JPH10120637A - Production of 5-amino-2,4,6-triiodoisophthaloyl dichloride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound having high purity and useful as a production intermediate for X-ray contrast medium in high yield while suppressing the formation of by-product by reacting thionyl chloride with 5- amino-2,4,6-triiodoisophthalic acid (abbreviated as ATIPA) while adding the latter compound to the system. SOLUTION: ATIPA dichloride is produced by reacting ATIPA with thionyl chloride. The reaction is carried out by slowly adding ATIPA to thionyl chloride heated usually at 50-80 deg.C and reacting at a temperature within the above range. The amount of thionyl chloride is 3-20mol based on 1mol of ATIPA. After the reaction, the reaction liquid is maintained in a temperature range of 50-80 deg.C usually for >=0.5hr, preferably >=1hr to complete the reaction, unreacted thionyl chloride is removed from the system and the residue is concentrated and dried in the form of crystal.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to 5-amino-2, 5-amino-2, which is an important intermediate in the production of radiographic contrast agents.
4,6-triiodoisophthalic acid dichloride (hereinafter, referred to as
More specifically, the present invention relates to a process for producing ATIPA-Cl), and more specifically, to reacting 5-amino-2,4,6-triiodoisophthalic acid (hereinafter abbreviated as ATIPA) with thionyl chloride.
The present invention relates to a method for producing ATIPA-Cl by suppressing the generation of by-products and thereby producing the above-mentioned target substance of high purity in good yield.

[0002]

2. Description of the Related Art Conventionally, various methods have been disclosed for producing ATIPA-Cl by reacting ATIPA with thionyl chloride. For example, a method in which ATIPA, thionyl chloride and dimethylformamide are mixed, and a suspension comprising these is heated and reacted (JP-A-59-193857),
A method in which a mixture of A and thionyl chloride is heated to cause a reaction under boiling (Japanese Patent Publication No. 56-42581), a method in which ATIPA is stirred in ethyl acetate, and thionyl chloride is added dropwise to the reaction to carry out the reaction. (Japanese Unexamined Patent Publication No. 5-502230) and the like are known.

[0003] As described above, in order to produce ATIPA-Cl by reacting ATIPA with thionyl chloride, ATIPA-Cl has conventionally been used.
In general, a method of heating a mixed solution of thionyl chloride and thionyl chloride or reacting ATIPA in a solvent with thionyl chloride is used.

[0004]

However, according to the study of the present inventors, in the reaction of ATIPA with thionyl chloride, which has been known and performed as described above,
It was clarified that the reaction product produced not only the desired ATIPA-Cl but also a by-product other than the desired. That is, when reacting ATIPA with thionyl chloride, not only ATIPA-Cl is directly produced from both of them, but also 5-amino-2,4,4 once as shown in the following formula (Formula 1).
After producing 6-triiodoisophthalic acid monochloride (hereinafter abbreviated as mono-Cl form), it is further reacted with thionyl chloride.

Embedded image It was clarified that there was a production process of ATIPA-Cl.

Further, 5-[(5-amino-2,4,6-triiodo-3) represented by the following formula (Chemical Formula 2) is considered to be caused by the formation of the above mono-Cl form. -Chlorocarbonyl) phenyl] It has been clarified that carbonylamino-2,4,6-triiodoisophthalic acid dichloride (hereinafter referred to as an amide) was formed.

Embedded image

[0006] The formation of such an amide form not only lowers the yield of the target product but also relatively easily precipitates as crystals.
A-Cl purity will be reduced, and AT
Even if IPA-Cl is used as an intermediate for producing an X-ray contrast agent, it is clear that it is not preferable to have an amide by-product.

Further, it is not impossible to purify the crude ATIPA-Cl crystal by a recrystallization method to obtain a purified ATIPA-Cl crystal having an extremely small number of amides.
Since the recovery yield of Cl is low, it is far from an industrially applicable method.

