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CN111925378A - 5-substituted icaritin derivative and anti-tumor application thereof - Google Patents

5-substituted icaritin derivative and anti-tumor application thereof Download PDF

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CN111925378A
CN111925378A CN202010942598.1A CN202010942598A CN111925378A CN 111925378 A CN111925378 A CN 111925378A CN 202010942598 A CN202010942598 A CN 202010942598A CN 111925378 A CN111925378 A CN 111925378A
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王先恒
赵长阔
何芋岐
崔晗琦
柯希
赵缘财
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Abstract

The invention provides a 5-substituted icaritin derivative with a structural formula shown as 4, a preparation method and anti-tumor application thereof.

Description

5-取代淫羊藿素衍生物及其抗肿瘤应用5-Substituted icariin derivatives and their antitumor applications

技术领域technical field

本发明属于新药设计与合成领域，具体涉及一类新型5-取代淫羊藿素衍生物及其抗肿瘤应用。The invention belongs to the field of new drug design and synthesis, and in particular relates to a new type of 5-substituted icariin derivative and its antitumor application.

背景技术Background technique

淫羊藿素(Icaritin,1)是一种从传统中药淫羊藿中提取出来的一种天然烯丙基取代的黄酮化合物，具有抗肿瘤、抗痴呆等多种药理活性，然而由于其溶解性能不佳且生物利用度不高，限制了其在临床中的使用。淫羊藿素在体内被代谢成为β-脱水淫羊藿素(化合物2)。Icaritin (Icaritin, 1) is a natural allyl-substituted flavonoid compound extracted from the traditional Chinese medicine Epimedium. It has various pharmacological activities such as anti-tumor and anti-dementia. However, due to its solubility Poor and low bioavailability limit its clinical use. Icariin is metabolized in the body to β-anhydroicariin (compound 2).

Figure BDA0002674137810000011
Figure BDA0002674137810000011

研究表明，淫羊藿素抗肿瘤作用机制独特，药物学家希望对其黄酮结构进行修饰来获得活性更好的衍生物。为了寻找药效更好，毒性更强的抗癌药物候选者，我们设计并全合成了如下的药物分子，将淫羊藿素5-位羟基进行C1-C5烷基、卤代烷基、烯丙基、炔丙基及苄基取代获得一类结构独特的新型5-取代淫羊藿素衍生物4。Studies have shown that icariin has a unique anti-tumor mechanism, and pharmacologists hope to modify its flavonoid structure to obtain derivatives with better activity. In order to search for anti-cancer drug candidates with better efficacy and more toxicity, we designed and fully synthesized the following drug molecules. The 5-position hydroxyl group of icariin was converted to C1-C5 alkyl, haloalkyl, allyl , propargyl and benzyl substitution to obtain a new class of 5-substituted icariin derivatives with unique structure 4.

发明内容SUMMARY OF THE INVENTION

一方面，本发明提供了一种新型的5-取代淫羊藿素衍生物；其结构式如式4所示，In one aspect, the present invention provides a novel 5-substituted icariin derivative; its structural formula is shown in formula 4,

Figure BDA0002674137810000012
Figure BDA0002674137810000012

另一方面，本发明提供了如上所述的5-取代淫羊藿素衍生物4的合成方法，包括：1)、淫羊藿素1与甲酸在适当的有机溶剂中反应得到化合物2，2)、化合物2与硫酸二甲酯在碱催化剂存在下在丙酮中反应得到化合物3，3)、化合物3与卤取代烷R-X反应得到式4的5-取代淫羊藿素衍生物，合成路线见以下：On the other hand, the present invention provides the above-mentioned synthesis method of 5-substituted icariin derivative 4, comprising: 1), icariin 1 and formic acid are reacted in a suitable organic solvent to obtain compounds 2, 2 ), compound 2 and dimethyl sulfate react in acetone in the presence of a base catalyst to obtain compound 3, 3), compound 3 reacts with halo-substituted alkane R-X to obtain the 5-substituted icaritin derivative of formula 4, see the synthetic route the following:

Figure BDA0002674137810000021
Figure BDA0002674137810000021

在一种优选的实施方式中，上述步骤3)所述的卤取代烷R-X，卤素X选自氯、溴或碘，烷基选自C1-C5烷基、卤代烷基、烯丙基、炔丙基及苄基。In a preferred embodiment, the halogenated alkane R-X described in the above step 3), the halogen X is selected from chlorine, bromine or iodine, and the alkyl group is selected from C1-C5 alkyl, haloalkyl, allyl, propargyl and benzyl.

在一种优选的实施方式中，上述步骤3)所述的卤取代烷R-X，卤素X选自溴或碘。In a preferred embodiment, in the halogen-substituted alkane R-X described in the above step 3), the halogen X is selected from bromine or iodine.

在一种优选的实施方式中，上述步骤3)所述的卤取代烷R-X，烷基选自C1-C3烷基、卤代C1-C3烷基及苄基。In a preferred embodiment, in the halogenated alkane R-X described in the above step 3), the alkyl group is selected from C1-C3 alkyl group, halogenated C1-C3 alkyl group and benzyl group.

活性测试证明，本发明设计并合成得到的式4所示的5-取代淫羊藿素衍生物具有很好的抗肿瘤效果；尤其是针对肝癌、结肠癌、肺癌以及乳腺癌；体外抑制率高达64％-72％，与阳性对照药物喜树碱和他莫昔芬的抑制活性相当；可作为新型淫羊藿黄酮类候选药物应用于抗肿瘤临床应用。因此，本发明的第四方面提供了式4所示的5-取代淫羊藿素衍生物用于制备抗肿瘤药物的用途；优选地，用于制备抗肝癌、结肠癌、肺癌以及乳腺癌的用途。The activity test proves that the 5-substituted icariin derivative represented by formula 4 designed and synthesized by the present invention has a good anti-tumor effect; especially for liver cancer, colon cancer, lung cancer and breast cancer; the in vitro inhibition rate is as high as 64%-72%, which is comparable to the inhibitory activity of the positive control drugs camptothecin and tamoxifen; it can be used as a new type of epimedium flavonoid drug candidate for anti-tumor clinical application. Therefore, the fourth aspect of the present invention provides the use of the 5-substituted icariin derivatives shown in formula 4 for preparing antitumor drugs; preferably, for preparing anticancer drugs against liver cancer, colon cancer, lung cancer and breast cancer use.

本发明的有益之处在于：通过在淫羊藿素母体黄酮结构上的5位羟基上引入烷基，获得了一类新型的淫羊藿黄酮衍生物4。活性试验表明，该类衍生物具备良好的抗肿瘤活性，尤其是针对肝癌、结肠癌、肺癌以及乳腺癌几种肿瘤。此外，本发明的5-取代淫羊藿素衍生物4的合成方法，原料易得，合成路线收率高，非常易于操作实施。The benefit of the present invention is that a new type of epimedium flavonoid derivative 4 is obtained by introducing an alkyl group on the 5-position hydroxyl group on the flavonoid structure of the parent icariin. Activity tests show that the derivatives have good antitumor activity, especially against several tumors of liver cancer, colon cancer, lung cancer and breast cancer. In addition, the method for synthesizing the 5-substituted icariin derivative 4 of the present invention has easily available raw materials, high yield of the synthesis route, and is very easy to operate and implement.

