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Publication numberCN104817519 B
Publication typeGrant
Application numberCN 201510235806
Publication dateNov 16, 2016
Filing dateMay 11, 2015
Priority dateMay 11, 2015
Also published asCN104817519A
Publication number201510235806.3, CN 104817519 B, CN 104817519B, CN 201510235806, CN-B-104817519, CN104817519 B, CN104817519B, CN201510235806, CN201510235806.3
Inventors徐云根, 刘坤, 宋晓翰, 陈泓竹, 张宏波, 张灵芝, 朱启华
Applicant中国药科大学
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
一类ca-4的衍生物、其制法及其医药用途 A derivative ca-4, and its preparation method and medical use translated from Chinese
CN 104817519 B
Abstract  translated from Chinese
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 the field of pharmaceutical chemistry, in particular to derivatives (I) a Class Combretastatin A-4, 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 of MCF-7 human breast cancer cell proliferation has a strong inhibitory effect, at the same time, some of the compounds as well as the proliferation of human umbilical chicken chorioallantoic membrane angiogenesis vein endothelial cells also have 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。 Thus, 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。 The compounds of this invention have good solubility in water.
Claims(7)  translated from Chinese
1. 通式(I)的化合物或其药学上可接受的盐: 1. The general 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. 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。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R represents a nitro group or Η.
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 of claim 1, wherein the representative of Υ
Figure CN104817519BC00023
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。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt of claim 1 of the formula (I) and acid addition salts of compounds of the following acids: 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, p-toluenesulfonic acid or ferulic acid.
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 claim 1 of formula (I), a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
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 or a pharmaceutically acceptable salt thereof as claimed in claim for the manufacture of therapeutic angiogenesis disease medicine.
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。 Use according to claim 6, wherein the angiogenic disease is cancer or chronic inflammation.
Description  translated from Chinese
一类CA-4的衍生物、其制法及其医药用途 A derivative of the CA-4, their preparation and their pharmaceutical use

技术领域 TECHNICAL 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。 As well as methods for their preparation Inhibition [0001] The present invention relates to the field of pharmaceutical chemistry, in particular to a class of Combretastatin A-4 (CA-4) derivative of tumor vessels.

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 out of a small molecule vascular blockers (Vascular Disrupting Agents, VDA), which binds to vascular endothelial cells β subunit of tubulin colchicine binding site point, resulting in the polymerization of tubulin, thereby changing its skeletal structure and morphology of endothelial cells, enhance its vascular permeability, disrupt blood flow, causing the tumor vascular endothelial cell apoptosis, 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 application.

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 compounds of formula I category. 本发明的化合物具有良好的水溶性。 The compounds of this invention have good solubility in water. 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 in MCF-7 human breast cancer cells have a strong inhibitory effect, at the same time, some of the compounds in human umbilical vein endothelial cells proliferation and the chick chorioallantoic membrane (Chicken chorioal Iactoic membrane, CAM) angiogenesis and has a good inhibition. 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。 Thus, compounds of formula I 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.

[0004] 本发明的化合物通式I如下: [0004] The compounds of formula I of the present invention are 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] Formula I may be combined with a pharmaceutically acceptable acid addition salts of the acid, the acid include 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, p-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-methyl-piperazin-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-yl-methyl) 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-yl-methyl) 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-methyl-piperazin-1-yl) methyl) 3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy 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- (morpholin-ylmethyl) -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] The present invention is a compound of formula (I) is prepared 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] From 3,4,5_ trimethoxy acid (1) and 3-hydroxymethyl-benzaldehyde (2) Preparation of compound 3, are the reactants of triethylamine and acetic anhydride condensation effect -4- 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 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] Compound 6 was prepared from the 5, is dissolved in chloroform and the reaction was added NBS and benzoyl peroxide initiator obtained.

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。 The 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 8 from compound 7, is placed in the reaction was 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] Preparation 9 by the compound 8, compound 12 is chlorinated with a chlorinating agent to give. 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] Compound 9 was prepared by the target compound I, is the compound 13 in the role of acid binding agent and compound 4 in a solvent condensation. 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。 Acid binding agent is selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium hydrogen 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。 The solvent is 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 to provide a pharmaceutical composition thereof comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of the present invention, 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 compound of the present invention may be added a pharmaceutically acceptable carrier common pharmaceutical formulations such as tablets, capsules, powders, syrups, solutions, suspensions, injections, may be added flavors, sweeteners , liquid or solid fillers or diluents and other 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 compound of the present invention in clinical administration may be oral, injection and other means.

