JP4918764B2 - Biodegradable aminopolycarboxylic acid derivatives - Google Patents

Description

  The present invention relates to metal ion concealing agents, particularly medical, cosmetic preparations, soaps, detergents, material analysis, coating on metal materials, plating, catalysts, colloid chemistry, photography, liquid crystals, environmental purification, etc. The present invention relates to a novel biodegradable aminopolycarboxylic derivative useful as an agent.

  Aminopolycarboxylic acids have been used as chelating agents for medical, cosmetic preparations, soaps, detergents, material analysis, coating on metal materials, plating, catalysts, colloid chemistry, photography, liquid crystals, environmental purification, etc. Yes. Until now, electrolyte polymers such as polyacrylic acid and polymaleic acid, aminocarboxylates such as ethylenediaminetetraacetic acid (EDTA), or polyphosphates such as sodium tripolyphosphate have been used as chelating agents for the above applications. However, all of these conventional chelating agents have low biodegradability, and in recent years there has been concern about adverse effects on the environment. For this reason, various chelating agents having biodegradability are desired. Nitrilotriacetic acid (NTA) or the like is known as a biodegradable chelating agent, but it cannot be put to practical use depending on the application because of its weak coordination power. The biodegradable chelating agent invented for the purpose of improving the coordinating power has been developed mainly with the aim of increasing the number of amino groups and carboxyl groups. For example, aspartic acid-N, N- Diaacetic acid, glutamic acid-N, N-diacetic acid, iminodisuccinic acid, S, S-ethylenediamine-N, N′-disuccinic acid (S, S-EDDS) and the like are on the market or are being studied. However, conventionally proposed chelating agents having biodegradability have a problem that chelating ability is low as compared with EDTA. (For example, refer nonpatent literature 1).

Market Outlook for Biodegradable Chemicals (CMC Publishing, 57 pages)

  The present invention provides a novel biodegradable aminopolycarboxylic acid derivative having a chelating ability exceeding EDTA with respect to silver ions while being an NTA derivative.

  As a result of intensive studies on the above problems, the present inventors have reached the present invention. That is, the present invention is an aminopolycarboxylic acid derivative represented by the following general formula (I).

［式中、Ｍ_１、Ｍ_２及びＭ_３はそれぞれ水素原子又はカチオンを表す。
Ｒは
・（水酸基、−ＣＯＯＭ_４基、（−ＯＭ_５基、−ＣＯＯＭ_６基、炭素数１〜６のアルコキシ基、ハロゲン原子、アミノ基、炭素数１〜６のアルキルアミノ基、炭素数１〜６のジアルキルアミノ基、または低級アルキル基で）置換されていてもよいフェニル基、（−ＯＭ_５基、−ＣＯＯＭ_６基、炭素数１〜６のアルコキシ基、ハロゲン原子、アミノ基、炭素数１〜６のアルキルアミノ基、炭素数１〜６のジアルキルアミノ基、または低級アルキル基で）置換されていてもよいナフチル基、および（−ＯＭ_５基、−ＣＯＯＭ_６基、炭素数１〜６のアルコキシ基、ハロゲン原子、アミノ基、炭素数１〜６のアルキルアミノ基、炭素数１〜６のジアルキルアミノ基、または低級アルキル基で）置換されていてもよいヘテロアリール基）からなる群から選ばれる一つ以上の置換基により置換されていてもよい炭素数１〜６のアルキル基、
・（−ＯＭ_５基、−ＣＯＯＭ_６基、炭素数１〜６のアルコキシ基、ハロゲン原子、アミノ基、炭素数１〜６のアルキルアミノ基、炭素数１〜６のジアルキルアミノ基、または低級アルキル基で）置換されていてもよいフェニル基、
・（−ＯＭ_５基、−ＣＯＯＭ_６基、炭素数１〜６のアルコキシ基、ハロゲン原子、アミノ基、炭素数１〜６のアルキルアミノ基、炭素数１〜６のジアルキルアミノ基、または低級アルキル基で）置換されていてもよいナフチル基、
または
・（−ＯＭ_５基、−ＣＯＯＭ_６基、炭素数１〜６のアルコキシ基、ハロゲン原子、アミノ基、炭素数１〜６のアルキルアミノ基、炭素数１〜６のジアルキルアミノ基、または低級アルキル基で）置換されていてもよいヘテロアリール基
を表し、
Ｍ_４、Ｍ_５およびＭ_６は水素原子又はカチオンを表す。
ただし、Ｒが−ＣＨ（ＣＯＯＭ_７）ＣＨ_２ＣＯＯＭ_８（式中、Ｍ_７及びＭ_８はそれぞれ水素原子又はカチオンを表す。）およびトリフェニルメチル基の場合を除く。］
また本発明は、一般式（Ｉ）で表されるアミノポリカルボン酸誘導体からなることを特徴とするキレート剤である。以下に本発明をさらに詳細に説明する。

