JPWO2006100731A1 - Method for acetylating 5-amino-2,4,6-triiodoisophthalic acid derivative - Google Patents

Abstract

5-acetamido-2,4,6-triiodo comprising acetylating a 5-amino-2,4,6-triiodoisophthalic acid derivative with acetic anhydride in the presence of an acid catalyst in an organic solvent This is a method for producing an isophthalic acid derivative. By a simple method, a high yield and high quality 5-acetamido-2,4,6-triiodoisophthalic acid derivative can be provided.

Description

  The present invention relates to a method for producing a 5-acetamido-2,4,6-triiodoisophthalic acid derivative, which comprises acetylating a 5-amino-2,4,6-triiodoisophthalic acid derivative.

  5-Amino-2,4,6-triiodoisophthalic acid or its derivatives are used in particular as non-ionic contrast agents or intermediates for producing them. Since the production of the nonionic contrast agent includes a number of processes, the yield and purity in each process greatly affect the quality and yield of the final product.

  Among 5-amino-2,4,6-triiodoisophthalic acid or its derivative, 5-acetamido-2,4,6-triiodoisophthalic acid or its derivative is used as an important intermediate of a nonionic contrast agent. In many cases, it is desirable to efficiently manufacture a product of good quality.

  The production methods disclosed so far for the production of 5-acetamido-2,4,6-triiodoisophthalic acid or its derivatives can be obtained by chlorination in a dipolar aprotic solvent such as dimethylacetamide or dimethylformamide. Reactions by adding acetyl and reactions by adding a catalytic amount of sulfuric acid in acetic anhydride are known.

  However, as described below, these production methods have problems such as complicated operation, a large amount of waste, and a low yield.

  In Patent Document 1, acetylation is carried out under relatively mild reaction conditions using acetyl chloride in a dimethylacetamide solvent. However, acetyl chloride used as an acetylating agent is water-inhibiting and industrial. It is difficult to transport and store it, and a special chemical drum is required. In addition, dipolar aprotic solvents such as dimethylacetamide and dimethylformamide have a high boiling point, and it takes a lot of time and labor to remove them, and also requires a lot of energy. Therefore, when the removal becomes insufficient, there is a concern that it becomes a residual solvent in the product.

In Patent Document 2, Patent Document 3 and Non-Patent Document 1, acetylation is carried out by adding a catalytic amount of sulfuric acid to acetic anhydride. Acetic anhydride serves as both an acetylating agent and a solvent. When sulfuric acid is added after mixing, the reaction proceeds explosively with intense heat generation. For this reason, it is difficult to control the reaction, and there is a risk of a serious accident. In addition, since it is necessary to treat a large amount of waste liquid containing acetic anhydride, acetic acid and sulfuric acid for industrial use, it is not only dangerous due to heat of neutralization and heat of decomposition, but also a large amount of waste liquid is produced as a by-product. This is difficult because of the great cost of processing.
Special Table 2000-505820 GB Patent Specification 785670 Japanese Examined Patent Publication No. 56-54310 J. et al. Havaldsen et. al, Acta Pharm. Suec. 20, 219 (1983).

  An object of the present invention is to produce 5-acetamido-2,4,6-triiodoisophthalic acid or a derivative thereof in a simpler, safer and higher yield.

〔式中、Ｘ_１及びＸ_２は、同一であるかまたは異なっていてもよく、水酸基、ハロゲン原子、−ＮＨＲ_２又は−ＯＲ_２を表し、Ｒ_１及びＲ_２は、同一であるかまたは異なっていてもよく、水素又は炭素原子が１〜５までの直鎖若しくは分岐鎖の低級アルキル基（ここで、該アルキル基は、水酸基、アミノ基、チオール基、ニトロ基、ニトリル基、カルボニル基及びアシルオキシ基からなる群から選択した１以上の置換基で置換されていてもよい）を表す〕で示される化合物を有機溶媒中、酸触媒の存在下、無水酢酸を用いてアセチル化することを含む、式２：