[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。 [0034] In general, CA-4 derivatives of the invention for use in therapy, 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。 Also be based on the severity of the disease and the different formulations, doses outside of 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 some compounds 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%CO2,37C孵育。 [0036] we, the proliferation of SRB assay test compounds on MCF-7 cells and HUVECs [0037] cells were passaged to a logarithmic growth phase were digested by trypsin -EDTA, adjusting final concentration of 5 X104 / mL, seeded in 96-well plates, each well 200yL, 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37C,5 % CO2培养箱中培养,各种药物每浓度设5个平行孔。 24h after (to confluent cell monolayer bottom of the hole (96-well flat-bottom)), each well was discarded board original liquid, then it was replaced with cell culture medium containing the appropriate concentration of the drug at 37 C, 5% CO2 incubator, various concentrations of the drug provided every five parallel holes. SRB用1 %醋酸配成0.4%溶液。 SRB in 1% acetic acid solution dubbed 0.4%. 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4C放置lh,这样细胞固定在培养孔的底部。 Cells cultured in the dosing end (48h) after trichloroacetic acid (TCA) is fixed: each hole plus adherent cells precooled solution 50 uL of 50% TCA (10% final concentration) is fixed; TCA must be added when gently added 5min then moved to 4 C tablet placed lh, such cells are immobilized in the wells of the bottom surface of the culture medium, the first to stand. 倒掉固定液,小孔用灭菌三蒸水洗5 遍,甩干,空气干燥。 Discard the fixative holes with sterilized triple-distilled water 5 times, drying, air drying. 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, dark, place IOmin at room temperature. 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 five times, 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。 Combining SRB with 150uL10mmol / L unbuffered Tris alkaline (pH 10.5) was dissolved, on the 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 an enzyme-linked immunosorbent assay, with a blank zero adjustment, at a wavelength of 490nm at the determination of each hole OD value. 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 tumor cell growth inhibition is defined as the ratio of drug to tumor cells in vitro inhibition rate and calculate the IC 5q value. 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 = (drug-free cell control well OD value - medication hole OD) control wells OD value / drug-free cell X 100%

[0038]表1化合物对人乳腺癌细胞MCF-7增殖抑制作用(ϊΙ,η = 3) [0038] Table 1 compound on human breast cancer MCF-7 cell proliferation (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_ "From Table 1 we buy mining experience junction η" to forgive the majority of the compounds of MCF-7 tumor cell growth inhibitory activity than positive drug CA-4 (IC5q = 0.0 58μΜ) stronger than the same time a strong doxorubicin magnitude, wherein the compound 1-3 (IC50 = 0.024μΜ) activity was significantly stronger than the 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, some of the compounds 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 experimental results show that the compounds tested on human umbilical vein endothelial cells have a strong inhibitory effect.

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

[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37C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 six days the eggs with warm water twice in 1: 1000 benzalkonium bromide soak after 3min into 37 C incubator relative humidity of 65%, egg chamber upwards, flipping eggs 1 / 2h, the first to hatch 6 days, in light observation egg egg growth, excluding unfertilized eggs. 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。 With a dissecting needle bar in the gas chamber to the top 1 hole, make chicken embryo chorioallantoic membrane and the inner shell membrane to separate eggs. 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)。 Candling lamp head looking embryos, fertilized eggs from in front of the projection portion Icm fetal egg shell yolk vein between the two former mark 1.0 cm X 1.0 cm square area, with the grinding wheel along the region to cut through the egg shell eggs shell plans to notch surface, exposing light depression shells, gently tear the inner shell membrane, seen at this time where the chick CAM together with subsidence, fake gas chamber is formed (as distinct from its own gas chamber). 用封口膜封贴假气室,形成透明观察窗,继续放入37C孵化箱孵化1天。 With parafilm seal affixed fake gas chamber to form a transparent viewing window, continue into the 37 C incubator hatching one day. 于第二天取出鸡蛋,剔除变质鸡蛋。 Remove the eggs the next day, remove the eggs degenerate. 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 the candidate compound group (IOyg / a), each group 3, gently tear sealing film, taking a diameter of about 0.5cm mixed cellulose microporous membrane sheet (previously autoclaved) as a carrier, being placed on the surface of the observation window of CAM, avoid large vessels with a sterile pipette to draw each set of corresponding liquid drops central carrier surface. 加药2d后,去除透明胶带纸,观察、记录观察窗周围CAM并拍照。 2d after dosing, removing transparent adhesive tape, observe and record the observation window around CAM and photographed. 用Graph Pad 5.0统计软件对微小血管数量进行统计。 Using Graph Pad 5.0 statistical software for statistical number of tiny blood vessels.

