WO2011113284A1 - Shikonin naphthazarin derivatives, preparation method and antitumor use thereof - Google Patents

Shikonin naphthazarin derivatives, preparation method and antitumor use thereof Download PDF

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WO2011113284A1
WO2011113284A1 PCT/CN2010/080048 CN2010080048W WO2011113284A1 WO 2011113284 A1 WO2011113284 A1 WO 2011113284A1 CN 2010080048 W CN2010080048 W CN 2010080048W WO 2011113284 A1 WO2011113284 A1 WO 2011113284A1
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shikonin
hydrazine
carbon atoms
isomer
olefin
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李绍顺
周文
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上海交通大学
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Abstract

Shikonin naphthazarin derivatives represented by formula I and their preparation method are disclosed, wherein Ri~R4 and R are defined as in the description. The antitumor use of the compounds is also disclosed.

Description

紫草素萘茜衍生物、 其制备方法及其抗肿瘤的用途 技术领域  Shikonin naphthoquinone derivative, preparation method thereof and use thereof for antitumor
本发明涉及一种医药化工技术领域的化合物及其制备方法、用途， 具体是一种紫草素萘茜 母核氧^ ¾化衍生物及其制备方法、 用途。  The invention relates to a compound in the technical field of medicinal chemical industry, a preparation method thereof and a use thereof, in particular to a shikonin naphthoquinone mother nucleus oxygenation derivative, a preparation method thereof and a use thereof.
背景技术  Background technique
紫草为 《中华人民共和国药典》 收载的临床常用中药， 可分为硬紫草（Lithospermum erythrohizon), 又名东北紫草和软紫草 (A. euchroma Johnst) , 又名新疆紫草。 硬紫草中的 主要有效成分为紫草素及其衍生物，软紫草中含有阿卡宁及其衍生物， 紫草素和阿卡宁互为对 映异构体， 紫草素为 R构型， 阿卡宁为 S构型。这些成分均具有抗菌、抗炎、抗癌、 治疗烧烫 伤等作用。紫草素的抗肿瘤作用已被许多研究报道 ffi实，但由于它的毒副作用限制其临床应 用。 紫草素及其衍生物的萘茜（5， 8-二羟基 - 1， 4-萘醌）结构可能是引起毒副作用的原因之 现有技术的文献检索发现， 公开号为 CN1420111A的中国发明专利申请披露了一类萘 茜衍生物及其制备方法和用途，报道了该类化合物对端粒酶的抑制作用和抗肿瘤作用，这些化 合物是紫草素的侧链羟基的酰化衍生物； 专利申请 W0 97/03940披露了了一类新的 6-取代的 5, 8-二氧- 1, 4-萘醌衍生物的抗肿瘤作用， 这些化合物包括 5, 8-二氧^ ¾化产物， 但侧链是与 紫草素不同的焼¾ 公开号为 CN101139287的中国发明专利申请披露了紫草素二甲醚衍生物 的合成方法，但这些合成方法合成路线较长，不适于合成某些紫草素萘茜母核氧^ ¾化衍生物。 我们此前研究（乙酰紫草素及其类似物调控孤儿受体 Nur77介导凋亡通路， 癌症研究， 68: 8871-8880, 2008)发现乙酰紫草素母核氧乙酰化后生成三乙酰化合物毒性降低并具有独特抗肿 瘤机制： 诱导孤儿核受体 Nur77出核， 靶向定位线粒体并与 Be 2交互作用， 使之构象发生改 变， 释放细胞色素 C， 导致细胞凋亡。 因此， 紫草 核氧的 W可能是解决紫草 性问题 有效方法之一。  Lithospermum is a commonly used traditional Chinese medicine contained in the Pharmacopoeia of the People's Republic of China. It can be divided into Lithospermum erythrohizon, also known as A. euchroma Johnst, also known as Xinjiang Lithospermum. The main active ingredient in hard comfrey is shikonin and its derivatives, soft comfrey contains akanin and its derivatives, shikonin and akanin are enantiomers, and shikonin is R. Configuration, Akanin is S configuration. These ingredients have antibacterial, anti-inflammatory, anti-cancer, therapeutic burns and other effects. The anti-tumor effect of shikonin has been reported by many studies, but its clinical application is limited by its toxic side effects. The naphthoquinone (5,8-dihydroxy-1,4-naphthoquinone) structure of shikonin and its derivatives may be the cause of toxic side effects. The literature search found that the Chinese invention patent with the publication number CN1420111A The application discloses a class of naphthoquinone derivatives, preparation methods and uses thereof, and reports the inhibitory effect and antitumor effect of the compounds on telomerase, which are acylated derivatives of the side chain hydroxyl groups of shikonin; Application WO 97/03940 discloses the anti-tumor effect of a new class of 6-substituted 5,8-dioxo-1,4-naphthoquinone derivatives, which include 5,8-dioxochemical products, However, the side chain is different from shikonin. The Chinese Patent Application No. CN101139287 discloses a method for synthesizing shikonin dimethyl ether derivatives, but these synthetic methods have a long synthetic route and are not suitable for synthesizing some purple Nutrient naphthoquinone mother nucleus oxygenated derivative. Our previous study (acetyl shikonin and its analogues modulate the orphan receptor Nur77-mediated apoptosis pathway, Cancer Research, 68: 8871-8880, 2008) found triacetyl toxicity after oxyacetylation of acetyl-shikonin Reduced and has a unique anti-tumor mechanism: induces nuclear export of orphan nuclear receptor Nur77, targeting mitochondria and interacting with Be 2 to change its conformation and release cytochrome C, leading to apoptosis. Therefore, W of uranium nuclear oxygen may be one of the effective methods to solve the problem of comfrey.
发明内容  Summary of the invention
本发明的目的在于克服现 术的不足， 一种紫草素萘茜母核氧^ ¾化衍生物及其制 备方法、用途。本发明的化合物为新的紫草素衍生物， 与紫草素比较体外肿瘤细胞抑制试验显 示细胞毒作用降低或消失，动物体内抗肿瘤试验显示出一定的抑制肿瘤生长作用，可用于恶性 肿瘤的治 作为前药用于恶髓瘤的治疗。同时，本发明的涉及的制备方法所需的原料易得， 合成路线短。 The object of the present invention is to overcome the shortcomings of the prior art, a shikonin naphthoquinone mother nucleus oxygenated derivative, a preparation method thereof and use thereof. The compound of the present invention is a novel shikonin derivative, and the tumor cell inhibition test is in vitro compared with shikonin. It shows that the cytotoxicity is reduced or disappeared. The anti-tumor test in animals shows a certain inhibition of tumor growth, and can be used as a prodrug for the treatment of malignant tumors. At the same time, the raw materials required for the preparation method of the present invention are readily available and the synthesis route is short.
本发明是通过以下的技术方案实现的，  The present invention is achieved by the following technical solutions,
一方面， 本发明涉及一种紫草素萘茜母核氧^ ¾化衍生物， 其结构式具他 I所示：  In one aspect, the invention relates to a shikonin naphthoquinone mother nucleus oxygenated derivative, the structural formula of which is shown in Figure I:
Figure imgf000004_0001
其中， R为 H、 1〜10个碳原子的烷烃、烯烃、芳烃、 1〜10个碳含氧原子的烷烃、烯烃、 环烷烃、环烯烃或 C0R， ， R， 为 1〜10个碳原子的烷烃、烯烃、芳烃、 1〜10个碳含氧原子 的烷烃、烯烃、环烷烃、环烯烃；
Figure imgf000004_0001
Wherein R is H, an alkane of 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, a cycloalkane, a cyclic olefin or a COR, R, having 1 to 10 carbon atoms Alkanes, olefins, aromatic hydrocarbons, alkanes, olefins, cycloalkanes, cyclic olefins having 1 to 10 carbon oxygen atoms;
其中，
Figure imgf000004_0002
CHs, 具 结构式 Π麻， among them,
Figure imgf000004_0002
CHs, structured ramie,
Figure imgf000004_0003
或者 = R2 = R3 = c2a, 具飾结构式 m所示，
Figure imgf000004_0003
Or = R 2 = R 3 = c 2 a, as shown by the decorative structure m,
Figure imgf000004_0004
Figure imgf000004_0004
或者 R1 : R2 S CH2， 具 结构式 IV所示，
Figure imgf000005_0001
或者 = R2 = H， R3= ¾= CHs, 具体如结构式 V麻， V 或者 Or R 1 : R 2 S CH 2 , as shown in Structural Formula IV,
Figure imgf000005_0001
Or = R 2 = H, R 3 = 3⁄4 = CHs, as specific as structural V, V or
或者 或者 or
或者or
Figure imgf000005_0002
Figure imgf000005_0002
或者 = R2= R3= H， C2ft， 具飾结构式 X所示 X 或者 = R3 = =H, R2 = CH3, 具 结构式 Xl^f^, Or = R 2 = R 3 = H, C 2 ft, X with the decorative structure X Or = R 3 = =H, R 2 = CH 3 , with the structural formula Xl^f^,
或者 = R3 = =H, R2 = C2H5, 具飾结构式 ΧΠ麻，
Figure imgf000006_0001
。 Or = R 3 = =H, R 2 = C 2 H 5 , with structured ramie,
Figure imgf000006_0001
.
第二方面，本发明还涉及一种前述的紫草素萘茜母核氧^ ¾化衍生物在制备抗肿瘤药物中 的用途。  In a second aspect, the present invention also relates to the use of the aforementioned shikonin naphthoquinone mother nucleus oxygenated derivative for the preparation of an antitumor drug.
第三方面， 本发明还涉及一种前述的紫草素萘茜母核氧^ ¾化衍生物的制备方法， 制备如结构式 Π所示化合物的方法， 其中， R为 Η、 1〜10个碳原子的烷烃、 烯烃、 芳烃、 In a third aspect, the present invention relates to a method for preparing a shikonin naphthoquinone mother nucleus oxygenated derivative, which is a method for preparing a compound of the formula ,, wherein R is Η, 1 to 10 carbons. Atoms, alkenes, aromatics,
1〜10个碳含氧原子的烷烃、烯烃、环烷烃、环餘经或 C0R， ， R， 为 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； 1 to 10 carbon atoms containing an alkane, an olefin, a cycloalkane, a ring or a COR, R, an alkane having 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, Olefins, cycloalkanes, cyclic olefins;
Figure imgf000006_0002
Figure imgf000006_0002
， 包括如下步骤:  , including the following steps:
步骤一， 在氮气 W下， 将紫草素与 5当 *¾水碳酸钾混合， 溶于无水 Ν, Ν-二甲酰胺中， 加入 5当量的碘甲烷， 25Ό搅拌过夜， 得 5， 8-0"二甲基紫草素；  Step one, under a nitrogen gas, the shikonin is mixed with 5*3⁄4 water potassium carbonate, dissolved in anhydrous hydrazine, hydrazine-dimethylformamide, added with 5 equivalents of methyl iodide, and stirred at 25 Torr overnight to obtain 5, 8 -0" dimethyl shikonin;
步骤二，在氮气保护下，将 5， 8-0"二甲基紫草素溶于四氢呋喃的水溶液中，之后依次加入 5倍当量保险粉、 10当量的氢氧化钠、 10当量的硫酸二甲酯， 充分搅拌， 加热回流 24小时， 得 1, 4， 5, 8- 0"四甲基紫草素；  Step 2: Dissolve 5, 8-0" dimethylshikonin in an aqueous solution of tetrahydrofuran under nitrogen protection, and then add 5 times equivalent of insurance powder, 10 equivalents of sodium hydroxide, 10 equivalents of dimethyl sulfate. The ester is stirred well and heated under reflux for 24 hours to obtain 1,4,5, 8- 0"tetramethylshikonin;
步骤三，在氮气 W下，将 1， 4， 5， 8-0"四甲基紫草素溶于二氯甲烷中，在 Ν， Ν二甲基吡啶、 Ν, N'—二环己基碳二亚胺存在下，与有机酸缩合酯化得 1， 4， 5， 8—0"四甲基紫草素侧链酯衍生物， 即 R为 C0R, ； 或者在氮气 下， 将 1，4，5，8-0"四甲基紫草素溶于1^_二甲基甲酰胺中， 加入 1. 5倍当龍化钠， 充分搅拌， 然后滴入溴代物， 室温搅拌反应 12小时， # 1, 4, 5, 8-0- 四甲基紫草素侧链醚衍生物； 或義备如结构式 m所示化合物的方法， 其中， R为 H、 1〜10个碳原子的烷烃、 烯烃、 芳烃、Step 3, in a nitrogen W, 1, 4, 5, 8-0" tetramethylshikonin is dissolved in methylene chloride, in hydrazine, hydrazine lutidine, hydrazine, N'-dicyclohexyl carbon Condensation with an organic acid in the presence of a diimine to give 1,4,5,8-0" tetramethylshikonin side chain ester derivative, ie, R is COR; or under nitrogen, 1,4 5,8-0"tetramethylshikonin dissolved in 1 ^ dimethylformamide, added 1.5 times of sodium sulphate, stirred well, then added dropwise bromine, stirring at room temperature for 12 hours, # 1, 4, 5, 8-0- tetramethylshikonin side chain ether derivative; Or a method of formulating a compound of the formula m, wherein R is H, an alkane of 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon,
1〜10个碳含氧原子的烷烃、烯烃、环烷烃、环餘经或 C0R， ， R， 为 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； 1 to 10 carbon atoms containing an alkane, an olefin, a cycloalkane, a ring or a COR, R, an alkane having 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, Olefins, cycloalkanes, cyclic olefins;
Figure imgf000007_0001
Figure imgf000007_0001
， 包括如下步骤: , including the following steps:
步骤一， 在氮气 W下， 将紫草素与 5当 *¾水碳酸钾混合， 溶于无水 Ν, Ν-二甲酰胺中， 加入 5当量的碘乙烷， 25 搅拌过夜， 得 5， 8-0"二乙基紫草素；  In the first step, the shikonin is mixed with 5 as *3⁄4 water potassium carbonate under nitrogen gas, dissolved in anhydrous hydrazine, hydrazine-dimethylformamide, 5 equivalents of ethyl iodide is added, and 25 is stirred overnight to obtain 5, 8-0" diethyl shikonin;
步骤二，在氮气 W下，将 5， 8-0"二乙基紫草素溶于四氢呋喃的水溶液中，之后依次加入 5倍当量保险粉、 10当量的氢氧化钠、 10当量的硫酸二乙酯， 充分搅拌， 加热回流 24小时， 得 1, 4， 5, 8- 0"四乙基紫草素；  Step two, in a nitrogen W, 5, 8-0" diethyl shikonin is dissolved in an aqueous solution of tetrahydrofuran, followed by 5 times equivalent of insurance powder, 10 equivalents of sodium hydroxide, 10 equivalents of sulfuric acid diethyl ether The ester is stirred well and heated under reflux for 24 hours to obtain 1,4,5, 8- 0"tetraethylshikonin;
步骤三， 在氮气 下， 将 1, 4， 5， 8-0"四乙基紫草素溶于二氯甲烷中， 在 Ν, Ν-二甲基吡 啶、 Ν, Ν'—二环己基碳二亚胺存在下， 与有机酸缩合酯化得 1, 4， 5， 8—0"四乙基紫草素侧链酯衍 生物， 即 R为 C0R， ；或者在氮气 下，将 1, 4， 5， 8-0"四乙基紫草素溶于 Ν, Ν-二甲基甲酰胺 中，加入 1. 5倍当龍化钠，充分搅拌，然后滴入溴代物，室温搅拌反应 12小时，得 1， 4, 5， 8-0- 四乙基紫草素侧链醚衍生物；  Step 3, dissolving 1, 4, 5, 8-0" tetraethyl shikonin in methylene chloride under nitrogen, in hydrazine, hydrazine-lutidine, hydrazine, Ν'-dicyclohexyl carbon Condensation with an organic acid in the presence of a diimine to give 1,4,5,8-0" tetraethylshikonin side chain ester derivative, ie, R is COR; or under nitrogen, 1, 4 , 5, 8-0" tetraethyl shikonin dissolved in hydrazine, hydrazine-dimethylformamide, added 1.5 times of sodium sulphate, fully stirred, then added dropwise bromine, stirring reaction at room temperature for 12 hours , obtaining 1, 4, 5, 8-0-tetraethyl shikonin side chain ether derivative;
或義备如结构式 IV所示化合物的方法， 其中， R为 Η、 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、烯烃、环烷烃、环餘经或 C0R， ， R， 为 1〜10个碳原子的烷烃、 烯烃 〜10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； Or a method of formulating a compound of the formula IV, wherein R is an alkane of 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, a cycloalkane, a ring Or C0R, , R, an alkane of 1 to 10 carbon atoms, an alkane of 10 to 10 carbon atoms, an olefin, a cycloalkane, a cycloalkene;
Figure imgf000007_0002
Figure imgf000007_0002
1V ， 包括如下步骤： 1V , including the following steps:
步骤一，在氮气 W下，将紫草素与 15当 *¾水碳酸钾混合，溶于无水 Ν, Ν-二甲酰胺中， 加入 5当量二溴甲垸和催化量的碘化钾， 迅速升到 160 ， 反应 20分钟得到 1 :8, 4: 5-0"二亚 甲基紫草素； 步骤二，在氮气保护下，在 N， N二甲基吡啶、 N， N' -二环己基碳二亚胺存在下，将 1： 8， 4： 5-0" 二亚甲基紫草素与有机酸缩合酯化得 1： 8， 4: 5-0"二亚甲基紫草素侧链酯衍生物，即 R为 C0R， ； 或者在氮气 下， 将 1 :8, 4: 5-二亚甲基紫草素溶于 Ν, Ν-二甲基甲酰胺中， 加入 1. 5倍 当龍化钠， 充分搅拌， 然后滴入溴代物， 室温搅拌反应 12小时， 得 1 :8, 4: 5-0"二亚甲基紫 草素侧链醚衍生物； Step one, under argon, mix shikonin with 15 as *3⁄4 potassium carbonate, dissolve in anhydrous hydrazine, hydrazine-dimethylformamide, add 5 equivalents of dibromoformamidine and catalytic amount of potassium iodide, and rapidly rise. At 160, the reaction is carried out for 20 minutes to obtain 1:8, 4: 5-0" dimethylene shikonin; Step 2, under the protection of nitrogen, in the presence of N, N-dimethylpyridine, N, N'-dicyclohexylcarbodiimide, 1:8, 5-: 5-0" dimethylene shikonin Condensation with an organic acid to give a 1:8, 4-: 5-0" dimethylene shikonin side chain ester derivative, ie, R is COR; or under nitrogen, 1:8, 4: 5- Dimethylene shikonin is dissolved in hydrazine, hydrazine-dimethylformamide, added 1.5 times as sodium hydride, stirred well, then added dropwise to the bromine, and stirred at room temperature for 12 hours to obtain 1:8. 4: 5-0" dimethylene shikonin side chain ether derivative;
或義备如结构式 V所示化合物的方法， 其中， R为 Η、 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、烯烃、环烷烃、环餘经或 C0R， ， R， 为 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； Or a method of formulating a compound of the formula V, wherein R is an alkane of 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, a cycloalkane, a ring Or C0R, R, an alkane of 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon oxygen atoms, an olefin, a cycloalkane, a cyclic olefin;
Figure imgf000008_0001
Figure imgf000008_0001
， 包括如下步骤:  , including the following steps:
步骤一， 在氮气 W下， 将紫草素与 5当 *¾水碳酸钾混合， 溶于无水 Ν, Ν-二甲酰胺中， 滴加 5当魏甲醚， 反应 30分钟， 得到 5， 8-0"二甲氧甲基紫草素 2位异构体；  Step one, under a nitrogen gas, the shikonin is mixed with 5 as *3⁄4 water potassium carbonate, dissolved in anhydrous hydrazine, hydrazine-dimethylformamide, and added with 5 as a methyl methyl ether, and reacted for 30 minutes to obtain 5, 8- 0" dimethoxymethylshikonin 2 isomer;
步骤二，在氮气保护下，将 5， 8-0"二甲氧甲基紫草素溶于四氢呋喃的水溶液中，然后依次 加入 5倍当量保险粉、 10当量的氢氧化钠、 10当量的硫酸二甲酯， 充分搅拌， 回流 24小时， 得 1， 4-0"二甲基 -5， 8-0"二甲氧甲基紫草素；  Step two, under nitrogen protection, 5, 8-0" dimethoxymethylshikonin is dissolved in an aqueous solution of tetrahydrofuran, and then 5 times equivalent of insurance powder, 10 equivalents of sodium hydroxide, 10 equivalents of sulfuric acid are sequentially added. Dimethyl ester, stirred well, refluxed for 24 hours to give 1, 4-0" dimethyl-5, 8-0" dimethoxymethyl shikonin;
步骤三，在氮气 下，将 1, 4- 0"二甲 ¾"5， 8-0"二甲氧甲基紫草素溶于无水二氯甲烷中， 在 Ν, Ν二甲基吡啶、 Ν, Ν' -二环己基碳二亚胺存在下， 与有机酸缩合酯化得 1, 4- 0"二甲基 -5， 8-0"二甲氧甲基紫草素侧链酯衍生物；  Step 3, in a nitrogen atmosphere, 1, 4- 0" dimethyl 3⁄4" 5, 8-0" dimethoxymethyl shikonin is dissolved in anhydrous dichloromethane, in hydrazine, hydrazine pyridine, Ν, in the presence of Ν'-dicyclohexylcarbodiimide, condensed with an organic acid to give 1, 4- 0" dimethyl-5, 8-0" dimethoxymethyl shikonin side chain ester derivative Object
或者在氮气保护下， 将 1, 4- 0-二甲基 - 5, 8- 0"二甲氧甲基紫草素溶于 Ν，Ν_二甲基甲酰胺 中， 加入 1. 5倍当量氢化钠， 充分搅拌， 然后滴入溴代物， 室温搅拌反应 12小时， 得 1, 4- 0" 二甲 ¾"5， 8-0"二甲氧甲基紫草素侧链醚衍生物；  5倍当量。 Adding 1, 5- 0-dimethyl- 5, 8- 0" dimethoxymethyl shikonin in hydrazine, hydrazine dimethyl dimethyl amide, adding 1.5 times equivalent Sodium hydride, stirred well, then dropwise added bromine, and stirred at room temperature for 12 hours to obtain 1, 4- 0" dimethyl 3⁄4" 5, 8-0" dimethoxymethyl shikonin side chain ether derivative;
步骤四，将 1， 4-0-二甲基 -5， 8-0"二甲氧甲基紫草素侧链酯衍生物或 1， 4-0"二甲基 -5， 8-0- 二甲氧甲基紫草素侧链醚衍生物溶入异丙醇中，在酸作用下脱甲氧甲基， 即得结构式 V所示化 合物；  Step four, 1, 4-0-dimethyl-5, 8-0" dimethoxymethyl shikonin side chain ester derivative or 1, 4-0" dimethyl-5, 8-0- The dimethoxymethylshikonin side chain ether derivative is dissolved in isopropanol and demethoxymethylated under the action of an acid to obtain a compound of the formula V;
或義备如结构式 VI所示化合物的方法， 其中， R为 Η、 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、烯烃、环烷烃、环餘经或 C0R， ， R， 为 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃; Or a method of formulating a compound of the formula VI, wherein R is an alkane having 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, a cycloalkane, or a ring Or C0R, , R, an alkane of 1 to 10 carbon atoms, Olefins, aromatic hydrocarbons, alkanes, olefins, cycloalkanes, cyclic olefins having 1 to 10 carbon oxygen atoms;
Figure imgf000009_0001
Figure imgf000009_0001
V1 ， 包括如下步骤： V1 , including the following steps:
步骤一， 在氮气 W下， 将紫草素与 5当 *¾水碳酸钾混合， 溶于无水 Ν, Ν-二甲酰胺中， 滴加 5当魏甲醚， 反应 30分钟， 得到 5， 8-0"二甲氧甲基紫草素 2位异构体；  Step one, under a nitrogen gas, the shikonin is mixed with 5 as *3⁄4 water potassium carbonate, dissolved in anhydrous hydrazine, hydrazine-dimethylformamide, and added with 5 as a methyl methyl ether, and reacted for 30 minutes to obtain 5, 8- 0" dimethoxymethylshikonin 2 isomer;
步骤二，在氮气保护下，将 5， 8-0"二甲氧甲基紫草素溶于四氢呋喃的水溶液中，然后依次 加入 5倍当量保险粉、 10当量的氢氧化钠、 10当量的硫酸二乙酯， 充分搅拌， 回流 24小时， 得 1， 4- 0"二乙 ¾"5， 8-0"二甲氧甲基紫草素；  Step two, under nitrogen protection, 5, 8-0" dimethoxymethylshikonin is dissolved in an aqueous solution of tetrahydrofuran, and then 5 times equivalent of insurance powder, 10 equivalents of sodium hydroxide, 10 equivalents of sulfuric acid are sequentially added. Diethyl ester, stirred well, refluxed for 24 hours to obtain 1, 4- 0"diethyl 3⁄4"5, 8-0" dimethoxymethyl shikonin;
步骤三，在氮气 下，将 1, 4- 0"二乙 ¾"5， 8-0"二甲氧甲基紫草素溶于无水二氯甲烷中， 在 Ν, Ν二甲基吡啶、 Ν, Ν' -二环己基碳二亚胺作用下， 与有机酸缩合酯化得 1, 4- 0"二乙基 -5， 8-0"二甲氧甲基紫草素侧链酯衍生物；  Step 3: Dissolve 1, 4- 0"diethyl 3⁄4"5, 8-0" dimethoxymethylshikonin in anhydrous dichloromethane under nitrogen, in hydrazine, hydrazine pyridine, Ν, Ν'-dicyclohexylcarbodiimide, condensed with an organic acid to give 1, 4- 0" diethyl-5, 8-0" dimethoxymethyl shikonin side chain ester derivative Object
或者将 1， 4- 0"二乙 ¾"5， 8-0"二甲氧甲基紫草素溶于 Ν, Ν—二甲基甲酰胺中， 加入 1. 5倍 当 化钠， 充分搅拌， 然后滴入溴代物， 室温搅拌反应 12小时， 得 1, 4- 0"二乙 ¾"5，8- 0- 二甲氧甲基紫草素侧链醚衍生物；  Or agitating, 1. Then, the bromine is added dropwise, and the reaction is stirred at room temperature for 12 hours to obtain 1, 4- 0"diethyl 3⁄4"5,8- 0-dimethoxymethylshikonin side chain ether derivative;
步骤四，将 1， 4- 0-二乙 ¾"5， 8-0"二甲氧甲基紫草素侧链酯衍生物或 1， 4- 0"二乙 ¾"5， 8-0- 二甲氧甲基紫草素侧链醚衍生物溶入异丙醇中，在酸作用下脱甲氧甲基， 即得结构式 VI所示化 合物；  Step four, 1, 4- 0-diethyl 3⁄4"5, 8-0" dimethoxymethyl shikonin side chain ester derivative or 1, 4- 0" diethyl 3⁄4" 5, 8-0- The dimethoxymethylshikonin side chain ether derivative is dissolved in isopropanol and demethoxymethylated under the action of an acid to obtain a compound of the formula VI;
或義备如结构式 VII所示化合物的方法， 其中， R为 Η、 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、烯烃、环烷烃、环餘经或 C0R， ， R， 为 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； Or a method of formulating a compound of the formula VII, wherein R is an alkane having 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, a cycloalkane, or a ring Or C0R, R, an alkane of 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon oxygen atoms, an olefin, a cycloalkane, a cyclic olefin;
Figure imgf000009_0002
Figure imgf000009_0002
W ， 包括如下步骤： W , including the following steps:
在氮气保护下，将紫草素与 5当量无水碳酸钾混合，溶于无水 Ν, Ν-二甲基甲酰胺中，加入 Under the protection of nitrogen, shikonin is mixed with 5 equivalents of anhydrous potassium carbonate, dissolved in anhydrous hydrazine, hydrazine-dimethylformamide, and added.
5当量的碘甲烷， 25Ό搅拌过夜， 得到 5， 8-0"二甲基紫草素 2位异构体； 之后在氮气 下， 将 5， 8-0"二甲基紫草素 2位异构体溶于二氯甲烷中， 在 Ν, Ν二甲基吡啶、 Ν, Ν' -二环己基碳二 亚胺存在下， 与有机酸缩合酯化得 5， 8-0"二甲基紫草素 2位侧链酯衍生物； 5 equivalents of methyl iodide, 25 Torr stirred overnight to obtain the 2, 8-0" dimethylshikonin 2 isomer; then under nitrogen, Dissolving the 2, 8-0" dimethylshikonin 2 isomer in methylene chloride in the presence of hydrazine, hydrazine lutidine, hydrazine, Ν'-dicyclohexylcarbodiimide, The organic acid is condensed and esterified to obtain a 5-, 8-0" dimethylshikonin 2-position side chain ester derivative;
或者将 1， 4, 5， 8-0"四甲基紫草素侧链醚衍生物溶于乙腈中，搅拌，滴入硝酸铈铵的水溶液， 室温搅拌反应 0. 5小时， 得到 5， 8-0"二甲基紫草素侧链醚衍生物 2位异构体和 6位异构体； 或義备如结构式珊所示化合物的方法， 其中， R为 Η、 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、烯烃、环烷烃、环餘经或 C0R， ， R， 为 1〜10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃；  Or the 5, 8 is obtained, and the mixture is stirred at room temperature for 0.5 hours to obtain 5, 8 -0" a method for the 2-isomer and the 6-isomer of a dimethylshikonin side chain ether derivative; or a method of formulating a compound of the formula: wherein R is Η, 1 to 10 carbon atoms Alkane, olefin, aromatic hydrocarbon, alkane, olefin, cycloalkane, ring residue or COR, R, of 1 to 10 carbon atoms, alkane, olefin, aromatic hydrocarbon, 1 to 10 carbon atoms of 1 to 10 carbon atoms An alkane, an olefin, a cycloalkane or a cyclic olefin having an oxygen atom;
Figure imgf000010_0001
Figure imgf000010_0001
， 包括如下步骤:  , including the following steps:
在氮气保护下，将紫草素与 5当量无水碳酸钾混合，溶于无水 Ν, Ν-二甲基甲酰胺中，加入 5当量的碘乙烷， 25Ό搅拌过夜， 得到 5， 8-0"二乙基紫草素 2位异构体； 之后在氮气 下， 将 5， 8-0"二乙基紫草素 2位异构体溶于二氯甲烷中， 在 Ν, Ν二甲基吡啶、 Ν, Ν' -二环己基碳二 亚胺作用下，与有机酸缩合酯化得 5， 8-0"二乙基紫草素 2位侧链酯衍生物;或者将 1， 4， 5， 8-0- 四乙基紫草素侧链醚衍生物溶于乙腈中， 充分搅拌， 慢慢滴入硝酸铈铵水溶液， 室温搅拌反应 0. 5小时， 得到 5， 8-0"二乙基紫草素侧链醚衍生物 2位异构体和 6位异构体；  Under a nitrogen atmosphere, shikonin was mixed with 5 equivalents of anhydrous potassium carbonate, dissolved in anhydrous hydrazine, hydrazine-dimethylformamide, and 5 equivalents of ethyl iodide was added thereto, and stirred at 25 Torr overnight to obtain 5, 8- 0" diethyl shikonin 2 isomer; then, under nitrogen, 5, 8-0" diethyl shikonin 2 isomer is dissolved in dichloromethane, in hydrazine, hydrazine Under the action of pyridine, hydrazine, Ν'-dicyclohexylcarbodiimide, condensed with an organic acid to give a 5, 8-0" diethyl shikonin 2-position side chain ester derivative; or 1, 4 5小时的得到5, 8-0", 5, 8-0", 5, 8-0", 5, 8-0", 5, 8-0", 5, 8-0" 2-position isomer and 6-isomer of diethyl shikonin side chain ether derivative;
或義备如结构式 Κ所示化合物的方法， 其中， R为 Η或 C0R, ， R， 为 1〜10个碳原子的烷 烃、 1〜10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； Or a method of formulating a compound of the formula ,, wherein R is hydrazine or COR, R, an alkane of 1 to 10 carbon atoms, an alkane of 1 to 10 carbon atoms, an olefin, a cycloalkane, a ring Olefins;
Figure imgf000010_0002
Figure imgf000010_0002
κ ， 包括如下步骤:  κ , including the following steps:
步骤一，将紫草素与 5当量无水碳酸钾混合，溶于无水 Ν, Ν-二甲基甲酰胺中，在氮气保护 下， 加入 5当量的碘甲烷， 25Ό搅拌过夜， 得到 5， 8-0"二甲基紫草素 2位异构体；  Step 1, mixing shikonin with 5 equivalents of anhydrous potassium carbonate, dissolving in anhydrous hydrazine, hydrazine-dimethylformamide, adding 5 equivalents of methyl iodide under nitrogen, stirring 25 rpm overnight to obtain 5, 8-0" dimethylshikonin 2-isomer;
步骤二，在氮气 W下，将 5， 8-0"二甲基紫草素 2位异构体溶于无水二氯甲烷中，分别加 入过 粉、 10当量的三乙胺、 催化量的无水乙酸酐， 充分搅拌， 25Ό反应过夜， 得 5， 8-0" 二甲 ¾"1，4，1' — 0"三乙 ¾¾紫草素； 步骤三， 将 5， 8-0-二甲 ¾"1， 4, 1' -0"三乙難紫草素溶入乙腈中， 滴加硝酸铈铵的水溶 液， 脱甲基化得 5, 8, -0"三乙難紫草素 6 ; Step 2, under nitrogen gas, the 5, 8-0" dimethylshikonin 2 isomer is dissolved in anhydrous dichloromethane, respectively, added powder, 10 equivalents of triethylamine, catalytic amount Anhydrous acetic anhydride, stirred well, 25 Ό overnight, to give 5, 8-0" dimethyl 3⁄4"1,4,1' - 0" triethyl 3⁄43⁄4 shikonin; Step 3, 5, 8-0-dimethyl 3⁄4"1, 4, 1'-0" triethylene shikonin is dissolved in acetonitrile, and an aqueous solution of cerium ammonium nitrate is added dropwise to demethylate to obtain 5, 8 , -0" Sanyi difficult shikonin 6;
步骤四，将 5， 8, 1' -0"三乙酰基紫草素 6位异构体溶入甲醇与四氢呋喃混合溶液中，滴加 质量百分比为 5%碳酸钾的水溶液， 得紫草素- 8-0"单甲醚 6位异构体；  Step 4, the 5, 8, 1 '-0" triacetyl shikonin 6 isomer is dissolved in a mixed solution of methanol and tetrahydrofuran, and a mass percentage of 5% potassium carbonate aqueous solution is added dropwise to obtain shikonin- 8-0" monomethyl ether 6 isomer;
步骤五， 在氮气 下， 将紫草素- 8-0-单甲醚 6位异构体溶于二氯甲烷中， 在 Ν, Ν二甲 基吡啶、 Ν, Ν' -二环己基碳二亚胺存在下，与有机酸缩合酯化得紫草素 -8-0-单甲醚 6位异构体 酯衍生物；  Step 5. Dissolve the 6-isomer of shikonin 8-0-monomethyl ether in methylene chloride under nitrogen, in hydrazine, hydrazine dimethylpyridine, hydrazine, Ν'-dicyclohexyl carbon In the presence of an imine, condensed with an organic acid to obtain a shikonin-8-0-monomethyl ether 6-isomer ester derivative;
或義备如结构式 X所示化合物的方法， 其中， R为 Η或 C0R, ， R， 为 1〜10个碳原子的烷 烃、烯烃、芳烃、 1〜10个碳含氧原子的烷烃、烯烃、环烷烃、环烯烃； Or a method of formulating a compound of the formula X, wherein R is hydrazine or COR, R, an alkane having 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, Cycloalkane, cycloolefin;
Figure imgf000011_0001
Figure imgf000011_0001
， 包括如下步骤:  , including the following steps:
步骤一，将紫草素与 5当量无水碳酸钾混合，溶于无水 Ν, Ν-二甲基甲酰胺中，在氮气保护 下， 加入 5当量的碘甲烷， 25Ό搅拌过夜， 得到 5， 8-0"二甲基紫草素 2位异构体；  Step 1, mixing shikonin with 5 equivalents of anhydrous potassium carbonate, dissolving in anhydrous hydrazine, hydrazine-dimethylformamide, adding 5 equivalents of methyl iodide under nitrogen, stirring 25 rpm overnight to obtain 5, 8-0" dimethylshikonin 2-isomer;
步骤二，在氮气 W下，将 5， 8-0"二甲基紫草素 2位异构体溶于无水二氯甲烷中，分别加 入过 粉、 10当量的三乙胺、催化量的无水乙酸酐， 充分搅拌， 25Ό反应过夜， 得 5， 8-0" 二甲 ¾"1，4，1' — 0"三乙 ¾¾紫草素；  Step 2, under nitrogen gas, the 5, 8-0" dimethylshikonin 2 isomer is dissolved in anhydrous dichloromethane, respectively, added powder, 10 equivalents of triethylamine, catalytic amount Anhydrous acetic anhydride, stirred well, 25 Ό overnight, to give 5, 8-0" dimethyl 3⁄4" 1,4,1' - 0" triethyl 3⁄43⁄4 shikonin;
步骤三， 将 5， 8-0-二甲 ¾"1， 4, 1' -0"三乙難紫草素溶入乙腈中， 滴加硝酸铈铵的水溶 液， 脱甲基化得 5, 8, -0"三乙難紫草素 6 ;  Step 3, 5, 8-0-dimethyl 3⁄4"1, 4, 1' -0" triethylene shikonin is dissolved in acetonitrile, and an aqueous solution of cerium ammonium nitrate is added dropwise to demethylate to obtain 5, 8 , -0" Sanyi difficult shikonin 6;
步骤四，将 5， 8, 1' -0"三乙 紫草素 6位异构 # ^入乙醇与四氢呋喃混合溶液中，滴加 质量百分比为 5%碳酸钾的水溶液， 得紫草素- 8-0"单乙醚 6位异构体；  Step 4, 5, 8, 1 ' -0" triethyl shikonin 6 isomer # ^ into a mixed solution of ethanol and tetrahydrofuran, adding a mass percentage of 5% potassium carbonate aqueous solution, to obtain shikonin - 8 -0" monoether 6 isomer;
步骤五， 在氮气 下， 将紫草素- 8-0-单乙醚 6位异构体溶于二氯甲烷中， 在 Ν, Ν二甲 基吡啶、 Ν，Ν，-二环己基碳二亚胺存在下，与有机酸缩合酯化得紫草素 -8-0-单乙醚 6位异构体 酯衍生物；  Step 5. Dissolve the 6-position of shikonin 8-0-monoethyl ether in methylene chloride under nitrogen, in hydrazine, hydrazine lutidine, hydrazine, hydrazine, and dicyclohexylcarbodiimide. Condensation and esterification with an organic acid in the presence of an amine to obtain a shikonin-8-0-monoethyl ether 6-isomer ester derivative;
或義备如结构式 XI所示化合物的方法， 其中， R为 Η或 C0R, ， R， 为 1〜10个碳原子的烷 烃、烯烃、芳烃、 1〜10个碳含氧原子的烷烃、烯烃、环烷烃、环烯烃；
Figure imgf000012_0001
Or a method of formulating a compound of the formula XI, wherein R is hydrazine or COR, R, an alkane having 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, Cycloalkane, cycloolefin;
Figure imgf000012_0001
， 包括如下步骤:  , including the following steps:
步骤一， 将紫草素溶入无水乙酸酐中， 加入催化量的碘， 反应 10分钟， 得到 5， 8, 1， -0- 三乙酰紫草素 -2位异构体；  Step one, dissolving shikonin in anhydrous acetic anhydride, adding a catalytic amount of iodine, and reacting for 10 minutes to obtain 5,8,1 -0-triacetylshikonin - 2 isomer;
步骤二，将 5， 8， 1' -0"三乙酰紫草素 2位异构体溶入甲醇与四氢呋喃混合溶液中，滴加质 量百分比为 5%的碳酸钾的水溶液， 得到紫草素- 5-0"单甲醚 2位异构体；  In the second step, the 2,8 1 -0" triacetylshikonin 2 isomer is dissolved in a mixed solution of methanol and tetrahydrofuran, and a 5% by mass aqueous solution of potassium carbonate is added dropwise to obtain shikonin- 5-0"monomethyl ether 2 isomer;
步骤三， 在氮气 下， 将紫草素- 5-0-单甲醚 2位异构体溶于二氯甲烷中， 在 Ν, Ν二甲 基吡啶、 Ν，Ν，-二环己基碳二亚胺存在下，与有机酸缩合酯化得紫草素 -5-0-单甲醚侧链酯衍生 物 2位异构体；  Step 3, in the nitrogen, the shikonin 5-0-monomethyl ether 2 isomer is dissolved in dichloromethane, in hydrazine, hydrazine pyridine, hydrazine, hydrazine, dicyclohexyl carbon Condensation and esterification with an organic acid in the presence of an imine to obtain a 2-isomer of a shikonin-5-0-monomethyl ether side chain ester derivative;
或義备如结构式 ΧΠ所示化合物的方法， 其中， R为 Η或 C0R,， R， 为 1〜10个碳原子的烷 烃、 烯烃、 芳烃、 1〜10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； Or a method of formulating a compound of the formula ,, wherein R is hydrazine or COR, R, an alkane having 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, Cycloalkane, cycloalkene;
Figure imgf000012_0002
， 包括如下步骤:
Figure imgf000012_0002
, including the following steps:
步骤一， 将紫草素溶入无水乙酸酐中， 加入催化量的碘， 反应 10分钟， 得到 5， 8, 1， -0- 三乙酰紫草素 -2位异构体；  Step one, dissolving shikonin in anhydrous acetic anhydride, adding a catalytic amount of iodine, and reacting for 10 minutes to obtain 5,8,1 -0-triacetylshikonin - 2 isomer;
步骤二，将 5， 8， 1' -0"三乙酰紫草素 2位异构体溶入乙醇与四氢呋喃混合溶液中，滴加质 量百分比为 5%的碳酸钾的水溶液， 得到紫草素- 5-0"单乙醚 2位异构体；  In the second step, the 2,8 1 -0" triacetyl shikonin 2 isomer is dissolved in a mixed solution of ethanol and tetrahydrofuran, and a 5% by mass aqueous solution of potassium carbonate is added dropwise to obtain shikonin- 5-0" monoether 2 isomer;
步骤三， 在氮气 下， 将紫草素- 5-0-单乙醚 2位异构体溶于二氯甲烷中， 在 Ν, Ν二甲 基吡啶、 Ν，Ν，-二环己基碳二亚胺存在下，与有机酸缩合酯化得紫草素 -5-0-单乙醚侧链酯衍生 物 2位异构体。  Step 3, dissolving the 2-inomer of shikonin 5-0-monoethyl ether in dichloromethane under argon, hydrazine, hydrazine, hydrazine, hydrazine, dicyclohexylcarbodiimide In the presence of an amine, it is condensed with an organic acid to give a 2-isomer of the shikonin-5-0-monoethyl ether side chain ester derivative.
与现有技术相比， 本发明具有如下的有益效果： 本发明的化合物为新的紫草素衍生物， 与 紫草素比较， 体外肿瘤细胞抑制试验显示细胞毒作用降低或消失，动物体内抗肿瘤试验显示出 一定的抑制肿瘤生长作用， 可用于恶髓瘤的治疗。 同时， 本发明的涉及的制备方法所需的原 料易得， 合成路线短。 附图说明 Compared with the prior art, the present invention has the following beneficial effects: The compound of the present invention is a novel shikonin derivative, and compared with shikonin, the tumor cell inhibition test in vitro shows that the cytotoxic effect is reduced or disappeared, and the animal has antibiotic resistance. Tumor tests have shown a certain inhibition of tumor growth and can be used for the treatment of malignant lymphoma. At the same time, the raw materials required for the preparation method of the present invention are readily available and the synthesis route is short. DRAWINGS
图 1为紫草素萘茜母核氧^ ¾化衍生物的结构式；  Figure 1 is a structural formula of a ruthenium naphthoquinone mother nucleus oxygenated derivative;
图 2为紫草素 1, 4， 5， 8-四甲醚衍生物（结构式 Π )的制备路线图；  2 is a preparation route diagram of a shikonin 1, 4, 5, 8-tetramethyl ether derivative (structural formula Π);
图 3为紫草素 1, 4， 5， 8-四乙醚衍生物（结构式 ΠΙ)的制备路线图；  Figure 3 is a preparation route diagram of shikonin 1, 4, 5, 8-tetraethyl ether derivative (structural formula);
图 4为即紫草素 1 :8， 4:5-二亚甲醚衍生物（结构式 IV) 的制备路线图；  Figure 4 is a preparation route diagram of a shikonin 1 :8,4:5-dimethylene ether derivative (Structure IV);
图 5为紫草素 5， 8-二甲醚 6位异构体衍生物（结构式 V ) 的制备路线图；  Figure 5 is a schematic diagram showing the preparation route of the 6-isomer derivative of shikonin 5, 8-dimethyl ether (structural formula V);
图 6为紫草素 5， 8-二乙醚 6位异构体衍生物（,式 VI) 的制备路线图；  Figure 6 is a schematic diagram showing the preparation route of the leucovorin 5, 8-diethyl ether 6-isomer derivative (Formula VI);
图 7为紫草素 5， 8-二甲醚 2位异构体衍生物（,式 W) 的制备路线图；  Figure 7 is a roadmap for preparing a shikonin 5,8-dimethyl ether 2-isomer derivative (Formula W);
图 8为紫草素 5， 8-二乙醚 2位异构体衍生物（,式 VI) 的制备路线图；  Figure 8 is a schematic diagram showing the preparation route of the 2,2-diethyl ether 2-isomer derivative of shikonin (Formula VI);
图 9为紫草素 8-单甲醚 6位异构体衍生物（结构式 IX) 的制备路线图；  Figure 9 is a schematic diagram of the preparation of a shikonin 8-monomethyl ether 6-isomer derivative (formula IX);
图 10为紫草素 8-单乙醚 6位异构体衍生物（结构式 X ) 的制备路线图；  Figure 10 is a schematic diagram showing the preparation route of the shikonin 8-monoethyl ether 6-isomer derivative (structural formula X);
图 11为紫草素 5-单甲醚 2位异构体衍生物（结构式 XI) 的制备路线图；  Figure 11 is a roadmap for preparing a shikonin 5-monomethyl ether 2 isomer derivative (structural formula XI);
图 12为紫草素 5-单乙醚 2位异构体衍生物（结构式 Π) 的制备路线图。  Fig. 12 is a diagram showing the preparation route of a shikonin 5-monoethyl ether 2-isomer derivative (structural formula Π).
具体实 式  Specific form
以下实例将结合附图对本发明作进一步说明。本实施例在以本发明技术方案为前提下进行 实施， 给出了详细的实施方式和过程， 但本发明的保护范围不限于下述的实施例。下列实施例 中未注明具体条件的实验方法， 通常按照常规条件， 或按照制造厂商所建议的条件。  The invention will be further illustrated by the following examples in conjunction with the accompanying drawings. The present embodiment is implemented on the premise of the technical solution of the present invention, and detailed embodiments and processes are given, but the scope of protection of the present invention is not limited to the following embodiments. The experimental methods in which the specific conditions are not specified in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer.
前述结构式 Π所示的化合物（紫草素 1, 4， 5， 8-四甲醚衍生物） 的制备路线见图 2。  The preparation route of the compound represented by the above formula 紫 (shikonin 1, 4, 5, 8-tetramethyl ether derivative) is shown in Fig. 2.
前述结构式 ΠΙ所示的化合物（紫草素 1, 4， 5， 8—四乙醚衍生物） 的制备路线见图 3。  The preparation route of the compound represented by the above formula 紫 (shikonin 1, 4, 5, 8-tetraethyl ether derivative) is shown in Fig. 3.
前述结构式 IV所示的化合物（紫草素 1 :8， 4:5-二亚甲醚衍生物） 的制备路线见图 4。 前述结构式 V所示的化合物（紫草素 5， 8-二甲醚 6位异构体衍生物） 的制备路线见图 5。 前述结构式 VI所示的化合物（紫草素 5， 8—二乙醚 6位异构体衍生物） 的制备路线见图 6。 前述结构式 VII所示的化合物（紫草素 5， 8-二甲醚 2位异构体衍生物） 的制备路线见图 7。 前述结构式珊所示的化合物（紫草素 5， 8—二乙醚 2位异构体衍生物） 的制备路线见图 8。 前述结构式 Κ所示的化合物（紫草素 8-单甲醚 6位异构体衍生物） 的制备路线见图 9。 前述结构式 X所示的化合物（紫草素 8-单乙醚 6位异构体衍生物） 的制备路线见图 10。 前述结构式 XI所示的化合物（紫草素 5-单甲醚 2位异构体衍生物） 的制备路线见图 11。 前述结构式 ΧΠ所示的化合物（紫草素 5—单乙醚 2位异构体衍生物） 的制备路线见图 12。 实施例 1 1，4，5，8-四甲氧 ¾"2- (1-羟¾~4-甲¾~3-戊烯基)萘（Π- 1) 的制备 The preparation route of the compound of the above formula IV (shikonin 1:8, 4:5-dimethylene ether derivative) is shown in Fig. 4. The preparation route of the compound represented by the above structural formula V (shikonin 5, 8-dimethyl ether 6-isomer derivative) is shown in Fig. 5. The preparation route of the compound represented by the above formula VI (shikonin 5, 8-diethyl ether 6-isomer derivative) is shown in Fig. 6. The preparation route of the compound represented by the above formula VII (shikonin 5, 8-dimethyl ether 2-isomer derivative) is shown in Fig. 7. The preparation route of the compound represented by the aforementioned structural formula (shikonin 5, 8-diethyl ether 2-isomer derivative) is shown in Fig. 8. The preparation route of the compound represented by the aforementioned structural formula ( (shikonin 8-monomethyl ether 6-isomer derivative) is shown in Fig. 9. The preparation route of the compound represented by the above structural formula X (shikonin 8-monoethyl 6-isomer derivative) is shown in Fig. 10. The preparation route of the compound represented by the above structural formula XI (shikonin 5-monomethyl ether 2-isomer derivative) is shown in Fig. 11. The preparation route of the compound represented by the aforementioned structural formula ( (shikonin 5-monoethyl ether isomer derivative) is shown in Fig. 12. Example 1 Preparation of 1,4,5,8-tetramethoxy 3⁄4"2-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)naphthalene (Π-1)
步骤一， 在 25 ml反 中， 加入紫草素 (144 mg, 0.50 mmol)、 的碳酸钾 (690 mg, 5.0 mmol), DMF (15 ml) 、 KI (20 mg), 碘甲烷（0.16 ml, 2.5mmol)。 在氮气 »下， 室 温（25Ό)反应 24 h. 反应结束后， 加入水 (10 ml)稀释， 用乙酸乙酯（20 ml X 3)萃取， 萃取液用水（15 ml X 2)洗涤， 无水硫酸 #¾， 过滤， 浓缩至干， 得粗品 139 mg, 经 PTLC 分离，得 5， 8-二甲氧 ¾"2- (卜羟¾~4-甲¾~3-戊烯基 )- 1， 4-萘醌 (Vn-1)橙红色固体 121.0 mg, 收率为 76.6%。 熔点： 56〜59°C， IR (KBr)： 3457, 2930， 1652， 1571， 1475, 826 cm—1. ¾ MR (300 MHz, CDCls, δ ppm)： δ 7.32 (s， 2H， ΗΑ,), 6.79 (s， 1H， Hquin)， 5.17 (t, 1H， J=7.80 Hz, CH=)， 4.75 (t, 1H， J= 7.20 Hz, CH0)， 3.98 (s， 6H， 2 X0CH3), 2.45—2.31 (m， 2H， CH2)， 1.72 (s， 3H， CH3)， 1.62 (s， 3H， CH3). 13C NMR (75 MHz, CDCls, δ ppm)： δ 185.5， 185.1， 154.2， 153.8， 150.6， 136.7， 133.9， 120.9， 120.4， 119.1， 69.2， 57.1， 57.0， 35.7， 29.4， 26.1， 18.3. MS (ESI, %) : 339 (it + Na+, 31)， 371 (it + NaOCHs, 100)； Step one, in a 25 ml counter, add shikonin (144 mg, 0.50 mmol), potassium carbonate (690 mg, 5.0 mmol), DMF (15 ml), KI (20 mg), methyl iodide (0.16 ml, 2.5 mmol). The reaction was carried out at room temperature (25 Torr) for 24 h under nitrogen. After completion of the reaction, it was diluted with water (10 ml) and extracted with ethyl acetate (20 ml X 3). Sulfuric acid #3⁄4, filtered, concentrated to dryness to give 139 mg of crude material, which was isolated by PTLC to give 5, 8-dimethoxy 3⁄4"2- (dihydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1 4-naphthoquinone (Vn-1) orange red solid 121.0 mg, yield 76.6%. Melting point: 56~59 ° C, IR (KBr): 3457, 2930, 1652, 1571, 1475, 826 cm- 1 . 3⁄4 MR (300 MHz, CDCls, δ ppm): δ 7.32 (s, 2H, ΗΑ,), 6.79 (s, 1H, H quin ), 5.17 (t, 1H, J=7.80 Hz, CH=), 4.75 (t , 1H, J= 7.20 Hz, CH0), 3.98 (s, 6H, 2 X0CH 3 ), 2.45—2.31 (m, 2H, CH 2 ), 1.72 (s, 3H, CH 3 ), 1.62 (s, 3H, CH 3 ). 13 C NMR (75 MHz, CDCls, δ ppm): δ 185.5, 185.1, 154.2, 153.8, 150.6, 136.7, 133.9, 120.9, 120.4, 119.1, 69.2, 57.1, 57.0, 35.7, 29.4, 26.1, 18.3. MS (ESI, %): 339 (it + Na + , 31), 371 (it + NaOCHs, 100);
步骤二， 在氮气 下， 将化合物 VI— 1 (157 mg, 0.5 mmol)溶于水 /四氢呋喃 (1:4, V/V, 8 ml) 中， 25Ό下分别加入 5倍当量保险粉、 10当量的氢氧化钠、 10当量的硫酸二甲酯， 充分 搅拌。 半小时后， 升温回流 12 h， 冷却至室温， 向反应液中加入二氯甲烷， 二氯甲垸层分别用 水和饱和食盐水洗涤， 无水 MgS04 ， 减压蒸去二氯甲烷。 用硅胶柱层析， 乙酸乙酯:石油醚 (1:4， V/V)洗脱得 1，4，5，8-四甲氧¾"2-(1-羟¾"4-甲¾"3-戊烯基)萘（Π- 1)淡黄色油状 化合物 121.1 mg, 收率 70.4%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 7.02 (s， 1Η， ΗΑ,), 6.82 (s， 2Η， ΗΑ,), 5.33 (m， 2Η， CHO, CH=)， 3.95 (s， 6Η， 2 X 0CH3), 3.93 (s， 3Η， 0CH3), 3.76 (s， 3H， OCHs), 2.55—2.51 (m， 2H， CH2)， 1.72 (s， 3H， CH3) ， 1.65 (s， 3H， CH3). 13C NMR (75 MHz, CDCls, δ ppm)： δ 153.6， 151.7， 150.5， 146.8， 135.4, 134.2， 122.9， 120.5， 108.6， 108.1， 106.4, 68.8， 63.0， 58.6， 58.1， 57.4, 57.2， 37.4, 25.1， 18.2. MS (ESI, %)： 369 (it + Na+, 100)， 401 (it + NaOCHs, 38). Step 2: Compound VI-1 (157 mg, 0.5 mmol) was dissolved in water/tetrahydrofuran (1:4, V/V, 8 ml) under nitrogen, and 5 times equivalent of insurance powder, 10 equivalents were added under 25 Torr. Sodium hydroxide, 10 equivalents of dimethyl sulfate, stir well. After half an hour, heated at reflux for 12 h, cooled to room temperature, methylene chloride was added to the reaction mixture, of dichloromethane layers are washed with water and saturated brine, dried over anhydrous MgS0 4, methylene chloride was distilled off under reduced pressure. Chromatography on silica gel, ethyl acetate: petroleum ether (1:4, V/V) eluted to give 1,4,5,8-tetramethoxy 3⁄4"2-(1-hydroxy 3⁄4"4-methyl 3⁄4" 3-pentenyl)naphthalene (Π-1) pale yellow oily compound 121.1 mg, yield 70.4%. 3⁄4sa (300 MHz, CDCls, δ ppm): δ 7.02 (s, 1Η, ΗΑ,), 6.82 (s , 2Η, ΗΑ,), 5.33 (m, 2Η, CHO, CH=), 3.95 (s, 6Η, 2 X 0CH 3 ), 3.93 (s, 3Η, 0CH 3 ), 3.76 (s, 3H, OCHs), 2.55—2.51 (m, 2H, CH 2 ), 1.72 (s, 3H, CH 3 ) , 1.65 (s, 3H, CH 3 ). 13 C NMR (75 MHz, CDCls, δ ppm): δ 153.6, 151.7, 150.5, 146.8, 135.4, 134.2, 122.9, 120.5, 108.6, 108.1, 106.4, 68.8, 63.0, 58.6, 58.1, 57.4, 57.2, 37.4, 25.1, 18.2. MS (ESI, %): 369 (it + Na + , 100), 401 (it + NaOCHs, 38).
实施例 2  Example 2
1， 4, 5， 8-四甲氧 ¾"2- (1-酰氧 ¾"4-甲¾~3-戊烯基)萘的制备  Preparation of 1,4,5, 8-tetramethoxy 3⁄4"2-(1-acyloxy 3⁄4"4-methyl 3⁄4~3-pentenyl)naphthalene
步骤一及步骤二同实施例 1;  Step 1 and step 2 are the same as embodiment 1;
步骤三，将化合物 Π-1溶于干燥的二氯甲烷中，加入 2倍摩尔量的二环己基碳二亚胺 (DCC) 和催化量的 4-二甲胺基吡啶 (DMAP)和 2倍量的相应羧酸， 室温搅拌 2h。 向反应液中加入适量石 油醚过滤， 滤液经减压浓缩， 残留物用硅胶柱层析， 石油醚：乙酸乙酯 (4/1， V/V) 洗脱， 得 Π -1的酯类衍生物。 In step three, the compound Π-1 is dissolved in dry dichloromethane, and a 2-fold molar amount of dicyclohexylcarbodiimide (DCC) and a catalytic amount of 4-dimethylaminopyridine (DMAP) and 2 times are added. The corresponding carboxylic acid was stirred at room temperature for 2 h. The reaction mixture was filtered with EtOAc (EtOAc) (EtOAc) An ester derivative of -1.
以 ±¾方法制得 1，4，5，8-四甲氧¾"2-(1-乙酰氧¾"4-甲¾"3-戊烯基)萘（Π- 2)橙红色 油状化合物 40.2 mg， 收率为 71.9%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 6.87 (s， 1Η， ΗΑ,), 6.82 (s， 2Η， ΗΑ,), 6.34 (dd, 1Η， J=4.2, 6.0 Hz, CH=)， 6.15 (t, 1H， J=4.5Hz, CHO), 3.93 (s， 6H， 2X OCHs), 3.86 (s， 3H， 0CH3), 3.83 (s， 3H， 0CH3), 2,59—2.54 (m， 2H， CH2)， 2.10 (s， 3H， COCHs), 1.65 (s， 3H， CH3)， 1.55 (s， 3H， CH3). 13C MR (75 MHz, CDCls, δ ppm)： δ 170.4， 153.5， 151.6， 150.8， 147.1， 134.8， 130.9， 122.9， 120.9， 119.44, 109.0， 108.2， 105.6， 71.1， 62.7， 58.1， 57.7， 57.3， 34.8， 25.9， 21.5， 18.1. MS (ESI, %) : 411 (M++Na+, 100)， 443 (Ht+NaOCHs, 18)。 1,4,5,8-tetramethoxy 3⁄4"2-(1-acetoxy 3⁄4"4-methyl 3⁄4"3-pentenyl)naphthalene (Π-2) orange-red oily compound 40.2 was obtained by the method of ±3⁄4 Mg, yield 71.9%. 3⁄4萨 (300 MHz, CDCls, δ ppm): δ 6.87 (s, 1Η, ΗΑ,), 6.82 (s, 2Η, ΗΑ,), 6.34 (dd, 1Η, J=4.2 , 6.0 Hz, CH=), 6.15 (t, 1H, J=4.5Hz, CHO), 3.93 (s, 6H, 2X OCHs), 3.86 (s, 3H, 0CH 3 ), 3.83 (s, 3H, 0CH 3 ), 2,59-2.54 (m, 2H, CH 2 ), 2.10 (s, 3H, COCHs), 1.65 (s, 3H, CH 3 ), 1.55 (s, 3H, CH 3 ). 13 C MR (75 MHz, CDCls, δ ppm): δ 170.4, 153.5, 151.6, 150.8, 147.1, 134.8, 130.9, 122.9, 120.9, 119.44, 109.0, 108.2, 105.6, 71.1, 62.7, 58.1, 57.7, 57.3, 34.8, 25.9, 21.5 , 18.1. MS (ESI, %): 411 (M + +Na + , 100), 443 (Ht+NaOCHs, 18).
同法制得 1， 4, 5， 8-四甲氧 ¾"2- [1- (3-甲¾~2-丁烯酰氧基) - 4-甲¾~3-戊烯基]萘（Π- 3 ) 淡黄色的油状化合物 46.5 mg, 收率 75.2%。 ¾ NMR (300MHz, CDCls, δ ppm)： δ 6.88 (s， 1Η， ΗΑ,), 6.81 (s， 2Η， ΗΑ,), 6.34 (t, 1Η， J=6.0 Hz, CH2CH=), 5.85 (s， 1H， C0CH=), 5.15 (t, 1H， J=4.8Hz, CHO), 3.93 (s， 3H， 0CH3), 3.91 (s， 3H， 0CH3), 3.88 (s， 3H， 0CH3), 3.85 (s， 3H， OCHs), 2, 59-2.54 (m， 2H， CH2)， 2.13 (s， 3H， CH3)， 1.89 (s， 3H， CH3)， 1.64 (s， 3H， CH3), 1.54 (s， 3H， CH3) . 1,4,5, 8-tetramethoxy 3⁄4"2- [1-(3-methyl 3⁄4~2-butenoyloxy)-4-methyl 3⁄4~3-pentenyl]naphthalene (Π) - 3 ) Light yellow oily compound 46.5 mg, yield 75.2%. 3⁄4 NMR (300MHz, CDCls, δ ppm): δ 6.88 (s, 1Η, ΗΑ,), 6.81 (s, 2Η, ΗΑ,), 6.34 ( t, 1Η, J=6.0 Hz, CH 2 CH=), 5.85 (s, 1H, C0CH=), 5.15 (t, 1H, J=4.8Hz, CHO), 3.93 (s, 3H, 0CH 3 ), 3.91 (s, 3H, 0CH 3 ), 3.88 (s, 3H, 0CH 3 ), 3.85 (s, 3H, OCHs), 2, 59-2.54 (m, 2H, CH 2 ), 2.13 (s, 3H, CH 3 ), 1.89 (s, 3H, CH 3 ), 1.64 (s, 3H, CH 3 ), 1.54 (s, 3H, CH 3 ) .
同法制得 1，4，5，8-四甲氧 ¾"2- (1-肉桂酰氧¾~4-甲¾~3-戊烯基)萘（Π- 4) 淡黄色的油 状化合物 51.9 mg， 收率 80.1%. ¾ NMR (300MHz, CDCls, δ ppm)： δ 7.38- 7.21 (m， 5Η， ΗΑ,), 7.03 (s， 1Η， HAT), 6.84 (s， 2Η， ΗΑ,), 6.56 (d， 1Η， J=15.6Ηζ， C0CH=), 6.29 (d, 1Η， J=15.6Ηζ， =CHAr), 6.26 (s， 1Η， J=6.0 Hz, CH=)， 5.29 (t, 1H， J=4.8Hz, CHO), 3.94 (s， 6H， 2X OCHs), 3.90 (s， 3H， 0CH3), 3.74 (s， 3H， 0CH3), 2,60-2.50 (m， 2H， CH2) ， 1.66 (s， 3H， CH3), 1.55 (s， 3H， CHs). 1,4,5,8-tetramethoxy 3⁄4"2-(1-cinnamoyloxy 3⁄4~4-methyl 3⁄4~3-pentenyl)naphthalene (Π-4) pale yellow oily compound 51.9 mg , yield 80.1%. 3⁄4 NMR (300MHz, CDCls, δ ppm): δ 7.38- 7.21 (m, 5Η, ΗΑ,), 7.03 (s, 1Η, HAT), 6.84 (s, 2Η, ΗΑ,), 6.56 (d, 1Η, J=15.6Ηζ, C0CH=), 6.29 (d, 1Η, J=15.6Ηζ, =CHAr), 6.26 (s, 1Η, J=6.0 Hz, CH=), 5.29 (t, 1H, J=4.8Hz, CHO), 3.94 (s, 6H, 2X OCHs), 3.90 (s, 3H, 0CH 3 ), 3.74 (s, 3H, 0CH 3 ), 2,60-2.50 (m, 2H, CH 2 ), 1.66 (s, 3H, CH 3 ), 1.55 (s, 3H, CHs).
同法制得 1，4，5，8-四甲氧 ¾"2- [1- (2-呋喃甲酰氧基 )- 4-甲¾~3-戊烯基]萘（Π- 5 )淡黄 色的油状化合物 42.6 mg, 收率 69.2%。 ¾ NMR (300MHz, CDCls, δ ppm)： δ 7.59 (s， 1Η， HFu)， 7.23—7.20 (m, 2H， HFu)， 6.94 (s， 1H， H^), 6.83 (m, 2H， H^), 6.56 (m, 1H， CH=)， 5.20 (t, 1H， J=7.2Hz, CHO), 3.94〜3.86 (s， 12H， 4X0CH3), 2,69— 2.64 (m， 2H， CH2)， 1.65 (s， 3H， CHs), 1.58 (s， 3H， CH3) . The same method can be used to prepare 1,4,5,8-tetramethoxy 3⁄4"2-[1-(2-furoyloxy)-4-methyl 3⁄4~3-pentenyl]naphthalene (Π-5) light yellow Oily compound 42.6 mg, yield 69.2%. 3⁄4 NMR (300MHz, CDCls, δ ppm): δ 7.59 (s, 1 Η, H Fu ), 7.23 - 7.20 (m, 2H, H Fu ), 6.94 (s, 1H , H^), 6.83 (m, 2H, H^), 6.56 (m, 1H, CH=), 5.20 (t, 1H, J=7.2Hz, CHO), 3.94~3.86 (s, 12H, 4X0CH 3 ) , 2,69— 2.64 (m, 2H, CH 2 ), 1.65 (s, 3H, CHs), 1.58 (s, 3H, CH 3 ) .
同法制得 1， 4, 5， 8-四甲氧 ¾"2- [1- (3-呋喃甲酰氧基) -4-甲¾~3-戊烯基]萘（ Π - 6 )淡黄 色的油状化合物 35.9 mg, 收率 56.7%。 MR (300 MHz, CDCls, δ ppm)： δ 8.05 (s， 1Η， HFU), 7.24 (m， 1H， HFU)， 6.92 (m， 1H， HFU)， 6.82 (s， 2H， H^), 6.77 (s， 1H， H^), 6.52 (dd, 1H， J=2.7, 7.2 Hz, CH=)， 5.21 (t, 1H， J=7.5Hz, CH0)， 3.93-3.87 (s， 12H， 4X0CH3), 2.70—2.65 (m, 2H， CH2)， 1.66 (s， 3H， CH3)， 1.59 (s， 3H， CH3) . 1,4, 5, 8-tetramethoxy 3⁄4"2-[1-(3-furoyloxy)-4-methyl 3⁄4~3-pentenyl]naphthalene ( Π - 6 ) is light yellow Oily compound 35.9 mg, yield 56.7%. MR (300 MHz, CDCls, δ ppm): δ 8.05 (s, 1 Η, HFU), 7.24 (m, 1H, H FU ), 6.92 (m, 1H, H FU ), 6.82 (s, 2H, H^), 6.77 (s, 1H, H^), 6.52 (dd, 1H, J=2.7, 7.2 Hz, CH=), 5.21 (t, 1H, J=7.5Hz, CH0), 3.93-3.87 (s, 12H, 4X0CH 3 ), 2.70—2.65 (m, 2H, CH 2 ) , 1.66 (s, 3H, CH 3 ), 1.59 (s, 3H, CH 3 ) .
同法制得 1， 4， 5， 8-四甲氧基- 2- [1- (2-四氢呋喃甲酰氧基) -4-甲基- 3-戊烯基]萘（Π- 7) 40.7 mg淡黄色的油状化合物 40.7 mg, 收率为 63.7%. ¾ MR (300 MHz, CDCls, δ ppm)： δ 6.86 (s，lH， ΗΑ,), 6.82 (s， 2Η， ΗΑ,), 6.40 (m， 1Η， CH=)， 5.18 (t, 1Η， J=6.6 Hz, COCHO), 4.53 (t, 1H， J=4.8 Hz, CH0)， 4.02—3.84 (m， 14H, 4X0CH3, 0CH2), 2.58—2.55 (m， 2H， CH2)， 2.24-2.12 (m， 1H， CHaCH=), 1.95-1.88 (m， 3H， CH2, Cft CH=), 1.66 (s， 3H， CH3) 1.57 (s， 3H， CHs). 1,4,5, 8-tetramethoxy-2- [1-(2-tetrahydrofuroyloxy)-4-methyl-3-pentenyl]naphthalene (Π-7) 40.7 mg by the same method Light yellow oily compound 40.7 mg, yield 63.7%. 3⁄4 MR (300 MHz, CDCls, δ ppm): δ 6.86 (s,lH, ΗΑ,), 6.82 (s, 2Η, ΗΑ,), 6.40 (m , 1Η, CH=), 5.18 (t, 1Η, J=6.6 Hz, COCHO), 4.53 (t, 1H, J=4.8 Hz, CH0), 4.02—3.84 (m, 14H, 4X0CH 3 , 0CH 2 ), 2.58—2.55 (m, 2H, CH 2 ), 2.24-2.12 (m, 1H, CHaCH=), 1.95-1.88 (m, 3H, CH 2 , Cft CH=), 1.66 (s, 3H, CH 3 ) 1.57 (s, 3H, CHs).
同法制得 1,4， 5， 8-四甲氧 ¾"2-[l- (3-四氢呋喃甲酰氧基) -4， -甲 ¾~3' -戊烯]萘（Π- 8 ) 淡黄色的油状化合物 37.1 mg, 收率 58.1%。 ¾ MR (300 MHz, CDCls, δ ppm)： δ 6.84 (s， 1Η， ΗΑ,), 6.82 (s， 2Η， ΗΑ,), 5.37 (m， 1Η， CH=)， 5.15 (t, 1Η， J=6.6 Hz, CH0)， 4.01-3.79 (m， 16H， 4X0CH3, 2X0CH2), 3.14 (m, 1H， COCH), 2.60 -2.55 (m， 2H， CH2CH=)， 2.20-2.11 (m， 2H， CHCH2CH2), 1.66 (s， 3H， CH3) 1.56(s， 3H， CH3) . 1,4, 5, 8-tetramethoxy 3⁄4"2-[l-(3-tetrahydrofuroyloxy)-4, -methyl 3⁄4~3'-pentene]naphthalene (Π-8) Yellow oily compound 37.1 mg, yield 58.1%. 3⁄4 MR (300 MHz, CDCls, δ ppm): δ 6.84 (s, 1Η, ΗΑ,), 6.82 (s, 2Η, ΗΑ,), 5.37 (m, 1Η , CH=), 5.15 (t, 1Η, J=6.6 Hz, CH0), 4.01-3.79 (m, 16H, 4X0CH 3 , 2X0CH 2 ), 3.14 (m, 1H, COCH), 2.60 -2.55 (m, 2H , CH 2 CH=), 2.20-2.11 (m, 2H, CHCH 2 CH 2 ), 1.66 (s, 3H, CH 3 ) 1.56 (s, 3H, CH 3 ) .
实施例 3  Example 3
1， 4, 5， 8-四甲氧 ¾"2- (1-垸氧 ¾"4-甲¾~3-戊烯基)萘的制备  Preparation of 1,4, 5, 8-tetramethoxy 3⁄4"2-(1-oxo 3⁄4"4-methyl 3⁄4~3-pentenyl)naphthalene
步骤一及步骤二同实施例 1;  Step 1 and step 2 are the same as embodiment 1;
步骤三， 将 1，4，5，8-四甲氧 ¾"2- (1-羟¾~4-甲¾~3-戊烯基)萘（Π- 1)溶于 的 Ν,Ν— 二甲基甲酰胺中，加入 1.5倍当量的 NaH，充分搅拌 10分钟后，再加入 1.1倍当量相应的溴代 物，室温搅拌 12小时。向反应液中加入 10ml乙酸乙酯 ，然后分别用水、饱和食盐水洗涤， 用无水 MgS04干燥， 减压蒸去乙酸乙酯。粗产品用硅胶柱层析， 乙酸乙酯： 石油醚（1: 4)洗 脱得 Π- 1的醚类衍生物。 Step 3, dissolving 1,4,5,8-tetramethoxy 3⁄4"2-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)naphthalene (Π-1) in hydrazine, hydrazine - 2 To the methylformamide, 1.5 times equivalent of NaH was added, and after stirring for 10 minutes, 1.1 times equivalent of the corresponding bromine was added, and the mixture was stirred at room temperature for 12 hours. 10 ml of ethyl acetate was added to the reaction liquid, and then water and saturated salt were respectively used. washed with water, dried over anhydrous MgSO 4, evaporated under reduced pressure and ethyl acetate the crude product was chromatographed on silica gel with ethyl acetate: petroleum ether (1: 4) as eluent to give the Π- ether derivative.
用上述方法制得 1， 4, 5， 8-四甲氧基- 2- (1-甲氧基 -4-甲基- 3-戊烯基)萘（Π- 9)黄色油状 41.4mg, 收率 79.5%。 ¾NMR (300 MHz, CDCls, δ ppm)： 6.95 (s， 1Η， ΗΑ,), 6.83 (s， 2H， ΗΑ,), 5.26 (t, 1H， J=7.2Hz, CH=)， 4.85 (t, 1H， J=6.3Hz， CHO )， 3.95 (s， 6H， 2X0CH3), 3.90 (s， 3H， OCHs), 3.75 (s， 3H， 0CH3), 3.24 (s， 3H， CHOCft,), 2, 50 - 2.43 (m， 2H， - CH2)， 1.69 (s， 3H， CHs), 1.55 (s， 3H， CH3)。 4,4,5,8-tetramethoxy-2-(1-methoxy-4-methyl-3-pentenyl)naphthalene (Π-9) yellow oil was obtained by the method described above, The rate is 79.5%. 3⁄4 NMR (300 MHz, CDCls, δ ppm): 6.95 (s, 1Η, ΗΑ,), 6.83 (s, 2H, ΗΑ,), 5.26 (t, 1H, J=7.2Hz, CH=), 4.85 (t, 1H, J=6.3Hz, CHO ), 3.95 (s, 6H, 2X0CH 3 ), 3.90 (s, 3H, OCHs), 3.75 (s, 3H, 0CH 3 ), 3.24 (s, 3H, CHOCft,), 2 , 50 - 2.43 (m, 2H, - CH 2 ), 1.69 (s, 3H, CHs), 1.55 (s, 3H, CH 3 ).
同法制得 1，4，5，8-四甲氧基-2-(1-乙氧基-4-甲基-3-戊烯基）萘（11-10) 黄色油状 39. Omg，收率 72.1%。 ¾薩 (300 MHz, CDCls, δ ppm)： 6.97 (s, 1H， ΗΑ,), 6.61 (s， 2H， H^), 5.25 (t, 1H， J=5.1Hz, CH=)， 4.90 (t, 1H， J=5.4Hz, CH0 )， 3.92 (s， 6H， 2X0CH3), 3.88 (s， 3H， OCHs), 3.72 (s, 3H， 0CH3), 3.36 (m, 3H， 0CH2CH3) 2.50-2.45 (m， 2H， CH2)， 1.64 (s， 3H， CHs), 1.51 (s， 3H， CH3)， 1.25 (t, 3H， J=5.1Hz, 0CH2CH3) . O. The yield of 1,4,5,8-tetramethoxy-2-(1-ethoxy-4-methyl-3-pentenyl)naphthalene (11-10) as a yellow oil. 72.1%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 6.97 (s, 1H, ΗΑ,), 6.61 (s, 2H, H^), 5.25 (t, 1H, J=5.1Hz, CH=), 4.90 (t , 1H, J=5.4Hz, CH0 ), 3.92 (s, 6H, 2X0CH 3 ), 3.88 (s, 3H, OCHs), 3.72 (s, 3H, 0CH 3 ), 3.36 (m, 3H, 0CH 2 CH 3 ) 2.50-2.45 (m, 2H, CH 2 ), 1.64 (s, 3H, CHs), 1.51 (s, 3H, CH 3 ), 1.25 (t, 3H, J = 5.1 Hz, 0CH 2 CH 3 ).
同法制得 1，4，5，8-四甲氧基-2-(1-丙氧基-4-甲基-3-戊烯基）萘（11-11) 黄色油状 31.6mg, 收率 56.3%。 ¾NMR (300 MHz, CDCls, δ ppm)： 7.00 (s， 1Η， ΗΑ,), 6.84 (s， 2H， ΗΑ,), 5.30 (t, 1H， J=5.4Hz, CH=)， 4.90 (t, 1H， J=5.1Hz, CHO), 3.95 (s， 6H， 2X0CH3), 3.92 (s， 3H， OCHs), 3.76 (s， 3H， 0CH3), 3.30 (t, 2H， J=6.9Hz， 0 CH2CH2CH3) ， 2.53—2.46 (m， 2H， CH2)， 1.68 (s， 3H， CH3)， 1.54 (s， 3H， CH3)， 0.91-0.93 (m， 5H， CH2CH2CH3) . The same method can be used to prepare 1,4,5,8-tetramethoxy-2-(1-propoxy-4-methyl-3-pentenyl)naphthalene (11-11) as a yellow oil, 31.6 mg, yield 56.3 %. 3⁄4 NMR (300 MHz, CDCls, δ ppm): 7.00 (s, 1Η, ΗΑ,), 6.84 (s, 2H, ΗΑ,), 5.30 (t, 1H, J=5.4Hz, CH=), 4.90 (t, 1H, J=5.1Hz, CHO), 3.95 (s, 6H, 2X0CH 3 ), 3.92 (s, 3H, OCHs), 3.76 (s, 3H, 0CH 3 ), 3.30 (t, 2H, J=6.9Hz, 0 CH 2 CH 2 CH 3 ) , 2.53—2.46 (m, 2H, CH 2 ), 1.68 (s, 3H, CH 3 ), 1.54 (s, 3H, CH 3 ), 0.91-0.93 (m, 5H, CH 2 CH 2 CH 3 ) .
同法制得 1， 4, 5， 8-四甲氧 ¾"2- [1- (2-羟基乙氧基) - 4-甲¾~3-戊烯基]萘（Π- 12) 黄色油 状 19.5 mg， 收率 34.6%。 ¾薩 (300 MHz, CDCls, δ ppm)： 6.95 (s， 1Η， ΗΑ,), 6.83 (s， 2H， HA.), 5.34-5.18 (m， 1H， CH =)， 5.02—4.87 (m， 1H， OCH), 4.05—3.80 (m， 9H， 3X0CH3), 3.78—3.60 (m， 5H， 0CH3, 0CH2), 3.44 (t, /= 4.5Hz, 2H， 0CH2), 2.62—2.37 (m， 2H)， 2.20 (brs， 1H， OH), 1.67 (s， 3H， CH3)， 1.58 (s， 3H， CH3). 1,4, 5, 8-tetramethoxy 3⁄4"2-[1-(2-hydroxyethoxy)-4-methyl-3⁄4~3-pentenyl]naphthalene (Π-12) yellow oily 19.5 Mg, yield 34.6%. 3⁄4sa (300 MHz, CDCls, δ ppm): 6.95 (s, 1Η, ΗΑ,), 6.83 (s, 2H, HA.), 5.34-5.18 (m, 1H, CH =) , 5.02—4.87 (m, 1H, OCH), 4.05—3.80 (m, 9H, 3X0CH 3 ), 3.78—3.60 (m, 5H, 0CH 3 , 0CH 2 ), 3.44 (t, /= 4.5Hz, 2H, 0CH 2 ), 2.62—2.37 (m, 2H), 2.20 (brs, 1H, OH), 1.67 (s, 3H, CH 3 ), 1.58 (s, 3H, CH 3 ).
实施例 4  Example 4
1，4，5，8-四乙氧 ¾"2- (1-羟¾~4-甲¾~3-戊烯基)萘（ΠΙ- 1) 的制备  Preparation of 1,4,5,8-tetraethoxy 3⁄4"2-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)naphthalene (ΠΙ-1)
操作 同实施例 1， 步骤一反应中用碘乙 替碘甲烷， 步骤二反应中用硫酸二乙酯代 替硫酸二甲酯， 制得 ΠΙ- 1淡黄色油状化合物 102.4 mg， 收率 51.2%。 ¾ MR (300 MHz, CDCls, δ ppm)： δ 6.98 (s， 1H， ΗΑ,), 6.78 (s， 2H， H^), 5.19 (m， 2H， CHO, CH=)， 4.10-3.85 (m， 8H， 4X0CH2CH3), 2.53-2.49 (m， 2H， CH2)， 1.72 (s， 3H， CH3)， 1.66 (s， 3H， CH3)， 1.62〜 1.25 ( m， 12H， 4X0CH2CH3)o The operation was the same as in the first embodiment. In the first step, iodoethyl iodide was used in the reaction. In the second step, diethyl sulfate was used in place of dimethyl sulfate to obtain 102.4 mg of a bismuth-1 pale yellow oil compound, yield 51.2%. 3⁄4 MR (300 MHz, CDCls, δ ppm): δ 6.98 (s, 1H, ΗΑ,), 6.78 (s, 2H, H^), 5.19 (m, 2H, CHO, CH=), 4.10-3.85 (m , 8H, 4X0CH 2 CH 3 ), 2.53-2.49 (m, 2H, CH 2 ), 1.72 (s, 3H, CH 3 ), 1.66 (s, 3H, CH 3 ), 1.62~ 1.25 ( m, 12H, 4X0CH 2 CH 3 ) o
实施例 5  Example 5
1，4，5，8-四乙氧 ¾"2- (1-乙酰氧 ¾"4-甲¾~3-戊烯基)萘（ΠΙ- 2) 的制备  Preparation of 1,4,5,8-tetraethoxy 3⁄4"2-(1-acetoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)naphthalene (ΠΙ-2)
步骤一及步骤二同实施例 1;  Step 1 and step 2 are the same as embodiment 1;
步骤三， 按实施例 2步骤三的同样方法对化合物 m-i的羟基进行酯化， 制得 m- 2 ¾m色 色油状化合物 47.7 mg， 收率为 86.3%。 ¾薩 (300 MHz, CDCls, δ ppm): δ 6.88 (s， 1Η， ΗΑ,), 6.80 (s， 2Η， HA.), 6.31 (t, J=7.2Hz, CH=)， 5.12 (m， 1H， CHO), 4.14—3.96 (m， 8H， 4 X0CH2CHs), 2.59-2.54 (m， 2H， CH2)， 2.11 (s， 3H， C0CH3), 1.67 (s， 3H， CH3)， 1.60 (s， 3H， CHs), 1.55-1.26 ( m， 12H， 4X0CH2CH3)o Step 3, the hydroxyl group of the compound mi was esterified in the same manner as in the third step of Example 2 to obtain 47.7 mg of the m- 2 3⁄4m color oily compound. The yield was 86.3%. 3⁄4萨 (300 MHz, CDCls, δ ppm): δ 6.88 (s, 1Η, ΗΑ,), 6.80 (s, 2Η, HA.), 6.31 (t, J=7.2Hz, CH=), 5.12 (m, 1H, CHO), 4.14—3.96 (m, 8H, 4 X0CH 2 CHs), 2.59-2.54 (m, 2H, CH 2 ), 2.11 (s, 3H, C0CH 3 ), 1.67 (s, 3H, CH 3 ) , 1.60 (s, 3H, CHs), 1.55-1.26 ( m, 12H, 4X0CH 2 CH 3 ) o
实施例 6  Example 6
1， 4， 5， 8-四乙氧 ¾"2- (1-垸氧 ¾"4-甲¾~3-戊烯基)萘的制备 步骤一及步骤二同实施例 1; Preparation of 1,4, 5, 8-tetraethoxy 3⁄4"2-(1-oxo 3⁄4"4-methyl 3⁄4~3-pentenyl)naphthalene Step 1 and step 2 are the same as Embodiment 1;
步骤三， 按实施例 3步骤三的同样方法对化合物 m-i的羟基进行醚化。  Step 3, the hydroxyl group of the compound m-i was etherified in the same manner as in the third step of Example 3.
以 ±¾方法制得 1，4，5，8-四乙氧¾"2-(1-甲氧¾"4-甲¾"3-戊烯基)萘（ΠΙ- 3) 色油 状 51.7mg，收率 69.6%。 ¾薩 (300 MHz, CDCls, δ ppm) ： 6.94 (s, 1H， ΗΑ,), 6.81 (s, 2H， H^), 5.29 (t, 1H， J=6.9Hz, CH=)， 4.81 (t, 1H， J=6.9Hz, CH0)， 4.10—3.86 (m， 8H， 4X0CH2CH3), 3.22 (s， 3H， OCHs), 2.53-2.47 (m， 2H， CH2)， 1.69 (s， 3H， CH3)， 1.57 (s， 3H， CH3), 1.53-1.17 ( m， 12H， 4X0CH2CH3)。 51.7 mg of 1,4,5,8-tetraethoxy 3⁄4"2-(1-methoxy 3⁄4"4-methyl 3⁄4"3-pentenyl)naphthalene (ΠΙ-3) oil was obtained in a ±3⁄4 method. Yield 69.6%. 3⁄4sa (300 MHz, CDCls, δ ppm): 6.94 (s, 1H, ΗΑ,), 6.81 (s, 2H, H^), 5.29 (t, 1H, J=6.9Hz, CH= ), 4.81 (t, 1H, J=6.9Hz, CH0), 4.10-3.86 (m, 8H, 4X0CH 2 CH 3 ), 3.22 (s, 3H, OCHs), 2.53-2.47 (m, 2H, CH 2 ) , 1.69 (s, 3H, CH 3 ), 1.57 (s, 3H, CH 3 ), 1.53-1.17 ( m, 12H, 4X0CH 2 CH 3 ).
同法制得 1， 4， 5， 8-四乙氧基 -2- (1-乙氧基 -4-甲基 -3-戊烯基)萘 (m-4) 浅黄色油状 53.5mg, 收率 57.3%。 ¾ MR (300 MHz, CDCls, δ ppm) ： 6.96 (s， 1H， ΗΑ,), 6.80 (d， 2H， J=4.2Hz, HA.), 5.27 (t, 1H， J=6.3Hz, CH=)， 4.84 (t, 1H， J=6.3Hz, CH0)， 4.15—3.84 (m， 8H， 4X0CH2CH3), 3.33 (m， 2H， 0CH2CH3), 2.53—2.47 (t, 2H， J=6.3Hz， — CH2— )， 1.68 (s， 3H， CH3), 1.57 (s， 3H， CH3)， 1.56- 1.41 ( m， 15H， 5X0CH2(¾)。 1,4,5, 8-tetraethoxy-2-(1-ethoxy-4-methyl-3-pentenyl)naphthalene (m-4), pale yellow oil, 53.5mg, yield 57.3%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 6.96 (s, 1H, ΗΑ,), 6.80 (d, 2H, J=4.2Hz, HA.), 5.27 (t, 1H, J=6.3Hz, CH= ), 4.84 (t, 1H, J=6.3Hz, CH0), 4.15—3.84 (m, 8H, 4X0CH 2 CH 3 ), 3.33 (m, 2H, 0CH 2 CH 3 ), 2.53—2.47 (t, 2H, J = 6.3 Hz, — CH 2 — ), 1.68 (s, 3H, CH 3 ), 1.57 (s, 3H, CH 3 ), 1.56- 1.41 (m, 15H, 5X0CH 2 (3⁄4).
实施例 7  Example 7
2- (卜羟基- 4-甲¾~3-戊烯基 )- 1,8:4， 5-双 (亚甲二氧基)萘（IV- 1) 的制备  Preparation of 2-(Buhydroxy-4-methyl 3⁄4~3-pentenyl)-1,8:4, 5-bis(methylenedioxy)naphthalene (IV-1)
在 25ml反赚中， 加入紫草素 (100 mg, 0.35mmol)、 无水碳酸钾 (239.6 mg 1.74 mmol)、 碘化钾 (10 mg) 和 Ν,Ν-二甲基甲酰胺 (5 ml), 缓慢加入二溴甲烷 （0.5 ml), 滴加完毕后， 在 160Ό反应 12 h, 减压蒸除 DMF， 加入水和乙酸乙酯， 分出乙酸乙酯层， 浓缩至干， 得粗品 125.3 mg。经 PTLC纯化，得 2- (卜羟 ¾~4-甲¾~3-戊烯基 )- 1， 8:4， 5-双 (亚甲基二氧基)萘 78.9 mg, 收率 76.3%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 7.04 (s， 1Η， ΗΑ,), 6.82 (s， 2Η， J=3.0 Hz, HA.), 5.59—5.53 (t, 2H， J=4.8 Hz, 0CH20), 5.49—5.47 (t, 2H， J=3.6 Hz, 0CH20)， 5.21-5.11 (m， 2H， CH0， CH=)， 2.53-2.35 (m， 2H， CH2)， 1.73 (s， 3H， CH3)， 1.63 (s， 3H， CH3). 13C MR (75 MHz, CDCls, δ ppm)： δ 144.7, 144.6, 144.6, 140.6， 136.1， 125.3， 119.6， 115.1， 114.6， 109.1， 108.4， 107.0， 92.0， 91.78， 68.07， 37.13， 26.15， 18.23. MS (EI, m/e): 314 [M+]. In 25 ml of anti-earning, add shikonin (100 mg, 0.35 mmol), anhydrous potassium carbonate (239.6 mg 1.74 mmol), potassium iodide (10 mg) and hydrazine, hydrazine-dimethylformamide (5 ml), slowly Dibromomethane (0.5 ml) was added, and after completion of the dropwise addition, the mixture was reacted at 160 Torr for 12 hr, and DMF was evaporated under reduced pressure. Water and ethyl acetate were evaporated, and ethyl acetate layer was evaporated. Purification by PTLC gave 2-(b hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,8:4, 5-bis(methylenedioxy)naphthalene 78.9 mg, yield 76.3%. 3⁄4萨 (300 MHz, CDCls, δ ppm): δ 7.04 (s, 1Η, ΗΑ,), 6.82 (s, 2Η, J=3.0 Hz, HA.), 5.59-5.53 (t, 2H, J=4.8 Hz , 0CH 2 0), 5.49-5.47 (t, 2H, J=3.6 Hz, 0CH 2 0), 5.21-5.11 (m, 2H, CH0, CH=), 2.53-2.35 (m, 2H, CH 2 ), 1.73 (s, 3H, CH 3 ), 1.63 (s, 3H, CH 3 ). 13 C MR (75 MHz, CDCls, δ ppm): δ 144.7, 144.6, 144.6, 140.6, 136.1, 125.3, 119.6, 115.1, 114.6, 109.1, 108.4, 107.0, 92.0, 91.78, 68.07, 37.13, 26.15, 18.23. MS (EI, m/e): 314 [M+].
实施例 8  Example 8
2- (1-酰氧基 - 4-甲¾~3-戊烯基 )- 1， 8:4, 5-双 (亚甲二氧基)萘的制备  Preparation of 2-(1-acyloxy-4-methyl 3⁄4~3-pentenyl)-1,8:4, 5-bis(methylenedioxy)naphthalene
步骤一， 见实施例 7的制备纖  Step one, see the preparation fiber of Example 7.
步骤二， 在氮气保护下， 温度控制于 0〜5Ό， 将 2-(1， -羟基 -4， -甲基 -3， -戊烯 基)- 1,8 :4， 5-双 (亚甲二氧基)萘 (IV- 1) (100 mg, 0.32 mmol) 溶入无水二氯甲烷 (5 ml) 中， 加入 1.5当量的相应羧酸、 1.1当量的 DCC和催化量的 DMAP, 相同温度搅拌 2 h. 加入石油醚 (4 ml)使沉淀，过滤，减压浓缩二氯甲垸和石油醚得 品。 S ^品用硅胶柱层析， 乙酸乙酯: 石油醚（1/5， V/V)洗脱得到 IV- 1的酯衍生物。 Step 2, under nitrogen protection, the temperature is controlled at 0~5Ό, 2-(1,-hydroxy-4, -methyl-3,-pentenyl)-1,8:4, 5-double (methylene Dioxy)naphthalene (IV-1) (100 mg, 0.32 mmol) dissolved in anhydrous dichloromethane (5 ml) 1.5 equivalents of the corresponding carboxylic acid, 1.1 equivalents of DCC and a catalytic amount of DMAP were added, and the mixture was stirred at the same temperature for 2 h. A petroleum ether (4 ml) was added to precipitate, filtered, and dichloromethane and petroleum ether were concentrated under reduced pressure. The product was eluted with silica gel column chromatography, ethyl acetate: petroleum ether (1/5, V/V) to give the ester derivative of IV-1.
以 ±¾方法制得 2- α-乙酰氧 ¾"4-甲¾~3-戊烯基 )- 1， 8:4， 5-双 (亚甲二氧基)萘（IV- 2) 油状物 71.2 mg， 收率 62.8%。 薩 (300 MHz, CDCls, δ ppm)： δ 6.89 (s， 1Η， ΗΑ,), 2-α-Acetoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1,8:4, 5-bis(methylenedioxy)naphthalene (IV-2) oil was prepared in a ±3⁄4 method 71.2 mg, yield 62.8% Sa (300 MHz, CDCls, δ ppm): δ 6.89 (s, 1 Η, ΗΑ,),
6.82 (s， 2Η， ΗΑ,), 6.22 (t, 1Η， J=6.0 Hz, CH=)， 5.56—5.53 (t, 2H， J=4.8 Hz, 0CH20), 5.48-5.46 (t, 2H， J=4.5 Hz, 0CH20), 5.07 (m， 1H， CHO), 2.59—2.50 (m， 2H， CH2)， 2.09 (s， 3H， COCHs), 1.65 (s， 3H， CH3)， 1.55 (s， 3H， CH3)。 6.82 (s, 2Η, ΗΑ,), 6.22 (t, 1Η, J=6.0 Hz, CH=), 5.56-5.53 (t, 2H, J=4.8 Hz, 0CH 2 0), 5.48-5.46 (t, 2H , J=4.5 Hz, 0CH 2 0), 5.07 (m, 1H, CHO), 2.59—2.50 (m, 2H, CH 2 ), 2.09 (s, 3H, COCHs), 1.65 (s, 3H, CH 3 ) , 1.55 (s, 3H, CH 3 ).
同法制得 2-[l- (3， 3-二甲基丙烯酰氧基） - 4-甲¾~3-戊烯基 ]- 1， 8:4, 5-双 (亚甲二氧基) 萘（IV- 3) 油状物 73.9 mg, 收率 58.3%。 ¾ MR (300 MHz, CDCls, δ ppm)： δ 6.90 (s， 1Η， ΗΑ,), 6.82 (s， 2Η， ΗΑ,), 6.19 (t, 1Η， J=6.6Hz, CH=)， 5.56—5.52 (t, 2Η， J=4.8 Hz, 0CH20), 5.48-5.46 (t, 2H， J=5.7 Hz, 0CH20), 5.30 (s， 1H， C0CH=), 5.08 (m， 1H， CHO), 2.59-2.47 (m， 2H， CH2)， 2.12 (s， 3H， CH3)， 1.88 (s， 3H， CH3)， 1.63 (s， 3H， CH3)， 1.53 (s， 3H， CHs). 2-[l-(3,3-Dimethylacryloyloxy)-4-methyl-3⁄4~3-pentenyl]- 1, 8:4, 5-bis(methylenedioxy) was prepared by the same method. Naphthalene (IV-3) oil 73.9 mg, yield 58.3%. 3⁄4 MR (300 MHz, CDCls, δ ppm): δ 6.90 (s, 1Η, ΗΑ,), 6.82 (s, 2Η, ΗΑ,), 6.19 (t, 1Η, J=6.6Hz, CH=), 5.56— 5.52 (t, 2Η, J=4.8 Hz, 0CH 2 0), 5.48-5.46 (t, 2H, J=5.7 Hz, 0CH 2 0), 5.30 (s, 1H, C0CH=), 5.08 (m, 1H, CHO), 2.59-2.47 (m, 2H, CH 2 ), 2.12 (s, 3H, CH 3 ), 1.88 (s, 3H, CH 3 ), 1.63 (s, 3H, CH 3 ), 1.53 (s, 3H , CHs).
实施例 9  Example 9
2- (1-垸氧基 - 4-甲¾~3-戊烯基 )- 1， 8:4, 5-双 (亚甲二氧基)萘的制备  Preparation of 2-(1-decyloxy-4-methyl 3⁄4~3-pentenyl)-1,8:4, 5-bis(methylenedioxy)naphthalene
步骤一， 见实施例 7的制备纖  Step one, see the preparation fiber of Example 7.
步骤二， 按实施例 3步骤三的方法对化合物 IV- 1的羟基进行醚化。  Step 2, the hydroxyl group of Compound IV-1 was etherified according to the procedure of Step 3 of Example 3.
以 ±¾方法制得 2- (卜甲氧 ¾"4-甲¾~3-戊烯基 )- 1，8:4，5-双 (亚甲二氧基)萘（IV- 4)浅 黄油状物 40.8 mg, 收率 78.1%. ¾ MR (300 MHz, CDCls, δ ppm)： δ 6.97 (s， 1Η， ΗΑ, ), 6.87—6.77 (m， 2Η， ΗΑ,), 5.57—5.43 (m， 4Η， 0CH20), 5.20—5.07 (m， 1Η， CH= )， 4.73 (t, 1Η， J = 6.6 Hz, CHO), 3.30-3.17 (m， 3H， 0CH3), 2.60-2.27 (m， 2H， CH2)， 1.65 (s， 3H， CHs), 1.51 (s， 3H， CHs). 2-(B-methoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1,8:4,5-bis(methylenedioxy)naphthalene (IV-4) light buttery form by ±3⁄4 method 40.8 mg, yield 78.1%. 3⁄4 MR (300 MHz, CDCls, δ ppm): δ 6.97 (s, 1Η, ΗΑ, ), 6.87—6.77 (m, 2Η, ΗΑ,), 5.57-5.43 (m, 4Η, 0CH 2 0), 5.20—5.07 (m, 1Η, CH= ), 4.73 (t, 1Η, J = 6.6 Hz, CHO), 3.30-3.17 (m, 3H, 0CH 3 ), 2.60-2.27 (m , 2H, CH 2 ), 1.65 (s, 3H, CHs), 1.51 (s, 3H, CHs).
同法制得 2- a-乙氧 ¾"4-甲¾~3-戊烯基 )- 1，8:4，5-双 (亚甲二氧基)萘（IV- 5)献油状 物 39.4 mg， 收率 72.3%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 6.99 (s， 1Η， HA, ), 6.86—6.79 (m， 2H， HA, ), 5.56-5.45 (m， 4H， 0CH20), 5.18—5.09 (m， 1H， CH=)， 4.83 (t, 1H， J = 6.6 Hz, CHO), 3.39 (q, 2H， J = 6.9 Hz, 0CH2CH3), 2.59-2.33 (m， 2H， CH2)， 1.64 (s， 3H， CH3)， 1.50 (s， 3H， CHs), 1.18 (t, 3H， J = 6.9 Hz, 0CH2CH3) . 2-a-ethoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1,8:4,5-bis(methylenedioxy)naphthalene (IV-5) oil 39.4 mg by the same method , yield 72.3%. 3⁄4sa (300 MHz, CDCls, δ ppm): δ 6.99 (s, 1Η, HA, ), 6.86—6.79 (m, 2H, HA, ), 5.56-5.45 (m, 4H, 0CH 2 0), 5.18—5.09 (m, 1H, CH=), 4.83 (t, 1H, J = 6.6 Hz, CHO), 3.39 (q, 2H, J = 6.9 Hz, 0CH 2 CH 3 ), 2.59-2.33 (m, 2H, CH 2 ), 1.64 (s, 3H, CH 3 ), 1.50 (s, 3H, CHs), 1.18 (t, 3H, J = 6.9 Hz, 0CH 2 CH 3 ) .
同法制得 2- (1-丙氧 ¾"4-甲¾~3-戊烯基 )- 1， 8:4, 5-双 (亚甲二氧基)萘（IV- 6)献油状 物 39.3mg， 收率 69.3%。 ¾薩 (300 MHz, CDCls, δ ppm): δ 6.99 (s， 1H， ΗΑ,), 6.89— 6.76 (m， 2H， HA, ), 5.60—5.37 (m， 4H， 0CH20), 5.20—5.07 (m， 1H， CH= )， 4.81 (t, 1H， J = 6.6 Hz, CHO)， 3.28 (t, 2H， J = 6.6Hz， 0CH2CH2CH3 ), 2.59—2.27 (m， 2H， CH2)， 1.70—1.36 (m， 8H， 2XCH3, 0CH2CH2CH3), 0.90 (t, 3H， J = 6.6 Hz, 0CH2CH2CH3) . 2-(1-propoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1,8:4, 5-bis(methylenedioxy)naphthalene (IV-6) is obtained in the same manner. Mg, yield 69.3%. 3⁄4sa (300 MHz, CDCls, δ ppm): δ 6.99 (s, 1H, ΗΑ,), 6.89-6.76 (m, 2H, HA, ), 5.60—5.37 (m, 4H, 0CH 2 0), 5.20—5.07 (m, 1H, CH= ), 4.81 (t, 1H, J = 6.6 Hz, CHO), 3.28 (t, 2H , J = 6.6Hz, 0CH 2 CH 2 CH 3 ), 2.59—2.27 (m, 2H, CH 2 ), 1.70—1.36 (m, 8H, 2XCH 3 , 0CH 2 CH 2 CH 3 ), 0.90 (t, 3H , J = 6.6 Hz, 0CH 2 CH 2 CH 3 ) .
实施例 10  Example 10
5,8-二甲氧 ¾"6- (1-羟¾~4-甲¾~3-戊烯基 )- 1,4-萘醌 (V- 1) 的制备  Preparation of 5,8-Dimethoxy 3⁄4"6-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (V-1)
步骤一， 将紫草素 (100 mg, 0.347 mmol)溶于无水 DMF (10 ml) 中， 分别加 10倍当量 K2C03, 10倍当量新蒸馏氯甲醚， - 10 下搅拌反应 2 h. 过滤反应液中过量 K2C03， 用乙酸乙酯 反应液，分别用水和饱和食盐水洗涤，无水 MgS04 ，减压蒸去乙酸乙酯得 物 180.3 mg。粗产物用硅胶柱层析， 用乙酸乙酯:石油醚（1:2， V/V)洗脱得 5，8-二甲氧甲氧¾"2-(l- 羟¾"4-甲¾"3-戊烯基 )- 1， 4-萘醌， 橙黄色油状物 110.2 mg, 收率为 74.5%。 ¾薩 (300 MHz, CDCls, δ ppm): δ 7.47 (s， 2H， lU， 6.80 (s， 1H， Hqul„), 5.30—5.15 (m， 5H， CH=， 2X0CH20CH3), 4.76 (t, 1H， J=6.3 Hz, CH0)， 3.56 (s， 6H， 2X0CH20CH3), 2.55—2.39 (m， 2H， CH2)， 1.72 (s， 3H， CH3), 1.62 (s， 3H， CH3)， 13C MR (75 MHz, CDCls, δ ppm)： δ 185.1， 184.8， 152.6， 152.1， 136.7， 134.4, 125.6， 125.0， 119.1， 102.6， 96.3， 96.2， 68.9， 57.9， 56.9， 56.8， 35.7， 26.1， 18.3. MS (ESI, %) : 399 (Ht+Na', 100), 431 (Ht+NaOCHs, 49)； Step 1. Dissolve shikonin (100 mg, 0.347 mmol) in anhydrous DMF (10 ml), add 10 times equivalent of K 2 C0 3 , 10 times equivalent of freshly distilled chloromethyl ether, and stir the reaction under -10 h. the reaction mixture was filtered excess of K 2 C0 3, the reaction solution with ethyl acetate, washed with water and saturated brine, dried over anhydrous MgS0 4, evaporated under reduced pressure to give ethyl acetate was 180.3 mg. The crude product was chromatographed on silica gel eluting with ethyl acetate: petroleum ether (1:2, V/V) to give 5,8-dimethoxymethoxy 3⁄4"2-(l-hydroxy 3⁄4"4-methyl 3⁄4 "3-pentenyl"- 1, 4-naphthoquinone, an orange-yellow oil, 110.2 mg, yield 74.5%. 3⁄4sa (300 MHz, CDCls, δ ppm): δ 7.47 (s, 2H, lU, 6.80 (s, 1H, H qul „), 5.30—5.15 (m, 5H, CH=, 2X0CH 2 0CH 3 ), 4.76 (t, 1H, J=6.3 Hz, CH0), 3.56 (s, 6H, 2X0CH 2 0CH 3 ), 2.55—2.39 (m, 2H, CH 2 ), 1.72 (s, 3H, CH 3 ), 1.62 (s, 3H, CH 3 ), 13 C MR (75 MHz, CDCls, δ ppm): δ 185.1 , 184.8, 152.6, 152.1, 136.7, 134.4, 125.6, 125.0, 119.1, 102.6, 96.3, 96.2, 68.9, 57.9, 56.9, 56.8, 35.7, 26.1, 18.3. MS (ESI, %) : 399 (Ht+Na' , 100), 431 (Ht+NaOCHs, 49);
步骤二， 在氮气保护下， 将 5,8-二甲氧甲氧 ¾"2- (1-羟基- 4-甲¾~3-戊烯基 )- 1,4-萘醌 (50 mg, 0.13 mmol)溶于水 /四氢呋喃 (1:4, V/V, 8 ml) 中， 25Ό下分别加入 5倍当量保险 粉、 10当量的氢氧化钠、 10当量的硫酸二甲酯， 充分搅拌。 半小时后， 升温回流 12 h, 冷却 至室温， 向反应液中加入二氯甲烷， 分别用水和饱和食盐水洗涤， 无水 MgS04fl , 减压蒸去 二氯甲烷。 得 品 61.2 mg， 用硅胶柱层析， 乙酸乙酯:石油醚（1:4， V/V)洗脱得到 2- (1- 经¾~4-甲¾~3-戊烯基 )- 1， 4-二甲氧 ¾"5， 8-二甲氧甲氧基萘淡黄色油状化合物 38.0 mg,收率 70.4%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 7.21—6.08 (m， 3Η， Η^), 5.28—5.14 (m， 6Η， CH=， CHO, 2X0CH20CH3), 3.94—3.77 (s， 6H， 2X0CH3), 3.57—3.56 (s， 6H， 2X0CH20CH3), 2.61—2.50 (m， 2H， CH2)， 1.74 (s， 3H， CH3)， 1.68 (s， 3H， CH3). 13C NMR (75 MHz, CDCls, δ ppm)： δ 153.3， 149.5， 148.9， 146.4, 135.6， 134.0， 120.4， 116.2， 115.2， 105.7， 98.2， 97.7， 68.7， 63.0， 57.1， 56.7， 56.6， 37.6， 26.1， 18.2. MS (ESI, %) : 429 (it + Na+, 100)， 461 (M+ + NaOCHs, 13)； Step 2, 5,8-Dimethoxymethoxy 3⁄4"2-(1-hydroxy-4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (50 mg, 0.13) under nitrogen protection Methyl) is dissolved in water/tetrahydrofuran (1:4, V/V, 8 ml), and 5 times equivalent of insurance powder, 10 equivalents of sodium hydroxide, 10 equivalents of dimethyl sulfate are added under 25 Torr, and stirred well. after hours, heated at reflux for 12 h, cooled to room temperature, the reaction mixture was added dichloromethane, washed with water and saturated brine, dried over anhydrous MgS0 4 fl, methylene chloride was distilled off under reduced pressure. goods obtained 61.2 mg, purified by silica gel Column chromatography, ethyl acetate: petroleum ether (1:4, V/V) eluted to give 2-(1-3⁄4~4-methyl 3⁄4~3-pentenyl)- 1, 4-dimethoxy 3⁄4 "5, 8-Dimethoxymethoxynaphthalene light yellow oily compound 38.0 mg, yield 70.4%. 3⁄4萨(300 MHz, CDCls, δ ppm): δ 7.21—6.08 (m, 3Η, Η^), 5.28—5.14 (m, 6Η, CH=, CHO, 2X0CH 2 0CH 3 ), 3.94—3.77 (s, 6H, 2X0CH 3 ), 3.57—3.56 (s, 6H, 2X0CH 2 0CH 3 ), 2.61—2.50 (m, 2H, CH 2 ), 1.74 (s, 3H, CH 3 ), 1.68 (s, 3H, CH 3 13 C NMR (75 MHz, CDCls, δ ppm): δ 153.3, 149.5, 148.9, 146.4, 135.6, 134.0, 120.4, 116.2, 115.2, 105.7, 98.2, 97.7, 68.7, 63.0, 57.1, 56.7, 56.6, 37.6, 26.1, 18.2. MS (ESI, %): 429 (it + Na + , 100), 461 (M + + NaOCHs, 13);
步骤三， 将 2- (1-羟基- 4-甲基- 3-戊烯基) -1， 4-二甲氧基 -5， 8-二甲氧甲氧基萘 (30mg, 0.07 mmol) 溶于四氢呋喃 (2 ml) 和异丙醇 (2 ml) 中， 加醋酸 （0.5 ml), 在 25Ό下， 搅 拌 12 h。减压蒸除四氢呋喃和异丙醇，加入碳酸钠溶液中和过量的酸，用乙酸乙酯稀释反应液， 分别用水和饱和食盐水洗涤， 无水 MgS04fl , 减压蒸去乙酸乙酯得 物 21.2 mg. 物 用硅胶柱层析， 用乙酸乙酯:石油醚（1/4， V/V)洗脱得到化合物 (V-1)橙黄色油状 15.3 mg, 收率为 65.5%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 7.55 (s， 1Η， ΗΑ,), 6.79 (s， 2Η， HQUIN)， 5.24 (m， 1Η， CH=)， 5.10 (t, 1H， J=5.7 Hz, CH0)， 3.97 (s， 3H， 0CH3), 3.89 (s， 3H， 0CH3), 2.35-2.19 (m， 2H， CH2)， 1.76 (s， 3H， CH3)， 1.65 (s， 3H， CH3). 13C MR (75 MHz, CDCls, δ ppm)： δ 185.1， 184.5， 156.5， 150.9， 147.9， 139.2， 137.9， 136.9， 125.1， 68.8， 62.4, 56.9， 37.2， 26.09， 18.21。 Step 3: Dissolve 2-(1-hydroxy-4-methyl-3-pentenyl)-1,4-dimethoxy-5,8-dimethoxymethoxynaphthalene (30 mg, 0.07 mmol) In tetrahydrofuran (2 ml) and isopropanol (2 ml), add acetic acid (0.5 ml), stir at 25 Torr. Mix for 12 h. Tetrahydrofuran was evaporated under reduced pressure, and isopropyl alcohol was added sodium carbonate and an excess of acid, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous MgS0 4 fl, ethyl acetate was distilled off under reduced pressure to give The title compound (V-1) was obtained as an orange-yellow oil (yield: 65.5%). 3⁄4萨(300 MHz, CDCls, δ ppm): δ 7.55 (s, 1Η, ΗΑ,), 6.79 (s, 2Η, H QUIN ), 5.24 (m, 1Η, CH=), 5.10 (t, 1H, J =5.7 Hz, CH0), 3.97 (s, 3H, 0CH 3 ), 3.89 (s, 3H, 0CH 3 ), 2.35-2.19 (m, 2H, CH 2 ), 1.76 (s, 3H, CH 3 ), 1.65 (s, 3H, CH 3 ). 13 C MR (75 MHz, CDCls, δ ppm): δ 185.1, 184.5, 156.5, 150.9, 147.9, 139.2, 137.9, 136.9, 125.1, 68.8, 62.4, 56.9, 37.2, 26.09 , 18.21.
