JPH0129177B2 - - Google Patents
Info
- Publication number
- JPH0129177B2 JPH0129177B2 JP59272021A JP27202184A JPH0129177B2 JP H0129177 B2 JPH0129177 B2 JP H0129177B2 JP 59272021 A JP59272021 A JP 59272021A JP 27202184 A JP27202184 A JP 27202184A JP H0129177 B2 JPH0129177 B2 JP H0129177B2
- Authority
- JP
- Japan
- Prior art keywords
- shikonin
- dihydroxy
- naphthoquinone
- acid halide
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 claims description 11
- 241001071917 Lithospermum Species 0.000 claims description 9
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 6
- 150000004820 halides Chemical class 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229910021536 Zeolite Inorganic materials 0.000 claims description 4
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 4
- 239000010457 zeolite Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000004558 dihydroxy-1,4-naphthoquinones Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000004585 5,8-dihydroxy-1,4-naphthoquinones Chemical class 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- FRASJONUBLZVQX-UHFFFAOYSA-N 1,4-naphthoquinone Chemical compound C1=CC=C2C(=O)C=CC(=O)C2=C1 FRASJONUBLZVQX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000010436 fluorite Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- KQPYUDDGWXQXHS-UHFFFAOYSA-N juglone Chemical compound O=C1C=CC(=O)C2=C1C=CC=C2O KQPYUDDGWXQXHS-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
〔産業上の利用分野〕
本発明は医薬等に有用な５，８−ジヒドロキシ
−１，４−ナフトキノン誘導体の新規な製法に関
する。
〔従来の技術〕
一般式〔〕
（Ｒは炭化水素基である。以下同じ。）で表わさ
れる５，８−ジヒドロキシ−１，４−ナフトキノ
ン誘導体の製法としては、西独特許公開公報
（Offenlegunsshnift）2831786に記載の方法、す
なわちシコニン〔２−（１−ヒドロキシ−４−メ
チル−３−ペンテン−１−イル）−５，８−ヒド
ロキシ−１，４−ナフトキノン〕のフエノール性
水酸基を特定の方法で保護したのち、酸ハロゲン
化物とシコニンの側鎖のアルコール性水酸基とを
反応させ、そのあと該保護を外す方法などが知ら
れている。しかしこの方法は工程数が多いため操
作が複雑であり、収率の点でも改善する余地があ
つた。
本発明者らはシコニンの誘導体の製法に関する
研究を進め、簡単な操作で収率よく５，８−ジヒ
ドロキシ−１，４−ナフトキノン誘導体を製造す
る方法を完成させた。
〔本発明の概要〕
すなわち本発明は、ゼオライトの存在下にシコ
ニンと酸ハロゲン化物RCOX（Ｒは炭化水素基、
Ｘはハロゲンを示す。）とを反応させることを特
徴とする一般式〔〕
（式中、Ｒは上記と同じ。）で表わされる５，８
−ジヒドロキシ−１，４−ナフトキノン誘導体の
製法に関するものである。
〔酸ハロゲン化物〕
本発明で使用する酸ハロゲン化物はRCOXで
表わされるものである。ここでＲは炭化水素基を
示し、例えばアルキル基、アリール基、アラルキ
ル基、シクロアルキル基、などを挙げることがで
きる。これらの中ではアルキル基であることが好
ましく、とくに炭素数１ないし12の直線状のもの
が好ましい。またハロゲンＸとしてはとくに塩素
であるものが好ましい。
〔ゼオライト〕
ゼオライトは別名フツ石と呼ばれ、合成品と天
然品があり、本発明においては合成品を用いるこ
とが好ましい。合成ゼオライトとしては、HClを
吸収し、シコニンを吸収しない孔径を有するもの
で、高品名「モレキユラシーブ」として市販され
ている3Aタイプ、4Aタイプ、5Aタイプ、13Xタ
イプなどを使用することが好ましい。
〔製造条件〕
反応は通常溶媒を用いる。この場合の溶媒とし
ては、反応に不活性なもの、例えばベンゼン、ト
ルエン、キシレンの如き芳香族炭化水素、塩化メ
チレン、クロロホルム、テトラクロロエタンの如
きハロゲン化炭化水素、エチルエーテル、プロピ
ルエーテル、テトラヒドロフラン、ジオキサンの
如きエーテル、酢酸エチル、酢酸プロピルの如き
エステルを使用することができ、これらの中では
酢酸エチルが好ましい。
反応条件としては、酸ハロゲン化物をシコニン
に対し0.5ないし10倍モル、好ましくは１ないし
５倍モル、モレキユラシーブをシコニン１ｇに対
し0.5ないし５ｇ用い、通常シコニンの濃度が
0.02ないし0.3モル／となるように溶媒中で反
応温度０ないし100℃、好ましくは20ないし70℃
にて１ないし100時間、好ましくは２ないし30時
間反応させる。
反応後は常法により目的物を分離、精製すれば
よい。
〔発明の効果〕
本発明によれば、シコニンより一般式〔〕で
表わされる５，８−ジヒドロキシ−１，４−ナフ
トキノン誘導体を一段の反応で効率よく製造する
ことができる。
〔実施例〕
以下実施例により本発明を具体的に説明する。
実施例 １
２−（１−アセトキシ−４−メチル−３−ペン
テン−１−イル）−５，８−ジヒドロキシ−１，
４−ナフトキノン（アチルシコニン）の合成
２−（１−ヒドロキシ−４−メチル−３−ペン
テン−１−イル）−５，８−ジヒドロキシ−１，
