CN104817519B - A class of derivatives of ca-4, their preparation, and pharmaceutical use - Google Patents

A class of derivatives of ca-4, their preparation, and pharmaceutical use Download PDF

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CN104817519B
CN104817519B CN 201510235806 CN201510235806A CN104817519B CN 104817519 B CN104817519 B CN 104817519B CN 201510235806 CN201510235806 CN 201510235806 CN 201510235806 A CN201510235806 A CN 201510235806A CN 104817519 B CN104817519 B CN 104817519B
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CN 201510235806
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CN104817519A (en )
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徐云根
刘坤
宋晓翰
陈泓竹
张宏波
张灵芝
朱启华
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中国药科大学
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Abstract

本发明涉及药物化学领域,具体涉及一类Combretastatin A‑4的衍生物(I),它们的制备方法以及对肿瘤血管生成的抑制作用。 The present invention relates to pharmaceutical chemistry, specifically relates to derivatives of (I) a class of Combretastatin A-4, methods for their preparation, and inhibition of tumor angiogenesis. 药理实验结果显示,本发明的化合物对MCF‑7人乳腺癌细胞增殖具有较强的抑制作用,同时,部分化合物对人脐静脉内皮细胞的增殖以及鸡胚绒毛尿囊膜新生血管的生成也有较好的抑制作用。 Pharmacological Experimental results show that the compounds of the present invention have a strong inhibitory effect on cell proliferation of human breast cancer MCF-7, while some compounds on Proliferation and generating a chick chorioallantoic membrane angiogenesis in human umbilical vein endothelial cells has a more good inhibition. 因此,本发明化合物可以用于治疗各种与血管生成相关的疾病,这些疾病包括各种癌症和慢性炎症以及其它血管原性的疾病。 Accordingly, the compounds of the present invention may be used to treat various diseases associated with angiogenesis, such diseases include various cancers and other chronic inflammatory and angiogenic diseases. 本发明的化合物具有良好的水溶性。 Compounds of the invention have good water solubility.

Description

一类CA-4的衍生物、其制法及其医药用途 A class of derivatives of CA-4, their preparation, and pharmaceutical use

技术领域 FIELD

[0001 ] 本发明涉及药物化学领域,具体涉及一类Combretastatin A-4(CA-4)的衍生物、 它们的制备方法以及对肿瘤血管的抑制作用。 Methods for their preparation as well as inhibition of tumor blood vessels [0001] The present invention relates to pharmaceutical chemistry, specifically relates to a class of derivatives of Combretastatin A-4 (CA-4), and.

背景技术 Background technique

[0002] CA-4是从南非的Combretum Caffnom树皮中分离出来的小分子血管阻断剂(Vascular Disrupting Agents,VDA),其能结合血管内皮细胞微管蛋白β亚基的秋水仙碱结合位点,导致微管蛋白的聚合,进而改变其内皮细胞的骨架结构与形态,增强其血管渗透性、扰乱血流,从而引起肿瘤血管内皮细胞凋亡,导致次级肿瘤细胞死亡。 [0002] CA-4 was isolated from the bark of the South African Combretum Caffnom of small molecule vascular disrupting agent (Vascular Disrupting Agents, VDA), which is capable of binding to the colchicine binding site of tubulin endothelial cells β subunit point, resulting in the polymerization of tubulin, thereby changing its skeletal structure and morphology of endothelial cells, vascular permeability enhancing its disrupt blood flow, causing apoptosis of tumor vascular endothelial cells, leading to secondary tumor cell death. 尽管CA-4具有潜在的生物活性,但其低水溶性和低生物利用度限制了进一步的应用。 Although the CA-4 having potential biological activity, but its low water solubility and low bioavailability limits further applications.

发明内容 SUMMARY

[0003] 本发明公开了一类通式I的化合物。 [0003] The present invention discloses a class of compounds of formula I. 本发明的化合物具有良好的水溶性。 Compounds of the invention have good water solubility. 药理实验结果显示,本发明的化合物对MCF-7人乳腺癌细胞增殖具有较强的抑制作用,同时,部分化合物对人脐静脉内皮细胞的增殖以及鸡胚绒毛尿囊膜(Chicken chorioal Iactoic membrane,CAM)新生血管的生成也有较好的抑制作用。 Pharmacological Experimental results show that the compounds of the present invention on MCF-7 human breast cancer cells has a strong inhibitory effect, at the same time, some of the compounds in human umbilical vein endothelial cell proliferation and the chick chorioallantoic membrane (Chicken chorioal Iactoic membrane, CAM) neovascularization has better inhibitory effect. 因此,本发明的式I化合物可以用于治疗各种与血管生成相关的疾病,这些疾病包括各种癌症和慢性炎症以及其它血管原性的疾病。 Accordingly, the compounds of formula I of the invention may be used for treating various diseases associated with angiogenesis, such diseases include various cancers and other chronic inflammatory and angiogenic diseases.

[0004] 本发明的化合物通式I如下: [0004] The compounds of formula I of the invention as follows:

Figure CN104817519BD00031

[0005] [0005]

[0006] [0006]

[0007] [0007]

[0008] [0008]

[0009] [0009]

[0010] 式I的化合物可与药学上可接受的酸形成酸加成盐,所述酸包括盐酸、氢溴酸、硫酸、碳酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。 Compound [0010] of formula I may form acid addition salts with pharmaceutically acceptable acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or ferulic acid.

[0011]本发明部分化合物是: [0011] Some compounds of the present invention are:

[0012] 4-((4-甲基哌嗪-1-基)甲基)苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基) 苯酯(II) [0012] 4 - ((4-methylpiperazin-1-yl) methyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy styryl) benzene ester (II)

[0013] 4-(吗啉甲基)苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-2) [0013] 4- (morpholinomethyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1-2)

[0014] 4-(哌啶-1-基甲基)苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(I- 3) [0014] 4- (piperidin-1-ylmethyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (I- 3)

[0015] 4-(吡咯烷-1-基甲基)苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-4) [0015] 4- (pyrrolidin-1-ylmethyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1-4)

[0016] 4-(二乙胺-1-基甲基)苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-5) [0016] 4- (diethylamino-1-ylmethyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1-5 )

[0017] 4-((4-甲基哌嗪-1-基)甲基)-3-硝基苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-6) [0017] 4 - ((4-methylpiperazin-1-yl) methyl) 3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxyphenyl styrene-yl) phenyl ester (1-6)

[0018] 4-(吗啉甲基)-3-硝基苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-7) [0018] 4- (morpholinomethyl) 3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1-7 )

[0019] 4-(哌啶-1-基甲基)-3-硝基苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基) 苯酯(1-8) [0019] 4- (piperidin-1-ylmethyl) -3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1-8)

[0020] 4-(吡咯烷-1-基甲基)-3-硝基苯甲酸-(Z)-2-甲氧基-5-(3,4,5_三甲氧苯乙烯基)苯酯(1-9) [0020] 4- (pyrrolidin-1-ylmethyl) -3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5_-trimethoxy styryl) phenyl ester (1-9)

[0021] 4-(二乙胺甲基)-3-硝基苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-10) [0021] 4- (diethylamino) -3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1- 10)

[0022] 本发明通式化合物(I)的制备方法如下: [0022] A method of the present invention compounds of general formula (I) as follows:

[0023] [0023]

Figure CN104817519BD00051

[0024] 由3,4,5_三甲氧基苯乙酸(1)与3-羟基-4-甲基苯甲醛(2)制备化合物3,是将反应物在三乙胺和醋酐作用下缩合得到。 [0024] -4-methyl-benzaldehyde (2) Preparation of compound 3, the reaction is a condensation 3,4,5_ trimethoxy phenylacetic acid (1) with 3-hydroxy acetic anhydride and triethylamine in effect get.

[0025]由化合物3制备4,是将反应物于喹啉/铜粉和200 °C高温脱羧得到。 [0025] 3 was prepared from compound 4, the reaction was a quinoline / copper powder and 200 ° C high temperature decarboxylation.

[0026]由化合物5制备6,是将反应物溶于氯仿中,加入NBS和引发剂过氧化苯甲酰反应得到。 [0026] Preparation of compound 5 of 6, is dissolved in chloroform and the reaction was added NBS and benzoyl peroxide initiator reaction.

Figure CN104817519BD00052

钾、碳酸氢钾、碳酸钠、碳酸氢钠,优选碳酸钾。 Potassium bicarbonate, potassium carbonate, sodium carbonate, preferably potassium carbonate. 溶剂选自甲苯/水、四氢呋喃/水、丙酮/水、乙腈/水,优选甲苯/水。 Solvent is selected from toluene / water, tetrahydrofuran / water, acetone / water, acetonitrile / water, preferably toluene / water.

[0028]由化合物7制备8,是将反应物置于20 %浓盐酸中回流得到。 [0028] Preparation of Compound 78, was placed in the reaction is 20% concentrated hydrochloric acid was refluxed.

[0029] 由化合物8制备9,是将化合物12与氯化剂进行氯代得到。 [0029], compound 12 is obtained from the compound 8-chloro-9 was prepared with a chlorinating agent. 其中氯化剂选自氯化亚砜、草酰氯、三氯氧磷,优选氯化亚砜。 Wherein the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, thionyl chloride is preferred.

[0030] 由化合物9制备目标化合物I,是将化合物13在缚酸剂作用下与化合物4在溶剂中缩合得到。 [0030] The title compound I is prepared from compound 9, 134 is the condensation compound in the acid binding agent action of the compound in a solvent. 缚酸剂选自三乙胺、二异丙基乙基胺、吡啶、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠,优选三乙胺。 The acid-binding agent is selected from triethylamine, diisopropyl ethyl amine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, preferably triethylamine. 溶剂选自二氯甲烷、四氢呋喃、乙腈、丙酮、DMF,优选二氯甲烷。 Solvent selected from dichloromethane, tetrahydrofuran, acetonitrile, acetone, DMF, preferably dichloromethane.

[0031] 本发明的另一目的在于提供一种药物组合物,其包括药物有效剂量的本发明的化合物或其盐和药学上可接受的载体。 [0031] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically effective dose of a drug of the present invention or a salt thereof and a pharmaceutically acceptable carrier.

[0032] 本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂,如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂,可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。 [0032] The compounds of the invention may be added to a pharmaceutically acceptable carrier made of usual pharmaceutical preparations such as tablets, capsules, powders, syrups, solutions, suspensions, injections, may be added flavors, sweeteners , or other liquid or solid filler diluents commonly used pharmaceutical excipients.

[0033] 本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。 [0033] The mode of administration of the compounds of the present invention may be employed in the clinical oral, injectable or the like.

[0034] 一般地,本发明的CA-4衍生物用于治疗时,人用剂量范围为Img~1000 mg/天。 When [0034] Generally, CA-4 derivatives of the present invention for the treatment, the human dose range Img ~ 1000 mg / day. 也可根据剂型的不同和疾病严重程度,使用剂量超出该范围。 It may be different according to the severity of disease and dosage forms, doses outside this range.

[0035]以下是本发明部分化合物的药理试验及结果。 [0035] The following are the results of pharmacological tests and of the compound of the present invention.

[0036] I、SRB法检测受试化合物对MCF-7和HUVECs细胞的增殖作用[0037] 细胞传代至对数生长期后,经胰酶-EDTA液消化,调终浓度为5 X104/mL,接种于96 孔板中,每孔200yL,边缘孔用无菌PBS填充,5%CO2,37°C孵育。 [0036] I, SRB proliferation assay test compound on MCF-7 cells and HUVECs [0037] Cells passaged to logarithmic growth phase were digested by trypsin -EDTA, adjusted to a final concentration of 5 X104 / mL, seeded in 96-well plates, each well 200yL, the edge of the hole is filled with sterile PBS, 5% CO2,37 ° C incubation. 24h后(至细胞单层铺满孔底(96孔平底板)),弃去板上各孔内原有液体,再分别换上含有相应浓度药物的细胞培养液, 于37°C,5 % CO2培养箱中培养,各种药物每浓度设5个平行孔。 After 24h (hole bottom to confluent cell monolayers (in 96-well flat bottom plate)), each well was discarded the original liquid board, then were put on the cell culture medium containing the corresponding concentration of the drug, at 37 ° C, 5% CO2 incubator, various drugs five parallel wells per concentration is provided. SRB用1 %醋酸配成0.4%溶液。 SRB in 1% acetic acid solution of 0.4% dubbed. 细胞在加药培养结束(48h)后用三氯醋酸(TCA)固定:贴壁细胞每个小孔加预冷的50 % TCA液50uL(终浓度为10 % )固定;加TCA时必须轻轻加在培养液表面,先静置5min然后再将平板移至4°C放置lh,这样细胞固定在培养孔的底部。 Dosing end of the culture cells (48h) after trichloroacetic acid (TCA) is fixed: adherent cells each orifice 50% TCA was added 50uL precooled (final concentration of 10%) is fixed; TCA must be added when gently 5min then added to the plates move placed LH 4 ​​° C, cells were fixed in wells so that the bottom surface of the culture solution, the first standing. 倒掉固定液,小孔用灭菌三蒸水洗5 遍,甩干,空气干燥。 Fixing solution drained, washed with water hole 5 with sterile distilled three times, drying, and air dried. 每孔加入0.4 % SRB溶液IOOyL,避光,在室温放置IOmin。 Added to each well 0.4% SRB solution IOOyL, protected from light, at room temperature IOmin placed. 未与蛋白结合的SRB用I %TCA液洗5遍,空气干燥。 Unbound SRB protein with I% TCA was washed 5 times and air dried. 结合的SRB用150uL10mmol/L非缓冲Tris碱液(pH 10.5) 溶解,放在微量振荡器上5min,避光。 SRB bound by 150uL10mmol / L unbuffered Tris alkaline (pH 10.5) was dissolved, on a micro oscillator 5min, protected from light. 在酶联免疫检测仪测定OD值,用空白对照调零,在波长为490nm处测定每个小孔的OD值。 OD value was measured in ELISA to zero by the control transfer, each well was measured at a wavelength of OD value at 490nm. 将所获肿瘤细胞生长抑制率定义为药物对肿瘤细胞的体外抑制率并计算IC 5q值。 The resulting inhibition of tumor cell growth inhibition is defined as the rate of drug on tumor cells in vitro and to calculate the value of IC 5q. 抑制率=(无药细胞对照孔OD值-用药孔OD值)/无药细胞对照孔OD 值X 100% Inhibition rate = (OD drug-free control wells cell value - hole medication OD) OD value of control wells / cell no drug X 100%

[0038]表1化合物对人乳腺癌细胞MCF-7增殖抑制作用(ϊ±Ι,η = 3) [0038] Table 1 Compound MCF-7 human breast cancer cell proliferation inhibitory effect (ϊ ± Ι, η = 3)

Figure CN104817519BD00071

LU_」从表1买验结采中我们η」以宥出大部分化合物的MCF-7肿瘤细胞增殖抑制活性较阳性药CA-4( IC5q = 0.0 58μΜ)更强,同时较阿霉素强一个数量级,其中化合物1-3( IC50 = 0.024μΜ)的活性明显强于CA-4。 LU_ "Buy From Table 1, we test Mining junction η" In the majority of compounds Yoga MCF-7 tumor cell proliferation inhibiting activity than the positive drug CA-4 (IC5q = 0.0 58μΜ) more, while a stronger than doxorubicin magnitude, wherein the compound 1-3 (IC50 = 0.024μΜ) activity was significantly stronger than that CA-4.