实施例 11  Example 11
5， 8—二甲氧 ¾~6— (1—酰氧 ¾~4—甲¾~3—戊烯基 )— 1， 4—萘醌的制备  Preparation of 1,8-dimethoxy 3⁄4~6-(1-acidooxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone
步骤一及步骤二同实施例 10;  Step 1 and step 2 are the same as embodiment 10;
步骤三，将 2- (1-羟¾~4-甲¾~3-戊烯基 )- 1， 4-二甲氧 ¾"5， 8-二甲氧甲氧基萘与相应的羧 酸反颇羟基进行酯化， 具條雑实施例 2步骤三的方法进行；  In the third step, 2-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)- 1, 4-dimethoxy 3⁄4"5, 8-dimethoxymethoxynaphthalene is reacted with the corresponding carboxylic acid. The esterification of the hydroxy group is carried out in the same manner as in the third step of the second embodiment;
步骤四， 具体操^ ¾实施例 10的步骤三方法进行脱甲氧甲基化。  Step 4, specifically performing the step 3-method of Example 10 for demethoxymethylation.
以上述方法制得 5， 8-二甲氧基- 6- (卜乙酰氧基- 4-甲基- 3-戊烯基 )-1， 4-萘醌 (V- 2)黄色 油状化合物 40.2 mg， 收率为 37.3%。 薩 (300 MHz, CDCls, δ ppm)： δ 7.26 (s， 1Η， H^), 6.79 (s， 2H， Hqul„), 6.16 (t, 1H， J=7.5 ft， CH=)， 5.12 (t, 1H， J=7.8 Hz, CH0)， 3.97 (s， 3H， OCHs), 3.82 (s， 3H， 0CH3)， 2.63-2.41 (m， 2H， CH2)， 2.10 (s， 3H， C0CH3)， 1.68 (s， 3H， CH3), 1.52 (s， 3H， CH3) . 5, 8-Dimethoxy-6-(b-acetoxy-4-methyl-3-pentenyl)-1,4-naphthoquinone (V-2) yellow oily compound 40.2 mg , the yield was 37.3%. Sa (300 MHz, CDCls, δ ppm): δ 7.26 (s, 1Η, H^), 6.79 (s, 2H, H qul „), 6.16 (t, 1H, J=7.5 ft, CH=), 5.12 ( t, 1H, J=7.8 Hz, CH0), 3.97 (s, 3H, OCHs), 3.82 (s, 3H, 0CH 3 ), 2.63-2.41 (m, 2H, CH 2 ), 2.10 (s, 3H, C0CH 3 ), 1.68 (s, 3H, CH 3 ), 1.52 (s, 3H, CH 3 ) .
同法制得 5， 8-二甲氧 ¾"6- (卜丙酰氧 ¾"4-甲¾~3-戊烯基 )- 1， 4-萘醌 (V- 3)黄色油状化 合物 32.3mg， 收率为 54.3%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 7.25 (s， 1Η， ΗΑ,), 6.77 (s， 2Η， Hqul„), 6.11 (t, 1Η， J=5.1 Hz, CH=)， 5.14 (t, 1H， J= 7.2 Hz, CH0)， 3.98 (s， 3H， OCHs), 3.91 (s， 3H， 0CH3), 2.55-2.36 (m， 4H， CH2CH=, CH2CH3), 1.68 (s， 3H， CH3)， 1.53 (s， 3H， CH3), 1.19 (t, 3H， J=6.9 Hz， CH2CH3) . 52.3 mg of 5-, 8-dimethoxy 3⁄4"6-(ppropionyloxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (V-3) yellow oil was obtained by the same method. The yield was 54.3%. 3⁄4萨(300 MHz, CDCls, δ ppm): δ 7.25 (s, 1Η, ΗΑ,), 6.77 (s, 2Η, H qul „), 6.11 (t, 1Η, J=5.1 Hz, CH=), 5.14 (t, 1H, J= 7.2 Hz, CH0), 3.98 (s, 3H, OCHs), 3.91 (s, 3H, 0CH 3 ), 2.55-2.36 (m, 4H, CH 2 CH=, CH 2 CH 3 ) , 1.68 (s, 3H, CH 3 ), 1.53 (s, 3H, CH 3 ), 1.19 (t, 3H, J=6.9 H z , CH 2 CH 3 ) .
同法制得 5， 8-二甲氧基- 6- (1-正丁酰氧¾~4-甲¾~3-戊烯基 )- 1， 4-萘醌 （V- 4)黄色油状 化合物 30.9mg， 收率 50.1%。 ¾ MR (300 MHz, CDCls, δ ppm)： δ 7.24 (s， 1Η， ΗΑ,), 6.77 (s， 2Η， Hqul„), 6.16 (t, 1Η， J=5.4 Hz, CH=)， 5.12 (t, 1H， J=7.8 Hz, CH0)， 3.95 (s， 3H， OCHs), 3.90 (s， 3H， 0CH3), 2.47-2.33 (m， 4H， CH2CH=, CH2CH2CH3), 1.71-1.64 (m， 5H， CH2CH2CH3, CH3), 1.62 (s， 3H， CH3), 0.98 (t, 3H， J=7.5 Hz， CH2CH2CH3) . 同法制得 5， 8-二甲氧 ¾"6- (1-已酰氧基)- 4-甲¾~3-戊烯基 )- 1， 4-萘醌 (V- 5)黄色油状化 合物 30.7mg， 收率 48.1%。 ¾ MR (300 MHz, CDCls, δ ppm)： δ 7.25 (s， 1Η， ΗΑ,), 6.78 (s， 2Η， Hqul„), 6.16 (m， 1Η， CH=)， 5.13 (t, 1H， J=7.2 Hz, CHO), 3.96 (s， 3H， 0CH3), 3.91 (s， 3H， OCHs), 2.59-2.32 (m， 4H， CH2CH=, C¾CH2CftCH2CH3)， 1.68-1.57 (m， 5H， 5, 8-Dimethoxy-6-(1-n-butyryloxy 3⁄4~4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (V-4) yellow oil compound 30.9 Mg, yield 50.1%. 3⁄4 MR (300 MHz, CDCls, δ ppm): δ 7.24 (s, 1Η, ΗΑ,), 6.77 (s, 2Η, H qul „), 6.16 (t, 1Η, J=5.4 Hz, CH=), 5.12 (t, 1H, J=7.8 Hz, CH0), 3.95 (s, 3H, OCHs), 3.90 (s, 3H, 0CH 3 ), 2.47-2.33 (m, 4H, CH 2 CH=, CH 2 CH 2 CH 3 ), 1.71-1.64 (m, 5H, CH 2 CH 2 CH 3 , CH 3 ), 1.62 (s, 3H, CH 3 ), 0.98 (t, 3H, J=7.5 H z , CH 2 CH 2 CH 3 ) . 5, 8-Dimethoxy 3⁄4"6-(1-hexanoyloxy)-4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (V-5) yellow oily compound 30.7 Mg, yield 48.1%. 3⁄4 MR (300 MHz, CDCls, δ ppm): δ 7.25 (s, 1Η, ΗΑ,), 6.78 (s, 2Η, H qul „), 6.16 (m, 1Η, CH=) , 5.13 (t, 1H, J=7.2 Hz, CHO), 3.96 (s, 3H, 0CH 3 ), 3.91 (s, 3H, OCHs), 2.59-2.32 (m, 4H, CH 2 CH=, C3⁄4CH 2 CftCH 2 CH 3 ), 1.68-1.57 (m, 5H,
CH3), 1.54 (s， 3H， CH3), 1.37-1.27 (m， 4H， CH2CH2CH2CH2CH3) , 0.92 (m， 3H， CH2CH2CH2CH2Cft) . 同法制得 5， 8-二甲氧 ¾"6- [1- (2-正丁烯酰氧基 )- 4-甲基- 3-戊烯基 ]- 1， 4-萘醌 (V- 6)黄 色油状化合物 29.3mg，收率 47.7%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 7.24 (s， 1Η， ΗΑ,), 7.04-6.93 (m， 1Η， C0CH=C), 6.78 (s， 2Η， Hquin)， 6.17-6.12 (m， 1H， CH=)， 5.94 (m， 1H， =CHCH3), 5.12 (t, 1H， J=7.8 Hz, CHO), 3.96 (s， 3H， 0CH3), 3.93 (s， 3H， 0CH3), 2.56—2.38 (m， 2H， CH2)， 1.93-1.90 (m， 3H， =CHCH3), 1.67 (s， 3H， CH3)， 1.53 (s， 3H， CH3) . CH 3 ), 1.54 (s, 3H, CH 3 ), 1.37-1.27 (m, 4H, CH 2 CH 2 CH 2 CH 2 CH 3 ) , 0.92 (m, 3H, CH 2 CH 2 CH 2 CH 2 Cft) By the same method, 5, 8-dimethoxy 3⁄4"6- [1-(2-n-butenyloxy)-4-methyl-3-pentenyl]- 1, 4-naphthoquinone (V- 6) 29.3 mg of yellow oily compound, yield 47.7%. 3⁄4 Sa (300 MHz, CDCls, δ ppm): δ 7.24 (s, 1 Η, ΗΑ,), 7.04-6.93 (m, 1 Η, C0CH=C), 6.78 (s, 2Η, H quin ), 6.17-6.12 (m, 1H, CH=), 5.94 (m, 1H, =CHCH 3 ), 5.12 (t, 1H, J=7.8 Hz, CHO), 3.96 (s, 3H, 0CH 3 ), 3.93 (s, 3H, 0CH 3 ), 2.56—2.38 (m, 2H, CH 2 ), 1.93-1.90 (m, 3H, =CHCH 3 ), 1.67 (s, 3H, CH 3 ) , 1.53 (s, 3H, CH 3 ) .
同法制得 5,8-二甲氧 ¾"6- [1， - (3,3-二甲基丙烯酰氧基) - 4-甲¾~3-戊烯基 ]- 1,4-萘醌 (V- 7)黄色油状化合物 36.6mg， 收率 56.9%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 7.24 (s， 1Η， ΗΑ,), 6.78 (s， 2Η， Hqul„), 5.90 (m， 1Η， CH=)， 5.43 (s， 1H， C0CH=), 5.13 (m， 1H， CHO), 3.94 (s， 3H， OCHs), 3.92 (s， 3H， 0CH3), 2.53-2.43 (m， 2H， CH2)， 2.15 (s， 3H， CH3)， 1.93 (s， 3H， CH3), 1.65 (s， 3H， CH3)， 1.54 (s， 3H， CH3)。 5,8-Dimethoxy 3⁄4"6-[1,-(3,3-dimethylacryloyloxy)-4-methyl-3⁄4~3-pentenyl]-1,4-naphthoquinone (V-7) yellow oily compound 36.6 mg, yield 56.9%. 3⁄4sa (300 MHz, CDCls, δ ppm): δ 7.24 (s, 1Η, ΗΑ,), 6.78 (s, 2Η, H qul „), 5.90 (m, 1Η, CH=), 5.43 (s, 1H, C0CH=), 5.13 (m, 1H, CHO), 3.94 (s, 3H, OCHs), 3.92 (s, 3H, 0CH 3 ), 2.53- 2.43 (m, 2H, CH 2 ), 2.15 (s, 3H, CH 3 ), 1.93 (s, 3H, CH 3 ), 1.65 (s, 3H, CH 3 ), 1.54 (s, 3H, CH 3 ).
同法制得 5， 8-二甲氧基- 6- (1-异丁酰氧¾~4-甲¾~3-戊烯基 )- 1， 4-萘醌 (V- 8)黄色油状 化合物 35.7mg， 收率 57.8%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 7.24 (s， 1Η， ΗΑ,), 6.77 (s， 2Η ， Hqul„), 6.10 (t, 1H， J=6.0 Hz, CH=)， 5.13 (m， 1H， CHO), 3.94 (s， 3H， 0CH3), 3.92 (s， 3H， OCHs), 2.66—2.44 (m， 3H， CH2， CH(CH3)2), 1.49 (s， 3H， CH3)， 1.47 (s， 3H， CH3), 1.21 (d， 3H， J=2.1 Hz， CH3)， 1.16 (d， 3H， J=2.1 Hz， CH3)。 5, 8-Dimethoxy-6-(1-isobutyryloxy 3⁄4~4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (V-8) yellow oily compound 35.7 Mg, yield 57.8%. 3⁄4萨 (300 MHz, CDCls, δ ppm): δ 7.24 (s, 1Η, ΗΑ,), 6.77 (s, 2Η, H qul „), 6.10 (t, 1H, J=6.0 Hz, CH=), 5.13 (m, 1H, CHO), 3.94 (s, 3H, 0CH 3 ), 3.92 (s, 3H, OCHs), 2.66—2.44 (m, 3H, CH 2 , CH(CH 3 ) 2 ), 1.49 (s, 3H, CH 3 ), 1.47 (s, 3H, CH 3 ), 1.21 (d, 3H, J = 2.1 H z , CH 3 ), 1.16 (d, 3H, J = 2.1 H z , CH 3 ).
同法制得 5， 8-二甲氧 ¾"6- [1- (2-甲基丁酰氧基 )- 4-甲基- 3-戊烯基 ]- 1， 4-萘醌 (V- 9)黄 色油状化合物 27.3 mg, 收率 42.7%。 ¾ MR (300 MHz, CDCls, δ ppm)： δ 7.24 (d， 1Η， J=l.5 Hz, ΗΑ,), 6.77 (s， 2H， Hquin)， 6.10 (ddd, 1H， J=4.5, 7.2， 3.6 Hz, CH=)， 5.13 (t, 1H， J=l.5 Hz, CHO), 3.93 (s， 3H， 0CH3), 3.92 (s， 3H， 0CH3), 2.64—1.91 (m， 3H， CH2， C0CH), 1.66 (s， 3H， CH3), 1.52 (s， 3H， CH3)， 1.19 (d， 6H， J=6.9 Hz， 2XCH3), 1.16 (m， 2H， CH2CH3) . 同法制得 5， 8-二甲氧基- 6- (1-苯甲酰基- 4-甲基- 3-戊烯基 )-1， 4-萘醌 (V- 10)黄色油状 化合物 33.13 mg， 收率 27.2%。 MR (300 MHz, CDCls, δ ppm)： δ 8.08 (m， 2Η， lU， 7.61-7.44 (m， 3H， ΗΑ,), 7.32 (s， 1H， H^), 6.74 ( s， 2H， Hquin)， 6.17 (m， 1H， CH=)， 5.21 (t, 1H， J=6.9 Hz, CHO), 4.01 (s， 3H， 0CH3), 3.97 (s， 3H， 0CH3), 2.72—2.56 (m， 2H， CH2)， 1.66 (s， 3H， CH3), 1.59 (s， 3H， CH3)。 5, 8-Dimethoxy 3⁄4"6-[1-(2-methylbutyryloxy)-4-methyl-3-pentenyl]- 1, 4-naphthoquinone (V-9) Yellow oily compound 27.3 mg, yield 42.7%. 3⁄4 MR (300 MHz, CDCls, δ ppm): δ 7.24 (d, 1Η, J=l.5 Hz, ΗΑ,), 6.77 (s, 2H, H quin ), 6.10 (ddd, 1H, J=4.5, 7.2, 3.6 Hz, CH=), 5.13 (t, 1H, J=l.5 Hz, CHO), 3.93 (s, 3H, 0CH 3 ), 3.92 (s , 3H, 0CH 3 ), 2.64—1.91 (m, 3H, CH 2 , C0CH), 1.66 (s, 3H, CH 3 ), 1.52 (s, 3H, CH 3 ), 1.19 (d, 6H, J=6.9 H z , 2XCH 3 ), 1.16 (m, 2H, CH 2 CH 3 ) . In the same manner, 5, 8-dimethoxy-6-(1-benzoyl-4-methyl-3-pentenyl) -1,4-naphthoquinone (V-10) yellow oily compound 33.13 mg, yield 27.2%. MR (300 MHz, CDCls, δ ppm): δ 8.08 (m, 2Η, lU, 7.61-7.44 (m, 3H, ΗΑ,), 7.32 (s, 1H, H^), 6.74 ( s, 2H, H quin ), 6.17 (m, 1H, CH=), 5.21 (t, 1H, J=6.9 Hz, CHO), 4.01 (s, 3H, 0CH 3 ), 3.97 (s, 3H, 0CH 3 ), 2.72—2.56 (m, 2H, CH 2 ), 1.66 (s, 3H, CH 3 ), 1.59 (s, 3H, CH 3 ).
同法制得 5， 8-二甲氧基- 6- (卜肉桂酰氧基- 4-甲基- 3-戊烯基 )-1， 4-萘醌 (V- 11)黄色油 状化合物 32.7 mg, 收率为 25.3%。 ¾ MR (300 MHz, CDCls, δ ppm )： δ 7.75 (d， 1Η， J=16.2 Hz, C0CH=), 7.58—7.20 (m， 6H， H^), 6.79 (s， 2H， Hquin)， 6.55 (d， 1H， J=16.2 Hz, =CH— Ar)， 6.25 (dd， 1H， J=7.6, 4.8 Hz， CH=)， 5.19 (t, 1H， J=6.0 Hz, CHO), 3.96 (s， 3H， 0CH3), 3.94 (s， 3H， OCHs), 2.57 ( m， 2H， CH2)， 1.69 (s， 3H， CH3)， 1.56 (s， 3H， CH3)。 5, 8-Dimethoxy-6-(buxoyloxy-4-methyl-3-pentenyl)-1,4-naphthoquinone (V-11) yellow oily compound 32.7 mg, The yield was 25.3%. 3⁄4 MR (300 MHz, CDCls, δ ppm ): δ 7.75 (d, 1Η, J=16.2 Hz, C0CH=), 7.58—7.20 (m, 6H, H^), 6.79 (s, 2H, H quin ), 6.55 (d, 1H, J = 16.2 Hz, =CH—Ar), 6.25 (dd, 1H, J=7.6, 4.8 H z , CH=), 5.19 (t, 1H, J=6.0 Hz, CHO), 3.96 (s, 3H, 0CH 3 ), 3.94 (s, 3H, OCHs), 2.57 (m, 2H, CH 2 ), 1.69 (s, 3H, CH 3 ), 1.56 (s, 3H, CH 3 ).
同法制得 5,8-二甲氧基- 6- (1-苯丙酰氧基- 4-甲基- 3-戊烯基 )- 1,4-萘醌（V- 12)黄色油 状化合物 28.45 mg, 收率为 21.9%。 ¾ MR (300 MHz, CDCls, δ ppm)： δ 7.29-7.16 (m， 6Η， ΗΑ,), 6.78 (s， 2Η， Hqul„), 6.17-6.13 (m， 1Η， CH=)， 5.10 (t, 1H， J=7.5Hz, CHO), 3.90 (s， 3H， OCHs), 3.87 (s， 3H， 0CH3), 2.99 (t, 2H， J=7.8 Hz, ArCH2), 2.75—2.68 (t, 2H， J=7.8 Hz, C0CH2), 2.53-2.45 (m， 2H， CH2)， 1.67(s， 3H， CH3)， 1.52 (s， 3H， CH3) . 5,8-Dimethoxy-6-(1-phenylpropanoyloxy-4-methyl-3-pentenyl)-1,4-naphthoquinone (V-12) yellow oily compound 28.45 Mg, the yield was 21.9%. 3⁄4 MR (300 MHz, CDCls, δ ppm): δ 7.29-7.16 (m, 6Η, ΗΑ,), 6.78 (s, 2Η, H qul „), 6.17-6.13 (m, 1Η, CH=), 5.10 ( t, 1H, J=7.5Hz, CHO), 3.90 (s, 3H, OCHs), 3.87 (s, 3H, 0CH 3 ), 2.99 (t, 2H, J=7.8 Hz, ArCH 2 ), 2.75—2.68 ( t, 2H, J = 7.8 Hz, C0CH 2 ), 2.53-2.45 (m, 2H, CH 2 ), 1.67 (s, 3H, CH 3 ), 1.52 (s, 3H, CH 3 ) .
同法制得 5,8-二甲氧基 -6-[l-(4-甲氧基苯甲酰氧基) -4-甲基 -3-戊烯基 ]-1， 4-萘醌 (V-13)黄色油状化合物 29.8 mg, 收率为 22.8%. ¾ MR (300 MHz, CDCls, δ ppm)： 8.10 (d， 1H， J=9.0 Hz, HA,), 8.09 (d， 1H， J=9.0 Hz, HA,), 7.31 (s, 1H， H^), 6.99 (d， 1H， J=9.0 Hz, HA,), 6.98 (d， 1H， J=9.0 Hz, HA,) 6.78 (s， 2H， Hquin)， 6.31 (m， 1H， CH=)， 5.23 (t, 1H， J=6.9 Hz, CHO), 3.97 (s， 3H， 0CH3), 3.88 (s， 3H， 0CH3), 3.83 (s， 3H， 0CH3), 2.68-2.59 (m， 2H， CH2)， 1.67 (s， 3H， CH3)， 1.56 (s， 3H， CH3)。 5,8-Dimethoxy-6-[l-(4-methoxybenzoyloxy)-4-methyl-3-pentenyl]-1,4-naphthoquinone (V) -13) Yellow oily compound 29.8 mg, yield 22.8%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 8.10 (d, 1H, J=9.0 Hz, HA,), 8.09 (d, 1H, J= 9.0 Hz, HA,), 7.31 (s, 1H, H^), 6.99 (d, 1H, J=9.0 Hz, HA,), 6.98 (d, 1H, J=9.0 Hz, HA,) 6.78 (s, 2H, H quin ), 6.31 (m, 1H, CH=), 5.23 (t, 1H, J=6.9 Hz, CHO), 3.97 (s, 3H, 0CH 3 ), 3.88 (s, 3H, 0CH 3 ), 3.83 (s, 3H, 0CH 3 ), 2.68-2.59 (m, 2H, CH 2 ), 1.67 (s, 3H, CH 3 ), 1.56 (s, 3H, CH 3 ).
同法制得 5,8-二甲氧基 -6-[l-(4-甲氧基苯乙酰氧基) -4-甲基 -3-戊烯基 ]-1， 4-萘醌 (V- 14)黄色油状化合物 35.4 mg， 收率为 26.3%. ¾薩 (300 MHz, CDCls, δ ppm): 7.24 (d， 2H， J=8.1 Hz, HA,), 6.93 (s， 1H， HA,), 6.87 (d， 2H， J=8.1Hz, H^), 6.75 (s， 2H， Hquin)， 6.11 (m， 1H， CH=)， 5.13 (t, 1H， J=8.4 Hz, CHO), 3.91 (s， 3H， 0CH3), 3.88( s， 3H， 0CH3), 3.73 (s， 3H， OCHs), 3.63 (s， 2H， CftAr )， 2.54-2.38 (m， 2H， CH2)， 1.67 (s， 3H， CH3)， 1.52 (s， 3H， CHs). The same method can be used to prepare 5,8-dimethoxy-6-[l-(4-methoxyphenylacetoxy)-4-methyl-3-pentenyl]-1,4-naphthoquinone (V- 14) Yellow oily compound 35.4 mg, yield 26.3%. 3⁄4 Sa (300 MHz, CDCls, δ ppm): 7.24 (d, 2H, J=8.1 Hz, HA,), 6.93 (s, 1H, HA,) , 6.87 (d, 2H, J=8.1Hz, H^), 6.75 (s, 2H, H quin ), 6.11 (m, 1H, CH=), 5.13 (t, 1H, J=8.4 Hz, CHO), 3.91 (s, 3H, 0CH 3 ), 3.88( s, 3H, 0CH 3 ), 3.73 (s, 3H, OCHs), 3.63 (s, 2H, CftAr ), 2.54-2.38 (m, 2H, CH 2 ), 1.67 (s, 3H, CH 3 ), 1.52 (s, 3H, CHs).
同法制得 5， 8-二甲氧基 -6-[l-(4-硝基苯甲酰氧基) -4-甲基 -3-戊烯基 ]-1， 4-萘醌 ( V- 15)黄色油状化合物 29.8 mg,收率为 68.3%. ¾ MR (300 MHz, CDCls, δ ppm)： 8.35-8.22 (m， 4H， ΗΑ,), 7.29 (s， 1H， H^), 6.80 (s， 2H， Hqul„), 6.40 (m， 1H， CH=)， 5.20 (t, 1H， J=7.2 Hz, CHO), 3.98 (s， 3H， 0CH3), 3.90 (s， 3H， 0CH3), 2.70-2.65 (m， 2H， CH2)， 1.69 (s， 3H，
Figure imgf000023_0001
5, 8-Dimethoxy-6-[l-(4-nitrobenzoyloxy)-4-methyl-3-pentenyl]-1,4-naphthoquinone (V- by the same method) 15) Yellow oily compound 29.8 mg, yield 68.3%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 8.35-8.22 (m, 4H, ΗΑ,), 7.29 (s, 1H, H^), 6.80 ( s, 2H, H qul „), 6.40 (m, 1H, CH=), 5.20 (t, 1H, J=7.2 Hz, CHO), 3.98 (s, 3H, 0CH 3 ), 3.90 (s, 3H, 0CH 3 ), 2.70-2.65 (m, 2H, CH 2 ), 1.69 (s, 3H,
Figure imgf000023_0001
同法制得 5， 8-二甲氧基 -6-[l-(2-甲氧基 -苯甲酰氧基 )-4-甲基 -3-戊烯基 ]-1， 4-萘醌 (V-16)黄色油状化合物 27.0 mg, 收率为 20.7%. ¾ MR (300 MHz, CDCls, δ ppm)： 7.86 (m， 1H， HA,), 7.53 (m， 1H， H^), 7.41 (s， 1H， H^), 7.04 (m， 2H， H^), 6.77 (s， 2H， Hquin)， 6.32 (m， 1H， CH=)， 5.24 (t, 1H， J=6.9 Hz, CHO)， 3.98 (s， 3H， 0CH3), 3.93 (s， 3H， 0CH3), 3.90 (s， 3H， OCHs), 2.67-2.56 (m， 2H， CH2)， 1.68 (s， 3H， CH3)， 1.52 (s， 3H， CH3)。 5, 8-Dimethoxy-6-[l-(2-methoxy-benzoyloxy)-4-methyl-3-pentenyl]-1,4-naphthoquinone prepared by the same method (V-16) Yellow oily compound 27.0 mg, yield 20.7%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.86 (m, 1H, HA,), 7.53 (m, 1H, H^), 7.41 (s, 1H, H^), 7.04 (m, 2H, H^), 6.77 (s, 2H, H quin ), 6.32 (m, 1H, CH=), 5.24 (t, 1H, J=6.9 Hz, CHO), 3.98 (s, 3H, 0CH 3 ), 3.93 (s, 3H, 0CH 3 ), 3.90 (s, 3H, OCHs), 2.67-2.56 (m, 2H, CH 2 ), 1.68 (s, 3H, CH 3 ), 1.52 (s, 3H, CH 3 ).
同法制得 5， 8-二甲氧 ¾"6- [1- (3-羟¾~3-甲¾ "丁酰氧基) - 4-甲¾~3-戊烯基 ]- 1， 4-萘醌 5, 8-Dimethoxy 3⁄4"6- [1-(3-hydroxy 3⁄4~3-methyl 3⁄4 "butyryloxy)-4-methyl 3⁄4~3-pentenyl]- 1, 4- Naphthoquinone
(V- 17)黄色油状化合物 20.3mg， 收率 30.5%。 ¾ MR (300 MHz, CDCls, δ ppm)： 7.27 (s， 1H， ΗΑ,), 6.67 (s， 2H， HQUIN)， 6.18 (m， 1H， CH=)， 5.04 (t, 1H， J=8.1 Hz, CH0)， 3.95 (s， 3H， OCHs), 3.94 (s， 3H， 0CH3), 2.58-2.38 (m， 4H， CH2CH=， C0CH2), 1.68 (s， 3H， CH3)， 1.55 (s， 3H， CHs), 1.29 (s， 3H， CH3)， 1.26 (s， 3H， CH3)。 (V-17) 20.3 mg of a yellow oily compound, yield 30.5%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.27 (s, 1H, ΗΑ,), 6.67 (s, 2H, H QUIN ), 6.18 (m, 1H, CH=), 5.04 (t, 1H, J= 8.1 Hz, CH0), 3.95 (s, 3H, OCHs), 3.94 (s, 3H, 0CH 3 ), 2.58-2.38 (m, 4H, CH 2 CH=, C0CH 2 ), 1.68 (s, 3H, CH 3 ), 1.55 (s, 3H, CHs), 1.29 (s, 3H, CH 3 ), 1.26 (s, 3H, CH 3 ).
同法制得 5， 8-二甲氧基- 6- [1- (2-呋喃甲酰氧基 )- 4-甲¾~3-戊烯基 ]- 1， 4-萘醌（V- 18) 黄色油状化合物 25.3 mg， 收率 27.1%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.69 (m， 1H， HFu)， 7.34 (s， 1H， HA,), 7.25 (m， 1H， HFU )， 6.79 (s， 2H， HQUIN)， 6.56 (m， 1H， HFU)， 6.34 (t, 1H， J= 5.1 Hz, CH=)， 5.10 (t, 1H， J=2.7Hz, CH0)， 3.96 (s， 3H， 0CH3), 3.92 (s， 3H， 0CH3), 2.67- 2.57 (m， 2H， CH2)， 1.68 (s， 3H， CH3)， 1.57 (s， 3H， CH3) . 5, 8-Dimethoxy-6-[1-(2-furoyloxy)-4-methyl 3⁄4~3-pentenyl]- 1, 4-naphthoquinone (V- 18) The yellow oily compound was 25.3 mg, yield 27.1%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 7.69 (m, 1H, H Fu ), 7.34 (s, 1H, HA,), 7.25 (m, 1H, H FU ), 6.79 (s, 2H, H QUIN ), 6.56 (m, 1H, H FU ), 6.34 (t, 1H, J = 5.1 Hz, CH=), 5.10 (t, 1H, J=2.7Hz, CH0), 3.96 (s, 3H, 0CH 3 ) , 3.92 (s, 3H, 0CH 3 ), 2.67- 2.57 (m, 2H, CH 2 ), 1.68 (s, 3H, CH 3 ), 1.57 (s, 3H, CH 3 ) .
同法制得 5， 8-二甲氧基- 6- [1- (3-呋喃甲酰氧基 )- 4-甲¾~3-戊烯基 ]- 1， 4-萘醌（V- 19) 黄色油状化合物 29.2 mg, 收率 30.2%。 ¾ MR (300 MHz, CDCls, δ ppm)： 8.10 (d， 1H， J=l.2 Hz, HFU), 7.49 (d， 1H， J=l.8 Hz, HFU)， 7.29 (s， 1H， H^), 6.82 (s， 2H， HQUIN)， 6.80 (s， 1H， HFU), 6.52 (dd， 1H， J=4.8, 4.8Hz, CH=)， 5.19 (t, 1H， J=7.5 Hz, CH0)， 3.97 (s， 3H， OCHs), 3.94 (s， 3H， 0CH3), 2,63-2.57 (m， 2H， CH2)， 1.69 (s， 3H， CH3)， 1.58 (s， 3H， CH3) . 同法制得 5， 8-二甲氧基- 6- [1- (2-四氢呋喃甲酰氧基) - 4-甲¾~3-戊烯基 ]- 1， 4-萘醌5, 8-Dimethoxy-6-[1-(3-furoyloxy)-4-methyl 3⁄4~3-pentenyl]- 1, 4-naphthoquinone (V-19) Yellow oily compound 29.2 mg, yield 30.2%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 8.10 (d, 1H, J=l.2 Hz, HFU), 7.49 (d, 1H, J=l.8 Hz, H FU ), 7.29 (s, 1H , H^), 6.82 (s, 2H, H QUIN ), 6.80 (s, 1H, HFU), 6.52 (dd, 1H, J=4.8, 4.8Hz, CH=), 5.19 (t, 1H, J=7.5 Hz, CH0), 3.97 (s, 3H, OCHs), 3.94 (s, 3H, 0CH 3 ), 2,63-2.57 (m, 2H, CH 2 ), 1.69 (s, 3H, CH 3 ), 1.58 ( s, 3H, CH 3 ) . In the same manner, 5, 8-dimethoxy-6-[1-(2-tetrahydrofuroyloxy)-4-methyl 3⁄4~3-pentenyl]- 1, 4 -naphthyl
(V- 20)黄色油状化合物 27.7 mg, 收率 29.7%。 ¾ MR (300 MHz, CDCls, δ ppm): 7.28 (d， 1H， J=3.3 Hz, HA,), 6.79 (s， 2H， Hquin)， 6.12 (m， 1H， CH=)， 5.14 (t, 1H， J=6.3 Hz, CH0)， 4.55 (m， 1H， J=4.8 Hz, C0CH0), 4.02-3.88 (m， 8H， 2X0CH3, 0CH2CH2), 2,58-2.48 (m， 2H， 0CH2CH2), 2.25—2.23 (m， 1H， CHaCH=), 2.08—1.92 ( m， 3H， 0CH2CH2CH2, CHbCH=, ), 1.68 (s， 3H， CHs), 1.55 (s， 3H， CH3) . (V-20) Yellow oily compound 27.7 mg, yield 29.7%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.28 (d, 1H, J=3.3 Hz, HA,), 6.79 (s, 2H, H quin ), 6.12 (m, 1H, CH=), 5.14 (t , 1H, J=6.3 Hz, CH0), 4.55 (m, 1H, J=4.8 Hz, C0CH0), 4.02-3.88 (m, 8H, 2X0CH 3 , 0CH 2 CH 2 ), 2,58-2.48 (m, 2H, 0CH 2 CH 2 ), 2.25—2.23 (m, 1H, CHaCH=), 2.08—1.92 ( m, 3H, 0CH 2 CH 2 CH 2 , CH b CH=, ), 1.68 (s, 3H, CHs) , 1.55 (s, 3H, CH 3 ) .
同法制得 5， 8-二甲氧基 -6-[l-(3-四氢呋喃甲酰氧基) -4-甲基- 3-戊烯基 ]-1， 4-萘醌 (V— 21)黄色油状化合物 27.7 mg, 收率 25.4%。 ¾ MR (300 MHz, CDCls, δ ppm): 7.24 (d， 1H， J=3.3 Hz, HA,), 6.78 (s， 2H， Hquin)， 6.16 (m， 1H， CH=)， 5.11 (t, 1H， J=6.3 Hz, CH0)， 4.02-3.79 (m， 10H， 2X0CH3, 2X 0CH2CH2), 3.19 (m， 1H， C0CH), 2.53-2.44 (m， 2H， CH2CH=)， 2.24-2.12 (m, 2H， 0CH2CH2), 1.68 (s， 3H， CH3)， 1.54 (s， 3H， CH3) . 5, 8-Dimethoxy-6-[l-(3-tetrahydrofuroyloxy)-4-methyl-3-pentenyl]-1,4-naphthoquinone (V-21) was prepared by the same method. Yellow oily compound 27.7 mg, yield 25.4%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.24 (d, 1H, J=3.3 Hz, HA,), 6.78 (s, 2H, H quin ), 6.16 (m, 1H, CH=), 5.11 (t , 1H, J=6.3 Hz, CH0), 4.02-3.79 (m, 10H, 2X0CH 3 , 2X 0CH 2 CH 2 ), 3.19 (m, 1H, C0CH), 2.53-2.44 (m, 2H, CH 2 CH= ), 2.24-2.12 (m, 2H, 0CH 2 CH 2 ), 1.68 (s, 3H, CH 3 ), 1.54 (s, 3H, CH 3 ) .
实施例 12  Example 12
5， 8—二甲氧 ¾~6— (1—垸氧 ¾~4—甲¾~3—戊烯基 )— 1， 4—萘醌的制备  Preparation of 5,8-dimethoxy 3⁄4~6-(1-oxo 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone
步骤一及步骤二同实施例 10;  Step 1 and step 2 are the same as embodiment 10;
步骤三，将 2- (1-羟¾~4-甲¾~3-戊烯基 )- 1， 4-二甲氧 ¾"5， 8-二甲氧甲氧基萘与相应的溴 代物反颇羟基进行醚化， 具條雑实施例 3步骤三的方法进行；  In the third step, 2-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)- 1,4-dimethoxy 3⁄4"5, 8-dimethoxymethoxynaphthalene is counter-inverted with the corresponding bromo compound. The hydroxyl group is etherified, and the method of the third step of the third embodiment is carried out;
步骤四， 具体操^ ¾实施例 10的步骤三方法进行脱甲氧甲基化。  Step 4, specifically performing the step 3-method of Example 10 for demethoxymethylation.
以 ±¾方法制得 5，8-二甲氧¾"6-(1-甲氧基-4-甲¾"3-戊烯基)-1，4-萘醌（V- 22)橙黄 色油状物 13.4mg， 收率 34.1%。 ¾ MR (300MHz, CDCls, δ ppm)： 7.41 (s, 1H， ΗΑ,), 6.79 (d， 2H， J=2.7Hz, Hqul„), 5.21 (dd， 1H， J=5.1, 1.2HZ， CH=)， 5.10 (dd, 1H， J=4.8 Hz, 5.1 Hz, CHO), 3.98 (s， 3H， 0CH3), 3.83 (s, 3H， 0CH3), 3.33 (s, 3H， 0CH3), 2.50-2.33 (m， 2H， CH2)，5,8-Dimethoxy 3⁄4"6-(1-methoxy-4-methyl 3⁄4"3-pentenyl)-1,4-naphthoquinone (V- 22) orange yellow oil was obtained by the method of ±3⁄4 13.4 mg, yield 34.1%. 3⁄4 MR (300MHz, CDCls, δ ppm): 7.41 (s, 1H, ΗΑ,), 6.79 (d, 2H, J=2.7Hz, H qul „), 5.21 (dd, 1H, J=5.1, 1.2H Z , CH=), 5.10 (dd, 1H, J=4.8 Hz, 5.1 Hz, CHO), 3.98 (s, 3H, 0CH 3 ), 3.83 (s, 3H, 0CH 3 ), 3.33 (s, 3H, 0CH 3 ), 2.50-2.33 (m, 2H, CH 2 ),
1.68 (s， 3H， CH3), 1.49 (s， 3H， CH3)。 1.68 (s, 3H, CH 3 ), 1.49 (s, 3H, CH 3 ).
同法制得 5，8-二甲氧¾"6-(1-乙氧¾"4-甲¾"3-戊烯基)-1，4-萘醌（V- 23)橙黄色油状 物 11.6mg，收率 29.5%。 ¾薩 (300MHz, CDCls , δ ppm)： 7.48 (s， 1Η， ΗΑ,), 6.77 (d， 2H， J=1.2 Hz, Hqul„), 5.19 (t, 1H， J=4.8Hz, CH=)， 4.78 (m， 1H， CHO ), 3.92 (s, 3H， 0CH3), 3.82 (s， 3H， OCHs), 3.38 (m， 2H， 0CH2CH3), 2, 32-2.47 (m， 2H， CH2)， 1.62 (s， 3H， CH3)， 1.47 (s， 3H， CH3), 1.20 (t, 3H， J=4.8Hz, 0CH2C )。 5,8-Dimethoxy 3⁄4"6-(1-ethoxyxo 3⁄4"4-methyl 3⁄4"3-pentenyl)-1,4-naphthoquinone (V- 23) orange yellow oil 11.6 mg , yield 29.5%. 3⁄4萨 (300MHz, CDCls, δ ppm): 7.48 (s, 1Η, ΗΑ,), 6.77 (d, 2H, J=1.2 Hz, H qul „), 5.19 (t, 1H, J =4.8Hz, CH=), 4.78 (m, 1H, CHO ), 3.92 (s, 3H, 0CH 3 ), 3.82 (s, 3H, OCHs), 3.38 (m, 2H, 0CH 2 CH 3 ), 2, 32-2.47 (m, 2H, CH 2 ), 1.62 (s, 3H, CH 3 ), 1.47 (s, 3H, CH 3 ), 1.20 (t, 3H, J=4.8Hz, 0CH 2 C ).
同法制得 5，8-二甲氧¾"6-(卜正丙氧¾"4-甲¾"3-戊烯基)-1，4-萘醌（V- 24)橙黄色油 状物 12.5mg， 收率 31.3%。 ¾ NMR (300MHz, CDCls, δ ppm)： 7.39 (s， 1H， ΗΑ,), 6.75 (d， 2H， J=2.4 Hz, Hqul„), 5.16 (m， 1H， CH=)， 4.79 (m， 1H， CHO ), 3.92 (s， 3H， 0CH3), 3.76 (s， 3H， OCHs), 3.28 (m， 2H， 0CH2CH2CH3), 2.37-2.26 (m， 2H， CH2)， 1.61 (s， 3H， CH3)， 1.56 (m， 2H， 0CH2CH2CH3), 1.49 (s， 3H， CH3)， 0.87 (t, 3H， J=7.5Hz, 0CH2CH2CH3) . 5,8-Dimethoxy 3⁄4"6-(Bu-propoxy 3⁄4"4-methyl 3⁄4"3-pentenyl)-1,4-naphthoquinone (V-24) orange yellow oil 12.5 mg , yield 31.3%. 3⁄4 NMR (300MHz, CDCls, δ ppm): 7.39 (s, 1H, ΗΑ,), 6.75 (d, 2H, J=2.4 Hz, H qul „), 5.16 (m, 1H, CH =), 4.79 (m, 1H, CHO ), 3.92 (s, 3H, 0CH 3 ), 3.76 (s, 3H, OCHs), 3.28 (m, 2H, 0CH 2 CH 2 CH 3 ), 2.37-2.26 (m , 2H, CH 2 ), 1.61 (s, 3H, CH 3 ), 1.56 (m, 2H, 0CH 2 CH 2 CH 3 ), 1.49 (s, 3H, CH 3 ), 0.87 (t, 3H, J=7.5 Hz, 0CH 2 CH 2 CH 3 ) .
同法制得 5，8-二甲氧¾"6-[卜(2-羟基乙氧基)-4-甲¾"3-戊烯基]-1，4-萘醌（V- 25)橙黄色 油状物 16.3mg， 收率 40.6%. 薩 (300 MHz, CDCls, δ ppm)： 7.46 (s， 1H， ΗΑ,), 6.88—6.75 (m, 2H， Hqul„), 5.30—5.18 (m, 1H， CH=)， 4.88—4.78 (m, 1H， CHO), 3.98 (s， 3H， 0CH3), 3.82 (s， 3H， OCHs), 3.78-3.65 (m， 2H，0CH2)， 3.54-3.40 (m， 2H， 0CH2), 2.55-2.29 (m， 2H，CH2)，5,8-Dimethoxy 3⁄4"6-[Bu(2-hydroxyethoxy)-4-methyl 3⁄4"3-pentenyl]-1,4-naphthoquinone (V-25) orange yellow Oil 16.3 mg, yield 40.6%. Sa (300 MHz, CDCls, δ ppm): 7.46 (s, 1H, ΗΑ,), 6.88-6.75 (m, 2H, H qul „), 5.30—5.18 (m, 1H, CH=), 4.88—4.78 (m, 1H, CHO), 3.98 (s, 3H, 0CH 3 ), 3.82 (s, 3H, OCHs), 3.78-3.65 (m, 2H, 0CH 2 ), 3.54- 3.40 (m, 2H, 0CH 2 ), 2.55-2.29 (m, 2H, CH 2 ),
1.69 (s， 3H， CH3), 1.54 (s， 3H， CH3). 实施例 13 1.69 (s, 3H, CH 3 ), 1.54 (s, 3H, CH 3 ). Example 13
5,8—二乙氧 ¾"6— (1—羟¾~4—甲¾~3—戊烯基 )— 1,4—萘醌（VI— 1) 的制备  Preparation of 1,8-diethoxy 3⁄4"6-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (VI-1)
步骤一同实施例 10步骤一；  Step 1 of the same embodiment 10 step 1;
步骤二， 用硫酸二乙酯代替实施例 10步骤二的硫酸二甲, fi¾原乙基化；  Step 2, replacing the dimethyl sulfate of the second step of the embodiment 10 with diethyl sulfate, the original ethylation of fi3⁄4;
步骤三，具條雑照同实施例 10步骤三制得 2- (卜羟 ¾"4-甲基- 3-戊烯基 )- 1， 4-二乙氧 ¾"5，8-二甲氧甲氧基萘， 最后经酸水解得到 VI- 1淡黄色油状化合物 30.0 mg， 收率 25.2%。 ¾ 薩 (300 MHz, CDCls, δ ppm)： 7.23 (s， 1H， ΗΑ,), 6.78 (s, 2H， uin)， 5.18 (m， 1H， CH=)， 4.82 (t, 1H， J=4.8Hz, CHO), 3.93—4.21 (m， 4H, 2X0CH2CH3), 2,46—2.58 (m， 2H， CH2)， 1.71 (s， 3H， CHs), 1.56 (s， 3H， CH3)， 1.41 (t, 6H， J=6.6Hz， 2X0CH2CH3). Step 3, with the same procedure as in Example 10, Step 3, 2-(Buxy 3⁄4"4-methyl-3-pentenyl)- 1, 4-diethoxy 3⁄4"5,8-Dimethoxy The methoxynaphthalene was finally acid-hydrolyzed to give a compound of the compound (1), (yield: 25.2%). 3⁄4 萨 (300 MHz, CDCls, δ ppm): 7.23 (s, 1H, ΗΑ,), 6.78 (s, 2H, uin ), 5.18 (m, 1H, CH=), 4.82 (t, 1H, J=4.8 Hz, CHO), 3.93—4.21 (m, 4H, 2X0CH 2 CH 3 ), 2,46—2.58 (m, 2H, CH 2 ), 1.71 (s, 3H, CHs), 1.56 (s, 3H, CH 3 ), 1.41 (t, 6H, J=6.6Hz, 2X0CH 2 CH 3 ).
实施例 14  Example 14
5， 8-二乙氧 ¾"6- (卜酰氧 ¾"4-甲¾~3-戊烯基 )- 1， 4-萘醌制备  Preparation of 5, 8-diethoxy 3⁄4"6-(buxoyloxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone
步骤一同实施例 10中的步骤一；  Step 1 is the same as step 1 in embodiment 10;
步骤二同实施例 11中的步骤二；  Step 2 is the same as step 2 in the embodiment 11;
步骤三，将 2- (1-羟¾~4-甲¾~3-戊烯基 )- 1， 4-二乙氧 ¾"5， 8-二甲氧甲氧基萘与相应的羧 酸反颇羟基进行酯化， 具條雑实施例 2步骤三的方法进行；  In the third step, 2-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)- 1, 4-diethoxy 3⁄4"5, 8-dimethoxymethoxynaphthalene is reacted with the corresponding carboxylic acid. The esterification of the hydroxy group is carried out in the same manner as in the third step of the second embodiment;
步骤四， 具体操^ ¾实施例 10的步骤三方法进行脱甲氧甲基化。  Step 4, specifically performing the step 3-method of Example 10 for demethoxymethylation.
以 ±¾方法制得 5， 8-二乙氧 ¾"6- (1-乙酰氧基- 4-甲¾~3-戊烯基 )- 1， 4-萘醌（VI- 2)橙红 色油状化合物 47.7 mg， 收率为 86.3%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.24 (s， 1H， ΗΑ,), 6.75 (s， 2H， Hqlnu), 6.07 (m， 1H， CH=)， 5.07 (t, 1H， J=4.5Hz, CHO), 3.94—4.20 (m， 4H， 2X0CH2CH3), 2,43—2.53 (m， 2H， CH2)， 2.11 (s， 3H， C0CH3), 1.67 (s， 3H， CH3)， 1.58 (s， 3H， CHs), 1.48 (t, 6H， J=6.9Hz, 2X0CH2CH3)o 5, 8-Diethoxy 3⁄4"6-(1-acetoxy-4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (VI-2) orange-red oil was obtained by the method of ±3⁄4 Compound 47.7 mg, yield 86.3%. 3⁄4sa (300 MHz, CDCls, δ ppm): 7.24 (s, 1H, ΗΑ,), 6.75 (s, 2H, H qlnu ), 6.07 (m, 1H, CH= ), 5.07 (t, 1H, J=4.5Hz, CHO), 3.94—4.20 (m, 4H, 2X0CH 2 CH 3 ), 2,43—2.53 (m, 2H, CH 2 ), 2.11 (s, 3H, C0CH 3 ), 1.67 (s, 3H, CH 3 ), 1.58 (s, 3H, CHs), 1.48 (t, 6H, J=6.9Hz, 2X0CH 2 CH 3 ) o
同法制得 5,8-二乙氧 ¾"6- [卜(2-甲基丁酰氧基 )- 4-甲¾~3-戊烯基 ]- 1,4-萘醌（VI- 3) 橙黄色油状化合物 30.9mg,收率 46.2%.¾ MR (300 MHz, CDCls, δ ppm)： 7.21 (d， 1H， J=2.7Hz， HA,), 6.72 (s， 2H， Hqul„), 6.07 (t, 1H， J=4.5 Hz, CH=)， 5.11 (t, 1H， J=4.8 Hz, CHO), 4.04-4.15 (m, 4H, 0CH2CH3), 2.61—2.12 (m, 3H， CH2， COCH), 1.65 (s， 3H， CH3)， 1.53 (s， 3H， CHs), 1.46 (m， 6H， 2X0CH2CH3). 1.12 (d， 6H， J=3.0 Hz， 2XCH3), 0.93-0.90 (m， 2H， 同法制得 5， 8-二乙氧基- 6- [卜(3-羟基- 3-甲基丁酰氧基 )-4-甲基- 3-戊烯基 ]-1， 4-萘醌 (VI— 4)橙黄色油状化合物 30.9mg, 收率 46.2%。 ¾ MR (300 MHz, CDCls, δ ppm)： 7.24 (s， 1H， ΗΑ,), 6.75 (d， 2H， J=0.9 Hz, Hquin)， 6.14 (m， 1H， CH=)， 5.13 (t, 1H， J=5.7 Hz, CHO)， 3.99— 4.18 (m， 4H， 2X0CH2CH3), 2.56—2.45 (m， 4H， CH2CH=， C0CH2), 1.68 (s， 3H， CH3)， 1.56 (s， 3H， CHs), 1.51-1.53 (m， 6H， 2XCH3), 1.25 (t, 6H， J=6.9Hz, 2X0CH2C )。 5,8-Diethoxy 3⁄4"6-[Bu(2-methylbutyryloxy)-4-methyl-3⁄4~3-pentenyl]-1,4-naphthoquinone (VI-3) 30.9 mg of orange-yellow oily compound, yield 46.2%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.21 (d, 1H, J = 2.7 Hz, HA,), 6.72 (s, 2H, H qul „), 6.07 (t, 1H, J=4.5 Hz, CH=), 5.11 (t, 1H, J=4.8 Hz, CHO), 4.04-4.15 (m, 4H, 0CH 2 CH 3 ), 2.61—2.12 (m, 3H , CH 2 , COCH), 1.65 (s, 3H, CH 3 ), 1.53 (s, 3H, CHs), 1.46 (m, 6H, 2X0CH 2 CH 3 ). 1.12 (d, 6H, J=3.0 H z , 2XCH 3 ), 0.93-0.90 (m, 2H, 5, 8-diethoxy-6-[Bu(3-hydroxy-3-methylbutanoyloxy)-4-methyl- 3- Pentenyl]-1,4-naphthoquinone (VI-4) orange yellow oily compound 30.9 mg, yield 46.2%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.24 (s, 1H, ΗΑ,), 6.75 (d, 2H, J=0.9 Hz, H quin ), 6.14 (m, 1H, CH=), 5.13 (t, 1H, J=5.7 Hz, CHO), 3.99— 4.18 (m , 4H, 2X0CH 2 CH 3 ), 2.56—2.45 (m, 4H, CH 2 CH=, C0CH 2 ), 1.68 (s, 3H, CH 3 ), 1.56 (s, 3H, CHs), 1.51-1.53 (m , 6H, 2XCH 3 ), 1.25 (t, 6H, J=6.9Hz, 2X0CH 2 C ).
实施例 15  Example 15
5， 8-二乙氧 ¾"6- (卜垸氧 ¾"4-甲¾~3-戊烯基 )- 1， 4-萘醌的制备  Preparation of 5, 8-diethoxy 3⁄4"6-(dioxax 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone
步骤一同实施例 10中的步骤一；  Step 1 is the same as step 1 in embodiment 10;
步骤二同实施例 11中的步骤二；  Step 2 is the same as step 2 in the embodiment 11;
步骤三，将 2- (1-羟¾~4-甲¾~3-戊烯基 )- 1， 4-二乙氧 ¾"5， 8-二甲氧甲氧基萘与相应的溴 代物反; 羟基进行醚化， 具 实施例 3中的步骤三的方法进行；  In the third step, 2-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)- 1, 4-diethoxy 3⁄4"5, 8-dimethoxymethoxynaphthalene is reacted with the corresponding bromo compound. The hydroxyl group is etherified, and the method of the third step in the third embodiment is carried out;
步骤四， 具体操^ ¾实施例 10中的步骤三方法进行脱甲氧甲基化。  Step 4, specifically performing the method of step 3 in Example 10 for demethoxymethylation.
以 ±¾方法制得 5， 8-二乙氧 ¾"6- (1-甲氧基 - 4-甲¾~3-戊烯基 )- 1， 4-萘醌（VI- 5)橙黄色 油状化合物 10.07mg， 收率 25.2%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.34 (s， 1H， lU， 6.76 (d， 2H， J=l.2 Hz, Hqul„), 5.23 (m， 1H， CH=)， 4.63 (t, 1H， J=5.7 Hz, CH0)， 3.97— 4.19 (m， 4H， 2X0CH2CH3), 3.33 (s， 3H， 0CH3), 2.54-2.34 (m， 2H， CH2)， 1.67 (s， 3H， CH3)， 1.56-1.27 (m， 9H， CHs, 2X0CH2(¾)。 5, 8-Diethoxy 3⁄4"6-(1-methoxy-4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (VI-5) orange-yellow oil was obtained by the method of ±3⁄4 Compound 10.07 mg, yield 25.2%. 3⁄4 Sa (300 MHz, CDCls, δ ppm): 7.34 (s, 1H, lU, 6.76 (d, 2H, J= l.2 Hz, H qul „), 5.23 (m , 1H, CH=), 4.63 (t, 1H, J=5.7 Hz, CH0), 3.97— 4.19 (m, 4H, 2X0CH 2 CH 3 ), 3.33 (s, 3H, 0CH 3 ), 2.54-2.34 (m , 2H, CH 2 ), 1.67 (s, 3H, CH 3 ), 1.56-1.27 (m, 9H, CHs, 2X0CH 2 (3⁄4).
同法制得 5， 8-二乙氧 ¾"6- (1-乙氧基 - 4-甲¾~3-戊烯基 )- 1， 4-萘醌（VI- 6)橙黄色油状化 合物 11.15mg， 收率 27.7%。 ¾薩 (300 MHz, CDCls, δ ppm)： δ 7.45 (s， 1Η， ΗΑ,), 6.77 (d， 2Η， J=3.0 Hz, Hqul„), 5.23 (m， 1H， CH=)， 4.43 (t, 1H， J=5.7 Hz, CH0)， 3.87—4.20 (m， 4H， 2X0CH2CH3), 3.42 (s， 2H， 0CH2CH3), 2.54-2.30 (m， 2H， CH2)， 1.70 (s， 3H， CH3)， 1.55-1.18 (m， 12H， CHs, 2X0CH2CH3, 0CH2CH3) 0 5, 8-Diethoxy 3⁄4"6-(1-ethoxy-4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (VI-6) orange yellow oily compound 11.15mg , yield 27.7%. 3⁄4萨 (300 MHz, CDCls, δ ppm): δ 7.45 (s, 1Η, ΗΑ,), 6.77 (d, 2Η, J=3.0 Hz, H qul „), 5.23 (m, 1H , CH=), 4.43 (t, 1H, J=5.7 Hz, CH0), 3.87—4.20 (m, 4H, 2X0CH 2 CH 3 ), 3.42 (s, 2H, 0CH 2 CH 3 ), 2.54-2.30 (m , 2H, CH 2 ), 1.70 (s, 3H, CH 3 ), 1.55-1.18 (m, 12H, CHs, 2X0CH 2 CH 3 , 0CH 2 CH 3 ) 0
实施例 16  Example 16
5， 8—二甲氧 ¾~2— (1—酰氧 ¾~4—甲¾~3—戊烯基 )— 1， 4—萘醌的制备  Preparation of 1,8-dimethoxy 3⁄4~2-(1-acyloxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone
步骤一同实施例 1中的步骤一；  Step 1 is the same as step 1 in embodiment 1;
步骤二， 化合物 VII- 1与相应的羧酸反; S fi羟基进行酯化， 具 实施例 2中的步骤 三的方法进行；  Step 2, the compound VII-1 is esterified with the corresponding carboxylic acid; the S fi hydroxyl group is esterified, and the method of the third step in the embodiment 2 is carried out;
以 ±¾方法制得 5， 8-二甲氧 ¾"2- α-乙酰氧 ¾"4-甲¾~3-戊烯基 )- 1， 4-萘醌 (W- 2)橙红 色油状化合物 40.7 mg， 收率为 71.9%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.31 (s， 2H， ΗΑ,), 6.69 (s， 1H， Hqul„), 5.90 (m， 1H， CH=)， 5.11 (t, 1H， J=7.20 Hz, CH0)， 3.96 (s， 3H， 0CH3), 3.92 (s， 3H， OCHs), 2.45—2.17 (m， 2H， CH2)， 2.15 (s， 3H， C0CH3), 1.68 (s， 3H， CH3)， 1.58 (s， 3H， CH3). 13C MR (75 MHz, CDCls, δ ppm)： 184.6， 184.1， 169.8， 155.9， 150.5， 144.3, 138.8， 137.7， 135.6， 125.1， 120.0， 118.0， 116.7， 70.4， 61.9， 56.6， 33.9， 25.5， 21.0， 17.7. 5, 8-Dimethoxy 3⁄4"2-α-acetoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (W-2) orange-red oily compound was prepared by the method of ±3⁄4 40.7 mg, yield 71.9%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 7.31 (s, 2H, ΗΑ,), 6.69 (s, 1H, H qul „), 5.90 (m, 1H, CH=), 5.11 (t, 1H, J =7.20 Hz, CH0), 3.96 (s, 3H, 0CH 3 ), 3.92 (s, 3H, OCHs), 2.45—2.17 (m, 2H, CH 2 ), 2.15 (s, 3H, C0CH 3 ), 1.68 ( s, 3H, CH 3 ), 1.58 (s, 3H, CH 3 ). 13 C MR (75 MHz, CDCls, δ ppm): 184.6, 184.1, 169.8, 155.9, 150.5, 144.3, 138.8, 137.7, 135.6, 125.1, 120.0, 118.0, 116.7, 70.4, 61.9, 56.6, 33.9, 25.5, 21.0, 17.7.
同法制得 5,8-二甲氧 ¾"2- (1-丙酰氧 ¾"4-甲¾~3-戊烯基 )- 1,4-萘醌 (VQ-3)橙红色油 状化合物 33.5mg， 收率 56.2%。 ¾薩 (300 MHz, CDCls, δ ppm): 7.29 (s， 2H， H^), 6.63 (d， 1H， J=1.5 Hz, Hqul„), 5.91 (m， 1H， CH=)， 5.10 (t, 1H， J= 7.8 Hz, CHO), 3.93 (s， 6H， 2 XOCHs), 2.57-2.33 (m， 4H， CH2CH=， CH2CH3), 1.64 (s， 3H， CH3)， 1.54 (s， 3H， CH3)， 1.15 (t, 3H， J=7.2 Hz, CH2CH3)。 5,8-Dimethoxy 3⁄4"2-(1-propionyloxy 3⁄4"4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (VQ-3) orange-red oily compound 33.5 Mg, yield 56.2%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 7.29 (s, 2H, H^), 6.63 (d, 1H, J=1.5 Hz, H qul „), 5.91 (m, 1H, CH=), 5.10 ( t, 1H, J= 7.8 Hz, CHO), 3.93 (s, 6H, 2 XOCHs), 2.57-2.33 (m, 4H, CH 2 CH=, CH 2 CH 3 ), 1.64 (s, 3H, CH 3 ) , 1.54 (s, 3H, CH 3 ), 1.15 (t, 3H, J = 7.2 Hz, CH 2 CH 3 ).
同法制得 5,8-二甲氧 ¾"2- (1-丁酰氧 ¾"4-甲¾~3-戊烯基 )- 1,4-萘醌 (VQ-4)橙红色油 状化合物 32.0mg， 收率为 51.8%。 ¾薩 (300 MHz, CDCls, δ ppm): δ 7.29 (s， 2H， ΗΑ,), 6.64 (s， 1H， Hqul„), 5.93 (t, 1H， J=5.1 Hz, CH=)， 6.12 (t, 1H， J=6.9 Hz, CHO), 3.94 (s， 6H， 2 XOCHs), 2.58-2.30 (m， 4H， CH2， CH2CH2Cft), 1.70 (m， 5H， CH2CH2CH3, CH3)， 1.49 (s， 3H， CH3), 0.96 (t, 3H， J=7.5 HZ， CH2CH2CH3) . 5,8-Dimethoxy 3⁄4"2-(1-butyryloxy 3⁄4"4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (VQ-4) orange-red oily compound 32.0 Mg, the yield was 51.8%. 3⁄4萨 (300 MHz, CDCls, δ ppm): δ 7.29 (s, 2H, ΗΑ,), 6.64 (s, 1H, H qul „), 5.93 (t, 1H, J=5.1 Hz, CH=), 6.12 (t, 1H, J=6.9 Hz, CHO), 3.94 (s, 6H, 2 XOCHs), 2.58-2.30 (m, 4H, CH 2 , CH 2 CH 2 Cft), 1.70 (m, 5H, CH 2 CH 2 CH 3 , CH 3 ), 1.49 (s, 3H, CH 3 ), 0.96 (t, 3H, J=7.5 H Z , CH 2 CH 2 CH 3 ) .
同法制得 5,8-二甲氧基- 2- (1-已酰氧基)- 4-甲¾~3-戊烯基 )- 1,4-萘醌 (VQ-5)橙红色油 状化合物 31.7mg， 收率为 49.5%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.31 (s， 2H， ΗΑ,), 6.65 (d， 1H， J=l.5 Hz, Hqul„), 5.93 (m， 1H， J=5.1 Hz, CH=)， 5.11 (t, 1H， J=5.1 Hz, CHO), 3.94 (s， 6H， 2 X OCHs), 2.59-2.32 (m， 4H， CH2CH=, CH2CH2 CH2CH2CH3)， 1.66-1.50 (m， 5H， CH2CH2CH2CH2CH3, Cft)， 1.48 (s， 3H， CH3)， 1.33-1.25 (m， 4H， CH2CH2(¾C¾CH3)， 0.91 (m， 3H，
Figure imgf000028_0001
5,8-Dimethoxy-2-(1-hexanoyloxy)-4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (VQ-5) orange-red oily compound 31.7 mg, the yield was 49.5%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 7.31 (s, 2H, ΗΑ,), 6.65 (d, 1H, J=l.5 Hz, H qul „), 5.93 (m, 1H, J=5.1 Hz , CH=), 5.11 (t, 1H, J=5.1 Hz, CHO), 3.94 (s, 6H, 2 X OCHs), 2.59-2.32 (m, 4H, CH 2 CH=, CH 2 CH 2 CH 2 CH 2 CH 3 ), 1.66-1.50 (m, 5H, CH 2 CH 2 CH 2 CH 2 CH 3 , Cft), 1.48 (s, 3H, CH 3 ), 1.33-1.25 (m, 4H, CH 2 CH 2 ( 3⁄4C3⁄4CH 3 ), 0.91 (m, 3H,
Figure imgf000028_0001
同法制得 5， 8-二甲氧 ¾"2- [卜 (2-丁烯酰氧基) - 4-甲¾~3-戊烯基 )- 1， 4-萘醌（VII- 6)橙红 色油状化合物 32.7mg, 收率 53.2%。 ¾ MR (300 MHz, CDCls, δ ppm)： 7.30 (s， 2Η， ΗΑ,), 7.03—6.97 (m， 1H， C0CH=), 6.65 (s， 1H， Hquin)， 5.97—5.92 (m， 1H， CH=)， 5.87 (m， 1H， =CHCH3), 5.13 (t, 1H， J=6.3Hz， CHO), 3.90 (s， 6H， 2X0CH3), 2.65—2.44 (m， 2H， CH2)， 1.92—1.89 (m， 3H， =CHCH3), 1.72 (s， 3H， CH3)， 1.54 (s， 3H， CH3) . 5, 8-Dimethoxy 3⁄4"2-[Bu(2-butenoyloxy)-4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (VII-6) Orange Red oily compound 32.7mg, yield 53.2%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.30 (s, 2Η, ΗΑ,), 7.03—6.97 (m, 1H, C0CH=), 6.65 (s, 1H , H quin ), 5.97—5.92 (m, 1H, CH=), 5.87 (m, 1H, =CHCH 3 ), 5.13 (t, 1H, J=6.3Hz, CHO), 3.90 (s, 6H, 2X0CH 3 ), 2.65—2.44 (m, 2H, CH 2 ), 1.92—1.89 (m, 3H, =CHCH 3 ), 1.72 (s, 3H, CH 3 ), 1.54 (s, 3H, CH 3 ) .
同法制得 5， 8-二甲氧基- 2- [1- (3， 3-二甲基丙烯酰氧基) -4-甲基- 3-戊烯基 )-1， 4-萘醌 5, 8-Dimethoxy-2- [1-(3, 3-dimethylacryloyloxy)-4-methyl-3-pentenyl)-1,4-naphthoquinone by the same method
(VQ-7)橙红色油状化合物 39.4 mg， 收率 62.4%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.30 (s， 2Η， ΗΑ,), 6.67 (d， 1H， J=l.5 Hz ， Hquin)， 5.91 (m， 1H， CH=)， 5.88 (s， 1H， C0CH=), 5.11 (t, 1H， J=6.3 Hz, CHO), 3.94 (s， 6H， 2 XOCHs), 2.70-2.55 (m， 1H， CHa), 2.54-2.42 (m， 1H， CHb), 2.15 (s， 3H， CH3)， 1.92 (s， 3H， CH3)， 1.67 (s， 3H， CH3)， 1.56 (s， 3H， CH3) . 同法制得 5,8-二甲氧基- 2- (1-异丁酰氧¾~4-甲¾~3-戊烯基 )- 1,4-萘醌 (VQ-8)橙红色 油状化合物 34.2mg， 收率 55.3%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.29 (s， 2H， ΗΑ,), 6.62 (d， 1H， J=0.9 Hz, Hqul„), 5.87 (m， 1H， CH=)， 5.10 (t, 1H， J=5.1 Hz, CH0)， 3.90 (s， 6H， 2X0CHs), 2.62-2.53 (m， 2H， CH2)， 2.43 (m， 1H， CH(CH3)2), 1.49 (s， 3H， CH3)， 1.47 (s， 3H， CHs), 1.17 (d， 3H， J=2.4 Hz, CH ((¾))， 1.15 (d， 3H， J=2.4 Hz, CH ((¾))。 (VQ-7) orange red oily compound 39.4 mg, yield 62.4%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 7.30 (s, 2Η, ΗΑ,), 6.67 (d, 1H, J=l.5 Hz, H quin ), 5.91 (m, 1H, CH=), 5.88 (s, 1H, C0CH=), 5.11 (t, 1H, J=6.3 Hz, CHO), 3.94 (s, 6H, 2 XOCHs), 2.70-2.55 (m, 1H, CHa), 2.54-2.42 (m, 1H, CH b ), 2.15 (s, 3H, CH 3 ), 1.92 (s, 3H, CH 3 ), 1.67 (s, 3H, CH 3 ), 1.56 (s, 3H, CH 3 ) . 5,8-Dimethoxy-2-(1-isobutyryloxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (VQ-8) orange-red oily compound 34.2 mg, yield 55.3%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 7.29 (s, 2H, ΗΑ,), 6.62 (d, 1H, J=0.9 Hz, H qul „), 5.87 (m, 1H, CH=), 5.10 ( t, 1H, J=5.1 Hz, CH0), 3.90 (s, 6H, 2X0CHs), 2.62-2.53 (m, 2H, CH 2 ), 2.43 (m, 1H, CH(CH 3 ) 2 ), 1.49 (s , 3H, CH 3 ), 1.47 (s, 3H, CHs), 1.17 (d, 3H, J=2.4 H z , CH ((3⁄4)), 1.15 (d, 3H, J=2.4 H z , CH (( 3⁄4)).
同法制得 5,8-二甲氧 ¾"2- [卜(2-甲基丁酰氧基 )- 4-甲¾~3-戊烯基 ]- 1,4-萘醌 (VQ-9) 橙红色油状化合物 28.9mg, 收率 45.3%。 m. p.59°C， ¾ MR (300 MHz, CDCls, δ ppm)： 7.27 (s， 2H， HA,), 6.62 (m， 1H， uin)， 5.89 (m， 1H， CH=)， 5.10 (t, 1H， J=5.1 Hz, CH0)， 3.91 (s, 6H， 2X0CHs), 2.60—1.88 (m， 3H， CH2CH=, COCH), 1.63 (s， 3H， CH3)， 1.54 (s， 3H， CH3)， 1.17 (d， 6H， J=3.0 HZ， 2XCH3), 0.94—0.86 (m， 2H， CH2CH3) . 5,8-Dimethoxy 3⁄4"2-[Bu(2-methylbutyryloxy)-4-methyl-3⁄4~3-pentenyl]-1,4-naphthoquinone (VQ-9) 28.9 mg of orange-red oily compound, yield 45.3%. mp59 ° C, 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.27 (s, 2H, HA,), 6.62 (m, 1H, uin ), 5.89 (m , 1H, CH=), 5.10 (t, 1H, J=5.1 Hz, CH0), 3.91 (s, 6H, 2X0CHs), 2.60—1.88 (m, 3H, CH 2 CH=, COCH), 1.63 (s, 3H, CH 3 ), 1.54 (s, 3H, CH 3 ), 1.17 (d, 6H, J=3.0 H Z , 2XCH 3 ), 0.94—0.86 (m, 2H, CH 2 CH 3 ) .
同法制得 5,8-二甲氧基- 2- (1-苯甲酰氧¾~4-甲¾~3-戊烯基 )- 1,4-萘醌 (VQ-10)橙红色 油状化合物 44.7 mg,收率 36.7%。 ¾薩 (300 MHz, CDCls, δ ppm)： 8.09 (m， 2H， ΗΑ,), 7.61-7.39 (m， 3H， HA,), 7.33 (s， 2H， H^), 6.78 (s， 1H， Hqul„), 6.34 (m， 1H， CH=)， 5.23 (t, 1H， J=6.9 Hz, CH0)， 3.98 (s， 3H， 0CH3), 3.88 (s， 3H， 0CH3), 2.66—2.56 (m， 2H， CH2)， 1.68 (s， 3H， CHs), 1.52 (s， 3H， CH3) . 5,8-Dimethoxy-2-(1-benzoyloxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (VQ-10) orange-red oily compound 44.7 mg, yield 36.7%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 8.09 (m, 2H, ΗΑ,), 7.61-7.39 (m, 3H, HA,), 7.33 (s, 2H, H^), 6.78 (s, 1H, H qul „), 6.34 (m, 1H, CH=), 5.23 (t, 1H, J=6.9 Hz, CH0), 3.98 (s, 3H, 0CH 3 ), 3.88 (s, 3H, 0CH 3 ), 2.66 —2.56 (m, 2H, CH 2 ), 1.68 (s, 3H, CHs), 1.52 (s, 3H, CH 3 ) .
同法制得 5,8-二甲氧基- 2- (1-肉桂酰氧¾~4-甲¾~3-戊烯基 )- 1,4-萘醌（W- 11)橙红色 油状化合物 53.4 mg, 收率 41.3%。 ¾ MR (300 MHz, CDCls, δ ppm)： 7.72 (d， 1H， J=15.9 Hz, C0CH=), 7.56-7.31 (m， 7H， H^), 6.72 (s， 1H， Hquin)， 6.51 (d， 1H， J=15.9 Hz, =CH)， 5.91 (ddd， 1H， J=7.2, 3.3， 3.6 Hz, CH=)， 5.11 (t, 1H， J=7.5 Hz, CH0)， 3.96 (s， 6H， 2X0CH3), 2.75-2.60 (m， 1H， CH2)， 2.58-2.49 (m， 1H， CH2)， 1.67 (s， 3H， CH3)， 1.58 (s， 3H， CH3) . 同法制得 5，8-二甲氧¾"2-(卜苯丙酰氧¾"4-甲¾"3-戊烯基)-1，4-萘醌 (Vn-12)橙红色 油状化合物 46.9 mg， 收率 36.1%。 ¾ MR (300 MHz, CDCls, δ ppm)： 7.31-7.17 (m， 7H， ΗΑ,), 6.56 (d， 1H， J=l.2 Hz, Hqul„) ， 5.92—5.88 (m， 1H， CH=)， 5.01 (t, 1H， J=6.3 Hz, CH0)， 3.90 (s， 6H， 2X0CH3), 2.97 (t, 2H， J=7.8 Hz, ArCH2), 2.71—2.53 (t, 2H， J=7.8 Hz, C0CH2), 2.43-2.38 (m， 2H， CH2)， 1.64 (s， 3H， CH3)， 1.53 (s， 3H， CH3) . 5,8-Dimethoxy-2-(1-cinnamoyloxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (W-11) orange red oily compound 53.4 Mg, yield 41.3%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.72 (d, 1H, J=15.9 Hz, C0CH=), 7.56-7.31 (m, 7H, H^), 6.72 (s, 1H, H quin ), 6.51 (d, 1H, J=15.9 Hz, =CH), 5.91 (ddd, 1H, J=7.2, 3.3, 3.6 Hz, CH=), 5.11 (t, 1H, J=7.5 Hz, CH0), 3.96 (s , 6H, 2X0CH 3 ), 2.75-2.60 (m, 1H, CH 2 ), 2.58-2.49 (m, 1H, CH 2 ), 1.67 (s, 3H, CH 3 ), 1.58 (s, 3H, CH 3 ) . 5,8-Dimethoxy 3⁄4"2-(Phenylpropionyloxy 3⁄4"4-methyl 3⁄4"3-pentenyl)-1,4-naphthoquinone (Vn-12) orange-red oily compound 46.9 mg, yield 36.1%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.31-7.17 (m, 7H, ΗΑ,), 6.56 (d, 1H, J= l.2 Hz, H qul „) , 5.92—5.88 (m, 1H, CH=), 5.01 (t, 1H, J=6.3 Hz, CH0), 3.90 (s, 6H, 2X0CH 3 ), 2.97 (t, 2H, J=7.8 Hz, ArCH 2 ) , 2.71—2.53 (t, 2H, J=7.8 Hz, C0CH 2 ), 2.43-2.38 (m, 2H, CH 2 ), 1.64 (s, 3H, CH 3 ), 1.53 (s, 3H, CH 3 ) .
同法制得 5,8-二甲氧基- 2- [1- (4-甲氧基苯甲酰氧基) -4-甲¾~3-戊烯基 ]- 1,4-萘醌 (VQ -13)橙红色油状化合物 44.0 mg， 收率 33.7%。 ¾薩 (300 MHz, CDCls, δ ppm): 8.03 (d， 1H， J=7.8 Hz, HA,), 8.02 (d， 1H， J=7.8 Hz, H^), 7.31 (s， 2H， H^), 6.95 (d， 1H， J=7.8 Hz, HA,), 6.94 (d， 1H， J=7.8 Hz, H^), 6.78 (s， 1H， Hquin)， 6.13 (t, 1H， J= 5.7 Hz, CH=)， 5.23 (t, 1H， J=6.9 Hz, CHO), 4.02 (s， 3H， 0CH3), 3.97 (s， 3H， 0CH3), 3.94 (s， 3H， 0CH3), 2.72—2.57 (m, 2H， CH2)， 1.69 (s， 3H， CH3)， 1.58 (s， 3H， CH3) . 5,8-Dimethoxy-2- [1-(4-methoxybenzoyloxy)-4-methyl 3⁄4~3-pentenyl]-1,4-naphthoquinone (VQ) -13) Orange red oily compound 44.0 mg, yield 33.7%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 8.03 (d, 1H, J=7.8 Hz, HA,), 8.02 (d, 1H, J=7.8 Hz, H^), 7.31 (s, 2H, H^ ), 6.95 (d, 1H, J=7.8 Hz, HA,), 6.94 (d, 1H, J=7.8 Hz, H^), 6.78 (s, 1H, H quin ), 6.13 (t, 1H, J= 5.7 Hz, CH=), 5.23 (t, 1H, J=6.9 Hz, CHO), 4.02 (s, 3H, 0CH 3 ), 3.97 (s, 3H, 0CH 3 ), 3.94 (s, 3H, 0CH 3 ), 2.72—2.57 (m, 2H , CH 2 ), 1.69 (s, 3H, CH 3 ), 1.58 (s, 3H, CH 3 ) .
同法制得 5,8-二甲氧 ¾"2- [卜(4-甲氧基苯乙酰氧基) - 4-甲¾~3-戊烯基 ]- 1,4-萘醌 (VQ -14)橙红色油状化合物 52.7 mg, 收率 39.2%。 ¾ MR (300 MHz, CDCls, δ ppm)： 7.29 (s， 2H， ΗΑ,), 7.20 (d， 2H， J= 2.7 Hz, HA,), 6.87 (d， 2H， J=2.7 Hz, HA,), 6.53 (s， 1H， Hquin)， 5.92 (m， 1H， CH=)， 5.03 (t, 1H， J=7.5 Hz, CHO), 3.90 (s， 6H， 2X0CH3), 3.79 (s， 3H， 0CH3), 3.61 (s， 2H， CHzAr )， 2.55-2.37 (m， 2H， CH2)， 1.63 (s， 3H， CH3)， 1.26 (s， 3H， CH3) . 同法制得 5,8-二甲氧基- 2- [1- (4-硝基苯甲酰氧基)- 4-甲基- 3-戊烯基 ]- 1,4-萘醌 (VQ -15)橙红色油状化合物 58.3mg, 收率 78.3%。 ¾薩 (300 MHz, CDCls, δ ppm)： 8.33-8.20 (m， 4H， ΗΑ,), 7.33 (s， 2H， H^), 6.79 (d， J=l.2 Hz, Hquin)， 6.17 (m， 1H， CH=)， 5.18 (t, 1H， J=7.2 Hz, CHO), 3.95 (s， 3H， 0CH3), 3.92 (s， 3H， 0CH3), 2.67-2.54 (m， 2H， CH2)， 1.66 (s， 3H， CHs), 1.57 (s， 3H， CH3)。 5,8-Dimethoxy 3⁄4"2-[Bu(4-methoxyphenylacetoxy)-4-methyl-3⁄4~3-pentenyl]-1,4-naphthoquinone (VQ-14) ) orange red oily compound 52.7 mg, yield 39.2%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.29 (s, 2H, ΗΑ,), 7.20 (d, 2H, J = 2.7 Hz, HA,), 6.87 (d, 2H, J=2.7 Hz, HA,), 6.53 (s, 1H, H quin ), 5.92 (m, 1H, CH=), 5.03 (t, 1H, J=7.5 Hz, CHO), 3.90 (s, 6H, 2X0CH 3 ), 3.79 (s, 3H, 0CH 3 ), 3.61 (s, 2H, CHzAr ), 2.55-2.37 (m, 2H, CH 2 ), 1.63 (s, 3H, CH 3 ), 1.26 (s, 3H, CH 3 ) . In the same manner, 5,8-dimethoxy-2- [1-(4-nitrobenzoyloxy)-4-methyl-3-pentenyl] - 1,4-naphthoquinone (VQ -15) orange red oily compound 58.3 mg, yield 78.3%. 3⁄4 Sa (300 MHz, CDCls, δ ppm): 8.33-8.20 (m, 4H, ΗΑ,), 7.33 ( s, 2H, H^), 6.79 (d, J=l.2 Hz, H quin ), 6.17 (m, 1H, CH=), 5.18 (t, 1H, J=7.2 Hz, CHO), 3.95 (s , 3H, 0CH 3 ), 3.92 (s, 3H, 0CH 3 ), 2.67-2.54 (m, 2H, CH 2 ), 1.66 (s, 3H, CHs), 1.57 (s, 3H, CH 3 ).
同法制得 5,8-二甲氧 ¾"2- [1- (2-甲氧基苯甲酰氧基) - 4-甲¾~3-戊烯基 ]- 1,4-萘醌 (VQ -16)橙红色油状化合物 41.1 mg, 收率 31.5%. ¾ MR (300 MHz, CDCls, δ ppm)： 7.83-7.80 (m， 1H， HA.), 7.51-7.46 (m， 1H， H^), 7.45 (d， 1H， J=2.4 Hz, H^), 7.44 (d， 1H， J=2.4 Hz, HA,), 7.02—6.97 (m， 2H， H^), 6.87 (d， 1H， J=l.2 Hz, HQUIN)， 6.17 (m， 1H， CH=)， 5.20 (t, 1H， J=8.1Hz, CHO), 3.96 (s， 3H， 0CH3), 3.94 (s， 3H， 0CH3), 3.88 (s， 3H， 0CH3), 2.57-2.38 (m， 2H， CH2)， 1.65 (s， 3H， CH3)， 1.54 (s， 3H， CH3)。 5,8-Dimethoxy 3⁄4"2- [1-(2-methoxybenzoyloxy)-4-methyl-3⁄4~3-pentenyl]-1,4-naphthoquinone (VQ) -16) Orange-red oily compound 41.1 mg, yield 31.5%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.83-7.80 (m, 1H, HA.), 7.51-7.46 (m, 1H, H^) , 7.45 (d, 1H, J=2.4 Hz, H^), 7.44 (d, 1H, J=2.4 Hz, HA,), 7.02—6.97 (m, 2H, H^), 6.87 (d, 1H, J = l.2 Hz, H QUIN ), 6.17 (m, 1H, CH=), 5.20 (t, 1H, J=8.1Hz, CHO), 3.96 (s, 3H, 0CH 3 ), 3.94 (s, 3H, 0CH 3 ), 3.88 (s, 3H, 0CH 3 ), 2.57-2.38 (m, 2H, CH 2 ), 1.65 (s, 3H, CH 3 ), 1.54 (s, 3H, CH 3 ).
同法制得 5，8—二甲氧¾"2—[1— (3—羟¾~3—甲基丁酰氧基）—4， —甲 ¾~3， —戊烯基]— 1,4— 萘醌 (VQ-17)橙红色油状化合物 27.3mg, 收率 37.1%。 ¾ MR (300 MHz, CDCls, δ ppm)： 7.31 (s， 2H， ΗΑ,), 6.67 (s， 1H， Hquin)， 5.98 (t, 1H， J=2.7 Hz, CH=)， 5.10 (t, 1H， J=8.4 Hz, CHO), 3.95 (s， 6H， 2X0CH3), 2.58-2.38 (m， 4H， CH2CH=， C0CH2), 1.66 (s， 3H， CH3)， 1.56 (s， 3H， CHs), 1.28 (s， 3H， CH3)， 1.27 (s， 3H， CH3)。 5,8-Dimethoxy 3⁄4"2-[1-(3-hydroxy 3⁄4~3-methylbutyryloxy)-4,-methyl 3⁄4~3,-pentenyl]-1,4 — Naphthoquinone (VQ-17) orange red oily compound 27.3 mg, yield 37.1%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.31 (s, 2H, ΗΑ,), 6.67 (s, 1H, H quin ), 5.98 (t, 1H, J=2.7 Hz, CH=), 5.10 (t, 1H, J=8.4 Hz, CHO), 3.95 (s, 6H, 2X0CH 3 ), 2.58-2.38 (m, 4H, CH 2 CH=, C0CH 2 ), 1.66 (s, 3H, CH 3 ), 1.56 (s, 3H, CHs), 1.28 (s, 3H, CH 3 ), 1.27 (s, 3H, CH 3 ).
同法制得 5， 8—二甲氧 ¾"2— [1— (2—呋喃甲酰氧基 )— 4—甲¾~3—戊烯基 ]— 1， 4—萘醌（VII— 18) 橙红色油状化合物 60.8 mg,收率 65.3%。 ¾ MR (300 MHz, CDCls, δ ppm)： 7.61 (d， 1H， J=0.9Hz, HFU), 7.32 (s， 2H， HA,) 7.23 (m， 1H， HFu )， 6.75 (d， 1H， J=0.9Hz, Hquin)， 6.67 (m， 1H， HFu)， 6.15 (t, 1H， J= 4.8, 4.2 Hz, CH=)， 5.18 (t, 1H， J= 3.6 Hz, CHO), 3.97 (s， 3H， 0CH3), 3.95 (s， 3H， OCHs), 2.69-2.56 (m， 2H， CH2)， 1.67 (s， 3H， CH3)， 1.59 (s， 3H， CH3) . 同法制得 5， 8-二甲氧 ¾"2- [1- (3-呋喃甲酰氧基 )- 4-甲¾~3-戊烯基 ]- 1， 4-萘醌（W- 19) 橙红色油状化合物 54.0 mg， 收率 55.8%。 ¾薩 (300 MHz, CDCls, δ ppm)： 8.06 (s， 1H， HFu)， 7.44 (s， 1H， HFU), 7.31 (s， 2H， H^), 6.82 (s， 1H， HQUIN)， 6.80 (s, 1H， HFU)， 6.09 (t, 1H， J=6.3 Hz, CH=)， 5.16 (t, 1H， J=6.3 Hz, CHO), 3.97 (s， 3H， 0CH3), 3.88 (s， 3H， 0CH3), 2,68—2.50 (m, 2H， CH2)， 1.66 (s， 3H， CH3) 1.58 (s， 3H， CH3) . 5,8-Dimethoxy 3⁄4"2-[1-(2-furoyloxy)-4-methyl-3⁄4~3-pentenyl]-1,4-naphthylquinone (VII-18) 60.8 mg of orange-red oily compound, yield 65.3%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.61 (d, 1H, J=0.9Hz, HFU), 7.32 (s, 2H, HA,) 7.23 (m , 1H, H Fu ), 6.75 (d, 1H, J=0.9Hz, H quin ), 6.67 (m, 1H, H Fu ), 6.15 (t, 1H, J= 4.8, 4.2 Hz, CH=), 5.18 (t, 1H, J = 3.6 Hz, CHO), 3.97 (s, 3H, 0CH 3 ), 3.95 (s, 3H, OCHs), 2.69-2.56 (m, 2H, CH 2 ), 1.67 (s, 3H, CH 3 ), 1.59 (s, 3H, CH 3 ). 5, 8-Dimethoxy 3⁄4 "2- [1-(3-furoyloxy)-4-methyl 3⁄4~3-pentene Base]- 1, 4-naphthoquinone (W-19) Orange red oily compound 54.0 mg, yield 55.8%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 8.06 (s, 1H, H Fu ), 7.44 (s, 1H, HFU), 7.31 (s, 2H, H^), 6.82 (s, 1H, H QUIN ) , 6.80 (s, 1H, H FU ), 6.09 (t, 1H, J=6.3 Hz, CH=), 5.16 (t, 1H, J=6.3 Hz, CHO), 3.97 (s, 3H, 0CH 3 ), 3.88 (s, 3H, 0CH 3 ), 2,68—2.50 (m, 2H, CH 2 ), 1.66 (s, 3H, CH 3 ) 1.58 (s, 3H, CH 3 ) .
同法制得 5， 8-二甲氧基- 2- [1- (2-四氢呋喃甲酰氧基) -4-甲基- 3-戊烯基 ]-1， 4-萘醌 (VQ 5, 8-Dimethoxy-2- [1-(2-tetrahydrofuroylcarbonyloxy)-4-methyl-3-pentenyl]-1,4-naphthoquinone (VQ)
-20)橙红色油状化合物 56.1 mg, 收率 60.2%。 ¾ MR (300 MHz, CDCls, δ ppm)： 6.79 (s， 2H， ΗΑ,), 6.68 (d， 1H， J=0.9 Hz, Hquin)， 6.00 (m， 1H， CH=)， 5.11 (t, 1H， J=6.6 Hz, CHO), 4.53 (m， 1H， J=4.8 Hz, C0CH0), 4.01-3.87 (m， 8H， 2X0CH3, 0CH2CH2), 2,56-2.44 (m， 2H， CH2)， 2.28-2.22 (m， 1H， CHaCH=), 2.05-1.91 (m， 3H， CHbCH=， 0CH2CH2 ), 1.67 (s， 3H， CH3)， 1.58 (s， 3H， CHs). -20) Orange-red oily compound 56.1 mg, yield 60.2%. 3⁄4 MR (300 MHz, CDCls, δ ppm): 6.79 (s, 2H, ΗΑ,), 6.68 (d, 1H, J=0.9 Hz, H quin ), 6.00 (m, 1H, CH=), 5.11 (t , 1H, J=6.6 Hz, CHO), 4.53 (m, 1H, J=4.8 Hz, C0CH0), 4.01-3.87 (m, 8H, 2X0CH 3 , 0CH 2 CH 2 ), 2,56-2.44 (m, 2H, CH 2 ), 2.28-2.22 (m, 1H, CHaCH=), 2.05-1.91 (m, 3H, CH b CH=, 0CH 2 CH 2 ), 1.67 (s, 3H, CH 3 ), 1.58 (s , 3H, CHs).
同法制得 5,8-二甲氧 ¾"2- [1- (3-四氢呋喃甲酰氧基) - 4-甲¾~3-戊烯基 ]- 1,4-萘醌 (VQ -21)橙红色油状化合物 48.5 mg， 收率 50.1%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.31 (s， 2H， ΗΑ,), 6.80 (d， 1H， J=4.2Hz, Hquin)， 6.16 (t, 1H， J=5.7 Hz, CH=)， 5.10 (t, 1H， J=7.8 Hz, CHO), 4.00-3.78 (m， 10H, 2X0CH3, 2X0CH2), 3.17 (m， 1H， C0CH), 2,60-2.31 (m， 2H， CH2CH), 2.21-2.13 (m， 2H， CH2)， 1.67 (s， 3H， CH3)， 1.57 (s， 3H， CH3) . 5,8-Dimethoxy 3⁄4"2- [1-(3-tetrahydrofuroyloxy)-4-methyl-3⁄4~3-pentenyl]-1,4-naphthoquinone (VQ-21) Orange red oily compound 48.5 mg, yield 50.1%. 3⁄4 Sa (300 MHz, CDCls, δ ppm): 7.31 (s, 2H, ΗΑ,), 6.80 (d, 1H, J=4.2Hz, H quin ), 6.16 (t, 1H, J=5.7 Hz, CH=), 5.10 (t, 1H, J=7.8 Hz, CHO), 4.00-3.78 (m, 10H, 2X0CH 3 , 2X0CH 2 ), 3.17 (m, 1H, C0CH ), 2,60-2.31 (m, 2H, CH 2 CH), 2.21-2.13 (m, 2H, CH 2 ), 1.67 (s, 3H, CH 3 ), 1.57 (s, 3H, CH 3 ) .
实施例 17  Example 17
5， 8—二甲氧 ¾~2— (1—垸氧 ¾~4—甲¾~3—戊烯基 )— 1， 4—萘醌的制备  Preparation of 5,8-dimethoxy 3⁄4~2—(1-oxo 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone
步骤一及步骤二同实施例 1;  Step 1 and step 2 are the same as embodiment 1;
步骤三，将 1，4，5，8-四甲氧¾"2-(1-羟¾"4-甲¾"3-戊烯基)萘（Π- 1)按实施例 3中的步 骤三的方法进行醚化， 制得 1， 4, 5， 8-四甲氧 ¾"2- (1-垸氧 ¾"4-甲基- 3-戊烯基)萘；  Step three, 1,4,5,8-tetramethoxy 3⁄4"2-(1-hydroxy 3⁄4"4-methyl 3⁄4"3-pentenyl) naphthalene (Π-1) according to the third step in the third embodiment Method for etherification to obtain 1,4,5, 8-tetramethoxy 3⁄4"2-(1-oxooxy 3⁄4"4-methyl-3-pentenyl)naphthalene;
步骤四，将 1，4，5，8-四甲氧¾"2-(1-垸氧¾"4-甲¾"3-戊烯基)萘溶于乙腈中，充分搅拌， 慢慢滴入硝酸铈铵水溶液， 25 反应 30分钟。 减压蒸去乙腈， 用乙酸乙酯分二次萃取残留物， 合并乙酸乙酯，用无水 MgS04 ， 减压蒸去乙酸乙酯。 品用硅胶柱层析， 乙酸乙酯：石油 醚（1: 4)洗脱，得到 5，8-二甲氧¾"2-(卜垸氧¾"4-甲¾"3-戊烯基)-1，4-萘醌（V 和 5,8- 二甲氧 ¾"6- (卜垸氧¾~4-甲¾~3-戊烯基 )- 1,4-萘醌 (V)o Step 4, Dissolve 1,4,5,8-tetramethoxy 3⁄4"2-(1-oxo 3⁄4"4-methyl 3⁄4"3-pentenyl)naphthalene in acetonitrile, stir well, and slowly drip in an aqueous solution of cerium ammonium nitrate, 25 for 30 minutes. acetonitrile is distilled off under reduced pressure, the residue was extracted twice points, combined with ethyl acetate and ethyl acetate, dried over anhydrous MgS0 4, ethyl acetate was distilled off under reduced pressure. product was purified by column Chromatography, ethyl acetate: petroleum ether (1: 4) eluted to give 5,8-dimethoxy 3⁄4"2-(dioxa 3⁄4"4-methyl 3⁄4"3-pentenyl)-1,4 -naphthoquinone (V and 5,8-dimethoxy 3⁄4"6- (dioxa 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (V)o
以 ±¾方法制得 5，8-二甲氧基-2-(1-甲氧¾"4-甲¾"3-戊烯基)-1，4-萘醌 (VQ-22)橙红 色油状物 24.5mg，收率 54.1%。 ¾ NMR ( 300MHz, CDCls, δ ppm)： 7.30 (s， 2H， ΗΑ,), 6.77 (d， 5,8-Dimethoxy-2-(1-methoxy 3⁄4"4-methyl 3⁄4"3-pentenyl)-1,4-naphthoquinone (VQ-22) orange-red oil was obtained by the method of ±3⁄4 24.5 mg, yield 54.1%. 3⁄4 NMR (300MHz, CDCls, δ ppm): 7.30 (s, 2H, ΗΑ,), 6.77 (d,
1H， J=0.9Hz, Hqul„), 5.17 (t, 1H， J=l.2Hz, CH=)， 4.75 (m， 1H， CHO), 3.96 (s， 6H， 2X1H, J=0.9Hz, H qul „), 5.17 (t, 1H, J=l.2Hz, CH=), 4.75 (m, 1H, CHO), 3.96 (s, 6H, 2X
OCHs), 3.30 (s， 3H， 0CH3), 2.51-2.46 (m， 2H， CH2)， 1.65 (s， 3H， CH3)， 1.58(s， 3H， CH3) . 同法制得 5，8-二甲氧¾"2-(卜乙氧¾"4-甲¾"3-戊烯基)-1，4-萘醌 (Vn-23)橙红色油状 物 25.6mg，收率 55.5%。 ¾NMR (300 MHz, CDCls, δ ppm)： 7.29 (s， 2Η， ΗΑ,), 6.80 (s， 1H， Hquin)， 5.17 (t, 1H， J=5.1Hz, CH=)， 4.57 (t, 1H， J=3.9Hz, CHO), 3.94 (s， 6H， 2 X0CH3), 3.40 (m， 2H， 0CH2CH3), 2,23-2.47 (m， 2H， CH2)， 1.61 (s， 3H， CH3)， 1.47 (s， 3H， CH3)， 1.20 (t, 3H， J=5.4Hz, 0CH2(¾)。 OCHs), 3.30 (s, 3H, 0CH 3 ), 2.51-2.46 (m, 2H, CH 2 ), 1.65 (s, 3H, CH 3 ), 1.58 (s, 3H, CH 3 ) . 5,8-Dimethoxy 3⁄4"2-(Buethoxy 3⁄4"4-methyl 3⁄4"3-pentenyl)-1,4-naphthoquinone (Vn-23) orange red oil 25.6 mg, Yield 55.5%. 3⁄4 NMR (300 MHz, CDCls, δ ppm): 7.29 (s, 2Η, ΗΑ,), 6.80 (s, 1H, H quin ), 5.17 (t, 1H, J=5.1Hz, CH=) , 4.57 (t, 1H, J=3.9Hz, CHO), 3.94 (s, 6H, 2 X0CH 3 ), 3.40 (m, 2H, 0CH 2 CH 3 ), 2,23-2.47 (m, 2H, CH 2 ), 1.61 (s, 3H, CH 3 ), 1.47 (s, 3H, CH 3 ), 1.20 (t, 3H, J=5.4Hz, 0CH 2 (3⁄4).
同法制得 5，8-二甲氧¾"2-(卜丙氧¾"4-甲¾"3-戊烯基)-1，4-萘醌 (Vn-24)橙红色油状 物 25.4mg，收率 53.6%。 ¾薩 (300 MHz, CDCls, δ (ppm): 7.23 (s， 2H， H^), 6.74 (d， 1H， J=l.2Hz, Hqul„), 5.14 (m， 1H， CH=)， 4.49 (m， 1H， CHO), 3.89 (s， 6H， 2X0CH3), 3.29 (m， 2H， 0CH2CH2CH3), 2.41-2.17 (m， 2H， CH2)， 1.67 (s， 3H， CH3)， 1.64 (m， 2H， 0CH2CH2CH3), 1.46 (s， 3H， CHs), 0.87 (t, 3H，J=7.2Hz， 0CH2CH2CH3) . 5,8-Dimethoxy 3⁄4"2-(Bupropoxy 3⁄4"4-methyl 3⁄4"3-pentenyl)-1,4-naphthoquinone (Vn-24) orange-red oil 25.4 mg, Yield 53.6%. 3⁄4sa (300 MHz, CDCls, δ (ppm): 7.23 (s, 2H, H^), 6.74 (d, 1H, J=l.2Hz, H qul „), 5.14 (m, 1H , CH=), 4.49 (m, 1H, CHO), 3.89 (s, 6H, 2X0CH 3 ), 3.29 (m, 2H, 0CH 2 CH 2 CH 3 ), 2.41-2.17 (m, 2H, CH 2 ), 1.67 (s, 3H, CH 3 ), 1.64 (m, 2H, 0CH 2 CH 2 CH 3 ), 1.46 (s, 3H, CHs), 0.87 (t, 3H, J=7.2Hz, 0CH 2 CH 2 CH 3 ) .
同法制得 5， 8-二甲氧基- 2- [1- (2-羟基乙氧基) -4-甲基- 3-戊烯基 ]- 1,4-萘醌（W- 25)橙红色 油状物 22.49 mg，收率 47.2 %。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.30 (s， 2H， ΗΑ,), 6.79 (s， 1H， Hqul„), 5.26—5.11 (m， 1H， CH=)， 4.66—4.55 (m， 1H， CHO), 3.94 (s， 6H， 2X0CH3), 3.73-3.65 (m， 2H， 0CH2), 3.62-3.40 (m, 2H， 0CH2)， 2.55-2.20 (m, 2H， CH2)， 1.66 (s, 3H， CHs), 1.55 (s， 3H， CH3). 实施例 18 5, 8-Dimethoxy-2- [1-(2-hydroxyethoxy)-4-methyl-3-pentenyl]-1,4-naphthoquinone (W-25) orange Red oil 22.49 mg, yield 47.2%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 7.30 (s, 2H, ΗΑ,), 6.79 (s, 1H, H qul „), 5.26—5.11 (m, 1H, CH=), 4.66—4.55 (m , 1H, CHO), 3.94 (s, 6H, 2X0CH 3 ), 3.73-3.65 (m, 2H, 0CH 2 ), 3.62-3.40 (m, 2H, 0CH 2 ), 2.55-2.20 (m, 2H, CH 2 ), 1.66 (s, 3H, CHs), 1.55 (s, 3H, CH 3 ). Example 18
5,8—二乙氧 ¾"2— (1—羟¾~4—甲¾~3—戊烯基 )— 1,4—萘醌（珊― 1) 的制备  Preparation of 5,8-diethoxy 3⁄4"2-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (Shan-1)
操作 按实施例 1中步骤一的方法，反应中用碘乙 替碘甲烷。制得珊 - 1淡黄色油状 物 61.1 mg, 收率 51.2%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.25 (s， 2H， ΗΑ,), 6.74 (s, 1H， Hqul„), 5.15 (t, 1H， J=4.2Hz, CH=)， 4.76 (t, 1H， J=4.5Hz, CHO), 4.10 (q, 4H， J=l.8, 4.5Hz, 2X0CH2CH3), 2.34—2.57 (m， 2H， CH2)， 1.70 (s， 3H， CH3)， 1.63 (s， 3H， CH3), 1.47 (t, 6H， J=6.9Hz, 2X0CH2CH3)o The procedure of the first step of Example 1 was carried out, and iodoethyl iodide was used in the reaction. The product was obtained as a pale yellow oil, 61.1 mg, yield 51.2%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 7.25 (s, 2H, ΗΑ,), 6.74 (s, 1H, H qul „), 5.15 (t, 1H, J=4.2Hz, CH=), 4.76 ( t, 1H, J=4.5Hz, CHO), 4.10 (q, 4H, J=l.8, 4.5Hz, 2X0CH 2 CH 3 ), 2.34—2.57 (m, 2H, CH 2 ), 1.70 (s, 3H , CH 3 ), 1.63 (s, 3H, CH 3 ), 1.47 (t, 6H, J=6.9Hz, 2X0CH 2 CH 3 )o
实施例 19  Example 19
5， 8—二乙氧 ¾"2— (1—酰氧 ¾"4—甲¾~3—戊烯基 )— 1， 4—萘醌的制备  Preparation of 5,8-diethoxy 3⁄4"2-(1-acidooxy 3⁄4"4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone
步骤一同实施例 18;  Steps are the same as embodiment 18;
步骤二， 将化合物珊- 1与相应的羧酸反歸行酯化， 具体操雑实施例 2中的步骤三的方 法进行。  In the second step, the compound Shan-1 is esterified with the corresponding carboxylic acid, and the method of the third step in the second embodiment is specifically carried out.
以±¾方法制得 5， 8-二乙氧 ¾"2- (1-乙酰氧基- 4-甲¾~3-戊烯基 )- 1， 4-萘醌（珊- 2)橙红 色油状化合物 151.7 mg，收率为 78.6%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.25 (s， 2H， ΗΑ,), 6.61 (s， 1H， Hqul„), 5.90 (dd， 1H， J=l.5, 4.2 Hz, CH=)， 5.10 (t, 1H， J=4.5Hz, CH0)， 4.12 (q, 4H， J=l.2, 1.8Hz, 2X0CH2CH3), 2,43-2.57 (m， 2H， CH2)， 2.10 (s， 3H， C0CH3), 1.65 (s， 3H， CHs), 1.54 (s， 3H， CH3), 1.46 (t, 6H， J=3.0Hz, 2X0CH2C )。 5, 8-Diethoxy 3⁄4"2-(1-acetoxy-4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (Shan-2) orange-red oil was obtained by the method of ±3⁄4 Compound 151.7 mg, yield 78.6%. 3⁄4sa (300 MHz, CDCls, δ ppm): 7.25 (s, 2H, ΗΑ,), 6.61 (s, 1H, H qul „), 5.90 (dd, 1H, J=l.5, 4.2 Hz, CH=), 5.10 (t, 1H, J=4.5Hz, CH0), 4.12 (q, 4H, J=l.2, 1.8Hz, 2X0CH 2 CH 3 ), 2,43-2.57 (m, 2H, CH 2 ), 2.10 (s, 3H, C0CH 3 ), 1.65 (s, 3H, CHs), 1.54 ( s, 3H, CH 3 ), 1.46 (t, 6H, J=3.0 Hz, 2X0CH 2 C ).
同法制得 5,8-二乙氧基- 2- [1- (2-甲基丁氧¾¾)- 4-甲¾~3-戊烯基)萘（珊- 3)橙红色油 状化合物 119.3mg， 收率 56.0%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.22 (s， 2H， ΗΑ,), 6.58 (d， 1H， J=2.1Hz, Hqul„), 5.89 (t, 1H， CH=)， 5.09 (t, 1H， J=5.1 Hz, CH0)， 4.07 (m， 4H， 2X0CH2CH3), 2.56—2.10 (m， 3H， CH2CH=， COCH), 1.63 (s， 3H， CH3)， 1.53 (s， 3H， CH3)， 1.46 (t, 6H， J=2.4Hz, 2X0CH2CH3). 1.13 (d， 6H， J=3.0 Hz, 2XCH3), 0.93—0.87 (m， 2H， C¾CH3)。 5,8-Diethoxy-2- [1-(2-methylbutoxy 3⁄43)- 4-methyl 3⁄4~3-pentenyl) naphthalene (Shan-3) orange-red oily compound 119.3mg , yield 56.0%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 7.22 (s, 2H, ΗΑ,), 6.58 (d, 1H, J=2.1Hz, H qul „), 5.89 (t, 1H, CH=), 5.09 ( t, 1H, J=5.1 Hz, CH0), 4.07 (m, 4H, 2X0CH 2 CH 3 ), 2.56-2.10 (m, 3H, CH 2 CH=, COCH), 1.63 (s, 3H, CH 3 ), 1.53 (s, 3H, CH 3 ), 1.46 (t, 6H, J=2.4Hz, 2X0CH 2 CH 3 ). 1.13 (d, 6H, J=3.0 Hz, 2XCH 3 ), 0.93—0.87 (m, 2H, C3⁄4CH 3 ).
同法制得 5， 8-二乙氧基- 2- [1- (3-羟基- 3-甲基丁酰氧基 )-4-甲基- 3-戊烯基]萘（珊- 4)橙 红色油状化合物 100.3mg， 收率 45.2%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.25 (s， 2H， ΗΑ,), The same method can be used to prepare 5, 8-diethoxy-2- [1-(3-hydroxy-3-methylbutanoyloxy)-4-methyl-3-pentenyl]naphthalene (Shan-4) orange The red oily compound was 100.3 mg, and the yield was 45.2%. 3⁄4sa (300 MHz, CDCls, δ ppm): 7.25 (s, 2H, ΗΑ,),
6.62 (s， 1H， Hqul„), 5.96 (m， 1H， CH=)， 5.07 (t, 1H， J=5.7 Hz, CH0)， 4.11 (m， 4H， 2 X0CH2CHs), 2.56-2.43 (m， 4H， CH2CH=, C0CH2), 1.65 (s， 3H， CH3)， 1.54 (s， 3H， CH3)， 1.50-1.45 (m， 6H， 2XCH3), 1.25(t, 6H， J=2.4Hz, 2X0CH2CH3)o 6.62 (s, 1H, H qul „), 5.96 (m, 1H, CH=), 5.07 (t, 1H, J=5.7 Hz, CH0), 4.11 (m, 4H, 2 X0CH 2 CHs), 2.56-2.43 (m, 4H, CH 2 CH=, C0CH 2 ), 1.65 (s, 3H, CH 3 ), 1.54 (s, 3H, CH 3 ), 1.50-1.45 (m, 6H, 2XCH 3 ), 1.25 (t, 6H, J=2.4Hz, 2X0CH 2 CH 3 ) o
实施例 20  Example 20
5， 8-二乙氧 ¾"2- (卜垸氧 ¾"4-甲¾~3-戊烯基 )- 1， 4-萘醌的制备  Preparation of 5, 8-diethoxy 3⁄4"2-(dioxax 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone
步骤一及步骤二同实施例 1， 所不同之处在于«乙烷、硫酸二乙酯分别代替碘甲烷、硫 酸二甲酯；  Steps 1 and 2 are the same as in the first embodiment, except that ethane and diethyl sulfate are substituted for methyl iodide and dimethyl sulfate, respectively;
步骤三，将化合物珊 -1与相应的溴代物反; «行醚化，具 实施例 3中的步骤三的 方法进行。  In the third step, the compound Shan-1 is reacted with the corresponding bromo compound; the line is etherified, and the method of the third step in the embodiment 3 is carried out.
步骤四， 同实施例 17中的步骤四。  Step 4 is the same as step four in Embodiment 17.
以 ±¾方法制得 5， 8-二乙氧 ¾"2- (1-甲氧基 - 4-甲¾~3-戊烯基 )- 1， 4-萘醌（珊- 5)橙黄色 油状化合物 22.25mg， 收率 51.7%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.28 (s， 2H， lU， 6.78 (d， 1H， J=l.5 Hz, Hqul„), 5.19 (m， 1H， CH=)， 4.53 (t, 1H， J=5.1 Hz, CH0)， 3.83-4.30 (m， 4H， 2X0CH2CH3), 3.32 (s， 3H， 0CH3), 2.56-2.35 (m， 2H， CH2)， 1.69 (s， 3H， CH3)， 1.57-1.10 (m， 9H， CHs, 2X0CH2(¾)。 5, 8-Diethoxy 3⁄4"2-(1-methoxy-4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (Shan-5) orange yellow oil was obtained by the method of ±3⁄4 Compound 22.25 mg, yield 51.7%. 3⁄4 Sa (300 MHz, CDCls, δ ppm): 7.28 (s, 2H, lU, 6.78 (d, 1H, J=l.5 Hz, H qul „), 5.19 (m , 1H, CH=), 4.53 (t, 1H, J=5.1 Hz, CH0), 3.83-4.30 (m, 4H, 2X0CH 2 CH 3 ), 3.32 (s, 3H, 0CH 3 ), 2.56-2.35 (m , 2H, CH 2 ), 1.69 (s, 3H, CH 3 ), 1.57-1.10 (m, 9H, CHs, 2X0CH 2 (3⁄4).
同法制得 5,8-二乙氧 ¾"2- (1-乙氧 ¾"4-甲¾~3-戊烯基 )- 1,4-萘醌（珊- 6)橙黄色油状 化合物 18.86mg， 收率 43.6%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.27 (s， 2H， ΗΑ,), 6.79 (s， 1H， Hqul„), 5.18 (t, 1H， J=2.7 Hz, CH=)， 4.59 (t, 1H， J=5.1 Hz, CH0)， 4.12—4.21 (m， 4H， 2X0CH2CH3), 3.39 (m， 2H， 0CH2CH3), 2.51-2.30 (m， 2H， CH2)， 1.66 (s， 3H， CH3)， 1.55-1.20 (m， 12H， CH3, 3X0CH2(¾)。 Preparation of 5,8-diethoxy 3⁄4"2-(1-ethoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (Shen-6) orange-yellow oil compound 18.86mg , the yield was 43.6%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 7.27 (s, 2H, ΗΑ,), 6.79 (s, 1H, H qul „), 5.18 (t, 1H, J=2.7 Hz, CH=), 4.59 ( t, 1H, J=5.1 Hz, CH0), 4.12—4.21 (m, 4H, 2X0CH 2 CH 3 ), 3.39 (m, 2H, 0CH 2 CH 3 ), 2.51-2.30 (m, 2H, CH 2 ), 1.66 (s, 3H, CH 3 ), 1.55-1.20 (m, 12H, CH 3 , 3X0CH 2 (3⁄4).
