WO2006100731A1

WO2006100731A1 - Method for acetylating 5-amino-2,4,6-triiodoisophthalic acid derivative

Info

Publication number: WO2006100731A1
Application number: PCT/JP2005/004992
Authority: WO
Inventors: Ryuji Takata
Original assignee: Manac Inc.
Priority date: 2005-03-18
Filing date: 2005-03-18
Publication date: 2006-09-28
Also published as: JP4801661B2; JPWO2006100731A1

Abstract

A method for producing a 5-acetamide-2,4,6-triiodoisophthalic acid derivative comprising acetylating a 5-amino-2,4,6-triiodoisophthalic acid derivative in an organic solvent in the presence of an acid catalyst using acetic anhydride is disclosed. By the convenient method, a 5-acetamide-2,4,6-triiodoisophthalic acid derivative with a high yield and high quality can be provided.

Description

Specification

5—Amino-2,4,6--triodoisophthalic acid derivative acetylene method Technical Field

[0001] The present invention relates to a method for producing a 5-acetamido-2,4,6-triodoisophthalic acid derivative, which comprises acetylating a 5-amino-2,4,6-triodoisophthalic acid derivative. Background art

[0002] 5-Amino-2,4,6-triodoisophthalic acid or a derivative thereof is particularly used as a nonionic contrast medium or an intermediate for producing the same. Since the production of non-ionic contrast agents involves a number of processes, the yield and purity at each process greatly affect the quality and yield of the final product.

[0003] Among 5-amino-2,4,6-triodoisophthalic acid or derivatives thereof, 5-acetoamide-2,4,6-triodoisophthalic acid or derivatives thereof is an important intermediate between nonionic contrast agents. It is desirable to produce a good and efficient product that is often used as a body.

[0004] The production methods that have been disclosed so far for the production of 5-acetoamide-2,4,6-triodoisophthalic acid or its derivatives are non-polar, such as dimethylacetamide or dimethylformamide. It is known that there is a reaction by adding a salty acetyl group in a protic solvent or a reaction by adding a catalytic amount of sulfuric acid in acetic anhydride.

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

[0006] In Patent Document 1, a salty acetyl which is used as a force acetylating agent in which acetylacetyl is used in a dimethylacetamide solvent under relatively mild reaction conditions. Is water-free and requires special chemical drums that are difficult to transport and store for industrial use. In addition, dipolar aprotic solvents such as dimethylacetamide and dimethylformamide have a high boiling point and require a great deal of time and effort to remove the high boiling energy. For this reason, if the removal becomes insufficient, there is a concern that it may become a residual solvent in the product.

[0007] In Patent Document 2, Patent Document 3, and Non-Patent Document 1, a catalytic amount of sulfuric acid is added to acetic anhydride. Addition of acetylic acid by adding acetic anhydride serves as a acetylating agent and a solvent. When sulfuric acid is added after mixing raw materials and acetic anhydride, the reaction proceeds explosively with intense heat generation. For this reason, there is a risk that the accident may become a serious accident that is difficult to control. In addition, wastewater containing a large amount of acetic anhydride and acetic acid and sulfuric acid must be treated for industrial use. However, it is difficult because a lot of costs are incurred for processing. Patent Literature 1: Japanese Translation of Special Publication 2000-505820

Patent Document 2: British Patent Specification No. 785670

Patent Document 3: Japanese Patent Publication No. 56-54310

Non-Patent Document 1: J. Haavaldsen et.al, Acta Pharm. Suec, 20, 219 (1983).

Disclosure of the invention

Problems to be solved by the invention

[0008] An object of the present invention is to produce 5-acetoamide-2,4,6-triodoisophthalic acid or a derivative thereof more easily and safely in a high yield.

Means for solving the problem

As a result of diligent investigations to solve the above-mentioned problems, the present inventor has obtained a 5-amino-2,4,6-triodoisophthalic acid derivative as an organic solvent using acetic anhydride in the presence of an acid catalyst. The present inventors have found a method of acetylene cake that can be obtained in high yield and high quality by carrying out acetylene in a simple manner with few steps.

That is, the present invention

(1) Equation 1:

[Wherein X and X are the same or different, a hydroxyl group or a halogen atom.

