CN107722035B - Artemisinin-piperazine derivatives, preparation method thereof and application thereof in preparation of anti-liver cancer drugs - Google Patents

Artemisinin-piperazine derivatives, preparation method thereof and application thereof in preparation of anti-liver cancer drugs Download PDF

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CN107722035B
CN107722035B CN201711072775.XA CN201711072775A CN107722035B CN 107722035 B CN107722035 B CN 107722035B CN 201711072775 A CN201711072775 A CN 201711072775A CN 107722035 B CN107722035 B CN 107722035B
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魏梦雪
于家瀛
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Ningxia University
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Abstract

本发明公开了一类青蒿素‑哌嗪衍生物及其制备方法和这类衍生物在制备抗肝癌药物中的应用。该方法以三乙胺为缚酸剂，通过“一锅法”制备青蒿素‑哌嗪衍生物，反应条件温和，操作简便，收率较好。此外，所制衍生物对人肝癌SMMC‑7721细胞具有明显的体外抑制作用，与一线抗肝癌临床化疗药物长春新碱的抑制效果相当。本发明为青蒿素‑哌嗪衍生物在制备抗肝癌药物中的应用提供了可行性策略。The invention discloses a class of artemisinin-piperazine derivatives, a preparation method thereof, and the application of such derivatives in the preparation of anti-cancer drugs. The method uses triethylamine as an acid binding agent to prepare artemisinin-piperazine derivatives through a "one-pot method", with mild reaction conditions, simple operation and good yield. In addition, the prepared derivatives have obvious inhibitory effect on human hepatoma SMMC-7721 cells in vitro, which is comparable to the inhibitory effect of vincristine, a first-line anti-liver cancer clinical chemotherapy drug. The invention provides a feasible strategy for the application of artemisinin-piperazine derivatives in the preparation of anti-cancer drugs.

Description

一类青蒿素-哌嗪衍生物及其制法和在制备抗肝癌药物中的 应用A class of artemisinin-piperazine derivatives and their preparation methods and their use in the preparation of anti-hepatocellular carcinoma drugs application

技术领域technical field

本发明涉及一类青蒿素-哌嗪衍生物及其制法和在制备抗肝癌药物中的应用。The present invention relates to a class of artemisinin-piperazine derivatives, a preparation method thereof, and application in the preparation of anti-hepatocellular carcinoma drugs.

背景技术Background technique

青蒿素具有良好的抗疟活性，但是其抗肿瘤活性研究较少。青蒿素及其衍生物虽然在临床上应用多年，但仍存在油溶性和水溶性不佳，热稳定性差，易受湿、热和还原性物质的影响而分解，临床复发率高等缺点使其应用受到限制。因此，通过化学改造的方法，设计和制备一系列新型青蒿素衍生物，并考察其抗肿瘤活性，是一项有意义的工作。Artemisinin has good antimalarial activity, but its antitumor activity is less studied. Although artemisinin and its derivatives have been used clinically for many years, they still have the disadvantages of poor oil-solubility and water-solubility, poor thermal stability, easy to decompose under the influence of humidity, heat and reducing substances, and high clinical recurrence rate. Apps are restricted. Therefore, it is a meaningful work to design and prepare a series of novel artemisinin derivatives and investigate their antitumor activity through chemical engineering.

哌嗪可以通过形成多个氢键或离子键的方式，提高药物的生物活性，还可以调节药物的溶解性和酸碱平衡，促进药物的药代动力学，在抗肿瘤方面有明显的效果。因此，常作为一类增效基团引入到药物分子中。Piperazine can improve the biological activity of drugs by forming multiple hydrogen bonds or ionic bonds, and can also adjust the solubility and acid-base balance of drugs, promote the pharmacokinetics of drugs, and have obvious effects in anti-tumor. Therefore, it is often introduced into drug molecules as a class of synergistic groups.

氨基二硫代甲酸酯类化合物是一类具有独特结构和性质的重要含硫化合物，在合成药物中占有重要的位置。其具有广泛的生物活性，如抗菌、抗病毒、抗氧化以及治疗慢性酒精中毒和重金属中毒等。近年来,越来越多的研究发现，氨基二硫代甲酸酯类化合物具有较好的肿瘤预防和抗肿瘤活性，引起了国内外学者的研究兴趣。Amino dithiocarbamates are a class of important sulfur-containing compounds with unique structures and properties, which occupy an important position in the synthesis of drugs. It has a wide range of biological activities, such as antibacterial, antiviral, antioxidant and treatment of chronic alcoholism and heavy metal poisoning. In recent years, more and more studies have found that aminodithiocarbamate compounds have good tumor preventive and antitumor activities, which has aroused the research interest of scholars at home and abroad.

本发明通过“一锅煮”的方法，以哌嗪为连接物，在温和的条件下，将氨基二硫代甲酸酯结构引入青蒿素分子中，制备的青蒿素-哌嗪衍生物，对人肝癌细胞(SMMC-7721)生长有明显的抑制作用，因此青蒿素-哌嗪衍生物作为很有潜力的抗肝癌药物的前景十分值得关注。The present invention adopts the method of "one-pot cooking", using piperazine as the linker, and under mild conditions, the aminodithiocarbamate structure is introduced into the artemisinin molecule, and the prepared artemisinin-piperazine derivative is suitable for The growth of human hepatoma cells (SMMC-7721) has obvious inhibitory effect, so the prospect of artemisinin-piperazine derivatives as a potential anti-hepatoma drug is very worthy of attention.

发明内容SUMMARY OF THE INVENTION

鉴于上述，本发明的目的在于提供一类青蒿素-哌嗪衍生物。该类衍生物制备方法简易，抗肝癌活性高。In view of the above, the object of the present invention is to provide a class of artemisinin-piperazine derivatives. The preparation method of the derivatives is simple and has high anti-cancer activity.

本发明的另一目的在于提供一类青蒿素-哌嗪衍生物的制备方法。Another object of the present invention is to provide a preparation method of a class of artemisinin-piperazine derivatives.

本发明还有一个目的在于提供一类青蒿素-哌嗪衍生物在抗肝癌方面的应用。Another object of the present invention is to provide the application of a class of artemisinin-piperazine derivatives in anti-hepatocellular carcinoma.

本发明的目的是通过以下技术方案实现：The purpose of this invention is to realize through the following technical solutions:

(一).一类青蒿素-哌嗪衍生物，其特征是它有如下通式：(1). A class of artemisinin-piperazine derivatives, characterized in that it has the following general formula:

Figure BDA0001457330180000021
Figure BDA0001457330180000021

式中R为：where R is:

Figure BDA0001457330180000022
Figure BDA0001457330180000022

(二).青蒿素-哌嗪衍生物的制备方法：(2). The preparation method of artemisinin-piperazine derivative:

将青蒿素-哌嗪和用量为青蒿素-哌嗪四倍量的二硫化碳溶于乙腈，然后加入用量为青蒿素-哌嗪十倍量的三乙胺，室温搅拌10min后，加入用量为青蒿素-哌嗪两倍量的卤代物乙腈溶液，逐渐升至60℃，反应4～12h，TLC跟踪，磷钼酸显色，反应结束后，蒸除溶剂，硅胶柱层析分离纯化(PE:EA＝16:1～6:1)，得到青蒿素-哌嗪衍生物。Dissolve artemisinin-piperazine and carbon disulfide four times the amount of artemisinin-piperazine in acetonitrile, then add triethylamine in ten times the amount of artemisinin-piperazine, stir at room temperature for 10 minutes, add the amount of The halide acetonitrile solution with twice the amount of artemisinin-piperazine was gradually raised to 60°C, reacted for 4-12 hours, followed by TLC, and phosphomolybdic acid developed color. After the reaction, the solvent was evaporated and purified by silica gel column chromatography. (PE:EA=16:1 to 6:1) to obtain an artemisinin-piperazine derivative.

青蒿素-哌嗪衍生物反应用化学式表示如下：The artemisinin-piperazine derivative reaction is represented by the chemical formula as follows:

Figure BDA0001457330180000031
Figure BDA0001457330180000031

本发明的优点和产生的有益效果是：The advantages of the present invention and the beneficial effects produced are:

1.本发明以三乙胺作为缚酸剂，在“一锅煮”条件下，通过多组分的串联反应，高效率制备该类青蒿素-哌嗪，该反应条件温和，实验操作简便可行，不必在苛刻的无水无氧条件下进行，无金属试剂，对环境友好，原子利用率高。1. the present invention uses triethylamine as acid binding agent, under the condition of "one-pot cooking", through the series reaction of multiple components, high-efficiency preparation of this artemisinin-piperazine, the reaction conditions are mild, and the experimental operation is simple and feasible, It does not have to be carried out under harsh anhydrous and oxygen-free conditions, has no metal reagents, is environmentally friendly, and has high atomic utilization.

2.本发明的青蒿素-哌嗪衍生物对人肝癌SMMC-7721细胞生长有明显的抑制作用，因此本发明的青蒿素-哌嗪衍生物可以应用于制备抗肝癌药物。2. The artemisinin-piperazine derivatives of the present invention have an obvious inhibitory effect on the growth of human hepatoma SMMC-7721 cells, so the artemisinin-piperazine derivatives of the present invention can be applied to prepare anti-hepatoma drugs.

具体实施方式Detailed ways

通过以下实施例进一步详细说明本发明，但本发明的范围并不受这些实施例的任何限制。The present invention is further illustrated in detail by the following examples, but the scope of the present invention is not limited in any way by these examples.

实施例一：青蒿素-哌嗪-氨基二硫代甲酸苄基酯(化合物1)的制备Example 1: Preparation of artemisinin-piperazine-amino dithiocarboxylate benzyl ester (compound 1)

Figure BDA0001457330180000032
Figure BDA0001457330180000032

室温下，向圆底烧瓶中依次加入(1.2mmol,0.42g)青蒿素哌嗪、(4.8mmol,0.36g)二硫化碳、20mL乙腈以及(12mmol,1mL)三乙胺，搅拌10分钟后，加入5mL溶有(2.5mmol,0.43g)溴苄的乙腈溶液，逐渐加热至60℃，反应12h，TLC跟踪反应结束后，蒸除溶剂，经硅胶柱层析[洗脱剂：V(石油醚)：V(乙酸乙酯)＝16:1]纯化得目标化合物。白色固体，产率72.6％，m.p.130.4-130.8℃,

Figure BDA0001457330180000041
1H NMR(400MHz,CDCl3)δ:7.37(t,J＝12.6Hz,2H),7.32–7.26(m,3H),5.29(d,J＝10.7Hz,1H),4.56(s,2H),4.35(s,2H),4.07(d,J＝9.8Hz,1H),3.89(s,2H),3.07(s,2H),2.79(s,2H),2.58(s,1H),2.34(td,J＝13.8,3.5Hz,1H),2.00(d,J＝14.4Hz,1H),1.94–1.81(m,1H),1.78–1.65(m,2H),1.55(d,J＝12.8Hz,2H),1.49–1.15(m,5H),1.03(dd,J＝18.0,7.7Hz,2H),0.95(d,J＝6.1Hz,3H),0.83(d,J＝6.5Hz,3H)；13C NMR(101MHz,CDCl3)δ:196.01,135.90,129.36,128.54,127.44,103.98,91.54,90.35,80.19,77.20,51.63,46.92,45.70,42.07,37.35,36.25,34.20,28.50,25.97,24.70,21.57,20.25,13.46；IR(KBr)ν/cm-1:2981,2941,2866,1600,1491,1447,1378,1310,1217,1161,1101,1039,999,955,926,880,842,743,712,611,550,486；HRMS m/z:calcd for C27H38N2NaO4S2 541.2168,found 541.2170[M+Na]+.At room temperature, (1.2 mmol, 0.42 g) artemisinin piperazine, (4.8 mmol, 0.36 g) carbon disulfide, 20 mL acetonitrile and (12 mmol, 1 mL) triethylamine were sequentially added to the round-bottomed flask, and after stirring for 10 minutes, added 5mL of acetonitrile solution dissolved with (2.5mmol, 0.43g) benzyl bromide was gradually heated to 60°C, and reacted for 12h. After the reaction was followed by TLC, the solvent was evaporated and subjected to silica gel column chromatography [eluent: V (petroleum ether) : V(ethyl acetate)=16:1] and purified to obtain the target compound. White solid, yield 72.6%, mp130.4-130.8℃,
Figure BDA0001457330180000041
1 H NMR (400 MHz, CDCl 3 ) δ: 7.37 (t, J=12.6 Hz, 2H), 7.32-7.26 (m, 3H), 5.29 (d, J=10.7 Hz, 1H), 4.56 (s, 2H) ,4.35(s,2H),4.07(d,J=9.8Hz,1H),3.89(s,2H),3.07(s,2H),2.79(s,2H),2.58(s,1H),2.34( td, J=13.8, 3.5Hz, 1H), 2.00 (d, J=14.4Hz, 1H), 1.94–1.81 (m, 1H), 1.78–1.65 (m, 2H), 1.55 (d, J=12.8Hz) ,2H),1.49–1.15(m,5H),1.03(dd,J＝18.0,7.7Hz,2H),0.95(d,J＝6.1Hz,3H),0.83(d,J＝6.5Hz,3H) ; 13 C NMR (101MHz, CDCl 3 )δ: 196.01, 135.90, 129.36, 128.54, 127.44, 103.98, 91.54, 90.35, 80.19, 77.20, 51.63, 46.92, 45.70, 42.07, 37.25, 36.2, 5.34 24.70, 21.57, 20.25, 13.46; IR(KBr)ν/cm -1 : 2981, 2941, 2866, 1600, 1491, 1447, 1378, 1310, 1217, 1161, 1101, 1039, 999, 955: 926, 880, 842, 743, 712,6; for C 27 H 38 N 2 NaO 4 S 2 541.2168, found 541.2170[M+Na] + .

实施例二：青蒿素-哌嗪-氨基二硫代甲酸-(2-甲基)苄基酯(化合物2)的制备Example 2: Preparation of artemisinin-piperazine-aminodithiocarboxylic acid-(2-methyl)benzyl ester (compound 2)

Figure BDA0001457330180000042
Figure BDA0001457330180000042

制备方法同实施例一，以邻甲基溴苄替代溴苄，得目标化合物，淡黄色固体，产率55.6％,m.p.87.4-88.4℃,

Figure BDA0001457330180000051
1H NMR(400MHz,CDCl3)δ:7.34(d,J＝7.1Hz,1H),7.16(tt,J＝6.2,3.7Hz,3H),5.27(s,1H),4.51(s,2H),4.35(s,2H),4.06(d,J＝10.2Hz,1H),3.89(s,2H),3.06(s,2H),2.78(s,2H),2.57(dqd,J＝11.2,7.3,4.7Hz,1H),2.44–2.27(m,4H),1.99(ddd,J＝14.6,5.0,2.9Hz,1H),1.86(ddt,J＝13.6,6.7,3.4Hz,1H),1.70(dp,J＝10.6,3.4Hz,2H),1.60–1.38(m,5H),1.38–1.16(m,4H),1.08–0.91(m,3H),0.82(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:196.11,137.36,133.17,130.40,130.38,127.85,126.13,103.92,91.49,90.29,80.14,51.58,50.16,46.87,45.65,40.67,37.29,36.20,34.15,28.45,25.93,24.65,21.52,20.22,19.28,13.42；IR(KBr)ν/cm-1:2924,2870,1462,1422,1376,1310,1275,1230,1209,1130,1101,1040,1020,982,879,734,550,510；HRMS m/z:calcd for C28H41N2O4S2 533.2429,found 533.2514[M+H]+.The preparation method is the same as that in Example 1, except that o-methyl benzyl bromide is used instead of benzyl bromide to obtain the target compound as a pale yellow solid, yield 55.6%, mp87.4-88.4°C,
Figure BDA0001457330180000051
1 H NMR (400 MHz, CDCl 3 ) δ: 7.34 (d, J=7.1 Hz, 1H), 7.16 (tt, J=6.2, 3.7 Hz, 3H), 5.27 (s, 1H), 4.51 (s, 2H) ,4.35(s,2H),4.06(d,J=10.2Hz,1H),3.89(s,2H),3.06(s,2H),2.78(s,2H),2.57(dqd,J=11.2,7.3 ,4.7Hz,1H),2.44–2.27(m,4H),1.99(ddd,J=14.6,5.0,2.9Hz,1H),1.86(ddt,J=13.6,6.7,3.4Hz,1H),1.70( dp, J=10.6, 3.4Hz, 2H), 1.60–1.38 (m, 5H), 1.38–1.16 (m, 4H), 1.08–0.91 (m, 3H), 0.82 (d, J=7.1Hz, 3H) ; 13 C NMR (101MHz, CDCl 3 )δ: 196.11,137.36,133.17,130.40,130.38,127.85,126.13,103.92,91.49,90.29,80.14,51.58,50.16,46.87,45.6,5,6.2,7,3 28.45, 25.93, 24.65, 21.52, 20.22, 19.28, 13.42; IR(KBr)ν/cm -1 : 2924, 2870, 1462, 1422, 1376, 1310, 1275, 1230, 1209, 1130, 1101, 1040, 1020, 982,879,734,550,510; HRMS m/z: calcd for C 28 H 41 N 2 O 4 S 2 533.2429, found 533.2514[M+H] + .

实施例三：青蒿素-哌嗪-氨基二硫代甲酸-(4-甲基)苄基酯(化合物3)的制备Example 3: Preparation of artemisinin-piperazine-aminodithiocarboxylic acid-(4-methyl)benzyl ester (compound 3)

Figure BDA0001457330180000052
Figure BDA0001457330180000052

制备方法同实施例一，以4-甲基溴苄替代溴苄，得目标化合物。白色固体，产率50.3％,m.p.135.9-136.9℃,

Figure BDA0001457330180000053
1H NMR(400MHz,CDCl3)δ:7.27(d,J＝7.5Hz,2H),7.12(d,J＝7.8Hz,2H),5.27(s,1H),4.52(s,2H),4.35(s,2H),4.06(d,J＝10.3Hz,1H),3.91(s,2H),3.05(s,2H),2.78(s,2H),2.57(ddd,J＝10.9,7.2,4.3Hz,1H),2.35–2.29(m,4H),2.00(ddd,J＝14.4,4.9,3.0Hz,1H),1.86(ddt,J＝13.6,6.8,3.6Hz,1H),1.70(ddd,J＝13.0,7.3,3.5Hz,2H),1.59(s,2H),1.55(dt,J＝13.8,4.4Hz,1H),1.49–1.40(m,1H),1.38(s,2H),1.32(td,J＝13.4,3.6Hz,1H),1.22(td,J＝11.3,6.5Hz,1H),1.00(dd,J＝12.1,3.7Hz,1H),0.94(d,J＝6.2Hz,3H),0.82(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:196.19,137.20,132.67,129.28,129.26,104.00,91.55,90.36,80.20,77.20,51.65,46.93,45.72,41.91,37.36,36.26,34.21,28.52,25.97,24.71,21.59,21.13,20.26,13.46；IR(KBr)ν/cm-1:2924,2869,2846,1512,1456,1416,1376,1278,1230,1135,1055,980,879,825,741,487；HRMS m/z:calcd forC28H40NaN2O4S2555.2429,found 555.2338[M+Na]+.The preparation method is the same as that in Example 1, except that 4-methyl benzyl bromide is used instead of benzyl bromide to obtain the target compound. White solid, yield 50.3%, mp135.9-136.9℃,
Figure BDA0001457330180000053
1 H NMR (400 MHz, CDCl 3 ) δ: 7.27 (d, J=7.5 Hz, 2H), 7.12 (d, J=7.8 Hz, 2H), 5.27 (s, 1H), 4.52 (s, 2H), 4.35 (s, 2H), 4.06 (d, J=10.3Hz, 1H), 3.91 (s, 2H), 3.05 (s, 2H), 2.78 (s, 2H), 2.57 (ddd, J=10.9, 7.2, 4.3 Hz, 1H), 2.35–2.29 (m, 4H), 2.00 (ddd, J=14.4, 4.9, 3.0Hz, 1H), 1.86 (ddt, J=13.6, 6.8, 3.6Hz, 1H), 1.70 (ddd, J=13.0, 7.3, 3.5Hz, 2H), 1.59(s, 2H), 1.55(dt, J=13.8, 4.4Hz, 1H), 1.49–1.40(m, 1H), 1.38(s, 2H), 1.32 (td, J=13.4, 3.6Hz, 1H), 1.22 (td, J=11.3, 6.5Hz, 1H), 1.00 (dd, J=12.1, 3.7Hz, 1H), 0.94 (d, J=6.2Hz, 3H), 0.82 (d, J=7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ: 196.19, 137.20, 132.67, 129.28, 129.26, 104.00, 91.55, 90.36, 80.20, 77.20, 51.65, 46.93, 45.72,41.91,37.36,36.26,34.21,28.52,25.97,24.71,21.59,21.13,20.26,13.46; IR(KBr)ν/cm -1 : 2924,2869,2846,1512,1456,1416,1376,1278, 1230, 1135, 1055, 980, 879, 825, 741, 487; HRMS m/z: calcd for C 28 H 40 NaN 2 O 4 S 2 555.2429, found 555.2338[M+Na] + .

实施例四：青蒿素-哌嗪-氨基二硫代甲酸-(2-氯)苄基酯(化合物4)的制备Example 4: Preparation of artemisinin-piperazine-aminodithiocarboxylic acid-(2-chloro)benzyl ester (compound 4)

Figure BDA0001457330180000061
Figure BDA0001457330180000061

制备方法同实施例一，以邻氯氯苄替代溴苄，加热反应4h，得目标化合物，粉色固体，产率50.6％,m.p.90.3-91℃,

Figure BDA0001457330180000062
1H NMR(400MHz,CDCl3)δ:7.56(dd,J＝5.8,3.6Hz,1H),7.37(dd,J＝5.7,3.6Hz,1H),7.21(dd,J＝5.9,3.5Hz,2H),5.27(s,1H),4.72(s,2H),4.35(s,2H),4.06(d,J＝10.2Hz,1H),3.91(s,2H),3.50(s,1H),3.06(s,2H),2.78(s,2H),2.57(ddd,J＝10.9,7.2,4.4Hz,1H),2.34(td,J＝13.9,3.9Hz,1H),2.03–1.96(m,1H),1.91–1.82(m,1H),1.71(ddd,J＝12.4,7.3,3.5Hz,2H),1.56(s,2H),1.48–1.41(m,1H),1.38(s,3H),0.94(d,J＝6.2Hz,3H),0.82(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:195.76,134.45,134.18,131.48,129.46,128.89,126.87,104.01,91.52,90.32,80.21,77.20,51.58,50.55,45.66,39.42,37.30,36.19,34.13,28.48,25.86,24.63,21.53,20.18,13.40；IR(KBr)ν/cm-1:3096,3023,1885,1472,1404,1275,1231,1208,1185,1130,1053,983,926,879,826,743,550；HRMS m/z:calcd for C27H37ClNaN2O4S2575.1776,found 575.1778[M+Na]+.The preparation method is the same as that of Example 1, except that o-chlorobenzyl chloride is used instead of benzyl bromide, and the reaction is heated for 4h to obtain the target compound as a pink solid, the yield is 50.6%, mp90.3-91°C,
Figure BDA0001457330180000062
1 H NMR (400 MHz, CDCl 3 ) δ: 7.56 (dd, J=5.8, 3.6 Hz, 1H), 7.37 (dd, J=5.7, 3.6 Hz, 1H), 7.21 (dd, J=5.9, 3.5 Hz, 2H), 5.27(s, 1H), 4.72(s, 2H), 4.35(s, 2H), 4.06(d, J=10.2Hz, 1H), 3.91(s, 2H), 3.50(s, 1H), 3.06(s, 2H), 2.78(s, 2H), 2.57(ddd, J=10.9, 7.2, 4.4Hz, 1H), 2.34(td, J=13.9, 3.9Hz, 1H), 2.03–1.96(m, 1H), 1.91–1.82 (m, 1H), 1.71 (ddd, J=12.4, 7.3, 3.5Hz, 2H), 1.56 (s, 2H), 1.48–1.41 (m, 1H), 1.38 (s, 3H) , 0.94 (d, J=6.2 Hz, 3H), 0.82 (d, J=7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ: 195.76, 134.45, 134.18, 131.48, 129.46, 128.89, 126.87, 104.01, 91.52, 90.32, 80.21, 77.20, 51.58, 50.55, 45.66, 39.42, 37.30, 36.19, 34.13, 28.48, 25.86, 24.63, 21.53, 20.18, 13.40; IR(KBr)ν/cm -1 :3096 1885, 1472, 1404, 1275, 1231, 1208, 1185, 1130, 1053, 983, 926, 879, 826, 743, 550; HRMS m/z: calcd for C 27 H 37 ClNaN 2 O 4 S 2 575.1776, found 575.1778[M+Na] + .

实施例五：青蒿素-哌嗪-氨基二硫代甲酸-(4-氯)苄基酯(化合物5)的制备Example 5: Preparation of artemisinin-piperazine-aminodithiocarboxylic acid-(4-chloro)benzyl ester (compound 5)

Figure BDA0001457330180000071
Figure BDA0001457330180000071

制备方法同实施例一，以对氯溴苄替代溴苄，得目标化合物，白色固体，产率71.5％,m.p.111.3-112.2℃,

Figure BDA0001457330180000072
1H NMR(400MHz,CDCl3)δ:7.35–7.30(m,2H),7.28(d,J＝2.3Hz,2H),5.27(s,1H),4.54(s,2H),4.34(s,2H),4.07(d,J＝10.2Hz,1H),3.97–3.83(m,2H),3.49(d,J＝5.0Hz,1H),3.06(s,2H),2.78(s,2H),2.57(ddd,J＝11.0,7.1,4.3Hz,1H),2.34(td,J＝13.9,3.9Hz,1H),2.00(dt,J＝14.6,3.8Hz,1H),1.90–1.82(m,1H),1.71(ddd,J＝12.5,7.4,3.5Hz,2H),1.58–1.42(m,3H),1.38(s,4H),1.04–0.97(m,1H),0.95(d,J＝6.2Hz,3H),0.82(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:195.48,134.85,133.20,130.67,128.64,104.00,91.56,90.35,80.20,77.20,51.63,50.90,45.70,41.02,37.36,36.25,34.19,28.51,25.98,24.69,21.58,20.26,13.46；IR(KBr)ν/cm-1:2926,2865,1738,1488,1424,1378,1305,1276,1159,1104,1052,978,926,879；HRMS m/z:calcd for C27H37ClNaN2O4S2 575.1780,found 575.1782[M+Na]+.The preparation method is the same as in Example 1, except that p-chlorobenzyl bromide is used instead of benzyl bromide to obtain the target compound as a white solid, the yield is 71.5%, mp111.3-112.2°C,
Figure BDA0001457330180000072
1 H NMR (400 MHz, CDCl 3 ) δ: 7.35-7.30 (m, 2H), 7.28 (d, J=2.3 Hz, 2H), 5.27 (s, 1H), 4.54 (s, 2H), 4.34 (s, 2H), 4.07(d, J＝10.2Hz, 1H), 3.97–3.83(m, 2H), 3.49(d, J＝5.0Hz, 1H), 3.06(s, 2H), 2.78(s, 2H), 2.57(ddd,J＝11.0,7.1,4.3Hz,1H),2.34(td,J＝13.9,3.9Hz,1H),2.00(dt,J＝14.6,3.8Hz,1H),1.90–1.82(m, 1H), 1.71 (ddd, J=12.5, 7.4, 3.5Hz, 2H), 1.58–1.42 (m, 3H), 1.38 (s, 4H), 1.04–0.97 (m, 1H), 0.95 (d, J= 6.2 Hz, 3H), 0.82 (d, J=7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ: 195.48, 134.85, 133.20, 130.67, 128.64, 104.00, 91.56, 90.35, 80.20, 77.20, 51.63 , 50.90, 45.70 , 41.02, 37.36, 36.25, 34.19, 28.51, 25.98, 24.69, 21.58, 20.26, 13.46; , 1159, 1104, 1052, 978, 926, 879; HRMS m/z: calcd for C 27 H 37 ClNaN 2 O 4 S 2 575.1780, found 575.1782[M+Na] + .

实施例六：青蒿素-哌嗪-氨基二硫代甲酸-(4-溴)苄基酯(化合物6)的制备Example 6: Preparation of artemisinin-piperazine-aminodithiocarboxylic acid-(4-bromo)benzyl ester (compound 6)

Figure BDA0001457330180000081
Figure BDA0001457330180000081

制备方法同实施例一，以对溴氯苄替代溴苄，得目标化合物，白色固体，产率55.7％,m.p.136.9-138℃,

Figure BDA0001457330180000082
1H NMR(400MHz,CDCl3)δ:7.45–7.40(m,2H),7.30–7.24(m,4H),5.27(s,1H),4.53(s,2H),4.34(s,2H),4.06(d,J＝10.3Hz,1H),3.90(d,J＝27.5Hz,2H),3.06(s,2H),2.78(s,2H),2.57(ddd,J＝10.7,7.2,4.3Hz,1H),2.38–2.29(m,1H),2.00(ddd,J＝14.5,4.9,2.9Hz,1H),1.86(ddt,J＝10.1,7.0,3.4Hz,1H),1.75–1.66(m,1H),1.59–1.46(m,2H),1.38(s,3H),1.30(dd,J＝13.7,3.7Hz,1H),1.22(td,J＝11.2,6.5Hz,1H),1.07–0.98(m,1H),0.95(d,J＝6.2Hz,3H),0.82(d,J＝7.2Hz,3H)；13C NMR(101MHz,CDCl3)δ:195.44,135.42,131.59,131.01,121.32,104.00,91.56,90.35,80.20,77.20,51.64,46.94,45.71,41.04,37.36,36.25,34.20,28.51,25.98,24.70,21.58,20.25,13.46；IR(KBr)ν/cm-1:2925,2865,1476,1425,1378,1305,1276,1229,1158,1042,1020,979,931,879,826,609；HRMS m/z:calcd forC27H38BrN2O4S2597.1378,found 597.1465[M+H]+.The preparation method is the same as that in Example 1, except that p-bromochlorobenzyl is used instead of benzyl bromide to obtain the target compound as a white solid, the yield is 55.7%, mp136.9-138°C,
Figure BDA0001457330180000082
1 H NMR (400MHz, CDCl 3 )δ: 7.45-7.40(m, 2H), 7.30-7.24(m, 4H), 5.27(s, 1H), 4.53(s, 2H), 4.34(s, 2H), 4.06(d,J＝10.3Hz,1H),3.90(d,J＝27.5Hz,2H),3.06(s,2H),2.78(s,2H),2.57(ddd,J＝10.7,7.2,4.3Hz ,1H),2.38–2.29(m,1H),2.00(ddd,J=14.5,4.9,2.9Hz,1H),1.86(ddt,J=10.1,7.0,3.4Hz,1H),1.75–1.66(m ,1H),1.59–1.46(m,2H),1.38(s,3H),1.30(dd,J=13.7,3.7Hz,1H),1.22(td,J=11.2,6.5Hz,1H),1.07– 0.98 (m, 1H), 0.95 (d, J=6.2Hz, 3H), 0.82 (d, J=7.2Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ: 195.44, 135.42, 131.59, 131.01, 121.32,104.00,91.56,90.35,80.20,77.20,51.64,46.94,45.71,41.04,37.36,36.25,34.20,28.51,25.98,24.70,21.58,20.25,13.46; IR(KBr)ν/cm -1 :292 2865, 1476, 1425, 1378, 1305, 1276, 1229, 1158, 1042, 1020, 979, 931, 879, 826, 609; HRMS m/z: calcd forC 27 H 38 BrN 2 O 4 S 2 597.1378, found 597.1465[M+H] + .