[Wherein, M ₁ , M ₂ and M ₃ each represent a hydrogen atom or a cation.
R is (hydroxyl group, -COOM ₄ group, (-OM ₅ group, -COOM ₆ group, alkoxy group having 1 to 6 carbon atoms, halogen atom, amino group, alkylamino group having 1 to 6 carbon atoms, 1 carbon atom) Optionally substituted phenyl group (with a dialkylamino group or lower alkyl group), (—OM ₅ group, —COOM ₆ group, C 1-6 alkoxy group, halogen atom, amino group, carbon number) 1-6 alkylamino group, a dialkylamino group having 1 to 6 carbon atoms or a lower alkyl group) optionally substituted naphthyl group, and (-OM ₅ group, -COOM ₆ group, having 1 to 6 carbon atoms An alkoxy group, a halogen atom, an amino group, an alkylamino group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, or a lower alkyl group). An alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the group
・ (-OM ₅ group, -COOM ₆ group, alkoxy group having 1 to 6 carbon atoms, halogen atom, amino group, alkylamino group having 1 to 6 carbon atoms, dialkylamino group having 1 to 6 carbon atoms, or lower alkyl An optionally substituted phenyl group,
・ (-OM ₅ group, -COOM ₆ group, alkoxy group having 1 to 6 carbon atoms, halogen atom, amino group, alkylamino group having 1 to 6 carbon atoms, dialkylamino group having 1 to 6 carbon atoms, or lower alkyl An optionally substituted naphthyl group,
Or (-OM ₅ group, -COOM ₆ group, alkoxy group having 1 to 6 carbon atoms, halogen atom, amino group, alkylamino group having 1 to 6 carbon atoms, dialkylamino group having 1 to 6 carbon atoms, or lower Represents an optionally substituted heteroaryl group (with an alkyl group),
M _{4, M 5} and _{M 6} represents a hydrogen atom or a cation.
However, the case where R is —CH (COOM ₇ ) CH ₂ COOM ₈ (wherein M ₇ and M ₈ each represent a hydrogen atom or a cation) and a triphenylmethyl group is excluded. ]
The present invention also provides a chelating agent comprising an aminopolycarboxylic acid derivative represented by the general formula (I). The present invention is described in further detail below.

In the general formula (I), M ₁ , M ₂ , M ₃ , M _4, M ₅ and M ₆ each represent a hydrogen atom or a cation. When two or more cations are present in the molecule, they may be different cations. Examples of the cation include ammonium, alkali metals (for example, lithium, sodium, and potassium), alkaline earth metals (for example, calcium, magnesium, and barium). M ₁ , M ₂ , M ₃ , M _4, M ₅ , and M ₆ are each a hydrogen atom, an alkali metal, or an alkaline earth metal, and more preferably a hydrogen atom or an alkali metal.

R is as described above. Preferably, R is an alkyl group having 1 to 3 carbon atoms which may be substituted with one or more hydroxyl groups or COOM ₄ groups, and more preferably substituted with a carboxy group. Or an alkyl group having 1 to 3 carbon atoms.

  In the present specification, the lower alkyl group includes a methyl group, an ethyl group, a propyl group and the like, and an isomer group thereof.