[0008] In the present invention, the conventional ATIPA-
In view of the above-mentioned problems in the Cl production process, when producing ATIPA-Cl by reacting ATIPA with thionyl chloride, the production of amides as by-products is suppressed, and the target product with high purity can be produced in good yield. It is intended to provide a method for obtaining the same.

[0009]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have reacted ATIPA and thionyl chloride under various conditions and embodiments, and have been able to suppress ATIPA capable of suppressing by-products of amides. We have been studying and examining the manufacturing method of -Cl. As a result, for thionyl chloride,
In the case of adopting a method in which the reaction is carried out while adding ATIPA, the formation of an amide compound can be particularly suppressed, and furthermore, according to this method, the above object can be sufficiently achieved. And completed the present invention.

That is, the present invention provides (1) a method for producing ATIPA-Cl, which comprises reacting ATIPA with thionyl chloride to produce ATIPA-Cl while adding ATIPA to thionyl chloride. (2) The method according to the above (1), wherein the reaction is carried out using an amount in the range of 3 to 20 mol of thionyl chloride per mol of ATIPA.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The reaction of ATIPA and thionyl chloride in the present invention is usually carried out while adding ATIPA gradually or in portions to stirred and heated thionyl chloride. In this case, ATIPA may be added as it is in the form of powder, or may be dissolved or suspended in a solvent such as toluene or ethyl acetate and then added to thionyl chloride. .

Examples of the reaction catalyst include pyridine and dimethylformamide. However, these catalysts are not always required, and the reaction may proceed sufficiently without a catalyst depending on the conditions. Generally, when ethyl acetate is used as a reaction solvent, the reaction proceeds easily even without a catalyst. On the other hand, when toluene is used as a solvent or the reaction is carried out in the absence of a solvent, better results can often be expected when the reaction is carried out in the presence of a catalyst. When a catalyst is used, its amount is usually in the range of about 1 to 10 mol% based on the reactant ATIPA.

In the reaction of thionyl chloride with ATIPA in the present invention, 3 to 20 thionyl chloride is used per mole of ATIPA.
It is preferred that the reaction be carried out using an amount in the molar range. This is because if the amount of thionyl chloride in this case is less than 3 mol, the formation of the amide form in the obtained reaction solution becomes remarkable, and more than 20 mol. At such a usage amount, not only the effect corresponding thereto is not seen, but also ATIP
This is because the separation of A-Cl is complicated, and undesired problems tend to occur outside of the above range.

In the reaction of thionyl chloride with ATIPA in the present invention, ATIPA is usually added to thionyl chloride, which has been heated to 50 to 80 ° C., continuously or in small portions. While reacting in the above-mentioned temperature range. In this case, the rate at which ATIPA is added largely depends on the production amount, the shape of the reactor, the reaction temperature, and the like, and is not constant. Going,
It is preferable because by-products of the amide can be suppressed. In addition, when the addition of ATIPA takes place over a long period of time, there is no particular adverse effect on the obtained reaction product solution and ATIPA-Cl.

After the addition of ATIPA is completed, it is preferable to further maintain the reaction solution in a temperature range of 50 to 80 ° C. to complete the reaction. The time required for this is not fixed depending on the temperature, but is usually 0.5 hour or more, preferably 1 hour or more. After the reaction is completed, unreacted thionyl chloride is removed, and then concentrated to dryness and dried to obtain the desired ATIPA-Cl crystals.

[0016]

EXAMPLES Hereinafter, the method for producing ATIPA-Cl according to the present invention will be described in more detail with reference to Examples and Comparative Examples. As a result, the reaction solution was subjected to high performance liquid chromatography (HPL).
C), the area of the ATIPA-Cl and the amide obtained thereby was determined in%, and the area was expressed by a method of evaluating with this numerical value.