实施例七：青蒿素-哌嗪-氨基二硫代甲酸-(4-氰基)苄基酯(化合物7)的制备Example 7: Preparation of artemisinin-piperazine-aminodithiocarboxylic acid-(4-cyano)benzyl ester (compound 7)

Figure BDA0001457330180000091
Figure BDA0001457330180000091

制备方法同实施例一，对氰基溴苄替代溴苄，加热反应4h，经硅胶柱层析[洗脱剂：V(石油醚)：V(乙酸乙酯)＝12：1]纯化得到淡黄色固体，产率65.8％，m.p.146.7-147.3℃,

Figure BDA0001457330180000092
1H NMR(400MHz,CDCl3)δ:7.62–7.57(m,2H),7.52–7.48(m,2H),5.27(s,1H),4.65(s,2H),4.34(s,2H),4.07(d,J＝10.3Hz,1H),3.91(d,J＝29.7Hz,2H),3.07(s,2H),2.79(s,2H),2.57(ddd,J＝10.9,7.3,4.4Hz,1H),2.34(ddd,J＝14.5,13.3,4.0Hz,1H),2.05–1.96(m,1H),1.86(ddt,J＝13.6,6.7,3.6Hz,1H),1.75–1.67(m,2H),1.57(d,J＝1.9Hz,1H),1.55–1.46(m,1H),1.38(s,4H),1.34–1.27(m,1H),1.27–1.19(m,1H),1.02(td,J＝13.1,12.2,4.0Hz,1H),0.95(d,J＝6.2Hz,3H),0.82(d,J＝7.2Hz,3H)；13C NMR(101MHz,CDCl3)δ:194.67,142.62,132.19,129.98,118.78,111.03,104.01,91.56,90.34,80.20,77.20,51.62,50.87,45.69,40.78,37.35,36.23,34.18,28.50,25.97,24.68,21.57,20.24,13.45；IR(KBr)ν/cm-1:3140,2937,2864,2229,1736,1606,1477,1378,1305,1276,1158,1051,980,926,880,543cm-1；HRMS m/z:calcd forC28H37NaN3O4S2 566.2116,found 566.2118[M+Na]+.The preparation method is the same as that in Example 1, except that p-cyanobenzyl bromide is substituted for benzyl bromide, and the reaction is heated for 4 h, and purified by silica gel column chromatography [eluent: V (petroleum ether): V (ethyl acetate) = 12:1] to obtain pale Yellow solid, yield 65.8%, mp146.7-147.3℃,
Figure BDA0001457330180000092
1 H NMR (400MHz, CDCl 3 )δ: 7.62-7.57(m, 2H), 7.52-7.48(m, 2H), 5.27(s, 1H), 4.65(s, 2H), 4.34(s, 2H), 4.07(d,J＝10.3Hz,1H),3.91(d,J＝29.7Hz,2H),3.07(s,2H),2.79(s,2H),2.57(ddd,J＝10.9,7.3,4.4Hz ,1H),2.34(ddd,J=14.5,13.3,4.0Hz,1H),2.05–1.96(m,1H),1.86(ddt,J=13.6,6.7,3.6Hz,1H),1.75–1.67(m ,2H),1.57(d,J＝1.9Hz,1H),1.55-1.46(m,1H),1.38(s,4H),1.34-1.27(m,1H),1.27-1.19(m,1H), 1.02 (td, J=13.1, 12.2, 4.0 Hz, 1H), 0.95 (d, J=6.2 Hz, 3H), 0.82 (d, J=7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 )δ :194.67,142.62,132.19,129.98,118.78,111.03,104.01,91.56,90.34,80.20,77.20,51.62,50.87,45.69,40.78,37.35,36.23,34.18,28.50,25.97,24.68,21.57,20.24,13.45；IR (KBr)ν/cm -1 :3140,2937,2864,2229,1736,1606,1477,1378,1305,1276,1158,1051,980,926,880,543cm -1 ; HRMS m/z:calcd forC 28 H 37 NaN 3 O 4 S 2 566.2116,found 566.2118[M+Na] + .

实施例八：青蒿素-哌嗪-氨基二硫代甲酸-(4-硝基)苄基酯(化合物8)的制备Example 8: Preparation of artemisinin-piperazine-aminodithiocarboxylic acid-(4-nitro)benzyl ester (compound 8)

Figure BDA0001457330180000101
Figure BDA0001457330180000101

制备方法同实施例一，以4-硝基溴苄替代溴苄，得目标化合物，黄色固体，产率67.6％，m.p.82.2-82.9℃,

Figure BDA0001457330180000102
1H NMR(400MHz,CDCl3)δ:8.19–8.13(m,2H),7.59–7.54(m,2H),5.27(s,1H),4.69(s,2H),4.34(s,2H),4.07(d,J＝10.3Hz,1H),3.92(d,J＝31.3Hz,2H),3.07(s,2H),2.80(s,2H),2.57(ddd,J＝10.9,7.2,4.3Hz,1H),2.39–2.29(m,1H),2.00(dt,J＝14.4,4.1Hz,1H),1.90–1.82(m,1H),1.71(ddd,J＝12.7,7.6,3.6Hz,2H),1.59–1.46(m,2H),1.42(s,1H),1.38(s,3H),1.34–1.18(m,2H),1.07–0.92(m,4H),0.90–0.78(m,3H)；13C NMR(101MHz,CDCl3)δ:196.96,194.68,142.62,132.20,129.98,111.04,104.02,103.98,91.56,90.34,80.21,77.20,51.63,50.88,45.69,40.79,37.35,37.16,36.26,34.20,31.16,28.51,28.32,25.97,24.69,22.28,21.58,20.25,13.96,13.46；IR(KBr)ν/cm-1:3316,3047,2924,2870,2011,1754,1599,1453,1345,1275,1159,1041,983,879,724cm-1；HRMS m/z:calcd for C27H37N3NaO6S2 586.2016,found586.2018[M+Na]+.The preparation method is the same as in Example 1, except that 4-nitrobenzyl bromide is used instead of benzyl bromide to obtain the target compound as a yellow solid, yield 67.6%, mp82.2-82.9°C,
Figure BDA0001457330180000102
1 H NMR (400MHz, CDCl 3 )δ: 8.19-8.13(m, 2H), 7.59-7.54(m, 2H), 5.27(s, 1H), 4.69(s, 2H), 4.34(s, 2H), 4.07(d,J＝10.3Hz,1H),3.92(d,J＝31.3Hz,2H),3.07(s,2H),2.80(s,2H),2.57(ddd,J＝10.9,7.2,4.3Hz ,1H),2.39–2.29(m,1H),2.00(dt,J=14.4,4.1Hz,1H),1.90–1.82(m,1H),1.71(ddd,J=12.7,7.6,3.6Hz,2H ), 1.59–1.46 (m, 2H), 1.42 (s, 1H), 1.38 (s, 3H), 1.34–1.18 (m, 2H), 1.07–0.92 (m, 4H), 0.90–0.78 (m, 3H) The _ ,34.20,31.16,28.51,28.32,25.97,24.69,22.28,21.58,20.25,13.96,13.46; IR(KBr)ν/cm -1 :3316,3047,2924,2870,2011,1754,1599,1453,1345 , 1275, 1159, 1041, 983, 879, 724 cm -1 ; HRMS m/z: calcd for C 27 H 37 N 3 NaO 6 S 2 586.2016, found586.2018[M+Na] + .