在上述合成及制备方法中，有机溶剂也可以依据反应对温度、溶剂极性的需求，从N,N-二甲基甲酰胺(缩写DMF)、二甲基亚砜(缩写DMSO)、二氯甲烷(缩写DCM)、氯仿、乙腈、四氢呋喃或乙醚中选取。反应温度可依据反应类型适当选取。反应时间可通过薄层层析TLC、高效液相色谱法HPLC或LC-MS液相质谱联用等监控手段追踪反应情况得出。In the above synthesis and preparation methods, the organic solvent can also be selected from N,N-dimethylformamide (abbreviated as DMF), dimethyl sulfoxide (abbreviated as DMSO), dichloride Methane (abbreviated DCM), chloroform, acetonitrile, tetrahydrofuran or diethyl ether. The reaction temperature can be appropriately selected according to the type of reaction. The reaction time can be tracked by monitoring methods such as thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) or LC-MS liquid chromatography-mass spectrometry.

具体实施方式Detailed ways

以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。在不脱离本发明构思的前提下，本领域技术人员可对权利要求的各参数或条件做出的改进或组合，这些改进或组合也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。本发明原料及试剂购自国药集团；溶剂够自遵义双巨化工有限公司。除特别说明外，所用试剂均为化学纯。The following will further illustrate the present invention through specific examples, which are not intended to limit the protection scope of the present invention. On the premise of not departing from the concept of the present invention, those skilled in the art can make improvements or combinations to the parameters or conditions of the claims, and these improvements or combinations should also be regarded as the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims. The raw materials and reagents of the present invention are purchased from Sinopharm Group; the solvent is sufficient from Zunyi Shuangju Chemical Co., Ltd. Unless otherwise specified, all reagents used are chemically pure.

实施例1、β-脱水淫羊藿素2的制备： Example 1 , preparation of β-anhydroicariin 2:

将Icaritin(3g，8.2mmol)的甲酸(50mL)溶液搅拌回流20h。然后将反应溶液倒入碎冰中。过滤收集固体，得到黄色粉末状的标题化合物(2，2.8g，93.3％)。熔点：221-222℃(照明温度：223℃，Akai等，1935)。A solution of icaritin (3 g, 8.2 mmol) in formic acid (50 mL) was stirred at reflux for 20 h. The reaction solution was then poured into crushed ice. The solid was collected by filtration to give the title compound (2, 2.8 g, 93.3%) as a yellow powder. Melting point: 221-222°C (illumination temperature: 223°C, Akai et al., 1935).

1H NMR(400MHz,CHCl3)δ＝11.47(s,1H,5-OH),8.17(d,J＝8.7Hz,2H,Ar-H),7.03(d,J＝8.7Hz,2H,Ar-H),6.64(s,1H,3-OH),6.24(s,1H,Ar-H),3.88(s,3H,CH3O),2.89(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.88(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.37(s,6H,(CH3)2). 1 H NMR (400 MHz, CHCl 3 ) δ=11.47 (s, 1H, 5-OH), 8.17 (d, J=8.7 Hz, 2H, Ar-H), 7.03 (d, J=8.7 Hz, 2H, Ar -H), 6.64 (s, 1H, 3-OH), 6.24 (s, 1H, Ar-H), 3.88 (s, 3H, CH 3 O), 2.89 (t, J=6.8 Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.88(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.37(s, 6H, (CH 3 ) 2 ).

实施例2、化合物3(R＝CH3)的制备： Example 2. Preparation of compound 3 (R=CH 3 ):

化合物2(100mg，0.27mmol)和K2CO3(75mg，0.54mmol)的丙酮(2ml)溶液在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入硫酸二甲酯(1equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物3(95％)。A solution of compound 2 (100 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) in acetone ( 2 ml) was stirred at room temperature for 10 minutes. Dimethyl sulfate (1 equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to give compound 3 (95%).

1H NMR(400MHz,CDCl3)δ＝12.36(s,1H,OH),8.08(d,J＝9.1Hz,2H,Ar-H),7.00(d,J＝9.1Hz,2H,Ar-H),6.21(s,1H,Ar-H),3.85(d,J＝14.6Hz,6H,2CH3O),2.83(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.84(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.34(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝178.7(C＝O),161.5(C＝C),160.0(C＝C),159.4(C＝C),155.1(C＝C),153.7(C＝C),139.0(C＝C),129.9(2C,C＝C),123.2(C＝C),114.1(2C,C＝C),105.7(C＝C),99.9(C＝C),99.5(C＝C),75.9(C(CH3)2),60.1(CH3O),55.4(CH3O),31.7(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.3(CH2-CH2-C(CH3)2). 1 H NMR (400 MHz, CDCl 3 ) δ=12.36 (s, 1H, OH), 8.08 (d, J=9.1 Hz, 2H, Ar-H), 7.00 (d, J=9.1 Hz, 2H, Ar-H ), 6.21(s, 1H, Ar-H), 3.85(d, J=14.6Hz, 6H, 2CH 3 O), 2.83(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.84(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.34(s, 6H, (CH 3 ) 2 ). 13 C NMR (101MHz, CDCl 3 )δ=178.7(C=O), 161.5(C=C), 160.0(C=C), 159.4(C=C), 155.1(C=C), 153.7(C=C), 139.0(C=C ),129.9(2C,C=C),123.2(C=C),114.1(2C,C=C),105.7(C=C),99.9(C=C),99.5(C=C),75.9( C(CH 3 ) 2 ), 60.1(CH 3 O), 55.4(CH 3 O), 31.7(CH 2 -CH 2 -C(CH 3 ) 2 ), 26.6(2C,C(CH 3 ) 2 ), 16.3(CH 2 -CH 2 -C(CH 3 ) 2 ).

实施例3、化合物4a-j(R＝CH3)的制备：Example 3. Preparation of compounds 4a-j (R=CH 3 ):

(1)化合物4a(R＝CH3)的制备(1) Preparation of compound 4a (R=CH 3 )