[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 inhibitors lenalidomide as a positive control to IOyg / egg doses of the compound were chicken chorioallantoic membrane angiogenesis inhibition experiments to study the compound 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] From Figure 1 we can see that in IOyg / egg dose, the target compounds possess varying degrees of CAM angiogenesis inhibitory activity, wherein the compound II, 1-2, I-3 and I- 6 activity is better, and positive drug lenalidomide fairly, and CA-4 (IOyg / egg) at this dose showed severe fetal toxicity, embryo development can not continue, suggesting that the target compound toxicity than 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 inhibitors lenalidomide and CA-4 as a positive control to 1,2.5, IOyg / egg three doses of compound II, 1-5 and 1-6 were chick chorioallantoic membrane angiogenesis inhibition experiments, they investigated further angiogenesis inhibitory activity. 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 IOyg / egg dose of the compounds II and 1-6 shows a strong CAM angiogenesis inhibitory activity. 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 in 2.5yg / egg embryo toxicity dose that is showing greater embryotoxicity at IOyg / egg dose, embryo development can not continue.

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 of the CAM angiogenesis inhibitory activity

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

[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10C,冰浴下缓慢滴加浓盐酸200mL,室温下搅拌过夜。 [0054] In a three-necked 500mL flask was added 3,4,5-trimethoxy phenyl acetic acid (50.0 g, 0.22mol), 3_-hydroxy-4-methoxybenzaldehyde (34. Og, 0.22mo 1), 62.5mL of triethylamine and 150mL of acetic anhydride, was stirred under N2 atmosphere was heated to 140 C, the reaction 12h, heating was stopped, cooled to 10 C, was slowly added dropwise under ice 200 mL 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 184~186C 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 to stop the reaction, with about 200mL recrystallized from ethanol to give 47.5g of yellow needles 3, a yield of 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'synthesis, _-stilbene (CA-4,4) 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200C,搅拌4h。 [0057] The reaction was heated at equipped with a thermometer, a reflux condenser, a 500 mL three-necked flask with a drying tube 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, diethyl ether was added an appropriate amount, 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 150 mL of diethyl ether, the aqueous layer was separated and washed with ether (3 X 150mL), the organic layers combined. 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 are washed once with 500mL saturated Na2CO3 (2 X 300mL), washed twice with saturated NaCl (2 X 300mL), washed twice, and 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%,mpll6~117C。 Sodium sulfate was filtered off, spin off under reduced pressure to 2/3 volume of diethyl ether, there is a slightly yellow solid 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 was 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) Goo bandit 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 (80mL) 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 suction filtered, 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, filtration, the filtrate was evaporated under reduced pressure to give the crude product as a pale yellow oily liquid 6b 22.50g, the next step without purification vote.

[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75C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100C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)4),2.81 (s,3H,CH 3).MS(ESI( + )70eV,m/z):235.1[Μ+Η] + [0066] 50mL equipped with a reflux condenser was added 6 & eggplant type flask (4.9 (^, dirty 〇1 21.49), ^ methylpiperazine (2.678, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), IOmL 6mL toluene and water, stirred at 75 C for 12 hours, TLC monitoring completion of the reaction materials, heating was stopped and stirring, the toluene layer was separated, and the aqueous layer extracted with ethyl acetate until no product was combined organic layers. The organic layer was washed with 10% The organic layer was washed with hydrochloric acid until no product was combined aqueous layer. The aqueous layer was washed with ethyl acetate until no impurities with a saturated aqueous sodium bicarbonate to adjust PH alkaline aqueous layer was extracted with ethyl acetate until no product was combined ethyl acetate acetate layer. the ethyl acetate layer was washed with water three times, three times with saturated brine, dried over anhydrous sodium sulfate overnight 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, stirring slowly at low temperature to precipitate a white solid, filtration to give intermediate 7 & 3.348, 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] +