实施例九：青蒿素-哌嗪-氨基二硫代甲酸-2-萘甲基酯(化合物9)的制备Example 9: Preparation of artemisinin-piperazine-aminodithiocarboxylate-2-naphthylmethyl ester (compound 9)

Figure BDA0001457330180000111
Figure BDA0001457330180000111

制备方法同实施例一，以2-溴甲基萘代替溴苄，经硅胶柱层析[洗脱剂：V(石油醚)：V(乙酸乙酯)＝12:1]纯化得到白色固体，产率60.3％,m.p.143.8-144.0℃,

Figure BDA0001457330180000112
1H NMR(400MHz,CDCl3)δ:7.86–7.77(m,5H),7.51–7.42(m,3H),5.27(s,1H),4.74(s,2H),4.37(s,2H),4.07(d,J＝10.2Hz,1H),3.93(s,2H),3.07(s,2H),2.79(s,2H),2.57(tt,J＝11.2,6.9Hz,1H),2.38–2.29(m,1H),1.99(dd,J＝14.4,4.2Hz,1H),1.86(ddd,J＝13.6,6.6,3.4Hz,1H),1.71(ddd,J＝12.7,7.6,3.6Hz,2H),1.58(s,3H),1.40(d,J＝16.5Hz,4H),1.34–1.18(m,1H),1.07–0.90(m,3H),0.90–0.78(m,3H)；13C NMR(101MHz,CDCl3)δ:195.88,133.41,133.26,132.64,128.27,128.11,127.70,127.59,127.27,126.11,125.87,103.96,91.52,90.33,80.17,77.20,51.61,46.91,45.68,42.28,40.07,37.32,36.23,34.17,28.49,26.85,25.95,24.67,21.55,20.23,13.44；IR(KBr)ν/cm-1:2924,2870,1599,1508,1422,1376,1309,1275,1231,1159,1130,1020,982,879,755,474；HRMS m/z:calcd for C31H40NaN2O4S2 591.2429,found 591.2342[M+Na]+.The preparation method is the same as that of Example 1, except that 2-bromomethylnaphthalene is used instead of benzyl bromide, and it is purified by silica gel column chromatography [eluent: V (petroleum ether): V (ethyl acetate)=12:1] to obtain a white solid, Yield 60.3%, mp143.8-144.0℃,
Figure BDA0001457330180000112
1 H NMR (400MHz, CDCl 3 )δ: 7.86-7.77(m,5H), 7.51-7.42(m,3H), 5.27(s,1H), 4.74(s,2H), 4.37(s,2H), 4.07(d, J＝10.2Hz, 1H), 3.93(s, 2H), 3.07(s, 2H), 2.79(s, 2H), 2.57(tt, J＝11.2, 6.9Hz, 1H), 2.38–2.29 (m, 1H), 1.99 (dd, J=14.4, 4.2Hz, 1H), 1.86 (ddd, J=13.6, 6.6, 3.4Hz, 1H), 1.71 (ddd, J=12.7, 7.6, 3.6Hz, 2H) ), 1.58 (s, 3H), 1.40 (d, J=16.5Hz, 4H), 1.34–1.18 (m, 1H), 1.07–0.90 (m, 3H), 0.90–0.78 (m, 3H); 13 C NMR(101MHz,CDCl 3 )δ:195.88,133.41,133.26,132.64,128.27,128.11,127.70,127.59,127.27,126.11,125.87,103.96,91.52,90.33,80.17,77.20,51.61,46.91,45.68,42.28,40.07 ,37.32,36.23,34.17,28.49,26.85,25.95,24.67,21.55,20.23,13.44; IR(KBr)ν/cm -1 :2924,2870,1599,1508,1422,1376,1309,1275,1231,1159 , 1130, 1020, 982, 879, 755, 474; HRMS m/z: calcd for C 31 H 40 NaN 2 O 4 S 2 591.2429, found 591.2342[M+Na] + .

实施例十：青蒿素-哌嗪-氨基二硫代甲酸戊基酯(化合物10)的制备Example 10: Preparation of Artemisinin-Piperazine-Aminodithiocarboxylate (Compound 10)

Figure BDA0001457330180000121
Figure BDA0001457330180000121

制备方法同实施例一，以氯戊烷替代溴苄，加热反应10h，得目标化合物，淡黄色固体，产率58.0％，m.p.135.8-136.2℃.

Figure BDA0001457330180000122
1H NMR(400MHz,CDCl3)δ:5.25(s,1H),4.32(s,2H),4.05(d,J＝10.2Hz,1H),4.00–3.82(m,2H),3.27(t,J＝7.4Hz,2H),3.04(dt,J＝11.8,5.2Hz,2H),2.76(p,J＝4.9Hz,2H),2.56(ddt,J＝10.1,7.1,3.6Hz,1H),2.32(td,J＝13.9,3.9Hz,1H),1.98(ddd,J＝14.5,5.0,3.0Hz,1H),1.84(ddt,J＝13.6,6.8,3.5Hz,2H),1.69(ddt,J＝14.8,10.2,5.4Hz,5H),1.53(dt,J＝13.6,4.3Hz,1H),1.47–1.26(m,8H),1.21(td,J＝11.2,6.4Hz,1H),1.07–0.96(m,1H),0.96–0.85(m,6H),0.81(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:196.89,103.92,91.51,90.29,80.16,51.60,50.11,46.87,45.68,37.31,37.11,36.22,34.17,31.12,28.48,28.28,25.93,24.66,22.24,21.55,20.23,13.93,13.44；IR(KBr)ν/cm-1:3232,3079,2937,1755,1423,1388,1277,1233,1160,1131,1022,999,932,881cm-1；HRMS m/z:calcd for C25H42N2NaO4S2521.2477,found 521.2479[M+Na]+.The preparation method is the same as in Example 1, except that chloropentane is used instead of benzyl bromide, and the reaction is heated for 10 h to obtain the target compound as a pale yellow solid, yield 58.0%, mp 135.8-136.2 ℃.
Figure BDA0001457330180000122
1 H NMR (400 MHz, CDCl 3 ) δ: 5.25 (s, 1H), 4.32 (s, 2H), 4.05 (d, J=10.2 Hz, 1H), 4.00-3.82 (m, 2H), 3.27 (t, J=7.4Hz, 2H), 3.04 (dt, J=11.8, 5.2Hz, 2H), 2.76 (p, J=4.9Hz, 2H), 2.56 (ddt, J=10.1, 7.1, 3.6Hz, 1H), 2.32(td,J＝13.9,3.9Hz,1H),1.98(ddd,J＝14.5,5.0,3.0Hz,1H),1.84(ddt,J＝13.6,6.8,3.5Hz,2H),1.69(ddt, J=14.8, 10.2, 5.4Hz, 5H), 1.53 (dt, J=13.6, 4.3Hz, 1H), 1.47–1.26 (m, 8H), 1.21 (td, J=11.2, 6.4Hz, 1H), 1.07 -0.96(m,1H),0.96-0.85(m,6H),0.81(d,J=7.1Hz,3H); 13 C NMR (101 MHz, CDCl 3 ) δ: 196.89, 103.92, 91.51, 90.29, 80.16, 51.60, 50.11, 46.87, 45.68, 37.31, 37.11, 36.22, 34.17, 31.12, 28.48 , 28.28, 25.93, 24.66, 22.24, 21.55, 20.23, 13.93, 13.44; 2937, 1755, 1423, 1388, 1277, 1233, 1160, 1131, 1022, 999, 932, 881 cm -1 ; HRMS m/z: calcd for C 25 H 42 N 2 NaO 4 S 2 521.2477, found 521.2479[M+Na] + .

