CN103804335A - 一种杨梅素含氮类衍生物及其制备方法和用途 - Google Patents
一种杨梅素含氮类衍生物及其制备方法和用途 Download PDFInfo
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- CN103804335A CN103804335A CN201410028019.7A CN201410028019A CN103804335A CN 103804335 A CN103804335 A CN 103804335A CN 201410028019 A CN201410028019 A CN 201410028019A CN 103804335 A CN103804335 A CN 103804335A
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- Prior art keywords
- trimethoxyphenyl
- chromene
- dimethoxy
- compound
- piperazine
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title claims abstract description 19
- IKMDFBPHZNJCSN-UHFFFAOYSA-N Myricetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC(O)=C(O)C(O)=C1 IKMDFBPHZNJCSN-UHFFFAOYSA-N 0.000 title abstract description 14
- PCOBUQBNVYZTBU-UHFFFAOYSA-N myricetin Natural products OC1=C(O)C(O)=CC(C=2OC3=CC(O)=C(O)C(O)=C3C(=O)C=2)=C1 PCOBUQBNVYZTBU-UHFFFAOYSA-N 0.000 title abstract description 14
- 235000007743 myricetin Nutrition 0.000 title abstract description 14
- 229940116852 myricetin Drugs 0.000 title abstract description 14
- 150000001875 compounds Chemical group 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- DCYOADKBABEMIQ-OWMUPTOHSA-N myricitrin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC1=C(C=2C=C(O)C(O)=C(O)C=2)OC2=CC(O)=CC(O)=C2C1=O DCYOADKBABEMIQ-OWMUPTOHSA-N 0.000 claims abstract description 9
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical class OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 6
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 6
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical class CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims abstract description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Chemical class O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229960003506 piperazine hexahydrate Drugs 0.000 claims abstract description 5
- AVRVZRUEXIEGMP-UHFFFAOYSA-N piperazine;hexahydrate Chemical compound O.O.O.O.O.O.C1CNCCN1 AVRVZRUEXIEGMP-UHFFFAOYSA-N 0.000 claims abstract description 5
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- KQILIWXGGKGKNX-UHFFFAOYSA-N dihydromyricetin Natural products OC1C(=C(Oc2cc(O)cc(O)c12)c3cc(O)c(O)c(O)c3)O KQILIWXGGKGKNX-UHFFFAOYSA-N 0.000 claims description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
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- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 claims description 26
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Abstract
本发明涉及一种杨梅素含氮类衍生物及其制备方法和用途，其化合物结构有下列通式(I)、(II)和(III)表示。本发明介绍了以杨梅苷、卤代烷烃、仲胺、六水合哌嗪、芳香酸、取代芳香酸、溴乙酸乙酯、水合肼、芳香醛以及取代芳香醛为原料，经取代、水解和缩合反应合成一系列杨梅素含氮类衍生物。该类化合物对癌细胞有较好的抑制作用，且毒性较小，可用于制备抗癌药物。
Description
技术领域
本发明涉及具有抗癌作用的含杨梅素氮类衍生物及制备方法和用途。
背景技术
杨梅素(3',4',5',3,5,7 -六羟基黄酮醇，Myricetin)，杨梅素广泛的存在于壳斗科(Fagaceae)、豆科(Leguminosae)、报春(Pfimulaceae)、葡萄科(Vitaceae)、菊科(Compositae)等植物中，杨梅素通常存在于我们日常食用的水果，蔬菜和和饮料中，例如：茶和红酒等。有研究表明：杨梅素具有抗癌、抗氧化(Ong, K. C.; Khoo, H. E. Biological effects of myricetin[J]. General Pharmacology: The Vascular System, 1997, 29(2): 121-126)、抗病毒(Ono, K.; Nakane, H.; Fukushima, M.; et al. Differential inhibitory effects of various flavonoids on the activities of reverse transcriptase and cellular DNA and RNA polymerases[J]. European Journal of Biochemistry, 1990, 190(3): 469-476)、抗炎(Lee, Y. S.; Choi, E. M. Myricetin inhibits IL-1β-induced inflammatory mediators in SW982 human synovial sarcoma cells[J]. International Immunopharmacology, 2010, 10(7): 812-814)、抑菌(El-Gammal, A. A.; Mansour, R. Antimicrobial activities of some flavonoid compounds[J]. Zentralblatt für Mikrobiologie, 1986, 141(7): 561-565)等多种药理活性。
目前其在抗癌活性方面的研究较多，对人类多种肿瘤细胞有明显的抑制作用(张秀娟, 黄清玲, 季宇彬. 杨梅素的药理活性研究进展[J]. 天津药学, 2008, 20(5): 57-60)。现代医学证明杨梅素在肿瘤发生发展的多个阶段均有作用，包括肿瘤细胞的增殖、诱导肿瘤细胞的分化和凋亡，以及抑制肿瘤的发生和转移。由于杨梅素具有抗肿瘤谱广泛，对正常细胞毒性低，同时能增强免疫力的作用，因此在开发新型的抗肿瘤药物领域，杨梅素以及杨梅素的衍生物得到了越来越多的关注。
2007年，Lee (K. W.; Kang, N. J.; Rogozin, E. A.; et al. Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1[J]. Carcinogenesis, 2007, 28(9): 1918-1927)发现杨梅素在浓度为10μmol/L下对JP6 P+小鼠表皮细胞的恶性肿瘤转化及增殖具有明显抑制作用，其机制是阻断MEK/ERK/AP-1信号路径；杨梅素还可以蛋氨酸及Akt的活性，影响成髓细胞瘤肌动蛋白细胞骨架重组，遏制成髓瘤细胞在转移过程中由肝细胞生长因子导致的形态学变化，从而抑制其转移，其IC50值为6 μmol/L(Labbé, D.; Provencal, M.; Lamy, S.; et al. The flavonols quercetin, kaempferol, and myricetin inhibit hepatocyte growth factor-induced medulloblastoma cell migration[J]. The Journal of nutrition, 2009, 139(4)：646-652)。
2009年，张莉静等(张莉静, 刘志国, 孟大利, 夏明钰. 杨梅树皮提取物及杨梅素抗肿瘤活性[J]. 沈阳药科大学学报, 2009, 26(4): 307-311)对杨梅素单体化合物进行体外抗肿瘤研究，研究表明：杨梅素对人宫颈癌HeLa细胞、人黑色素瘤A375-S2细胞、人乳腺癌MCF-7细胞和人肝癌HepG2细胞均具有明显的细胞毒作用，杨梅素明显抑制HeLa细胞的增殖，诱导HeLa细胞调亡。
2010年，张秀娟等(张秀娟, 凌云, 于华, 季宇彬. 杨梅树皮素诱导人肝癌HepG-2细胞凋亡机制的研究[J]. 中国中药杂志, 2010, 35(8): 1046-1050)探讨了杨梅素对人肝癌HepG-2抑制生长和诱导凋亡作用及其机制，研究表明：杨梅素对人肝癌HepG-2细胞生长具有明显的抑制作用，并具有剂量依赖性，IC50为58.6617 mg/L；杨梅素作用72 h后，HepG-2细胞呈现典型细胞凋亡特征，细胞周期阻滞于G2/M期，凋亡率最高为64.73%。2011年，Zhang等(Zhang, X.; Zou, Z.; Xu, C.; et al. Myricetin induces G2/M phase arrest in HepG2 cells by inhibiting the activity of the cyclin B/Cdc2 complex[J]. Mol Med Report, 2011, 4: 273-277)进一步研究了杨梅素对肝癌细胞的作用机制，发现杨梅素是通过降低肝癌细胞中Cdc2和周期蛋白B1的水平，从而抑制肝癌细胞的生长繁殖。
2010年，韦伟等(Wei, W., Effects of myricetin on the apoptosis of bladder cancer cell BIU-87[J]. Journal of Chongqing Medical University, 2010, 35(12): 1791-1793)研究了杨梅素诱导膀胱癌细胞株BIU-87凋亡的机制，通过培养人膀胱癌细胞株BIU- 87，加入不同浓度杨梅素干扰，在倒置显微镜下观察细胞形态学变化；并利用MTT及Hoechst 33258染色法检测杨梅素对膀胱癌细胞株BIU-87凋亡的影响；后用RT-PCR检测细胞凋亡相关基因survivin 及caspase-3转录水平的改变，免疫印迹法检测survivin和caspase-3的表达情况，结果表明：杨梅素能诱导膀胱癌细胞BIU-87细胞凋亡，并明显抑制survivin 的转录和表达，同时对caspase-3有上调作用。
2011年，Phillips等(Phillips, P.; Sangwan, V.; Borja-Cacho, D.; et al. Myricetin induces pancreatic cancer cell death via the induction of apoptosis and inhibition of the phosphatidylinositol 3-kinase (PI3K) signaling pathway[J]. Cancer letters, 2011, 308(2): 181-188)研究了杨梅素对胰腺癌细胞在体内与体外的作用。研究发现，杨梅素在25μmol/L~200μmol/L呈剂量依耐性地抑制AktL磷酸化，能降低PI3激酶的活性，诱导体外胰腺癌细胞凋亡死亡；在体内，杨梅素通过对肿瘤的消减和癌细胞的转移来治疗胰腺肿瘤。
2011年，Kang等(Kang, N. J.; Jung, S. K.; Lee, K. W.; et al. Myricetin is a potent chemopreventive phytochemical in skin carcinogenesis[J]. Annals of the New York Academy of Sciences, 2011, 1229(1): 124-132)研究了杨梅素对小鼠皮肤癌细胞的抑制作用，研究发现：杨梅素是通过减弱紫外线B，诱导COX-2的表达，从而抑制皮肤癌凋亡；通过作用靶标抑菌作用PI3-K诱导的血管生成，因此，杨梅素是一个有前途的抑制癌细胞生长的化学预防剂。
发明内容
