1.5-34 hours at a temperature of 60-100 ° C. Treatment with a base, after which the reaction solution is neutralized and then treated with an aqueous potassium permanganate solution or an aqueous sodium permanganate solution at a temperature of 60-100 ° C. for 1-24 hours. A process for producing triiodotrimesic acid, characterized in that   The process according to claim 1, wherein the reaction to the intermediate product is carried out at 40-80 ° C.   The process according to claim 1, characterized in that the reaction to the intermediate product is carried out for 15 to 25 hours.   The method according to claim 1, wherein the base treatment of the intermediate product is performed at 80 to 100 ° C.   The method according to claim 1, wherein the base treatment of the intermediate product is performed for 3 to 12 hours.   The process according to claim 1, characterized in that the oxidation of the intermediate product is carried out at 80-100 ° C.   The process according to claim 1, characterized in that the oxidation of the intermediate product is carried out for 2 to 4 hours.   1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene.