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Publication numberCN104817519 A
Publication typeApplication
Application numberCN 201510235806
Publication dateAug 5, 2015
Filing dateMay 11, 2015
Priority dateMay 11, 2015
Also published asCN104817519B
Publication number201510235806.3, CN 104817519 A, CN 104817519A, CN 201510235806, CN-A-104817519, CN104817519 A, CN104817519A, 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
CA-4 derivatives as well as preparation method and medical application of CA-4 derivatives
CN 104817519 A
Abstract
The invention relates to the field of medicinal chemistry and particularly relates to Combretastatin A-4 derivatives (I), a preparation method of the Combretastatin A-4 derivatives and application of the Combretastatin A-4 derivatives to inhibition of tumor angiogenesis. A pharmacological experiment result shows that the compounds have a relatively strong effect on inhibiting MCF-7 human breast cancer cell proliferation, and meanwhile, parts of the compounds also have a relatively good effect on inhibiting the proliferation of human umbilical vein endothelial cells and the generation of new chick chorioallantoic membrane vessels. Therefore, the compounds provided by the invention can be used for treating various diseases related to angiogenesis, and the diseases include various cancers and chronic inflammations as well as other vascular diseases. The compounds provided by the invention have favorable water solubility.
Claims(7)  translated from Chinese
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 CN104817519AC00021
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H或硝基。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R represents H or a nitro group.
3. 权利要求1的化合物或其药学上可接受的盐,其中Y代表 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y represents
Figure CN104817519AC00022
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 thereof as claimed in claim 1 of the formula (I) and the 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血管生成性疾病中的用途。 Compound 1 or a pharmaceutically acceptable salt thereof in angiogenic diseases in claim.
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
-类CA-4的衍生物、其制法及其医药用途 - Derivatives CA-4, and their preparation and 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CombretastatinA-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。 Their preparation and inhibited [0001] The present invention relates to the field of pharmaceutical chemistry, in particular to derivatives CombretastatinA-4 (CA-4) a class of tumor blood 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0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 Combretum Caffnom South Africa out of a small molecule vascular blocker (Vascular Disrupting Agents, VDA), which binds to vascular endothelial cells tubulin subunit 0 colchicine binding site point, leading to 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 the further application.

发明内容 SUMMARY OF THE INVENTION

[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 of a class. 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 chorioallactoic 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 of MCF-7 human breast cancer cell proliferation has a strong inhibitory effect, at the same time, some of the compounds in human umbilical vein endothelial cell proliferation and chick chorioallantoic membrane (Chicken chorioallactoic 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。 Accordingly, the compounds of formula I of the present invention can be used to treat various diseases associated with angiogenesis, such diseases include various cancers and chronic inflammation, and other 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 CN104817519AD00031

[0006] R代表:H、卤素、硝基、氨基或三氟甲基。 [0006] R on behalf of: H, halo, nitro, amino or trifluoromethyl.

[0007] R优选:H或硝基。 [0007] R is preferably: H or a nitro group.

[0008] 其中Y代表: [0008] wherein Y represents:

Figure CN104817519AD00032

[0009] Y 优选: [0009] Y is preferably:

Figure CN104817519AD00033

[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 to form an acid addition salt of 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(1-1) [0012] 4 - ((4_ methyl-piperazin-1-yl) methyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy styryl) benzene ester (1-1)

[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- (morpholino-methyl) 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(1-3) [0014] 4- (piperidin-1-ylmethyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy styryl) phenyl ester (1-3)

[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-⑵-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 -⑵-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- (morpholino-methyl) -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 CN104817519AD00051

[0024] 由3, 4, 5-三甲氧基苯乙酸⑴与3-羟基-4-甲基苯甲醛⑵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 the 3, 4, 5- trimethoxy ⑴ acid with 3-hydroxy-4-methyl-benzaldehyde ⑵ preparation of compounds 3, it is the reactants of triethylamine and acetic anhydride effect condensation.

[0025] 由化合物3制备4,是将反应物于喹啉/铜粉和200C高温脱羧得到。 [0025] 3 was prepared from compound 4, is 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 5, a reaction was dissolved in chloroform, was added NBS and benzoyl peroxide initiator reaction.

[0027] 由化合物6制备7,是将6溶于溶剂中,在缚酸剂作用下与 [0027] prepared from compound 6 7, 6 is dissolved in a solvent, in the role of acid-binding agent

Figure CN104817519AD00052

缩合得到。 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,优选碳酸钾。 Acid binding agent is selected from triethylamine, diisopropyl ethyl amine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, preferably potassium carbonate. 溶剂选自甲苯/水、四氢呋喃/水、丙酮/水、乙腈/ 7JC,优选甲苯/水。 Solvent is selected from toluene / water, tetrahydrofuran / water, acetone / water, acetonitrile / 7JC, 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 obtained.