Figure BDA0002674137810000031
Figure BDA0002674137810000031

化合物3(50mg，0.136mmol)和K2CO3(放置在丙酮(2ml)中的38mg，2equ.)在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入碘甲烷(2equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物4a(85％)。1H NMR(400MHz,CDCl3)δ＝8.06(d,J＝9.0Hz,2H,Ar-H),6.97(d,J＝9.0Hz,2H,Ar-H),6.22(s,1H,Ar-H),3.88(s,3H,OCH3),3.84(s,3H,OCH3),3.83(s,3H,OCH3),2.85(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.85(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.35(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.3(C＝O),161.0(C＝C),159.0(C＝C),158.2(C＝C),155.7(C＝C),151.9(C＝C),141.0(C＝C),129.6(2C,C＝C),123.6(C＝C),113.9(2C,C＝C),108.8(C＝C),101.0(C＝C),96.5(C＝C),75.9(C(CH3)2),59.8(CH3O),56.2(CH3O),55.3(CH3O),31.9(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C23H24O6:396.43,Found:397.18[M+1].Compound 3 (50 mg, 0.136 mmol) and K2CO3 (38 mg in acetone ( 2 ml), 2 equ.) were stirred at room temperature for 10 minutes. To the suspension was added iodomethane (2 equ.) dropwise over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to give compound 4a (85%). 1 H NMR (400 MHz, CDCl 3 ) δ=8.06 (d, J=9.0 Hz, 2H, Ar-H), 6.97 (d, J=9.0 Hz, 2H, Ar-H), 6.22 (s, 1H, Ar -H), 3.88 (s, 3H, OCH 3 ), 3.84 (s, 3H, OCH 3 ), 3.83 (s, 3H, OCH 3 ), 2.85 (t, J=6.7Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.85(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.35(s, 6H, (CH 3 ) 2 ). 13 C NMR (101MHz, CDCl 3 )δ=174.3(C=O), 161.0(C=C), 159.0(C=C), 158.2(C=C), 155.7(C=C), 151.9(C=C), 141.0 (C=C), 129.6 (2C, C=C), 123.6 (C=C), 113.9 (2C, C=C), 108.8 (C=C), 101.0 (C=C), 96.5 (C=C) C), 75.9(C(CH 3 ) 2 ), 59.8(CH 3 O), 56.2(CH 3 O), 55.3(CH 3 O), 31.9(CH 2 -CH 2 -C(CH 3 ) 2 ), 26.6(2C,C( CH3 ) 2 ),16.6( CH2 - CH2 -C( CH3 ) 2 ).HRMS(TOF):calculated for C23H24O6 :396.43,Found: 397.18 [ M + 1].

(2)化合物4b(R＝C2H5)的制备(2) Preparation of compound 4b (R=C 2 H 5 )

Figure BDA0002674137810000041
Figure BDA0002674137810000041

化合物3(50mg，0.136mmol)和K2CO3(放置于丙酮(2ml)中的38mg，2equ.)在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入溴乙烷(2equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物4b(60％)，为白色固体，熔点M.p.165.6-168.7℃.Rf＝0.19(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.07(d,J＝8.9Hz,2H,Ar-H),6.98(d,J＝8.9Hz,2H,Ar-H),6.21(s,1H,Ar-H),4.09(q,J＝7.0Hz,2H,CH2CH3),3.85(s,3H,OCH3),3.84(s 3H,OCH3),2.85(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.85(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.51(t,J＝7.0Hz,3H,CH2CH3),1.35(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.3(C＝O),160.9(C＝C),158.3(C＝C),158.1(C＝C),155.7(C＝C),151.9(C＝C),141.0(C＝C),129.6(2C,C＝C),123.7(C＝C),113.9(2C,C＝C),109.0(C＝C),100.9(C＝C),97.5(C＝C),75.8(C(CH3)2),64.8(OCH2),59.9(CH3O),55.4(CH3O),31.9(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2),14.6(CH2CH3).HRMS(TOF):calculatedfor C24H26O6:410.46,Found:411.20[M+1].Compound 3 (50 mg, 0.136 mmol) and K2CO3 (38 mg in acetone ( 2 ml), 2 equ.) were stirred at room temperature for 10 minutes. Ethyl bromide (2 equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to give compound 4b (60%) as a white solid, melting point Mp165.6-168.7°C. R f =0.19 (PE:EA=3:1). 1 H NMR (400MHz, CDCl 3 )δ =8.07(d,J=8.9Hz,2H,Ar-H),6.98(d,J=8.9Hz,2H,Ar-H),6.21(s,1H,Ar-H),4.09(q,J= 7.0 Hz, 2H, CH 2 CH 3 ), 3.85 (s, 3H, OCH 3 ), 3.84 (s 3H, OCH 3 ), 2.85 (t, J=6.7 Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.85(t, J＝6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.51(t, J＝7.0 Hz, 3H, CH 2 CH 3 ), 1.35(s , 6H, (CH 3 ) 2 ). 13 C NMR (101 MHz, CDCl 3 ) δ=174.3 (C=O), 160.9 (C=C), 158.3 (C=C), 158.1 (C=C), 155.7 (C=C), 151.9 (C=C), 141.0 (C=C), 129.6 (2C, C=C), 123.7 (C=C), 113.9 (2C, C=C), 109.0 (C=C) ), 100.9(C=C), 97.5(C=C), 75.8(C(CH 3 ) 2 ), 64.8(OCH 2 ), 59.9(CH 3 O), 55.4(CH 3 O), 31.9(CH 2 -CH 2 -C(CH 3 ) 2 ), 26.6(2C,C(CH 3 ) 2 ), 16.6(CH 2 -CH 2 -C(CH 3 ) 2 ), 14.6(CH 2 CH 3 ).HRMS( TOF):calculatedfor C 24 H 26 O 6 :410.46,Found:411.20[M+1].

(3)化合物4c(R＝nC3H7)的制备(3) Preparation of compound 4c (R=nC 3 H 7 )

Figure BDA0002674137810000042
Figure BDA0002674137810000042

化合物3(50mg，0.136mmol)和K2CO3(放置于丙酮(2ml)中的38mg，2equ.)在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入正溴丙烷(2equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物4c(64％)，为白色固体，熔点168.4-171.3℃.Rf＝0.38(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.07(d,J＝9.0Hz,2H,Ar-H),6.98(d,J＝9.0Hz,2H,Ar-H),6.22(s,1H,Ar-H),3.97(t,J＝6.7Hz,2H,OCH2),3.86(s,3H,OCH3),3.83(s,3H,OCH3),2.85(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.92(q,J＝7.1Hz,2H,CH2CH3),1.85(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.35(s,3H,CH3),1.34(s,3H,CH3),1.07(t,J＝7.4Hz,3H,CH2CH3).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),160.9(C＝C),158.5(C＝C),158.1(C＝C),155.7(C＝C),151.9(C＝C),141.0(C＝C),129.6(2C,C＝C),123.7(C＝C),113.9(2C,C＝C),109.0(C＝C),100.8(C＝C),97.5(C＝C),75.8(C(CH3)2),70.7(OCH2),59.9(CH3O),55.3(CH3O),31.9(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),22.3(CH2CH3),16.6(CH2-CH2-C(CH3)2),10.5(CH2CH3).HRMS(TOF):calculated for C25H28O6:424.49,Found:425.21[M+1].Compound 3 (50 mg, 0.136 mmol) and K2CO3 (38 mg in acetone ( 2 ml), 2 equ.) were stirred at room temperature for 10 minutes. To the suspension was added n-bromopropane (2 equ.) dropwise over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to give compound 4c (64%) as a white solid, mp 168.4-171.3°C. R f =0.38 (PE:EA=3:1). 1 H NMR (400MHz, CDCl 3 )δ=8.07 (d, J=9.0Hz, 2H, Ar-H), 6.98 (d, J=9.0Hz, 2H, Ar-H), 6.22 (s, 1H, Ar-H), 3.97 (t, J=6.7Hz) , 2H, OCH 2 ), 3.86(s, 3H, OCH 3 ), 3.83(s, 3H, OCH 3 ), 2.85(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.92(q, J=7.1Hz, 2H, CH 2 CH 3 ), 1.85(t, J=6.8 Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.35(s, 3H, CH 3 ), 1.34 (s, 3H, CH 3 ), 1.07 (t, J=7.4 Hz, 3H, CH 2 CH 3 ). 13 C NMR (101 MHz, CDCl 3 ) δ=174.2 (C=O), 160.9 (C=C), 158.5 (C=C), 158.1 (C=C), 155.7 (C=C), 151.9 (C=C), 141.0 (C=C), 129.6 (2C, C=C), 123.7(C=C), 113.9(2C,C=C), 109.0(C=C), 100.8(C=C), 97.5(C=C), 75.8(C(CH 3 ) 2 ), 70.7(OCH 2 ), 59.9(CH3O), 55.3(CH3O), 31.9( CH2 - CH2 -C( CH3 ) 2 ), 26.6(2C,C( CH3 )2 ) , 22.3 ( CH2CH 3 ), 16.6(CH 2 -CH 2 -C(CH 3 ) 2 ), 10.5(CH 2 CH 3 ).HRMS(TOF): calculated for C 25 H 28 O 6 :424.49,Found:425.21[M+1 ].