[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 Benzoic acid hydrochloride (7b) of [0068] 4- (4-morpholino-methyl)

[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75C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] equipped with a reflux condenser 50mL round-bottom flask 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 hours, TLC monitoring completion of the reaction materials, heating was stopped and stirring, the toluene layer was separated, and the aqueous layer extracted with ethyl acetate until no product was combined organic layers. 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 and the organic layer was washed until no product was combined aqueous layer. 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 no impurities with saturated aqueous sodium bicarbonate PH adjusted to alkaline, the aqueous layer 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, three times with saturated brine, 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。 Filtration, the solvent was distilled off 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]+. Cooling, low temperature slow stirring to precipitate a white solid, filtration 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75C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] equipped with a reflux condenser 50mL round-bottom flask 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 hours, TLC monitoring completion of the reaction materials, heating was stopped and stirring, the toluene layer was separated, and the aqueous layer extracted with ethyl acetate until no product was combined organic layers. 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 and the organic layer was washed until no product was combined aqueous layer. 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 no impurities with saturated aqueous sodium bicarbonate PH adjusted to alkaline, the aqueous layer 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, three times with saturated brine, 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。 Filtration, the solvent was distilled off 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, low temperature slow stirring to precipitate a white solid, filtration to give 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--- Synthesis (pyrrolidin -I ylmethyl) benzoic acid hydrochloride (7d) 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75C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 = 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] + . [0075] 50mL equipped with a reflux condenser was added 6 & eggplant-shaped flask (4.9 (^, 21.49111111 〇1), pyrrolidine (1.918, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), IOmL 6mL toluene and water at 75 C the reaction was stirred for 12 hours, TLC monitoring completion of the reaction materials, heating was stopped and stirring, the toluene layer was separated, and the aqueous layer extracted with ethyl acetate until no product was combined organic layers. The organic layer was washed with 10% hydrochloric acid to the organic no product layers were combined aqueous layer. The aqueous layer was washed with ethyl acetate until no impurities with a saturated aqueous sodium bicarbonate to adjust PH alkaline aqueous layer was extracted with ethyl acetate until no product was combined ethyl acetate layers. acetic acid ethyl layer was washed with water three times, three times with saturated brine, dried over anhydrous sodium sulfate overnight 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 at low temperature slow stirring to precipitate a white solid, filtration 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] +.

[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 [0077] 4- (diethylamino) benzoic acid hydrochloride (7E) Synthesis 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75C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] equipped with a reflux condenser 50mL round-bottom flask 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 hours, TLC monitoring completion of the reaction materials, heating was stopped and stirring, the toluene layer was separated, and the aqueous layer extracted with ethyl acetate until no product was combined organic layers. 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 and the organic layer was washed until no product was combined aqueous layer. 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 no impurities with saturated aqueous sodium bicarbonate PH adjusted to alkaline, the aqueous layer 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, three times with saturated brine, 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。 Filtration, the solvent was distilled off 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] + . Cooling, low temperature slow stirring to precipitate a white solid, filtration to give 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 Synthesis of [0080] 4- ((4-methyl-piperazin--I--yl) methyl) -3-nitro benzoic acid hydrochloride (7F) 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75C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%,πκρ315~318Γ</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),3.88-3.15(m,8H,N(CH2)4N),2.81(s,3H,CH3).MS(ESI( + )70eV,m/z):280.1[M+H] + . [0081] 25mL equipped with a reflux condenser was added 6 dagger eggplant type flask (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 of water, stirred at 75 C for 12 hours, TLC monitoring completion of the reaction materials, heating was stopped and stirring, the toluene layer was separated, and the aqueous layer extracted with ethyl acetate until no product was combined organic layers. The organic layer was washed with The organic was washed with 10% hydrochloric acid until no product layer was combined aqueous layer. The aqueous layer was washed with ethyl acetate until no impurities with a saturated aqueous sodium bicarbonate to adjust PH alkaline aqueous layer was extracted with ethyl acetate until no product was combined the ethyl acetate layer. the ethyl acetate layer was washed with water three times was stirred, washed three times with saturated brine, dried over anhydrous sodium sulfate overnight filtration, the solvent was distilled off under reduced pressure, the residue was added hydrochloric IOmL 20%, temperature in IOOtC The reaction overnight, cooled to low temperatures slow stirring to precipitate a white solid, filtration to give 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] +.