本发明的目的在于设计合成一系列结构新颖的杨梅素含氮类衍生物，该类化合物以天然产物杨梅苷为先导，通过结构修饰合成了一系列杨梅素衍生物，经抗癌活性测试表明，杨梅素衍生物和杨梅素及现有商品化药剂Epirubicin Hydrochloride相比抗癌活性明显提高，并且杨梅素衍生物对乳腺癌细胞(MDA-MB-231)的细胞毒性较小，该类化合物可作为抑制癌细胞的药物。所制备的杨梅素含氮类衍生物结构由下列通式(I)、(II)和(III)表示：
所述结构中n为2、3和或4；R1为(1)卤原子；(2)二乙胺基；(3)哌啶基；(4)吡咯烷基；(5)吗啉基；(6)对甲基哌嗪基；R2为(1)苯基或取代苯基；(3)吡啶基或取代吡啶基；R3为(1)苯基或取代苯基；(2)杂环基或取代杂环基。
本发明内容中，取代苯基可为苯环上含有一个或多个甲基、乙基、甲氧基、乙氧基、
正丙基、异丙基、三氟甲基、硝基、胺基以及卤原子，卤原子可为氟、氯、溴、碘。
本发明内容中，化合物具有抗肿瘤活性，特征是对人乳腺癌细胞(MDA-MB-231)有着良好的活性，用途是在制备抗癌药物中的应用。
本发明(I)化合物的制备方法是以杨梅苷、卤代烷烃、仲胺为原料，经两步取代和一步水解反应合成目标产物，其合成路线为如下：
合成方法为：
第一步：3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在圆底烧瓶中加入杨梅苷和K2CO3溶于DMF中，搅拌均匀后，缓慢的滴加碘甲烷，
室温搅拌数小时，停止反应，用水分散，用乙酸乙酯萃取，合并滤液，合并有机相，减压浓缩，然后将浓缩物溶于无水乙醇，升温至回流，溶液澄清后，回流下加入浓盐酸，慢慢的有黄色固体析出，继续反应2 h，冷却，冰箱放置过夜，过滤，得到粗产物，不需要纯化，直接用于下一步的反应，
第二步：3-卤代基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备在圆底烧瓶中加入第一步的反应产物和K2CO3, 用DMF溶解后，加入溴代烷烃，在室温下反应数小时，停止反应后，用水分散，以乙酸乙酯萃取，得到有机相，依次用HCl，饱和NaHCO3，饱和NaCl水溶液分别洗涤后，合并乙酸乙酯层，以无水硫酸钠干燥后蒸去溶剂，用硅胶柱层析分离，得到目标产物，
第三步：含杂环烷基类杨梅素衍生物的制备
在圆底烧瓶中加入第二步的产物和K2CO3，用DMF溶解后，加入仲胺，在室温下反应数小时，停止反应后，用水分散，以乙酸乙酯萃取，合并有机相依次用HCl，饱和NaHCO3，饱和NaCl水溶液分别洗涤后，合并乙酸乙酯层，以无水硫酸钠干燥后蒸去溶剂，用硅胶柱层析分离，得到目标产物。
本发明通式(II)化合物的制备方法是以杨梅苷、卤代烷烃、六水合哌嗪、芳香酸、以及取代芳香酸为原料，经取代、水解和缩合反应合成目标产物，其合成路线为：
合成方法为：
第一步：与通式(I)中3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备一致，
第二步：与通式(I)中3-卤代基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备一致，
第三步：5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4- 酮的制备
在圆底烧瓶中加入第二步的产物和K2CO3，用DMF溶解，搅拌几分钟后加入六水合哌嗪，在室温下反应数小时后，停止反应，用水分散，以乙酸乙酯萃取，合并有机相，用HCl，饱和NaHCO3，饱和NaCl水溶液分别洗涤后，合并乙酸乙酯层，以无水硫酸钠干燥后蒸去溶剂，用硅胶柱层析分离得到目标产物。
第四步：含哌嗪酰胺类杨梅素衍生物的制备
在圆底烧瓶中，在冰浴条件下加入酸以及HATU，用干燥二氯甲烷溶解后加入几滴三乙胺在冰浴下搅拌，加入第三步的产物，在室温下反应数小时后，停止反应，用水洗涤反应液，以无水硫酸钠干燥，然后硅胶柱层析分离得到目标产物。
本发明通式(III)化合物的制备方法是以杨梅苷、卤代烷烃、溴乙酸乙酯、水合肼、芳香醛以及取代芳香醛为原料，经取代、水解和缩合反应合成目标产物，其合成路线为：
合成方法如下：
第一步：与通式(I)中3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备一致，
第二步：3-氧乙酸乙酯-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在三口瓶中依次加入第一步的产物，K2CO3和无水丙酮，室温搅拌均匀后，滴加溴乙酸乙酯，滴毕，回流反应数小时，停止反应后，冷却至室温，浓缩后倒入冰水中，析晶，抽滤，滤饼用氯仿/水重结晶得到目标产物，
第三步：2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼的制备
在三口瓶中依次加入第二步的产物，80%水合肼和无水乙醇，回流反应，TCL点板跟踪，直至反应完全，减压浓缩除去大量溶剂后，冷却，有沉淀产生析出，抽滤，滤饼用无水乙醇重结晶得到目标产物，
第四步：杨梅素酰腙类衍生物的制备
在三口瓶中依次加入第三步的产物和芳香醛，用无水乙醇溶解，滴入催化量的醋酸，搅拌加热回流，TLC点板跟踪，直至反应完全，浓缩反应液，冷却，有大量的沉淀析出，抽滤，滤饼用无水乙醇重结晶得到目标产物。
本步骤适用于所有上述目标化合物杨梅素含氮类衍生物的合成。
本发明路线和制备方法已合成并证明有抗癌作用的化合物如下：
化合物1:3-(3-(二乙基氨-1-基)丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物2: 5,7-二甲氧基-3-(3-(吡咯烷-1-基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物3: 5,7-二甲氧基-3-(3-(哌啶-1-基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物4: 5,7-二甲氧基-3-(3-(吗啉-1-基)-丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物5: 5,7-二甲氧基-3-(3-(4-甲基哌嗪-1-基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物6: 3-(4-(二乙氨基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物7: 5,7-二甲氧基-3-(4-(吡咯烷-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4- 酮
化合物8: 5,7-二甲氧基-3-(4-(哌啶-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物9: 5,7-二甲氧基-3-(4-吗啉-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物10: 5,7-二甲氧基-3-(4-(4-甲基哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物11: 5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物12: 3-(4-(4-(4-氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物13: 3-(4-(4-(4-氯苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物14: 5,7-二甲氧基-3-(4-(4-(4-硝基苯甲酰基)哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物15: 5,7-二甲氧基-3-(4-(4-(4-(三氟甲基)苯甲酰基)哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物16: 3-(4-(4-(2-氯-6-氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物17: 3-(4-(4-(2,4-二氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物18: 3-(4-(4-(5-氯-2-硝基苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物19: 3-(4-(4 -(3,5-二硝基苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物20: 3-(4-(4-苯甲酰基-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物21: 3-(4-(4-异烟酰基-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物22: 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(2- 氟苄基)乙酰肼
化合物23: 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(4- 甲基亚苄基)乙酰肼
化合物24: 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(吡啶-2-基亚甲基)乙酰肼
化合物25: 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(呋喃-2-基亚甲基)乙酰肼
化合物26: 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-((3- 甲基噻吩-2-基)亚甲基)乙酰肼
化合物27: N'-((1H-吡咯-2-基)亚甲基)-2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼
本发明合成的杨梅素含氮类衍生物具有较好的抗癌活性，可用于制备抗癌药物。
附图说明
图1：化合物(1-9)在设定浓度下对乳腺癌细胞MDA-MB-231作用24、48、72小时的形态学影响。
图2：化合物(9-18)在设定浓度下对乳腺癌细胞MDA-MB-231作用24、48、72小时的形态学影响。
图3：化合物(19-27)在设定浓度下对乳腺癌细胞MDA-MB-231作用24、48、72小时的形态学影响。
本专利涉及到的27个杨梅素含氮类衍生物都对目标肿瘤有良好的抑制活性，阳性药对肿瘤细胞的毒性明显太大(使得细胞全部破碎裂解)，而本实验合成的化合物基本对目标细胞损伤很小，这种抑制活性主要体现在抑制细胞的增殖(细胞数量与对照相比明显变少)，或者诱导细胞分化(从形态学观察得出，细胞在数目减少的同时，细胞发生了变形，但是损伤不是很明显)，所以这些药对目标肿瘤有非常的抑制活性，值得进一步进行深入研究。
具体实施方式
本具体实施实例仅仅是对本发明的解释，但不限制本发明，本领域及时人员在阅读完本说明书后可以根据需要对本实施实例做出没有创造性贡献的修改，但只要在本发明的权利要求范围内的都受到专利法的保护。
实施实例一、3-(3-(二乙基氨-1-基)丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物1)
(1) 3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
在圆底烧瓶中加入杨梅苷2.32 g(5 mmol)溶于60 mL DMF中11.06 g (16 mmol)K2CO3
搅拌10 min后，缓慢的加入10 mL (32 mmol)碘甲烷，室温搅拌60 h，过滤沉淀，并用乙酸乙酯洗涤，合并滤液，将滤液倒入100 mL水中，用乙酸乙酯萃取三次，合并有机相，减压浓缩，然后将浓缩物溶于30 mL的无水乙醇，升温至回流，溶液澄清后，回流下加入8 mL浓盐酸，慢慢的有黄色固体析出，继续反应2 h，冷却，冰箱放置过夜，过滤，得到粗产物A，粗产物A不需要纯化，直接用于下一步的反应。
(2) 3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
在圆底烧瓶中加入上一步的产物A 1.17 g (3 mmol)和1.66 g (12 mmol) K2CO3, 用30 mL的DMF溶解后，加入2.42 g (12 mmol) 1,3 -二溴丙烷，在室温下反应12 h，乙酸乙酯为展开剂点板跟踪反应，停止反应后，用50 mL的水分散，以乙酸乙酯萃取3次，每次25 ml，得到有机相依次用1N的HCl，饱和NaHCO3，饱和NaCl水溶液分别洗涤2次后，合并乙酸乙酯层，用无水硫酸钠干燥后蒸去溶剂，用减压柱层析(石油醚：乙酸乙酯=2:1, V/V)，得到中间体B1。
(3)目标化合物3-(3-(二乙基氨-1-基)丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成：
在圆底烧瓶中加入上一步的产物B1 0.25 g(0.5 mmol)，无水K2CO3 0.14 g(1 mmol)，和25 mLDMF，搅拌10 min后加入0.70 g(1 mmol)二乙胺，在室温下反应24 h，以(氯仿：甲醇=5:1, V/V)为展开剂点板跟踪反应，停止反应后，加入50 mL水分散，用乙酸乙酯萃取三次，每次25 ml，合并有机相1N的HCl，饱和NaHCO3，饱和NaCl水溶液分别洗涤2次后，合并乙酸乙酯层， 用无水硫酸钠干燥后蒸去溶剂，用减压柱层析(氯仿：甲醇=10:1, V/V)，得到目标产物。
实施实例二、5,7-二甲氧基-3-(4-(吡咯烷-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4 -酮(化合物7)
(1) 3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2) 3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(2)条件和方法合成，区别在于加入2.56 g的1,4-二溴丁烷。
(3) 5,7-二甲氧基-3-(4-(吡咯烷-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成：