1 2

, -NHR or 10R, R and R may be the same or different,

2 2 1 2

A straight or branched lower alkyl group of up to 115 hydrogen or carbon atoms (wherein The alkyl group is a hydroxyl group, an amino group, a thiol group, a nitro group, a nitrile group, a carbonyl group, and an acyloxy group, which may be substituted with one or more selected substituents. And acetylating the compound represented by the above formula with acetic anhydride in an organic solvent in the presence of an acid catalyst:

(Where X

1, X and R have the same meaning as in formula 1)

twenty one

(2) The method according to (1), wherein both X and X represent a hydroxyl group or a halogen atom;

1 2

(3) The method according to (1), wherein both X and X represent NHR;

1 2 2

(4) The method according to (1), wherein both X and X represent OR;

1 2 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 acid catalyst is sulfuric acid, (1) one (5) method according to any one of the above; and

(7) The amount of the acid catalyst is 1 to 2 mol% with respect to the compound represented by formula 1, (1) one (6)! The method according to item 1

It is.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] In the present invention, the reaction is usually carried out by dissolving the 5 amino-2,4,6-triodoisophthalic acid derivative represented by the formula 1 in an organic solvent. However, surprisingly, in the present invention, even if the 5-amino 2,4,6-triodoisophthalic acid derivative does not dissolve in the organic solvent, both of them react in a solid-liquid two-phase system. It is particularly preferable to suspend the 5-amino-2,4,6-triodoisophthalic acid derivative of 1 in an organic solvent, add an acid catalyst, and add acetic anhydride dropwise to the slurry. In this case, after completion of the reaction, no troublesome operations such as concentration and crystallization are required, and the reaction slurry is filtered by a simple operation of filtering 5-acetoami-2,4,6-triodoisophthalic acid represented by the target formula 2. Derivatives can be obtained.

In the present invention, both X and X are particularly preferable as the compound represented by Formula 1.

1 2 represents a hydroxyl group, X and X both represent a halogen atom, X and X Are compounds in which both represent NHR, and both X and X represent OR.

2 1 2 2

In the present invention, R and R in formula 1 are each hydrogen or a carbon atom.

1 2 1 to 5 linear or branched lower alkyl group (wherein the alkyl group is a group consisting of a hydroxyl group, an amino group, a thiol group, a nitro group, a nitrile group, a carbonyl group, and an acyloxy group) Force is substituted with one or more selected substituent (s). As the substituent of the alkyl group, a hydroxyl group is particularly preferable. The acyl of the acyloxy group has 1 to 15 carbon atoms. Hydroxyl group, amino group, thiol group, nitro group, carbonyl group, and acyloxy group group force Selected straight or branched lower chain up to 5 carbon atoms substituted with one or more selected substituents Examples of the alkyl group include -CH CH (OH) CH OH

2 2, — CH (CH OH)

2 2 CH CH OH CH (CH OH) CH (OH) CH OH, preferably C

2 2 2 2

H CH (OH) CH OH CH (CH OH).

2 2 2 2

The organic solvent in the present invention is preferably an organic solvent that does not react with acetic anhydride. Examples thereof include halogenated hydrocarbon solvents such as methane tetrachloride, chloroform, methylene chloride, dichloroethane, and chloroform, dimethyl ether, and jetyl. Examples thereof include aliphatic ether solvents such as ether, methyl ethyl ether, and tetrahydrofuran, and organic solvents having a tolyl group such as acetonitrile, propio-tolyl, and petit-tolyl. Considering the ease of the drying process and the possibility of residual solvent, methylene chloride with a boiling point of 100 ° C or less, jetyl ether, acetonitrile, and propio-tolyl are preferred. Considering industrial handling and environmental aspects, acetonitrile and propio -Trill is preferred.

[0012] The amount of the organic solvent used in the present invention is not particularly limited, but it is 1 to 5 times by weight, preferably 1.5 to 2 times by weight of 5-amino-2,4,6 tolyoisophthalic acid derivative. It is.

[0013] The acid catalyst used in the present invention is not particularly limited, but specific examples thereof include hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, etc., preferably sulfuric acid. It is. The amount of the acid catalyst is not particularly limited, 5-amino-2, 4 of the formula 1, 6-preparative RHO de isophthalic acid derivatives 0.5 1 5 mole ^_0/0, preferably 1 one 2 mole ^_0/0 is there.

[0014] The amount of acetic anhydride used in the present invention is 1 to 12 molar equivalents, preferably 1.0 to 1.2 molar equivalents, of the 5 amino-2, 4, 6, 6 triode isophthalic acid derivative represented by Formula 1.

[0015] The reaction temperature in the present invention is not particularly limited, but is preferably 0 to 100 ° C. It is preferably 10-50 ° C.