[0041 ]表2部分化合物对人脐静脉内皮细胞增殖的抑制作用(^η = 3) [0041] Table 2 Inhibition of the compound in human umbilical vein endothelial cell proliferation (^ η = 3)

Figure CN104817519BD00081

[0043] 实验结果显示,所测化合物对人脐静脉内皮细胞具有强烈的抑制作用。 [0043] The results show that the test compound has a strong inhibitory effect on human umbilical vein endothelial cells.

[0044] 2、鸡胚绒毛尿囊膜新生血管生成抑制实验 [0044] 2, chick chorioallantoic membrane angiogenesis inhibition assay

[0045] 将6天种蛋用温水清洗2次,于1:1000新洁尔灭中浸泡3min后放入37°C孵化箱相对湿度65%,种蛋气室向上,翻转种蛋1次/2h,至孵蛋第6天,在照蛋灯下观察种蛋生长情况, 剔除未受精卵。 [0045] The eggs six days with warm water washed twice in 1: 3min after immersion into 37 ° C incubator benzalkonium 1000 65% relative humidity, the eggs plenum upwardly inverted eggs 1 / 2h, the first to brood 6 days growth was observed in the eggs egg lamp, unfertilized eggs removed. 用解剖针在气室顶端扎1小洞,可使鸡胚的尿囊绒毛膜与鸡蛋的内壳膜分开。 1 bar with a hole in the top plenum dissecting needle, make the chicken chorioallantoic membrane and the inner shell membrane of the egg separated. 照蛋灯下寻找胚头,在受精卵距胎头前Icm两条前卵黄静脉之间的卵壳投影部位标记1.0 cm X 1.0 cm的正方形区域,用砂轮沿这个区域磨切透卵壳至蛋壳表面划刻出凹痕,轻揭凹陷处蛋皮,轻轻撕掉内壳膜,此时可见该处CAM连同鸡胚下陷,假气室形成(区别于自身的气室)。 Egg lamp head looking embryos, fetal head before the fertilized egg from the shell portion between the projection vitelline vein before Icm two markers 1.0 cm X 1.0 cm square area, with a grinding wheel along the grinding area to cut through the egg shell eggs shell surface designated to notch, recess exposing light shells, the inner shell membrane and gently tear, where seen at this time, along with the chick embryo CAM subsidence, false air chamber is formed (as distinguished from the gas chamber itself). 用封口膜封贴假气室,形成透明观察窗,继续放入37°C孵化箱孵化1天。 Sealed with parafilm posted false air chamber, a transparent observation window, to continue into the 37 ° C incubator for incubation for 1 day. 于第二天取出鸡蛋,剔除变质鸡蛋。 Remove the eggs the next day, remove bad eggs. 将剩余鸡蛋分成:空白组,DMSO组,阳性药组(10,2.5,Iyg/个),和候选化合物组(IOyg/个),每组各3只,轻轻撕掉封口膜,取直径约0.5cm的混合纤维素微孔滤膜片(预先高压灭菌)作为载体,置于正对观察窗的CAM表面,避开大血管,用无菌加样器吸取各组相应的药液滴于载体表面中央。 The remaining eggs into: control group, DMSO group, positive drug group (10,2.5, Iyg / a), and a candidate compound group (IOyg / a), each group 3, gently tear parafilm, take a diameter of about 0.5cm mixed cellulose microporous membrane sheet (previously autoclaved) as a carrier, is placed on the surface of the CAM positive observation window, to avoid large blood vessels, with a sterile pipette to draw each set corresponding to liquid droplets the support surface of the center. 加药2d后,去除透明胶带纸,观察、记录观察窗周围CAM并拍照。 After dosing 2d, remove the transparent adhesive tape was observed, recorded and photographed observation window surrounding CAM. 用Graph Pad 5.0统计软件对微小血管数量进行统计。 Statistics on the number of small blood vessels using Graph Pad 5.0 statistical software.

[0046] 我们以血管生成抑制剂来那度胺为阳性对照,以IOyg/蛋的剂量对合成的化合物进行鸡胚绒毛尿囊膜新生血管生成抑制实验,考察化合物在动物体内的血管生成抑制活性。 [0046] We angiogenesis inhibitor lenalidomide as a positive control at a dose IOyg / egg is the chick chorioallantoic membrane angiogenesis inhibiting generation of the synthesized test compound, a compound investigated in vivo angiogenesis inhibitory activity . 结果见图1。 The results shown in Figure 1.

[0047] 从图1中我们可以看出,在IOyg/蛋的剂量下,所测目标化合物均有不同程度的CAM 新生血管生成抑制活性,其中化合物II、1-2、I-3和I-6的活性较好,与阳性药来那度胺相当,而CA-4在此剂量(IOyg/蛋)下显示出严重的胚胎毒性,鸡胚无法继续发育,提示目标化合物的毒性较CA-4明显降低。 [0047] We can see from Figure 1, at a dose IOyg / egg, the target compounds of varying degrees measured CAM angiogenesis inhibitory activity, wherein the compound II, 1-2, I-3 and I- preferably 6 activity, and positive drug lenalidomide considerable, and the CA-4 (IOyg / egg) at this dose showed severe embryotoxic, chicken can not continue to develop, suggesting toxic than the target compound CA-4 Obvious reduction.

[0048]我们以血管生成抑制剂来那度胺和CA-4为阳性对照,以1、2.5、IOyg/蛋三个剂量对化合物II和1-6进行鸡胚绒毛尿囊膜新生血管生成抑制实验,进一步考察它们对血管生成的抑制活性。 [0048] We angiogenesis inhibitor lenalidomide and CA-4 as a positive control, 1,2.5, IOyg / egg three doses of Compound II and 1-6 for the chick chorioallantoic membrane angiogenesis inhibition experimental further investigated for their inhibitory activity on angiogenesis. 结果见图2。 The results shown in Figure 2.

[0049] 从图2可以看出,在IOyg/蛋的剂量下,化合物II和1-6显示出了较强的CAM新生血管生成抑制活性。 [0049] As can be seen from Figure 2, at a dose of IOyg / egg, and 1-6 Compound II showed strong angiogenesis inhibitory activity CAM. CA-4在2.5yg/蛋剂量下即显示出胚胎毒性,在IOyg/蛋剂量下胚胎毒性更大,鸡胚无法继续发育。 CA-4 at 2.5yg / dose i.e. exhibits egg embryo toxicity, greater at IOyg / dose embryotoxic egg, chicken can not continue to develop.

附图说明 BRIEF DESCRIPTION

[0050] 图1是化合物对CAM新生血管生成抑制活性[0051 ]图2是化合物对CAM新生血管生成抑制活性 [0050] FIG. 1 is a compound of the CAM angiogenesis inhibitory activity [0051] FIG. 2 is a compound to generate CAM angiogenesis inhibiting activity

具体实施方式[0052] 实施例1 DETAILED DESCRIPTION Example 1 [0052]

[0053] (E)-3-(3'_羟基-4'-甲氧基)苯基-2-(3",4",5"_三甲氧基)苯基-丙烯酸(3)的合成 [0053] (E) -3- (3'_-hydroxy-4'-methoxy) phenyl-2- (3 ", 4", 5 "_ trimethoxy) phenyl - acrylic acid (3) Synthesis of

[0054] 在500mL三颈瓶中加入3,4,5-三甲氧基苯乙酸(50.0 g,0.22mol)、3_羟基-4-甲氧基苯甲醛(34. Og,0.22mo 1)、62.5mL三乙胺和150mL乙酸酐,N2保护下搅拌升温至140 °C,反应12h,停止加热,冷却至10°C,冰浴下缓慢滴加浓盐酸200mL,室温下搅拌过夜。 [0054] Add 3,4,5 acid (50.0 g, 0.22mol) in 500mL three-necked flask, 3_-hydroxy-4-methoxybenzaldehyde (34. Og, 0.22mo 1), 62.5mL of triethylamine and 150mL of acetic anhydride, was stirred under N2 protection was raised to 140 ° C, the reaction 12h, heating was stopped, cooled to 10 ° C, was slowly added dropwise under ice 200mL of concentrated hydrochloric acid, stirred at room temperature overnight. 有土黄色固体析出,停止反应过滤出固体,用约200mL乙醇重结晶,得47.5g黄色针状物3,产率为59.6%,mp· 184~186°C NMR(300MHz,DMSO-(I6),δ(ρρπ〇: Sl2.46(brs, 1H,C00H) ,8.97 (s,lH,0H) ,7.58(s,lH,=CH),6.81(d ,J = 8.5Hz,lH,ArH) ,6.61 (dd ,Ji = 8.5 J2= 1.8Hz , IH1ArH) ,6.54(d, J=I ,8Hz,lH, ArH) ,6.44(s,2H, ArH) ,3.73( s,3H, OCH3) ,3.71( s,3H, 0CH3),3.69(s,6H,2X0CH3)· There khaki solid precipitated solid was filtered off and the reaction was stopped with about 200mL recrystallized from ethanol to give yellow needles 3 47.5g, yield 59.6%, mp · 184 ~ 186 ° C NMR (300MHz, DMSO- (I6) , δ (ρρπ〇: Sl2.46 (brs, 1H, C00H), 8.97 (s, lH, 0H), 7.58 (s, lH, = CH), 6.81 (d, J = 8.5Hz, lH, ArH), 6.61 (dd, Ji = 8.5 J2 = 1.8Hz, IH1ArH), 6.54 (d, J = I, 8Hz, lH, ArH), 6.44 (s, 2H, ArH), 3.73 (s, 3H, OCH3), 3.71 ( s, 3H, 0CH3), 3.69 (s, 6H, 2X0CH3) ·

[0055] 实施例2 [0055] Example 2

[0056] (Z)-3",4',4", 5"_四甲氧基-3'-羟基二苯乙烯(CA-4,4)的合成 [0056] (Z) -3 ", 4 ', 4", 5 "_ tetramethoxy-3'-hydroxy-stilbene (CA-4,4) Synthesis of

[0057] 在装有温度计、回流冷凝管、干燥管的500mL三颈瓶中加入3 (7.2g,20mmo I),新制铜粉(6.6g,0.103mol),喹啉72mL,N2保护下反应加热至200°C,搅拌4h。 [0057] The reaction was heated at equipped with a thermometer, reflux condenser, drying tube 500 mL three-necked flask was added 3 (7.2g, 20mmo I), freshly prepared copper powder (6.6g, 0.103mol), quinoline 72mL, N2 protection to 200 ° C, stirred for 4h. 冷却至室温,加入乙醚适量,用硅藻土滤除铜粉。 Cooled to room temperature, an appropriate amount of diethyl ether was added, the copper powder was filtered off through celite. 用300mL 5M HCl把喹啉洗掉,用乙醚150mL萃取,将分出的水层用乙醚洗(3 X 150mL),合并有机层。 With the quinoline 300mL 5M HCl wash was extracted with ether 150mL, (3 X 150mL), the combined organic layers were separated and the aqueous layer was washed with diethyl ether. 有机层分别用500mL水洗一次,饱和Na2CO3 (2 X 300mL) 洗两次,饱和NaCl (2 X 300mL)洗两次,无水Na2SO4干燥过夜。 The organic layers were once with saturated Na2CO3 (2 X 300mL) and washed twice with 500mL water, saturated NaCl (2 X 300mL) and washed twice, dried over anhydrous Na2SO4 overnight. 滤去硫酸钠,减压旋掉2/3体积的乙醚,有微黄色固体析出,滤出固体并用适量乙醚洗涤,回收母液,再除去部分溶剂,将析出的固体滤出,共得产物45 · Og,产率79 .l%,mpll6~117°C。 Sodium sulfate was filtered off, spin off under reduced pressure to 2/3 volume of ether, yellowish solid has precipitated solid was filtered off and washed with an appropriate amount of diethyl ether, recovered mother liquor, and removing part of the solvent, the precipitated solid was filtered off, the product to give a total of 45 · Og, yield 79 .l%, mpll6 ~ 117 ° C. 咕匪以300Hz,DMSO-Cl6): δ 8.94(s,lH,0H),6.83(d ,J = 8.3Hz,lH,ArH),6.78(d ,J=1.8Hz,lH,ArH),6.68(dd ,J = 8.2, 1.8Hz,lH,ArH),6.57(s,2H,ArH),6.39(q ,J=12.3Hz,2H,HC = CH),3.72(s,3H,0CH3),3.63 (s,3H,0CH3),3.59(s,6H,2X0CH 3)· Bandit cushions to 300Hz, DMSO-Cl6): δ 8.94 (s, lH, 0H), 6.83 (d, J = 8.3Hz, lH, ArH), 6.78 (d, J = 1.8Hz, lH, ArH), 6.68 ( dd, J = 8.2, 1.8Hz, lH, ArH), 6.57 (s, 2H, ArH), 6.39 (q, J = 12.3Hz, 2H, HC = CH), 3.72 (s, 3H, 0CH3), 3.63 ( s, 3H, 0CH3), 3.59 (s, 6H, 2X0CH 3) ·

[0058] 实施例3 [0058] Example 3

[0059] 4-溴甲基苯甲酸甲酯(6a)的合成 [0059] 4-bromomethyl-benzoic acid methyl ester (6a) Synthesis of

[0060] 将5a(15.0g,0.1mol)溶于氯仿(80mL)中,加入NBS(17.8g,0.1mol)和BP0(45mg, O.lSmmol),加热至回流,搅拌反应2.5h,冷却析出白色固体,抽滤,滤液减压蒸除溶剂,得粗品淡黄色油状液体14.50g,硅胶柱层析(石油醚/乙酸乙酯= 100/1),得无色透明液体6a 12.788,收率82.34%。 [0060] The 5a (15.0g, 0.1mol) was dissolved in chloroform (80 mL) was added NBS (17.8g, 0.1mol) and BP0 (45mg, O.lSmmol), heated to reflux, the reaction was stirred for 2.5h, cooled to precipitate white solid was filtered off with suction, the filtrate was evaporated under reduced pressure to give the crude product as a pale yellow oily liquid 14.50 g, silica gel column chromatography (petroleum ether / ethyl acetate = 100/1) to give a colorless transparent liquid 6a 12.788, yield 82.34 %. 1!1匪1?(30冊!^,〇0(:13)38.03((1,了= 8.0!^,2!1,厶也),7.47((1,了= 7.9Hz,2H,ArH),4.51(s,2H,CH2),3.93(s,3H,0CH3).MS(ESI( + )70eV,m/z):229.0[M+H] + · ! 1 1 1 bandit (30 ^, 〇0 (:?! 13) 38.03 ((1, a ^ = 8.0, 21, also Si), 7.47 ((1, a = 7.9Hz, 2H, ArH!! ), 4.51 (s, 2H, CH2), 3.93 (s, 3H, 0CH3) .MS (ESI (+) 70eV, m / z): 229.0 [m + H] + ·

[0061 ] 实施例4 [0061] Example 4

[0062] 4-溴甲基-3-硝基苯甲酸甲酯(6b)的合成 [0062] 4-bromomethyl-3-nitrobenzoate (6b) Synthesis of

[0063] 将5a(19.50g,0.1mol)溶于氯仿(IOOmL)中,加入NBS(17.8g,0.1mol)和BP0(45mg, O.lSmmol),加热至回流,搅拌反应2.5h,冷却析出白色固体,抽滤,滤液减压蒸除溶剂,得粗品淡黄色油状液体6b 22.50g,不经纯化直接投下一步。 [0063] The 5a (19.50g, 0.1mol) was dissolved in chloroform (IOOmL) was added NBS (17.8g, 0.1mol) and BP0 (45mg, O.lSmmol), heated to reflux, the reaction was stirred for 2.5h, cooled to precipitate white solid was filtered off with suction, the filtrate was evaporated under reduced pressure to give the crude product as a pale yellow oily liquid 6b 22.50g, next step without purification administered.

[0064] 实施例5 [0064] Example 5

[0065] 4-((4-甲基哌嗪-1-基)甲基)苯甲酸盐酸盐(7a)的合成 [0065] 4 - ((4-methyl-piperazin-1-yl) methyl) benzoic acid hydrochloride (7a) of

[0066] 装有回流冷凝管的50mL茄型瓶中加入6&(4.9(^,21.49臟〇1)、^甲基哌嗪(2.678, 26.87mmol)、碳酸钾(2.31g,16.74mmol)、IOmL甲苯和6mL水,于75°C搅拌反应12小时,TLC监测原料反应完毕,停止加热和搅拌,分出甲苯层,水层用乙酸乙酯萃至无产物,合并有机层。 有机层用10%盐酸洗涤至有机层无产物,合并水层。水层再用乙酸乙酯洗至无杂质后用饱和碳酸氢钠水溶液调PH至碱性,用乙酸乙酯萃取至水层无产物,合并乙酸乙酯层。乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,无水硫酸钠干燥过夜。抽滤,减压蒸除溶剂,剩余物中加入20mL 20%盐酸,控温于100°C搅拌反应过夜。冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体7&3.348,收率50.76%,1114.310~311°(:。1!1匪1?(3001〇^,020)37.90((1,了= 8.3Hz,2H,ArH),7.43(d,J = 8.3Hz,2H,ArH),4.32(s,2H,PhCH2),3.44(m,8H,N(CH2 [0066] eggplant flask equipped with a reflux condenser 50mL was added & 6 (4.9 (^, dirty 〇1 21.49), ^ methylpiperazine (2.678, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), IOmL 6mL toluene and water, at 75 ° C the reaction was stirred for 12 h, TLC monitoring completion of the reaction starting material, the heating was stopped and stirring, the toluene layer was separated, the aqueous layer extracted with ethyl acetate until no product, the organic layers were combined. The organic layer was washed with 10% the organic layer was washed with hydrochloric acid until no product, the aqueous layers combined. the aqueous layer was washed with ethyl acetate after the impurity-free with saturated aqueous sodium bicarbonate to adjust PH to basic, aqueous layer was extracted with ethyl acetate until no product was combined ethyl acetate ester layer. the ethyl acetate layer was washed with water three times, washed with brine three times, dried over anhydrous sodium sulfate overnight by suction filtration, the solvent was distilled off under reduced pressure, the residue was added 20mL 20% hydrochloric acid, stirred controlled at 100 ° C The reaction was cooled overnight, slowly with stirring at a low temperature, the precipitated white solid was suction filtered to give 3.348 & intermediate 7, yield 50.76%, 1114.310 ~ 311 ° (:..! 1 1 1 bandit (3001〇 ^, 020)? 37.90 ((1, a = 8.3Hz, 2H, ArH), 7.43 (d, J = 8.3Hz, 2H, ArH), 4.32 (s, 2H, PhCH2), 3.44 (m, 8H, N (CH2 )4),2.81 (s,3H,CH 3).MS(ESI( + )70eV,m/z):235.1[Μ+Η] + · ) 4), 2.81 (s, 3H, CH 3) .MS (ESI (+) 70eV, m / z): 235.1 [Μ + Η] + ·

[0067] 实施例6 [0067] Example 6

[0068] 4-( 4-吗啉甲基)苯甲酸盐酸盐(7b)的合成 [0068] 4- (4-morpholinomethyl) benzoic acid hydrochloride (7b) of

[0069] 装有回流冷凝管的50mL茄型瓶中加入6a(4.90g,21.49mmol)Ji^#(2.34g, 26.87mmol)、碳酸钾(2.31g,16.74mmol)、IOmL甲苯和6mL水,于75°C搅拌反应12小时,TLC监测原料反应完毕,停止加热和搅拌,分出甲苯层,水层用乙酸乙酯萃至无产物,合并有机层。 [0069] eggplant flask equipped with a reflux condenser 50mL were added 6a (4.90g, 21.49mmol) Ji ^ # (2.34g, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), IOmL 6mL toluene and water, at 75 ° C the reaction was stirred for 12 h, TLC monitoring completion of the reaction starting material, the heating was stopped and stirring, the toluene layer was separated, the aqueous layer extracted with ethyl acetate until no product, the organic layers combined. 有机层用10%盐酸洗涤至有机层无产物,合并水层。 The organic layer was washed with 10% hydrochloric acid to the organic layer without product, the aqueous layers combined. 水层再用乙酸乙酯洗至无杂质后用饱和碳酸氢钠水溶液调PH至碱性,用乙酸乙酯萃取至水层无产物,合并乙酸乙酯层。 The aqueous layer was washed with ethyl acetate until free of impurities after with saturated sodium bicarbonate solution PH adjusted to basic, aqueous layer was extracted with ethyl acetate until no product was combined ethyl acetate layers. 乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,无水硫酸钠干燥过夜。 The ethyl acetate layer was washed with water three times, washed with brine three times, dried over anhydrous sodium sulfate overnight. 抽滤,减压蒸除溶剂,剩余物中加入20mL 20 %盐酸,控温于100 °C搅拌反应过夜。 Suction filtration, the solvent was evaporated under reduced pressure, the residue was added 20mL 20% hydrochloric acid at 100 ° C temperature and stirred overnight. 冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体7匕3.648,收率65.94%,111.?.295~297°(:。1!1匪1?(30010^,〇2〇)57.84((1,了= 8.3Hz,2H,ArH) ,7.39(d,J = 8.3Hz,2H,ArH) ,4.23(s,2H,PhCH2) ,3.88(d,J=11.3Hz,2H, OCH2) ,3.56( t, J = 12.1Ηz,2Η, OCH2) ,3.23(d, J= 12.5Hz, 2H, NCH2) ,3.14-2.98 (m,2H, NCH2).MS(ESI(+)70eV,m/z):222.1[M+H]+. Cooled and stirred slowly at a low temperature, the precipitated white solid was suction filtered to give Intermediate 7 3.648 dagger, yield 65.94%, 111 295 ~ 297 ° (:.?..!? 1 1 1 bandit (30010 ^, 〇2 square) 57.84 ((1, a = 8.3Hz, 2H, ArH), 7.39 (d, J = 8.3Hz, 2H, ArH), 4.23 (s, 2H, PhCH2), 3.88 (d, J = 11.3Hz, 2H , OCH2), 3.56 (t, J = 12.1Ηz, 2Η, OCH2), 3.23 (d, J = 12.5Hz, 2H, NCH2), 3.14-2.98 (m, 2H, NCH2) .MS (ESI (+) 70eV , m / z): 222.1 [m + H] +.

[0070] 实施例7 [0070] Example 7

[0071] 4-(哌啶-I-基甲基)苯甲酸盐酸盐(7c)的合成 (-I- piperidin-ylmethyl) benzoic acid hydrochloride (7c) Synthesis of [0071] 4-

[0072] 装有回流冷凝管的50mL茄型瓶中加入6a(4.90g,21.49mmol)dJ^jg(2.29g, 26.87mmol)、碳酸钾(2.31g,16.74mmol)、IOmL甲苯和6mL水,于75°C搅拌反应12小时,TLC监测原料反应完毕,停止加热和搅拌,分出甲苯层,水层用乙酸乙酯萃至无产物,合并有机层。 [0072] eggplant flask equipped with a reflux condenser 50mL were added 6a (4.90g, 21.49mmol) dJ ^ jg (2.29g, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), IOmL 6mL toluene and water, at 75 ° C the reaction was stirred for 12 h, TLC monitoring completion of the reaction starting material, the heating was stopped and stirring, the toluene layer was separated, the aqueous layer extracted with ethyl acetate until no product, the organic layers combined. 有机层用10%盐酸洗涤至有机层无产物,合并水层。 The organic layer was washed with 10% hydrochloric acid to the organic layer without product, the aqueous layers combined. 水层再用乙酸乙酯洗至无杂质后用饱和碳酸氢钠水溶液调PH至碱性,用乙酸乙酯萃取至水层无产物,合并乙酸乙酯层。 The aqueous layer was washed with ethyl acetate until free of impurities after with saturated sodium bicarbonate solution PH adjusted to basic, aqueous layer was extracted with ethyl acetate until no product was combined ethyl acetate layers. 乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,无水硫酸钠干燥过夜。 The ethyl acetate layer was washed with water three times, washed with brine three times, dried over anhydrous sodium sulfate overnight. 抽滤,减压蒸除溶剂,剩余物中加入20mL 20 %盐酸,控温于100 °C搅拌反应过夜。 Suction filtration, the solvent was evaporated under reduced pressure, the residue was added 20mL 20% hydrochloric acid at 100 ° C temperature and stirred overnight. 冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体7〇3.418,收率62.23%,1114.282~284°(:。1!1匪1?(3001〇^,020)37.86((1,了= 8.3Hz,2H,ArH) ,7.38(d,J = 8.3Hz,2H,ArH) ,4.13(s,2H,PhCH2) ,3.26(d,J=11.9Hz,2H, NCH2),2.77(dd,Ji = 12.4,10.0Hz,j2 = 2H,NCH2),1.82~1.13(m,6H,CH2CH2CH2).MS(ESI( + ) 70eV,m/z):220.3[M+H]+. Cooling, stirring slowly at a low temperature, the precipitated white solid was suction filtered, yielding intermediate 7〇3.418, yield 62.23%, 1114.282 ~ 284 ° (:.!? 1 1 1 bandit (3001〇 ^, 020) 37.86 (( 1, a = 8.3Hz, 2H, ArH), 7.38 (d, J = 8.3Hz, 2H, ArH), 4.13 (s, 2H, PhCH2), 3.26 (d, J = 11.9Hz, 2H, NCH2), 2.77 (dd, Ji = 12.4,10.0Hz, j2 = 2H, NCH2), 1.82 ~ 1.13 (m, 6H, CH2CH2CH2) .MS (ESI (+) 70eV, m / z): 220.3 [m + H] +.

[0073] 实施例8 [0073] Example 8

[0074] 4-(吡咯烷-I -基甲基)苯甲酸盐酸盐(7d)的合成 [0074] 4- (pyrrolidin -I - ylmethyl) benzoic acid hydrochloride (7d) Synthesis of

[0075] 装有回流冷凝管的50mL茄型瓶中加入6&(4.9(^,21.49111111 〇1)、吡咯烷(1.918, 26.87mmol)、碳酸钾(2.31g,16.74mmol)、IOmL甲苯和6mL水,于75°C搅拌反应12小时,TLC监测原料反应完毕,停止加热和搅拌,分出甲苯层,水层用乙酸乙酯萃至无产物,合并有机层。 有机层用10%盐酸洗涤至有机层无产物,合并水层。水层再用乙酸乙酯洗至无杂质后用饱和碳酸氢钠水溶液调PH至碱性,用乙酸乙酯萃取至水层无产物,合并乙酸乙酯层。乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,无水硫酸钠干燥过夜。抽滤,减压蒸除溶剂,剩余物中加入20mL 20 %盐酸,控温于100 °C搅拌反应过夜。冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体7d 3. Ilg,收率60.04%,mp278~281Γ</Η NMR(300MHz,D2〇)S7.81(d,J = 8.3Hz,2H,ArH),7.36(d ,J = 8.3Hz,2H,ArH),4.21(s,2H,PhCH2),3.28(dd ,J=10.6,5.3Hz, 2H,NCH2),2.97(dt,Ji [0075] eggplant flask equipped with a reflux condenser 50mL was added & 6 (4.9 (^, 21.49111111 〇1), pyrrolidine (1.918, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), IOmL 6mL toluene and water The reaction at 75 ° C for 12 h, TLC monitoring completion of the reaction starting material, the heating was stopped and stirring, the toluene layer was separated, the aqueous layer extracted with ethyl acetate until no product, the organic layers were combined. The organic layer was washed with 10% hydrochloric acid to the organic no product layer, the aqueous layers combined. the aqueous layer was washed with ethyl acetate until free of impurities after adjusted with saturated aqueous sodium bicarbonate until basic PH, and extracted with ethyl acetate until the aqueous layer no product combined ethyl acetate layers acetic acid ethyl layer was washed with water three times, washed with brine three times, dried over anhydrous sodium sulfate overnight by suction filtration, the solvent was distilled off under reduced pressure, the residue was added 20mL 20% hydrochloric acid at 100 ° C temperature and stirred overnight. cooling , stirring slowly at a low temperature, the precipitated white solid was suction filtered to give intermediate 7d 3. Ilg, a yield of 60.04%, mp278 ~ 281Γ </ Η NMR (300MHz, D2〇) S7.81 (d, J = 8.3Hz , 2H, ArH), 7.36 (d, J = 8.3Hz, 2H, ArH), 4.21 (s, 2H, PhCH2), 3.28 (dd, J = 10.6,5.3Hz, 2H, NCH2), 2.97 (dt, Ji = 10.7,j2 = 7.7Hz,2H,NCH2) ,2.04-1.87(m,2H,CH2) ,1.84~1.69(m, 2H,CH2).MS(ESI( + )70eV,m/z):206.1[M+H] + . = 10.7, j2 = 7.7Hz, 2H, NCH2), 2.04-1.87 (m, 2H, CH2), 1.84 ~ 1.69 (m, 2H, CH2) .MS (ESI (+) 70eV, m / z): 206.1 [ M + H] +.

[0076] 实施例9 [0076] Example 9

[0077] 4-(二乙胺甲基)苯甲酸盐酸盐(7e)的合成 Synthesis of [0077] 4- (diethylamino) benzoic acid hydrochloride (7E) of

[0078] 装有回流冷凝管的50mL茄型瓶中加入6a(4.90g,21.49mm〇l)、:ZK(1.97g, 26.87mmol)、碳酸钾(2.31g,16.74mmol)、IOmL甲苯和6mL水,于75°C搅拌反应12小时,TLC监测原料反应完毕,停止加热和搅拌,分出甲苯层,水层用乙酸乙酯萃至无产物,合并有机层。 [0078] eggplant flask equipped with a reflux condenser 50mL were added 6a (4.90g, 21.49mm〇l) ,: ZK (1.97g, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), IOmL and 6mL toluene water, stirred at 75 ° C for 12 h, TLC monitoring completion of the reaction starting material, the heating was stopped and stirring, the toluene layer was separated, the aqueous layer extracted with ethyl acetate until no product, the organic layers combined. 有机层用10%盐酸洗涤至有机层无产物,合并水层。 The organic layer was washed with 10% hydrochloric acid to the organic layer without product, the aqueous layers combined. 水层再用乙酸乙酯洗至无杂质后用饱和碳酸氢钠水溶液调PH至碱性,用乙酸乙酯萃取至水层无产物,合并乙酸乙酯层。 The aqueous layer was washed with ethyl acetate until free of impurities after with saturated sodium bicarbonate solution PH adjusted to basic, aqueous layer was extracted with ethyl acetate until no product was combined ethyl acetate layers. 乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,无水硫酸钠干燥过夜。 The ethyl acetate layer was washed with water three times, washed with brine three times, dried over anhydrous sodium sulfate overnight. 抽滤,减压蒸除溶剂,剩余物中加入20mL 20 %盐酸,控温于100 °C搅拌反应过夜。 Suction filtration, the solvent was evaporated under reduced pressure, the residue was added 20mL 20% hydrochloric acid at 100 ° C temperature and stirred overnight. 冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体7〇3.278,收率62.64%,1114.285~288°(:。 1!1匪1?(3001〇^,020)37.83((1,了= 8.3Hz,2H,ArH),7.37(d,J = 8.3Hz,2H,ArH),4.17(s,2H,PhCH2) ,3.26-2.72(m,4H,N (CH2CH3)2), 1.09(t,J = 7.3Hz,6H,N(CH2CH3)2).MS(ESI( + )70eV,m/z) :208.1 [M+H] + . Cooled and stirred slowly at a low temperature, the precipitated white solid was suction filtered, yielding intermediate 7〇3.278, yield 62.64%, 1114.285 ~ 288 ° (:. 1! 1 1 bandit? (^ 3001〇, 020) 37.83 (( 1, a = 8.3Hz, 2H, ArH), 7.37 (d, J = 8.3Hz, 2H, ArH), 4.17 (s, 2H, PhCH2), 3.26-2.72 (m, 4H, N (CH2CH3) 2), 1.09 (t, J = 7.3Hz, 6H, N (CH2CH3) 2) .MS (ESI (+) 70eV, m / z): 208.1 [m + H] +.

[0079] 实施例10 [0079] Example 10

[0080] 4-( (4-甲基哌嗪-I-基)甲基)-3-硝基苯甲酸盐酸盐(7f)的合成 [0080] 4- ((4-methylpiperazin--I- yl) methyl) nitrobenzoic acid hydrochloride (7F) -3- Synthesis of

[0081 ] 装有回流冷凝管的25mL茄型瓶中加入6匕(1.0(^,3.66111111〇1)、^甲基哌嗪(0.46 8, 4.58 mmol)、碳酸钾(0.39g,2.85mmol)、2mL甲苯和1.2mL水,于75°C搅拌反应12小时,TLC监测原料反应完毕,停止加热和搅拌,分出甲苯层,水层用乙酸乙酯萃至无产物,合并有机层。 有机层用10%盐酸洗涤至有机层无产物,合并水层。水层再用乙酸乙酯洗至无杂质后用饱和碳酸氢钠水溶液调PH至碱性,用乙酸乙酯萃取至水层无产物,合并乙酸乙酯层。乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,无水硫酸钠干燥过夜。抽滤,减压蒸除溶剂,剩余物中加入IOmL 20%盐酸,控温于IOOtC搅拌反应过夜。冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体7f 0.95g,收率73.64%,πκρ·315~318Γ</Η 匪R(300MHz,D2〇)S8.58(s,1H, ArH),8.16(d,J = 7.5Hz,lH,ArH),7.65(d,J = 7.8Hz,lH,ArH),4.56(s,2H,PhCH2 [0081] eggplant flask equipped with a reflux condenser 25mL added dagger 6 (1.0 (^, 3.66111111〇1), ^ methylpiperazine (0.46 8, 4.58 mmol), potassium carbonate (0.39g, 2.85mmol), 2mL of toluene, and 1.2mL water, stirred at 75 ° C for 12 hours. After completion of reaction was monitored by TLC starting material, the heating was stopped and stirring, the toluene layer was separated, the aqueous layer extracted with ethyl acetate until no product, the organic layers were combined. The organic layer was the organic layer was washed with 10% hydrochloric acid until no product was combined aqueous layer. the aqueous layer was washed with ethyl acetate after the impurity-free with saturated aqueous sodium bicarbonate to adjust PH to basic, aqueous layer was extracted with ethyl acetate until no product was combined the ethyl acetate layer was stirred ethyl acetate layer was washed with water three times, washed with brine three times, dried over anhydrous sodium sulfate overnight by suction filtration, the solvent was distilled off under reduced pressure, the residue was added IOmL 20% hydrochloric acid, in the temperature IOOtC overnight cooling, slow stirring at a low temperature, the precipitated white solid was suction filtered, yielding intermediate 7f 0.95g, yield 73.64%, πκρ · 315 ~ 318Γ </ Η bandit R (300MHz, D2〇) S8.58 ( s, 1H, ArH), 8.16 (d, J = 7.5Hz, lH, ArH), 7.65 (d, J = 7.8Hz, lH, ArH), 4.56 (s, 2H, PhCH2 ),3.88-3.15(m,8H,N(CH2)4N),2.81(s,3H,CH3).MS(ESI( + )70eV,m/z):280.1[M+H] + . ), 3.88-3.15 (m, 8H, N (CH2) 4N), 2.81 (s, 3H, CH3) .MS (ESI (+) 70eV, m / z): 280.1 [M + H] +.

[0082] 实施例11 [0082] Example 11

[0083] 4-(吗啉甲基)-3-硝基苯甲酸盐酸盐(7g)的合成 [0083] 4- (morpholinomethyl) -3-nitrobenzoic acid hydrochloride (7g) of

[0084] 装有回流冷凝管的25mL茄型瓶中加入6b( 1 · OOg,3 · 66mmol)、吗啉(0 · 40g, 4 · 58mmol)、碳酸钾(0 · 39g,2 · 85mmol)、2mL甲苯和I · 2mL水,于75°C搅拌反应12小时,TLC监测原料反应完毕,停止加热和搅拌,分出甲苯层,水层用乙酸乙酯萃至无产物,合并有机层。 [0084] eggplant flask equipped with a reflux condenser 25mL were added 6b (1 · OOg, 3 · 66mmol), morpholine (0 · 40g, 4 · 58mmol), potassium carbonate (0 · 39g, 2 · 85mmol), 2mL of toluene and I · 2mL of water, stirred at 75 ° C for 12 h, TLC monitoring completion of the reaction starting material, the heating was stopped and stirring, the toluene layer was separated, the aqueous layer extracted with ethyl acetate until no product, the organic layers combined. 有机层用10%盐酸洗涤至有机层无产物,合并水层。 The organic layer was washed with 10% hydrochloric acid to the organic layer without product, the aqueous layers combined. 水层再用乙酸乙酯洗至无杂质后用饱和碳酸氢钠水溶液调PH至碱性,用乙酸乙酯萃取至水层无产物,合并乙酸乙酯层。 The aqueous layer was washed with ethyl acetate until free of impurities after with saturated sodium bicarbonate solution PH adjusted to basic, aqueous layer was extracted with ethyl acetate until no product was combined ethyl acetate layers. 乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,无水硫酸钠干燥过夜。 The ethyl acetate layer was washed with water three times, washed with brine three times, dried over anhydrous sodium sulfate overnight. 抽滤,减压蒸除溶剂,剩余物中加入IOmL 20%盐酸,控温于IOOtC搅拌反应过夜。 Suction filtration, the solvent was evaporated under reduced pressure, the residue IOmL 20% hydrochloric acid was added, the reaction temperature in IOOtC stirred overnight. 冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体7区0.76 8,收率68.47%,1114.303~305°(:。1!1匪1?(3001〇^,020)38.61((1,了= 1.6Hz,lH,ArH) ,8.17(dd,Ji = 7.9 j2=1.7Hz,lH,ArH) ,7.66(d,J = 7.9Hz,lH,ArH),4.53 (s,2H,PhCH2),3.59(m,8H,N(CH2) 4O).MS(ESI( + )70eV,m/z) :267.1[M+H] + . Cooled and stirred slowly at a low temperature, the precipitated white solid was suction filtered to give 0.76 Intermediate 7 zone 8, a yield of 68.47%, 1114.303 ~ 305 ° (:.!? 1 1 1 bandit (3001〇 ^, 020) 38.61 ( (1, a = 1.6Hz, lH, ArH), 8.17 (dd, Ji = 7.9 j2 = 1.7Hz, lH, ArH), 7.66 (d, J = 7.9Hz, lH, ArH), 4.53 (s, 2H, PhCH2), 3.59 (m, 8H, N (CH2) 4O) .MS (ESI (+) 70eV, m / z): 267.1 [m + H] +.

[0085] 实施例12 [0085] Example 12

[0086] 4-((哌啶-I-基)甲基)-3-硝基苯甲酸盐酸盐(7h)的合成 [0086] 4 - ((-I- piperidin-yl) methyl) -3-nitrobenzoic acid hydrochloride (7H) of

[0087] 装有回流冷凝管的25mL茄型瓶中加入6b (1 · OOg,3 · 66mmo 1)、哌啶(0 · 39g, 4 · 58mmol)、碳酸钾(0 · 39g,2 · 85mmol)、2mL甲苯和I · 2mL水,于75°C搅拌反应12小时,TLC监测原料反应完毕,停止加热和搅拌,分出甲苯层,水层用乙酸乙酯萃至无产物,合并有机层。 [0087] eggplant flask equipped with a reflux condenser 25mL were added 6b (1 · OOg, 3 · 66mmo 1), piperidine (0 · 39g, 4 · 58mmol), potassium carbonate (0 · 39g, 2 · 85mmol) , 2 mL toluene, and I · 2mL of water, stirred at 75 ° C for 12 h, TLC monitoring completion of the reaction starting material, the heating was stopped and stirring, the toluene layer was separated, the aqueous layer extracted with ethyl acetate until no product, the organic layers combined. 有机层用10%盐酸洗涤至有机层无产物,合并水层。 The organic layer was washed with 10% hydrochloric acid to the organic layer without product, the aqueous layers combined. 水层再用乙酸乙酯洗至无杂质后用饱和碳酸氢钠水溶液调PH至碱性,用乙酸乙酯萃取至水层无产物,合并乙酸乙酯层。 The aqueous layer was washed with ethyl acetate until free of impurities after with saturated sodium bicarbonate solution PH adjusted to basic, aqueous layer was extracted with ethyl acetate until no product was combined ethyl acetate layers. 乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,无水硫酸钠干燥过夜。 The ethyl acetate layer was washed with water three times, washed with brine three times, dried over anhydrous sodium sulfate overnight. 抽滤,减压蒸除溶剂,剩余物中加入IOmL 20%盐酸,控温于IOOtC搅拌反应过夜。 Suction filtration, the solvent was evaporated under reduced pressure, the residue IOmL 20% hydrochloric acid was added, the reaction temperature in IOOtC stirred overnight. 冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体7110.818,收率73.64%,1114.298~301°(:。 1!1匪1?(3001〇^,020)38.59((1,了= 1.6Hz,lH,ArH) ,8.15(dd,Ji = 7.9 j2=1.6Hz,lH,ArH) ,7.63(d,J = 7.9Hz,lH,ArH),4.41 (s,2H,PhCH2) ,3.44(d,J=12.1Hz,2H,NCH2) ,3.02(t,J=12.0Hz,2H,NCH2) ,1.75(d J = 14.8Hz,2H CH2CH2CH2) , I . 66-I .44(m,2H CH2CH2CH2) , I · 34(dd,J = 16.2,8.2Hz, 2HCH2CH2CH2). MS(ESI(+)70eV,m/z):265.1[M+H]+. Cooling, stirring slowly at a low temperature, the precipitated white solid was suction filtered, yielding intermediate 7,110.818, yield 73.64%, 1114.298 ~ 301 ° (:. 1! 1 1 bandit? (^ 3001〇, 020) 38.59 ((1, a = 1.6Hz, lH, ArH), 8.15 (dd, Ji = 7.9 j2 = 1.6Hz, lH, ArH), 7.63 (d, J = 7.9Hz, lH, ArH), 4.41 (s, 2H, PhCH2), 3.44 (d, J = 12.1Hz, 2H, NCH2), 3.02 (t, J = 12.0Hz, 2H, NCH2), 1.75 (d J = 14.8Hz, 2H CH2CH2CH2), I. 66-I .44 (m, 2H CH2CH2CH2), I · 34 (dd, J = 16.2,8.2Hz, 2HCH2CH2CH2) MS (ESI (+.) 70eV, m / z): 265.1 [m + H] +.

[0088] 实施例13 [0088] Example 13

[0089] 4-((吡咯烷-I-基)甲基)-3-硝基苯甲酸盐酸盐(7i)的合成 [0089] 4 - ((-I- pyrrolidin-yl) methyl) -3-nitrobenzoic acid hydrochloride (7i) of

[0090] 装有回流冷凝管的25mL茄型瓶中加入6匕(1.0(^,3.66111111〇1)、吡咯烷(3.268, 4 · 58mmol)、碳酸钾(0 · 39g,2 · 85mmol)、2mL甲苯和1 · 2mL水,于75°C搅拌反应12小时,TLC监测原料反应完毕,停止加热和搅拌,分出甲苯层,水层用乙酸乙酯萃至无产物,合并有机层。 有机层用10%盐酸洗涤至有机层无产物,合并水层。水层再用乙酸乙酯洗至无杂质后用饱和碳酸氢钠水溶液调PH至碱性,用乙酸乙酯萃取至水层无产物,合并乙酸乙酯层。乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,无水硫酸钠干燥过夜。抽滤,减压蒸除溶剂,剩余物中加入IOmL 20%盐酸,控温于IOOtC搅拌反应过夜。冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体710.69 8,收率65.71%,1114.293~296°(:。1!1匪1?(3001〇^,020)38.59((1,了= 1.5Hz,lH,ArH) ,8.17(dd,Ji = 7.9 j2=1.6Hz,lH,ArH) ,7.66(d,J = 8.0Hz,lH,ArH),4.53 [0090] eggplant flask equipped with a reflux condenser 25mL added dagger 6 (1.0 (^, 3.66111111〇1), pyrrolidine (3.268, 4 · 58mmol), potassium carbonate (0 · 39g, 2 · 85mmol), 2mL 1 · 2mL of toluene and water, stirred at 75 ° C for 12 hours. After completion of reaction was monitored by TLC starting material, the heating was stopped and stirring, the toluene layer was separated, the aqueous layer extracted with ethyl acetate until no product, the organic layers were combined. The organic layer was the organic layer was washed with 10% hydrochloric acid until no product was combined aqueous layer. the aqueous layer was washed with ethyl acetate after the impurity-free with saturated aqueous sodium bicarbonate to adjust PH to basic, aqueous layer was extracted with ethyl acetate until no product was combined the ethyl acetate layer was stirred ethyl acetate layer was washed with water three times, washed with brine three times, dried over anhydrous sodium sulfate overnight by suction filtration, the solvent was distilled off under reduced pressure, the residue was added IOmL 20% hydrochloric acid, in the temperature IOOtC The reaction was cooled overnight, slowly with stirring at a low temperature, the precipitated white solid was suction filtered to give intermediate 8 710.69, yield 65.71%, 1114.293 ~ 296 ° (:..!? 1 1 1 bandit (3001〇 ^, 020) 38.59 ((1, a = 1.5Hz, lH, ArH), 8.17 (dd, Ji = 7.9 j2 = 1.6Hz, lH, ArH), 7.66 (d, J = 8.0Hz, lH, ArH), 4.53 (s,2H,PhCH2),3.48((1, J = 5 · IHz,2H,NCH2),3· 32-3.00(m,2H,NCH2),2.03(s,2H,CH2) ,1.83 (dd,Ji = 7.4,j2 = 5.1Hz,2H,CH2).MS(ESI( + )70eV,m/z):251.1[M+H] + . (S, 2H, PhCH2), 3.48 ((1, J = 5 · IHz, 2H, NCH2), 3 · 32-3.00 (m, 2H, NCH2), 2.03 (s, 2H, CH2), 1.83 (dd, Ji = 7.4, j2 = 5.1Hz, 2H, CH2) .MS (ESI (+) 70eV, m / z): 251.1 [m + H] +.

[0091] 实施例14 [0091] Example 14

[0092] 4-(二乙胺甲基)-3-硝基苯甲酸盐酸盐(7j)的合成 [0092] 4- (diethylamine meth) Synthesis of 3-nitrobenzoic acid hydrochloride (. 7J) of

[0093] 装有回流冷凝管的25mL茄型瓶中加入6b(1.00g,3.66mm〇l)、:ZK(0.33g, 4 · 58mmol)、碳酸钾(0 · 39g,2 · 85mmol)、2mL甲苯和1 · 2mL水,于75°C搅拌反应12小时,TLC监测原料反应完毕,停止加热和搅拌,分出甲苯层,水层用乙酸乙酯萃至无产物,合并有机层。 [0093] eggplant flask equipped with a reflux condenser 25mL were added 6b (1.00g, 3.66mm〇l) ,: ZK (0.33g, 4 · 58mmol), potassium carbonate (0 · 39g, 2 · 85mmol), 2mL 1 · 2mL of toluene and water, stirred at 75 ° C for 12 h, TLC monitoring completion of the reaction starting material, the heating was stopped and stirring, the toluene layer was separated, the aqueous layer extracted with ethyl acetate until no product, the organic layers combined. 有机层用10%盐酸洗涤至有机层无产物,合并水层。 The organic layer was washed with 10% hydrochloric acid to the organic layer without product, the aqueous layers combined. 水层再用乙酸乙酯洗至无杂质后用饱和碳酸氢钠水溶液调PH至碱性,用乙酸乙酯萃取至水层无产物,合并乙酸乙酯层。 The aqueous layer was washed with ethyl acetate until free of impurities after with saturated sodium bicarbonate solution PH adjusted to basic, aqueous layer was extracted with ethyl acetate until no product was combined ethyl acetate layers. 乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,无水硫酸钠干燥过夜。 The ethyl acetate layer was washed with water three times, washed with brine three times, dried over anhydrous sodium sulfate overnight. 抽滤,减压蒸除溶剂,剩余物中加入IOmL 20%盐酸,控温于IOOtC搅拌反应过夜。 Suction filtration, the solvent was evaporated under reduced pressure, the residue IOmL 20% hydrochloric acid was added, the reaction temperature in IOOtC stirred overnight. 冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体7j 0.78g,收率73.58%,mp286~28%~</Η NMR(300MHz,D2〇)S 8.63(d,J = 1.7Hz,lH,ArH) ,8.17(dd,Ji = 7.9 j2=1.7Hz,lH,ArH) ,7.65(d,J = 8.0Hz,lH,ArH),4.49 (s,2H,PhCH2),3.16(q,J = 7.3Hz,4H,NCH2),1.17(t,J = 7.3Hz,6H,CH3).MS(ESI( + )70eV,m/ z):253.1[M+H]+. Cooled and stirred slowly at a low temperature, the precipitated white solid was suction filtered to give Intermediate 7j 0.78g, yield 73.58%, mp286 ~ 28% ~ </ Η NMR (300MHz, D2〇) S 8.63 (d, J = 1.7 hz, lH, ArH), 8.17 (dd, Ji = 7.9 j2 = 1.7Hz, lH, ArH), 7.65 (d, J = 8.0Hz, lH, ArH), 4.49 (s, 2H, PhCH2), 3.16 (q , J = 7.3Hz, 4H, NCH2), 1.17 (t, J = 7.3Hz, 6H, CH3) .MS (ESI (+) 70eV, m / z): 253.1 [m + H] +.

[0094] 实施例15 [0094] Example 15

[0095] 4-((4-甲基哌嗪-I-基)甲基)苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基) 苯酯(I -I) [0095] 4 - ((4-methylpiperazin--I- yl) methyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy styryl) benzene ester (I -I)

[0096] 在装有回流冷凝管的25mL茄型瓶中加入7a(0.27g,lmmol)和5mL氯化亚砜,回流搅拌反应过夜,减压蒸除溶剂尽干,直接投下一步。 [0096] Add 25mL round-flask equipped with a reflux condenser 7a (0.27g, lmmol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent evaporated under reduced pressure to make dry, cast the next step directly. 将04-4(0.3168,1.01111]1〇1)溶于511^二氯甲烷中,然后倒入装有上述新鲜制备酰氯的茄型瓶中,加入三乙胺(0.20g,0.28mL,2.0mmol), 于室温搅拌反应2h,TLC监测反应完毕,减压蒸除溶剂,剩余物加入饱和食盐水,用乙酸乙酯萃至水层无产物,乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,有机层无水硫酸钠干燥过夜。 The 04-4 (0.3168,1.01111] 1〇1) ^ 511 was dissolved in dichloromethane, and then poured into a eggplant flask containing freshly prepared above acid chloride, was added triethylamine (0.20g, 0.28mL, 2.0mmol ), the reaction was stirred at room temperature for 2h, TLC monitoring completion of the reaction, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate and the aqueous layer until no product was ethyl acetate layer was washed with water three times and brine three times, the organic layer was dried over anhydrous sodium sulfate overnight. 抽滤,滤液旋干,剩余物柱层析(二氯甲烷:甲醇= 200:1)分离纯化,得白色固体II 0 · 23g,收率43 · 40%,m·p · 102~104Γ。 Filtered off with suction, the filtrate by rotary evaporation, the residue was by column chromatography (dichloromethane: methanol = 200: 1) separation and purification, to give a white solid II 0 · 23g, yield 43 · 40%, m · p · 102 ~ 104Γ. IR(KBr,υαιΓ1): 3431,9277,2938,2794,2739,2504, 2530,2497,1739,1611,1578,1504,1451,1415,1398,1384,1328,1263,1209,1126,1068, 1035,1011,901,851,807,768,749,694,580,462.¾ Mffi(300MHz,CDCl3)δ8· 11(d,J = 8.0Hz,2H,ArH),7.44(d ,J = 8.0Hz,2H,ArH),7.17(d ,J = 8.6Hz,lH,ArH),7.13(s,lH,ArH), 6.90(d,J = 8.4Hz,lH,ArH) ,6.54(s,2H,ArH) ,6.48(d,J = 2.8Hz,2H,ArH) ,3.81(s,3H, 0〇13),3.79(8,3!1,0〇13),3.73(8,6!1,2\0〇13),3.62(8,2!1,?11〇12),2.77~2.60(111,8!1,哌嗪氢),2.48(8,3!1,~〇13).服45頂5 111/2 533.2656[]\1+!1] + (。&1。(1€(^〇31出7吣06,533.2646)· IR (KBr, υαιΓ1): 3431,9277,2938,2794,2739,2504, 2530,2497,1739,1611,1578,1504,1451,1415,1398,1384,1328,1263,1209,1126,1068, 1035 , 1011,901,851,807,768,749,694,580,462.¾ Mffi (300MHz, CDCl3) δ8 · 11 (d, J = 8.0Hz, 2H, ArH), 7.44 (d, J = 8.0Hz, 2H, ArH), 7.17 (d, J = 8.6Hz , lH, ArH), 7.13 (s, lH, ArH), 6.90 (d, J = 8.4Hz, lH, ArH), 6.54 (s, 2H, ArH), 6.48 (d, J = 2.8Hz, 2H, ArH ), 3.81 (s, 3H, 0〇13), 3.79 (8,3! 1,0〇13), 3.73 (8,6! 2 \ 0〇13), 3.62 (8,2! 1 ,? 11〇12), 2.77 ~ 2.60 (111,8! 1, piperazine hydrogen), 2.48 (8,3! 1 ~ 〇13). 5 45 served 111/2 533.2656 [] \ 1+! 1] + (. & 1. (1 € (^ 〇31 a 7 Qin 06,533.2646) ·

[0097] 将II (0.1 Og,0.19mmol)溶于2mL二氯甲烷中,滴加饱和HCl的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得II · HCl 0.07g,收率61.57%,mp234~236°C。 [0097] The II (0.1 Og, 0.19mmol) was dissolved in 2mL of dichloromethane, saturated HCl in ether was added dropwise, stirred for 5 minutes, the precipitated white solid was suction filtered to give II · HCl 0.07g, yield 61.57% , mp234 ~ 236 ° C.

[0098] 实施例16 [0098] Example 16

[0099] 4-(吗啉甲基)苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-2)盐酸盐 [0099] 4- (morpholinomethyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1-2) hydrochloride

[0100] 在装有回流冷凝管的25mL茄型瓶中加入7b(0.26g,lmmol)和5mL氯化亚砜,回流搅拌反应过夜,减压蒸除溶剂尽干,直接投下一步。 [0100] Add 25mL round-flask equipped with a reflux condenser 7b (0.26g, lmmol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent evaporated under reduced pressure to make dry, cast the next step directly. 将04-4(0.3168,1.01111]1〇1)溶于511^二氯甲烷中,然后倒入装有上述新鲜制备酰氯的茄型瓶中,加入三乙胺(0.20g,0.28mL,2.0mmol), 于室温搅拌反应2h,TLC监测反应完毕,减压蒸除溶剂,剩余物加入饱和食盐水,用乙酸乙酯萃至水层无产物,乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,有机层无水硫酸钠干燥过夜。 The 04-4 (0.3168,1.01111] 1〇1) ^ 511 was dissolved in dichloromethane, and then poured into a eggplant flask containing freshly prepared above acid chloride, was added triethylamine (0.20g, 0.28mL, 2.0mmol ), the reaction was stirred at room temperature for 2h, TLC monitoring completion of the reaction, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate and the aqueous layer until no product was ethyl acetate layer was washed with water three times and brine three times, the organic layer was dried over anhydrous sodium sulfate overnight. 抽滤,滤液旋干,剩余物柱层析(二氯甲烷:甲醇= 200:1)分离纯化,得白色固体1-2 0.198,收率36.53%,111.?.50~52。 Filtered off with suction, the filtrate by rotary evaporation, the residue was by column chromatography (dichloromethane: methanol = 200: 1) separation and purification, to give 0.198 1-2 as a white solid, yield 36.53%, 52 ~ 11 150.?. (:。11?(诎1时111- 1):3456,3001,2936,2836,1739,1612, 1578,1509, 1453,1415,1350,1328,1263,1208,1174,1116,1067,1007,912,867,797,768, 749,719,693,623,580,526.¾ NMR(300MHz,CDCl3)S8.11 (d,J = 8.2Hz,2H,ArH),7.47(d,J = 8.1Hz,2H,ArH),7.17(dd ,Ji = 8.4 j2 = 2.0Hz,lH,ArH),7.14(d ,J=1.9Hz,lH,ArH),6.90 (d ,J = 8.4Hz,lH,ArH) ,6.54(s , 2H,ArH), 6.47(d ,J = 3.2Hz , 2H, ArH), 3.81 (s , 3H,OCH3), 3.79(s,3H,0CH3),3.73(m,10H,PhCH2,2X0CH 3and OCH2),3.58(m,2H,OCH2) ,2.40~2.57(m, 4H,N(CH2)2) .13C 匪R(75MHz,CDC13)S163.96,152.46,149.98,143.60,139.08,136.57, 131.98,129.81,129.57,128.98,128.61,128.11,127.64,127.35,122.79,111.55,105.27, 66.49,62.54,60.41,55.48,55.45,53.15.HR-ESIMS m/z 520.2330[M+H]+(calcd for C30H34NO7,520.2330). (:? .11 (Qu 1:00 111-1): 3456,3001,2936,2836,1739,1612, 1578,1509, 1453,1415,1350,1328,1263,1208,1174,1116,1067,1007, 912,867,797,768, 749,719,693,623,580,526.¾ NMR (300MHz, CDCl3) S8.11 (d, J = 8.2Hz, 2H, ArH), 7.47 (d, J = 8.1Hz, 2H, ArH), 7.17 (dd, Ji = 8.4 j2 = 2.0Hz, lH, ArH), 7.14 (d, J = 1.9Hz, lH, ArH), 6.90 (d, J = 8.4Hz, lH, ArH), 6.54 (s, 2H, ArH), 6.47 (d, J = 3.2Hz, 2H, ArH), 3.81 (s, 3H, OCH3), 3.79 (s, 3H, 0CH3), 3.73 (m, 10H, PhCH2,2X0CH 3and OCH2), 3.58 (m, 2H, OCH2), 2.40 ~ 2.57 (m, 4H, N (CH2) 2) .13C bandit R (75MHz, CDC13) S163.96,152.46,149.98,143.60,139.08,136.57, 131.98,129.81,129.57,128.98,128.61,128.11,127.64,127.35, 122.79,111.55,105.27, 66.49,62.54,60.41,55.48,55.45,53.15.HR-ESIMS m / z 520.2330 [m + H] + (calcd for C30H34NO7,520.2330).

[0101] 将1-2(0.1 Og,0.19mmol)溶于2mL二氯甲烷中,滴加饱和HCl的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-2 · HCl 0 · 08g,收率74 · 77 %,m· p · 128~130°C。 [0101] The 1-2 (0.1 Og, 0.19mmol) was dissolved in 2mL of dichloromethane was added dropwise a saturated solution of HCl in ether, stirred for 5 minutes, the precipitated white solid was suction filtered to give 1-2 · HCl 0 · 08g yield 74 · 77%, m · p · 128 ~ 130 ° C. IR(KBr,υαιι _1):3426,2936,2837,2536,2368,1742,1613,1578,1509,1455,1422,1327,1263,1209, 1183,1125,1072,1020,974,911,870,797,757,698,581,526,459.¾ NMR(300MHz,CDC13)S 13.39(s,1H) ,8.22(d ,J = 5.1Hz,2H,ArH) ,7.85(d ,J = 4.5Hz,2H,ArH) ,7.17(d ,J = 8.4Hz , lH,ArH),7.14(m,lH,ArH),6.90(d J = 8.4Hz,lH,ArH),6.52(s,2H,ArH),6.47(s,2H,ArH), 4.30(s,2H,PhCH2),4.27(m,2H,0CH2),4.02~3.88(m,2H,0CH2),3.80(s,3H,0CH 3),3.78(s, 3H,0CH3),3.72(s,6H,2X0CH3),3.35(m,2H,NCH2),2.92(m,2H,NCH2)· IR (KBr, υαιι _1): 3426,2936,2837,2536,2368,1742,1613,1578,1509,1455,1422,1327,1263,1209, 1183,1125,1072,1020,974,911,870,797,757,698,581,526,459.¾ NMR (300MHz , CDC13) S 13.39 (s, 1H), 8.22 (d, J = 5.1Hz, 2H, ArH), 7.85 (d, J = 4.5Hz, 2H, ArH), 7.17 (d, J = 8.4Hz, lH, ArH), 7.14 (m, lH, ArH), 6.90 (d J = 8.4Hz, lH, ArH), 6.52 (s, 2H, ArH), 6.47 (s, 2H, ArH), 4.30 (s, 2H, PhCH2 ), 4.27 (m, 2H, 0CH2), 4.02 ~ 3.88 (m, 2H, 0CH2), 3.80 (s, 3H, 0CH 3), 3.78 (s, 3H, 0CH3), 3.72 (s, 6H, 2X0CH3), 3.35 (m, 2H, NCH2), 2.92 (m, 2H, NCH2) ·