  A heteroaryl group is a monocyclic or bicyclic heterocycle having 1 to 3 heteroatoms such as oxygen, sulfur, and nitrogen atoms as ring-forming atoms, such as pyrrole, pyrazole, Examples include imidazole, triazole, pyridine, triazine, furan, thiophene, thiazole, oxazole, isoxazole, isothiazole, benzothiazole, benzoxazole, indazole, indole, quinoline, purine, and pteridine ring.

  A halogen atom is a fluorine, chlorine, bromine, or iodine atom.

  Specific examples of the compound represented by the general formula (I) are listed in Table 1. In the table, Bn represents a benzyl group.

一般式（Ｉ）で表される本発明のアミノポリカルボン酸誘導体は、例えば下記反応工程式に表される方法により合成することができる。

The aminopolycarboxylic acid derivative of the present invention represented by the general formula (I) can be synthesized by, for example, a method represented by the following reaction process formula.

（反応工程中、Ｘ_１およびＸ_２は水素原子又はカチオンを表し、Ｌはハロゲン等の脱離基を表し、Ｒは前記と同じ意味を表す。なおＸ_２は、Ｘ_１または使用する塩基のカチオンに由来する。）
［工程１］一般式（ＩＩ）で表されるＳ−置換システイン誘導体と一般式（ＩＩＩ）で表される酢酸誘導体を適当な溶媒中にて塩基存在下で反応させ、アミン部位をアルキル化した一般式（ＩＶ）で表される化合物を得た。

(In the reaction step, X ₁ and X ₂ represent a hydrogen atom or a cation, L represents a leaving group such as halogen, R represents the same meaning as described above, and X ₂ represents X ₁ or the base used. Derived from cations.)
[Step 1] The S-substituted cysteine derivative represented by the general formula (II) and the acetic acid derivative represented by the general formula (III) were reacted in an appropriate solvent in the presence of a base to alkylate the amine moiety. A compound represented by the general formula (IV) was obtained.

  As the base used in the reaction of Step 1, those generally used for this kind of reaction can be used without particular limitation. For example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, triethylamine, trimethylamine, N, N -Dimethylaniline, pyridine, N-methylpiperidine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene ( DBU) and the like.

  The solvent used in the reaction of step 1 may be any solvent that does not inhibit the reaction, hydrocarbons such as hexane, pentane, and cyclohexane, aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol, and n-propanol. Primary alcohols such as tetrahydrofuran, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, water, or any of these And the like.

  The reaction temperature of the process 1 is -80-150 degreeC normally, Preferably it is -15-120 degreeC.

  The reaction time in Step 1 varies depending on the reaction temperature, reaction substrate and reaction reagent, but is usually completed in 30 minutes to 3 days.

  [Step 2] An aminopolycarboxylic acid derivative represented by the general formula (I) is produced by treating the compound represented by the general formula (IV) with an appropriate acid and, if necessary, treating with a cation. be able to.

  As the acid used for protonation, those generally used for this kind of reaction can be used without particular limitation. For example, mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, strong cation exchange resins and the like can be mentioned.

  The solvent used in the reaction in step 2 may be any solvent that does not inhibit the reaction. For example, the same solvent as in step 1 can be used. The same conditions as in Step 1 can be applied to both the reaction temperature and the reaction time.

  The compound represented by the general formula (I), which is the reaction target, is collected from the reaction mixture by ordinary post-treatment. For example, it can be obtained by distilling off the solvent under reduced pressure. The obtained target mixture can be purified by operations such as column chromatography and recrystallization, if necessary.