[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- (morpholin-methyl) -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75C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] equipped with a reflux condenser was added 25mL eggplant flask 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 hours, TLC monitoring completion of the reaction materials, heating was stopped and stirring, the toluene layer was separated, and the aqueous layer extracted with ethyl acetate until no product was combined organic layers. 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 and the organic layer was washed until no product was combined aqueous layer. 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 no impurities with saturated aqueous sodium bicarbonate PH adjusted to alkaline, the aqueous layer 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, three times with saturated brine, 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。 Filtration, the solvent was distilled off under reduced pressure, the residue was added hydrochloric IOmL 20%, at IOOtC 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] + . Cooling, low temperature slow stirring to precipitate a white solid, suction filtration to give the intermediate zone 7 0.76 8, yield 68.47%, 1114.303 ~ 305 (:.!? 1 1 1 bandit (3001〇 ^ 020) 38.61 ( (a, 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75C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] equipped with a reflux condenser was added 25mL eggplant flask 6b (1 OOg, 3 66mmo 1), piperidine (0 39g, 4 58mmol), potassium carbonate (0 39g, 2 85mmol) , I 2mL 2mL of toluene and water, stirred at 75 C for 12 hours, TLC monitoring completion of the reaction materials, heating was stopped and stirring, the toluene layer was separated, and the aqueous layer extracted with ethyl acetate until no product was combined organic layers. 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 and the organic layer was washed until no product was combined aqueous layer. 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 no impurities with saturated aqueous sodium bicarbonate PH adjusted to alkaline, the aqueous layer 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, three times with saturated brine, 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。 Filtration, the solvent was distilled off under reduced pressure, the residue was added hydrochloric IOmL 20%, at IOOtC 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, low temperature slow stirring to precipitate a white solid, filtration to give intermediate 7110.818 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75C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 (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] + . [0090] 25mL equipped with a reflux condenser was added 6 dagger eggplant type flask (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, TLC monitoring completion of the reaction materials, heating was stopped and stirring, the toluene layer was separated, and the aqueous layer extracted with ethyl acetate until no product was combined organic layers. The organic layer was washed with The organic was washed with 10% hydrochloric acid until no product layer was combined aqueous layer. The aqueous layer was washed with ethyl acetate until no impurities with a saturated aqueous sodium bicarbonate to adjust PH alkaline aqueous layer was extracted with ethyl acetate until no product was combined the ethyl acetate layer. the ethyl acetate layer was washed with water three times was stirred, washed three times with saturated brine, dried over anhydrous sodium sulfate overnight filtration, the solvent was distilled off under reduced pressure, the residue was added hydrochloric IOmL 20%, temperature in IOOtC The reaction was cooled overnight, stirring slowly at low temperature to precipitate a white solid, filtration to give intermediate 8 710.69, yield 65.71%, 1114.293 ~ 296 (:..!? 1 1 1 bandit (3001〇 ^ 020) 38.59 ((a, 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] +.