[0102] 实施例17 [0102] Example 17

[0103] 4-(哌啶-I-基甲基)苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(I- 3)盐酸盐 [0103] 4- (piperidin--I--ylmethyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (I- 3) Hydrochloride

[0104] 在装有回流冷凝管的25mL茄型瓶中加入7c(255. Img,Immo 1)和5mL氯化亚砜,回流搅拌反应过夜,减压蒸除溶剂尽干,直接投下一步。 [0104] Add 25mL round-flask equipped with a reflux condenser 7c (255. Img, Immo 1) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, solvent was distilled off under reduced pressure to make a dry, cast the next step directly. 将CA-4(0.316g,1.0 mmol)溶于5mL二氯甲烷中,然后倒入装有上述新鲜制备酰氯的茄型瓶中,加入三乙胺(0.20g,0.28mL, 2. Ommol ),于室温搅拌反应2h,TLC监测反应完毕,减压蒸除溶剂,剩余物加入饱和食盐水, 用乙酸乙酯萃至水层无产物,乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,有机层无水硫酸钠干燥过夜。 The CA-4 (0.316g, 1.0 mmol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride with eggplant-shaped flask, added triethylamine (0.20g, 0.28mL, 2. Ommol), The reaction was stirred at room temperature for 2h, TLC monitored the reaction is completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, the aqueous layer extracted with ethyl acetate until no product was ethyl acetate layer was washed with water three times and brine three times, The organic layer was dried over anhydrous sodium sulfate overnight. 抽滤,滤液旋干,剩余物柱层析(二氯甲烷:甲醇= 200:1)分离纯化,得1-3白色固体0.21g,收率40.62%,πκρ·100~102°C。 Filtered off with suction, the filtrate by rotary evaporation, the residue was by column chromatography (dichloromethane: methanol = 200: 1) separation and purification, to give 0.21 g of 1-3 as a white solid, a yield of 40.62%, πκρ · 100 ~ 102 ° C. 将I-3(0.10g,0.193mmol)溶于2mL二氯甲烷中, 滴加饱和HCl的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-3 · HCl 0.09g,收率84.11% ,1114.132-1351^11^(1(8100114):3426,2939,2837,2636,2536,2384,1742,1613, 1579,1509,1454,1424,1327,1265,1210,1183,1125,1072,1020,946,902,859,796,768, 754,698,576.¾ NMR(300MHz,CDC13)S12.47(s,1H),8.22((1, J = 3.6Hz,2H,ArH) ,7.92-7.76 (m,2H,ArH),7.19(dd ,J = 8.4,1.8Hz,lH,ArH),7.14(d ,J=1.9Hz,lH,ArH),6.91(d ,J = 8.5 Hz,lH,ArH),6.54(s,2H,ArH),6.48(s,2H,ArH),4.22(s,2H,PhCH2),3.82(s,3H,0CH3),3.80 (s,3H,0CH 3) ,3.74(s,6H,2X0CH3) ,2.64(m,2H,NCH2) ,2.34(m,2H,NCH2) ,1.99(m,2H, C虫CH2CH2),I · 89(m,2H,CH2CH2C^2),I · 88~I · 77 (m,2H,CH2C^2CH2) · 13C NMR(75MHz,CDCl3) δ 163.23,152.45,149.78,138.80,133.02,131.98,131.38,131.30,130.52,130.38,129.55, 129.03,128.01,127.61,122.55,111.59,105.21,60.42,59.91,55.49,55.44,52.53, 22.06,21.50.HR-ESIMS m/z 518.2532[M+H] + (calcd for C3IH36NO6,518.2537). The I-3 (0.10g, 0.193mmol) was dissolved in 2mL of dichloromethane was added dropwise a saturated solution of HCl in ether, stirred for 5 minutes, the precipitated white solid was suction filtered to give 1-3 · HCl 0.09g, yield 84.11 %, 1114.132-1351 ^ 11 ^ (1 (8100114): 3426,2939,2837,2636,2536,2384,1742,1613, 1579,1509,1454,1424,1327,1265,1210,1183,1125,1072, 1020,946,902,859,796,768, 754,698,576.¾ NMR (300MHz, CDC13) S12.47 (s, 1H), 8.22 ((1, J = 3.6Hz, 2H, ArH), 7.92-7.76 (m, 2H, ArH), 7.19 ( dd, J = 8.4,1.8Hz, lH, ArH), 7.14 (d, J = 1.9Hz, lH, ArH), 6.91 (d, J = 8.5 Hz, lH, ArH), 6.54 (s, 2H, ArH) , 6.48 (s, 2H, ArH), 4.22 (s, 2H, PhCH2), 3.82 (s, 3H, 0CH3), 3.80 (s, 3H, 0CH 3), 3.74 (s, 6H, 2X0CH3), 2.64 (m , 2H, NCH2), 2.34 (m, 2H, NCH2), 1.99 (m, 2H, C insect CH2CH2), I · 89 (m, 2H, CH2CH2C ^ 2), I · 88 ~ I · 77 (m, 2H , CH2C ^ 2CH2) · 13C NMR (75MHz, CDCl3) δ 163.23,152.45,149.78,138.80,133.02,131.98,131.38,131.30,130.52,130.38,129.55, 129.03,128.01,127.61,122.55,111.59,105.21,60.42, 59.91,55.49,55.44,52.53, 22.06,21.50.HR-ESIMS m / z 518.2532 [m + H] + (calcd for C3IH36NO6,518.2537).

[0105] 实施例18 [0105] Example 18

[0106] 4-(吡咯烷-I-基甲基)苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-4)盐酸盐 [0106] 4- (-I- pyrrolidin-ylmethyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1-4) Hydrochloride

[0107] 在装有回流冷凝管的25mL茄型瓶中加入7d(241.1mg,lmmol)和5mL氯化亚砜,回流搅拌反应过夜,减压蒸除溶剂尽干,直接投下一步。 [0107] Add 25mL round-flask equipped with a reflux condenser 7d (241.1mg, lmmol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, solvent was distilled off under reduced pressure to make a dry, cast the next step directly. 将CA-4(0.316g,1.0 mmol)溶于5mL二氯甲烷中,然后倒入装有上述新鲜制备酰氯的茄型瓶中,加入三乙胺(0.20g,0.28mL, 2. Ommol ),于室温搅拌反应2h,TLC监测反应完毕,减压蒸除溶剂,剩余物加入饱和食盐水, 用乙酸乙酯萃至水层无产物,乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,有机层无水硫酸钠干燥过夜。 The CA-4 (0.316g, 1.0 mmol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride with eggplant-shaped flask, added triethylamine (0.20g, 0.28mL, 2. Ommol), The reaction was stirred at room temperature for 2h, TLC monitored the reaction is completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, the aqueous layer extracted with ethyl acetate until no product was ethyl acetate layer was washed with water three times and brine three times, The organic layer was dried over anhydrous sodium sulfate overnight. 抽滤,滤液旋干,剩余物柱层析(二氯甲烷:甲醇=500:1)分离纯化,得1-4白色固体0.20g,收率39.76%,mp .98~10(TC dlUKBr,ucm-3 :3434,2938,2383,2348,2314, 1741,1612,1579,1509,1460,1420,1327,1265,1184,1125,1071,1019,860,797,769,703, 582.将1-4(0.1 Og,0.199mmol)溶于2mL二氯甲烷中,滴加饱和HCl的乙醚溶液,搅拌5分钟, 析出白色固体,抽滤,得1-4 · HCl 0.08g,收率- 3422,2938,2837,2569,2469,2362,1747,1624,1578,1541,1508,1454,1427,1345,1327, 1257,1207,1153,1126,1006,919,894,856,797,771,747,580,462.¾ NMR(300MHz,CDC13)S 12.86(s,lH),8.22(d ,J = 7.5Hz,2H,ArH),7.84(d ,J = 7.6Hz,2H,ArH),7.19(dd ,Ji = 8.4 J2 = 2.0Hz,lH,ArH) ,7.14(d,J = 2.0Hz,lH,ArH) ,6.91(d,J = 8.5Hz,lH,ArH) ,6.54(s,2H, ArH),6.48(d J=1.7Hz,2H,ArH),4.30(s,2H,PhCH2),3.82(s,3H,0CH3),3.80(s,3H,0CH3), 3.73(s,6H,2XOCH 3) ,3.70~3.68(m,2H,NCH2),2.88(m,2H,NCH2),2.27(m,2H,CH 2) ,2.08 (m,2H,CH2)· 13C 匪R(75MHz,CDC13)S163· 25 Filtered off with suction, the filtrate by rotary evaporation, the residue was by column chromatography (dichloromethane: methanol = 500: 1) separation and purification, to give 1-4 as a white solid 0.20 g, yield 39.76%, mp .98 ~ 10 (TC dlUKBr, ucm -3: 3434,2938,2383,2348,2314, 1741,1612,1579,1509,1460,1420,1327,1265,1184,1125,1071,1019,860,797,769,703, 582. the 1-4 (0.1 Og, 0.199 mmol) was dissolved in 2mL of dichloromethane was added dropwise a saturated solution of HCl in ether, stirred for 5 minutes, the precipitated white solid was suction filtered to give 1-4 · HCl 0.08g, yield - 3422,2938,2837,2569,2469 , 2362,1747,1624,1578,1541,1508,1454,1427,1345,1327, 1257,1207,1153,1126,1006,919,894,856,797,771,747,580,462.¾ NMR (300MHz, CDC13) S 12.86 (s, lH), 8.22 ( d, J = 7.5Hz, 2H, ArH), 7.84 (d, J = 7.6Hz, 2H, ArH), 7.19 (dd, Ji = 8.4 J2 = 2.0Hz, lH, ArH), 7.14 (d, J = 2.0 hz, lH, ArH), 6.91 (d, J = 8.5Hz, lH, ArH), 6.54 (s, 2H, ArH), 6.48 (d J = 1.7Hz, 2H, ArH), 4.30 (s, 2H, PhCH2 ), 3.82 (s, 3H, 0CH3), 3.80 (s, 3H, 0CH3), 3.73 (s, 6H, 2XOCH 3), 3.70 ~ 3.68 (m, 2H, NCH2), 2.88 (m, 2H, NCH2), 2.27 (m, 2H, CH 2), 2.08 (m, 2H, CH2) · 13C bandit R (75MHz, CDC13) S163 · 25 ,152.43,149.77,138.83,136.46,134.65, 131.98,130.59,130.33,130.16,129.55,129.03,128.03,127.54,122.57,111.58,105.22, 102.77,60.41,57.32,55.48,55.43,52.81,22.68.HR-ESIMS m/z 504.2384[M+H]+(calcd for C30H34NO6,504.2381). , 152.43,149.77,138.83,136.46,134.65, 131.98,130.59,130.33,130.16,129.55,129.03,128.03,127.54,122.57,111.58,105.22, 102.77,60.41,57.32,55.48,55.43,52.81,22.68.HR-ESIMS m / z 504.2384 [m + H] + (calcd for C30H34NO6,504.2381).

[0108] 实施例19 [0108] Example 19

[0109] 4-(二乙胺-I-基甲基)苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-5)盐酸盐 [0109] 4- (diethylamino -I--ylmethyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1-5 )Hydrochloride

[0110] 在装有回流冷凝管的25mL茄型瓶中加入7e(243. Img,Immo 1)和5mL氯化亚砜,回流搅拌反应过夜,减压蒸除溶剂尽干,直接投下一步。 [0110] Add 25mL round-flask equipped with a reflux condenser 7e (243. Img, Immo 1) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, solvent was distilled off under reduced pressure to make a dry, cast the next step directly. 将CA-4(0.316g,1.0 mmol)溶于5mL二氯甲烷中,然后倒入装有上述新鲜制备酰氯的茄型瓶中,加入三乙胺(0.20g,0.28mL, 2. Ommol ),于室温搅拌反应2h,TLC监测反应完毕,减压蒸除溶剂,剩余物加入饱和食盐水, 用乙酸乙酯萃至水层无产物,乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,有机层无水硫酸钠干燥过夜。 The CA-4 (0.316g, 1.0 mmol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride with eggplant-shaped flask, added triethylamine (0.20g, 0.28mL, 2. Ommol), The reaction was stirred at room temperature for 2h, TLC monitored the reaction is completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, the aqueous layer extracted with ethyl acetate until no product was ethyl acetate layer was washed with water three times and brine three times, The organic layer was dried over anhydrous sodium sulfate overnight. 抽滤,滤液旋干,剩余物柱层析(二氯甲烷:甲醇= 500:1)分离纯化,得白色固体1-5 0.25g,收率49.50%。 Filtered off with suction, the filtrate by rotary evaporation, the residue was by column chromatography (dichloromethane: methanol = 500: 1) separation and purification, to give a white solid 1-5 0.25g, yield 49.50%. 将1-5(0.1 Og,0.198mmol)溶于2mL二氯甲烷中,滴加饱和HCl的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得I-5-HC1 0.09g,收率84 .ll%,mpll5~118 2H,ArH) ,7.21(dd,Ji = 8.4 j2 = 2.0Hz,lH,ArH) ,7.16(d,J = 2.0Hz,lH,ArH),6.90(d J = 8.5Hz,lH,ArH),6.51(s,2H,ArH),6.46(d,J=1.7Hz,2H,ArH),4.27(s,2H,PhCH2),3.86(s, 3H,0CH3),3.80(s,3H,0CH3),3.65(s,6H,0CH3),3.16(s,2H,NCH2),3.02(s,2H,NCH2),1.42 (s,6H,N(CH2(^3)2) .13C 匪R(75MHz,CDC13)S163.49,152.15,146.88,136.40,135.96, 132.35,132.03,131.04,129.68,129.01,128.65,127.32,126.75,124.38,120.14,109.07, 105.48,60.30,55.48,55.34,54.95,45.72,8.05.HR-ESIMS m/z 506.2536[M+H]+(calcd for C30H36NO6,506.2537). The 1-5 (0.1 Og, 0.198mmol) was dissolved in 2mL of dichloromethane was added dropwise a saturated solution of HCl in ether, stirred for 5 minutes, the precipitated white solid was suction filtered to give I-5-HC1 0.09g, yield 84 .ll%, mpll5 ~ 118 2H, ArH), 7.21 (dd, Ji = 8.4 j2 = 2.0Hz, lH, ArH), 7.16 (d, J = 2.0Hz, lH, ArH), 6.90 (d J = 8.5Hz , lH, ArH), 6.51 (s, 2H, ArH), 6.46 (d, J = 1.7Hz, 2H, ArH), 4.27 (s, 2H, PhCH2), 3.86 (s, 3H, 0CH3), 3.80 (s , 3H, 0CH3), 3.65 (s, 6H, 0CH3), 3.16 (s, 2H, NCH2), 3.02 (s, 2H, NCH2), 1.42 (s, 6H, N (CH2 (^ 3) 2) .13C bandit R (75MHz, CDC13) S163.49,152.15,146.88,136.40,135.96, 132.35,132.03,131.04,129.68,129.01,128.65,127.32,126.75,124.38,120.14,109.07, 105.48,60.30,55.48,55.34,54.95,45.72 , 8.05.HR-ESIMS m / z 506.2536 [m + H] + (calcd for C30H36NO6,506.2537).