４−ナフトキノン（シコニン）432mgを酢酸エチ
ル25mlに溶解し、塩化アセチル236mgおよびモレ
キユラーシーブ4A 1.8ｇを加えて時々振りまぜ
ながら３日間常温で反応させた。酢酸エチルと未
反応の塩化アセチルを減圧下に留去し、残つた赤
色油状物を薄層クロマトグラフイーで分離して赤
色結晶376mgを得た。この結晶の融点、赤外線吸
収スペクトル、 1H−核磁気共鳴スペクトルはア
セチルシコニンの標品と一致した。収率76％。
実施例 ２〜５
実施例１と同様にして合成したシコニン誘導体
を表１に示した。
[Industrial Application Field] The present invention relates to a novel method for producing 5,8-dihydroxy-1,4-naphthoquinone derivatives useful in medicine and the like. [Prior art] General formula [] The 5,8-dihydroxy-1,4-naphthoquinone derivative represented by (R is a hydrocarbon group. The same applies hereinafter) is produced by the method described in Offenlegunsshnift 2831786, that is, Shikonin [2 After protecting the phenolic hydroxyl group of -(1-hydroxy-4-methyl-3-penten-1-yl)-5,8-hydroxy-1,4-naphthoquinone] by a specific method, the acid halide and shikonin A known method is to react with the alcoholic hydroxyl group of the side chain and then remove the protection. However, this method has a large number of steps and is complicated to operate, and there is room for improvement in terms of yield. The present inventors have conducted research on a method for producing shikonin derivatives, and have completed a method for producing 5,8-dihydroxy-1,4-naphthoquinone derivatives in good yield with simple operations. [Summary of the present invention] That is, the present invention provides shikonin and an acid halide RCOX (R is a hydrocarbon group,
X represents halogen. ) General formula characterized by reacting with (In the formula, R is the same as above.) 5,8
This invention relates to a method for producing -dihydroxy-1,4-naphthoquinone derivatives. [Acid halide] The acid halide used in the present invention is represented by RCOX. Here, R represents a hydrocarbon group, such as an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, and the like. Among these, alkyl groups are preferred, and linear ones having 1 to 12 carbon atoms are particularly preferred. Further, as the halogen X, chlorine is particularly preferred. [Zeolite] Zeolite is also called fluorite, and there are synthetic products and natural products, and it is preferable to use synthetic products in the present invention. The synthetic zeolite has a pore size that absorbs HCl but does not absorb shikonin, and it is preferable to use 3A type, 4A type, 5A type, 13X type, etc., which are commercially available under the high-quality name "Molecular Sieve". [Manufacturing conditions] A solvent is usually used in the reaction. In this case, solvents that are inert to the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as methylene chloride, chloroform, and tetrachloroethane, ethyl ether, propyl ether, tetrahydrofuran, and dioxane. Ethers such as, ethyl acetate, esters such as propyl acetate can be used, of which ethyl acetate is preferred. As for the reaction conditions, the acid halide is used at 0.5 to 10 times the mole of shikonin, preferably 1 to 5 times the mole, and 0.5 to 5 g of molecular sieve is used per 1 g of shikonin.