（式中、Ｘ_１、Ｘ_２及びＲ_１は、式１中と同じ意味を有する）で示される化合物の製造方法；
（２）Ｘ_１及びＸ_２の両方が水酸基又はハロゲン原子を表す、（１）記載の方法；
（３）Ｘ_１及びＸ_２の両方が−ＮＨＲ_２を表す、（１）記載の方法；
（４）Ｘ_１及びＸ_２の両方が−ＯＲ_２を表す、（１）記載の方法；
（５）有機溶媒がニトリル基を持つ有機溶媒である、（１）〜（４）のいずれか１項記載の方法；
（６）酸触媒が硫酸である、（１）〜（５）のいずれか１項記載の方法；及び
（７）酸触媒の量が、式１で示される化合物に対して、１〜２モル％である、（１）〜（６）のいずれか１項記載の方法
である。As a result of intensive studies to solve the above-mentioned problems, the present inventor obtained a 5-amino-2,4,6-triiodoisophthalic acid derivative in an organic solvent using acetic anhydride in the presence of an acid catalyst. The present inventors have found a method of acetylation that provides an acetylated product with high yield and high quality by carrying out acetylation, which is simple with few steps.
That is, the present invention
(1) Formula 1:

[Wherein, X ₁ and X ₂ may be the same or different and each represents a hydroxyl group, a halogen atom, —NHR ₂ or —OR ₂ , and R ₁ and R ₂ are the same or different. Or a linear or branched lower alkyl group having 1 to 5 carbon atoms (wherein the alkyl group includes a hydroxyl group, an amino group, a thiol group, a nitro group, a nitrile group, a carbonyl group, and Which may be substituted with one or more substituents selected from the group consisting of acyloxy groups), and acetylating with acetic anhydride in the presence of an acid catalyst in an organic solvent. , Formula 2:

(Wherein X ₁ , X ₂ and R ₁ have the same meaning as in formula 1);
(2) The method according to (1), wherein both X ₁ and X ₂ represent a hydroxyl group or a halogen atom;
(3) The method according to (1), wherein both X ₁ and X ₂ represent —NHR ₂ ;
(4) The method according to (1), wherein both X ₁ and X ₂ represent —OR ₂ ;
(5) The method according to any one of (1) to (4), wherein the organic solvent is an organic solvent having a nitrile group;
(6) The method according to any one of (1) to (5), wherein the acid catalyst is sulfuric acid; and (7) The amount of the acid catalyst is 1 to 2 moles relative to the compound represented by Formula 1. % Is the method according to any one of (1) to (6).

  In the present invention, the reaction is usually carried out by dissolving the 5-amino-2,4,6-triiodoisophthalic acid derivative represented by the formula 1 in an organic solvent. However, surprisingly, in the present invention, even though the 5-amino-2,4,6-triiodoisophthalic acid derivative does not dissolve in the organic solvent, both of them react in a solid-liquid two-phase system. It is particularly preferred that the 5-amino-2,4,6-triiodoisophthalic acid derivative of No. 1 is suspended in an organic solvent, an acid catalyst is added, and acetic anhydride is dropped into the slurry. In this case, there is no need for troublesome operations such as concentration and crystallization after completion of the reaction, and 5-acetamido-2,4,6-triiodoisophthalic acid represented by the target formula 2 is obtained by a simple operation of filtering the reaction slurry Derivatives can be obtained.