[0111] 实施例20 [0111] Example 20

[0112] 4-((4-甲基哌嗪-I-基)甲基)-3-硝基苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-6)盐酸盐 [0112] 4 - ((4-methylpiperazin--I- yl) methyl) 3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxyphenyl (1-6) of the hydrochloride salt of styrene-yl) phenyl acetate

[0113] 在装有回流冷凝管的25mL茄型瓶中加入7以0.328,1臟〇1)和51^氯化亚砜,回流搅拌反应过夜,减压蒸除溶剂尽干,直接投下一步。 [0113] In 25mL eggplant flask equipped with a reflux condenser was added 7 0.328,1 dirty 〇1) 51 ^ and thionyl chloride, the reaction was stirred at reflux overnight, solvent was distilled off under reduced pressure to make a dry, cast the next step directly. 将04-4(0.3168,1.01111]1〇1)溶于511^二氯甲烷中,然后倒入装有上述新鲜制备酰氯的茄型瓶中,加入三乙胺(0.20g,0.28mL,2.0mmol), 于室温搅拌反应2h,TLC监测反应完毕,减压蒸除溶剂,剩余物加入饱和食盐水,用乙酸乙酯萃至水层无产物,乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,有机层无水硫酸钠干燥过夜。 The 04-4 (0.3168,1.01111] 1〇1) ^ 511 was dissolved in dichloromethane, and then poured into a eggplant flask containing freshly prepared above acid chloride, was added triethylamine (0.20g, 0.28mL, 2.0mmol ), the reaction was stirred at room temperature for 2h, TLC monitoring completion of the reaction, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate and the aqueous layer until no product was ethyl acetate layer was washed with water three times and brine three times, the organic layer was dried over anhydrous sodium sulfate overnight. 抽滤,滤液旋干,剩余物柱层析(二氯甲烷:甲醇= 200:1)分离纯化,得1-6白色固体0.23g,收率39.86%,m. p .70~72。 Filtered off with suction, the filtrate by rotary evaporation, the residue was by column chromatography (dichloromethane: methanol = 200: 1) separation and purification, to give 1-6 as a white solid 0.23g, yield 39.86%, m p .70 ~ 72.. (:。1以诎1时111-3 :3438,2937,2837,2796,1746,1618, 1579,1537,1509,1455,1426,1355,1328,1282,1263,1241,1208,1127,1011,919,856,819, 797,772,742,580,462.¾ NMR(300MHz,CDCl3)S8.57(d, J= 1.3Hz, 1H,ArH),8.29(dd, J = 8.0,1.5Hz,lH,ArH) ,7.74(d,J = 8.0Hz,lH,ArH) ,7.19(dd,J = 8.5,1.9Hz,lH,ArH) ,7.12 (d ,J=1.9Hz,lH,ArH),6.91(d J = 8.5Hz,lH,ArH),6.52(s,lH,ArH),6.49(s,lH,HC = CH), 3.87(s,2H,PhCH2N),3.82(s,3H,0CH3),3.80(s,3H,0CH3),3.73(s,6H,2X0CH3),2.70-2.38 (m,8H,哌嗪氢),2.33(s,3H,NCH 3) .13C 匪R(75MHz,CDC13)S162.00,152.50,149.66, 149.29,138.83,138.64,133.04,131.88,130.79,129.70,129.24,129.04,127.90,127.72, 125.61,122.50,111.63,105.33,60.39,58.37,55.44,54.40,52.32,45.27.HR-ESIMS m/z 578.2488[M+H] + (calcd for C3IH36N3Os,578.2497). (: .1 to 1 111-3 Qu: 3438,2937,2837,2796,1746,1618, 1579,1537,1509,1455,1426,1355,1328,1282,1263,1241,1208,1127,1011, 919,856,819, 797,772,742,580,462.¾ NMR (300MHz, CDCl3) S8.57 (d, J = 1.3Hz, 1H, ArH), 8.29 (dd, J = 8.0,1.5Hz, lH, ArH), 7.74 (d, J = 8.0 hz, lH, ArH), 7.19 (dd, J = 8.5,1.9Hz, lH, ArH), 7.12 (d, J = 1.9Hz, lH, ArH), 6.91 (d J = 8.5Hz, lH, ArH), 6.52 (s, lH, ArH), 6.49 (s, lH, HC = CH), 3.87 (s, 2H, PhCH2N), 3.82 (s, 3H, 0CH3), 3.80 (s, 3H, 0CH3), 3.73 (s , 6H, 2X0CH3), 2.70-2.38 (m, 8H, piperazine hydrogen), 2.33 (s, 3H, NCH 3) .13C bandit R (75MHz, CDC13) S162.00,152.50,149.66, 149.29,138.83,138.64 , 133.04,131.88,130.79,129.70,129.24,129.04,127.90,127.72, 125.61,122.50,111.63,105.33,60.39,58.37,55.44,54.40,52.32,45.27.HR-ESIMS m / z 578.2488 [m + H] + (calcd for C3IH36N3Os, 578.2497).

[0114] 将1-6(0.1 Og,0.173mmol)溶于2mL二氯甲烷中,滴加饱和HCl的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-6 · HCl 0 · 08g,收率75 · 47 %,m· p · 144~146°C。 [0114] The 1-6 (0.1 Og, 0.173mmol) was dissolved in 2mL of dichloromethane was added dropwise a saturated solution of HCl in ether, stirred for 5 minutes, the precipitated white solid was suction filtered to give 1-6 · HCl 0 · 08g yield 75 · 47%, m · p · 144 ~ 146 ° C. IR(KBr,υαιι -4 :3422,2938,2837,2647,2388,1747,1624,1579,1541,1509,1454,1426,1345,1327, 1295,1261,1206,1182,1153,1124,1010,948,857,770,747,610,581. IR (KBr, υαιι -4: 3422,2938,2837,2647,2388,1747,1624,1579,1541,1509,1454,1426,1345,1327, 1295,1261,1206,1182,1153,1124,1010, 948,857,770,747,610,581.

[0115] 实施例21 [0115] Example 21

[0116] 4-(吗啉甲基)-3-硝基苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-7)盐酸盐 [0116] 4- (morpholinomethyl) 3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1-7 )Hydrochloride

[0117] 在装有回流冷凝管的25mL茄型瓶中加入7g(0.30g,lmmol)和5mL氯化亚砜,回流搅拌反应过夜,减压蒸除溶剂尽干,直接投下一步。 [0117] Add 25mL round-flask equipped with a reflux condenser 7g (0.30g, lmmol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent evaporated under reduced pressure to make dry, cast the next step directly. 将04-4(0.3168,1.01111]1〇1)溶于511^二氯甲烷中,然后倒入装有上述新鲜制备酰氯的茄型瓶中,加入三乙胺(0.20g,0.28mL,2.0mmol), 于室温搅拌反应2h,TLC监测反应完毕,减压蒸除溶剂,剩余物加入饱和食盐水,用乙酸乙酯萃至水层无产物,乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,有机层无水硫酸钠干燥过夜。 The 04-4 (0.3168,1.01111] 1〇1) ^ 511 was dissolved in dichloromethane, and then poured into a eggplant flask containing freshly prepared above acid chloride, was added triethylamine (0.20g, 0.28mL, 2.0mmol ), the reaction was stirred at room temperature for 2h, TLC monitoring completion of the reaction, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate and the aqueous layer until no product was ethyl acetate layer was washed with water three times and brine three times, the organic layer was dried over anhydrous sodium sulfate overnight. 抽滤,滤液旋干,剩余物柱层析(二氯甲烷:甲醇= 300:1)分离纯化,得白色固体0.23g, 收率40.78%,m. p .82~84°C oIlUKBr,ucm-3 :3467,2960,2932,2852,1745,1615,1578, 1530,1511,1451,1426,1412,1351,1339,1322,1269,1243,1207,1115,1082,1027,1009, 913,881,868,841,803,767,740,707,582.¾ NMR(300MHz,CDCl3)S8.58(s,lH,ArH),8.29 (d,J = 7.1Hz,lH,ArH) ,7.77(d,J = 7.4Hz,lH,ArH) ,7.23-7.09(m,2H,ArH) ,6.91(d J = 7.9Hz,lH,ArH) ,6.52(s, 2H, ArH), 6.49(s , 2H,HC = CH), 3.86(s, 2H,PhCH2N), 3.82(s, 3H, OCH3),3.80(s,3H,OCH3),3.73(s,6H,2XOCH3),3.68(m,4H,0(q^)2),2.46(m,4H,N(C§〇2) .13C NMR(75MHz,CDC13)S161.94,152.50,149.64,149.32,138.60,138.43,133.06,131.89, 130.83,129.68,129.24,129.13,127.88,127.76,125.65,122.46,111.63,105.31,66.38, 60.37,58.85,55.43,53.05,29.18.HR-ESIMS m/z 565.2178[M+H] + (calcd for C30H33N2O9, 565.2181). Filtered off with suction, the filtrate by rotary evaporation, the residue was by column chromatography (dichloromethane: methanol = 300: 1) separation and purification, to give a white solid 0.23g, yield 40.78%, m p .82 ~ 84 ° C oIlUKBr, ucm-. 3: 3467,2960,2932,2852,1745,1615,1578, 1530,1511,1451,1426,1412,1351,1339,1322,1269,1243,1207,1115,1082,1027,1009, 913,881,868,841,803,767,740,707,582.¾ NMR (300MHz, CDCl3) S8.58 (s, lH, ArH), 8.29 (d, J = 7.1Hz, lH, ArH), 7.77 (d, J = 7.4Hz, lH, ArH), 7.23-7.09 (m, 2H, ArH), 6.91 (d J = 7.9Hz, lH, ArH), 6.52 (s, 2H, ArH), 6.49 (s, 2H, HC = CH), 3.86 (s, 2H, PhCH2N), 3.82 (s , 3H, OCH3), 3.80 (s, 3H, OCH3), 3.73 (s, 6H, 2XOCH3), 3.68 (m, 4H, 0 (q ^) 2), 2.46 (m, 4H, N (C§〇2 ) .13C NMR (75MHz, CDC13) S161.94,152.50,149.64,149.32,138.60,138.43,133.06,131.89, 130.83,129.68,129.24,129.13,127.88,127.76,125.65,122.46,111.63,105.31,66.38, 60.37,58.85 , 55.43,53.05,29.18.HR-ESIMS m / z 565.2178 [m + H] + (calcd for C30H33N2O9, 565.2181).

[0118] 将1-7(0.1 Og,0.177mmol)溶于2mL二氯甲烷中,滴加饱和HCl的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-7 · HCl 0.08g,收率75.47%,mp216~219°C。 [0118] The 1-7 (0.1 Og, 0.177mmol) was dissolved in 2mL of dichloromethane was added dropwise a saturated solution of HCl in ether, stirred for 5 minutes, the precipitated white solid was suction filtered to give 1-7 · HCl 0.08g, yield 75.47%, mp216 ~ 219 ° C.

[0119] 实施例22 [0119] Example 22

[0120] 4-(哌啶-1-基甲基)-3-硝基苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基) 苯酯(1-8)盐酸盐 [0120] 4- (piperidin-1-ylmethyl) -3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1-8) hydrochloride

[0121] 在装有回流冷凝管的25mL茄型瓶中加入7h(0.30g,lmmol)和5mL氯化亚砜,回流搅拌反应过夜,减压蒸除溶剂尽干,直接投下一步。 [0121] Add 25mL round-flask equipped with a reflux condenser 7h (0.30g, lmmol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, solvent was distilled off under reduced pressure to make a dry, cast the next step directly. 将04-4(0.3168,1.01111]1〇1)溶于511^二氯甲烷中,然后倒入装有上述新鲜制备酰氯的茄型瓶中,加入三乙胺(0.20g,0.28mL,2.0mmol), 于室温搅拌反应2h,TLC监测反应完毕,减压蒸除溶剂,剩余物加入饱和食盐水,用乙酸乙酯萃至水层无产物,乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,有机层无水硫酸钠干燥过夜。 The 04-4 (0.3168,1.01111] 1〇1) ^ 511 was dissolved in dichloromethane, and then poured into a eggplant flask containing freshly prepared above acid chloride, was added triethylamine (0.20g, 0.28mL, 2.0mmol ), the reaction was stirred at room temperature for 2h, TLC monitoring completion of the reaction, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate and the aqueous layer until no product was ethyl acetate layer was washed with water three times and brine three times, the organic layer was dried over anhydrous sodium sulfate overnight. 抽滤,滤液旋干,剩余物柱层析(二氯甲烷:甲醇= 400:1)分离纯化,得白色固体0.19g, 收率33.80%,m. p .74~76°C dlUKBr,ucm-3 :3467,3002,2931,2853,2782,2747,2335, 2330,1745,1615,1578,1528,1512,1464,1447,1424,1412,1348,1337,1320,1290,1274, 1239,1222,1176,1158,1112,1081,1027,1012,994,978,912,881,867,841,803,766,740, 582.¾ 匪R(300MHz,CDCl3)δ8·58(s,1H,ArH),8.29(d,J = 7.7Hz,lH,ArH),7.83((1, J = 7.4Hz,lH,ArH),7.19(d ,J = 8.3Hz,lH,ArH),7.13(s,lH,ArH),6.91(d ,J = 8.4Hz,lH,ArH), 6.52(s,2H,ArH),6.48(s,2H,HC = CH),3.81(d ,J = 5.9Hz,8H,2X0CH3and PhCH2N) ,3.73( s, 6H,2 XOCH3) ,2.28-2.48(m,4H,N(C虫)2),1.38-1.49(m,4H,OT2CH2(^ 2),0.97-0.81(m,2H, CH2CH2CH2). 13C NMR(75MHz,CDCl3)δ162.10,152.50,149.69,149.22,139.84,138.69, 133.01,131.89,130.76,129.70,129.23,128.65,127.92,127.68,125.50,122.54,111.62, 105.33,77.04,76.62,76.19,60.38,59.14,55.44,54.17,29.21,25.47,23.61.HR-ESIMS m/z 563.2389[M+H] + (calcd for C31H35N2O8,563.2388). Filtered off with suction, the filtrate by rotary evaporation, the residue was by column chromatography (dichloromethane: methanol = 400: 1) separation and purification, to give 0.19 g of a white solid, a yield of 33.80%, m p .74 ~ 76 ° C dlUKBr, ucm-. 3: 3467,3002,2931,2853,2782,2747,2335, 2330,1745,1615,1578,1528,1512,1464,1447,1424,1412,1348,1337,1320,1290,1274, 1239,1222, 1176,1158,1112,1081,1027,1012,994,978,912,881,867,841,803,766,740, 582.¾ bandit R (300MHz, CDCl3) δ8 · 58 (s, 1H, ArH), 8.29 (d, J = 7.7Hz, lH, ArH) , 7.83 ((1, J = 7.4Hz, lH, ArH), 7.19 (d, J = 8.3Hz, lH, ArH), 7.13 (s, lH, ArH), 6.91 (d, J = 8.4Hz, lH, ArH), 6.52 (s, 2H, ArH), 6.48 (s, 2H, HC = CH), 3.81 (d, J = 5.9Hz, 8H, 2X0CH3and PhCH2N), 3.73 (s, 6H, 2 XOCH3), 2.28- 2.48 (m, 4H, N (C worm) 2), 1.38-1.49 (m, 4H, OT2CH2 (^ 2), 0.97-0.81 (m, 2H, CH2CH2CH2). 13C NMR (75MHz, CDCl3) δ162.10,152.50, 149.69,149.22,139.84,138.69, 133.01,131.89,130.76,129.70,129.23,128.65,127.92,127.68,125.50,122.54,111.62, 105.33,77.04,76.62,76.19,60.38,59.14,55.44,54.17,29.21,25.47, 23.61.HR-ESIMS m / z 563.2389 [m + H] + (calcd for C31H35N2O8,563.2388).