[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] The title compound was prepared from compound 9 I, it is the compound 13 in the role of acid-binding agent, 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, diisopropyl ethyl amine, 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 spices, 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 the clinic can be used for oral administration, injections 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lmg~lOOOmg/天。 [0034] In general, CA-4 derivative of the present invention are useful in the treatment, the human dose range of lmg ~ lOOOmg / 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。 But also according to the severity of the disease in different forms and using 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] 1、SRB法检测受试化合物对MCF-7和HUVECs细胞的增殖作用 [0036] 1, the proliferation of SRB assay test compounds on MCF-7 cells and HUVECs

[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 X 104/mL,接种于96孔板中,每孔200iiL,边缘孔用无菌PBS填充,5%C02 , 37C孵育。 [0037] The cells were passaged to the logarithmic growth phase, after trypsin digestion -EDTA liquid, adjusting final concentration of 5 X 104 / mL, were seeded in 96-well plates, each well 200iiL, the edge of the hole is filled with sterile PBS, 5 % C02, 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%C0 2培养箱中培养,各种药物每浓度设5个平行孔。 24h after (bottom of the hole to confluent cell monolayer (96-well flat-bottom)), discard the plate each well of the original liquid, then were replaced with cell culture medium containing the appropriate concentration of the drug at 37 C, 5% C0 2 incubator, the concentration of a variety of drugs 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 in the dosing end of the culture (48h) after using trichloroacetic acid (TCA) is fixed: each hole plus adherent cells prechilled 50% TCA solution 50uL (final concentration of 10%) is fixed; TCA must be applied when lightly plus flat in 5min then moved to 4 C place lh, such cells are immobilized in the wells of the bottom surface of the culture solution, 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100 y L,避光,在室温放置lOmin。 Each hole by adding 0. 4% SRB solution 100 y L, dark, place lOmin at room temperature. 未与蛋白结合的SRB用1% TCA液洗5遍,空气干燥。 SRB unbound protein was washed with 1% TCA 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 combined 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0D值,用空白对照调零,在波长为490nm处测定每个小孔的0D值。 0D value measured in ELISA detector, with blank zero, at a wavelength of 490nm at the determination of the value of each hole of 0D. 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ICjt。 The resulting tumor cell growth inhibition rate is defined as the drugs on tumor cells in vitro inhibition rate and calculate ICjt. 抑制率=(无药细胞对照孔0D 值-用药孔0D值)/无药细胞对照孔0D值X 100% Inhibition rate = (no drug cell control wells 0D value - the value of medication hole 0D) / drug-free cell control wells 0D value X 100%

[0038] 表1化合物对人乳腺癌细胞MCF-7增殖抑制作用(f ,n = 3) [0038] The compound in Table 1 on the MCF-7 human breast cancer cell proliferation (f , n = 3)

[0039] [0039]

Figure CN104817519AD00071

[0040] 从表1实验结果中我们可以看出大部分化合物的MCF-7肿瘤细胞增殖抑制活性较阳性药CA-4(IC 5Q= 0.058UM)更强,同时较阿霉素强一个数量级,其中化合物I-3(IC5Q = 0. 024 ii M)的活性明显强于CA-4。 [0040] The results in Table 1 we can see that most of the compound of MCF-7 tumor cell proliferation inhibition activity than positive drug CA-4 (IC 5Q = 0.058UM) stronger, while representing an order of magnitude stronger doxorubicin, Compounds I-3 (IC5Q = 0. 024 ii M) 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(n = 3) [0041] Table 2, some of the compounds in human umbilical vein endothelial cell proliferation (n = 3)

[0042] [0042]

Figure CN104817519AD00081

[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 measured compounds in 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, chick 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, at 1: 1000 benzalkonium bromide after 3min soak into the 37 C incubator relative humidity of 65%, egg chamber upward, flipping eggs 1 / 2h, to incubate first 6 days, in light observation Egg Eggs growth, excluding the 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。 In the gas chamber with a dissecting needle bar 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lcm两条前卵黄静脉之间的卵壳投影部位标记1. OcmX 1. 0cm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 looking embryos head, in front of the projector fertilized egg shell from fetal parts lcm vein yolk between the two front marks 1. OcmX 1. 0cm square area, this area along with the grinding wheel cutting through the egg shell to carved draw eggshell surface dents, light exposing 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, forming 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 bad eggs. 将剩余鸡蛋分成:空白组,DMSO组,阳性药组(10, 2. 5, 1 U g/个),和候选化合物组(10 U g/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 group (10, 2. 5, 1 U g / a), and the candidate compound group (10 U g / a), each group 3, gently tear sealing film, taking in diameter mixed cellulose microporous membrane film about 0. 5cm (pre-autoclaving) as a carrier, is placed is on the surface of the observation window of CAM, avoid large vessels, with a sterile pipette for each draw set of corresponding liquid droplets in a carrier central 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 to remove 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10U g/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, 10U g / egg dose of the compound will be chicken chorioallantoic membrane angiogenesis inhibition experiments to study the compound in vivo angiogenesis inhibition active. 结果见图1。 The results shown in Figure 1.

[0047] 从图1中我们可以看出,在10Ug/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1-1、1-2、1-3和1-6的活性较好,与阳性药来那度胺相当,而CA-4在此剂量(lOyg/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 the 10Ug / egg dose, the target compound in varying degrees of CAM angiogenesis inhibitory activity measurement, and wherein the compound 1-1,1-2,1-3 1-6 better activity, and positive drug lenalidomide fairly, while CA-4 (lOyg / egg) at this dose showed severe fetal toxicity, embryo can not continue to develop, suggesting that the target compound toxic than CA -4 decreased.