如实施实例一(3)条件和方法合成，区别在于加入0.68 g的吡咯烷。
利用类似的合成方法，已合成的部分含杂环烷基类杨梅素衍生物的结构如下所示：
实施实例三、5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-
(1) 3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2) 3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例二(2)条件和方法合成。
(3) 5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成：
在圆底烧瓶中加入上一步的产物 1.05 g(2 mmol)，无水K2CO3 1.38 g(10 mmol)，和50 mL DMF，搅拌10 min后加入1.94 g (10 mmol)六水合哌嗪哌嗪，在室温下反应24 h，以(氯仿：甲醇=5:1, V/V)为展开剂点板跟踪反应，停止反应后，加入50 mL水分散，用乙酸乙酯萃取三次，合并有机相1N的HCl，饱和NaHCO3，饱和NaCl水溶液分别洗涤2次后，合并乙酸乙酯层，用无水硫酸钠干燥后蒸去溶剂，用减压柱层析(氯仿：甲醇=15:1, V/V)，得到目标产物。
实施实例四、3-(4-(4-(4-氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物12)
(1) 3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2) 3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
如实施实例二(2)条件和方法合成。
(3) 5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例三(3)条件和方法合成。
(4) 3-(4-(4-(4-氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成：
在圆底烧瓶中，在冰浴条件下，加入对氟苯甲酸0.046 g(0.33 mmoL)以及HATU 0.137 g(0.36 mmoL)，以10 mL的干燥DCM溶解后加入1 mL的三乙胺一起在冰浴下搅拌30 min，然后除去冰浴，加入第三步的产物0.159 g(0.3 mmoL)在室温下反应12 h，TLC跟踪反应至无明显变化(展开剂: 氯仿: 甲醇=5: 1, V/V)，停止反应后，用水洗涤反应液3次，每次20 mL，无水硫酸钠干燥后减压除去DCM，然后减压柱层析分离(氯仿:甲醇=10:1, V/V)，得到目标产物。
实施实例五、3-(4-(4-(4-氯苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物13)
(1) 3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2) 3-氧(4-溴代丁基)-3’, 4’, 5, 5’,7-五甲氧基杨梅素的制备
如实施实例二(2)条件和方法合成。
(3) 5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例三(3)条件和方法合成。
(4) 3-(4-(4-(4-氯苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成：
如实施实例三(4)条件和方法合成，区别在于加入0.052 g的对氯苯甲酸。
利用类似的合成方法，已合成的部分哌嗪酰胺类杨梅素的衍生物的结构如下所示：
实施实例六、2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(2- 氟苄基)乙酰肼(化合物22)
(1) 3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2) 3-氧乙酸乙酯-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在三口瓶中依次加入第一步的产物1.17 g (3 mmol)，无水K2CO3 0.5 g (3.6 mmol)和无水丙酮30 mL，室温搅拌30 min后，滴加溴乙酸乙酯0.4 mL (3.6 mmol)，滴毕，回流反应24 h，冷却至室温，减压浓缩后倒入冰水中，析晶，抽滤，滤饼用氯仿/水重结晶得到目标产物。
(3) 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼的制备
在三口瓶中依次加入第二步的产物 1.42 g (3 mmol)，80%水合肼 0.66 mL (10 mmol)和无水乙醇30 mL，搅拌下回流反应2 h，TCL点板跟踪，直至反应完全，减压除去大量溶剂，冷却，析晶，抽滤，滤饼用无水乙醇重结晶得到目标产物。
(4) 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(2-氟苄基)乙酰肼的合成：
在三口瓶中依次加入第三步的产物 0.15 g (0.33 mmol)，邻氟苯甲醛0.045 g (0.36 mmol)，25 mL无水乙醇及催化量醋酸，搅拌加热回流2 h，TLC点板跟踪，直至反应完全，浓缩反应液，冷却，析晶，抽滤，滤饼用无水乙醇重结晶得到目标产物。
实施实例七、2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(4-甲基亚苄基)乙酰肼(化合物23)
(1) 3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2) 3-氧乙酸乙酯-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
如实施实例六(2)条件和方法合成。
(3) 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼的制备
如实施实例六(3)条件和方法合成。
(4) 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(4-甲基亚苄基)乙酰肼的合成：
如实施实例六(4)条件和方法合成，区别在于加入加入0.044 g的对甲基苯甲醛。
利用类似的合成方法，已合成的部分杨梅素酰腙类衍生物的结构如下所示：
合成的杨梅素含氮类衍生物的波谱数据如下：
3-(3-(二乙基氨-1-基)丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物1)
淡黄色固体，产率：68.5%, m.p.195~197 ℃; IR (KBr, cm-1): ν max 1622, 1600, 1558, 1506, 1417, 1346, 1244, 1213, 1122, 1039, 1001, 831; 1H NMR (500 MHz, CDCl3) δ: 1.32 (t, J= 14.3Hz, 6H, CH3), 2.16-2.19 (m, 2H, CH2 ), 3.28 (q, J= 21.75Hz, 4H, CH2), 3.45 (t, J= 12.6Hz, 2H, CH2), 3.77- 3.83 (m, 17H, 5×OCH3, OCH2), 6.24 (d, J= 1.7 Hz, 1H, H-6), 6.48 (d, J= 2.3 Hz, 1H, H-8), 7.16 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 174.9 (C-4), 165.1 (C-7), 160.7 (C-9), 159.0 (C-2), 154.3 (C-5), 153.2 (C-3’, C-5’), 140.6 (C-4’), 139.3 (C-3), 124.7 (C-1’), 108.2 (C-10), 105.6 (C-6’, C-2’), 96.5 (C-6), 92.9 (C-8), 70.4 (OCH2), 61.0 (4’-OCH3), 56.7 (3’, 5’-2OCH3,), 56.6 (7-OCH3 ), 56.4 (5-OCH3), 51.8 (CH2), 47.4 (2CH2), 22.4 (CH2), 9.0 (2CH3); MS (ESI, m/z): 502.3 [M+ H]+.
5,7-二甲氧基-3-(3-(吡咯烷-1-基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物2)
淡黄色固体，产率：55.6%, m.p. 207~209℃; IR (KBr, cm-1): ν max 1624, 1598, 1558, 1506, 1411, 1348, 1211, 1122, 1014, 854, 829; 1H NMR (500 MHz, CDCl3) δ: 2.09 (m, 4H, CH2), 2.13-2.16 (m, 2H, CH2 ), 3.47 (m, 4H, CH2), 3.57 (t, J= 12.6 Hz, 2H, CH2), 3.82- 3.85 (m, 17H, 5×OCH3, OCH2), 6.29 (d, J= 1.7 Hz, 1H, H-6), 6.50 (d, J= 2.3 Hz, 1H, H-8), 7.20 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 175.1 (C-4), 165.0 (C-7), 160.7 (C-9), 159.0 (C-2), 154.2 (C-5), 153.3 (C-3’, C-5’), 140.6 (C-4’), 139.5 (C-3), 124.8 (C-1’), 108.3 (C-10), 105.6 (C-6’, C-2’), 96.6 (C-6), 92.9 (C-8), 70.6 (OCH2), 61.0 (4’-OCH3), 56.7 (3’, 5, 7- 3OCH3,), 56.3 (5-OCH3), 54.3 (2CH2), 54.1 (CH2), 26.4 (CH2), 23.4 (2CH2); MS (ESI, m/z): 500.3 [M+ H]+.
5,7-二甲氧基-3-(3-(哌啶-1-基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物3)
淡黄色固体，产率：67.4%, m.p. 166~168℃; IR (KBr, cm-1): ν max 1625, 1597, 1558, 1506, 1417, 1354, 1209, 1126, 1016, 852, 815; 1H NMR (500 MHz, CDCl3) δ: 1.66 (brm, 2H, CH2), 1.89-1.91 (m, 4H, CH2), 2.21 (m, J= 10.9 Hz, 2H, CH2), 3.38 (brm, 4H, CH2), 3.49 (t, J= 12.6 Hz, 2H, CH2), 3.87- 3.93 (m, 17H, 5×OCH3, OCH2), 6.34 (d, J= 1.7 Hz, 1H, H-6), 6.55 (d, J = 1.7 Hz, 1H, H-8), 7.26 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 175.0 (C-4), 165.2 (C-7), 160.9 (C-9), 159.1 (C-2), 154.4 (C-5), 153.4 (C-3’, C-5’), 140.8 (C-4’), 139.5 (C-3), 124.9 (C-1’), 108.3 (C-10), 105.7 (C-6’, C-2’), 96.6 (C-6), 92.9 (C-8), 71.0 (OCH2), 61.1 (4’-OCH3), 56.7 (7-OCH3), 56.6 (3’, 5’-2OCH3), 56.4 (5-OCH3), 53.37 (2CH2), 53.6 (CH2), 24.6 (CH2), 23.4 (2CH2), 22.0 (CH2); MS (ESI, m/z): 514.3 [M+ H]+.
5,7-二甲氧基-3-(3-(吗啉-1-基)-丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物4)
淡黄色固体，产率：72.8%, m.p. 172~174℃; IR (KBr, cm-1): ν max 1635, 1600, 1558, 1506, 1411, 1350, 1242, 1211, 1122, 1008, 858, 825; 1H NMR (500 MHz, CDCl3) δ: 1.80-1.86 (m, 2H, CH2), 2.29 (brs, 4H, CH2 ), 2.38 (t, J= 14.9 Hz, 2H, CH2), 3.59 (t, J= 9.15 Hz, 4H, CH2), 3.84-3.88 (m, 15H, 5×OCH3), 4.01 (t, J= 12.5Hz, 2H, OCH2), 6.26 (d, J= 2.3 Hz, 1H, H-6), 6.50 (d, J= 1.9 Hz, 1H, H-8), 7.27 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 174.0 (C-4), 164.0 (C-7), 161.0 (C-9), 158.7 (C-2), 152.9 (C-5), 152.5 (C-3’, C-5’), 140.6 (C-4’), 139.8 (C-3), 126.1 (C-1’), 109.4 (C-10), 105.9 (C-6’, C-2’), 95.8 (C-6), 92.4 (C-8), 70.8 (OCH2), 66.9 (2CH2), 61.0 (4’-OCH3), 56.3 (CH2), 56.4 (3’, 5’-2OCH3), 55.8 (7-OCH3), 55.8 (5-OCH3), 53.7 (2CH2), 27.5 (CH2); MS (ESI, m/z): 516.3 [M+ H]+.
5,7-二甲氧基-3-(3-(4-甲基哌嗪-1-基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物5)
淡黄色固体，产率：64.3%, m.p.150~152℃; IR (KBr, cm-1): ν max 1627, 1600, 1558, 1506, 1417, 1348, 1213, 1126, 1012, 854, 817; 1H NMR (500 MHz, CDCl3) δ: 1.94-1.98 (m, 2H, CH2), 2.35 (s, 3H, CH3 ), 2.67-2.71 (m, 10H, CH2), 3.86-3.90 (m, 15H, 5×OCH3), 3.99 (t, J= 12.05 Hz, 2H, OCH2), 6.30 (d, J= 2.3 Hz, 1H, H-6), 6.50 (d, J= 2.3 Hz, 1H, H-8), 7.27 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 174.0 (C-4), 164.1 (C-7), 161.0 (C-9), 158.8 (C-2), 153.0 (C-5), 152.9 (C-3’, C-5’), 140.3 (C-4’), 140.0 (C-3), 125.9 (C-1’), 109.3 (C-10), 105.9 (C-6’, C-2’), 95.9 (C-6), 92.5 (C-8), 70.4 (OCH2), 61.0 (4’-OCH3), 56.4 (3’, 5’,7-3OCH3), 55.9 (5-OCH3), 55.1 (CH2), 53.8 (2CH2), 52.0 (CH2), 45.2 (CH3), 27.0 (CH2); MS (ESI, m/z): 529.3 [M+ H]+.
3-(4-(二乙氨基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物6)
淡黄色固体，产率：74.8%, m.p.93~95℃; IR (KBr, cm-1): ν max 1627, 1602, 1558, 1506, 1417, 1350, 1249, 1213, 1130, 1018, 856, 813; 1H NMR (500 MHz, CDCl3) δ: 0.96 (t, J= 14.3Hz, 6H, CH3), 1.49-1.55 (m, 2H, CH2 ), 1.66-1.71 (m, 2H, CH2) , 2.43 (t, J= 15.45 Hz, 2H, CH2), 2.48 (q, J= 21.8 Hz, 4H, CH2), 3.85-3.90 (m, 15H, 5×OCH3), 3.99 (t, J= 13.15 Hz, 2H, OCH2 ), 6.28 (d, J= 2.3 Hz, 1H, H-6), 6.44 (d, J= 2.3 Hz, 1H, H-8), 7.32 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 164.0 (C-7), 161.0 (C-9), 158.8(C-2), 152.9 (C-5), 152.5 (C-3’, C-5’), 140.7 (C-4’), 139.8 (C-3), 126.1 (C-1’), 109.4 (C-10), 105.9 (C-6’, C-2’), 95.8 (C-6), 92.4 (C-8), 72.4 (OCH2), 61.0 (4’-OCH3), 56.4 (3’, 5’-2OCH3,), 56.3 (7-OCH3 ), 55.8 (5-OCH3), 52.4 (CH2), 46.7 (3CH2), 28.4 (CH2), 22.9 (CH2), 11.3 (2CH3); MS (ESI, m/z): 516.4 [M+ H]+.
5,7-二甲氧基-3-(4-(吡咯烷-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物7)
淡黄色固体，产率：59.1%, m.p.111~113℃; IR (KBr, cm-1): ν max 1635, 1602, 1558, 1506, 1417, 1350, 1246, 1211, 1126, 999, 852, 819; 1H NMR (500 MHz, CDCl3) δ: 1.70-1.73 (m, 2H, CH2), 1.77 (m, 2H, CH2 ), 1.84 (m, 4H, CH2), 2.75 (m, 6H, CH2), 3.83-3.88 (m, 15H, 5×OCH3), 3.92 (t, J= 11.05 Hz, 2H, OCH2), 6.29 (d, J= 2.3 Hz, 1H, H-6), 6.50 (d, J= 2.3 Hz, 1H, H-8), 7.27 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 164.1 (C-7), 160.9 (C-9), (158.8C-2), 153.0 (C-5), 152.7 (C-3’, C-5’), 140.5 (C-4’), 139.9 (C-3), 126.0 (C-1’), 109.3 (C-10), 105.7 (C-6’, C-2’), 95.9 (C-6), 92.5 (C-8), 71.6 (OCH2), 61.0 (4’-OCH3), 56.4 (7- OCH3), 56.3 (3’, 5-2OCH3), 55.9 (5-OCH3), 55.6 (CH2), 53.8 (2CH2), 27.9 (CH2), 24.2 (CH2), 23.3 (2CH2); MS (ESI, m/z): 514.3 [M+ H]+.
5,7-二甲氧基-3-(4-(哌啶-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物8)
淡黄色固体，产率：82.1%, m.p.71~73℃; IR (KBr, cm-1): ν max 1625, 1602, 1558, 1506, 1417, 1350, 1244, 1213, 1128, 1016, 850, 813; 1H NMR (500 MHz, CDCl3) δ: 1.33 (brm, 2H, CH2), 1.48-1.57(m, 6H, CH2 ), 1.61-1.66 (m, 2H, CH2), 2.26-2.29 (m, 6H, CH2), 3.81- 3.84 (m, 15H, 5×OCH3), 3.94 (t, J= 12.6 Hz, 2H, OCH2), 6.23 (d, J= 2.3 Hz, 1H, H-6), 6.39 (d, J= 2.3 Hz, 1H, H-8), 7.27 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 174.0 (C-4), 163.9 (C-7), 160.9 (C-9), 158.7 (C-2), 152.9 (C-5), 152.4 (C-3’, C-5’), 140.6 (C-4’), 139.8 (C-3), 126.1 (C-1’), 109.3 (C-10), 105.8 (C-6’, C-2’), 95.8 (C-6), 92.4 (C-8), 72.3 (OCH2), 61.0 (4’-OCH3), 58.9 (CH2), 56.3 (7-OCH3), 56.3 (3’, 5’-2OCH3), 55.8 (5-OCH3), 54.3 (CH2), 28.5 (CH2), 25.5 (2CH2), 24.2 (CH2), 23.0 (CH2); MS (ESI, m/z): 528.4 [M+ H]+.
5,7-二甲氧基-3-(4-吗啉-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物9)
淡黄色固体，产率：77.4%, m.p.109~111℃; IR (KBr, cm-1): ν max 1635, 1600, 1558, 1506, 1417, 1348, 1244, 1213, 1134, 1114, 1016, 850, 812; 1H NMR (500 MHz, CDCl3) δ: 1.50-1.56 (m, 2H, CH2), 1.66-1.71 (m, 2H, CH2 ), 2.26 (t, J= 14.9 Hz, 2H, CH2), 2.3 (brs, 4H, CH2), 3.61 (t, J= 9.15 Hz, 4H, CH2), 3.84-3.88 (m, 15H, 5×OCH3), 3.98 (t, J= 13.15 Hz, 2H, OCH2), 6.26 (d, J= 1.7 Hz, 1H, H-6), 6.50 (d, J= 1.7 Hz, 1H, H-8), 7.30 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 174.0 (C-4), 164.0 (C-7), 161.0 (C-9), 158.7 (C-2), 152.9 (C-3’, C-5’), 152.4 (C-5), 140.7 (C-4’), 139.8 (C-3), 126.1 (C-1’), 109.4 (C-10), 105.9 (C-6’, C-2’), 95.8 (C-6), 92.4 (C-8), 72.3 (OCH2), 66.9 (2CH2), 61.0 (4’-OCH3), 58.6 (CH2), 56.4 (3’, 5’-2OCH3), 56.3 (7-OCH3), 55.8 (5-OCH3), 53.6 (2CH2), 28.2 (CH2), 22.9 (CH2); MS (ESI, m/z): 530.3 [M+ H]+.
5,7-二甲氧基-3-(4-(4-甲基哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物10)
淡黄色固体，产率：76.7%, m.p.82~84℃; IR (KBr, cm-1): ν max 1627, 1602, 1558, 1506, 1417, 1350, 1244, 1211, 1128, 1014, 852, 815; 1H NMR (500 MHz, CDCl3) δ: 1.44-1.50 (m, 2H, CH2), 1.56-1.61 (m, 2H, CH2), 2.17 (s, 3H, CH3 ), 2.26 (t, J=14.9 Hz, 2H, CH2), 2.41 (brm, 6H, CH2), 3.74-3.78 (m, 15H, 5×OCH3), 3.87 (t, J= 13.15 Hz, 2H, OCH2), 6.15 (d, J= 2.3 Hz, 1H, H-6), 6.32 (d, J= 2.3 Hz, 1H, H-8), 7.19 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 173.9 (C-4), 163.9 (C-7), 160.8 (C-9), 158.6 (C-2), 152.8 (C-3’, C-5’), 152.3 (C-5), 140.5 (C-4’), 139.7 (C-3), 126.0 (C-1’), 109.2 (C-10), 105.7 (C-6’, C-2’), 95.7 (C-6), 92.3 (C-8), 72.0 (OCH2), 60.9 (4’-OCH3), 57.7 (CH2), 56.2 (3’, 5’, 7-3OCH3), 55.8 (5-OCH3), 54.2 (2CH2), 52.2 (2CH2), 45.3 (CH3), 28.1 (CH2), 22.9 (CH2); MS (ESI, m/z): 543.4 [M+ H]+.
5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物11)
淡黄色固体，产率：64.2%, m.p.107~109 ℃; IR (KBr, cm-1): ν max 1627, 1602, 1558, 1506, 1417, 1350, 1244, 1211, 1128, 1014, 852, 815; 1H NMR (500 MHz, CDCl3) δ: 1.56-1.59 (m, 2H, CH2), 1.71-1.74 (m, 2H, CH2), 1.87 (brs, 4H, H in piperazine), 2.31 (t, J= 15.45 Hz, 2H, CH2), 2.36 (brm, 1H, H in piperazine), 2.87 (t, J= 9.75 Hz, 4H, H in piperazine), 3.92-3.95 (m, 15H, 5×OCH3), 4.03 (t, J= 13.15 Hz, 2H, OCH2), 6.34 (d, J= 2.3 Hz, 1H, H-6), 6.48 (d, J= 2.3 Hz, 1H, H-8), 7.35 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 164.0 (C-7), 161.1 (C-9), 158.8 (C-2), 153.0 (C-3’, C-5’), 152.5 (C-5), 140.8 (C-4’), 139.8 (C-3), 126.2 (C-1’), 109.5 (C-10), 105.9 (C-6’, C-2’), 95.8 (C-6), 92.4 (C-8), 72.4 (OCH2), 61.1 (4’-OCH3), 58.9 (CH2), 56.5 (7-OCH3), 56.4 (3’, 5’-2OCH3), 55.9 (5-OCH3), 54.3 (2CH2), 45.9 (2CH2), 28.4 (CH2), 23.1 (CH2); MS (ESI, m/z): 529.4 [M+ H]+.
3-(4-(4-(4-氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物12)
淡黄色固体，产率：60.5%, m.p.124~126 ℃; IR (KBr, cm-1): ν max 1627, 1602, 1558, 1506, 1417, 1350, 1244, 1211, 1126, 1016, 852, 819; 1H NMR (500 MHz, CDCl3) δ: 1.53-1.59 (m, 2H, CH2), 1.67-1.72 (m, 2H, CH2), 2.29-2.41 (m, 6H, CH2), 3.3 (brm, 2H, H in piperazine), 3.69 (brm, 2H, H in piperazine), 3.69-3.90 (m, 15H, 5×OCH3), 3.99 (t, J= 12.6 Hz, 2H, OCH2), 6.29 (d, J= 2.3 Hz, 1H, H-6), 6.44 (d, J= 2.3 Hz, 1H, H-8), 7.04 (t, J= 17.15 Hz, 2H, CH), 7.30 (overlapping s, 2H, H-2’, H-6’), 7.35 (t, J= 14.3Hz, 2H); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 169.3 (C=O), 164.0 (C-7), 161.0 (C-9), 158.8 (C-2), 152.9 (C-3’, C-5’), 152.5 (C-5), 140.7 (C-4’), 139.9 (C-3), 131.8 (C), 129.4(CH), 129.4 (CH), 126.2 (C-1’), 115.6 (CH), 115.4 (CH), 109.4 (C-10), 105.9 (C-6’, C-2’), 95.8 (C-6), 92.4 (C-8), 72.2 (OCH2), 61.0 (4’-OCH3), 58.0 (CH2), 56.4 (7-OCH3), 56.3 (3’, 5’-2OCH3), 55.8 (5-OCH3), 53.3 (CH2), 52.8 (CH2), 47.7 (CH2), 42.3 (CH2), 28.2 (CH2), 23.2 (CH2); MS (ESI, m/z):651.5 [M+ H]+, 673.4 [M+ Na]+.
3-(4-(4-(4-氯苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物13)
淡黄色固体：产率：64.3%, m.p.102~104℃; IR (KBr, cm-1): ν max 1633, 1600, 1558, 1506, 1417, 1348, 1244, 1213, 1126, 1109, 1008, 862, 819; 1H NMR (500 MHz, CDCl3) δ: 1.58-1.62 (m, 2H, CH2), 1.69-1.75 (m, 2H, CH2), 2.30 (brm, 2H, CH2), 2.34 (t, J= 14.35 Hz, 2H, CH2), 2.45 (brm, 2H, CH2), 3.36 (brm, 2H, H in piperazine), 3.72 (brm, 2H, H in piperazine), 3.88-3.94 (m, 15H, 5×OCH3), 4.02 (t, J= 12.6 Hz, 2H, OCH2), 6.33 (d, J= 2.3 Hz, 1H, H-6), 6.47 (d, J= 2.3 Hz, 1H, H-8), 7.31-7.37 (m, 6H, 2H, H-2’, H-6’, PhH); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 169.2 (C=O), 164.0 (C-7), 161.1 (C-9), 158.8 (C-2), 153.0 (C-3’, C-5’), 152.6 (C-5), 140.7 (C-4’), 139.9 (C-3), 135.7 (C), 134.2 (C), 128.8 (2CH), 128.7 (2CH),126.2 (C-1’), 115.6 (CH), 115.4 (CH), 109.4 (C-10), 106.0 (C-6’, C-2’), 95.8 (C-6), 92.5 (C-8), 72.2 (OCH2), 61.0 (4’-OCH3), 58.0 (CH2), 56.5 (7-OCH3), 56.4 (3’, 5’-2OCH3), 55.9 (5-OCH3), 53.4 (CH2), 52.8 (CH2), 47.7 (CH2), 42.3 (CH2), 28.2 (CH2), 23.2 (CH2); MS (ESI, m/z): 667.5 [M+ H]+, 689.4 [M+ Na]+.
5,7-二甲氧基-3-(4-(4-(4-硝基苯甲酰基)哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物14)
淡黄色固体：产率：58.7%, m.p.149~151℃; IR (KBr, cm-1): ν max 1627, 1598, 1558, 1506, 1417, 1348, 1246, 1213, 1128, 1109, 1016, 852, 819; 1H NMR (500 MHz, CDCl3) δ: 1.55-1.61 (m, 2H, CH2), 1.68-1.72 (m, 2H, CH2), 2.29 (brm, 2H, H in piperazine), 2.34 (t, J=14.85 Hz, 2H, CH2), 2.46 (brm, 2H, H in piperazine), 3.30 (brm, 2H, H in piperazine), 3.74 (brm, 2H, H in piperazine), 3.88-3.93 (m, 15H, 5×OCH3), 4.00 (t, J= 12.6 Hz, 2H, OCH2), 6.32 (d, J= 2.3 Hz, 1H, H-6), 6.47 (d, J= 2.3 Hz, 1H, H-8), 7.32 (overlapping s, 2H, H-2’, H-6’), 7.53 (d, J= 9.15 Hz, 2H, CH), 8.24 (d, J= 9.2 Hz, 2H, CH); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 167.9 (C=O), 164.0 (C-7), 161.0 (C-9), 158.8 (C-2), 153.0 (C-3’, C-5’), 152.6 (C-5), 148.3 (C), 142.1 (C), 140.7 (C-4’), 139.9 (C-3), 128.1 (2CH), 126.1 (C-1’), 123.9 (2CH), 109.4 (C-10), 105.9 (C-6’, C-2’), 95.9 (C-6), 92.5 (C-8), 72.2 (OCH2), 61.0(4’-OCH3), 58.0 (CH2), 56.5 (7-OCH3), 56.4 (3’, 5’-2OCH3), 55.9 (5-OCH3), 53.2 (CH2), 52.7 (CH2), 47.7 (CH2), 42.2 (CH2), 28.2 (CH2), 23.2 (CH2); MS (ESI, m/z): 678.5 [M+ H]+, 700.4 [M+ Na]+.
5,7-二甲氧基-3-(4-(4-(4-(三氟甲基)苯甲酰基)哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物15)
淡黄色固体，产率：65.7%, mp: 90~92℃; IR (KBr, cm-1): ν max 1625, 1602, 1558, 1506, 1417, 1350, 1243, 1211, 1128, 1016, 852, 817; 1H NMR (500 MHz, CDCl3) δ: 1.54-1.60 (m, 2H, CH2), 1.68-1.72 (m, 2H, CH2), 2.26 (m, 2H, H in piperazine), 2.32 (t, J= 14.85 Hz, 2H, CH2), 2.41-2.46 (m, 2H, H in piperazine), 3.11 (t, J= 9.7 Hz, 2H, H in piperazine), 3.75 (brm, 2H, H in piperazine), 3.88-3.93 (m, 15H, 5×OCH3), 4.00 (t, J=12.6 Hz, 2H, OCH2), 6.32 (d, J= 2.3 Hz, 1H, H-6), 6.46 (d, J= 2.3 Hz, 1H, H-8), 7.28-7.30 (d, J= 8.05 Hz, 1H, PhH), 7.32 (overlapping s, 2H, H-2’, H-6’), 7.48 (t, J= 15.45 Hz, 1H, PhH), 7.56 (t, J= 14.90 Hz, 1H, PhH),7.65-7.67 (d, J= 8.05 Hz, 1H, PhH); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 167.3 (C=O), 164.0 (C-7), 161.0 (C-9), 158.8 (C-2), 153.0 (C-3’, C-5’), 152.6 (C-5), 140.7 (C-4’), 139.9 (C-3), 134.9 (C), 132.2 (CH), 129.1(CH), 127.3 (CH), 126.7 (CH), 126.7 (C), 124.7 (C), 126.1 (C-1’), 109.4 (C-10), 105.9 (C-6’, C-2’), 95.9 (C-6), 92.5 (C-8), 72.2 (OCH2), 61.0 (4’-OCH3), 58.0 (CH2), 56.5 (7-OCH3), 56.4 (3’, 5’-2OCH3), 55.9 (5-OCH3), 52.7 (CH2), 52.6 (CH2), 47.1 (CH2), 41.7 (CH2), 28.2 (CH2), 23.2 (CH2); MS (ESI, m/z): 701.5 [M+ H]+, 723.4 [M+ Na]+.
3-(4-(4-(2-氯-6-氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物16)
淡黄色固体，产率：48.7%, m.p.105~107℃; IR (KBr, cm-1): ν max 1625, 1600, 1558, 1506, 1417, 1350, 1246, 1211, 1130, 1014, 852, 815; 1H NMR (500 MHz, CDCl3) δ: 1.56-1.60 (m, 2H, CH2), 1.68-1.72 (m, 2H, CH2), 2.31-2.34 (m, 4H, H in piperazine), 2.45 (t, J= 10.3 Hz, 2H, CH2), 3.21 (brm, 2H, H in piperazine), 3.78 (brm, 2H, H in piperazine), 3.88-3.92 (m, 15H, 5×OCH3), 3.99 (t, J= 13.15 Hz, 2H, OCH2), 6.31 (d, J= 1.7 Hz, 1H, H-6), 6.46 (d, J= 2.3 Hz, 1H, H-8), 7.01 (t, J= 16.6 Hz, 1H, PhH), 7.18 (d, J= 8.05 Hz, 1H, PhH), 7.24-7.29 (m, 1H, PhH),7.29 (overlapping s, 2H, H-2’, H-6’); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 164.0 (C-7), 161.8 (C), 161.0 (C-9), 159.7 (C), 158.8 (C-2), 157.7 (C), 153.0 (C-3’, C-5’), 152.6 (C-5), 140.7 (C-4’), 139.9 (C-3), 131.9 (CH), 130.8 (CH), 126.1 (C-1’), 124.5 (CH), 114.5 (CH), 109.4 (C-10), 105.9 (C-6’, C-2’), 95.9 (C-6), 92.5 (C-8), 72.2 (OCH2), 61.0 (4’-OCH3), 58.0 (CH2), 56.4 (7-OCH3), 56.4 (3’, 5’-2OCH3), 55.9 (5-OCH3), 53.2 (CH2), 52.6 (CH2), 46.5 (CH2), 41.7 (CH2), 28.2 (CH2), 23.2 (CH2); MS (ESI, m/z): 685.5 [M+ H]+, 707.4 [M+ Na]+.
3-(4-(4-(2,4-二氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物17)
淡黄色固体：产率：46.6%, m.p.89~91℃; IR (KBr, cm-1): ν max 1625, 1600, 1558, 1506, 1417, 1350, 1244, 1211, 1128, 1016, 852, 821; 1H NMR (500 MHz, CDCl3) δ: 1.63 (brm, 2H, CH2), 1.71-1.76 (m, 2H, CH2), 2.38 (m, 4H, H in piperazine), 2.49 (m, 2H, CH), 3.31 (brm, 2H, H in piperazine), 3.78 (brm, 2H, H in piperazine), 3.89-3.94 (m, 15H, 5×OCH3), 4.01 (t, J= 12.6 Hz, 2H, OCH2), 6.34 (d, J= 2.3 Hz, 1H, H-6), 6.48 (d, J= 2.3 Hz, 1H, H-8), 6.83 (t, J= 18.3 Hz, 1H, PhH), 6.93 (t, J= 16.05 Hz, 1H, PhH), 7.33 (overlapping s, 2H, H-2’, H-6’), 7.38 (q, J = 22.3 Hz, 1H, PhH); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 164.4 (C=O), 164.0 (C-7), 161.1 (C-9), 158.8 (C-2), 153.0 (C-3’, C-5’), 152.6 (C-5), 140.7 (C-4’), 140.0 (C-3), 130.6 (CH), 126.1 (C-1’), 112.3 (C), 112.1(C), 109.4 (C-10), 106.0 (C-6’, C-2’), 104.4 (CH), 104.4 (CH), 104.2 (CH), 95.9 (C-6), 92.5 (C-8), 72.2 (OCH2), 61.0 (4’-OCH3), 58.0 (CH2), 56.4 (7-OCH3), 56.4 (3’, 5’-2OCH3), 55.9 (5-OCH3), 53.2 (CH2), 52.6 (CH2), 46.5 (CH2), 41.7 (CH2), 28.2 (CH2), 23.2 (CH2); MS (ESI, m/z): 669.5 [M+ H]+, 691.4 [M+ Na]+.
3-(4-(4-(5-氯-2-硝基苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物18)
淡黄色固体：产率：48.5%, m.p.94~96 ℃; IR (KBr, cm-1): ν max 1627, 1600, 1558, 1506, 1411, 1344, 1246, 1211, 1163, 1130, 1016, 854, 815; 1H NMR (500 MHz, CDCl3) δ: 1.56-1.61 (m, 2H, CH2), 1.68-1.72 (m, 2H, CH2), 2.27 (brm, 2H, H in piperazine), 2.35 (t, J= 14.35 Hz, 2H, CH2), 2.54 (brm, 2H, H in piperazine), 3.17 (m, 2H, H in piperazine), 3.73 (m, 2H, H in piperazine), 3.89-3.94 (m, 15H, 5×OCH3), 4.01 (t, J= 13.1 Hz, 2H, OCH2), 6.33 (d, J= 2.3 Hz, 1H, H-6), 6.47 (d, J= 2.3 Hz, 1H, H-8), 7.33 (overlapping s, 2H, H-2’, H-6’), 7.34 (d, J= 2.3 Hz, 1H, PhH), 7.50 (dd, J= 2.3, 2.25 Hz, 1H, PhH), 8.14 (d, J= 8.6 Hz, 1H, PhH); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 164.8 (C=O), 164.0 (C-7), 161.1 (C-9), 158.8 (C-2), 153.0 (C-3’, C-5’), 152.6 (C-5), 143.6 (C), 141.3 (C), 140.7 (C-4’), 139.9 (C-3), 134.5 (CH), 129.9 (CH),128.2 (C), 126.3 (CH), 126.1 (C-1’), 109.4 (C-10), 106.0 (C-6’, C-2’), 95.9 (C-6), 92.5 (C-8), 72.2 (OCH2), 61.0 (4’-OCH3), 58.0 (CH2), 56.4 (7-OCH3), 56.4 (3’, 5’-2OCH3), 55.9 (5-OCH3), 52.6 (CH2), 52.2 (CH2), 46.9 (CH2), 41.9 (CH2), 28.2 (CH2), 23.2 (CH2); MS (ESI, m/z): 712.5 [M+ H]+, 734.4 [M+ Na]+.
3-(4-(4-(3,5-二硝基苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物19)
黄色固体, 产率：82%, m.p. 123~125℃; IR (KBr, cm-1): ν max 1627, 1602, 1558, 1506, 1417, 1348, 1246, 1211, 1128, 1109, 1016, 852, 819; 1H NMR (500 MHz, CDCl3) δ: 1.58-1.62 (m, 2H, CH2), 1.69-1.74 (m, 2H, CH2), 2.32 (brm, 2H, H in piperazine), 2.36 (t, J= 14.85 Hz, 2H, CH2), 2.50 (brm, 2H, H in piperazine ), 3.36 (brm, 2H, H in piperazine), 3.77 (m, 2H, H in piperazine), 3.86-3.92 (m, 15H, 5×OCH3), 4.02 (t, J= 12.6 Hz, 2H, OCH2), 6.33 (d, J= 1.7 Hz, 1H, H-6), 6.47 (d, J= 2.3 Hz, 1H, H-8), 7.31 (overlapping s, 2H, H-2’, H-6’), 8.56 (d, J= 2.3 Hz, 2H, PhH), 9.06 (t, J= 4 Hz, 1H, PhH); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 165.1 (C=O), 164.0 (C-7), 161.1 (C-9), 158.8 (C-2), 153.0 (C-3’, C-5’), 152.6 (C-5), 148.5 (2C), 140.7 (C-4’), 139.9 (C-3), 139.3 (2CH),127.5 (CH), 126.2 (C-1’), 119.6 (C), 109.4 (C-10), 106.0 (C-6’, C-2’), 95.9 (C-6), 92.5 (C-8), 72.1 (OCH2), 61.0 (4’-OCH3), 57.9 (CH2), 56.5 (7-OCH3), 56.4 (3’, 5’-2OCH3), 55.9 (5-OCH3), 53.0 (CH2), 52.6 (CH2), 46.9 (CH2), 42.7 (CH2), 28.1 (CH2), 23.2 (CH2); MS (ESI, m/z): 723.5 [M+ H]+, 745.4 [M+ Na]+.
3-(4-(4-苯甲酰基-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物20)
黄色固体，产率：68.4%, m.p.76~78℃; IR (KBr, cm-1): ν max 1627, 1602, 1558, 1506, 1417, 1348, 1242, 1211, 1128, 1008, 852, 819; 1H NMR (500 MHz, CDCl3) δ: 1.67-1.73 (m, 4H, CH2), 2.47-2.55 (m, 6H, CH2), 3.45 (brm, 2H, H in piperazine), 3.80 (brm, 2H, H in piperazine), 3.88-3.93 (m, 15H, 5×OCH3), 3.99 (t, J= 12.06 Hz, 2H, OCH2), 6.33 (d, J= 1.7 Hz, 1H, H-6), 6.47 (d, J= 2.3 Hz, 1H, H-8), 7.32 (overlapping s, 2H, H-2’, H-6’), 7.37 (s, 5H, PhH); 13C NMR (125 MHz, CDCl3) δ: 174.1 (C-4), 170.3 (C=O), 164.1 (C-7), 161.1 (C-9), 158.8 (C-2), 153.0 (C-3’, C-5’), 152.6 (C-5), 140.7 (C-4’), 140.0 (C-3), 135.6 (C), 129.8 (CH), 128.5 (2CH), 127.1 (2CH), 126.1 (C-1’), 109.4 (C-10), 105.9 (C-6’, C-2’), 95.9 (C-6), 92.5 (C-8), 72.0 (OCH2), 61.0 (4’-OCH3), 58.0 (CH2), 56.5 (7-OCH3), 56.4 (3’, 5’-2OCH3), 55.9 (5-OCH3), 53.2 (CH2), 52.7 (CH2), 47.2 (CH2), 41.7 (CH2), 28.1 (CH2), 22.9 (CH2); MS (ESI, m/z): 633.5 [M+ H]+, 655.4 [M+ Na]+.
3-(4-(4-异烟酰基-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物21)
黄色固体，产率：65.5%, m.p. 81~83℃; IR (KBr, cm-1): ν max 1653, 1653, 1558, 1506, 1417, 1350, 1246, 1213, 1128, 1016, 819; 1H NMR (500 MHz, CDCl3) δ: 1.49-1.54 (m, 2H, CH2), 1.62-1.66 (m, 2H, CH2), 2.22 (brm, 2H, H in piperazine), 2.26 (t, J= 14.9 Hz, 2H, CH2), 2.38 (brm, 2H, H in piperazine), 3.23 (brm, 2H, H in piperazine), 3.65 (brm, 2H, H in piperazine), 3.79-3.83 (m, 15H, 5×OCH3), 3.92 (t, J= 12.6 Hz, 2H, OCH2), 6.23 (d, J= 2.3 Hz, 1H, H-6), 6.39 (d, J= 2.3 Hz, 1H, H-8), 7.18 (d, J= 5.7 Hz, 2H, CH),7.24 (overlapping s, 2H, H-2’, H-6’), 8.57 (d, J= 5.7 Hz, 2H, CH); 13C NMR (125 MHz, CDCl3) δ: 174.0 (C-4), 167.5 (C=O), 164.0 (C-7), 160.9 (C-9), 158.7 (C-2), 152.9 (C-3’, C-5’), 152.5 (C-5), 150.2 (2CH), 143.5 (CH), 140.6 (C-4’), 139.8 (C-3), 126.0 (C-1’), 121.3 (2CH), 109.3 (C-10), 105.8 (C-6’, C-2’), 95.8 (C-6), 92.5 (C-8), 72.1 (OCH2), 60.9 (4’-OCH3), 57.9 (CH2), 56.4 (7-OCH3), 56.3 (3’, 5’-2OCH3), 55.9 (5-OCH3), 53.1 (CH2), 52.6 (CH2), 47.4 (CH2), 41.9 (CH2), 28.1 (CH2), 23.1 (CH2); MS (ESI, m/z): 634.5 [M+ H]+, 656.4 [M+ Na]+.
2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(2-氟苄基)乙酰肼(化合物22)
黄色固体，产率：78.4%, m.p. 136~138 ℃; IR (KBr, cm-1): ν max 1699, 1683, 1620, 1604, 1558, 1417, 1361, 1246, 1207, 1124, 1109, 1012, 819; 1H NMR (500 MHz, CDCl3) δ: 3.92-3.99 (m, 15H, 5×OCH3), 4.35 (s, 2H, CH2), 6.40 (d, J= 2.3 Hz, 1H, H-6), 6.54 (d, J= 2.3 Hz, 1H, H-8), 7.07 (J= 18.9 Hz, 1H), 7.16 (t, J= 14.9 Hz, 1H), 7.22 (overlapping s, 2H, H-2’, H-6’), 7.35 (q, J= 20.6 Hz, 1H), 8.15 (t, J= 13.7 Hz, 1H), 9.65 (s, 1H, NH ), 12.35 (s, 1H, N=CH); 13C NMR (125 MHz, CDCl3) δ: 174.7 (C-4), 165.6 (C=O), 164.7 (C-7), 161.1 (C-9), 160.6 (C), 159.1 (C-2), 154.2 (C-5), 153.6 (C-3’, C-5’), 142.6 (CH), 141.3 (C-4’), 140.8 (C-3), 132.0 (CH), 127.6 (CH), 124.8 (C-1’), 124.4 (CH), 121.8 (C), 115.7 (CH), 108.8 (C-10), 105.7 (C-6’, C-2’), 96.5 (C-6), 92.7 (C-8), 73.2 (OCH2), 61.2 (4’-OCH3), 56.6 (7-OCH3), 56.5 (3’, 5’ -OCH3), 56.0 (8-OCH3) ; MS (ESI, m/z): 567.3 [M+ H]+, 589.2 [M+ Na]+.