Example 1 0.6 g of pyridine was added to 170.3 g (1.43 mol) of thionyl chloride, and the temperature of the solution was raised to 60 ° C. with stirring. While maintaining the same temperature, 80.0 g (0.143 mol) of ATIPA was added thereto over 2.5 hours (feeding 8.0 g every 15 minutes). After the addition was completed, the reaction was further performed for 1 hour at a temperature of 60 ° C., and the reaction solution was analyzed by HPLC. Table 1 shows the results.

Comparative Example 1 In Example 1, instead of adding ATIPA to thionyl chloride, 80.0 g of ATIPA and 170.3 g of thionyl chloride were previously prepared.
g and pyridine 0.6 g, and then stirred at 60 ° C.
And the reaction was allowed to proceed for 3 hours. Thereafter, the reaction solution was analyzed as in Example 1, and the results are shown in Table 1.

Example 2 To 400 ml of ethyl acetate was added 85.2 g (0.72 mol) of thionyl chloride, and the mixture was heated to 75 ° C. with stirring. While maintaining the same temperature, 80.0 g (0.143 mol) of ATIPA was continuously added thereto.
Added over time. After the addition is completed, 75 ° C for another 2 hours
After reaction at a temperature of, the reaction solution was analyzed by HPLC. Table 1 shows the results.

Comparative Example 2 80.0 g of ATIPA was added to 400 ml of ethyl acetate, and the temperature of the solution was raised to 75 ° C. with stirring. While maintaining the same temperature, 85.2 g of thionyl chloride was continuously added thereto over 2 hours (that is, the addition form of the reactants in Example 2 was reversed). After the addition was completed, the reaction was further performed at a temperature of 75 ° C. for 2 hours, and the reaction solution was analyzed by HPLC. Table 1 shows the results.

Example 3 170.3 g (1.43 mol) of thionyl chloride and 1.2 g of pyridine were added to 80 ml of toluene, and the solution was heated to 75 ° C. with stirring. At the same temperature, a mixed slurry of 80.0 g (0.143 mol) of ATIPA and 160 ml of toluene was continuously added over 1.5 hours. After completion of the addition, the reaction was further performed at a temperature of 75 ° C. for 2.5 hours, and the reaction solution was analyzed by HPLC. Table 1 shows the results.

Comparative Example 3 To 240 ml of toluene, 80.0 g of ATIPA and 1.2 g of pyridine were added, and the solution was heated to 75 ° C. with stirring. At the same temperature, 170.3 g of thionyl chloride was continuously added thereto over 1.5 hours (that is, the addition form of the reactants in Example 3 was reversed), and after completion of the addition, the mixture was further added at 75 ° C. for 2.5 hours.
At a temperature of. Thereafter, the reaction solution was analyzed by HPLC. Table 1 shows the results.

[0023]

[Table 1]

[0024]

As is clear from the results of the examples and comparative examples, according to the process for producing ATIPA-Cl according to the present invention in which the reaction is carried out while adding ATIPA to thionyl chloride, the amide compound is obtained. Can be significantly suppressed. Therefore, according to the method of the present invention, it is possible to produce a higher-purity ATIPA-Cl with higher yield as compared with the conventionally known production method of ATIPA-Cl.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Yoshinori Tanaka 1900 Togo, Mobara-shi, Chiba Mitsui Toatsu Chemicals Co., Ltd.

Claims (2)

[Claims] 1. The reaction of 5-amino-2,4,6-triiodoisophthalic acid with thionyl chloride to give 5-amino-
In producing 2,4,6-triiodoisophthalic acid dichloride, 5-amino-2,4,4 in thionyl chloride is used.
A method for producing 5-amino-2,4,6-triiodoisophthalic acid dichloride, wherein the reaction is carried out while adding 6-triiodoisophthalic acid. 2. The process according to claim 1, wherein the reaction is carried out using an amount in the range of from 3 to 20 mol of thionyl chloride per mol of 5-amino-2,4,6-triiodoisophthalic acid.