[0122] 将1-8(0.1 Og,0.178mmol)溶于2mL二氯甲烷中,滴加饱和HCl的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-8 · HCl 0.08g,收率75.12%,mp202~204°C。 [0122] The 1-8 (0.1 Og, 0.178mmol) was dissolved in 2mL of dichloromethane was added dropwise a saturated solution of HCl in ether, stirred for 5 minutes, the precipitated white solid was suction filtered to give 1-8 · HCl 0.08g, yield 75.12%, mp202 ~ 204 ° C.

[0123] 实施例23 [0123] Example 23

[0124] 4-(吡咯烷-1-基甲基)-3-硝基苯甲酸-(Z)-2-甲氧基-5-(3,4,5_三甲氧苯乙烯基)苯酯(Π -9)盐酸盐 [0124] 4- (pyrrolidin-1-ylmethyl) -3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5_-trimethoxy styryl) phenyl ester (Π -9) hydrochloride

[0125] 在装有回流冷凝管的25mL茄型瓶中加入7i (286. Img,Immol)和5mL氯化亚砜,回流搅拌反应过夜,减压蒸除溶剂尽干,直接投下一步。 [0125] 7i added in 25mL round-bottom flask equipped with a reflux condenser (286. Img, Immol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, solvent was distilled off under reduced pressure to make a dry, cast the next step directly. 将CA-4(0.316g,1.0 mmol)溶于5mL二氯甲烷中,然后倒入装有上述新鲜制备酰氯的茄型瓶中,加入三乙胺(0.20g,0.28mL, 2. Ommol),于室温搅拌反应2h,TLC监测反应完毕,减压蒸除溶剂,剩余物加入饱和食盐水, 用乙酸乙酯萃至水层无产物,乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,有机层无水硫酸钠干燥过夜。 The CA-4 (0.316g, 1.0 mmol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride with eggplant-shaped flask, added triethylamine (0.20g, 0.28mL, 2. Ommol), The reaction was stirred at room temperature for 2h, TLC monitored the reaction is completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, the aqueous layer extracted with ethyl acetate until no product was ethyl acetate layer was washed with water three times and brine three times, The organic layer was dried over anhydrous sodium sulfate overnight. 抽滤,滤液旋干,剩余物柱层析(二氯甲烷:甲醇= 200:1)分离纯化,得白色固体1-9 0.2(^,收率36.50%,111.?.56~58。(:。11?(诎1此111-1):3447,2935,2835,2362,1746, 1618,1579,1535,1508,1460,1426,1350,1328,1265,1240,1206,1126,1024,1006,915, 892,854,795,739,578.¾ 匪R(300MHz,CDCl3)S8.63((1, J = 1.5Hz,lH,ArH),8.31((1, J = 8.1Hz,lH, ArH),7.88(d,J = 8.1Hz,lH,ArH),7.19(dd,J = 8.5,2.1Hz,lH,ArH),7.13(dJ = 2.0Hz,lH,ArH),6.91(d J = 8.5Hz,lH,ArH),6.53(s,2H,ArH),6.49(s,2H,ArH),4.01(s, 2H,PhCH 2N),3.82(s,3H,OCH3),3.80(s,3H,OCH3),3.73(s,6H,2XOCH 3) ,2.54(s,4H N (OT2)2),1.80(s,4H,OT2OT2) .13C 匪R(75MHz,CDCl3)δ162·13,152.49,149.67,148.65, 140.33,138.66,136.61,133.37,131.91,130.61,129.68,129.22,128.54,127.94,127.68, 125.59,122.56,111.59,105.26,60.42,56.11,55.55,55.44,53.76,23.24.HR-ESIMS m/z 549.2234[M+H] + (calcd for C30H33N2Os,549.2231). Filtered off with suction, the filtrate by rotary evaporation, the residue was by column chromatography (dichloromethane: methanol = 200: 1) separation and purification, to give a white solid 0.2 1-9 (^, yield 36.50%, 58 ~ 11 156 (.?. :? .11 (1 this Qu 111-1): 3447,2935,2835,2362,1746, 1618,1579,1535,1508,1460,1426,1350,1328,1265,1240,1206,1126,1024,1006 , 915, 892,854,795,739,578.¾ bandit R (300MHz, CDCl3) S8.63 ((1, J = 1.5Hz, lH, ArH), 8.31 ((1, J = 8.1Hz, lH, ArH), 7.88 (d, J = 8.1Hz, lH, ArH), 7.19 (dd, J = 8.5,2.1Hz, lH, ArH), 7.13 (dJ = 2.0Hz, lH, ArH), 6.91 (d J = 8.5Hz, lH, ArH), 6.53 (s, 2H, ArH), 6.49 (s, 2H, ArH), 4.01 (s, 2H, PhCH 2N), 3.82 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.73 (s, 6H, 2XOCH 3), 2.54 (s, 4H N (OT2) 2), 1.80 (s, 4H, OT2OT2) .13C bandit R (75MHz, CDCl3) δ162 · 13,152.49,149.67,148.65, 140.33,138.66,136.61,133.37 , 131.91,130.61,129.68,129.22,128.54,127.94,127.68, 125.59,122.56,111.59,105.26,60.42,56.11,55.55,55.44,53.76,23.24.HR-ESIMS m / z 549.2234 [m + H] + (calcd for C30H33N2Os, 549.2231).

[0126] 将1-9(0.1 Og,0.182mmol)溶于2mL二氯甲烷中,滴加饱和HCl的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-9 · HCl 0.08g,收率75.47%,mpl06~108°C<JR(KBr,ucm -4 :3426,2938,2837,2564,1748,1624,1578,1541,1508,1454,1426,1412,1345,1327, 1258,1207,1125,1006,856,797,771,747,581,461.¾ NMR(300MHz,CDC13)S12.93(s,1H, ArH),8.73(m,2H,ArH),8.51(d ,J = 6.3Hz,lH,ArH),7.18(dd ,Ji = 8.4 j2 = 1.4Hz,lH,ArH), 7.1l(d,J= 1.4Hz,lH,ArH) ,6.90(d,J = 8.4Hz,lH,ArH) ,6.50(s,2H,ArH) ,6.47(s,2H, ArH),4.73(s,2H,PhOT2N),3.84~3.66(m,14H,4X0Cfe,NOT2),3.17~2.94(m,2H,NC^), 2.21(m,4H,CH2CH2). [0126] The 1-9 (0.1 Og, 0.182mmol) was dissolved in 2mL of dichloromethane was added dropwise a saturated solution of HCl in ether, stirred for 5 minutes, the precipitated white solid was suction filtered to give 1-9 · HCl 0.08g, yield 75.47%, mpl06 ~ 108 ° C <JR (KBr, ucm -4: 3426,2938,2837,2564,1748,1624,1578,1541,1508,1454,1426,1412,1345,1327, 1258,1207 , 1125,1006,856,797,771,747,581,461.¾ NMR (300MHz, CDC13) S12.93 (s, 1H, ArH), 8.73 (m, 2H, ArH), 8.51 (d, J = 6.3Hz, lH, ArH), 7.18 ( dd, Ji = 8.4 j2 = 1.4Hz, lH, ArH), 7.1l (d, J = 1.4Hz, lH, ArH), 6.90 (d, J = 8.4Hz, lH, ArH), 6.50 (s, 2H, ArH), 6.47 (s, 2H, ArH), 4.73 (s, 2H, PhOT2N), 3.84 ~ 3.66 (m, 14H, 4X0Cfe, NOT2), 3.17 ~ 2.94 (m, 2H, NC ^), 2.21 (m, 4H, CH2CH2).

[0127] 实施例24 [0127] Example 24

[0128] 4-(二乙胺甲基)-3-硝基苯甲酸-(Z)-2-甲氧基-5-(3,4,5-三甲氧苯乙烯基)苯酯(1-10)盐酸盐 [0128] 4- (diethylamino) -3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy-styryl) phenyl ester (1- 10) hydrochloride

[0129] 在装有回流冷凝管的25mL茄型瓶中加入7 j (288. Img,Immol)和5mL氯化亚砜,回流搅拌反应过夜,减压蒸除溶剂尽干,直接投下一步。 [0129] Add 7 j (288. Img, Immol) in a 25mL round-bottom flask equipped with a reflux condenser and 5mL thionyl chloride, the reaction was stirred at reflux overnight, solvent was distilled off under reduced pressure to make a dry, cast the next step directly. 将CA-4(0.316g,1.0 mmol)溶于5mL二氯甲烷中,然后倒入装有上述新鲜制备酰氯的茄型瓶中,加入三乙胺(0.20g,0.28mL, 2. Ommol ),于室温搅拌反应2h,TLC监测反应完毕,减压蒸除溶剂,剩余物加入饱和食盐水, 用乙酸乙酯萃至水层无产物,乙酸乙酯层用水洗三遍,饱和食盐水洗三遍,有机层无水硫酸钠干燥过夜。 The CA-4 (0.316g, 1.0 mmol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride with eggplant-shaped flask, added triethylamine (0.20g, 0.28mL, 2. Ommol), The reaction was stirred at room temperature for 2h, TLC monitored the reaction is completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, the aqueous layer extracted with ethyl acetate until no product was ethyl acetate layer was washed with water three times and brine three times, The organic layer was dried over anhydrous sodium sulfate overnight. 抽滤,滤液旋干,剩余物柱层析(二氯甲烷:甲醇= 200:1)分离纯化,得白色固体1-10 0.23g,收率41.82%,πκρ·96~98°C。 Filtered off with suction, the filtrate by rotary evaporation, the residue was by column chromatography (dichloromethane: methanol = 200: 1) separation and purification, to give a white solid 1-10 0.23g, yield 41.82%, πκρ · 96 ~ 98 ° C. 将1-10(0.1(^,0.182臟〇1)溶于211^二氯甲烷中,滴加饱和HCl的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-10 · HCl 0.08g,收率75.05% ,1114.104-1061^11^(01^11^):3431,2939,2838,2561,1748,1624,1578,1541, 1508,1463,1426,1346,1327,1295,1260,1205,1125,1009,857,797,771,741,580. 1H NMR (300MHz,CDC13)512.89(s,1H) ,8.92(d,J = 5.1Hz,lH,ArH),8.76(s,lH,ArH) ,8.54(d J = 6.1Hz,lH,ArH),7.21(dd ,J = 8.5,1.8Hz,lH,ArH),7.13(d ,J=1.8Hz,lH,ArH),6.92(d J = 8.5Hz,lH,ArH) ,6.52(s, 2H, ArH), 6.49(s , 2H,HC = CH) ,4.62(s,2H,PhCH2N) ,3.82(s,3H, OCH3) ,3.81( s,3H,0CH3) ,3.73( s,6H,2 XOCH3) ,3.22( s,4H, N(CH2CH3)2) ,1.47( s,6H, N (CH2(^3)2) .13C 匪R (75MHz,CDCl3)δ161.18,152.49,149.47,149.33,138.42,134.87, 134.84,131.89,131.86,129.69,129.31,128.12,127.93,127.80,126.34,122.30 ,111. 66, 105.28,77.02,76.59,76.17,60.39,55.46,55.43,50.54,46.26,8·14.HR-ESIMS m/z 551.2383[M+H] + (calcd for C30H35N2Os,551.2388). The 1-10 (0.1 (^, 0.182 dirty 〇1) ^ 211 was dissolved in dichloromethane, saturated HCl in ether was added dropwise, stirred for 5 minutes, the precipitated white solid was suction filtered to give 1-10 · HCl 0.08g yield 75.05%, 1114.104-1061 ^ 11 ^ (01 ^ 11 ^): 3431,2939,2838,2561,1748,1624,1578,1541, 1508,1463,1426,1346,1327,1295,1260,1205 , 1125,1009,857,797,771,741,580. 1H NMR (300MHz, CDC13) 512.89 (s, 1H), 8.92 (d, J = 5.1Hz, lH, ArH), 8.76 (s, lH, ArH ), 8.54 (d J = 6.1Hz, lH, ArH), 7.21 (dd, J = 8.5,1.8Hz, lH, ArH), 7.13 (d, J = 1.8Hz, lH, ArH), 6.92 (d J = 8.5Hz, lH, ArH), 6.52 (s, 2H, ArH), 6.49 (s, 2H, HC = CH), 4.62 (s, 2H, PhCH2N), 3.82 (s, 3H, OCH3), 3.81 (s, 3H, 0CH3), 3.73 (s, 6H, 2 XOCH3), 3.22 (s, 4H, N (CH2CH3) 2), 1.47 (s, 6H, N (CH2 (^ 3) 2) .13C bandit R (75MHz, CDCl3) δ161.18,152.49,149.47,149.33,138.42,134.87, 134.84,131.89,131.86,129.69,129.31,128.12,127.93,127.80,126.34,122.30, 111. 66, 105.28,77.02,76.59,76.17,60.39,55.46, 55.43,50.54,46.26,8 · 14.HR-ESIMS m / z 551.2383 [m + H] + (calcd for C30H35N2Os, 551.2388).

[0130] 实施例25 [0130] Example 25

[0131] 片剂 [0131] Tablets

[0132] 取实施例20中所得化合物0.5g,淀粉2. Og,糊精1.0 g混合,用适量30%乙醇作湿润剂,制粒,压片。 [0132] Take the compound obtained in Example 20. 0.5g, starch 2. Og, dextrin 1.0 g were mixed with an appropriate amount of 30% ethanol as wetting agents, granulating, tabletting.

Claims (7)

  1. 1. 通式(I)的化合物或其药学上可接受的盐: 1. Formula (I) compound or a pharmaceutically acceptable salt thereof:
    Figure CN104817519BC00021
    其中R代表:H、卤素、硝基或三氟甲基; Wherein R represents: H, halogen, nitro or trifluoromethyl;
    Figure CN104817519BC00022
  2. 2. 权利要求1的化合物或其药学上可接受的盐,其中R代表Η或硝基。 Pharmaceutically acceptable salt thereof, or a compound as claimed in claim 2, wherein R represents a nitro group or Η.
  3. 3. 权利要求1的化合物或其药学上可接受的盐,其中Υ代表 The compound or a pharmaceutically acceptable salt thereof wherein one of the representative Υ claim,
    Figure CN104817519BC00023
  4. 4. 权利要求1的化合物或其药学上可接受的盐,其中药学上可接受的盐为权利要求1的通式(I)化合物与下列酸形成的酸加成盐:盐酸、氢溴酸、硫酸、碳酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。 Pharmaceutically acceptable salt thereof, or a compound as claimed in claim 4, wherein the pharmaceutically acceptable salt of the general formula 1 (I) acid addition salts formed with the following acids claim: hydrochloric, hydrobromic, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or ferulic acid.
  5. 5. -种药物组合物,其中含有权利要求1的通式(I)化合物或其药学上可接受的盐及药学上可接受的载体。 5 - pharmaceutical compositions containing as claimed in claim formula (I) a pharmaceutically acceptable salt thereof and a compound or a pharmaceutically acceptable carrier.
  6. 6. 权利要求1的化合物或其药学上可接受的盐在制备治疗血管生成性疾病的药物中的用途。 The compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament treating angiogenic diseases in claim.
  7. 7. 权利要求6的用途,其中血管生成性疾病是肿瘤或慢性炎症。 The use of claim 6, wherein the angiogenic disorder is cancer or chronic inflammation.
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