实施例十一：青蒿素-哌嗪-氨基二硫代甲酸十八烷基酯(化合物11)的制备Example 11: Preparation of artemisinin-piperazine-octadecyl aminodithiocarboxylate (compound 11)

Figure BDA0001457330180000131
Figure BDA0001457330180000131

制备方法同实施例一，以1-氯十八烷替代溴苄，得目标化合物，黄色蜡状固体，产率49.3％,

Figure BDA0001457330180000132
1H NMR(400MHz,CDCl3)δ:5.25(s,1H),4.32(s,2H),4.05(d,J＝10.2Hz,1H),3.27(t,J＝7.5Hz,2H),3.04(dt,J＝11.0,4.9Hz,2H),2.76(dt,J＝11.3,4.8Hz,2H),2.56(ddd,J＝11.2,7.2,4.2Hz,1H),2.32(td,J＝13.9,3.9Hz,1H),1.98(ddd,J＝14.5,4.9,2.9Hz,1H),1.84(ddt,J＝13.5,6.7,3.5Hz,1H),1.74–1.63(m,4H),1.53(dt,J＝13.9,4.4Hz,1H),1.30(d,J＝49.8Hz,39H),1.01(td,J＝13.1,12.3,4.0Hz,1H),0.93(d,J＝6.2Hz,3H),0.89–0.77(m,6H)；13C NMR(101MHz,CDCl3)δ:196.84,103.87,91.47,90.27,80.12,51.58,46.87,45.66,37.28,37.12,36.20,34.16,31.84,29.62,29.60,29.58,29.53,29.44,29.29,29.15,28.97,28.56,28.45,25.90,24.64,22.61,21.52,20.20,14.07,13.41；IR(KBr)ν/cm-1:2923,2852,1466,1421,1376,1310,1275,1231,1130,1055,983,880,834,721,551；HRMS m/z:calcd for C38H69N2O4S2681.4621,found681.4713[M+H]+.The preparation method is the same as that in Example 1, except that 1-chlorooctadecane is used instead of benzyl bromide to obtain the target compound as a yellow waxy solid with a yield of 49.3%.
Figure BDA0001457330180000132
1 H NMR (400 MHz, CDCl 3 ) δ: 5.25 (s, 1H), 4.32 (s, 2H), 4.05 (d, J=10.2 Hz, 1H), 3.27 (t, J=7.5 Hz, 2H), 3.04 (dt, J=11.0, 4.9Hz, 2H), 2.76 (dt, J=11.3, 4.8Hz, 2H), 2.56 (ddd, J=11.2, 7.2, 4.2Hz, 1H), 2.32 (td, J=13.9 ,3.9Hz,1H),1.98(ddd,J=14.5,4.9,2.9Hz,1H),1.84(ddt,J=13.5,6.7,3.5Hz,1H),1.74–1.63(m,4H),1.53( dt, J＝13.9, 4.4Hz, 1H), 1.30 (d, J＝49.8Hz, 39H), 1.01 (td, J＝13.1, 12.3, 4.0Hz, 1H), 0.93 (d, J＝6.2Hz, 3H) The _ 29.60, 29.58, 29.53, 29.44, 29.29, 29.15, 28.97, 28.56, 28.45, 25.90, 24.64, 22.61, 21.52, 20.20, 14.07, 13.41; IR(KBr)ν/cm -1 : 2923,2852,1466,14 1376, 1310, 1275, 1231, 1130, 1055, 983, 880, 834, 721, 551; HRMS m/z: calcd for C 38 H 69 N 2 O 4 S 2 681.4621, found681.4713[M+H] + .

实施例十二：青蒿素-哌嗪-氨基二硫代甲酸-(苄氧酰基)甲酯(化合物12)的制备Example 12: Preparation of artemisinin-piperazine-aminodithiocarboxylic acid-(benzyloxyacyl) methyl ester (compound 12)

Figure BDA0001457330180000141
Figure BDA0001457330180000141

制备方法同实施例一，以溴乙酸苄酯替代溴苄，经硅胶柱层析[洗脱剂：V(石油醚)：V(乙酸乙酯)＝6:1]纯化得到橙黄色固体，产率35％,m.p.82.3-83.3℃,

Figure BDA0001457330180000142
1H NMR(400MHz,CDCl3)δ:7.40–7.36(m,4H),7.33(dddd,J＝11.4,4.9,2.9,1.8Hz,1H),5.28(s,1H),5.19(s,2H),4.31(s,2H),4.21(s,2H),4.07(d,J＝10.2Hz,1H),3.95(d,J＝32.2Hz,2H),3.08(dt,J＝11.3,5.0Hz,2H),2.80(dt,J＝11.5,5.2Hz,2H),2.63–2.53(m,1H),2.34(ddd,J＝14.5,13.3,3.9Hz,1H),2.05–1.96(m,1H),1.87(ddd,J＝13.6,6.6,3.4Hz,1H),1.71(ddt,J＝11.2,6.5,3.5Hz,2H),1.60(s,1H),1.55(dt,J＝13.6,4.3Hz,1H),1.49–1.41(m,1H),1.38(s,3H),1.35–1.18(m,2H),1.07–0.98(m,1H),0.95(d,J＝6.2Hz,3H),0.83(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:194.32,168.57,135.47,128.52,128.30,128.29,104.01,91.54,90.36,80.20,67.46,51.64,46.91,45.71,38.91,37.36,36.26,34.21,28.53,26.88,25.97,24.71,21.59,20.26,13.46；IR(KBr)ν/cm-1:2925,2871,1738,1425,1376,1275,1235,1040,980,925,878,741,697,550；HRMS m/z:calcd for C29H40NaN2O6S2 599.2328,found 599.2246[M+Na]+.The preparation method is the same as in Example 1, except that benzyl bromoacetate is used instead of benzyl bromide, and the product is purified by silica gel column chromatography [eluent: V (petroleum ether): V (ethyl acetate)=6:1] to obtain an orange-yellow solid. rate 35%, mp82.3-83.3℃,
Figure BDA0001457330180000142
1 H NMR (400 MHz, CDCl 3 ) δ: 7.40-7.36 (m, 4H), 7.33 (dddd, J=11.4, 4.9, 2.9, 1.8 Hz, 1H), 5.28 (s, 1H), 5.19 (s, 2H) ),4.31(s,2H),4.21(s,2H),4.07(d,J＝10.2Hz,1H),3.95(d,J＝32.2Hz,2H),3.08(dt,J＝11.3,5.0Hz ,2H),2.80(dt,J＝11.5,5.2Hz,2H),2.63-2.53(m,1H),2.34(ddd,J＝14.5,13.3,3.9Hz,1H),2.05-1.96(m,1H) ),1.87(ddd,J=13.6,6.6,3.4Hz,1H),1.71(ddt,J=11.2,6.5,3.5Hz,2H),1.60(s,1H),1.55(dt,J=13.6,4.3 Hz, 1H), 1.49–1.41 (m, 1H), 1.38 (s, 3H), 1.35–1.18 (m, 2H), 1.07–0.98 (m, 1H), 0.95 (d, J=6.2Hz, 3H) , 0.83 (d, J=7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ: 194.32, 168.57, 135.47, 128.52, 128.30, 128.29, 104.01, 91.54, 90.36, 80.20, 67.46, 51.64, 46.91, 45.71,38.91,37.36,36.26,34.21,28.53,26.88,25.97,24.71,21.59,20.26,13.46; IR(KBr)ν/cm -1 : 2925,2871,1738,1425,1376,1275,1235,1040, 980,925,878,741,697,550; HRMS m/z: calcd for C 29 H 40 NaN 2 O 6 S 2 599.2328, found 599.2246[M+Na] + .