实施例 21  Example 21
8-羟¾~5-甲氧基 - 6- (1-羟¾~4-甲¾~3-戊烯基 )- 1,4-萘醌（K- 1) 的制备  Preparation of 8-hydroxy-3⁄4~5-methoxy-6-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (K-1)
步骤一同实施例 1中步骤一；  Step 1 is the same as step 1 in embodiment 1;
步骤二， 5,8-二甲氧基 -2-(1-羟基 -4-甲基 -3-戊烯基 )-1，4-萘醌 （VI-1 ) (lOOmg, Step two, 5,8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4-naphthoquinone (VI-1) (100 mg,
0.316mmol), 用无水二氯甲烷 (10 ml)溶解。 在氮气保护下， 加入乙酸酐 3 ml和干燥的三乙胺 (1.5 ml), 室温搅拌半小时。 然后加入醋酸处理过的锌粉， 继续反应 lh。 加入甲醇 (5 ml)和 乙酸乙酯 (10 ml) , 然后分别用 4%盐酸、水、饱和食盐水洗涤， 无水硫酸 #m ， 过滤， 减压蒸去乙酸乙酯。粗产品用硅胶柱层析， 乙酸乙酯:石油醚（1:2， V/V)洗脱得到 1,4-二乙 酰氧 ¾"5， 8-二甲氧基- 2- (卜乙酰氧 ¾"4-甲¾~3-戊烯基)萘淡黄色油状化合物 109.2 mg,收率 78.2%。 ¾薩 (300 MHz, CDCls, δ ppm)： 7.11—7.04 (m， 1H， ΗΑ,), 6.76 (s， 2H， H^), 6.03 (m， 1H， CH0)， 5.05 (dd， 1H， J=7.5, 1.5 Hz， CH=)， 3.83 (s， 3H， 0CH3), 3.81 (s， 3H， 0CH3), 2.58-2.43 (m, 2H， CH2)， 2.36 (s， 3H， ArOCOCHs), 2.34 (s， 3H， ArOCOCHs), 2.05 (s， 3H， COCHs), 1.68 (s， 3H， CH3)， 1.58 (s， 3H， CH3); 0.316 mmol), dissolved in anhydrous dichloromethane (10 ml). Under nitrogen, 3 ml of acetic anhydride and dry triethylamine (1.5 ml) were added and stirred at room temperature for half an hour. Then, acetic acid-treated zinc powder was added, and the reaction was continued for 1 hour. Methanol (5 ml) and ethyl acetate (10 ml) were added, and then washed with 4% hydrochloric acid, water, and brine, and then evaporated. The crude product was chromatographed on silica gel eluting with ethyl acetate: petroleum ether (1:2, V/V) to give 1,4-diacetyloxy 3⁄4"5, 8-dimethoxy-2- 3⁄4"4-methyl 3⁄4~3-pentenyl) naphthalene pale yellow oily compound 109.2 mg, yield 78.2%. 3⁄4萨(300 MHz, CDCls, δ ppm): 7.11—7.04 (m, 1H, ΗΑ,), 6.76 (s, 2H, H^), 6.03 (m, 1H, CH0), 5.05 (dd, 1H, J =7.5, 1.5 H z , CH=), 3.83 (s, 3H, 0CH 3 ), 3.81 (s, 3H, 0CH 3 ), 2.58-2.43 (m, 2H, CH 2 ), 2.36 (s, 3H, ArOCOCHs ), 2.34 (s, 3H, ArOCOCHs), 2.05 (s, 3H, COCHs), 1.68 (s, 3H, CH 3 ), 1.58 (s, 3H, CH 3 );
步骤三， 将 1， 4-二乙酰氧¾~5， 8-二甲氧 ¾"2- (1-乙酰氧 ¾"4-甲¾~3-戊烯基)萘 (lOOmg, 0.226mmol)溶于乙腈 （5 ml)中， 充分搅拌均勾， 滴入硝酸铈铵溶液（615 mg硝酸铈溶入 5 ml 水中)， 25 反应 30 min. 减压蒸去乙腈， 用乙酸乙酯分二次萃取残留物， 合并乙酸乙酯层， 用无水 MgS04干燥， 减压蒸去乙酸乙酯。粗产品用硅胶柱层析， 乙酸乙酯:石油醚（4:6， V/V) 洗脱得到 5， 8-二乙酰氧基- 6- (1-乙酰氧基- 4-甲基- 3-戊烯基 )-1， 4-萘醌浅黄色油状化合物 87.9 mg, 收率为 94.02%。 薩 (300 MHz, CDCls, δ ppm )： 7.39 (s， 1H， ΗΑ,), 6.74 (s， 2H， Hqul„), 6.02 (m， 1H， CH=)， 5.00 ( t, 1H， J=7.2 Hz, CH0)， 3.95 (s， 6H， 2X0CH3), 2.54-2.37 (m， 8H， CH2， 2 X ArOCOCHs), 2.03 (s， 3H， C0CH3), 1.64 (s， 3H， CH3)， 1.49 (s， 3H， CH3); Step 3: Dissolve 1, 4-diacetoxy 3⁄4~5, 8-dimethoxy 3⁄4"2-(1-acetoxy 3⁄4"4-methyl 3⁄4~3-pentenyl) naphthalene (100 mg, 0.226 mmol) In acetonitrile (5 ml), stir well, add ammonium cerium nitrate solution (615 mg lanthanum nitrate into 5 ml water), 25 reaction for 30 min. Evaporate acetonitrile under reduced pressure and extract twice with ethyl acetate. The residue was combined ethyl acetate layer was dried over anhydrous MgS0 4, ethyl acetate was distilled off under reduced pressure. The crude product was chromatographed on silica gel eluting with ethyl acetate: petroleum ether (4:6, V/V) to give 5, 8-diacetoxy-6-(1-acetoxy-4-methyl-3 -pentenyl)-1,4-naphthoquinone pale yellow oily compound 87.9 mg, yield 94.02%. Sa (300 MHz, CDCls, δ ppm): 7.39 (s, 1H, ΗΑ,), 6.74 (s, 2H, H qul „), 6.02 (m, 1H, CH=), 5.00 ( t, 1H, J= 7.2 Hz, CH0), 3.95 (s, 6H, 2X0CH 3 ), 2.54-2.37 (m, 8H, CH 2 , 2 X ArOCOCHs), 2.03 (s, 3H, C0CH 3 ), 1.64 (s, 3H, CH 3 ), 1.49 (s, 3H, CH 3 );
步骤四，将化合物 5， 8-二乙酰氧¾~6- (1-乙酰氧 ¾"4-甲¾~3-戊烯基 )- 1， 4-萘醌 (lOOmg, 0.242 mmol) 溶于甲醇 /四氢呋喃（ 1： 1 V/V, 4 ml )中，反应温度控制 -16 ，慢慢加入 5% Ce2C03 水溶液 2.5 ml, - 16Ό继续反应 10 min. 加入饱和氯化铵溶液 (5 ml), 用乙酸乙酯萃取， 用 水和饱和食盐水分别洗涤乙酸乙酯层， 无水 MgS04fl , 减压蒸去乙酸乙酯。 品用硅胶柱 层析， 乙酸乙酯:石油醚（1:8， V/V)洗脱得到 8-羟¾~5-甲氧基 - 6- (1-羟¾~4-甲基- 3-戊烯 基)- 1,4-萘醌 (K-1)黄色油状物 37.61 mg， 收率为 50.8%。 ¾薩 (300 MHz, CDCls, δ ppm): 12.49 (s， 1H， ArOH), 7.26 (d， 1H， J=l.2 Hz, H^), 6.86 (s， 2H， Hquin)， 6.26 (m， 1H， CH=)， 5.27 (t, 1H， J=6.6Hz， CH0)， 4.00 (s， 3H， 0CH3), 2.62—2.49 (m， 2H， CH2)， 1.74 (s， 3H， CH3), 1.61 (s， 3H， CHs). Step 4, the compound 5, 8-diacetoxy 3⁄4~6-(1-acetoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (100 mg, 0.242 mmol) was dissolved in methanol. /tetrahydrofuran (1 1 V / V, 4 ml), the reaction temperature is controlled -16, slowly add 5% Ce 2 C0 3 aqueous solution 2.5 ml, - 16 Ό continue to react for 10 min. Add saturated ammonium chloride solution (5 ml) ), washed with water and saturated brine and extracted with ethyl acetate, the ethyl acetate layer, respectively, dried over anhydrous MgS0 4 fl, ethyl acetate was distilled off under reduced pressure and product was chromatographed on silica gel with ethyl acetate: petroleum ether (1: 8, V/V) elution to give 8-hydroxy 3⁄4~5-methoxy-6-(1-hydroxy 3⁄4~4-methyl-3-pentenyl)-1,4-naphthoquinone (K-1 ) Yellow oil 37.61 mg, yield 50.8%. 3⁄4 Sa (300 MHz, CDCls, δ ppm): 12.49 (s, 1H, ArOH), 7.26 (d, 1H, J=l.2 Hz, H^), 6.86 (s, 2H, H quin ), 6.26 (m, 1H, CH=), 5.27 (t, 1H, J=6.6Hz, CH0), 4.00 (s, 3H, 0CH 3 ), 2.62—2.49 (m, 2H, CH 2 ), 1.74 (s, 3H, CH 3 ), 1.61 (s, 3H, CHs) .
实施例 22  Example 22
8—羟¾~5—甲氧基 6— (1—酰氧 ¾~4—甲¾~3—戊烯基)— 1， 4—萘醌的制备  Preparation of 8-hydroxy-3⁄4~5-methoxy 6-(1-acyloxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone
步骤一、 步骤二、 步骤三及步骤四同实施例 21;  Step 1, step two, step three and step four are the same as embodiment 21;
步骤五， 将化合物 K-1与相应的羧酸反; «行酯化， 具体操 实施例 2步骤三的方法进 行。  In the fifth step, the compound K-1 is reacted with the corresponding carboxylic acid; the esterification is carried out, and the method of the second step of the second embodiment is carried out.
以 ±¾方法制得 8-羟¾~5-甲氧 ¾"6- (卜乙酰氧 ¾"4-甲¾~3-戊烯基 )- 1， 4-萘醌 (K-1) 黄色油状物 83.4 mg， 收率 73.2%。 ¾薩 (300 MHz, CDCls, δ ppm)： 12.55 (s， 1H， ArOH), 7.30 (s， 1H， HA,), 6.92 (s， 2H， uin)， 6.05 (m， 1H， CH=)， 5.13 (t, 1H， J=6.9Hz， CH0)， 3.94 (s， 3H， OCHs), 2.42—2.25 (m， 2H， CH2)， 2.10 (s， 3H， C0CH3), 1.60 (s， 3H， CH3)， 1.58(s， 3H， CHs). 8-Hydroxy 3⁄4~5-methoxy 3⁄4"5-(b-acetoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (K-1) yellow oil 83.4 mg, yield 73.2%. 3⁄4萨(300 MHz, CDCls, δ ppm): 12.55 (s, 1H, ArOH), 7.30 (s, 1H, HA,), 6.92 (s, 2H, uin ), 6.05 (m, 1H, CH=), 5.13 (t, 1H, J=6.9Hz, CH0), 3.94 (s, 3H, OCHs), 2.42—2.25 (m, 2H, CH 2 ), 2.10 (s, 3H, C0CH 3 ), 1.60 (s, 3H , CH 3 ), 1.58(s, 3H, CHs).
同法制得 8-羟¾~5-甲氧 ¾"6- [1- (3， 3-二甲基丙烯酰氧基) - 4-甲¾~3-戊烯基 )- 1， 4-萘醌 (K-3) 黄色油状物 83.8 mg， 收率 65.9%。 ¾薩 (300 MHz, CDCls, δ ppm)： 12.42 (s， 1H， ArOH), 7.37 (s， 1H， lU， 6.86 (s， 2H， Hqul„), 6.04 (m， 1H， CH=)， 5.82 (s， 1H， C0CH=), 5.15 (t, 1H， J=7.2Hz, CH0)， 3.99 (s， 3H， 0CH3), 2.60—2.45 (m， 2H， CH2)， 2.14 (s， 3H， CHs), 1.89 (s， 3H， CHs), 1.67 (s， 3H， CH3)， 1.57 (s， 3H， CH3)。 8-Hydroxy 3⁄4~5-methoxy 3⁄4"6- [1-(3, 3-dimethylacryloyloxy)-4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthalene醌(K-3) Yellow oil 83.8 mg, yield 65.9%. 3⁄4 Sa (300 MHz, CDCls, δ ppm): 12.42 (s, 1H, ArOH), 7.37 (s, 1H, lU, 6.86 (s, 2H, H qul „), 6.04 (m, 1H, CH=), 5.82 (s, 1H, C0CH=), 5.15 (t, 1H, J=7.2Hz, CH0), 3.99 (s, 3H, 0CH 3 ) , 2.60—2.45 (m, 2H, CH 2 ), 2.14 (s, 3H, CHs), 1.89 (s, 3H, CHs), 1.67 (s, 3H, CH 3 ), 1.57 (s, 3H, CH 3 ) .
实施例 23  Example 23
5-羟基- 8-甲氧基 -2- (1-羟基- 4-甲基- 3-戊烯基 )- 1,4-萘醌（XI- 1) 的制备  Preparation of 5-hydroxy-8-methoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4-naphthoquinone (XI-1)
步骤一， 称取紫草素（288 mg, 1 mmol)溶入醋酸酐 (5 ml) 中， 加入碘 （28.8 mg) 催 化。 25Ό下反应 20min。 加入甲醇 (10 ml) ， 再加入过量亚硫酸钠还原催化量的碘。 乙酸乙酯 萃取后， 分别加入 5%碳酸氢钠， 水和饱和食盐水洗涤乙酸乙酯层，无水硫酸 #m ，过滤，浓 缩至干， 得 S ^品 450 mg. 经柱层棚备， 得 5，8-二乙酰氧¾"2-(1-乙酰氧¾"4-甲¾"3-戊 烯)- 1， 4-萘醌（三乙酰紫草素） 391.3 mg。收率 94.5%。m. p.102〜104.5°C. (lit. m. p.102- 104Ό). ¾ MR (300 MHz, CDCls, δ ppm)： 7.38 (s， 2H， H^), 6.66 (d， 1H， J=l.2 Hz, Hquin)， 5.87 (ddd， 1H， J=3.3, 7.2， 4.8Hz, CH=)， 5.07 (dd， 1H， J=7.8, 1.3 Hz, CH0)， 2.38—2.44 (s， 8H， 2XAr0C0CH3, CH2)， 2.09 (s， 3H， C0CH3), 1.75 (s， 3H， CH3)， 1.65 (s， 3 H， CH3)。 Step 1. Weigh shikonin (288 mg, 1 mmol) in acetic anhydride (5 ml) and catalyze with iodine (28.8 mg). The reaction was carried out for 20 min at 25 Torr. Methanol (10 ml) was added and an excess of sodium sulfite was added to reduce the catalytic amount of iodine. After ethyl acetate extraction, the ethyl acetate layer was washed with 5% sodium hydrogencarbonate, water and saturated brine, anhydrous sulfuric acid #m, filtered, and concentrated to dryness to give s. 5,8-Diacetoxy 3⁄4"2-(1-acetoxy 3⁄4"4-methyl 3⁄4"3-pentene)- 1, 4-naphthoquinone (triacetylshikonin) 391.3 mg. Yield 94.5% Mp102~104.5°C. (lit. mp102- 104Ό). 3⁄4 MR (300 MHz, CDCls, δ ppm): 7.38 (s, 2H, H^), 6.66 (d, 1H, J=l.2 Hz, H quin ), 5.87 (ddd, 1H, J=3.3, 7.2, 4.8Hz, CH=), 5.07 (dd, 1H, J=7.8, 1.3 Hz, CH0), 2.38—2.44 (s, 8H, 2XAr0C0CH 3 , CH 2 ), 2.09 (s, 3H, C0CH 3 ), 1.75 (s, 3H, CH 3 ), 1.65 (s, 3 H, CH 3 ).
步骤二， 取三乙酰紫草素（207 mg, 0.5 mmol)溶入甲醇（10 ml)和 5%碳酸钠 (15 ml) 的混合溶液中， 在 -16Ό温度下， 反应 9h， 反应液颜色逐步加深。加入过量的氯化氨溶液中和 过量的碳酸钠， 然后用乙酸乙酯 （20 ml)萃取， 用水和饱和食盐水洗涤乙酸乙酯层， 无水硫酸 过滤，浓缩至干，得 品 310 mg。 经柱层棚备，得化合物 XI- 1紫红色油状物 138.0 mg, 收率 91.4%。 ¾薩 (300 MHz, CDCls, δ ppm)： 12.52 (s， 1H， ArOH), 7.32 (s， 2H， H^), 6.94 (d， 1H， J=7.2 Hz, Hquin)， 5.19 (m， 1H， CH=)， 4.82 (t, 1H， J=6.90 Hz, CH0)， 3.99 (s， 3H， OCHs), 2.61—2.53 (m, 1H， CIL), 2.37—2.33 (m, 1H， CHb)， 1.75 (s， 3H， CH3)， 1.65 (s， 3H， CH3). 'C MR (75 MHz, CDCls, δ ppm)： δ 189.6， 182.7， 155.5， 153.4， 153.3， 136.1 131.0， 126.0， 122.0， 117.8， 113.8， 68.2， 55.9， 34.8， 25.0， 17.2。 Step 2, take triacetyl shikonin (207 mg, 0.5 mmol) dissolved in methanol (10 ml) and 5% sodium carbonate (15 ml) In the mixed solution, at a temperature of -16 Torr, the reaction was carried out for 9 hours, and the color of the reaction solution was gradually deepened. An excess of sodium chloride solution was added to neutralize an excess of sodium carbonate, and then extracted with ethyl acetate (20 ml). The ethyl acetate layer was washed with water and brine, filtered and evaporated. The mixture was packed in a column to give the compound XI-1 as a purple-red oil, 138.0 mg, yield 91.4%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 12.52 (s, 1H, ArOH), 7.32 (s, 2H, H^), 6.94 (d, 1H, J=7.2 Hz, H quin ), 5.19 (m, 1H, CH=), 4.82 (t, 1H, J=6.90 Hz, CH0), 3.99 (s, 3H, OCHs), 2.61—2.53 (m, 1H, CIL), 2.37—2.33 (m, 1H, CH b ), 1.75 (s, 3H, CH 3 ), 1.65 (s, 3H, CH 3 ). 'C MR (75 MHz, CDCls, δ ppm): δ 189.6, 182.7, 155.5, 153.4, 153.3, 136.1 131.0, 126.0 , 122.0, 117.8, 113.8, 68.2, 55.9, 34.8, 25.0, 17.2.
实施例 24  Example 24
5-羟¾~8-甲氧基 - 2- (1-酰氧 ¾"4-甲¾~3-戊烯基 )- 1， 4-萘醌的制备  Preparation of 5-hydroxy 3⁄4~8-methoxy-2-(1-acyloxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1,4-naphthoquinone
步骤一及步骤二同实施例 23;  Step 1 and step 2 are the same as embodiment 23;
实施三， 将化合物 XI- 1与相应的羧酸反应进行酯化， 具体操作按实施例 2步骤三的方法进 行。  In the third embodiment, the compound XI-1 is reacted with the corresponding carboxylic acid for esterification, and the specific operation is carried out in the same manner as in the third step of the second embodiment.
以 ±¾方法制得 5-羟¾~8-甲氧 ¾"2- (卜乙酰氧 ¾"4-甲¾~3-戊烯基 )- 1， 4-萘醌（XI- 2) 紫红色油状物 152.6 mg, 收率为 94.2%。 ¾薩 (300 MHz, CDCls, δ ppm)： 12.44 (s， 1H， ArOH), 7.38 (d， 1H， J=9.6 Hz, H^), 7.36 (d， 1H， J=9.3 Hz, H^), 6.75 (d， 1H， J=l.2 Hz, Hquin)， 5.96 (m， 1H， CH=)， 5.14 (t, 1H， J=7.2 Hz, CH0)， 4.05 (s， 3H， 0CH3), 2.58-2.39 (m， 2H， CH2)， 2.12 (s， 3H， COCHs), 1.68 (s， 3H， CH3)， 1.57 (s, 3 H， CH3)。 5-Hydroxy 3⁄4~8-methoxy 3⁄4"2-(Bus acetyloxy 3⁄4"4-methyl 3⁄4~3-pentenyl)- 1, 4-naphthoquinone (XI- 2) purplish red by ±3⁄4 method The oil was 152.6 mg in a yield of 94.2%. 3⁄4萨(300 MHz, CDCls, δ ppm): 12.44 (s, 1H, ArOH), 7.38 (d, 1H, J=9.6 Hz, H^), 7.36 (d, 1H, J=9.3 Hz, H^) , 6.75 (d, 1H, J=l.2 Hz, H quin ), 5.96 (m, 1H, CH=), 5.14 (t, 1H, J=7.2 Hz, CH0), 4.05 (s, 3H, 0CH 3 ), 2.58-2.39 (m, 2H, CH 2 ), 2.12 (s, 3H, COCHs), 1.68 (s, 3H, CH 3 ), 1.57 (s, 3 H, CH 3 ).
同法制得 5-羟基- 8-甲氧基 -2- [1- (3， 3-二甲基丙烯酰氧基) -4-甲基- 3-戊烯基) -1， 4-萘 醌（XI- 3)紫红色油状物 85.6mg， 收率 67.3%。 ¾薩 (300 MHz, CDCls, δ ppm)： 12.46 (s， 1H， A0H)， 7.36 (d， 1H， J=6.9 Hz, H^), 7.35 (d， 1H， J=6.6 Hz, H^), 6.74 (d， 1H， J=3.9 Hz Hqul„), 6.04 (m， 1H， CH=)， 5.76 (s， 1H， C0CH), 5.14 (t, 1H， J=5.7HZ， CH0)， 3.96(s， 3H， OCHs, )， 2.64-2.38 (m， 2H， CH2， ）， 2.14 (s， 3H， CH3)， 1.92 (s， 3H， CH3)， 1.68 (s， 3H， CH3), 1.57 (s， 3H， CH3) . 5-hydroxy-8-methoxy-2-[1-(3,3-dimethylacryloyloxy)-4-methyl-3-pentenyl)-1,4-naphthoquinone (XI-3) 85.6 mg of purplish red oil, yield 67.3%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 12.46 (s, 1H, A0H), 7.36 (d, 1H, J=6.9 Hz, H^), 7.35 (d, 1H, J=6.6 Hz, H^) , 6.74 (d, 1H, J=3.9 Hz H qul „), 6.04 (m, 1H, CH=), 5.76 (s, 1H, C0CH), 5.14 (t, 1H, J=5.7H Z , CH0), 3.96(s, 3H, OCHs, ), 2.64-2.38 (m, 2H, CH 2 , ), 2.14 (s, 3H, CH 3 ), 1.92 (s, 3H, CH 3 ), 1.68 (s, 3H, CH 3 ), 1.57 (s, 3H, CH 3 ) .
同法制得 5-羟¾~8-甲氧 ¾"2- [1- (3-羟¾~3-甲基丁酰氧基 )- 4-甲¾~3-戊烯基 )- 1， 4-萘 醌（XI- 4)紫红色油状物 84.8 mg， 收率 63.7%。 ¾薩 (300 MHz, CDCls, δ ppm)： 12.45 (s， 1H， ArOH), 7.38 (s， 2H， H^), 6.79 (d， 1H， J=3.9 Hz, Hquin)， 6.04 (m， 1H， CH=)， 5.13 (t, 1H， J=6.6Hz, CH0)， 4.01 (s， 3H， 0CH3), 2.62—2.40 (m， 4H， CH2， C0CH2), 1.68 (s， 3H， Cft)， 1.59(s， 3H， CH3), 1.29 (s， 3H， CH3)， 1.28 (s， 3H， CH3)。 实施例 25 5-Hydroxy 3⁄4~8-methoxy 3⁄4"2- [1-(3-hydroxy 3⁄4~3-methylbutyryloxy)-4-methyl 3⁄4~3-pentenyl)- 1, 4 -naphthoquinone (XI-4) purple red oil 84.8 mg, yield 63.7%. 3⁄4 Sa (300 MHz, CDCls, δ ppm): 12.45 (s, 1H, ArOH), 7.38 (s, 2H, H^) , 6.79 (d, 1H, J=3.9 Hz, H quin ), 6.04 (m, 1H, CH=), 5.13 (t, 1H, J=6.6Hz, CH0), 4.01 (s, 3H, 0CH 3 ), 2.62—2.40 (m, 4H, CH 2 , C0CH 2 ), 1.68 (s, 3H, Cft), 1.59(s, 3H, CH 3 ), 1.29 (s, 3H, CH 3 ), 1.28 (s, 3H, CH 3 ). Example 25
8-羟¾~5-乙氧基 - 6- (卜羟¾~4-甲¾~3-戊烯基 )- 1,4-萘醌（X- 1) 的制备  Preparation of 8-hydroxy-3⁄4~5-ethoxy- 6-(Buxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (X-1)
步骤一、 步骤二及步骤三同实施例 21;  Step 1, step two and step three are the same as embodiment 21;
步骤四， 具條雑实施例 21的方法， 在步骤四中用乙醇代替甲醇， 得 X- 1黄色油状目 标化合物 36.9mg， 收率 48.4%。 ¾薩 (300 MHz, CDCls, δ ppm)： 12.51 (s， 1H， ArOH), 7.35 (s， 1H， HA,), 6.72 (s， 2H， Hquin)， 5.95 (m， 1H， CH=)， 5.19 (t, 1H， J=5.7HZ， CHO), 4.18 (m， 2H， 0CH2CH3), 2.57-2.31 (m， 2H， CH2)， 1.64 (s， 3H， CH3)， 1.57(s， 3H， CH3)， 1.49 (t, 3 H， J=4.5 Hz, 0CH2CH3) . In the fourth step, the method of Example 21 was carried out. In the fourth step, methanol was used instead of methanol to obtain 36.9 mg of the title compound as a yellow oil. 3⁄4萨 (300 MHz, CDCls, δ ppm): 12.51 (s, 1H, ArOH), 7.35 (s, 1H, HA,), 6.72 (s, 2H, H quin ), 5.95 (m, 1H, CH=) , 5.19 (t, 1H, J=5.7H Z , CHO), 4.18 (m, 2H, 0CH 2 CH 3 ), 2.57-2.31 (m, 2H, CH 2 ), 1.64 (s, 3H, CH 3 ), 1.57(s, 3H, CH 3 ), 1.49 (t, 3 H, J=4.5 Hz, 0CH 2 CH 3 ) .
实施例 26  Example 26
8-羟¾~5-乙氧基 - 6- (卜乙酰氧 ¾"4-甲¾~3-戊烯基 )- 1,4-萘醌（X- 2) 的制备 步骤一、 步骤二及步骤三同实施例 21;  Preparation of 8-hydroxy-3⁄4~5-ethoxy-6-(b-acetoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (X-2) Step 1 and Step 2 Step 3 is the same as embodiment 21;
步骤四同实施例 25中的步骤四；  Step 4 is the same as step 4 in embodiment 25;
步骤五， 将 X-1与乙酸按实施例 2步骤三的方法进行酯化， 得 X- 2黄色油状目标化合物 42.8 mg, 收率 75.3%。 ¾薩 (300 MHz, CDCls, δ ppm)： 12.53 (s， 1H， ArOH), 7.32 (s， 1H， HA,), 6.74 (s， 2H， Hqul„), 6.05 (t, 1H， J=2.7 Hz, CH=)， 5.11 (t, 1H， J=0.6 Hz, CHO), 4.21 (m， 2H， 0CH2CH3), 2.62-2.36 (m， 2H， CH2)， 2.14 (s， 3H， C0CH3), 1.67 (s， 3H， CH3)， 1.54(s, 3 H， CHs), 1.47 (t, 3 H， J=4.8 Hz, 0CH2CH3) . Step 5, X-1 and acetic acid were esterified in the same manner as in Step 3 of Example 2 to obtain 42.8 mg of the title compound (yield: 75.3%). 3⁄4萨 (300 MHz, CDCls, δ ppm): 12.53 (s, 1H, ArOH), 7.32 (s, 1H, HA,), 6.74 (s, 2H, H qul „), 6.05 (t, 1H, J= 2.7 Hz, CH=), 5.11 (t, 1H, J=0.6 Hz, CHO), 4.21 (m, 2H, 0CH 2 CH 3 ), 2.62-2.36 (m, 2H, CH 2 ), 2.14 (s, 3H , C0CH 3 ), 1.67 (s, 3H, CH 3 ), 1.54 (s, 3 H, CHs), 1.47 (t, 3 H, J = 4.8 Hz, 0CH 2 CH 3 ) .
实施例 27  Example 27
5-羟¾~8-乙氧基 - 2- (1-羟¾~4-甲¾~3-戊烯基 )- 1,4-萘醌（ΧΠ- 1) 的制备  Preparation of 5-hydroxy 3⁄4~8-ethoxy- 2-(1-hydroxy 3⁄4~4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (ΧΠ-1)
步骤一同实施例 23中的步骤一；  Step 1 is the same as step 1 in embodiment 23;
步骤二， 具條雑实施例 23中的的方法的步骤二进行， 用乙醇代替甲醇， 得 ΧΠ- 1紫红 色油状目标化合物 140.69 mg， 收率 78.6%。 ¾薩 (300 MHz, CDCls, δ ppm)： 12.50 (s， 1H， ArOH), 7.29 (s， 2H， H^), 6.82 (d， 1H， J=6.9 Hz, Hquin)， 5.19 (m， 1H， CH=)， 4.82 (t, 1H， J=5.70 Hz, CHO), 4.18 (m， 2H， 0CH2CH3), 2.56-2.33 (m， 2H， CH2)， 1.75 (s， 3H， CH3)， 1.65 (s， 3H， CHs), 1.51 (t, 3 H， J=3.9 Hz, 0CH2C )。 In the second step, the second step of the method of Example 23 was carried out, and ethanol was used instead of methanol to obtain 140.69 mg of the target compound of the iridium- 1 purplish red oil, yield 78.6%. 3⁄4萨 (300 MHz, CDCls, δ ppm): 12.50 (s, 1H, ArOH), 7.29 (s, 2H, H^), 6.82 (d, 1H, J=6.9 Hz, H quin ), 5.19 (m, 1H, CH=), 4.82 (t, 1H, J=5.70 Hz, CHO), 4.18 (m, 2H, 0CH 2 CH 3 ), 2.56-2.33 (m, 2H, CH 2 ), 1.75 (s, 3H, CH 3 ), 1.65 (s, 3H, CHs), 1.51 (t, 3 H, J = 3.9 Hz, 0CH 2 C ).
实施例 28  Example 28
5-羟¾~8-乙氧基 - 2- (1-乙酰氧 ¾"4-甲¾~3-戊烯基 )- 1,4-萘醌（ΧΠ- 2) 的制备 步骤一同实施例 23中的步骤一；  Preparation steps of 5-hydroxy 3⁄4~8-ethoxy-2-(1-acetoxy 3⁄4"4-methyl 3⁄4~3-pentenyl)-1,4-naphthoquinone (ΧΠ-2) Step one in
步骤二同实施例 27中的步骤二； 步骤三， 将 ΧΠ-l与乙酸按实施例 2中的步骤三的方法进行酯化， 得 ΧΠ- 2紫红色油状目标 化合物 140.69 mg， 收率 78.6%。 ¾薩 (300 MHz, CDCls, δ ppm)： 12.49 (s， 1H， ArOH), 7.35 (d， 1H， J=9.3 Hz, HA,), 7.34 (d， 1H， J=9.3 Hz, H^), 6.74 (s， 1H， Hquin)， 5.95 (t, 1H， J=1.5 Hz, CH=)， 5.11 (t, 1H， J=0.6 Hz, CH0)， 4.21 (q， 2H， J=4.2, 4.2 Hz, 0CH2CH3), 2.60-2.42 (m， 2H， CH2)， 2.11 (s， 3H， C0CH3), 1.68 (s， 3H， CH3)， 1.55(s， 3 H， CH3)， 1.53 (t, 3 H， J=4.2 Hz, 0CH2CHs) 0 Step 2 is the same as step 2 in the embodiment 27; Step 3: Esterification of hydrazine-l and acetic acid according to the procedure of Step 3 in Example 2 gave the title compound 140.69 mg (yield: 78.6%). 3⁄4萨 (300 MHz, CDCls, δ ppm): 12.49 (s, 1H, ArOH), 7.35 (d, 1H, J=9.3 Hz, HA,), 7.34 (d, 1H, J=9.3 Hz, H^) , 6.74 (s, 1H, H quin ), 5.95 (t, 1H, J=1.5 Hz, CH=), 5.11 (t, 1H, J=0.6 Hz, CH0), 4.21 (q, 2H, J=4.2, 4.2 Hz, 0CH 2 CH 3 ), 2.60-2.42 (m, 2H, CH 2 ), 2.11 (s, 3H, C0CH 3 ), 1.68 (s, 3H, CH 3 ), 1.55(s, 3 H, CH 3 ), 1.53 (t, 3 H, J=4.2 Hz, 0CH 2 CHs) 0
实施例 29  Example 29
1、 体外肿瘤细胞抑制试验  1. In vitro tumor cell inhibition test
本实验采用 MTT比色法，试验肿瘤细胞株：人白血病细胞 K562 (^f*对人慢性髄细胞性 白血病 K562细胞增殖与凋亡及 c- myc基因表达的影响， 中华肿瘤防治杂志， 16 (20)： 1541, 2009). 细胞以含 10%的小牛血清培养， 传代时贴壁细胞以 0.05%的胰酶 -EDTA消化液消化， 使 细胞处于对数生长期。试验时细胞接种于 96孔培养板， 接种 200μ 1，浓度为 5X104cellS/ml 的细胞悬液。于 37 、 C02培养箱预培养过夜。预培养后， 每孔加 2μ 1药物溶液。药物作用细 胞 2天。 药物作用结束后， ΜΤΤ法测定时于 96孔培养板每孔加入浓度为 5mg/ml的 MTT工作液 20μ 1， 37Ό孵育 4小时， 弃上清液， 加 200μ 1 DMS0, 在 570nm波长下用酶标仪测定 0D值。 In this experiment, MTT colorimetric assay was used to test the effect of human leukemia cell K562 on the proliferation and apoptosis of human chronic leukemia K562 cells and the expression of c-myc gene. Chinese Journal of Cancer Prevention and Treatment, 16 ( 20): 1541, 2009). The cells were cultured in 10% calf serum, and the adherent cells were digested with 0.05% trypsin-EDTA digested solution to pass the cells in logarithmic growth phase. At the time of the test, the cells were seeded in a 96-well culture plate, and 200 μl of a cell suspension having a concentration of 5× 10 4 cell S /ml was inoculated. Pre-culture overnight in 37, C0 2 incubator. After pre-incubation, 2 μl of drug solution was added to each well. The drug acts on the cells for 2 days. After the drug is applied, the MTT solution at a concentration of 5 mg/ml is added to the 96-well culture plate at 20 μl, 37 Ό for 4 hours, and the supernatant is discarded. 200 μl DMS0 is added to the ΜΤΤ method. The standard meter measures the 0D value.
錄评价方法：  Record evaluation method:
细胞生长抑制率 = (对照组值 - 试验组值） I对照组值 X 100%  Cell growth inhibition rate = (control group value - test group value) I control group value X 100%
剂量设置： 对细胞作用时， 设 4个浓度， 主要在 0.1〜100 μ M /ml范围内。  Dose setting: When acting on cells, set 4 concentrations, mainly in the range of 0.1~100 μ M /ml.
生物统计： 根据试验药物在不同浓度下对细胞生长的抑制率以 Logit方法计算 IC5。值。 试验对照： 阳性对照药应用 5氟尿嘧啶（5— Fu) Biostatistics: IC 5 was calculated by the Logit method based on the inhibition rate of cell growth at different concentrations of the test drug. value. Test Control: Positive control drug applied with 5-fluorouracil (5-Fu)
试验结果： 见表 1。  Test results: See Table 1.
表 1  Table 1
Figure imgf000038_0001
Figure imgf000039_0002
Figure imgf000039_0001
Figure imgf000038_0001
Figure imgf000039_0002
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
010ZN3/X3d mcimioz OAV
Figure imgf000044_0001
Figure imgf000043_0001
010ZN3/X3d mcimioz OAV
Figure imgf000044_0001
CH3 0 CH 3 0
XI- 3 8. 5  XI- 3 8. 5
, CH3 0 , CH 3 0
XI- 4 11. 0 χπ-ι H 3. 9  XI- 4 11. 0 χπ-ι H 3. 9
0  0
ΧΠ-2 6. 4  ΧΠ-2 6. 4
H3C人 H 3 C people
紫草素 0. 6 Shikonin 0. 6
5-FU 1. 0 5-FU 1. 0
2、 动物体内抗肿瘤实验 2. Anti-tumor experiments in animals
本实验以小鼠 S180移植瘤（乙酰紫草素注射液对 S180荷瘤小鼠抑瘤作用研究， 中药药理 与临床， 24 (1)： 22， 2008)为模型， 以 5- FU为阳性对照。  In this study, a mouse S180 transplanted tumor (inhibition of acetyl-shikonin injection on S180 tumor-bearing mice, Chinese Pharmacology and Clinical Practice, 24 (1): 22, 2008) was used as a model, and 5-FU was used as a positive control. .
配制方法：样品配制时先用吐温 -80研磨，再用生«水溶解， 吐温- 80含量为 2. 5%。 对 照品： 配制时用生《水溶解。  Preparation method: When the sample is prepared, it is firstly sterilized with Tween-80, and then dissolved with raw water, and the Tween-80 content is 2.5%. For the care products: use water to dissolve when preparing.
动物和瘤株： 昆明小鼠， 雌性， 体重 18-20g, 由斯莱克实验动物有限责任公司 ， 合 格证： SCXK (沪） 2007- 0005。瘤株：小鼠 S180腹水瘤 2只， 由上海交通大学药学院传代维持。  Animals and tumor strains: Kunming mice, female, weighing 18-20g, by Slack Laboratory Animals Co., Ltd., Syndicate: SCXK (Shanghai) 2007-0005. Tumor strain: mouse S180 ascites tumor 2, maintained by the Shanghai Jiaotong University School of Pharmacy.
试验方法： 取生长旺盛期的小鼠 S180腹水瘤 2只， 无菌条件下抽取腹水， 用生纖水稀 释至 2X 107,按 0. 2ml/只给小鼠腋皮下接种。次日将小鼠随机均分组，每组 9只。分别为空白 对照组、 阳性对照组 5- FU 25 mg/kg和样品组 6mg/kg， 腹腔注射给药。 Test method: Two S180 ascites tumors in the vigorous growth period were taken, and ascites was taken under aseptic conditions, diluted to 2×10 7 with fibrillated water, and inoculated subcutaneously with 0.2 ml/mouse. The mice were randomly assigned to the next day, 9 in each group. They were blank control group, positive control group 5-FU 25 mg/kg and sample group 6 mg/kg, respectively, and administered intraperitoneally.
小鼠接种次日开始按体重给药，其中样品组和阳性对照组连续给药 8天，接种第 9天处死， 取瘤块称重， 计算抑瘤率  The mice were dosed according to the weight of the next day, and the sample group and the positive control group were continuously administered for 8 days, and sacrificed on the 9th day of inoculation. The tumor pieces were weighed and the tumor inhibition rate was calculated.
抑瘤率 = (对照组瘤重—给药组瘤重） /对照组瘤重 X 100%  Tumor inhibition rate = (control group tumor weight - tumor weight of the administration group) / control tumor weight X 100%
结果： 样品腹腔注射对小鼠 S180移植瘤的抑瘤率见表 2。  Results: The anti-tumor rate of intraperitoneal injection of mouse S180 xenografts is shown in Table 2.