In the present invention, the compound represented by the formula 1 is particularly preferably a compound in which both X ₁ and X ₂ represent a hydroxyl group, a compound in which both X ₁ and X ₂ represent a halogen atom, and both X ₁ and X ₂ Is a compound in which X represents -NHR ₂ and both X ₁ and X ₂ represent -OR ₂ .
In the present invention, R ₁ and R ₂ in Formula 1 are hydrogen or a linear or branched lower alkyl group having 1 to 5 carbon atoms (wherein the alkyl group is a hydroxyl group, an amino group, a thiol group). , Optionally substituted with one or more substituents selected from the group consisting of nitro, nitrile, carbonyl and acyloxy groups. As the substituent for the alkyl group, a hydroxyl group is particularly preferred. Acyl of the acyloxy group has 1 to 5 carbon atoms. As a linear or branched lower alkyl group having 1 to 5 carbon atoms substituted with one or more substituents selected from the group consisting of hydroxyl group, amino group, thiol group, nitro group, carbonyl group and acyloxy group , For example, —CH ₂ CH (OH) CH ₂ OH, —CH (CH ₂ OH) ₂ , —CH ₂ CH ₂ OH, —CH (CH ₂ OH) CH (OH) CH ₂ OH, preferably _{, -CH 2 CH (OH) CH} 2 OH, a _-CH (CH _{2 OH)} 2.
The organic solvent in the present invention is preferably an organic solvent that does not react with acetic anhydride, such as halogenated hydrocarbon solvents such as methane tetrachloride, chloroform, methylene chloride, dichloroethane, chlorobenzene, dimethyl ether, diethyl ether, methyl ethyl ether, tetrahydrofuran, and the like. And an organic solvent having a nitrile group such as acetonitrile, propionitrile, butyronitrile. Considering the ease of the drying process and the possibility of residual solvent, methylene chloride, diethyl ether, acetonitrile and propionitrile having a boiling point of 100 ° C. or less are preferable, and acetonitrile and propionitrile are considered in view of industrial handling and environmental aspects. Is preferred.

  The amount of the organic solvent used in the present invention is not particularly limited, but is 1 to 5 times, preferably 1.5 to 2 times the weight of the 5-amino-2,4,6-triiodoisophthalic acid derivative.

  Although the acid catalyst used in this invention is not specifically limited, As a specific example, hydrochloric acid, a sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid etc. are mentioned, Preferably it is a sulfuric acid. Although the usage-amount of an acid catalyst is not specifically limited, It is 0.1-5 mol% of the 5-amino-2,4,6-triiodoisophthalic acid derivative of Formula 1, Preferably it is 1-2 mol%.

  The amount of acetic anhydride used in the present invention is 1-2 molar equivalents, preferably 1.0-1.2 molar equivalents, of the 5-amino-2,4,6-triiodoisophthalic acid derivative represented by Formula 1. .

  Although the reaction temperature in this invention is not specifically limited, Preferably it is 0-100 degreeC, More preferably, it is 10-50 degreeC.

  Although the reaction time in this invention is not specifically limited, Preferably it is 0.5 hour or more, More preferably, it is 2 hours or more.

  After completion of the reaction, after a simple operation of filtration and drying, a high purity 5-acetamido-2,4,6-triiodoisophthalic acid derivative represented by Formula 2 can be obtained. The filtered mother liquor can be easily discarded by neutralizing with a small amount of caustic soda or its aqueous solution.

  Examples of the present invention will be described below in more detail, but the present invention is not limited to these examples.

(Measurement method of purity)
The purity of the 5-acetamido-2,4,6-triiodoisophthalic acid derivative is determined by HPLC equipment (manufactured by Tosoh Corporation), UV detector (UV-8010), column oven (CO-8010), liquid feed pump (CCPD), It measured using the column (TSK-GEL).

The measurement conditions are as follows.
Sample preparation: A sample was dissolved in a developing solvent at a rate of 1 mg / ml to obtain a sample solution.
Developing solvent: acetonitrile / H ₂ O = 60/40
Flow rate: 1000 μl / min.
Column temperature: 40 ° C
Injection volume: 2 μl
Measurement wavelength: 254 nm

Example 1
100 g (0.18 mol) of 5-amino-2,4,6-triiodoisophthalic acid was suspended in 200 ml of acetonitrile, and 0.2 g (5-amino-2,4,6-triiodoisophthalic acid) of sulfuric acid was suspended. 1 mol%). 22 g (0.21 mol) of acetic anhydride was added dropwise under water cooling. After completion of the reaction, the crystals obtained by filtration were dried to obtain 104 g of 5-acetamido-2,4,6-triiodoisophthalic acid in a yield of 97%. Furthermore, the HPLC purity was 99.8%. The filtered mother liquor was neutralized with 38 g of 25% sodium hydroxide and discarded.