[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- (diethylamino-methyl) -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75C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] equipped with a reflux condenser was added 25mL eggplant flask 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 hours, TLC monitoring completion of the reaction materials, heating was stopped and stirring, the toluene layer was separated, and the aqueous layer extracted with ethyl acetate until no product was combined organic layers. 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 and the organic layer was washed until no product was combined aqueous layer. 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 no impurities with saturated aqueous sodium bicarbonate PH adjusted to alkaline, the aqueous layer 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, three times with saturated brine, 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。 Filtration, the solvent was distilled off under reduced pressure, the residue was added hydrochloric IOmL 20%, at IOOtC 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]+. Cooling, stirring 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-methylpiperazinyl -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] equipped with a reflux condenser was added 25mL eggplant flask 7a (0.27g, lmmol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent was distilled off 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) was dissolved in 511 ^ dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant flask, was added triethylamine (0.20g, 0.28mL, 2.0mmol ), the reaction mixture was stirred at room temperature for 2h, TLC monitored the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate until the aqueous layer no product layer was washed three times with ethyl acetate, washed with 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%,mp 102~104Γ。 Suction filtered and the filtrate was spin dry the residue by column chromatography (dichloromethane: methanol = 200: 1) isolated and purified as 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. 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. 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, piperazine hydrogen), 2.48 (8,3! 1 ~ 〇13). 5 111/2 serving 45 533.2656 [] \ 1+! 1] + (. & 1. (1 € (^ 7 〇31 the 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%,mp234~236C。 [0097] The II (0.1 Og, 0.19mmol) was dissolved in 2mL of dichloromethane, was added dropwise a saturated solution of HCl in diethyl ether, stirred for 5 minutes, a white solid was precipitated, suction filtration to afford 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] equipped with a reflux condenser was added 25mL eggplant flask 7b (0.26g, lmmol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent was distilled off 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) was dissolved in 511 ^ dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant flask, was added triethylamine (0.20g, 0.28mL, 2.0mmol ), the reaction mixture was stirred at room temperature for 2h, TLC monitored the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate until the aqueous layer no product layer was washed three times with ethyl acetate, washed with 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。 Suction filtered and the filtrate was spin dry the residue by column chromatography (dichloromethane: methanol = 200: 1) isolated and purified to give a white solid 0.198 1-2, yield 36.53%, 11 150 to 52.?. (:。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. 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 (Bend 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. 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 128~130C。 [0101] The 1-2 (0.1 Og, 0.19mmol) was dissolved in 2mL of dichloromethane, was added dropwise a saturated solution of HCl in diethyl ether, stirred for 5 minutes, a white solid was precipitated, suction filtration 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. 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. 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] equipped with a reflux condenser 25mL round-bottom flask 7c (255. Img, Immo 1) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent was evaporated under reduced pressure to make dry, direct investment next step. 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 containing eggplant flask, was added triethylamine (0.20g, 0.28mL, 2. Ommol), The reaction was stirred at room temperature for 2h, TLC monitored the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate until the aqueous layer no product layer was washed three times with ethyl acetate, washed with 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%,πκρ100~102C。 Filtration, the filtrate was spin-dried, the residue was column chromatographed (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. 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 diethyl ether, stirred for 5 minutes, a white solid was precipitated, suction filtration 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. 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 worm 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-yl-methyl) 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] equipped with a reflux condenser 25mL round-bottom flask 7d (241.1mg, lmmol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent was evaporated under reduced pressure to make dry, direct investment next step. 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 containing eggplant flask, was added triethylamine (0.20g, 0.28mL, 2. Ommol), The reaction was stirred at room temperature for 2h, TLC monitored the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate until the aqueous layer no product layer was washed three times with ethyl acetate, washed with 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. 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 25,152.43,149.77,138.83,136.46,134.65, 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). Suction filtered and the filtrate was spin dry the residue by column chromatography (dichloromethane: methanol = 500: 1) isolated and purified to give 1-4 as a white solid 0.20g, 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) were dissolved in 2mL of dichloromethane, was added dropwise a saturated solution of HCl in diethyl ether, stirred for 5 minutes, a white solid was precipitated, suction filtration 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. 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).

[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] equipped with a reflux condenser 25mL round-bottom flask 7e (243. Img, Immo 1) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent was evaporated under reduced pressure to make dry, direct investment next step. 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 containing eggplant flask, was added triethylamine (0.20g, 0.28mL, 2. Ommol), The reaction was stirred at room temperature for 2h, TLC monitored the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate until the aqueous layer no product layer was washed three times with ethyl acetate, washed with 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%。 Suction filtered and the filtrate was spin dry the residue by column chromatography (dichloromethane: methanol = 500: 1) isolated and purified as 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 diethyl 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-methylpiperazinyl -I--yl) methyl) 3-nitrobenzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy styrene-yl) phenyl ester (1-6) hydrochloride