The compound represented by general formula (I) can be used as a chelating agent. In particular, since the compound represented by the general formula (I) has both the structure of NTA, which is a biodegradable chelating agent, and a thioether structure, the electronegativity such as amino group and carboxyl group of NTA is large and the polarizability is high. It has not only a so-called hard base, but also a so-called soft base property having a low electronegativity derived from a thiol ether structure and a high polarizability. Therefore, the compound represented by the general formula (I) is R.I. Hard acids (Li ⁺ , Na ⁺ , K ⁺ , Be ²⁺ , Mg ²⁺ , Ca ²⁺ , Sr ²⁺ , Al ³⁺ , Ga ³⁺ , La ³⁺ , Cr ³⁺ , Co ³⁺ in the class of Lewis acids of Pearson (R. Pearson) , Fe ³⁺ , As ³⁺ , Si ⁴⁺ , Ti ⁴⁺ , Zr ⁴⁺ , Sn ⁴⁺ ), intermediate acids (Fe ²⁺ , Co ²⁺ , Ni ²⁺ , Cu ²⁺ , Zn ²⁺ , Pb ²⁺ , Sn ²⁺ , Sb ³⁺ , Bi ³⁺ , Rh ³⁺ , Ir ³⁺ , Ru ²⁺ , Os ²⁺ ), soft acid (Cu ⁺ , Ag ⁺ , Au ⁺ , Hg ⁺ , Pd ²⁺ , Cd ²⁺ , Hg ²⁺ , Tl ³⁺ , Pt ²⁺ ) Also exhibits coordinating power and can be used as a chelating agent. Among them, since it shows a stronger coordinating power with respect to soft acids, it is preferable as a chelating agent for them, and particularly preferable as a chelating agent for Pb ²⁺ and Ag ⁺ .

  The compound of the present invention is a derivative of cysteine, which is a natural amino acid, and is a biodegradable compound. For this reason, it is a useful compound as a chelating agent having biodegradability.

  Although the compound represented by the general formula (I) is an NTA derivative, it has a high chelating ability from an alkaline earth metal such as calcium to a heavy metal such as lead, and in particular, a chelate that surpasses EDTA for silver. In addition, it has a high biodegradability.

  EXAMPLES Next, examples are given to specifically describe the present invention, but the present invention is not limited to these examples.

In the examples, nuclear magnetic resonance (NMR) spectra were measured with an apparatus manufactured by “BRUKER DPX-250”. Regarding the chemical shift value, tetramethylsilane (TMS) was used as an internal standard substance when the measurement solvent was CDCl ₃ , and when D ₂ O was used, the chemical shift value of the solvent was used as a reference value and expressed in ppm. As the adsorbent for column chromatography, the trade name “Kanto Chemical Silica Gel 60N” (spherical, neutral, 40-50 μm) was used. The anhydrous solvent used for the reaction was a commercial product.

Example 1 Synthesis of Compound Represented by Compound No. 3 Synthesis of N, N-biscarboxymethyl-S-carboxymethyl-L-cysteine: (Compound No. 3)
10.0 g (67.0 mmol) of S-carboxymethylcysteine was dissolved in 70 ml of 4M aqueous sodium hydroxide solution, and 16.25 g (139.5 mmol) of sodium chloroacetate was added under ice cooling. The reaction solution was stirred for 1 hour under ice cooling, then the temperature was raised to 60 ° C., and the mixture was stirred overnight. Concentrated hydrochloric acid was added to the reaction solution to raise the pH to 2, and then water was distilled off under reduced pressure to obtain a crude product of the target compound.

  In addition, in the present Example, the following processes were added in order to improve the purity of the target compound. That is, 50 ml of ethanol and 1 ml of concentrated sulfuric acid were added to the above residue and heated under reflux overnight. After concentrating ethanol to 2/3, water was added and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate: hexane) and 3.9 g (9.57 mmol) of N, N-bisethoxycarbonylmethyl-S-ethoxycarbonylmethyl-L-cysteine ethyl ester as a pale yellow oil. 17%) and 2.3 g (7.16 mmol) of monoadduct.

¹ H-NMR (250 MHz, CDCl ₃ ) δ of N, N-bisethoxycarbonylmethyl-S-ethoxycarbonylmethyl-L-cysteine ethyl ester: 4.30-4.10 (m, 9H), 3.72- 3.63 (m, 4H), 3.35 (d, J = 14 Hz, 1H), 3.28 (d, J = 14 Hz, 1H), 3.08-2.90 (m, 2H), 1. 33-1.20 (m, 12H).

