JPH10251210A - Production of purified 5-amino-2,4,6-triiodoisophthalic dichloride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject high-purity compound by purifying crude 5- amino-2,4,6-triiodoisophthalic acid dichloride with dioxane. SOLUTION: Crude crystals of 5-amino-2,4,6-triiodoisophthalic acid dichloride (ATIPA-Cl) obtained by reacting 5-amino-2,4,6-triiodoisophthalic acid (ATIPA) with thionyl chloride are reacted with dioxane in an amount of 0.5-10 pts.wt. based on 1 pt.wt. ATIPA and water in an amount of 0.25-0.70 pt.wt. based on 1 pt.wt. dioxane is added thereto to provide the objective high-purity ATIPA-Cl. The high-purity ATIPA-Cl can similarly be obtained also by bringing 50-90wt.% aqueous dioxane solution into contact with reaction product solution containing the crude crystals without separately adding dioxane and water thereto.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 5-amino-2,4,6 which is an important intermediate in the production of radiographic contrast agents.
-Triiodoisophthalic acid dichloride (hereinafter ATIPA-
Cl) (abbreviated as Cl).
The present invention relates to a method for obtaining high-purity ATIPA-Cl with good yield.

[0002]

2. Description of the Related Art Conventionally, ATIPA-Cl has been known as 5-amino-
It is known that it is synthesized from the reaction of 2,4,6-triiodoisophthalic acid (hereinafter abbreviated as ATIPA) and thionyl chloride, and various production methods have been disclosed.

Usually, in the above reaction, the obtained product is not only the desired ATIPA-Cl but also 5- by-product as a by-product.
Amino-2,4,6-triiodoisophthalic acid monochloride (hereinafter abbreviated as mono-Cl form)
5-[(5-amino-2,4,6) is thought to be caused by the formation of the body or by dimerization of ATIPA-Cl.
-Triiodo-3-chlorocarbonyl) phenyl] carbonylamino-2,4,6-triiodoisophthalic acid dichloride (hereinafter referred to as an amide) is produced.

[0004] In particular, the contamination of the above-mentioned amide compound not only lowers the purity of the target ATIPA-Cl, but also reduces the ATIPA-Cl.
Since Cl is used as an intermediate for the production of radiographic contrast agents, it is clear that its high contamination is undesirable.

Conventionally, by-products and impurities are removed from crude ATIPA-Cl crystals or reaction products obtained by the reaction,
JP-A-59-193857 discloses, for example, a method of obtaining ATIPA-Cl with higher purity.
A method is shown in which A, thionyl chloride and dimethylformamide are mixed and reacted by heating, and the resulting crude crystals are washed with diisopropyl ether (yield 87.3%).

JP-A-5-502230 discloses a method of reacting ATIPA in ethyl acetate by dropwise addition of thionyl chloride, and then purifying the resulting paste with 1,1,1-trichloroethane (yield). In Japanese Patent Publication No. 56-42581, a mixed solution of ATIPA and thionyl chloride is allowed to react under boiling, then extracted with ethyl acetate-water, dried, and the resulting crystals are re-used with toluene. The method of crystallizing is shown.

[0007] As described above, ATIPA- having a relatively high purity
Conventionally, to obtain Cl, diisopropyl ether,
Methods for washing or recrystallizing with trichloroethane, ethyl acetate or toluene have been known.

[0008]

The above-mentioned conventional ATIPA-Cl purification method is not yet obtained with sufficient purity, and the loss of the target crystal is relatively large. However, it is not a method that is satisfactory as an industrial production method.

The present invention relates to a conventional ATIPA-Cl
To solve the problems of purification, especially purification, and to obtain higher-purity ATIPA-Cl from crude crystals of ATIPA-Cl or from the reaction product of ATIPA and thionyl chloride as compared with the conventionally known method. It is an object to provide a method which can be obtained in a yield.