(4)化合物4d(R＝nC5H11)的制备(4) Preparation of compound 4d (R=nC 5 H 11 )

Figure BDA0002674137810000051
Figure BDA0002674137810000051

化合物3(50mg，0.136mmol)和K2CO3(放置于丙酮(2ml)中的38mg，2equ.)在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入正溴戊烷(2equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物4d(67％)，为白色固体，熔点M.p.137.2～140.2℃.Rf＝0.47(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.03(d,J＝7.4Hz,2H,Ar-H),6.95(d,J＝6.7Hz,2H,Ar-H),6.18(s,1H,Ar-H),3.96(t,J＝4Hz,2H,OCH2),3.82(s,3H,OCH3),3.79(s,3H,OCH3),2.83(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.89(t,J＝6.7Hz,2H,OCH2CH2),1.83(d,J＝6.6Hz,2H,CH2-CH2-C(CH3)2),1.47–1.42(m,2H,CH2CH3),1.32(s,6H,(CH3)2),1.15-1.24(m,2H,CH2CH2CH3),0.86(t,J＝6.8Hz,3H,CH2CH3).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),160.9(C＝C),158.5(C＝C),158.1(C＝C),155.7(C＝C),151.9(C＝C),141.0(C＝C),129.6(2C,C＝C),123.7(C＝C),113.9(2C,C＝C),109.0(C＝C),100.8(C＝C),97.4(C＝C),75.8(C(CH3)2),69.3(OCH2),59.9(CH3O),55.3(CH3O),31.9(CH2-CH2-C(CH3)2),28.6(OCH2CH2),28.0(OCH2CH2CH2),26.6(2C,C(CH3)2),22.4,16.6(CH2-CH2-C(CH3)2),14.0(CH2CH3).HRMS(TOF):calculated for C27H32O6:452.54,Found:453.25[M+1].Compound 3 (50 mg, 0.136 mmol) and K2CO3 (38 mg in acetone ( 2 ml), 2 equ.) were stirred at room temperature for 10 minutes. To the suspension was added n-bromopentane (2 equ.) dropwise over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to obtain compound 4d (67%) as a white solid with a melting point of Mp137.2～140.2°C. R f =0.47 (PE:EA=3:1). 1 H NMR (400MHz, CDCl 3 )δ =8.03(d,J=7.4Hz,2H,Ar-H),6.95(d,J=6.7Hz,2H,Ar-H),6.18(s,1H,Ar-H),3.96(t,J= 4Hz, 2H, OCH 2 ), 3.82 (s, 3H, OCH 3 ), 3.79 (s, 3H, OCH 3 ), 2.83 (t, J=6.8 Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.89 (t, J=6.7Hz, 2H, OCH 2 CH 2 ), 1.83 (d, J=6.6 Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.47–1.42 (m ,2H,CH 2 CH 3 ),1.32(s,6H,(CH 3 ) 2 ),1.15-1.24(m,2H,CH 2 CH 2 CH 3 ),0.86(t,J＝6.8Hz,3H,CH 2 CH 3 ). 13 C NMR (101 MHz, CDCl 3 ) δ=174.2 (C=O), 160.9 (C=C), 158.5 (C=C), 158.1 (C=C), 155.7 (C=C) ,151.9(C＝C),141.0(C＝C),129.6(2C,C＝C),123.7(C＝C),113.9(2C,C＝C),109.0(C＝C),100.8(C =C), 97.4(C=C), 75.8(C( CH3 ) 2 ), 69.3(OCH2), 59.9(CH3O), 55.3(CH3O), 31.9 ( CH2 - CH2 - C (CH 3 ) 2 ), 28.6 (OCH 2 CH 2 ), 28.0 (OCH 2 CH 2 CH 2 ), 26.6 (2C, C(CH 3 ) 2 ), 22.4, 16.6 (CH 2 -CH 2 -C(CH 2 ) 3 ) 2 ), 14.0(CH 2 CH 3 ).HRMS(TOF): calculated for C 27 H 32 O 6 : 452.54, Found: 453.25[M+1].

(5)化合物4e(R＝-CH2CH2Br)的制备(5) Preparation of compound 4e (R=-CH 2 CH 2 Br)

Figure BDA0002674137810000052
Figure BDA0002674137810000052

化合物3(50mg，0.136mmol)和K2CO3(放置于丙酮(2ml)中的38mg，2equ.)在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入1,2-二溴乙烷(2equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物4e(44％)，为淡黄色固体，熔点M.p.143.5-148.7℃.Rf＝0.28(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.06(d,J＝7.9Hz,2H,Ar-H),6.98(d,J＝7.8Hz,2H,Ar-H),6.26(s,1H,Ar-H),4.31(t,J＝6.7Hz,2H,OCH2),3.85(s,3H,OCH3),3.82(s,3H,OCH3),3.68(d,J＝7.5Hz,2H,CH2Br),2.86(t,J＝6.0Hz,2H,CH2-CH2-C(CH3)2),1.85(t,J＝6.6Hz,2H,CH2-CH2-C(CH3)2),1.35(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.0(C＝O),161.1(C＝C),158.1(C＝C),157.1(C＝C),153.5(C＝C),152.3(C＝C),140.9(C＝C),129.6(2C,C＝C),123.5(C＝C),114.0(2C,C＝C),109.4(C＝C),102.5(C＝C),99.5(C＝C),76.0(C(CH3)2),69.5(OCH2),59.9(CH3O),55.3(CH3O),31.8(CH2-CH2-C(CH3)2),28.3(CH2Br),26.6(2C,C(CH3)2),16.7(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C24H25BrO6:490.08,Found:491.09[M+1].Compound 3 (50 mg, 0.136 mmol) and K2CO3 (38 mg in acetone ( 2 ml), 2 equ.) were stirred at room temperature for 10 minutes. 1,2-Dibromoethane (2 equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to give compound 4e (44%) as pale yellow solid, melting point Mp143.5-148.7°C. R f =0.28 (PE:EA=3:1). 1 H NMR (400MHz, CDCl 3 ) δ=8.06(d,J=7.9Hz,2H,Ar-H),6.98(d,J=7.8Hz,2H,Ar-H),6.26(s,1H,Ar-H),4.31(t,J = 6.7 Hz, 2H, OCH 2 ), 3.85 (s, 3H, OCH 3 ), 3.82 (s, 3H, OCH 3 ), 3.68 (d, J=7.5 Hz, 2H, CH 2 Br), 2.86 (t, J=6.0Hz, 2H, CH2 - CH2 -C( CH3 ) 2 ), 1.85(t, J=6.6Hz, 2H, CH2 - CH2 -C( CH3 ) 2 ), 1.35(s, 6H, (CH 3 ) 2 ). 13 C NMR (101 MHz, CDCl 3 ) δ=174.0 (C=O), 161.1 (C=C), 158.1 (C=C), 157.1 (C=C), 153.5 ( C=C), 152.3 (C=C), 140.9 (C=C), 129.6 (2C, C=C), 123.5 (C=C), 114.0 (2C, C=C), 109.4 (C=C) , 102.5(C=C), 99.5(C=C), 76.0(C(CH 3 ) 2 ), 69.5(OCH 2 ), 59.9(CH 3 O), 55.3(CH 3 O), 31.8(CH 2 - CH 2 -C(CH 3 ) 2 ), 28.3(CH 2 Br), 26.6(2C,C(CH 3 ) 2 ), 16.7(CH 2 -CH 2 -C(CH 3 ) 2 ).HRMS(TOF) :calculated for C 24 H 25 BrO 6 :490.08,Found:491.09[M+1].