[0016] The reaction time in the present invention is not particularly limited, but is preferably 0.5 hours or more.

More preferably, it is 2 hours or more.

[0017] After completion of the reaction, after a simple operation of filtration, if it is dried, the high purity formula 2 is obtained.

5-acetoamide-2,4,6-triodoisophthalic acid derivatives can be obtained. The filtered mother liquor can be easily discarded by neutralizing with a small amount of caustic soda or its aqueous solution.

Example

[0018] The present invention will now be illustrated in more detail with reference to the following examples. The present invention is not limited to these examples.

[0019] (Measurement of purity)

The purity of 5-acetoamide-2, 4, 6-triodoisophthalic acid derivatives is determined by HPLC (Tosohichi), 11 detector (1; ¥ —8010), column oven (CO—8010), liquid pump (CCP D) and column (TSK-GEL).

[0020] The measurement conditions are as follows.

Sample preparation: The sample was dissolved in a developing solvent at a rate of 1 mg, ml to obtain a sample solution. Developing solvent: Acetonitrile ZH 2 O = 60/40

2

Nagasato: 1000 μ 1 / min.

Column temperature: 40 ° C

Injection volume: 2 1

Measurement wavelength: 254nm

[0021] Example 1

Case-tolyl Suspend 5-gamino-2,4,6-triodoisophthalic acid in 100 g (0.18 mol) in 200 ml, and add 0.2 g of sulfuric acid (5-amino-2, 4, 6- 1 mol% relative to triodoisophthalic acid). Under water cooling, 22 g (0.21 mol) of acetic anhydride was added dropwise. After completion of the reaction, the crystals obtained by filtration were dried to obtain 104 g of 5-acetamido-2,4,6-triodoisophthalic 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. [0022] Comparative Example 1

To 150 ml of acetic anhydride, add 50 g (0.09 mol) of 5-amino-2,4,6-triodoisophthalic acid and add a few drops of sulfuric acid (0.2 g; 5-amino-2, 4, 6 —2 mol% relative to triodoisophthalic acid). The mixture was stirred for 30 minutes while controlling rapid exotherm. Pour the reaction mixture into 500 ml of water and neutralize 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-triodoisophthalic acid in a yield of 83%. Furthermore, the HPLC purity was 99.6%.

[0023] Example 2

L-Og (0.17 mol) of 5-amino-2,4,6-triodoisophthalic acid dichloride was suspended in 200 ml of acetonitrile and 0.2 g (5-amino-2,4,6-triodoisophthalic acid) of sulfuric acid. 1 mol% relative to dichloride). Under water cooling, 21 g (0.2 mol) of acetic anhydride was added dropwise. 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.

[0024] Comparative Example 2

Suspend 50 g (0.08 mol) of 5-amino-2,4,6-triodoisophthalic acid dichloride in 150 ml of acetic anhydride and add a few drops of sulfuric acid (0.2 g; 0.2-amino; 2, 4 , 6-triodoisophthalic 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-triodoisophthalic 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. Industrial applicability

[0025] When acetylene lysis is carried out in an organic solvent according to the present invention, a 5-acetamido-2,4,6-triodoisophthalic acid derivative can be safely obtained in a high yield, high purity and by a simple operation of filtration. The derivative can be easily dried and eliminates the need for a large amount of waste liquid treatment.

Claims

The scope of the claims

[Wherein X and X are the same or different, a hydroxyl group or a halogen atom.

1 2

, -NHR or 10R, R and R may be the same or different,

2 2 1 2

Straight chain or branched lower alkyl groups up to 5 or 5 carbon atoms (wherein the alkyl group is a hydroxyl group, an amino group, a thiol group, a nitro group, a nitrile group, a carbonyl group, and an acyloxy group). The group power represented by the group is acetylated with an acetic anhydride in the presence of an acid catalyst in an organic solvent, which is substituted with one or more selected substituents. Including formula 2:

(Wherein X, X and R have the same meaning as in formula 1)

1 2 1

[2] The method according to claim 1, wherein X and X each represent a hydroxyl group or a halogen atom.

1 2

[3] The method of claim 1, wherein X and X represent -NHR.

1 2 2

[4] The method of claim 1, which represents X and XOR.

1 2 2

[5] The method according to any one of claims 1 to 4, wherein the organic solvent is an organic solvent having a -tolyl group.

6. The method according to any one of claims 1 to 5, wherein the acid catalyst is sulfuric acid.

[7] 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 the formula 1.