2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(4-甲基亚苄基)乙酰肼(化合物23)
灰白色固体，产率：82.3%, m.p. 152~154℃; IR (KBr, cm-1): ν max 1699, 1683, 1620, 1604, 1558, 1506, 1417, 1354, 1247, 1219, 1124, 1109, 1011, 819; 1H NMR (500 MHz, CDCl3) δ: 2.36 (s, 3H, CH3), 3.92-3.99 (m, 15H, 5×OCH3), 4.35 (s, 2H, CH2), 6.40 (d, J= 2.3 Hz, 1H, H-6), 6.54 (d, J= 2.3 Hz, 1H, H-8), 7.19 (d, J= 8 Hz, 2H, 2CH), 7.21 (overlapping s, 2H, H-2’, H-6’), 7.71 (d, J= 8 Hz, 2H, CH), 8.35 (s, 1H, NH ), 12.10 (s, 1H, N=CH); 13C NMR (125 MHz, CDCl3) δ: 174.7 (C-4), 165.2 (C=O), 164.9 (C-7), 161.1 (C-9), 159.1 (C-2), 154.2 (C-5), 153.6 (C-3’, C-5’), 149.5 (C),141.5 (C-4’), 140.8 (C-3), 131.1 (C), 129.6 (CH), 129.4 (CH), 128.5 (CH), 127.9 (CH), 124.8 (C-1’), 108.8 (C-10), 105.7 (C-6’, C-2’), 96.5 (C-6), 92.8 (C-8), 73.3 (OCH2), 61.2 (4’-OCH3), 56.7 (7-OCH3), 56.5 (3’, 5’-OCH3), 56.0 (8-OCH3), 21.7 (CH3); MS (ESI, m/z): 563.3 [M+ H]+, 585.3 [M+ Na]+.
2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(吡啶-2-基甲基)乙酰肼(化合物24)
淡黄色固体，产率：55.6%, m.p. 176~178 ℃; IR (KBr, cm-1): ν max 1699, 1683, 1602, 1588, 1506, 1417, 1361, 1244, 1211, 1126, 1012, 819; 1H NMR (500 MHz, CDCl3) δ: 3.92-3.99 (m, 15H, 5×OCH3), 4.36 (s, 2H, CH2), 6.40 (d, J= 2.3 Hz, 1H, H-6), 6.53 (d, J= 2.3 Hz, 1H, H-8), 7.22 (overlapping s, 2H, H-2’, H-6’), 7.27 (t, J= 13.3 Hz, 1H), 7.71 (t, J= 15.4 Hz, 1H), 8.20 (d, J= 8 Hz, 1H), 8.53 (s, 1H, NH ), 8.62 (d, J= 4.6 Hz, 1H), 12.53 (s, 1H, N=CH); 13C NMR (125 MHz, CDCl3) δ: 174.7 (C-4), 165.9 (C=O), 164.8 (C-7), 161.2 (C-9), 159.1 (C-2), 154.1 (C-5), 153.6 (C-3’, C-5’), 153.3 (C), 149.6 (CH), 149.4 (CH),141.4 (C-4’), 140.8 (C-3), 136.4 (CH), 127.6 (CH), 124.8 (C-1’), 121.3 (CH), 108.8 (C-10), 105.7 (C-6’, C-2’), 96.5 (C-6), 92.7 (C-8), 73.2 (OCH2), 61.2 (4’-OCH3), 56.6 (7-OCH3), 56.5 (3’, 5’-OCH3), 56.0 (8-OCH3); MS (ESI, m/z): 550.3 [M+ H]+, 572.2 [M+ Na]+.
2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(呋喃-2-基亚甲基)乙酰肼(化合物25)
灰白色固体，产率：73.2%, m.p. 172~174 ℃; IR (KBr, cm-1): ν max 1699, 1683, 1608, 1558, 1506, 1417, 1359, 1246, 1217, 1126, 1066, 1014, 819; 1H NMR (500 MHz, CDCl3) δ: 3.92-3.99 (m, 15H, 5×OCH3), 4.32 (s, 2H, CH2), 6.41 (d, J= 2.3 Hz, 1H, H-6), 6.48 (q, J= 5.1 Hz, 1H, CH ), 6.54 (d, J= 2.3 Hz, 1H, H-8), 6.86 (d, J= 3.4 Hz, 1H, CH), 7.20 (overlapping s, 2H, H-2’, H-6’), 7.51 (d, J= 1.15 Hz, 1H, CH), 8.30 (s, 1H, NH ), 12.25 (s, 1H, N=CH); 13C NMR (125 MHz, CDCl3) δ: 174.8 (C-4), 165.2 (C=O), 164.9 (C-7), 161.1 (C-9), 159.1 (C-2), 154.2 (C-5), 153.6 (C-3’, C-5’), 149.5 (C), 144.7 (CH), 141.5 (C-4’), 140.8 (C-3), 138.8 (CH), 124.8 (C-1’), 113.3 (CH), 111.9 (CH), 108.8 (C-10), 105.7 (C-6’, C-2’), 96.6 (C-6), 92.8 (C-8), 73.3 (OCH2), 61.2 (4’-OCH3), 56.7 (7-OCH3), 56.5 (3’, 5’-OCH3), 56.0 (8-OCH3); MS (ESI, m/z): 539.3 [M+ H]+, 561.2 [M+ Na]+.
2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-((3-甲基噻吩-2- 基)亚甲基)乙酰肼(化合物26)
灰白色固体，产率：65.9%, m.p. 132~134 ℃; IR (KBr, cm-1): ν max 1699, 1681, 1620, 1606, 1558, 1506, 1417, 1354, 1246, 1217, 1126, 1107, 1064, 1010, 816; 1H NMR (500 MHz, CDCl3) δ: 2.42 (s, 3H, CH3), 3.92-3.99 (m, 15H, 5×OCH3), 4.32 (s, 2H, CH2), 6.41 (d, J= 2.3 Hz, 1H, H-6), 6.54 (d, J= 2.3 Hz, 1H, H-8), 6.84 (d, J= 5.15 Hz, 1H, CH), 7.21 (overlapping s, 2H, H-2’, H-6’), 7.28 (d, J= 5.15 Hz, 1H, CH), 8.63 (s, 1H, NH ), 12.08 (s, 1H, N=CH); 13C NMR (125 MHz, CDCl3) δ: 174.7 (C-4), 164.9 (C=O), 164.9 (C-7), 161.1 (C-9), 159.1 (C-2), 154.1 (C-5), 153.6 (C-3’, C-5’), 144.1 (C),141.4 (C-4’), 140.8 (C-3), 140.5 (C), 132.5 (CH), 130.5 (CH), 128.0 (CH), 124.8 (C-1’), 108.8 (C-10), 105.7 (C-6’, C-2’), 96.5 (C-6), 92.8 (C-8), 73.3 (OCH2), 61.2 (4’-OCH3), 56.7 (7-OCH3), 56.5 (3’, 5’-OCH3), 56.0 (8-OCH3), 14.2 (CH3); MS (ESI, m/z): 569.2 [M+ H]+, 591.2 [M+ Na]+.