表 2  Table 2
Figure imgf000045_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000046_0001

Claims

权 利 要 求 书 Claim
1、 一种紫草素萘茜母核氧烷基化衍生物， 其特征在于， 其结构式具体如式 I所示: A ruthenium naphthoquinone parent oxyalkylated derivative, characterized in that the structural formula is as shown in formula I:
IIII
IIII
Figure imgf000047_0001
其中， R为 H、 1~10个碳原子的烷烃、烯烃、 芳烃、 1~10个碳含氧原子的烷烃、 烯烃、 环烧烃、 环烯烃或 C0R， ， R， 为 1~10个碳原子的垸烃、 烯烃、 芳烃、 1-10个碳含氧原子 的烷烃、 烯烃、 环烷烃、 环烯烃；
Figure imgf000047_0001
Wherein R is H, an alkane of 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon, an alkane of 1 to 10 carbon atoms, an olefin, a cycloalkylene, a cyclic olefin or a COR, R, which is 1 to 10 carbons. Atom hydrocarbons, olefins, aromatic hydrocarbons, 1-10 carbon atoms containing oxygen atoms, olefins, cycloalkanes, cyclic olefins;
其中， R, = CH:i; Where R, = CH :i ;
或者 R' = R2 = = R. = C2H5! Or R' = R2 = = R. = C 2 H 5!
或者 R'： Ri = R2 = Cft;  Or R': Ri = R2 = Cft;
或者 R' = R2 = H， R, = C¾;  Or R' = R2 = H, R, = C3⁄4;
或者 Ri = H，  Or Ri = H,
或者 R = R2 = H， ¾ = ― C2H5;  Or R = R2 = H, 3⁄4 = ― C2H5;
或者 Ri = H， R2 = C2H5；  Or Ri = H, R2 = C2H5;
或者 R' = R2 = = H， R, = CH3; Or R' = R2 = = H, R, = CH 3 ;
或者 R. = R2 = ¾ = H， R4― C2H5；  Or R. = R2 = 3⁄4 = H, R4 - C2H5;
或者 R' = R, =H， R2 = C¾;  Or R' = R, =H, R2 = C3⁄4;
或者 R. = R. =H，  Or R. = R. =H,
2、 种根据权利要求 1所述的紫草素萘茜母核氧垸基化衍生物的用途， 其特征在于， 是 在制各抗肿瘤药物中的用途。 The use of the shikonin naphthoquinone mother oxothiolated derivative according to claim 1, which is used for the manufacture of each antitumor drug.
3、 一种根据权利要求 1所述的紫草素萘茜母核氧烷基化衍生物的制备方法， 其特征在于， 制备如结构式 II所示化合物的方法， 其中， R为 Η、 1~10个碳原子的垸烃、烯烃、 芳烃、3. A method for preparing a shikonin naphthoquinone mother oxyalkylated derivative according to claim 1, wherein a method of preparing a compound of the formula II, wherein R is Η, 1~ 10 carbon atoms of terpenes, olefins, aromatics,
1~10个碳含氧原子的烷烃、烯烃、环烷烃、环烯烃或 C0R' ， R， 为 1~10个碳原子的烷烃、 烯烃、 芳烃、 1〜10个碳含氧原子的垸烃、 烯烃、 环垸烃、 环烯烃; 1 to 10 carbon atoms containing an alkane, an olefin, a cycloalkane, a cyclic olefin or C0R', R, an alkane having 1 to 10 carbon atoms, Olefins, aromatic hydrocarbons, 1 to 10 carbon atoms containing anthracene hydrocarbons, olefins, cyclic hydrocarbons, cyclic olefins;
Figure imgf000048_0001
Figure imgf000048_0001
， 包括如下步骤:  , including the following steps:
步骤一， 在氮气保护下， 将紫草素与 5当量无水碳酸钾混合， 溶于无水 N，N-二甲酰胺中， 加入 5当量的碘甲烷， 25Ό搅拌过夜， 得 5， 8-0-二甲基紫草素；  Step 1 Under the protection of nitrogen, the shikonin is mixed with 5 equivalents of anhydrous potassium carbonate, dissolved in anhydrous N,N-dimethylformamide, added with 5 equivalents of methyl iodide, and stirred at 25 Torr overnight to obtain 5, 8- 0-dimethylshikonin;
步骤二，在氮气保护下，将 5， 8-0-二甲基紫草素溶于四氢呋喃的水溶液中，之后依次加入 5倍当量保险粉、 10当量的氢氧化钠、 10当量的硫酸二甲酯， 充分搅拌， 加热回流 24小时， 得 1, 4， 5， 8-0-四甲基紫草素；  Step 2: Dissolve 5, 8-0-dimethylshikonin in an aqueous solution of tetrahydrofuran under nitrogen protection, and then add 5 times equivalent of insurance powder, 10 equivalents of sodium hydroxide, and 10 equivalents of dimethyl sulfate. The ester is stirred well and heated under reflux for 24 hours to obtain 1,4,5, 8-0-tetramethylshikonin;
步骤三，在氮气保护下，将 1, 4, 5, 8-0 "四甲基紫草素溶于二氯甲烷中，在 N，N二甲基吡啶、 N, N' -二环己基碳二亚胺存在下，与有机酸縮合酯化得 1， 4， 5， 8_0 -四甲基紫草素侧链酯衍生物， 即 R为 C0R' ； 或者在氮气保护下， 将 1, 4， 5， 8-0 "四甲基紫草素溶于 N，N—二甲基甲酰胺中， 加入 1. 5倍当量氢化钠， 充分搅拌， 然后滴入溴代物， 室温搅拌反应 12小时， 得 1, 4， 5, 8-0- 四甲基紫草素侧链醚衍生物；  Step 3, under nitrogen protection, dissolve 1, 4, 5, 8-0 "tetramethylshikonin in dichloromethane, N, N-dimethylpyridine, N, N'-dicyclohexyl carbon Condensation with an organic acid in the presence of a diimine to obtain a 1,4, 5, 8_0-tetramethylshikonin side chain ester derivative, ie, R is C0R'; or under nitrogen protection, 1, 4, 5, 8-0 "Tetramethyl shikonin was dissolved in N, N-dimethylformamide, 1.5 parts of sodium hydride was added, stirred well, then the bromine was added dropwise, and the reaction was stirred at room temperature for 12 hours. 1, 4, 5, 8-0-tetramethylshikonin side chain ether derivative;
或者制备如结构式 m所示化合物的方法， 其中， R为 H、 1~10个碳原子的垸烃、烯烃、 芳烃、Or a method of preparing a compound of the formula m, wherein R is H, an anthracene hydrocarbon of 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon,
1~10个碳含氧原子的烷烃、烯烃、环烷烃、环烯烃或 C0R' ， R' 为 1~10个碳原子的烷烃、 烯烃、 芳烃、 1~10个碳含氧原子的垸烃、 烯烃、 环垸烃、 环烯烃； 1 to 10 carbon atoms containing oxygen atoms, olefins, cycloalkanes, cyclic olefins or C0R', R' is an alkane of 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon, an alkylene hydrocarbon having 1 to 10 carbon atoms, Olefin, cyclononene, cycloolefin;
Figure imgf000048_0002
Figure imgf000048_0002
， 包括如下步骤: , including the following steps:
步骤一， 在氮气保护下， 将紫草素与 5当量无水碳酸钾混合， 溶于无水 N，N-二甲酰胺中， 加入 5当量的碘乙垸， 25Ό搅拌过夜， 得 5，8_0 -二乙基紫草素；  Step one, under the protection of nitrogen, the shikonin is mixed with 5 equivalents of anhydrous potassium carbonate, dissolved in anhydrous N,N-dimethylformamide, added with 5 equivalents of iodonium, and stirred at 25 Torr overnight to obtain 5,8_0. -diethyl shikonin;
步骤二，在氮气保护下，将 5， 8-0-二乙基紫草素溶于四氢呋喃的水溶液中，之后依次加入 5倍当量保险粉、 10当量的氢氧化钠、 10当量的硫酸二乙酯， 充分搅拌， 加热回流 24小时， 得 1, 4， 5， 8-0-四乙基紫草素； 步骤三， 在氮气保护下， 将 1, 4, 5, 8-0 "四乙基紫草素溶于二氯甲垸中， 在 Ν, Ν-二甲基吡 啶、 N， N' -二环己基碳二亚胺存在下， 与有机酸縮合酯化得 1， 4， 5， 8_0 -四乙基紫草素侧链酯衍 生物， 即 R为 C0R， ；或者在氮气保护下，将 1， 4, 5, 8-0 "四乙基紫草素溶于 N, N_二甲基甲酰胺 中，加入 1. 5倍当量氢化钠，充分搅拌，然后滴入溴代物，室温搅拌反应 12小时，得 1， 4， 5， 8-0- 四乙基紫草素侧链醚衍生物； Step 2: Dissolve 5, 8-0-diethylshikonin in an aqueous solution of tetrahydrofuran under nitrogen protection, and then add 5 times equivalent of insurance powder, 10 equivalents of sodium hydroxide, 10 equivalents of sulfuric acid diethyl ether. The ester is stirred well and heated under reflux for 24 hours to obtain 1, 4, 5, 8-0-tetraethyl shikonin; Step 3, under nitrogen protection, dissolve 1, 4, 5, 8-0 "tetraethyl shikonin in dichloromethane, in hydrazine, hydrazine-lutidine, N, N'-bicyclic ring Condensation with an organic acid in the presence of hexylcarbodiimide to give 1,4,5,8_0-tetraethylshikonin side chain ester derivative, ie, R is COR; or under nitrogen protection, 1, 4, 5, 8-0 "Tetraethyl shikonin is dissolved in N, N-dimethylformamide, 1.5 times equivalent of sodium hydride is added, stirred well, then bromine is added dropwise, and the reaction is stirred at room temperature for 12 hours. , obtaining 1, 4, 5, 8-0-tetraethyl shikonin side chain ether derivative;
或者制备如结构式 IV所示化合物的方法， 其中， R为 II、 1~10个碳原子的烷烃、烯烃、 芳烃、 1~10个碳含氧原子的垸烃、烯烃、环垸烃、环烯烃或 C0R， ， R， 为 1~10个碳原子的垸烃、 烯烃 ~10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； Or a method of preparing a compound of the formula IV, wherein R is II, an alkane of 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon, an anthracene hydrocarbon having 1 to 10 carbon atoms, an olefin, a cyclic anthracene, a cyclic olefin Or C0R, , R, an alkane of 1 to 10 carbon atoms, an alkane of 10 to carbon atoms, an olefin, a cycloalkane, a cycloalkene;
Figure imgf000049_0001
Figure imgf000049_0001
， 包括如下步骤:  , including the following steps:
步骤一，在氮气保护下，将紫草素与 15当量无水碳酸钾混合，溶于无水 N，N_二甲酰胺中， 加入 5当量二溴甲垸和催化量的碘化钾， 迅速升到 160Ό , 反应 20分钟得到 1 :8， 4:5-0 -二亚 甲基紫草素；  Step one, under the protection of nitrogen, the shikonin is mixed with 15 equivalents of anhydrous potassium carbonate, dissolved in anhydrous N,N-dimethylformamide, and 5 equivalents of dibromoformamidine and a catalytic amount of potassium iodide are added, and rapidly rise to 160 Ό , reaction for 20 minutes to obtain 1:8, 4:5-0 -dimethylene shikonin;
步骤二，在氮气保护下，在 N， N二甲基吡啶、 N， N' -二环己基碳二亚胺存在下，将 1 :8， 4:5-0- 二亚甲基紫草素与有机酸縮合酯化得 1 :8, 4: 5_0 "二亚甲基紫草素侧链酯衍生物，即 R为 C0R， ： 或者在氮气保护下， 将 1 :8， 4 :5-二亚甲基紫草素溶于 N，N-二甲基甲酰胺中， 加入 1. 5倍当量 氢化钠， 充分搅拌， 然后滴入溴代物， 室温搅拌反应 12小时， 得 1 :8, 4: 5-0-二亚甲基紫草素 侧链醚衍生物；  Step 2, under the protection of nitrogen, in the presence of N, N-dimethylpyridine, N, N'-dicyclohexylcarbodiimide, 1:8, 4:5-0-dimethylene shikonin Condensation with an organic acid to give a 1:8, 4: 5_0 "dimethylene shikonin side chain ester derivative, ie R is COR, : or under nitrogen protection, 1:8, 4:5-two Methylene shikonin is dissolved in N,N-dimethylformamide, 1.5 parts by weight of sodium hydride is added, and the mixture is stirred well, then the bromine is added dropwise, and the reaction is stirred at room temperature for 12 hours to obtain 1:8, 4: 5-0-dimethylene shikonin side chain ether derivative;
或者制备如结构式 V所示化合物的方法， 其中， R为 H、 1~10个碳原子的烷烃、烯烃、 芳烃、 1~10个碳含氧原子的垸烃、烯烃、环垸烃、环烯烃或 C0R， ， R， 为 1~10个碳原子的垸烃、 烯烃、 芳烃、 1~10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； Or a method of preparing a compound of the formula V, wherein R is H, an alkane of 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon, an anthracene hydrocarbon having 1 to 10 carbon atoms, an olefin, a cyclic anthracene, a cycloolefin Or C0R, , R, a terpene hydrocarbon of 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon, an alkane of 1 to 10 carbon atoms, an olefin, a cycloalkane, a cyclic olefin;
Figure imgf000049_0002
Figure imgf000049_0002
， 包括如下步骤: 步骤一， 在氮气保护下， 将紫草素与 5当量无水碳酸钾混合， 溶于无水 Ν, Ν-二甲酰胺中， 滴加 5当量氯甲醚， 反应 30分钟， 得到 5， 8-0-二甲氧甲基紫草素 2位异构体； , including the following steps: Step one, under the protection of nitrogen, the shikonin is mixed with 5 equivalents of anhydrous potassium carbonate, dissolved in anhydrous hydrazine, hydrazine-dimethylformamide, and 5 equivalents of chloromethyl ether is added dropwise, and the reaction is carried out for 30 minutes to obtain 5, 8 -0-Dimethoxymethylshikonin 2-isomer;
步骤二，在氮气保护下，将 5， 8-0-二甲氧甲基紫草素溶于四氢呋喃的水溶液中，然后依次 加入 5倍当量保险粉、 10当量的氢氧化钠、 10当量的硫酸二甲酯， 充分搅拌， 回流 24小时， 得 1, 4-0~二甲基 -5, 8-0-二甲氧甲基紫草素；  Step two, under nitrogen protection, 5, 8-0-dimethoxymethylshikonin is dissolved in an aqueous solution of tetrahydrofuran, and then 5 times equivalent of insurance powder, 10 equivalents of sodium hydroxide, 10 equivalents of sulfuric acid are sequentially added. Dimethyl ester, stirred well, refluxed for 24 hours to obtain 1, 4-0~ dimethyl-5, 8-0-dimethoxymethyl shikonin;
步骤三，在氮气保护下，将 1，4_0~二甲基 _5，8_0_二甲氧甲基紫草素溶于无水二氯甲烷中， 在 Ν, Ν二甲基吡啶、 Ν, Ν' -二环己基碳二亚胺存在下， 与有机酸縮合酯化得 1， 4-0-二甲基 -5, 8_0_二甲氧甲基紫草素侧链酯衍生物；  Step 3, under nitrogen protection, dissolve 1,4_0~dimethyl_5,8_0_dimethoxymethylshikonin in anhydrous dichloromethane, in hydrazine, hydrazine dimethylpyridine, hydrazine, hydrazine Condensation with an organic acid in the presence of '-dicyclohexylcarbodiimide to give 1,4-0-dimethyl-5,8_0-dimethoxymethylshikonin side chain ester derivative;
或者在氮气保护下， 将 1, 4-0-二甲基 -5， 8-0~二甲氧甲基紫草素溶 Τ Ν, Ν_二甲基甲酰胺 中， 加入 1. 5倍当量氢化钠， 充分搅拌， 然后滴入溴代物， 室温搅拌反应 12小时， 得 1，4_0_ 二甲基 -5, 8-0-二甲氧甲基紫草素侧链醚衍生物；  5倍当量。 Adding 1, 4-0-dimethyl-5, 8-0~ dimethoxymethyl shikonin Τ Ν, Ν dimethyl dimethyl amide, adding 1.5 times equivalent Sodium hydride, stirred well, then dropwise added bromine, and stirred at room temperature for 12 hours to obtain 1,4_0-dimethyl-5, 8-0-dimethoxymethylshikonin side chain ether derivative;
步骤四，将 1， 4-0-二甲基 -5， 8-0--甲氧甲基紫草素侧链酯衍生物或 1， 4-0--甲基 -5， 8-0- 二甲氧甲基紫草素侧链醚衍生物溶入异丙醇中，在酸作用下脱甲氧甲基， 即得结构式 V所示化 合物；  Step four, 1, 4-0-dimethyl-5, 8-0-methoxymethyl shikonin side chain ester derivative or 1, 4-0--methyl-5, 8-0- The dimethoxymethylshikonin side chain ether derivative is dissolved in isopropanol and demethoxymethylated under the action of an acid to obtain a compound of the formula V;
或者制备如结构式 VI所示化合物的方法， 其中， R为 Η、 1~10个碳原子的垸烃、烯烃、 芳烃、 1~10个碳含氧原子的垸烃、烯烃、环垸烃、环烯烃或 C0R， ， R' 为 1~10个碳原子的垸烃、 烯烃、 芳烃、 1~10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； Or a method of preparing a compound of the formula VI, wherein R is an anthracene, an alkene, an aromatic hydrocarbon, an anthracene hydrocarbon having 1 to 10 carbon atoms, an olefin, a cyclic hydrocarbon, or a ring of 1 to 10 carbon atoms. Olefin or C0R, R' is a terpene hydrocarbon of 1 to 10 carbon atoms, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, a cycloalkane or a cycloalkene;
Figure imgf000050_0001
， 包括如下步骤:
Figure imgf000050_0001
, including the following steps:
步骤一， 在氮气保护下， 将紫草素与 5当量无水碳酸钾混合， 溶于无水 N，N-二甲酰胺中， 滴加 5当量氯甲醚， 反应 30分钟， 得到 5， 8-0-二甲氧甲基紫草素 2位异构体；  Step one, under the protection of nitrogen, the shikonin is mixed with 5 equivalents of anhydrous potassium carbonate, dissolved in anhydrous N,N-dimethyl amide, and 5 equivalents of chloromethyl ether is added dropwise, and the reaction is carried out for 30 minutes to obtain 5, 8 -0-Dimethoxymethylshikonin 2-isomer;
步骤二，在氮气保护下，将 5， 8-0-二甲氧甲基紫草素溶于四氢呋喃的水溶液中，然后依次 加入 5倍当量保险粉、 10当量的氢氧化钠、 10当量的硫酸二乙酯， 充分搅拌， 回流 24小时， 得 1， 4-0~二乙基 -5， 8-0-二甲氧甲基紫草素；  Step two, under nitrogen protection, 5, 8-0-dimethoxymethylshikonin is dissolved in an aqueous solution of tetrahydrofuran, and then 5 times equivalent of insurance powder, 10 equivalents of sodium hydroxide, 10 equivalents of sulfuric acid are sequentially added. Diethyl ester, stirred well, refluxed for 24 hours to obtain 1, 4-0~diethyl-5, 8-0-dimethoxymethylshikonin;
步骤三，在氮气保护下，将 1，4_0~二乙基 _5，8_0_二甲氧甲基紫草素溶于无水二氯甲垸中， 在 N，N二甲基吡啶、 Ν，Ν' -二环己基碳二亚胺作用下， 有机酸縮合酯化得 1， 4-0-二乙基 -5, 8-0-二甲氧甲基紫草素侧链酯衍生物;或者将 1， 4-0-二乙基 -5， 8-0-二甲氧甲基紫草素溶于 N，N—二甲基甲酰胺中， 加入 1. 5倍当量氢化钠， 充分搅拌， 然后滴入溴代物， 室温搅拌反应 12小时， 得 1, 4-0~二乙基 -5, 8-0-二甲氧甲基紫草素侧链醚衍生物； Step 3, under nitrogen protection, dissolve 1,4_0~diethyl_5,8_0_dimethoxymethylshikonin in anhydrous dichloromethane, in N,N-dimethylpyridine, hydrazine, Under the action of Ν'-dicyclohexylcarbodiimide, the organic acid is condensed and esterified to obtain 1,4-0-diethyl -5, 8-0-dimethoxymethylshikonin side chain ester derivative; or 1,4-0-diethyl-5, 8-0-dimethoxymethylshikonin dissolved in N To the N-dimethylformamide, 1.5 parts of sodium hydride was added, stirred well, then the bromine was added dropwise, and the reaction was stirred at room temperature for 12 hours to obtain 1,4-0~diethyl-5, 8-0. - dimethoxymethylshikonin side chain ether derivative;
步骤四，将 1， 4_0_二乙基 _5， 8_0~二甲氧甲基紫草素侧链酯衍生物或 1， 4_0~二乙基 _5， 8-0- 二甲氧甲基紫草素侧链醚衍生物溶入异丙醇中，在酸作用下脱甲氧甲基， 即得结构式 VI所示化 合物；  Step four, 1, 4_0_diethyl_5, 8_0~dimethoxymethylshikonin side chain ester derivative or 1, 4_0~diethyl_5, 8-0-dimethoxymethyl violet The oxalic acid side chain ether derivative is dissolved in isopropanol and demethoxymethylated under the action of an acid to obtain a compound of the formula VI;
或者制备如结构式 W所示化合物的方法， 其中， R为 Η、 1~10个碳原子的垸烃、烯烃、 芳烃、 1~10个碳含氧原子的烷烃、烯烃、环烷烃、环烯烃或 C0R， ， R' 为 1~10个碳原子的烷烃、Or a method of preparing a compound of the formula W, wherein R is an anthracene, an alkene, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, a cycloalkane, a cyclic olefin, or 1 to 10 carbon atoms or C0R, , R' is an alkane of 1 to 10 carbon atoms,
~10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃；  ~10 carbon atoms containing oxygen atoms, olefins, cycloalkanes, cycloolefins;
Figure imgf000051_0001
Figure imgf000051_0001
， 包括如下步骤:  , including the following steps:
在氮气保护下，将紫草素与 5当量无水碳酸钾混合，溶于无水 N，N-二甲基甲酰胺中，加入 5当量的碘甲垸， 25Ό搅拌过夜， 得到 5， 8-0~二甲基紫草素 2位异构体： 之后在氮气保护下， 将 5， 8-0-二甲基紫草素 2位异构体溶于二氯甲垸中， 在 N，N二甲基吡啶、 Ν, Ν' -二环己基碳二 亚胺存在下，与有机酸缩合酯化得 5， 8-0-二甲基紫草素 2位侧链酯衍生物；或者将 1， 4， 5， 8-0- 四甲基紫草素侧链醚衍生物溶于乙腈中， 搅拌， 滴入硝酸铈铵的水溶液， 室温搅拌反应 0. 5小 时， 得到 5， 8-0~二甲基紫草素侧链醚衍生物 2位异构体和 6位异构体：  Under a nitrogen atmosphere, shikonin was mixed with 5 equivalents of anhydrous potassium carbonate, dissolved in anhydrous N,N-dimethylformamide, and 5 equivalents of iodothymidine were added, and 25 Torr was stirred overnight to obtain 5, 8- 0~ Dimethylshikonin 2 isomer: After the nitrogen protection, the 2, 8-0-dimethylshikonin 2 isomer is dissolved in dichloromethane, in N, N In the presence of lutidine, hydrazine, Ν'-dicyclohexylcarbodiimide, condensed with an organic acid to give a 5, 8-0-dimethylshikonin 2 side chain ester derivative; or 1 5小时的得到5, 8-0~, 4, 5, 8-0~ Tetramethyl shikonin side chain ether derivative was dissolved in acetonitrile, stirred, dripped into an aqueous solution of cerium ammonium nitrate, stirred at room temperature for 0.5 hours, 5, 8-0~ 2-isomer and 6-isomer of dimethylshikonin side chain ether derivative:
或者制备如结构式珊所示化合物的方法， 其中， R为 Η、 1~10个碳原子的垸烃、烯烃、 芳烃、 1~10个碳含氧原子的垸烃、烯烃、环烷烃、环烯烃或 C0R' ， R' 为 1~10个碳原子的垸烃、 烯烃、 芳烃、 1~10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； Or a method for preparing a compound as shown in the structural formula, wherein R is an anthracene hydrocarbon having 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon, an anthracene hydrocarbon having 1 to 10 carbon atoms, an olefin, a cycloalkane or a cycloalkene Or C0R', R' is a terpene hydrocarbon of 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, a cycloalkane, a cyclic olefin;
Figure imgf000051_0002
Figure imgf000051_0002
W ， 包括如下步骤： W , including the following steps:
在氮气保护下，将紫草素与 5当量无水碳酸钾混合，溶于无水 N，N-二甲基甲酰胺中，加入 5当量的碘乙垸， 25Ό搅拌过夜， 得到 5， 8-0~二乙基紫草素 2位异构体； 之后在氮气保护下， 将 5， 8-0-二乙基紫草素 2位异构体溶于二氯甲垸中， 在 Ν, Ν二甲基吡啶、 Ν, Ν' -二环己基碳二 亚胺作用下，与有机酸縮合酯化得 5， 8-0-二乙基紫草素 2位侧链酯衍生物；或者将 1， 4， 5， 8-0- 四乙基紫草素侧链醚衍生物溶于乙腈中， 充分搅拌， 慢慢滴入硝酸铈铵水溶液， 室温搅拌反应 0. 5小时， 得到 5， 8_0~二乙基紫草素侧链醚衍生物 2位异构体和 6位异构体； Under a nitrogen atmosphere, shikonin was mixed with 5 equivalents of anhydrous potassium carbonate, dissolved in anhydrous N,N-dimethylformamide, and 5 equivalents of iodoethyl hydrazine were added thereto, and stirred at 25 Torr overnight to obtain 5, 8- 0~Diethylshikonin 2 isomer; then under nitrogen protection, Dissolving the 2,4-0-diethylshikonin 2 isomer in methylene chloride, under the action of hydrazine, hydrazine lutidine, hydrazine, Ν'-dicyclohexylcarbodiimide, Condensation with an organic acid to give a 5, 8-0-diethylshikonin 2 side chain ester derivative; or 1, 4, 5, 8-0-tetraethyl shikonin side chain ether derivative Dissolve in acetonitrile, stir well, slowly drip into an aqueous solution of ammonium cerium nitrate, and stir the reaction at room temperature for 0.5 hours to obtain the 2 isomer and 6-position of 5, 8_0~ diethyl shikonin side chain ether derivative. Structure
或者制备如结构式 Κ所示化合物的方法， 其中， R为 Η或 C0R， ， R' 为 1~10个碳原子的烷 烃、 1~10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃； Or a method of preparing a compound of the formula ,, wherein R is hydrazine or COR, an alkane having 1 to 10 carbon atoms, an alkane having 1 to 10 carbon atoms, an olefin, a cycloalkane or a cycloalkene ;
Figure imgf000052_0001
， 包括如下步骤:
Figure imgf000052_0001
, including the following steps:
步骤一，将紫草素与 5当量无水碳酸钾混合，溶于无水 Ν, Ν-二甲基甲酰胺中，在氮气保护 下， 加入 5当量的碘甲浣， 25Ό搅拌过夜， 得到 5， 8-0~二甲基紫草素 2位异构体；  Step one, mixing shikonin with 5 equivalents of anhydrous potassium carbonate, dissolving in anhydrous hydrazine, hydrazine-dimethylformamide, adding 5 equivalents of iodoformamidine under nitrogen, stirring 25 过夜 overnight to obtain 5 , 8-0~dimethyl shikonin 2 isomer;
步骤二，在氮气保护下，将 5， 8-0-二甲基紫草素 2位异构体溶于无水二氯甲烷中，分别加 入过量锌粉、 10当量的三乙胺、 催化量的无水乙酸酑， 充分搅拌， 25Ό反应过夜， 得 5，8-0~ 二甲基 _1， 4, 1， _0 "三乙酰基紫草素；  Step 2, under nitrogen protection, the 2, 8-0-dimethylshikonin 2 isomer is dissolved in anhydrous dichloromethane, and an excess of zinc powder, 10 equivalents of triethylamine, and a catalytic amount are respectively added. Anhydrous barium acetate, stirred well, 25 Ό overnight, giving 5,8-0~dimethyl-1,4,1, _0 "triacetyl shikonin;
步骤三， 将 5， 8-0-二甲基 -1，4，Γ -0-三乙酰基紫草素溶入乙腈中， 滴加硝酸铈铵的水溶 液， 脱甲基化得 5, 8, 1 ' _0 -三乙酰基紫草素 6位异构体：  Step 3, dissolving 5, 8-0-dimethyl-1,4,Γ-0-triacetyl shikonin into acetonitrile, adding an aqueous solution of cerium ammonium nitrate dropwise, and demethylating to obtain 5, 8, 1 ' _0 -Triacetyl shikonin 6 isomer:
步骤四，将 5，8，1' -0 "三乙酰基紫草素 6位异构体溶入甲醇与四氢呋喃混合溶液中，滴加 质量百分比为 5% 酸钾的水溶液， 得紫草素 -8-0-单甲醚 6位异构体；  Step 4, the 5,8,1'-0 "triacetyl shikonin 6 isomer is dissolved in a mixed solution of methanol and tetrahydrofuran, and a mass percentage of 5% potassium acid aqueous solution is added dropwise to obtain shikonin- 8-0-monomethyl ether 6 isomer;
步骤五， 在氮气保护下， 将紫草素 -8-0-单甲醚 6位异构体溶于二氯甲垸中， 在 Ν，Ν二甲 基吡啶、 Ν, Ν' -二环己基碳二亚胺存在下， 与有机酸縮合酯化得紫草素 -8-0~单甲醚 6位异构体 酯衍生物；  Step 5: Dissolve the 6-isomer of shikonin-8-0-monomethyl ether in dichloromethane under the protection of nitrogen, in hydrazine, hydrazine dimethylpyridine, hydrazine, Ν'-dicyclohexyl In the presence of carbodiimide, condensed with an organic acid to obtain a leucovorin-8-0~monomethyl ether 6-isomer ester derivative;
或者制备如结构式 X所示化合物的方法， 其中， R为 Η或 C0R' ， R' 为 1~10个碳原子的垸 烃、 烯烃、 芳烃、 1~10个碳含氧原子的垸烃、 烯烃、 环垸烃、 环烯烃； Or a method of preparing a compound of the formula X, wherein R is hydrazine or C0R', an anthracene hydrocarbon having 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon, an anthracene hydrocarbon having 1 to 10 carbon atoms, and an olefin , a cyclic hydrocarbon, a cyclic olefin;
Figure imgf000052_0002
Figure imgf000052_0002
， 包括如下步骤: 步骤一，将紫草素与 5当量无水碳酸钾混合，溶于无水 Ν, Ν-二甲基甲酰胺中，在氮气保护 下， 加入 5当量的碘甲烷， 25Ό搅拌过夜， 得到 5， 8-0~二甲基紫草素 2位异构体； , including the following steps: Step 1, mixing shikonin with 5 equivalents of anhydrous potassium carbonate, dissolving in anhydrous hydrazine, hydrazine-dimethylformamide, adding 5 equivalents of methyl iodide under nitrogen, stirring 25 rpm overnight to obtain 5, 8-0-dimethyl shikonin 2-isomer;
步骤二，在氮气保护下，将 5， 8-0-二甲基紫草素 2位异构体溶于无水二氯甲烷中，分别加 入过量锌粉、 10当量的三乙胺、 催化量的无水乙酸酑， 充分搅拌， 25Ό反应过夜， 得 5，8-0~ 二甲基 -1, 4, 1， _0 "三乙酰基紫草素；  Step 2, under nitrogen protection, the 2, 8-0-dimethylshikonin 2 isomer is dissolved in anhydrous dichloromethane, and an excess of zinc powder, 10 equivalents of triethylamine, and a catalytic amount are respectively added. Anhydrous barium acetate, stirred well, 25 Ό overnight, to give 5,8-0~ dimethyl-1,4, 1, _0 "triacetyl shikonin;
步骤三， 将 5， 8-0-二甲基 -1, 4, 1 ' -0-三乙酰基紫草素溶入乙腈中， 滴加硝酸铈铵的水溶 液， 脱甲基化得 5, 8, 1 ' _0 -三乙酰基紫草素 6位异构体；  Step 3, dissolving 5, 8-0-dimethyl-1,4,1 '-0-triacetyl shikonin into acetonitrile, adding an aqueous solution of cerium ammonium nitrate dropwise, and demethylating to obtain 5, 8 , 1 ' _0 - triacetyl shikonin 6 isomer;
步骤四，将 5, 8, 1' _0~=-乙酰基紫草素 6位异构体溶入乙醇与四氢呋喃混合溶液中，滴加 质量百分比为 5«酸钾的水溶液， 得紫草素 -8-0-单乙醚 6位异构体；  Step 4, the 5, 8, 1' _0~=-acetyl shikonin 6 isomer is dissolved in a mixed solution of ethanol and tetrahydrofuran, and an aqueous solution of 5« acid potassium is added dropwise to obtain shikonin- 8-0-monoethyl ether 6 isomer;
步骤五， 在氮气保护下， 将紫草素 -8-0-单乙醚 6位异构体溶于二氯甲烷中， 在 Ν，Ν二甲 基吡啶、 Ν, Ν' -二环己基碳二亚胺存在下， 与有机酸縮合酯化得紫草素 -8-0~单乙醚 6位异构体 酯衍生物；  Step 5, under the protection of nitrogen, the chlorophyll-8-0-monoethyl ether 6 isomer is dissolved in dichloromethane, in hydrazine, hydrazine dimethylpyridine, hydrazine, Ν'-dicyclohexyl carbon two In the presence of an imine, condensed with an organic acid to obtain a shikonin-8-0-monoethyl ether 6-isomer ester derivative;
或者制备如结构式 XI所示化合物的方法， 其中， R为 Η或 C0R' ， R' 为 1~10个碳原子的烷 烃、 1~10个碳含氧原子的垸烃、 烯烃、 环垸烃、 环烯烃； Or a method of preparing a compound of the formula XI, wherein R is hydrazine or C0R', R' is an alkane having 1 to 10 carbon atoms, 1 to 10 carbon atoms containing an oxygen atom, an olefin, a hydrazine hydrocarbon, Cycloolefin
Figure imgf000053_0001
， 包括如下步骤:
Figure imgf000053_0001
, including the following steps:
步骤一， 将紫草素溶入无水乙酸酐中， 加入催化量的碘， 反应 10分钟， 得到 5, 8， -0- 三乙酰紫草素 -2位异构体；  Step one, dissolving shikonin in anhydrous acetic anhydride, adding a catalytic amount of iodine, and reacting for 10 minutes to obtain 5,8-0-triacetylshikonin- 2 isomer;
步骤二，将 5，8，1' -0~三乙酰紫草素 2位异构体溶入甲醇与四氢呋喃混合溶液中，滴加质 量百分比为 5%的碳酸钾的水溶液， 得到紫草素 -5-0-单甲醚 2位异构体；  In the second step, the 2,8,1'-0-triacetylshikonin 2-isomer is dissolved in a mixed solution of methanol and tetrahydrofuran, and a 5% by mass aqueous solution of potassium carbonate is added dropwise to obtain shikonin- 2-0-monomethyl ether 2 isomer;
步骤三， 在氮气保护下， 将紫草素 -5-0-单甲醚 2位异构体溶于二氯甲烷中， 在 Ν，Ν二甲 基吡啶、 Ν, Ν' -二环己基碳二亚胺存在下， 与有机酸縮合酯化得紫草素 -5-0 "单甲醚侧链酯衍生 物 2位异构体；  Step 3, under nitrogen protection, the oxalicin-5-0-monomethyl ether 2 isomer is dissolved in dichloromethane, in hydrazine, hydrazine lutidine, hydrazine, Ν'-dicyclohexyl carbon Condensation with an organic acid in the presence of a diimine to obtain a shikonin-5-0 "monomethyl ether side chain ester derivative 2 isomer;
或者制备如结构式 ΧΠ所示化合物的方法， 其中， R为 Η或 C0R， ， R' 为 1~10个碳原子的垸 烃、 烯烃、 芳烃、 1~10个碳含氧原子的烷烃、 烯烃、 环烷烃、 环烯烃；
Figure imgf000054_0001
Or a method of preparing a compound of the formula ,, wherein R is hydrazine or COR, R' is an anthracene hydrocarbon having 1 to 10 carbon atoms, an olefin, an aromatic hydrocarbon, an alkane having 1 to 10 carbon atoms, an olefin, Cycloalkane, cycloalkene;
Figure imgf000054_0001
™ ， 包括如下步骤：  TM includes the following steps:
步骤一， 将紫草素溶入无水乙酸酐中， 加入催化量的碘， 反应 10分钟， 得到 5，8， -0- 三乙酰紫草素 -2位异构体；  Step one, dissolving shikonin in anhydrous acetic anhydride, adding a catalytic amount of iodine, and reacting for 10 minutes to obtain 5,8,0-triacetylshikonin- 2 isomer;
步骤二，将 5，8，1' -0~三乙酰紫草素 2位异构体溶入乙醇与四氢呋喃混合溶液中，滴加质 量百分比为 5%的碳酸钾的水溶液， 得到紫草素 -5-0-单乙醚 2位异构体；  In the second step, the 2,8,1'-0-triacetylshikonin 2-isomer is dissolved in a mixed solution of ethanol and tetrahydrofuran, and a 5% by mass aqueous solution of potassium carbonate is added dropwise to obtain shikonin- 5-0-monoethyl ether 2 isomer;
步骤三， 在氮气保护下， 将紫草素 -5-0-单乙醚 2位异构体溶 T二氯甲烷中， 在 Ν, Ν二甲基吡 啶、 Ν，Ν' _二环己基碳二亚胺存在下， 与有机酸縮合酯化得紫草素 _5_0~单乙醚侧链酯衍生物 2 位异构体。 Step 3, under nitrogen protection, the shikonin-5-0-monoethyl ether 2 isomer is dissolved in T dichloromethane, in hydrazine, hydrazine dimethylpyridine, hydrazine, Ν' _ dicyclohexyl carbon two In the presence of an imine, it is condensed with an organic acid to obtain a 2-isomer of shikonin _5_0~monoethyl ether side chain ester derivative.
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