[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] equipped with a reflux condenser 25mL round-bottom flask to 0.328,1 dirty 〇1 7) and 51 ^ thionyl chloride, the reaction was stirred at reflux overnight, the solvent was evaporated under reduced pressure to make dry, direct investment next step. 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) was dissolved in 511 ^ dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant flask, was added triethylamine (0.20g, 0.28mL, 2.0mmol ), the reaction mixture was stirred at room temperature for 2h, TLC monitored the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate until the aqueous layer no product layer was washed three times with ethyl acetate, washed with 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。 Filtration, the filtrate was spin-dried, the residue was column chromatographed (dichloromethane: methanol = 200: 1) separation and purification to give 0.23 g of 1-6 as a white solid, a yield of 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. 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 Bend 1:00 111-3: 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. 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 144~146C。 [0114] The 1-6 (0.1 Og, 0.173mmol) was dissolved in 2mL of dichloromethane, was added dropwise a saturated solution of HCl in diethyl ether, stirred for 5 minutes, a white solid was precipitated, suction filtration 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- (morpholin-ylmethyl) -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] equipped with a reflux condenser was added 25mL eggplant flask 7g (0.30g, lmmol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent was distilled off 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) was dissolved in 511 ^ dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant flask, was added triethylamine (0.20g, 0.28mL, 2.0mmol ), the reaction mixture was stirred at room temperature for 2h, TLC monitored the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate until the aqueous layer no product layer was washed three times with ethyl acetate, washed with 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 .82~84C 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. 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). Suction filtered and the filtrate was spin dry the residue 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. 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%,mp216~219C。 [0118] The 1-7 (0.1 Og, 0.177mmol) was dissolved in 2mL of dichloromethane, was added dropwise a saturated solution of HCl in diethyl ether, stirred for 5 minutes, a white solid was precipitated, suction filtration 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] equipped with a reflux condenser 25mL round-bottom flask 7h (0.30g, lmmol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent was evaporated under reduced pressure to make dry, direct investment next step. 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) was dissolved in 511 ^ dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant flask, was added triethylamine (0.20g, 0.28mL, 2.0mmol ), the reaction mixture was stirred at room temperature for 2h, TLC monitored the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate until the aqueous layer no product layer was washed three times with ethyl acetate, washed with 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 .74~76C 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. 匪R(300MHz,CDCl3)δ858(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). Suction filtered and the filtrate was spin dry the residue by column chromatography (dichloromethane: methanol = 400: 1) separation and purification, to give a white solid 0.19g, yield 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. 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 worms) 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%,mp202~204C。 [0122] The 1-8 (0.1 Og, 0.178mmol) was dissolved in 2mL of dichloromethane, was added dropwise a saturated solution of HCl in diethyl ether, stirred for 5 minutes, a white solid was precipitated, suction filtration 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] equipped with a reflux condenser 25mL round-bottom flask 7i (286. Img, Immol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent was evaporated under reduced pressure to make dry, direct investment next step. 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 containing eggplant flask, was added triethylamine (0.20g, 0.28mL, 2. Ommol), The reaction was stirred at room temperature for 2h, TLC monitored the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate until the aqueous layer no product layer was washed three times with ethyl acetate, washed with 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. 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)δ16213,152.49,149.67,148.65, 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). Suction filtered and the filtrate was spin dry the residue by column chromatography (dichloromethane: methanol = 200: 1) isolated and purified to give a white solid 0.2 1-9 (^, yield 36.50%, 11 156 to 58 (.?. :? .11 (1 this bend 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. 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%,mpl06~108C<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. 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 diethyl ether, stirred for 5 minutes, a white solid was precipitated, suction filtration 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. 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] equipped with a reflux condenser 25mL round-bottom flask was added 7 j (288. Img, Immol) and 5mL thionyl chloride, the reaction was stirred at reflux overnight, the solvent was evaporated under reduced pressure to make dry, direct investment next step. 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 containing eggplant flask, was added triethylamine (0.20g, 0.28mL, 2. Ommol), The reaction was stirred at room temperature for 2h, TLC monitored the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added saturated brine, extracted with ethyl acetate until the aqueous layer no product layer was washed three times with ethyl acetate, washed with 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%,πκρ96~98C。 Suction filtered and the filtrate was spin dry the residue by column chromatography (dichloromethane: methanol = 200: 1) isolated and purified as 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, 105.28,77.02,76.59,76.17,60.39,55.46,55.43,50.54,46.26,814.HR-ESIMS m/z 551.2383[M+H] + (calcd for C30H35N2Os,551.2388). The 1-10 (0.1 (^, dirty 〇1 0.182) was dissolved in 211 ^ dichloromethane, was added dropwise a saturated solution of HCl in diethyl ether, stirred for 5 minutes, the precipitated white solid was suction filtered to afford 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] 20 to take the compound obtained 0.5g, Example 2. Og starch, dextrin 1.0 g were mixed with an appropriate amount of 30% ethanol as wetting agents, granulating, tabletting.

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