N'-((1H-吡咯-2-基)亚甲基)-2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3- 基)氧基)乙酰肼(化合物27)
灰白色固体，产率：72.4%, m.p. 135~137 ℃; IR (KBr, cm-1): ν max 1699, 1681, 1620, 1602, 1558, 1506, 1417, 1354, 1244, 1213, 1126, 1107, 1039, 1006, 815; 1H NMR (500 MHz, CDCl3) δ: 3.92-4.00 (m, 15H, 5×OCH3), 4.32 (s, 2H, CH2), 6.25 (d, J= 2.3 Hz, 1H, H-6), 6.41 (d, J= 2.3 Hz, 1H, H-8), 6.54 (m, 2H, 2CH), 6.91 (s, 1H, CH), 7.21 (overlapping s, 2H, H-2’, H-6’), 8.23 (s, 1H, NH), 9.54 (s, 1H, NH), 12.11 (s, 1H, N=CH); 13C NMR (125 MHz, CDCl3) δ: 174.8 (C-4), 165.2 (C=O), 164.9 (C-7), 161.0 (C-9), 159.1 (C-2), 154.1 (C-5), 153.6 (C-3’, C-5’), 141.4 (C-4’), 140.8 (C-3), 140.8 (CH), 127.2 (C), 124.8 (C-1’), 124.3 (CH), 114.8 (CH), 109.8 (CH), 108.8 (C-10), 105.7 (C-6’, C-2’), 96.5 (C-6), 92.8 (C-8), 73.2 (OCH2), 61.2 (4’-OCH3), 56.7 (7-OCH3), 56.5 (3’, 5’-OCH3), 56.0 (8-OCH3); MS (ESI, m/z): 538.3 [M+ H]+, 560.2 [M+ Na]+. 实施实例八、化合物对癌细胞MDA-MB-231、A549、PC-3、HeLa和SiHa的体外增殖抑制活性测试
人乳腺癌细胞MDA-MB-231用10% FBS的DMEM培养，人肺癌细胞A549、人前列腺癌PC-3、增殖表皮癌细胞HeLa和人子宫颈鳞癌细胞SiHa用10% FBS的RPMI 1640培养，37℃、5% CO2的饱和湿度培养箱中培养，2 天换一次培养液，4-6 天传一次代。取对数生长期细胞为实验对象。细胞用0.025％胰蛋白酶（含0.5 mM EDTA）消化处理。20 mM化合物溶解于DMSO作为储备液。在使用前，直接用培养基将其稀释到所需浓度。阴性对照组加入与药物同体积的DMSO，阳性对照组加入与被测药物同浓度的盐酸表阿霉素和吉非替尼。处理药剂中的DMSO最终浓度不超过0.1％(v/v)。
取对数生长期细胞，用0.025%胰蛋白酶消化后，重悬于含10 % FBS的DMEM或RPMI 1640培养基中，以4.5×104个/mL的终浓度接种于96孔培养板上，每孔100 μL，最右侧一列为空白对照组，加无细胞的有血清DMEM或RPMI 1640培养基，置于37 oC、5 % CO2的饱和湿度培养箱中培养。24 h后吸掉培养基，加入含不同浓度药物的有血清培养基，每孔200 μL，空白对照组每孔加200 μL完全培养基分别处理实验要求时间，去除上清，加100 μL/well浓度0.5 mg/mL的MTT。培养4 h后再补加100 μL/well的10%的SDS。37℃下10 h使结晶物充分溶解后取出，微震荡5 min，放置室温下30 min，在A595波长下测OD值，并计算细胞活性、抑制率和P值。
以药物的浓度或处理时间为横轴，OD值或者抑制率为纵轴，绘制曲线。每样本浓度重复六个孔，每个实验重复三次，取平均值为最终结果。
实验结果以SPSS软件进行方差分析，P<0.05时为差异显著，p<0.01时为差异极显著。细胞增殖的抑制率计算公式如下：
表1 杨梅素含氮衍生物对乳腺癌细胞MDA-MB-231的体外增殖抑制活性
注：*化合物在设定浓度下对MDA-MB-231抑制率与阴性对照组(DMSO)抑制率差异性分析有显著性差异（P＜0.05）。
表2 杨梅素含氮衍生物对A549、PC-3、HeLa和 SiHa癌细胞的体外增殖抑制活性(10 μM)
注：*化合物在浓度为10 μM下对癌细胞A549、PC-3、HeLa和SiHa抑制率与阴性对照组(DMSO)抑制率差异性分析有显著性差异（P＜0.05）。
从表1的数据和附图表明，以上化合物都对目标肿瘤细胞MDA-MB-231有良好的抑制活性，其中化合物25的抑制活性与阳性药盐酸表阿霉素相比，在同样的剂量和作用时间要高于阳性药，最值得一提的是阳性药对肿瘤细胞的毒性明显太大(使得细胞全部破碎裂解)，本专利所合成的新化合物基本对目标细胞损伤很小，这种抑制活性主要体现在抑制细胞的增殖(细胞数量与对照相比明显变少)，或者诱导细胞分化(从形态学观察我们不难发现，细胞在数目减少的同时，细胞发生了变形，但是损伤不是很明显)；从表2的数据可看出，所合成的杨梅素含氮类衍生物对A549、PC-3、HeLa和SiHa等癌细胞也具有良好的抑制效果，部分化合物的抑制效果优于阳性对照药剂，表明这一系列化合物可作为抗癌药物进行进一步的研究。
Claims (5)
1. 杨梅素含氮类衍生物，其特征是结构由下列通式(I)、(II)或(III)表示：
所述化合物结构中n为2、3或4；R1为(1)卤原子；(2)二乙胺基；(3)哌啶基；(4)吡咯烷基；(5)吗啉基；(6)对甲基哌嗪基；R2为 (1)苯基或取代苯基；(3)吡啶基或取代吡啶基；R3为(1)苯基或取代苯基；(2)杂环基或取代杂环基；
取代苯基为苯环上含有一个或多个甲基、乙基、甲氧基、乙氧基、正丙基、异丙基、三氟甲基、硝基、胺基以及卤原子，卤原子可为氟、氯、溴、碘。
2.根据权利要求1所述的化合物，其特征在于所述化合物如下所示：
化合物1:3-(3-(二乙基氨-1-基)丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物2: 5,7-二甲氧基-3-(3-(吡咯烷-1-基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物3: 5,7-二甲氧基-3-(3-(哌啶-1-基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物4: 5,7-二甲氧基-3-(3-(吗啉-1-基)-丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物5: 5,7-二甲氧基-3-(3-(4-甲基哌嗪-1-基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物6: 3-(4-(二乙氨基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物7: 5,7-二甲氧基-3-(4-(吡咯烷-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4- 酮
化合物8: 5,7-二甲氧基-3-(4 -(哌啶-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物9: 5,7-二甲氧基-3-(4-吗啉-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物10: 5,7-二甲氧基-3-(4-(4-甲基哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物11: 5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物12: 3-(4-(4-(4-氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物13: 3-(4-(4-(4-氯苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物14: 5,7-二甲氧基-3-(4-(4-(4-硝基苯甲酰基)哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物15: 5,7-二甲氧基-3-(4-(4-(4-(三氟甲基)苯甲酰基)哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物16: 3-(4-(4-(2-氯-6-氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物17: 3-(4-(4-(2,4-二氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物18: 3-(4-(4-(5-氯-2-硝基苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物19: 3-(4-(4-(3,5-二硝基苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物20: 3-(4-(4-苯甲酰基-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物21: 3-(4-(4-异烟酰基-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮
化合物22: 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(2- 氟苄基)乙酰肼
化合物23: 2-((5,7-二甲氧基-4-氧代-2-(3,4,5 -三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(4- 甲基亚苄基)乙酰肼
化合物24: 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(吡啶-2-基亚甲基)乙酰肼
化合物25: 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(呋喃-2-基亚甲基)乙酰肼
化合物26: 2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-((3- 甲基噻吩-2-基)亚甲基)乙酰肼
化合物27: N'-((1H-吡咯-2-基)亚甲基)-2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼。
3.按照权利要求1或2所述的杨梅素含氮类衍生物，其特征是所属的化合物在制备抗癌药物中的应用。
4.按照权利要求1所述杨梅素含氮类衍生物的制备方法，其特征在于通式(I)、(II)
和(III)化合物的制备方法是以杨梅苷、卤代烷烃、仲胺、六水合哌嗪、芳香酸、取代芳香酸、溴乙酸乙酯、水合肼、芳香醛以及取代芳香醛为原料，经取代、水解和缩合反应合成目标产物，其合成路线为：
化合物通式(I)的反应路线
化合物通式(II)的反应路线
化合物通式(III)的反应路线
5.根据权利要求4所述的杨梅素含氮类衍生物的制备方法，其特征是经取代、水解和
缩合合成，通式(I)、(II)和(III)的合成方法为：
通式(I)的制备方法
第一步：3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在圆底烧瓶中加入杨梅苷和K2CO3溶于DMF中，搅拌均匀后，缓慢的滴加碘甲烷，
室温搅拌数小时，停止反应后，用水分散，用乙酸乙酯萃取，合并滤液，合并有机相，减压浓缩，然后将浓缩物溶于无水乙醇，升温至回流，溶液澄清后，回流下加入浓盐酸，慢慢的有黄色固体析出，继续反应2 h，冷却，冰箱放置过夜，过滤，得到粗产物，不需要纯化，直接用于下一步的反应，
第二步：3-(卤代基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在圆底烧瓶中加入第一步的反应产物和K2CO3, 用DMF溶解后，加入溴代烷烃，在室温下反应数小时，停止反应后，用水分散，以乙酸乙酯萃取，得到有机相，依次用HCl，饱和NaHCO3，饱和NaCl水溶液分别洗涤后，合并乙酸乙酯层，以无水硫酸钠干燥后蒸去溶剂，用硅胶柱层析分离，得到目标产物，
第三步：含杂环烷基类杨梅素衍生物的制备
在圆底烧瓶中加入第二步的产物和K2CO3，用DMF溶解后，加入仲胺，在室温下反应数小时，停止反应后，用水分散，以乙酸乙酯萃取，合并有机相依次用HCl，饱和NaHCO3，饱和NaCl水溶液分别洗涤后，合并乙酸乙酯层， 以无水硫酸钠干燥后蒸去溶剂，用硅胶柱层析分离，得到目标产物，
通式(II)的制备方法
第一步：与通式(I)中3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备一致，
第二步：与通式(I)中3-(卤代基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备一致，
第三步：3-氧(4-(哌嗪-1-基)-丁基)-3’, 4’, 5, 5’,7-五甲氧基杨梅素的制备
在圆底烧瓶中加入3-氧 (4-溴代丁基) -3’, 4’, 5, 5’,7-五甲氧基杨梅素和K2CO3，DMF溶解，搅拌几分钟后加入六水合哌嗪，在室温下反应数小时后，停止反应后，用水分散，用乙酸乙酯萃取，合并有机相用HCl，饱和NaHCO3，饱和NaCl水溶液分别洗涤后，合并乙酸乙酯层，以无水硫酸钠干燥后蒸去溶剂，用硅胶柱层析分离得到目标产物；
第四步：含哌嗪酰胺类杨梅素衍生物的制备
在圆底烧瓶中，在冰浴条件下加入酸以及HATU(2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)，用干燥二氯甲烷(DCM)溶解后加入几滴三乙胺在冰浴下搅拌，然后加入3-氧(4-(哌嗪-1-基)-丁基)-3’, 4’, 5, 5’,7-五甲氧基杨梅素在室温下反应数小时，停止反应，用水洗涤反应液，以无水硫酸钠干燥，用硅胶柱层析分离得到目标产物；
通式(III)的制备方法
第一步：与通式(I)中3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备方法一致，
第二步：3-氧乙酸乙酯-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在三口瓶中依次加入第一步的产物，K2CO3和无水丙酮，室温搅拌均匀后，滴加溴乙酸乙酯，滴毕，回流反应数小时，停止反应后，冷却至室温，浓缩后倒入冰水中，析晶，抽滤，滤饼用氯仿/水重结晶得到目标产物，
第三步：2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼的制备
在三口瓶中依次加入第二步的产物，80%水合肼和无水乙醇，回流反应2 h，TCL点板跟踪，直至反应完全，减压浓缩除去大量溶剂后，冷却，有沉淀产生析出，抽滤，滤饼用无水乙醇重结晶得到目标产物，
第四步：杨梅素酰腙类衍生物的制备
在三口瓶中依次加入第三步的产物和芳香醛，用无水乙醇溶解，滴入催化量的醋酸，搅拌加热回流2 h，TLC点板跟踪，直至反应完全，浓缩反应液，冷却，有大量的沉淀析出，抽滤，滤饼用无水乙醇重结晶得到目标产物。
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| CN112679458A (zh) * | 2020-12-15 | 2021-04-20 | 贵州大学 | 一类含磺酸酯的杨梅素衍生物及其制备方法和应用 |
| CN112759581A (zh) * | 2020-11-16 | 2021-05-07 | 贵州大学 | 一种含苯并咪唑磺酰胺杨梅素衍生物、制备方法及用途 |
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| CN106699718A (zh) * | 2016-12-28 | 2017-05-24 | 佳木斯大学 | 杨梅素4,4’‑联吡啶乙醇共晶及其制备方法 |
| CN111961039B (zh) * | 2020-08-28 | 2022-11-08 | 贵州大学 | 一种含取代嘧啶的杨梅素衍生物、其制备方法及用途 |
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| US20230219935A1 (en) * | 2019-06-18 | 2023-07-13 | Guizhou University | 4-(n-methyl) aminopiperidine myricetin derivative containing dithiocarbamate, preparation method and application |
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|---|---|
| CN105237504B (zh) | 2018-07-06 |
| CN103804335B (zh) | 2016-05-18 |
| CN105237504A (zh) | 2016-01-13 |
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