[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、10 ii g/蛋三个剂量对化合物1-1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. 5,10 ii g / egg three doses of the compounds 1-1 and 1-6 were Chick Embryo capsular 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10 iig/蛋的剂量下,化合物1-1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 10 iig / egg dose, compounds 1-1 and 1-6 shows a strong CAM angiogenesis inhibitory activity. CA-4在2. 5 yg/蛋剂量下即显示出胚胎毒性,在10 yg/蛋剂量下胚胎毒性更大,鸡胚无法继续发育。 CA-4 at 2. 5 yg / egg embryo toxic dose that is showing greater embryo toxicity at 10 yg / egg dose, 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 [0050] FIG. 1 is a compound of the CAM angiogenesis inhibitory activity

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

具体实施方式 detailed description

[0052] 实施例1 [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⑶的合成 [0053] (E) -3- (3, - hydroxy-4'-methoxy) phenyl-2- (3 ', 4 "5" - trimethoxy) phenyl - Synthesis of Acrylic ⑶

[0054] 在50011^三颈瓶中加入3,4,5-三甲氧基苯乙酸(50.(^,0.22111〇1)、3-羟基-4-甲氧基苯甲醛(34. 0g,0. 22mol)、62. 5mL三乙胺和150mL乙酸酐,N2保护下搅拌升温至140C, 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。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。屮NMR(300MHz,DMS0-d6),S (ppm) : S 12. 46(brs,1H,C00H) ,8. 97 (s, 1H,OH),7. 58 (s, 1H, =CH),6. 81(d, J =8. 5Hz, 1H,ArH),6. 61(dd, J:=8. 5,J 2 =1.8Hz, 1H,ArH),6. 54(d, J= 1.8Hz, 1H,ArH),6. 44 (s, 2H,ArH),3. 73 (s, 3H, 0CH3),3. 71 (s, 3 H, 0CH3),3. 69 (s,6H, 2X0CH3). [0054] In a three-necked flask 50011 ^ 3,4,5-trimethoxy phenyl acetic acid (50. (^, 0.22111〇1), 3-hydroxy-4-methoxybenzaldehyde (34. 0g, 0 . 22mol), 62. 5mL of triethylamine and 150mL of acetic anhydride, was stirred under N2 protection was heated to 140 C, the reaction 12h, heating was stopped, was slowly added dropwise under cooling to 10 C, the ice bath was concentrated hydrochloric acid 200mL, stirred at room temperature overnight. There khaki solid precipitated solids were filtered reaction was stopped with about 200mL recrystallized from ethanol to give yellow needles 47. 5g 3, a yield of 59. 6%, mp 184 ~ 186 C. Che NMR (300MHz , DMS0-d6), S (ppm):... S 12. 46 (brs, 1H, C00H), 8 97 (s, 1H, OH), 7 58 (s, 1H, = CH), 6 81 ( d, J = 8 5Hz, 1H, ArH), 6 61 (dd, J:... = 8 5, J 2 = 1.8Hz, 1H, ArH), 6 54 (d, J = 1.8Hz, 1H,. ArH), 6. 44 (s, 2H, ArH), 3. 73 (s, 3H, 0CH3), 3. 71 (s, 3 H, 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 1), 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] equipped with a thermometer, a reflux condenser, 500mL three-necked flask with a drying tube was added 3 (7. 2g, 20mmo 1), freshly prepared copper powder (6. 6g, 0. 103mol), quinoline 72mL, N2 protection reaction was heated 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 HC1把喹啉洗掉,用乙醚150mL萃取,将分出的水层用乙醚洗(3X150mL),合并有机层。 With the quinoline 300mL 5M HC1 wash was extracted with ether 150mL, the separated aqueous layer was washed with ether (3X150mL), and the combined organic layers. 有机层分别用500mL水洗一次, 饱和Na 2C03 (2 X 300mL)洗两次,饱和NaCl (2 X 300mL)洗两次,无水似2504干燥过夜。 The organic layers are washed once with 500mL saturated Na 2C03 (2 X 300mL) washed twice with saturated NaCl (2 X 300mL), washed twice, and dried overnight over anhydrous like 2504. 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. 0g,产率79. 1%,mp 116~ 117 C。 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, to obtain a total of 45 products. 0g, yield 79. 1%, mp 116 ~ 117 C. 屯匪1? (300Hz,DMS0-d6) : S 8. 94 (s,1H,0H),6. 83 (d,J = 8. 3Hz,1H,ArH),6. 78 (d,J =1. 8Hz, 1H, ArH), 6. 68(dd, J = 8. 2, 1. 8Hz, 1H, 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, 2 X 0CH3). ? Tuen bandit 1 (300Hz, DMS0-d6):.. S 8. 94 (s, 1H, 0H), 6 83 (d, J = 8. 3Hz, 1H, ArH), 6 78 (d, J = 1 . 8Hz, 1H, ArH), 6. 68 (dd, J = 8. 2, 1. 8Hz, 1H, 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, 2 X 0CH3).

[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. lmol)溶于氯仿(80mL)中,力卩入NBS(17.8g,0. lmol)和BP0 (45mg, 0. 18mmol),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6&12.78,收率82.34 %。 [0060] The 5a (15.0g, 0. Lmol) was dissolved in chloroform (80mL), the force Jie into NBS (17.8g, 0. Lmol) and BP0 (45mg, 0. 18mmol), was heated to reflux, the reaction was stirred for 2 . 5h, cooled to precipitate a white solid was suction filtered, the filtrate was evaporated under reduced pressure to give the crude product as a pale yellow oily liquid 14. 50g, silica gel column chromatography (petroleum ether / ethyl acetate = 100/1) to give a colorless transparent liquid 6 & 12.78, a yield of 82.34%. 111匪1?(3001抱,0)(:13)8 8.03((1,了=8. 0Hz, 2H, ArH), 7. 47 (d, J = 7. 9Hz, 2H, ArH), 4. 51 (s, 2H, CH2), 3. 93 (s, 3H, 0CH3). MS (ESI (+) 70eV, m/z) : 229. 0 [M+H]+. ? 111 bandit 1 (3001 holds, 0) (: 13) 8 8.03 ((1, a = 8 0Hz, 2H, ArH), 7. 47 (d, J = 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. lmol)溶于氯仿(100mL)中,力卩入NBS(17.8g,0. lmol)和BP0(45mg, 0. 18mmol),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. Lmol) was dissolved in chloroform (100mL), the force Jie into NBS (17.8g, 0. Lmol) and BP0 (45mg, 0. 18mmol), was heated to reflux, the reaction was stirred for 2 . 5h, cooled to precipitate a white solid, filtration, the filtrate was evaporated under reduced pressure to give crude pale yellow oily liquid 6b 22. 50g, the next step without further 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爺型瓶中加入6a(4. 90g, 21. 49mmol)、N-甲基哌嗪(2.67,26.87臟〇1)、碳酸钾(2.31,16.74臟〇1)、101^甲苯和611^水,于751: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。 [0066] equipped with a reflux condenser was added 50mL Ye-flasks 6a (4. 90g, 21. 49mmol), N- methylpiperazine (2.67, 26.87 dirty 〇1), potassium carbonate (2.31, 16.74 dirty 〇1), 101 ^ 611 ^ toluene and water, at 751: The reaction was stirred for 12 hours, TLC monitoring completion of the reaction raw materials, heating was stopped and stirring, the toluene layer was separated, the aqueous layer was 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 to the organic layer was washed free product were 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 a saturated aqueous sodium bicarbonate adjusted to an alkaline pH, 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20mL20%盐酸,控温于100C搅拌反应过夜。 Filtration, the solvent was distilled off under reduced pressure, the residue was added 20mL20% 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7a3. 34g,收率50. 76%,mp 310~311C。 Cooling, stirring slowly at low temperature to precipitate a white solid, leaching, have intermediate 7a3. 34g, a yield of 50. 76%, mp 310 ~ 311 C. 屮NMR(300MHz,D20)87. 90 (d,J=8. 3Hz, 2H,ArH),7. 43 (d,J=8. 3Hz, 2H,ArH),4. 32 (s, 2H,P hCH2), 3. 44 (m,8H,N(CH2) 4), 2. 81 (s, 3H,CH3).MS(ESI(+) 70eV,m/z) : 235. 1 [M+H]+. Che NMR (300MHz, D20) 87. 90 (d, J = 8. 3Hz, 2H, ArH), 7. 43 (d, J = 8. 3Hz, 2H, ArH), 4. 32 (s, 2H, P hCH2), 3. 44 (m, 8H, N (CH2) 4), 2. 81 (s, 3H, CH3) .MS (ESI (+) 70eV, m / z): 235. 1 [M + H] +.

[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 the [0068] 4- (4-morpholino-methyl)

[0069] 装有回流冷凝管的50mL爺型瓶中加入6a(4. 90g, 21. 49mmol)、吗啉(2. 34g, 26. 87mmol)、碳酸钾(2. 31g, 16. 74mmol)、10mL 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] equipped with a reflux condenser was added 50mL Ye-flasks 6a (4. 90g, 21. 49mmol), morpholine (2. 34g, 26. 87mmol), potassium carbonate (2. 31g, 16. 74mmol), 6mL toluene and 10mL of water, stirred at 75 C for 12 hours, TLC monitoring completion of the reaction raw materials, heating was stopped and stirring, the toluene layer was separated, the aqueous layer was 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 to the organic layer was washed free product were 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 a saturated aqueous sodium bicarbonate adjusted to an alkaline pH, 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100C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7b 3. 64g,收率65. 94%,mp 295~297C。 Cooling, stirring slowly at low temperature to precipitate a white solid, leaching, have intermediate 7b 3. 64g, a yield of 65. 94%, mp 295 ~ 297 C. :H NMR(300MHz,D20) 8 7. 84(d, J = 8. 3Hz, 2H, ArH), 7. 39 (d, J = 8. 3Hz, 2H, ArH), 4. 23 (s ,2H, PhCH2), 3. 88 (d, J = 11. 3Hz, 2H, 0CH2), 3. 56 (t, J = 12. 1Hz, 2H, 0CH2), 3. 23 (d, J = 12. 5Hz, 2H, NCH2), 3. 14 - 2. 98 (m, 2H, NCH2). MS (ESI (+) 70eV, m/z) : 222. 1 [M+H]+. : H NMR (300MHz, D20) 8 7. 84 (d, J = 8. 3Hz, 2H, ArH), 7. 39 (d, J = 8. 3Hz, 2H, ArH), 4. 23 (s, 2H , PhCH2), 3. 88 (d, J = 11. 3Hz, 2H, 0CH2), 3. 56 (t, J = 12. 1Hz, 2H, 0CH2), 3. 23 (d, J = 12. 5Hz, (. m, 2H, NCH2) MS (ESI (+) - 2H, NCH2), 3. 14 2. 98 70eV, m / z): 222. 1 [M + H] +.

[0070] 实施例7 [0070] Example 7

[0071] 4-(哌啶-1-基甲基)苯甲酸盐酸盐(7c)的合成 (Piperidin-1-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)、哌啶(2. 29g, 26. 87mmol)、碳酸钾(2. 31g, 16. 74mmol)、10mL 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 eggplant type flask 6a (4. 90g, 21. 49mmol), piperidine (2. 29g, 26. 87mmol), potassium carbonate (2. 31g, 16. 74mmol), 6mL toluene and 10mL of water, stirred at 75 C for 12 hours, TLC monitoring completion of the reaction raw materials, heating was stopped and stirring, the toluene layer was separated, the aqueous layer was 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 to the organic layer was washed free product were 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 a saturated aqueous sodium bicarbonate adjusted to an alkaline pH, 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100C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7c3. 41g,收率62. 23%,mp282~284C。 Cooling, stirring slowly at low temperature to precipitate a white solid, leaching, have intermediate 7c3. 41g, a yield of 62. 23%, mp282 ~ 284 C. 屮NMR(300MHz,D20)87.86(d,J=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 (ddJi: 12.4, 10. 0Hz,J2= 2H,NCH2), 1.82 ~ 1. 13 (m,6H,CH2CH2CH2).MS(ESI(+) 70eV,m/z) : 220. 3 [M+H]+. Che NMR (300MHz, D20) 87.86 (d, J = 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 (ddJi: 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-1-基甲基)苯甲酸盐酸盐(7d)的合成 (Pyrrolidin-1-ylmethyl) benzoic acid hydrochloride (7d) Synthesis of [0074] 4-