Comparative Example 1
50 g (0.09 mol) of 5-amino-2,4,6-triiodoisophthalic acid is added to 150 ml of acetic anhydride, and a few drops of sulfuric acid (0.2 g; 5-amino-2,4,6-) 2 mol% relative to triiodoisophthalic acid). The mixture was stirred for 30 minutes while controlling rapid exotherm. The reaction solution is poured into 500 ml of water and neutralized with 500 g of 25% sodium hydroxide. After decolorization using activated carbon, the pH was adjusted to 2-3 with concentrated hydrochloric acid and the crystals were filtered. The crystals were dried to obtain 45 g of 5-acetamido-2,4,6-triiodoisophthalic acid in a yield of 83%. Furthermore, the HPLC purity was 99.6%.

Example 2
100 g (0.17 mol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride was suspended in 200 ml of acetonitrile, and 0.2 g (5-amino-2,4,6-triiodoisophthalic acid) of sulfuric acid was suspended. 1 mol% relative to dichloride). 21 g (0.2 mol) of acetic anhydride was added dropwise under water cooling. After completion of the reaction, the crystals obtained by filtration were dried to obtain 104 g of 5-acetamido-2,4,6-triiodoisophthalic acid dichloride in a yield of 97%. Furthermore, the HPLC purity was 99.8%. The filtered mother liquor was neutralized with 40 g of 25% sodium hydroxide and discarded.

Comparative Example 2
50 g (0.08 mol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride is suspended in 150 ml of acetic anhydride, and a few drops (0.2 g; 5-amino-2,4) of sulfuric acid. , 6-triiodoisophthalic acid dichloride, 2.5 mol%). After stirring for 1 hour while controlling rapid heat generation, the crystals were filtered. The crystals were dried to obtain 38 g of 5-acetamido-2,4,6-triiodoisophthalic acid dichloride in a yield of 76%. Furthermore, the HPLC purity was 99.7%. The filtered mother liquor was neutralized with 500 g of 25% -aqueous sodium hydroxide and discarded.

  If acetylation is carried out in an organic solvent according to the present invention, a 5-acetamido-2,4,6-triiodoisophthalic acid derivative can be produced by a simple operation of filtration with high yield and high purity safely. Yes, the derivatives can be easily dried, eliminating the need for bulk wastewater treatment.

Claims (7)

Formula 1:

[Wherein, X ₁ and X ₂ may be the same or different and each represents a hydroxyl group, a halogen atom, —NHR ₂ or —OR ₂ , and R ₁ and R ₂ are the same or different. Or a linear or branched lower alkyl group having 1 to 5 carbon atoms (wherein the alkyl group includes a hydroxyl group, an amino group, a thiol group, a nitro group, a nitrile group, a carbonyl group, and Which may be substituted with one or more substituents selected from the group consisting of acyloxy groups), and acetylating with acetic anhydride in the presence of an acid catalyst in an organic solvent. , Formula 2:

(Wherein, X ₁ , X _{2 and} R ₁ have the same meaning as in formula 1). The method according to claim 1, wherein X ₁ and X ₂ represent a hydroxyl group or a halogen atom. The method of claim 1, wherein X ₁ and X ₂ represent —NHR ₂ . The method of claim 1, wherein X ₁ and X ₂ represent —OR ₂ .   The method according to claim 1, wherein the organic solvent is an organic solvent having a nitrile group.   The process according to any one of claims 1 to 5, wherein the acid catalyst is sulfuric acid.   The method according to any one of claims 1 to 6, wherein the amount of the acid catalyst is 1 to 2 mol% based on the compound represented by Formula 1.