[0010]

Means for Solving the Problems The present inventors have intensively studied and studied to achieve the above object, and dioxane is useful for purifying ATIPA-Cl.
It was found that the solubility of ATIPA-Cl in the aqueous dioxane solution changes drastically depending on its concentration. That is, for example, in a 10% by weight aqueous dioxane solution, AT
While the solubility of IPA-Cl is 0.01% by weight or less, the solubility of ATIPA-Cl is 0.2% in a 64% by weight aqueous dioxane solution.
The aqueous solution of dioxane having a concentration of 81% by weight has a solubility of ATIPA-Cl of 5.50% by weight.

Due to the special interaction between ATIPA-Cl and dioxane as described above, it is extremely effective to contact the reaction product of ATIPA with thionyl chloride or the crude crystals of ATIPA-Cl with dioxane. It has been found that by employing, it is possible to sufficiently remove impurities in the reaction product or crude crystals, especially amides, and to obtain highly pure ATIPA-Cl with a very high yield. Thus, the present invention has been completed.

That is, the present invention provides (1) purified ATIPA-Cl characterized by purifying crude ATIPA-Cl using dioxane.
And (2) dissolving the crude ATIPA-Cl in dioxane, then adding water to the solution, and crystallizing the ATIPA-Cl, thereby producing a purified ATIPA-Cl. And (3) a method for producing purified ATIPA-Cl, which comprises contacting the crude ATIPA-Cl with a 50 to 90% by weight aqueous dioxane solution. The method for producing purified ATIPA-Cl according to any one of the above (1) to (3), which is a reaction product of ATIPA with thionyl chloride.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, crude ATIPA-Cl to be purified is not particularly limited. For example, crude ATIPA-Cl may be in the form of its own crystal, or a reaction product of ATIPA and thionyl chloride. It may be a thing. Above all
If it is the reaction product of ATIPA and thionyl chloride, use AT
It is also possible to directly obtain high-purity ATIPA-Cl from the reaction mixture without extracting it as IPA-Cl crystals, which is industrially very advantageous in terms of the number of steps, operability, and the like. Becomes

ATIPA-Cl is usually prepared by adding ATIPA in thionyl chloride.
It can be synthesized by reacting while adding A, or by reacting ATIPA and thionyl chloride in a solvent such as toluene, benzene, ethyl acetate or 1,3-dimethyl-2-imidazolidinone. The reaction mixture thus obtained is concentrated under reduced pressure and then
It is subjected to purification by use of dioxane in the present invention.

In the purification operation of the present invention, dioxane is allowed to act on the above reaction mixture. The amount of dioxane used is 0.5 to 10 times by weight, more preferably 1 to 3 times by weight, based on the amount of ATIPA used in the reaction. If this is less than 0.5 times by weight, high purity ATIPA-Cl
Is difficult to obtain, and when the amount is more than 10 times by weight, the yield of the target ATIPA-Cl decreases, which is not preferable.

In the present invention, ATIPA-Cl crystals can be crystallized by adding water to the reaction solution to which dioxane has been added while stirring. When the amount of water to be added is too small, sufficient crystallization is not performed and the yield decreases, and when the amount is too large, impurities are mixed in the crystals. 0.25-0.70
The amount is in the range of weight times, more preferably in the range of 0.30 to 0.55 times weight.

In the method of the present invention,
ATIPA-Cl crystals can be crystallized not only by separately adding dioxane and water but also by contacting a 50-90 wt% aqueous solution of dioxane with the reaction product solution. It is. In this case, 1,3-
After adding dimethyl-2-imidazolidinone, the solution can be brought into contact with an aqueous dioxane solution,
By doing so, it is possible to further improve the efficiency of purification and separation.

In the above-mentioned crystallization of ATIPA-Cl, if the temperature is too high, sufficient crystallization is not performed, the yield decreases, and the hydrolysis of ATIPA-Cl tends to proceed. If the temperature is too low, the solvent may be solidified, or impurities may be mixed into the crystal.
C., more preferably at a temperature in the range of 5-30.degree.

The crystals of ATIPA-Cl crystallized as described above are separated by filtration or the like, and then dried to obtain
It can be obtained as high-purity ATIPA-Cl.