实施例十三：青蒿素-哌嗪衍生物体外抗人肝癌SMMC-7721细胞活性研究Example 13: In vitro activity of artemisinin-piperazine derivatives against human liver cancer SMMC-7721 cells

采用MTT(四甲基偶氮唑盐比色法)，选取青蒿素-哌嗪衍生物(化合物1～12)，测定其对人肝癌SMMC-7721细胞的抑制率，计算IC50值(μM)。具体操作步骤如下：MTT (tetramethylazolium salt colorimetry) was used to select artemisinin-piperazine derivatives (compounds 1 to 12) to determine their inhibitory rate on human hepatoma SMMC-7721 cells, and to calculate the IC 50 value (μM ). The specific operation steps are as follows:

1、细胞复苏1. Cell recovery

细胞培养基：1640+10％FBS+1％(Penicillin-Streptomycin Solution)Cell culture medium: 1640+10%FBS+1% (Penicillin-Streptomycin Solution)

(1)将SMMC7721细胞分别从液氮中取出，快速放入37℃水浴锅中，轻摇冻存管使冻存液溶解；(1) Take the SMMC7721 cells out of liquid nitrogen, quickly put them into a 37°C water bath, and gently shake the cryopreservation tube to dissolve the cryopreservation solution;

(2)溶解后把细胞分别转移到含有5mL培养基的离心管中，离心收集细胞，室温1000rpm离心5min，弃上清；(2) After dissolving, transfer the cells to centrifuge tubes containing 5 mL of culture medium, collect cells by centrifugation, centrifuge at 1000 rpm for 5 min at room temperature, and discard the supernatant;

(3)用含10％胎牛血清的完全培养基悬浮细胞，接种到培养皿中，轻轻吹打混匀，37℃、5％CO2、饱和湿度条件下培养。(3) Suspend the cells in a complete medium containing 10% fetal bovine serum, inoculate the cells into a petri dish, mix by gently pipetting, and culture at 37° C., 5% CO 2 , and saturated humidity.

2、细胞传代2. Cell passage

细胞的密度达到80％时，对细胞进行传代：Passage cells when the density of cells reaches 80%:

(1)弃去培养基，用PBS洗一遍；(1) Discard the culture medium and wash it with PBS;

(2)加1-2mL 0.25％胰蛋白酶消化细胞，显微镜下观察，消化30-60s，可看到细胞相互分离变圆，即消化完成；(2) Add 1-2 mL of 0.25% trypsin to digest the cells, observe under a microscope, digest for 30-60 s, and it can be seen that the cells are separated from each other and become round, that is, the digestion is completed;

(3)快速弃去胰酶，加入完全培养基，吹打细胞，制成单细胞悬液，按1:3的比例传代，37℃、5％CO2、饱和湿度条件下扩大培养。(3) Quickly discard the trypsin, add complete medium, pipet the cells to prepare a single-cell suspension, passage at a ratio of 1:3, and expand the culture at 37°C, 5% CO 2 , and saturated humidity.

3、细胞处理及MTT检测3. Cell processing and MTT detection

(1)取处于对数生长期，生长状态良好的SMMC7721细胞，用1640培养基调整细胞密度到1×104个/mL，接入96孔板，每孔100μL细胞悬液，同时设空白组，37℃培养过夜(在细胞孔周围孔内加入100μL无菌PBS)；(1) Take SMMC7721 cells in logarithmic growth phase and in good growth state, adjust the cell density to 1×10 4 cells/mL with 1640 medium, and insert into a 96-well plate with 100 μL of cell suspension per well, and set a blank group at the same time , cultured at 37°C overnight (add 100 μL of sterile PBS to the surrounding holes of the cells);

(2)待细胞贴壁生长良好24h后，吸收旧的培养液，向各个培养孔中加入不同浓度化合物1～12的供试液。每浓度设5个平行重复孔，同时设等体积二甲基亚砜(DMSO)溶剂的和不含药物培养基的空白对照孔，于37℃，5％CO2的培养箱内继续培养。(2) After 24 hours of cell adhesion and good growth, absorb the old culture medium, and add test solutions of compounds 1-12 with different concentrations into each culture well. Five parallel replicate wells were set for each concentration, and blank control wells with equal volume of dimethyl sulfoxide (DMSO) solvent and drug-free medium were set up, and the culture was continued in an incubator at 37° C., 5% CO 2 .

分别培养24h、48h、72h后，弃去上清液，每孔加10μL(2mg/mL in PBS)MTT，继续培养4h后，吸出孔内培养上清液，每孔加入150μL二甲基亚砜,振荡10min使蓝紫色结晶物溶解充分后，于波长568nm处用酶标仪测定每孔样品的吸光度值(OD值)，去除最高值与最低值，取剩余值的平均值。After culturing for 24h, 48h, and 72h, discard the supernatant, add 10 μL (2 mg/mL in PBS) MTT to each well, and continue to culture for 4 hours, aspirate the culture supernatant in the well, and add 150 μL dimethyl sulfoxide to each well. , shake for 10min to fully dissolve the blue-violet crystals, measure the absorbance value (OD value) of each well sample with a microplate reader at a wavelength of 568nm, remove the highest value and the lowest value, and take the average value of the remaining values.

抑制率的计算：细胞生长的抑制率按照下列公式计算：Calculation of inhibition rate: The inhibition rate of cell growth was calculated according to the following formula:

抑制率(％)＝[1-(测试样品OD值-空白OD值)/(阴性对照OD值-空白OD值)]×100％Inhibition rate (%)=[1-(OD value of test sample-OD value of blank)/(OD value of negative control-OD value of blank)]×100%

表1青蒿素-哌嗪衍生物1～12对人肝癌SMMC-7721细胞的抑制率Table 1 Inhibitory rate of artemisinin-piperazine derivatives 1-12 on human hepatoma SMMC-7721 cells

Figure BDA0001457330180000161
Figure BDA0001457330180000161

Figure BDA0001457330180000171
Figure BDA0001457330180000171

表2青蒿素-哌嗪衍生物1～12对人肝癌SMMC-7721细胞的抑制IC50值(μM)Table 2 Inhibitory IC 50 values (μM) of artemisinin-piperazine derivatives 1-12 on human hepatoma SMMC-7721 cells

Figure BDA0001457330180000181
Figure BDA0001457330180000181

[a]赵晨阳,邱嵘,郑荣梁.兰州大学学报(自科版),2000,36(4),66-68.(长春新碱:IC50＝63.2±1.8μg/mL＝0.074±0.002μM)；[b]J.J.Lu,L.H.Meng,Y.J.Cai,etal.Cancer.Biol.Ther.2008,7,1017-1023.[a] Zhao Chenyang, Qiu Rong, Zheng Rongliang. Journal of Lanzhou University (Self-Science Edition), 2000, 36(4), 66-68. (Vincristine: IC 50 =63.2±1.8μg/mL=0.074±0.002μM) ;[b]JJLu,LHMeng,YJCai,etal.Cancer.Biol.Ther.2008,7,1017-1023.

Claims (3)

1.一类青蒿素-哌嗪衍生物，其特征在于，具有如下通式(I)：1. a class of artemisinin-piperazine derivatives, is characterized in that, has following general formula (I):
Figure FDA0002339435770000011
Figure FDA0002339435770000011
 式中R为：
Figure FDA0002339435770000012
where R is:
Figure FDA0002339435770000012
 2.如权利要求1所述的一类青蒿素-哌嗪衍生物的制备方法：其特征是将青蒿素-哌嗪和用量为青蒿素-哌嗪四倍量的二硫化碳溶于乙腈，然后加入用量为青蒿素-哌嗪十倍量的三乙胺，室温搅拌10min后，加入用量为青蒿素-哌嗪两倍量的卤代物乙腈溶液，逐渐升至60℃，反应4～12h，TLC跟踪，磷钼酸显色，反应结束后，蒸除溶剂，硅胶柱层析分离纯化PE:EA＝16:1～6:1，得到青蒿素-哌嗪衍生物。2. the preparation method of a class of artemisinin-piperazine derivatives as claimed in claim 1: it is characterized in that the carbon disulfide that artemisinin-piperazine and consumption are four times the amount of artemisinin-piperazine are dissolved in acetonitrile , then add the triethylamine whose consumption is ten times of the amount of artemisinin-piperazine, after stirring at room temperature for 10min, add the halide acetonitrile solution whose consumption is twice the amount of artemisinin-piperazine, gradually rise to 60 ℃, reaction 4 ～12h, TLC tracking, phosphomolybdic acid color development, after the reaction, the solvent was evaporated, and silica gel column chromatography was used to separate and purify PE:EA=16:1～6:1 to obtain an artemisinin-piperazine derivative. 3.权利要求1所述的一类青蒿素-哌嗪衍生物在制备抗人肝癌细胞SMMC-7721药物中的应用。3. The application of a class of artemisinin-piperazine derivatives according to claim 1 in the preparation of medicines against human hepatoma cell SMMC-7721.
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