JP4072430B2 - Process for producing 2-amino-3-carboxy-1,4-naphthoquinone - Google Patents
Process for producing 2-amino-3-carboxy-1,4-naphthoquinone Download PDFInfo
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- JP4072430B2 JP4072430B2 JP2002380372A JP2002380372A JP4072430B2 JP 4072430 B2 JP4072430 B2 JP 4072430B2 JP 2002380372 A JP2002380372 A JP 2002380372A JP 2002380372 A JP2002380372 A JP 2002380372A JP 4072430 B2 JP4072430 B2 JP 4072430B2
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- naphthoquinone
- carboxy
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Description
【０００１】
【発明の属する技術分野】
本発明は、極めて低濃度でビフィズス菌増殖促進活性を有する２−アミノ−３−カルボキシ−１，４−ナフトキノンの新規な製造方法に関するものである。
【０００２】
【従来の技術】
近年の研究で、各種消化管疾病等や老化に伴い、腸内のビフィズス菌（Bifido bacterium longum、B. breve、B. adolescentis、B. bifidum、B. infantis、B. animalis、B. pseudolongum等）が有意に低下すること、腸内ビフィズス菌の増殖を促進することが、発癌抑制、腸内腐敗の抑制、感染症の防止等に有効であることが確認されている。従って、腸内のビフィズス菌を選択的に増殖させることは、健康保持や各種成人病等の予防・治療の観点から極めて重要である。
ビフィズス菌の増殖を選択的に促進する物質としては、ある種のナフトキノン誘導体、中でもPropionibacterium属菌が菌体内外に産生する２−アミノ−３−カルボキシ−１，４−ナフトキノンが極めて低い濃度で強いビフィズス菌増殖促進活性を有することが知られている（特許文献１参照）。この２−アミノ−３−カルボキシ−１，４−ナフトキノンの製造については、１，４−ジヒドロキシ−２−ナフトエ酸を出発物質として４工程で製造する方法が知られている（特許文献２参照）。しかし、上記の製造方法においては、１，４−ジヒドロキシ−２−ナフトエ酸のメチル化剤として使用しているジアゾメタンが、爆発性を有し有毒なため取り扱いが困難であり、また、脱メチル化の過程で三臭化ホウ素を用いているが、目的物の単離が困難であるという問題点を有する。
【０００３】
【特許文献１】
特開平８−９８６７７号公報
【特許文献２】
特開平１０−３６３２８号公報
【０００４】
また、１，４−ジヒドロキシ−２−ナフトエ酸から３工程で、２−アミノ−３−カルボキシ−１，４−ナフトキノンを製造する方法も出願されている（特願２００１−２８４９７１号明細書）。
【０００５】
【発明が解決しようとする課題】
本発明の目的は、２−アミノ−３−カルボキシ−１，４−ナフトキノンを短工程で収率よく、大量かつ安価に製造する方法を提供することにある。
【０００６】
【課題を解決するための手段】
本発明者らは、２−アミノ−３−カルボキシ−１，４−ナフトキノンの製造方法について鋭意検討した結果、１，４−ジヒドロキシ−２−ナフトエ酸に、アミノ化化合物を反応させることにより、２−アミノ−３−カルボキシ−１，４−ナフトキノンをわずか一工程かつ高収率で製造できることを見出し、本発明を完成するに至った。
【０００７】
【発明の実施の形態】
本発明の製造方法は、例えば下記の反応式（１）で表すことができる。
【０００８】
【化１】
本発明の製造方法は、出発物質である１，４−ジヒドロキシ−２−ナフトエ酸にアミノ化化合物を反応させることにより、この化合物から一工程で２−アミノ−３−カルボキシ−１，４−ナフトキノンを製造する方法である。１，４−ジヒドロキシ−２−ナフトエ酸の自動酸化後の副反応を抑え、１，４−ジヒドロキシ−２−ナフトエ酸とアミノ化化合物との反応を優先させるべく、高濃度のアミノ化化合物を用いて実施する。１，４−ジヒドロキシ−２−ナフトエ酸は、商業的に入手容易な化合物である。
【００１０】
アミノ化化合物、即ち、アミノ化するための化合物としては、アンモニウム塩、アンモニアまたはアンモニウム塩とアンモニアとを組み合わせて使用することができる。アンモニウム塩は、塩化アンモニウムまたは水酸化アンモニウムであることが好ましい。具体的には、例えば、アンモニア水溶液に塩化アンモニウムを溶解させた水溶液を使用することが好ましい。
アンモニア水溶液中の塩化アンモニウムの濃度は、高濃度であることが好ましく、５０ｍＭ〜１Ｍの範囲であることがより好ましく、５００ｍＭ〜１Ｍの範囲であることが特に好ましい。
水溶液のｐＨは、８．０〜１０．０の範囲であることが好ましく８．５〜９．５の範囲であることがより好ましく、９．０であることが特に好ましい。
【００１１】
反応は、冷却下（例えば、―２０〜０℃の温度範囲）、常温下または加熱下（例えば、３０〜５０℃の温度範囲）にて行うことができるが、常温下で行うことが好ましい。
【００１２】
反応終了後、目的化合物は一般法に従って反応混合物より採取される。例えば、反応溶媒を留去することにより得られる。必要ならば再結晶、クロマトグラフィー等によりさらに精製することもできる。
【００１３】
【実施例】
以下に本発明を実施例によって具体的に説明するが、本発明はこれに限定されるものではない。
【００１４】
実施例１
２−アミノ−３−カルボキシ−１，４−ナフトキノンの製造