(6)化合物4f(R＝-CH2CH2CH2Br)的制备(6) Preparation of compound 4f (R=-CH 2 CH 2 CH 2 Br)

Figure BDA0002674137810000061
Figure BDA0002674137810000061

化合物3(50mg，0.136mmol)和K2CO3(放置于丙酮(2ml)中的38mg，2equ.)在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入1,2-二溴丙烷(2equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物4f(53％)，为淡黄色固体，熔点M.p.180.2-185.5℃.Rf＝0.31(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.06(d,J＝8.9Hz,2H,Ar-H),6.99(d,J＝8.9Hz,2H,Ar-H),6.24(s,1H,Ar-H),4.14(t,J＝5.6Hz,2H,OCH2),3.86(s,3H,OCH3),3.80(s,3H,OCH3),3.69(d,J＝7.0Hz,2H,CH2Br),2.86(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),2.40(p,J＝5.9Hz,2H,CH2CH2Br),1.86(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.36(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),161.0(C＝C),158.1(2C,C＝C),155.6(C＝C),152.2(C＝C),151.2(C＝C),141.0(C＝C),129.6(2C,C＝C),123.6(C＝C),113.9(2C,C＝C),101.3(C＝C),97.7(C＝C),75.9(C(CH3)2),66.3(OCH2),59.8(CH3O),55.3(CH3O),32.0(CH2-CH2-C(CH3)2),30.9(CH2CH2Br),29.6(CH2Br),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C25H27BrO6:504.38,Found:505.25[M+1].Compound 3 (50 mg, 0.136 mmol) and K2CO3 (38 mg in acetone ( 2 ml), 2 equ.) were stirred at room temperature for 10 minutes. 1,2-Dibromopropane (2equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to give compound 4f (53%) as pale yellow solid, melting point Mp180.2-185.5°C. R f =0.31 (PE:EA=3:1). 1 H NMR (400MHz, CDCl 3 ) δ=8.06(d,J=8.9Hz,2H,Ar-H),6.99(d,J=8.9Hz,2H,Ar-H),6.24(s,1H,Ar-H),4.14(t,J = 5.6 Hz, 2H, OCH 2 ), 3.86 (s, 3H, OCH 3 ), 3.80 (s, 3H, OCH 3 ), 3.69 (d, J=7.0 Hz, 2H, CH 2 Br), 2.86 (t, J=6.7Hz, 2H, CH2 - CH2 - C( CH3 ) 2 ), 2.40 (p, J=5.9Hz, 2H, CH2CH2Br), 1.86 (t, J=6.7Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.36 (s, 6H, (CH 3 ) 2 ). 13 C NMR (101 MHz, CDCl 3 ) δ=174.2 (C=O), 161.0 (C=C ), 158.1 (2C, C=C), 155.6 (C=C), 152.2 (C=C), 151.2 (C=C), 141.0 (C=C), 129.6 (2C, C=C), 123.6 ( C=C), 113.9 (2C, C=C), 101.3 (C=C), 97.7 (C=C), 75.9 (C(CH 3 ) 2 ), 66.3 (OCH 2 ), 59.8 (CH 3 O) , 55.3(CH 3 O), 32.0(CH 2 -CH 2 -C(CH 3 ) 2 ), 30.9(CH 2 CH 2 Br), 29.6(CH 2 Br), 26.6(2C,C(CH 3 ) 2 ),16.6(CH 2 -CH 2 -C(CH 3 ) 2 ).HRMS(TOF):calculated for C 25 H 27 BrO 6 :504.38,Found:505.25[M+1].

(7)化合物4g(R＝-CH2CH2CH2CH2Br)的制备(7) Preparation of compound 4g (R=-CH 2 CH 2 CH 2 CH 2 Br)

Figure BDA0002674137810000062
Figure BDA0002674137810000062

化合物3(50mg，0.136mmol)和K2CO3(放置于丙酮(2ml)中的38mg，2equ.)在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入1,2-二溴丁烷(2equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物4g(78％)，为白色固体，熔点M.p.139.4-142.6℃.Rf＝0.41(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.07(d,J＝8.9Hz,2H,Ar-H),6.99(d,J＝8.9Hz,2H,Ar-H),6.21(s,1H,Ar-H),4.04(t,J＝5.9Hz,2H,OCH2),3.86(s,3H,OCH3),3.81(s,3H,OCH3),3.53(t,J＝6.4Hz,2H,CH2Br),2.86(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),2.22–2.15(m,2H,CH2CH2Br),2.09–2.02(m,2H,CH2CH2O),1.86(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.36(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),160.1(C＝C),158.2(C＝C),158.1(C＝C),155.7(C＝C),152.1(C＝C),141.0(C＝C),129.6(2C,C＝C),123.6(C＝C),113.9(2C,C＝C),109.0(C＝C),101.1(C＝C),97.5(C＝C),75.9(C(CH3)2),67.9(OCH2),59.9(CH3O),55.4(CH3O),34.3(CH2Br),31.8(CH2-CH2-C(CH3)2),29.2(CH2CH2Br),27.4(CH2CH2O),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C26H29BrO6:518.41,Found:519.12[M+1].Compound 3 (50 mg, 0.136 mmol) and K2CO3 (38 mg in acetone ( 2 ml), 2 equ.) were stirred at room temperature for 10 minutes. 1,2-Dibromobutane (2 equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to give compound 4g (78%) as a white solid, melting point Mp139.4-142.6°C. R f =0.41 (PE:EA=3:1). 1 H NMR (400MHz, CDCl 3 )δ =8.07(d,J=8.9Hz,2H,Ar-H),6.99(d,J=8.9Hz,2H,Ar-H),6.21(s,1H,Ar-H),4.04(t,J= 5.9 Hz, 2H, OCH 2 ), 3.86 (s, 3H, OCH 3 ), 3.81 (s, 3H, OCH 3 ), 3.53 (t, J=6.4 Hz, 2H, CH 2 Br), 2.86 (t, J = 6.7Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 2.22–2.15 (m, 2H, CH 2 CH 2 Br), 2.09–2.02 (m, 2H, CH 2 CH 2 O), 1.86 (t, J=6.7 Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.36 (s, 6H, (CH 3 ) 2 ). 13 C NMR (101 MHz, CDCl 3 )δ=174.2 (C=O), 160.1 (C=C), 158.2 (C=C), 158.1 (C=C), 155.7 (C=C), 152.1 (C=C), 141.0 (C=C), 129.6 ( 2C, C=C), 123.6 (C=C), 113.9 (2C, C=C), 109.0 (C=C), 101.1 (C=C), 97.5 (C=C), 75.9 (C(CH 3 ) 2 ), 67.9 (OCH 2 ), 59.9 (CH 3 O), 55.4 (CH 3 O), 34.3 (CH 2 Br), 31.8 (CH 2 -CH 2 -C(CH 3 ) 2 ), 29.2 (CH 2 ) 2 CH 2 Br), 27.4(CH 2 CH 2 O), 26.6(2C,C(CH 3 ) 2 ), 16.6(CH 2 -CH 2 -C(CH 3 ) 2 ).HRMS(TOF):calculated for C 26 H 29 BrO 6 : 518.41, Found: 519.12 [M+1].