  Water in a solution of 3.9 g (9.57 mmol) of N, N-bisethoxycarbonylmethyl-S-ethoxycarbonylmethyl-L-cysteine ethyl ester dissolved in 90 ml of a 4: 1: 1 mixed solvent of tetrahydrofuran: methanol: water Lithium oxide monohydrate 1.81 g (43.07 mmol) was added. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure. Water was added to the residue, and Amberlite IR-120 (H) was added until the pH was 3. The ion exchange resin was filtered off and washed with water until the washing solution became neutral. The collected aqueous layer was distilled off under reduced pressure, and the pasty product was washed with methanol to obtain 0.56 g (1.90 mmol: 20% yield from S-carboxymethylcysteine) of the colorless powder. Obtained.

¹ H-NMR (250 MHz, D ₂ O) δ: 4.19-4.11 (m, 1H), 3.94 (s, 2H), 3.93 (s, 2H), 3.53-3. 36 (m, 2H), 3.37-3.00 (m, 2H).

(Example 2) Evaluation of chelating ability The chelating ability of the compound represented by Compound No. 3 was measured. That is, the pH of the chelating agent solution was measured in the presence of calcium ion, lead ion, or silver ion by potentiometric titration method, and after calculating the acid dissociation constant, the condition stability constant was calculated by the method of Schwarzenbach. At this time, the measurement temperature was 25 ° C., KNO ₃ was used, and the ionic strength was set to μ = 0.1. The measurement was performed under the conditions of a calcium ion, lead ion, or silver ion concentration of 10 mM and a chelating agent concentration of 1 mM. The results are shown in Table 2.

(Comparative Example 1) Evaluation of chelating ability The chelating ability was evaluated in the same manner as in Example 2, except that comparative compounds ac were used. The results are shown in Table 2.

表中の「−」は化合物のキレート形成能が低いため、本測定条件では条件安定度定数の算出ができなかったことを表す。なお、比較化合物ａ〜ｃは以下の通りである。

“-” In the table indicates that the condition stability constant could not be calculated under the present measurement conditions because of the low chelate-forming ability of the compound. Comparative compounds a to c are as follows.

表２から明らかなように本発明による化合物は、カルシウム、鉛、銀の各イオンに対してキレート能を示すものである。特に化合物番号３で表される化合物は、カルシウム、鉛に対して比較化合物ａを上回るキレート能を示し、また銀に対しては、比較化合物ａ、ｂ、ｃのすべてを上回るキレート能を示した。

As apparent from Table 2, the compound according to the present invention exhibits chelating ability with respect to calcium, lead and silver ions. In particular, the compound represented by Compound No. 3 showed a chelating ability that exceeded that of Comparative Compound a for calcium and lead, and showed a chelating ability that exceeded all of Comparative Compounds a, b, and c for silver. .

(Example 3) Evaluation of biodegradability The biodegradability test was performed according to the OECD test guideline 301 modified MITI test.

(Test conditions) Test sample concentration: 30 mg / l, activated sludge: standard activated sludge activated sludge concentration: 100 mg / l, test temperature: 25 ± 1 ° C., test period: 28 days For compound No. 3 and comparative compound a, biodegradation A sex test was performed. The results are shown in FIG. As is clear from FIG. 1, the compound represented by Compound No. 3 is readily degradable, and has a higher biodegradability than the comparative compound a known to be biodegradable, Degradation was observed from an early stage, and the biodegradability test result exceeded 60% in about 15 days.

It is a figure which shows the result of the biodegradability test obtained in Example 3.

Claims (2)

A chelating agent comprising an aminopolycarboxylic acid derivative represented by the following general formula (I):

[Wherein, M ₁ , M ₂ and M ₃ each represent a hydrogen atom or a cation.
R represents an alkyl group having 1 to 3 carbon atoms which may be substituted by a —COOM ₄ group, and M ₄ represents a hydrogen atom or a cation.
However, the case where R is —CH (COOM ₇ ) CH ₂ COOM ₈ (wherein M ₇ and M ₈ each represent a hydrogen atom or a cation) and a triphenylmethyl group is excluded. ]. In aminopolycarboxylic acid derivative according to claim 1, chelating agent, wherein R is _-CH 2 COOM _4.

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