The reaction temperature is 0 to 100°C, preferably 20 to 70°C in a solvent so that the amount is 0.02 to 0.3 mol/
The reaction is carried out for 1 to 100 hours, preferably for 2 to 30 hours. After the reaction, the target product may be separated and purified by conventional methods. [Effects of the Invention] According to the present invention, a 5,8-dihydroxy-1,4-naphthoquinone derivative represented by the general formula [] can be efficiently produced from shikonin in a single reaction. [Example] The present invention will be specifically explained below with reference to Examples. Example 1 2-(1-acetoxy-4-methyl-3-penten-1-yl)-5,8-dihydroxy-1,
Synthesis of 4-naphthoquinone (acylshikonin) 2-(1-hydroxy-4-methyl-3-penten-1-yl)-5,8-dihydroxy-1,
432 mg of 4-naphthoquinone (shikonin) was dissolved in 25 ml of ethyl acetate, 236 mg of acetyl chloride and 1.8 g of molecular sieve 4A were added, and the mixture was allowed to react at room temperature for 3 days with occasional shaking. Ethyl acetate and unreacted acetyl chloride were distilled off under reduced pressure, and the remaining red oil was separated by thin layer chromatography to obtain 376 mg of red crystals. The melting point, infrared absorption spectrum, and 1 H-nuclear magnetic resonance spectrum of this crystal matched those of the standard acetylshikonine. Yield 76%. Examples 2 to 5 Shikonin derivatives synthesized in the same manner as in Example 1 are shown in Table 1.
【表】
実施例 ６
２−〔１−（３−メチルクロトノイルオキシ）−
４−メチル−３−ペンテン−１−イル〕−５，８
−ジヒドロキシ−１，４−ナフトキノンの合成
塩化アセチルの代りに塩化３−メチルクロトノ
イイルを用いた他は実施例１と同様にして２−
〔１−（３−メチルクロトノイルオキシ）−４−メ
チル−３−ペンテン−１−イル）−５，８−ジヒ
ドロキシ−１，４−ナフトキノンを得た。収率76
％。この化合物の融点、 1H−核磁気共鳴スペク
トルは標品と一致した。[Table] Example 6 2-[1-(3-methylcrotonoyloxy)-
4-methyl-3-penten-1-yl]-5,8
-Synthesis of dihydroxy-1,4-naphthoquinone 2-
[1-(3-Methylcrotonoyloxy)-4-methyl-3-penten-1-yl)-5,8-dihydroxy-1,4-naphthoquinone was obtained. Yield 76
%. The melting point and 1 H-nuclear magnetic resonance spectrum of this compound matched those of the standard product.
Claims (1)
化物RCOX（Ｒは炭化水素基、Ｘはハロゲンを示
す。）とを反応させることを特徴とする一般式
〔〕 （式中、Ｒは上記と同じ。）で表わされる５，８
−ジヒドロキシ−１，４−ナフトキノン誘導体の
製法。[Claims] 1. A general formula characterized by reacting shikonin with an acid halide RCOX (R is a hydrocarbon group and X is a halogen) in the presence of zeolite [] (In the formula, R is the same as above.) 5,8
-Production method of dihydroxy-1,4-naphthoquinone derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59272021A JPS61151151A (en) | 1984-12-25 | 1984-12-25 | Production of 5,8-dihydroxy-1,4-naphthoquinone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59272021A JPS61151151A (en) | 1984-12-25 | 1984-12-25 | Production of 5,8-dihydroxy-1,4-naphthoquinone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61151151A JPS61151151A (en) | 1986-07-09 |
| JPH0129177B2 true JPH0129177B2 (en) | 1989-06-08 |
Family
ID=17508021
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59272021A Granted JPS61151151A (en) | 1984-12-25 | 1984-12-25 | Production of 5,8-dihydroxy-1,4-naphthoquinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61151151A (en) |
-
1984
- 1984-12-25 JP JP59272021A patent/JPS61151151A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61151151A (en) | 1986-07-09 |
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