[0075] 装有回流冷凝管的50mL茄型瓶中加入6a(4. 90g,21. 49mmol)、吡咯烷(1.91g,26.87mmol)、碳酸钾(2.31g, 16.74mmol)、10mL 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。 [0075] equipped with a reflux condenser 50mL eggplant type flask 6a (4. 90g, 21. 49mmol), pyrrolidine (1.91g, 26.87mmol), potassium carbonate (2.31g, 16.74mmol), 10mL toluene and 6mL water, at 75 C the reaction was stirred for 12 hours, TLC monitoring completion of the reaction raw materials, heating was stopped and stirring, the toluene layer was separated, the aqueous layer was 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 to the organic layer was washed free product were 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 a saturated aqueous sodium bicarbonate adjusted to an alkaline pH, 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100C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7d 3.1 lg,收率60. 04%,mp 278~ 281 C。 Cooling, stirring slowly at low temperature to precipitate a white solid, leaching, have intermediate 7d 3.1 lg, a yield of 60. 04%, mp 278 ~ 281 C. 屮NMR (300MHz,D20) S 7.81 (d,J = 8. 3Hz,2H,ArH), 7.36 (d,J = 8. 3Hz,2H,Ar H),4. 21(s, 2H, PhCH2),3. 28(dd, J = 10. 6, 5. 3Hz, 2H, NCH2), 2. 97 (dt, J:= 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]+. Che NMR (300MHz, D20) S 7.81 (d, J = 8. 3Hz, 2H, ArH), 7.36 (d, J = 8. 3Hz, 2H, Ar H), 4. 21 (s, 2H, PhCH2), 3. 28 (dd, J = 10. 6, 5. 3Hz, 2H, NCH2), 2. 97 (dt, J: = 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] Synthesis 4_ (diethylamine methyl) benzoic acid hydrochloride (7e) of

[0078] 装有回流冷凝管的50mL爺型瓶中加入6a(4. 90g, 21. 49mmol)、二乙胺(1. 97g, 26. 87mmol)、碳酸钾(2. 31g, 16. 74mmol)、10mL 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] 50mL Lord equipped with a reflux condenser type flask 6a (4. 90g, 21. 49mmol), diethylamine (1. 97g, 26. 87mmol), potassium carbonate (2. 31g, 16. 74mmol) , 10mL toluene and 6mL water, at 75 C the reaction was stirred for 12 hours, TLC monitoring completion of the reaction raw materials, heating was stopped and stirring, the toluene layer was separated, the aqueous layer was 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 to the organic layer was washed free product were 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 a saturated aqueous sodium bicarbonate adjusted to an alkaline pH, 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100C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7e 3. 27g,收率62. 64%,mp 285~ 288 C。 Cooling, stirring slowly at low temperature to precipitate a white solid, leaching, have intermediate 7e 3. 27g, a yield of 62. 64%, mp 285 ~ 288 C. 屮NMR(300MHz,D20) S 7. 83 (d,J = 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]+. Che NMR (300MHz, D20) S 7. 83 (d, J = 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-1-基)甲基)-3-硝基苯甲酸盐酸盐(7f)的合成 Synthesis of ((4-methyl-piperazin-1-yl) methyl) -3-nitro-benzoic acid hydrochloride (7f) of - [0080] 4

[0081] 装有回流冷凝管的25mL爺型瓶中加入6b (1. 00g, 3. 66mmol)、N-甲基哌嗪(0. 46g,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。 [0081] equipped with a reflux condenser was added 25mL Ye-flasks 6b (1. 00g, 3. 66mmol), N- methylpiperazine (0. 46g, 4. 58 mmol), potassium carbonate (0. 39g, 2. 85mmol), 2mL 1.2mL toluene and water, at 75 C the reaction was stirred for 12 hours, TLC monitoring completion of the reaction raw materials, heating was stopped and stirring, the toluene layer was separated, the aqueous layer was extracted with ethyl acetate until no product was combined organic layer. 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 was washed free product were 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 a saturated aqueous sodium bicarbonate adjusted to an alkaline pH, 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lOmL 20%盐酸,控温于100C搅拌反应过夜。 Filtration, the solvent was distilled off under reduced pressure, the residue was added lOmL 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7f 0. 95g,收率73. 64%,mp 315~318C。 Cooling, stirring slowly at low temperature to precipitate a white solid, leaching, have intermediate 7f 0. 95g, a yield of 73. 64%, mp 315 ~ 318 C. 屮NMR (300MHz, D20) 8 8. 58 (s, 1H, ArH), 8. 16 (d, J = 7. 5Hz, 1H, ArH), 7. 65 (d, J = 7. 8Hz, 1H, 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]+. Che NMR (300MHz, D20) 8 8. 58 (s, 1H, ArH), 8. 16 (d, J = 7. 5Hz, 1H, ArH), 7. 65 (d, J = 7. 8Hz, 1H, 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- (morpholino-methyl) -3-nitrobenzoic acid hydrochloride (7g) of