(8)化合物4h(R＝allyl)的制备(8) Preparation of compound 4h (R=allyl)

Figure BDA0002674137810000071
Figure BDA0002674137810000071

化合物3(50mg，0.136mmol)和K2CO3(放置于丙酮(2ml)中的38mg，2equ.)在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入烯丙基溴(2equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物4h(76％)，为白色固体，熔点M.p.167.0～169.8℃.Rf＝0.25(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.07(d,J＝9.1Hz,2H,Ar-H),6.98(d,J＝9.1Hz,2H,Ar-H),6.22(s,1H,Ar-H),6.09(ddd,J＝21.9,10.5,4.7Hz,1H,CH2＝CH),5.67(dd,J＝17.3,1.6Hz,1H,CH2＝CH),5.31(dd,J＝10.6,1.6Hz,1H,CH2＝CH),4.60(d,J＝4.7Hz,2H,OCH2),3.86(s,3H,OCH3),3.83(s,3H,OCH3),2.86(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.85(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.35(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),161.0,158.2(C＝C),157.8(C＝C),155.7(C＝C),152.0(C＝C),141.9(C＝C),141.0(C＝C),132.4(C＝C),129.6(2C,C＝C),123.7(C＝C),117.6(C＝C),113.9(2C,C＝C),101.2(C＝C),98.0(C＝C),75.9(C(CH3)2),69.6(OCH2),59.9(CH3O),55.3(CH3O),31.9(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C25H26O6:422.47,Found:423.20[M+1].Compound 3 (50 mg, 0.136 mmol) and K2CO3 (38 mg in acetone ( 2 ml), 2 equ.) were stirred at room temperature for 10 minutes. To the suspension was added allyl bromide (2 equ.) dropwise over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to obtain compound 4h (76%) as a white solid with a melting point of Mp167.0～169.8°C. R f =0.25 (PE:EA=3:1). 1 H NMR (400MHz, CDCl 3 )δ =8.07(d,J=9.1Hz,2H,Ar-H),6.98(d,J=9.1Hz,2H,Ar-H),6.22(s,1H,Ar-H),6.09(ddd,J= 21.9, 10.5, 4.7Hz, 1H, CH2 =CH), 5.67 (dd, J=17.3, 1.6Hz, 1H, CH2 =CH), 5.31 (dd, J=10.6, 1.6Hz, 1H, CH2 = CH), 4.60(d, J=4.7Hz, 2H, OCH 2 ), 3.86(s, 3H, OCH 3 ), 3.83(s, 3H, OCH 3 ), 2.86(t, J=6.8 Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.85(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.35(s, 6H, (CH 3 ) 2 ) . 13 C NMR (101 MHz, CDCl 3 ) δ=174.2 (C=O), 161.0, 158.2 (C=C), 157.8 (C=C), 155.7 (C=C), 152.0 (C=C), 141.9 (C=C), 141.0 (C=C), 132.4 (C=C), 129.6 (2C, C=C), 123.7 (C=C), 117.6 (C=C), 113.9 (2C, C=C) ), 101.2(C＝C), 98.0(C＝C), 75.9(C(CH 3 ) 2 ), 69.6(OCH 2 ), 59.9(CH 3 O), 55.3(CH 3 O), 31.9(CH 2 -CH 2 -C(CH 3 ) 2 ), 26.6(2C,C(CH 3 ) 2 ), 16.6(CH 2 -CH 2 -C(CH 3 ) 2 ).HRMS(TOF):calculated for C 25 H 26 O 6 :422.47,Found:423.20[M+1].

(9)化合物4i(R＝炔丙基)的制备(9) Preparation of compound 4i (R=propargyl)

Figure BDA0002674137810000081
Figure BDA0002674137810000081

化合物3(50mg，0.136mmol)和K2CO3(放置于丙酮(2ml)中的38mg，2equ.)在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入炔丙基溴(2equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物4i(45％)，为白色固体，熔点M.p.155.7-161.5℃.Rf＝0.16(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.06(d,J＝8.9Hz,2H,Ar-H),6.98(d,J＝8.9Hz,2H,Ar-H),6.41(s,1H,Ar-H),4.80(s,2H,OCH2),3.85(s,3H,OCH3),3.83(s,3H,OCH3),2.87(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),2.51(t,J＝2.4Hz,1H,CH),1.86(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.36(s,6H,(CH3)2).13C NMR(101MHz,CDCl3)δ＝174.0(C＝O),161.0(C＝C),158.0(C＝C),156.5(C＝C),155.6(C＝C),152.1(C＝C),141.0(C＝C),129.6(2C,C＝C),123.5(C＝C),113.9(2C,C＝C),109.3(C＝C),102.3(C＝C),99.6(C＝C),78.2(HC≡C-),76.2(HC≡C-),76.0(C(CH3)2),59.8(CH3O),57.1(OCH2),55.4(CH3O),31.8(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.7(CH2-CH2-C(CH3)2).HRMS(TOF):calculatedfor C25H24O6:420.45,Found:421.18[M+1].Compound 3 (50 mg, 0.136 mmol) and K2CO3 (38 mg in acetone ( 2 ml), 2 equ.) were stirred at room temperature for 10 minutes. To the suspension was added propargyl bromide (2 equ.) dropwise over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to give compound 4i (45%) as a white solid, melting point Mp155.7-161.5°C. R f =0.16 (PE:EA=3:1). 1 H NMR (400MHz, CDCl 3 )δ =8.06(d,J=8.9Hz,2H,Ar-H),6.98(d,J=8.9Hz,2H,Ar-H),6.41(s,1H,Ar-H),4.80(s,2H, OCH 2 ), 3.85 (s, 3H, OCH 3 ), 3.83 (s, 3H, OCH 3 ), 2.87 (t, J=6.7 Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 2.51 (t, J=2.4Hz, 1H, CH), 1.86 (t, J=6.7Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.36(s, 6H, (CH 3 ) 2 ) . 13 C NMR (101 MHz, CDCl 3 ) δ=174.0 (C=O), 161.0 (C=C), 158.0 (C=C), 156.5 (C=C), 155.6 (C=C), 152.1 (C =C),141.0(C=C),129.6(2C,C=C),123.5(C=C),113.9(2C,C=C),109.3(C=C),102.3(C=C), 99.6(C=C), 78.2(HC≡C-), 76.2(HC≡C-), 76.0(C( CH3 ) 2 ), 59.8(CH3O ) , 57.1(OCH2 ) , 55.4( CH3 O), 31.8(CH 2 -CH 2 -C(CH 3 ) 2 ), 26.6(2C,C(CH 3 ) 2 ), 16.7(CH 2 -CH 2 -C(CH 3 ) 2 ).HRMS(TOF ):calculatedfor C 25 H 24 O 6 :420.45,Found:421.18[M+1].