１Ｍの塩化アンモニウムのアンモニア水溶液（ｐＨ９．０）に１，４−ジヒドロキシ−２−ナフトエ酸（５００μＭ）を溶解させ、２５℃にて１時間攪拌した。反応終了後、１規定塩酸を加えｐＨ５に調整した後、酢酸エチルで抽出した。溶媒留去前の酢酸エチル溶液を、サイクリックボルタンメトリー（ＣＶ）、高速液体クロマトグラフィー（ＨＰＬＣ）［装置：LC-10ADVP chromatograph pump、DGU-12A degasser、Pheodyne 7125 sample injector、SPD-M10AVPR on-line photodyode array spectrophotometer、STR-ODS column（250×4.6mm）（いずれも（株）島津製作所製)、移動相：０．０８％トリフルオロ酢酸水溶液/０．１％トリフルオロ酢酸のアセトニトリル溶液＝１：１（ｖ/ｖ）、検出波長：４１８ｎｍ］、およびＥＩ−ＭＳで分析した結果、標品とよい一致を示した。
1H-NMR(400MHz,CDCl3)δ(ppm)
7.76(t,1H,J=7.56Hz);7.88(t,1H,J=7.59Hz);8.16(d,1H,J=7.74Hz);8.28(d,1H, J=7.71Hz);10.09(broad,1H)
また、１，４−ジヒドロキシ−２−ナフトエ酸のピークが消失し、標題化合物に相当するピークが現れたことにより、定量的に標題化合物に変換されていることが明らかとなった（図１）。
【００１５】
【発明の効果】
本発明の製造方法によれば、出発原料からわずか一工程で目的化合物を収率良く合成できる。また、有害な試薬を使用しないため、工業的な利用が可能である。
【図面の簡単な説明】
【図１】ＨＰＬＣのクロマトグラムを示す図である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel method for producing 2-amino-3-carboxy-1,4-naphthoquinone having bifidobacteria growth promoting activity at an extremely low concentration.
[0002]
[Prior art]
In recent studies, intestinal bifidobacteria (Bifido bacterium longum, B. breve, B. adolescentis, B. bifidum, B. infantis, B. animalis, B. pseudolongum, etc.) due to various gastrointestinal diseases and aging Has been confirmed to be effective in suppressing carcinogenesis, intestinal rot, preventing infections, and the like. Therefore, it is extremely important to selectively proliferate Bifidobacteria in the intestines from the viewpoint of maintaining health and preventing / treating various adult diseases.
As a substance that selectively promotes the growth of bifidobacteria, certain naphthoquinone derivatives, particularly 2-amino-3-carboxy-1,4-naphthoquinone produced by Propionibacterium spp. It is known to have a bifidobacteria growth promoting activity (see Patent Document 1). As for the production of 2-amino-3-carboxy-1,4-naphthoquinone, a method of producing it in 4 steps using 1,4-dihydroxy-2-naphthoic acid as a starting material is known (see Patent Document 2). . However, in the above production method, diazomethane used as a methylating agent for 1,4-dihydroxy-2-naphthoic acid is difficult to handle because it is explosive and toxic. In this process, boron tribromide is used, but there is a problem that it is difficult to isolate the target product.
[0003]
[Patent Document 1]
Japanese Patent Laid-Open No. 8-98677 [Patent Document 2]
Japanese Patent Laid-Open No. 10-36328
A method for producing 2-amino-3-carboxy-1,4-naphthoquinone from 1,4-dihydroxy-2-naphthoic acid in three steps has also been filed (Japanese Patent Application No. 2001-284971).
[0005]
[Problems to be solved by the invention]
An object of the present invention is to provide a method for producing 2-amino-3-carboxy-1,4-naphthoquinone in a short process with a high yield and in a large amount at a low cost.