[0084] 装有回流冷凝管的25mL爺型瓶中加入6b (1. 00g, 3. 66mmol)、吗啉(0• 40g, 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。 [0084] 25mL Lord equipped with a reflux condenser type flask 6b (1. 00g, 3. 66mmol), morpholine (0 • 40g, 4. 58mmol), potassium carbonate (0 • 39g, 2. 85mmol), 1. 2mL of toluene and 2mL of water, at 75 C the reaction was stirred for 12 hours, TLC monitoring completion of the reaction raw materials, heating was stopped and stirring, the toluene layer was separated, the aqueous layer was 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 to the organic layer was washed free product were 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 a saturated aqueous sodium bicarbonate adjusted to an alkaline pH, 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10mL 20 %盐酸,控温于100C搅拌反应过夜。 Filtration, the solvent was distilled off under reduced pressure, the residue was added 10mL 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7g 0.76g,收率68. 47%,mp 303~ 305 C。 Cooling, stirring slowly at low temperature to precipitate a white solid, leaching, have intermediate 7g 0.76g, yield 68. 47%, mp 303 ~ 305 C. 屮NMR(300MHz,D20)S8.61(d,J = l.eHz.l^ArHhS.nQdJi: 7.9,J2 = l. 7Hz, 1H, ArH), 7. 66 (d, J = 7. 9Hz, 1H, ArH), 4. 53 (s, 2H, PhCH2), 3. 59 (m, 8H, N (CH2) 40). MS (ESI (+) 70eV, m/z) : 267. 1 [M+H]+. Che NMR (300MHz, D20) S8.61 (d, J = l.eHz.l ^ ArHhS.nQdJi:. 7.9, J2 = l 7Hz, 1H, ArH), 7. 66 (d, J = 7. 9Hz, . 1H, ArH), 4. 53 (s, 2H, PhCH2), 3. 59 (m, 8H, N (CH2) 40) MS (ESI (+) 70eV, m / z): 267. 1 [M + H] +.

[0085] 实施例12 [0085] Example 12

[0086] 4-((哌啶-1-基)甲基)-3-硝基苯甲酸盐酸盐(7h)的合成 [0086] 4 - ((piperidin-1-yl) methyl) -3-nitrobenzoic acid hydrochloride (7h) of

[0087] 装有回流冷凝管的25mL爺型瓶中加入6b (1. 00g, 3. 66mmol)、哌陡(0• 39g, 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。 [0087] 25mL Lord equipped with a reflux condenser type flask 6b (1. 00g, 3. 66mmol), piperazine steep (0 • 39g, 4. 58mmol), potassium carbonate (0 • 39g, 2. 85mmol), 1. 2mL of toluene and 2mL of water, at 75 C the reaction was stirred for 12 hours, TLC monitoring completion of the reaction raw materials, heating was stopped and stirring, the toluene layer was separated, the aqueous layer was 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 to the organic layer was washed free product were 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 a saturated aqueous sodium bicarbonate adjusted to an alkaline pH, 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10mL 20%盐酸,控温于100C搅拌反应过夜。 Filtration, the solvent was distilled off under reduced pressure, the residue was added 10mL 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7h 0.81g,收率73. 64%, mp298~301C。 Cooling, stirring slowly at low temperature to precipitate a white solid, leaching, have intermediate 7h 0.81g, yield 73. 64%, mp298 ~ 301 C. 屮NMR(300MHz,D20)S 8. 59 (d,J=1. 6Hz,1H,ArH),8. 15 (dd,丄=7. 9,J2= 1.6Hz,1H,ArH), 7. 63(d,J=7. 9Hz, 1H,ArH),4. 41(s,2H,PhCH2),3. 4 4(d,J= 12.1Hz, 2H,NCH2), 3.02 (t,J= 12.0Hz, 2H,NCH2), 1.75 (d,J= 14.8Hz, 2H C^CHrt), 1. 66 - 1. 44(m, 2HCH^C^),1. 34 (dd,J= 16. 2, 8. 2Hz, 2HCH2CH2CH2). MS(ESI(+)70eV,m/z):265. 1 [M+H]+. Che NMR (300MHz, D20) S 8. 59 (d, J = 1. 6Hz, 1H, ArH), 8. 15 (dd, Shang = 7. 9, J2 = 1.6Hz, 1H, ArH), 7. 63 (d, J = 7. 9Hz, 1H, ArH), 4. 41 (s, 2H, PhCH2), 3. 4 4 (d, J = 12.1Hz, 2H, NCH2), 3.02 (t, J = 12.0Hz , 2H, NCH2), 1.75 (d, J = 14.8Hz, 2H C ^ CHrt), 1. 66 -. 1. 44 (m, 2HCH ^ C ^), 1 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-1-基)甲基)-3-硝基苯甲酸盐酸盐(7i)的合成 [0089] 4 - ((pyrrolidin-1-yl) methyl) -3-nitrobenzoic acid hydrochloride (7i) of