[0020]

EXAMPLES Hereinafter, the method for producing purified ATIPA-Cl of the present invention will be described in more detail with reference to Examples and Comparative Examples. The purity of the product is evaluated by analyzing ATIPA-Cl and the amide compound in the reaction product solution or finally obtained crystals by high performance liquid chromatography (hereinafter abbreviated as HPLC), and obtained by the method. The areas of ATIPA-Cl and the amide form were determined in%, and the values were expressed by a method of evaluating the values.

Example 1 0.6 g of pyridine was added to 170.3 g (1.43 mol) of thionyl chloride, and the solution was heated to 60 ° C. While maintaining the same temperature, 80.0 g (0.143 mol) of ATIPA was added thereto over 2.5 hours. After reacting at a temperature of 60 ° C. for another hour after the addition was completed, the reaction solution was analyzed by HPLC. Next, thionyl chloride in the reaction solution was distilled off under reduced pressure, 80 g of dioxane was added to the obtained reaction mixture, and 40 g of water was added to the system while stirring the solution, whereby crystals were crystallized. Next, the temperature of the crystallized solution was lowered to 10 ° C., and the crystals were separated by filtration. The obtained crystals were washed with 20 g of a 75% by weight aqueous dioxane solution and then dried at a temperature of 55 ° C. for 1 hour to obtain ATIPA-Cl as pale yellowish white crystals. The results of HPLC analysis and the yields are shown in Table 1.

Example 2 To 200 g of toluene were added 85.2 g (0.72 mol) of thionyl chloride and 0.6 g of pyridine, and the temperature of the solution was raised to 60 ° C.
While maintaining the same temperature, 80.0 g (0.143 mol) of ATIPA was added thereto over 2.5 hours. 1 hour after addition is complete
After reacting at a temperature of 60 ° C., the reaction solution was analyzed by HPLC. Next, toluene and thionyl chloride were distilled off from this reaction solution under reduced pressure, and 80 g of dioxane was added to the obtained reaction mixture. Further, 40 g of water was added to the system while stirring the solution to effect crystallization. Then lower the temperature of the crystallization liquid to 10 ° C,
The crystals were filtered off. The obtained crystals were washed with 20 g of a 75% by weight aqueous dioxane solution and then dried at a temperature of 55 ° C. for 1 hour to obtain ATIPA-Cl as pale yellowish white crystals. The results of HPLC analysis and the yields are shown in Table 1.

Comparative Example 1 0.6 g of pyridine was added to 170.3 g (1.43 mol) of thionyl chloride, and the solution was heated to 60 ° C. While maintaining the same temperature, 80.0 g (0.143 mol) of ATIPA was added thereto over 2.5 hours. After reacting at a temperature of 60 ° C. for another hour after the addition was completed, the reaction solution was analyzed by HPLC. Next, thionyl chloride in the reaction solution was distilled off under reduced pressure, 80 g of ethyl acetate was added to the obtained reaction mixture, and 20 g of hexane was added to the system while stirring the solution to cause crystallization. Next, the temperature of the crystallized solution was lowered to 10 ° C., and the crystals were separated by filtration. The obtained crystals were washed with 10 g of a mixed solution of ethyl acetate-hexane at a weight ratio of 1/1, and then dried at a temperature of 55 ° C. for 1 hour to obtain ATIPA-Cl as yellow-red crystals. The results of HPLC analysis and the yields are shown in Table 1.

Comparative Example 2 85.2 g (0.72 mol) of thionyl chloride and 0.6 g of pyridine were added to 200 g of toluene, and the solution was heated to 60 ° C. While maintaining the same temperature, add 80.0 g of ATIPA (0.143
Mol) was added over 2.5 hours. After the addition, the reaction was further performed at a temperature of 60 ° C. for 1 hour.
Was analyzed. Next, toluene and thionyl chloride in the reaction solution were distilled off under reduced pressure, and then 80 g of toluene was added again to the obtained reaction mixture. Then, 40 g of hexane was added to the system while stirring the solution, and crystallization was performed. I let it. Thereafter, the temperature of the crystallization liquid was lowered to 10 ° C., and the crystals were separated by filtration. The obtained crystals were washed with 20 g of a 1/1 weight ratio solution of toluene / hexane and then dried at a temperature of 55 ° C. for 1 hour to obtain ATIPA-Cl as yellow-red crystals. The results of HPLC analysis and the yields are shown in Table 1.