[0006]
[Means for Solving the Problems]
As a result of intensive studies on a method for producing 2-amino-3-carboxy-1,4-naphthoquinone, the present inventors have made 2,4-dihydroxy-2-naphthoic acid react with an aminated compound. The inventors have found that amino-3-carboxy-1,4-naphthoquinone can be produced in only one step and in high yield, and have completed the present invention.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The production method of the present invention can be represented, for example, by the following reaction formula (1).
[0008]
[Chemical 1]
In the production method of the present invention, 1,4-dihydroxy-2-naphthoic acid which is a starting material is reacted with an aminated compound, whereby 2-amino-3-carboxy-1,4-naphthoquinone is produced from this compound in one step. It is a method of manufacturing. In order to suppress the side reaction after auto-oxidation of 1,4-dihydroxy-2-naphthoic acid and prioritize the reaction between 1,4-dihydroxy-2-naphthoic acid and aminated compound, a high concentration of aminated compound is used. To implement. 1,4-dihydroxy-2-naphthoic acid is a commercially available compound.
[0010]
As an aminated compound, that is, a compound for amination, an ammonium salt, ammonia, or a combination of an ammonium salt and ammonia can be used. The ammonium salt is preferably ammonium chloride or ammonium hydroxide. Specifically, for example, it is preferable to use an aqueous solution in which ammonium chloride is dissolved in an aqueous ammonia solution.
The concentration of ammonium chloride in the aqueous ammonia solution is preferably high, more preferably in the range of 50 mM to 1M, and particularly preferably in the range of 500 mM to 1M.
The pH of the aqueous solution is preferably in the range of 8.0 to 10.0, more preferably in the range of 8.5 to 9.5, and particularly preferably 9.0.
[0011]
The reaction can be performed under cooling (for example, a temperature range of −20 to 0 ° C.) at room temperature or under heating (for example, a temperature range of 30 to 50 ° C.), but is preferably performed at room temperature.
[0012]
After completion of the reaction, the target compound is collected from the reaction mixture according to a general method. For example, it can be obtained by distilling off the reaction solvent. If necessary, it can be further purified by recrystallization, chromatography or the like.
[0013]
【Example】
EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.
[0014]
Example 1
Preparation of 2-amino-3-carboxy-1,4-naphthoquinone 1,4-dihydroxy-2-naphthoic acid (500 μM) was dissolved in 1M ammonium chloride aqueous ammonia solution (pH 9.0), and the mixture was stirred at 25 ° C. for 1 Stir for hours. After completion of the reaction, 1N hydrochloric acid was added to adjust the pH to 5, followed by extraction with ethyl acetate. Before distilling off the solvent, the ethyl acetate solution was subjected to cyclic voltammetry (CV), high performance liquid chromatography (HPLC) [apparatus: LC-10ADVP chromatograph pump, DGU-12A degasser, Pheodyne 7125 sample injector, SPD-M10AVPR on-line photodyode array spectrophotometer, STR-ODS column (250 × 4.6 mm) (both manufactured by Shimadzu Corporation), mobile phase: 0.08% trifluoroacetic acid aqueous solution / 0.1% trifluoroacetic acid acetonitrile solution = 1: 1 (V / v), detection wavelength: 418 nm], and analysis by EI-MS showed good agreement with the standard.
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm)
7.76 (t, 1H, J = 7.56Hz); 7.88 (t, 1H, J = 7.59Hz); 8.16 (d, 1H, J = 7.74Hz); 8.28 (d, 1H, J = 7.71Hz); 10.09 ( broad, 1H)
In addition, the peak of 1,4-dihydroxy-2-naphthoic acid disappeared and the peak corresponding to the title compound appeared, which revealed that it was quantitatively converted to the title compound (FIG. 1). .
[0015]
【The invention's effect】
According to the production method of the present invention, the target compound can be synthesized with high yield from the starting material in only one step. In addition, since no harmful reagent is used, industrial utilization is possible.
[Brief description of the drawings]
FIG. 1 is a diagram showing a chromatogram of HPLC.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002380372A JP4072430B2 (en) | 2002-12-27 | 2002-12-27 | Process for producing 2-amino-3-carboxy-1,4-naphthoquinone |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002380372A JP4072430B2 (en) | 2002-12-27 | 2002-12-27 | Process for producing 2-amino-3-carboxy-1,4-naphthoquinone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2004210676A JP2004210676A (en) | 2004-07-29 |
| JP4072430B2 true JP4072430B2 (en) | 2008-04-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2002380372A Expired - Fee Related JP4072430B2 (en) | 2002-12-27 | 2002-12-27 | Process for producing 2-amino-3-carboxy-1,4-naphthoquinone |
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| Country | Link |
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| JP (1) | JP4072430B2 (en) |
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| Publication number | Publication date |
|---|---|
| JP2004210676A (en) | 2004-07-29 |
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