[0090] 装有回流冷凝管的25mL茄型瓶中加入6b (1. 00g, 3. 66mmol)、吡咯烷(3. 26g, 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。 [0090] equipped with a reflux condenser 25mL eggplant type flask 6b (1. 00g, 3. 66mmol), pyrrolidine (3. 26g, 4. 58mmol), potassium carbonate (0 • 39g, 2. 85mmol), 1. 2mL of toluene and 2mL of water, at 75 C the reaction was stirred for 12 hours, TLC monitoring completion of the reaction raw materials, heating was stopped and stirring, the toluene layer was separated, the aqueous layer was 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 to the organic layer was washed free product were 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 a saturated aqueous sodium bicarbonate adjusted to an alkaline pH, 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l〇mL 20%盐酸,控温于100C搅拌反应过夜。 Filtration, the solvent was distilled off under reduced pressure, the residue was added 20% hydrochloric acid l〇mL, temperature at 100 C and stirred overnight. 冷却,于低温慢速搅拌,析出白色固体,抽滤,得中间体710.69,收率65.71%,1114.293 ~2961:。 Cooling, stirring slowly at low temperature to precipitate a white solid, leaching, have intermediate 710.69, a yield of 65.71%, 1114.293 ~ 2961 :. 111匪1?(3001抱,020) 8 8. 59 (d, J = 1. 5Hz, 1H, ArH), 8. 17 (dd, J:= 7. 9, J2= 1. 6Hz, 1H, ArH), 7. 66 (d, J = 8. 0Hz ,1H, ArH), 4. 53 (s, 2H, PhCH2), 3. 48 (d, J = 5. 1Hz, 2H, NCH2), 3. 32 - 3. 00 (m, 2H, NCH2), 2. 03 ( s, 2H, CH2), 1.83(dd, J:= 7. 4, J2= 5. 1Hz, 2H, CH 2). MS (ESI (+) 70eV, m/z) :251. 1[M+H]+. 111 bandit 1 (3001 hold, 020) 8 8. 59 (d, J = 1. 5Hz, 1H, ArH), 8. 17 (dd, J:? = 7. 9, J2 = 1. 6Hz, 1H, ArH ), 7. 66 (d, J = 8. 0Hz, 1H, ArH), 4. 53 (s, 2H, PhCH2), 3. 48 (d, J = 5. 1Hz, 2H, NCH2), 3. 32 - 3. 00 (m, 2H, NCH2), 2. 03 (s, 2H, CH2), 1.83 (dd, J: = 7. 4, J2 = 5. 1Hz, 2H, CH 2) 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] Synthesis 4_ (diethylamide meth) -3_ nitro-benzoic acid hydrochloride (7j) of

[0093] 装有回流冷凝管的25mL爺型瓶中加入6b (1. 00g, 3. 66mmol)、二乙胺(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] 25mL Lord equipped with a reflux condenser type flask 6b (1. 00g, 3. 66mmol), diethylamine (0 • 33g, 4. 58mmol), potassium carbonate (0 • 39g, 2. 85mmol) , 2mL 1. 2mL of toluene and water, at 75 C the reaction was stirred for 12 hours, TLC monitoring completion of the reaction raw materials, heating was stopped and stirring, the toluene layer was separated, the aqueous layer was 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 to the organic layer was washed free product were 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 a saturated aqueous sodium bicarbonate adjusted to an alkaline pH, 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l〇mL 20%盐酸,控温于100C搅拌反应过夜。 Filtration, the solvent was distilled off under reduced pressure, the residue was added 20% hydrochloric acid l〇mL, temperature at 100 C 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」0.78,收率73.58%,1114.286~2891:。 Cooling, stirring slowly at low temperature to precipitate a white solid, leaching, have intermediate 7 "0.78, a yield of 73.58%, 1114.286 ~ 2891 :. 111匪1?(3001抱,020) 8 8. 63(d, J= 1. 7Hz, 1H, ArH), 8. 17 (dd, J:= 7. 9, J2= 1. 7Hz, 1H, ArH), 7. 65 (d, J = 8. 0Hz ,1H, 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]+. 111 bandit 1 (3001 hold, 020) 8 8. 63 (d, J = 1. 7Hz, 1H, ArH), 8. 17 (dd, J:? = 7. 9, J2 = 1. 7Hz, 1H, ArH ), 7. 65 (d, J = 8. 0Hz, 1H, 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-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(1-1) [0095] 4 - ((4-methyl-piperazin-1-yl) methyl) benzoic acid _ (Z) -2- methoxy-5- (3, 4, 5- trimethoxy styryl) benzene ester (1-1)

[0096] 在装有回流冷凝管的25mL爺型瓶中加入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] 25mL equipped with a reflux condenser Lord type flask 7a (0. 27g, 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. Ommol) 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. Ommol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant-type flask, was added triethylamine (0. 20g, 0. 28mL, 2 . Ommol), 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 until the aqueous layer no product, the ethyl acetate layer was washed with water three times, saturated brine washed with water 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1-10.23 ,收率43.40%,111邛.102~1041:。 Filtration, the filtrate was spin-dry the residue by column chromatography (dichloromethane: methanol = 200: 1) separation and purification, as a white solid 1-10.23 , yield 43.40%, 111 Qiong .102 ~ 1041 :. 11?(11',。 cnT1) :3431,9277, 2938, 2794, 2739, 2504, 2530, 2497, 1739, 1611,1578, 1504, 1451,1415, 13 98, 1384, 1328, 1263, 1209, 1126, 1068, 1035, 1011,901,851,807, 768, 749, 694, 580, 462.屮NMR (300MHz,CDC13) S 8. 11 (d,J = 8. 0Hz,2H,ArH),7. 44 (d,J = 8. 0Hz,2H,ArH),7. 17 (d,J =8. 6Hz, 1H, ArH) ,7.13 (s, 1H, ArH), 6. 90 (d, J = 8. 4Hz, 1H, ArH), 6. 54 (s, 2H, ArH), 6 .48 (d, J = 2. 8Hz, 2H, ArH) ,3.81 (s, 3H, 0CH3), 3. 79 (s, 3H, 0CH3), 3. 73 (s, 6H, 2 X 0CH3 ),3. 62 (s, 2H, PhCH2), 2. 77 ~2. 60 (m, 8H,哌嗪氢),2. 48 (s, 3H, NCH3) • HR-ESMS m/z 533. 2656 [M+H]+ (calcd for C31H37N206, 533. 2646). ? 11 (1 1 ',. cnT1): 3431,9277, 2938, 2794, 2739, 2504, 2530, 2497, 1739, 1611,1578, 1504, 1451,1415, 13 98, 1384, 1328, 1263, 1209 , 1126, 1068, 1035, 1011,901,851,807, 768, 749, 694, 580, 462. Che NMR (300MHz, CDC13) S 8. 11 (d, J = 8. 0Hz, 2H, ArH), 7. 44 (d, J = 8. 0Hz, 2H, ArH), 7. 17 (d, J = 8. 6Hz, 1H, ArH), 7.13 (s, 1H, ArH), 6. 90 (d, J = 8. 4Hz, 1H, ArH), 6. 54 (s, 2H, ArH), 6 .48 (d, J = 2. 8Hz, 2H, ArH), 3.81 (s, 3H, 0CH3), 3. 79 (s, 3H, 0CH3), 3. 73 (s, 6H, 2 X 0CH3), 3. 62 (s, 2H, PhCH2), 2. 77 ~ 2. 60 (m, 8H, piperazine hydrogen), 2 . 48 (s, 3H, NCH3) • HR-ESMS m / z 533. 2656 [M + H] + (calcd for C31H37N206, 533. 2646).