(10)化合物4j(R＝苄基)的制备(10) Preparation of compound 4j (R=benzyl)

Figure BDA0002674137810000082
Figure BDA0002674137810000082

化合物3(50mg，0.136mmol)和K2CO3(放置于丙酮(2ml)中的38mg，2equ.)在室温下搅拌10分钟。在10分钟内向悬浮液中逐滴加入苄基溴(2equ.)。将反应加热至回流6小时。冷却至室温后，在减压下将溶剂完全蒸发。将残余物在二氯甲烷和水中稀释。分离的有机层经MgSO4干燥。减压完全蒸发溶剂，得到化合物4j(63％)，为白色固体，熔点M.p.200.1-203.5℃.Rf＝0.34(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ＝8.08(d,J＝9.0Hz,2H,Ar-H),7.62(d,J＝7.4Hz,2H,Ar-H),7.37(t,J＝7.5Hz,2H,Ar-H),7.27(d,J＝7.1Hz,1H,Ar-H),6.99(d,J＝9.1Hz,2H,Ar-H),6.29(s,1H,Ar-H),5.18(s,2H,OCH2),3.86(s,3H,OCH3),3.84(s,3H,OCH3),2.86(t,J＝6.8Hz,2H,CH2-CH2-C(CH3)2),1.85(t,J＝6.7Hz,2H,CH2-CH2-C(CH3)2),1.35(s,3H,CH3),1.33(s,3H,CH3).13C NMR(101MHz,CDCl3)δ＝174.2(C＝O),161.0(C＝C),158.1(C＝C),157.7(C＝C),155.7(C＝C),152.1(C＝C),141.1(C＝C),136.7(C＝C),129.6(2C,C＝C),128.5(2C,C＝C),127.4(C＝C),126.5(2C,C＝C),123.6(C＝C),113.9(2C,C＝C),109.2(C＝C),101.4(C＝C),98.2(C＝C),75.9(C(CH3)2),70.5(OCH2),59.9(CH3O),55.4(CH3O),31.8(CH2-CH2-C(CH3)2),26.6(2C,C(CH3)2),16.6(CH2-CH2-C(CH3)2).HRMS(TOF):calculated for C29H28O6:472.53,Found:473.20[M+1].Compound 3 (50 mg, 0.136 mmol) and K2CO3 (38 mg in acetone ( 2 ml), 2 equ.) were stirred at room temperature for 10 minutes. Benzyl bromide (2 equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was dried over MgSO4 . The solvent was completely evaporated under reduced pressure to give compound 4j (63%) as a white solid, melting point Mp 200.1-203.5°C. R f =0.34 (PE:EA=3:1). 1 H NMR (400MHz, CDCl 3 )δ =8.08(d,J=9.0Hz,2H,Ar-H),7.62(d,J=7.4Hz,2H,Ar-H),7.37(t,J=7.5Hz,2H,Ar-H),7.27 (d, J=7.1Hz, 1H, Ar-H), 6.99 (d, J=9.1Hz, 2H, Ar-H), 6.29 (s, 1H, Ar-H), 5.18 (s, 2H, OCH 2 ), 3.86(s, 3H, OCH 3 ), 3.84(s, 3H, OCH 3 ), 2.86(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.85(t , J=6.7Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.35(s, 3H, CH 3 ), 1.33(s, 3H, CH 3 ). 13 C NMR (101MHz, CDCl 3 )δ=174.2(C=O), 161.0(C=C), 158.1(C=C), 157.7(C=C), 155.7(C=C), 152.1(C=C), 141.1(C=C) ), 136.7 (C=C), 129.6 (2C, C=C), 128.5 (2C, C=C), 127.4 (C=C), 126.5 (2C, C=C), 123.6 (C=C), 113.9(2C,C=C), 109.2(C=C), 101.4(C=C), 98.2(C=C), 75.9(C(CH 3 ) 2 ), 70.5(OCH 2 ), 59.9(CH 3 O), 55.4(CH 3 O), 31.8(CH 2 -CH 2 -C(CH 3 ) 2 ), 26.6(2C,C(CH 3 ) 2 ), 16.6(CH 2 -CH 2 -C(CH 3 ) ) 2 ).HRMS(TOF):calculated for C 29 H 28 O 6 :472.53,Found:473.20[M+1].

实施例4、新型5-取代淫羊藿素衍生物5的活性测试Example 4. Activity Test of Novel 5-Substituted Icariin Derivative 5

细胞株和溶剂Cell Lines and Solvents

人肝癌细胞HEPG2；Human hepatoma cell HEPG2;

人结肠癌细胞SW480；Human colon cancer cell SW480;

人肺癌细胞A549；Human lung cancer cell A549;

人乳腺癌细胞MCF7；Human breast cancer cell MCF7;

细胞培养于含10％胎牛血清的RPMI 1640中培养基；Cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum;

溶剂：二甲亚砜(简称为DMSO)。Solvent: Dimethyl sulfoxide (abbreviated as DMSO).

CCK-8染色法检测细胞抗肿瘤活性实施方案Embodiment of CCK-8 staining method for detecting cell antitumor activity

选用待测肿瘤活细胞比例达90％以上的细胞进行实验。细胞增殖抑制试验采用EnoGeneCellTMCounting Kit-8(简称为CCK-8)细胞活力检测试剂盒。细胞消化、计数、制成浓度为1×105个/mL的细胞悬液，96孔板中每孔加入100μL细胞悬液(每孔1×104个细胞)；96孔板置于37℃，5％CO2培养箱中培养24小时；每孔加入100μL相应的含药物的培养基，作用浓度为50μMol/L(即：微摩尔/升)，同时设立阴性对照组，溶媒对照组，阳性对照组(阳性对照分别选用淫羊藿素和喜树碱)，每组5复孔；96孔板置于37℃，5％CO2培养箱中培养72小时后；每孔加入10μL CCK-8溶液，将培养板在培养箱内孵育4小时，用酶标仪测定在450nm处的吸光值(简称OD值)，计算各个化合物对人肝癌细胞HEPG2、人结肠癌细胞SW480、人肺癌细胞A549以及人乳腺癌细胞MCF7的抑制率。Cells with the proportion of viable tumor cells to be tested over 90% were selected for the experiment. The cell proliferation inhibition test adopts EnoGeneCell ™ Counting Kit-8 (abbreviated as CCK-8) cell viability detection kit. Cells were digested, counted, and made into a cell suspension with a concentration of 1 × 105 cells/mL, and 100 μL of cell suspension was added to each well of a 96-well plate (1 × 104 cells per well); the 96-well plate was placed at 37°C, 5 Incubate for 24 hours in a %CO2 incubator; add 100 μL of the corresponding drug-containing medium to each well at a concentration of 50 μMol/L (ie: micromol/L), and set up a negative control group, a vehicle control group, and a positive control group ( The positive controls were icariin and camptothecin, respectively, with 5 duplicate wells in each group; the 96-well plate was placed in a 37°C, 5% CO2 incubator for 72 hours; 10 μL of CCK-8 solution was added to each well, and the cultured The plate was incubated in the incubator for 4 hours, and the absorbance value at 450nm (abbreviated as OD value) was measured with a microplate reader, and the effect of each compound on human liver cancer cells HEPG2, human colon cancer cells SW480, human lung cancer cells A549 and human breast cancer cells was calculated. Inhibition rate of MCF7.

