JP4402497B2 - Method for producing iopamidol - Google Patents

Description

  The present invention relates to a method for producing iopamidol, which can be used as a main agent of an X-ray contrast medium.

N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-hydroxypropanoylamino] 2,4,6-triiodophthalamide (generic name: iopamidol) Was first described in GB14772050 (Savac AG). The compound is used for diagnosis as a nonionic X-ray contrast agent.
Japanese Patent Publication No. 56-42581

In Patent Document 1, the precursor N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino] -2,4,6- Dissolve triiodophthalamide in water, add concentrated caustic soda to achieve a pH value of 11, and proceed to the reaction by adding caustic soda to keep the pH value constant by heating to 40 ° C. A synthetic method of hydrolyzing an acetoxy group is shown.
Japanese Patent Laid-Open No. 7-278081

  In Patent Document 2, the precursor N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino] -2,4,6- A synthesis method is shown in which a solution of triiodophthalamide is passed through a column packed with a strong anion exchange resin, and acetoxy groups are hydrolyzed in the column using the basicity of the resin.

  It has been found that the method of Patent Document 1 requires a reaction time of 24 hours or more in order to achieve complete hydrolysis. Considering industrial production, this reaction time significantly reduces productivity. Further, when the amount of caustic soda is increased to accelerate the reaction or the reaction temperature exceeds 40 ° C., not only the target acetoxy group but also the amide bond site will be hydrolyzed. Impurities produced in this reaction step are very difficult to remove in the production step after the reaction.

  An X-ray contrast agent may be injected into a patient's body by injection at 100 g or more as a drug substance for a single diagnostic action. Therefore, the presence of a very small amount of impurities is not allowed, and the generation of impurities in the final reaction step must be suppressed as much as possible.

  In the method of Patent Document 2, since a column filled with a strong anion exchange resin is used, manufacturing equipment becomes complicated. In addition, a large amount of acid and base is required for the regeneration of the ion exchange resin, and the amount of drainage becomes large. This is not a very desirable form for industrial production.

  The development of a production method that can suppress the generation of impurities as much as possible and perform the reaction in a short time with a simple production facility is an issue when considering production on an industrial scale.

  The present invention is characterized in that the acetoxy group decomposition reaction is not hydrolysis in an alkaline aqueous solution but solvolysis in an alkaline alcohol solution.

  According to the present invention, N, N'-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino]-is produced in a short time without causing an increase in impurities. Acetoxy group solvolysis of 2,4,6-triiodophthalamide can be carried out.

  N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino] -2,4,6-triiodophthalate, which is a target precursor The amide can be obtained by a known method according to Japanese Patent Publication No. 56-42581.

  When the precursor taken out as crystals is used, 1 to 10 times, preferably 2 to 4 times the volume of alcohol is added to the amount of crystals and dissolved. When using a crude product obtained by simply concentrating the precursor reaction solution, 1 to 10 times, preferably 2 to 4 times the volume of alcohol is added and dissolved with respect to the theoretical precursor production. To this precursor alcohol solution, 1 to 4 times mol, preferably 2 times mol of alkali metal hydroxide or basic nitrogen-containing organic compound is added as a molar ratio to the precursor.

  The alkaline alcohol solution of this precursor is heated to 20 to 60 ° C., preferably 40 ° C., and stirred for reaction. The progress of the reaction and the production status of impurities can be observed by measurement with an HPLC system using a reverse phase column and detecting with a UV detector. The disappearance of the precursor peak is confirmed by HPLC, and the reaction is completed.

  After the reaction, the solvent alcohol is distilled off under reduced pressure below the reaction temperature to obtain a crude iopamidol containing salts produced as a by-product in the reaction. This crude product can be purified, crystallized, filtered and dried according to known methods to obtain the desired iopamidol.

  N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino] -2,4,6-triiodophthalamide (3.1 g) Methanol (10 ml) was added and dissolved, 25 wt% aqueous sodium hydroxide solution (1.22 g) was added thereto, and the reaction was stirred at 40 ° C. After 150 minutes, the reaction solution was subjected to HPLC measurement, and the raw material N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino] -2 , 4,6-triiodophthalamide peak is not detected, and the main product is the desired N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) — 2-hydroxypropanoylamino] -2,4,6-triiodophthalamide.

  Reaction solution in which N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino] -2,4,6-triiodophthalamide was synthesized The solvent was concentrated to obtain a tar residue. Theoretically contains 3.1 g of reaction product. Ethanol (10 ml) was added to the concentrated residue to dissolve it, and 25 wt% aqueous sodium hydroxide solution (1.22 g) was added thereto, followed by stirring reaction at 40 ° C. After 150 minutes, the reaction solution was subjected to HPLC measurement, and the raw material N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino] -2 , 4,6-triiodophthalamide peak is not detected, and the main product is the desired N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) — 2-hydroxypropanoylamino] -2,4,6-triiodophthalamide.

  {Comparative Example} N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino] -2,4,6-triiodophthalamide The solvent of the synthesized reaction solution was concentrated to obtain a residue on tar. Theoretically contains 3.1 g of reaction product. Water (10 ml) was added to the concentrated residue to dissolve it, and 25 wt% aqueous sodium hydroxide solution (1.22 g) was added thereto, followed by stirring reaction at 40 ° C. After 18 hours, the reaction solution was subjected to HPLC measurement. The raw material N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino] Since a peak of -2,4,6-triiodophthalamide was detected, the reaction was continued at 40 ° C. 39 hours after the start of the reaction, HPLC measurement of the reaction solution was performed to confirm that no starting material peak was detected, and the reaction was completed.

It is a production method for industrially efficiently producing iopamidol, which is the main agent of an X-ray contrast medium.

Claims (4)

Below 1

N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-acetoxypropanoylamino] -2,4,6-triiodophthalamide represented by the formula A deacetylation reaction is carried out by solvolysis by the action of an alkali as a solution using a diol as a solvent.

N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2S) -2-hydroxypropanoylamino] -2,4,6-triiodophthalamide ( (Generic name: iopamidol).   The method according to claim 1, wherein the alcohol used as the solvent is methanol, ethanol, or a mixture thereof.   The method according to claim 1, wherein the alkali component used is an alkali metal hydroxide or a basic nitrogen-containing organic compound. The method according to claim 2, wherein the alkali component used is an alkali metal hydroxide or a basic nitrogen-containing organic compound.