Example 3 Thionyl chloride and ATIPA were reacted in exactly the same manner as described in Example 1. After the reaction, thionyl chloride in the liquid was distilled off under reduced pressure, and the resulting reaction mixture was added with 10 g of dioxane. After dissolution, the resultant was put into 106 g of a 75% by weight aqueous dioxane solution, whereby crystals were crystallized. Next, the temperature of the crystallized solution was lowered to 10 ° C., and the crystals were separated by filtration. The obtained crystals were washed with 20 g of a 75% by weight aqueous dioxane solution and then dried at a temperature of 55 ° C. for 1 hour to obtain ATIPA-Cl as pale yellowish white crystals. The results of HPLC analysis and the yields are shown in Table 1.

Example 4 Thionyl chloride and ATIPA were reacted in exactly the same manner as described in Example 2, and after the reaction, toluene and thionyl chloride were distilled off under reduced pressure. Then, the resulting reaction mixture was added with 10 g of dioxane. After dissolution, the resulting solution was put into 106 g of a 75% by weight aqueous dioxane solution to crystallize crystals. Next, the temperature of the crystallized solution was lowered to 10 ° C., and the crystals were separated by filtration. The obtained crystals were washed with 20 g of a 75% by weight aqueous dioxane solution, and then dried at a temperature of 55 ° C. for 1 hour to obtain pale yellow-white crystals.
ATIPA-Cl was obtained. The results of HPLC analysis and the yields are shown in Table 1.

Example 5 Thionyl chloride and ATIPA were reacted in exactly the same manner as described in Example 1, and after the reaction, thionyl chloride in the liquid was distilled off under reduced pressure. After adding and dissolving dimethyl-2-imidazolidinone, this was put into 106 g of a 75% by weight aqueous dioxane solution to precipitate crystals. Next, the temperature of the crystallized solution was lowered to 10 ° C., and the crystals were separated by filtration. The obtained crystals were washed with 20 g of a 75% by weight aqueous dioxane solution and then dried at a temperature of 55 ° C. for 1 hour to obtain ATIPA-Cl as pale yellowish white crystals. The results of HPLC analysis and the yields are shown in Table 1.

[0028]

[Table 1]

[0029]

As is clear from the results of the above Examples and Comparative Examples, according to the method for producing purified ATIPA-Cl of the present invention by using dioxane, a conventionally known method, for example, ethyl acetate-hexane The crystallization method from the system or the crystallization method from the toluene-water system is also increased, and it is possible to obtain a very high-purity product with a higher yield.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Takeshi Matsushita 1502-5 Mobara, Mobara-shi, Chiba Mariana Heights 101 (72) Yoshinori Tanaka 1900 Togo, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemicals Co., Ltd.

Claims (4)

[Claims] 1. A method for purifying 5-amino-2,4,6-triiodoisophthalic acid dichloride, comprising purifying crude 5-amino-2,4,6-triiodoisophthalic acid dichloride using dioxane. Production method. 2. After dissolving crude 5-amino-2,4,6-triiodoisophthalic acid dichloride in dioxane, water is then added to the solution to give 5-amino-2,4,6.
A process for producing purified 5-amino-2,4,6-triiodoisophthalic acid dichloride, characterized by crystallizing triiodoisophthalic acid dichloride. 3. The purified 5-amino-2,4,6-diamine is contacted with a 50-90% strength by weight aqueous dioxane solution of crude 5-amino-2,4,6-triiodoisophthalic acid dichloride. A method for producing triiodoisophthalic acid dichloride. 4. The crude 5-amino-2,4,6-triiodoisophthalic acid dichloride comprises 5-amino-2,4,6
The method for producing purified 5-amino-2,4,6-triiodoisophthalic acid dichloride according to any one of claims 1 to 3, which is a reaction product of triiodoisophthalic acid and thionyl chloride.