实验结果详见表1-3。The experimental results are shown in Table 1-3.

表1淫羊藿素衍生物4a-j的肿瘤抑制率(％)Table 1 Tumor inhibition rate (%) of icariin derivatives 4a-j

Figure BDA0002674137810000091
Figure BDA0002674137810000091

Figure BDA0002674137810000101
Figure BDA0002674137810000101

表1的实验结果看出，本发明5-取代淫羊藿素衍生物4具有很好体外抗肿瘤活性，50μMol/L作用浓度对于人肝癌细胞HEPG2、人结肠癌细胞SW480、人肺癌细胞A549以及人乳腺癌细胞MCF7的体外抑制率高达57％-72％，与阳性对照药物淫羊藿素和喜树碱的抑制活性相当；可作为新型淫羊藿黄酮类候选药物应用于抗肿瘤临床应用。The experimental results in Table 1 show that the 5-substituted icariin derivative 4 of the present invention has very good in vitro anti-tumor activity, and the concentration of 50 μMol/L is effective on human hepatoma cells HEPG2, human colon cancer cells SW480, human lung cancer cells A549 and The in vitro inhibition rate of human breast cancer cell MCF7 is as high as 57%-72%, which is comparable to the inhibitory activity of the positive control drugs icariin and camptothecin; it can be used as a novel epimedium flavonoid candidate drug for clinical anti-tumor applications.

Claims (7)

  1. The 1.5-substituted icaritin derivative has a structural formula shown in formula 4,
    Figure FDA0002674137800000011
  2. 2. the method for synthesizing 5-substituted icaritin derivative 4 according to claim 1, comprising: 1) the icaritin 1 and formic acid react in a proper organic solvent to obtain a compound 2, 2), the compound 2 reacts with dimethyl sulfate in acetone in the presence of an alkali catalyst to obtain a compound 3, 3), and the compound 3 reacts with a halogen substituted alkane R-X to obtain a 5-substituted icaritin derivative shown in a formula 4, wherein the synthetic route is shown as follows:
    Figure FDA0002674137800000012
  3. 3. the method as claimed in claim 2, wherein the alkyl group in step 3) is selected from the group consisting of alkyl groups consisting of C1-C5 alkyl, haloalkyl, allyl, propargyl and benzyl.
  4. 4. The method of claim 2, wherein the alkyl R-X in step 3) is halo-substituted, and the halogen X is selected from bromine or iodine.
  5. 5. The method as claimed in claim 3, wherein the alkyl group of the halogen-substituted alkyl R-X in step 3) is selected from the group consisting of C1-C3 alkyl, halogenated C1-C3 alkyl, and benzyl.
  6. 6. The use of the 5-substituted icaritin derivative 4 according to claim 1 for preparing an antitumor drug.
  7. 7. The use of claim 5, wherein the tumor comprises liver cancer, colon cancer, lung cancer and breast cancer.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112375059A (en) * 2021-01-05 2021-02-19 遵义医科大学 Icaritin methylation structure modified compound and preparation method and application thereof
CN113717135A (en) * 2021-01-07 2021-11-30 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) Synthesis method of carbonyl substituted benzodihydropyran and benzodihydropyran compound
CN115181112A (en) * 2022-08-19 2022-10-14 遵义医科大学 Synthesis of 6-Bromocyclic Epimedium Chloran 3,4-Dione Derivatives and Its Antitumor Application
CN115353522A (en) * 2022-08-22 2022-11-18 遵义医科大学 Regioselective synthesis and anti-tumor application of icaritin-norcantharidin conjugate
CN116789723A (en) * 2022-03-16 2023-09-22 遵义医科大学 Icaritin derivative and application thereof in resisting liver cancer
CN116789679A (en) * 2022-03-16 2023-09-22 遵义医科大学 Cyclicariin 5-glycosylated derivatives and preparation methods and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107184573A (en) * 2017-06-10 2017-09-22 上海佐赫实业有限公司 Application of the ring icariine in preventing skin damage medicine is prepared
CN109776559A (en) * 2019-03-22 2019-05-21 苏州广奥医药开发有限公司 A kind of fully synthetic method for preparing anhydroicartin
CN110172064A (en) * 2019-05-15 2019-08-27 苏州广奥医药开发有限公司 Flavone derivatives and preparation method thereof and medical usage
CN110317208A (en) * 2019-05-15 2019-10-11 苏州广奥医药开发有限公司 A kind of preparation method and medical usage of icariine derivative

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107184573A (en) * 2017-06-10 2017-09-22 上海佐赫实业有限公司 Application of the ring icariine in preventing skin damage medicine is prepared
CN109776559A (en) * 2019-03-22 2019-05-21 苏州广奥医药开发有限公司 A kind of fully synthetic method for preparing anhydroicartin
CN110172064A (en) * 2019-05-15 2019-08-27 苏州广奥医药开发有限公司 Flavone derivatives and preparation method thereof and medical usage
CN110317208A (en) * 2019-05-15 2019-10-11 苏州广奥医药开发有限公司 A kind of preparation method and medical usage of icariine derivative

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DING, PEILAN等: "Cytotoxic Isoprenylated Flavonoids from the Roots of Sophora flavescens", 《HELVETICA CHIMICA ACTA》 *
MIZUNO, MIZUO等: "Two flavonol glycosides from the underground parts of Vancouveria hexandra", 《PHYTOCHEMISTRY》 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112375059A (en) * 2021-01-05 2021-02-19 遵义医科大学 Icaritin methylation structure modified compound and preparation method and application thereof
CN113717135A (en) * 2021-01-07 2021-11-30 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) Synthesis method of carbonyl substituted benzodihydropyran and benzodihydropyran compound
CN116789723A (en) * 2022-03-16 2023-09-22 遵义医科大学 Icaritin derivative and application thereof in resisting liver cancer
CN116789679A (en) * 2022-03-16 2023-09-22 遵义医科大学 Cyclicariin 5-glycosylated derivatives and preparation methods and uses thereof
CN115181112A (en) * 2022-08-19 2022-10-14 遵义医科大学 Synthesis of 6-Bromocyclic Epimedium Chloran 3,4-Dione Derivatives and Its Antitumor Application
CN115353522A (en) * 2022-08-22 2022-11-18 遵义医科大学 Regioselective synthesis and anti-tumor application of icaritin-norcantharidin conjugate

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