[0097] 将1-1 (0. 10g,0. 19mmol)溶于2mL二氯甲烷中,滴加饱和HC1的乙醚溶液,搅拌5 分钟,析出白色固体,抽滤,得I-1.HC1 0. 07g,收率61.57%,mp234 ~ 236C。 [0097] The 1-1 (0. 10g, 0. 19mmol) was dissolved in 2mL of dichloromethane, saturated HC1 in ether was added dropwise, and stirred for 5 minutes, the precipitated white solid was suction filtered to give I-1.HC1 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] 25mL equipped with a reflux condenser, an eggplant-shaped flask 7b (0. 26g, 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. Ommol) 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. Ommol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant-type flask, was added triethylamine (0. 20g, 0. 28mL, 2 . Ommol), 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 until the aqueous layer no product, the ethyl acetate layer was washed with water three times, saturated brine washed with water 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. 19g,收率36. 53 %,mp 50~52 C。 Filtration, the filtrate was spin-dry the residue by column chromatography (dichloromethane: methanol = 200: 1) separation and purification, as a white solid 1-2 0. 19g, yield 36. 53%, mp 50 ~ 52 C. IR (KBr,u cnf1) :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.屮NMR(300MHz,CDC13) S 8. 11 (d,J = 8. 2Hz,2H,ArH),7. 47 (d,J = 8. 1Hz,2H,ArH),7. 17 (dd,1 =8. 4, J2= 2. 0Hz, 1H, ArH), 7. 14(d, J = 1. 9Hz, 1H, ArH), 6. 90 (d, J = 8. 4Hz, 1H, ArH) ,6. 54 (s, 2H, ArH), 6. 47 (d, J = 3. 2Hz, 2H, ArH), 3. 81 (s, 3H, 0CH3), 3. 79 (s, 3H, 0CH3), 3. 73 (m, 10H, PhCH2, 2 X 0CH3and 0CH2),3. 58 (m, 2H, 0CH2),2. 40 ~2. 57 (m, 4H, N (CH2) 2) • 13C NMR(75MHz,CDC13) S 163. 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 C30H34N07, 5 20 . 2 3 30). IR (KBr, u cnf1): 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. Che NMR (300MHz, CDC13) S 8. 11 (d, J = 8. 2Hz, 2H, ArH), 7. 47 (d, J = 8. 1Hz , 2H, ArH), 7. 17 (dd, 1 = 8. 4, J2 = 2. 0Hz, 1H, ArH), 7. 14 (d, J = 1. 9Hz, 1H, ArH), 6. 90 ( d, J = 8. 4Hz, 1H, ArH), 6. 54 (s, 2H, ArH), 6. 47 (d, J = 3. 2Hz, 2H, ArH), 3. 81 (s, 3H, 0CH3 ), 3. 79 (s, 3H, 0CH3), 3. 73 (m, 10H, PhCH2, 2 X 0CH3and 0CH2), 3. 58 (m, 2H, 0CH2), 2. 40 ~ 2. 57 (m, 4H, N (CH2) 2) • 13C NMR (75MHz, CDC13) S 163. 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 C30H34N07, 5 20. 2 3 30).

[0101] 将1-2(0. 10g,0. 19mmol)溶于2mL二氯甲烷中,滴加饱和HC1的乙醚溶液,搅拌5 分钟,析出白色固体,抽滤,得1_2*11(:10.08 8,收率74.77%,1114.128~13〇1:。11?〇『 ,u cm-1) : 3426, 2936, 2837, 2536, 2368, 1742, 1613, 1578, 1509, 1455, 1422, 1327, 1263, 120 9, 1183, 1125, 1072, 1020, 974, 911,870, 797, 757, 698, 581,526, 459.屮NMR (300MHz,CDC13) 8 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, 1H, ArH), 7. 14 (m, 1H, ArH), 6. 90 (d, J = 8. 4Hz, 1H, ArH), 6. 52 (s, 2H, ArH), 6. 47 (s, 2 H, ArH),4. 30 (s, 2H, PhCH2),4. 27 (m, 2H, 0CH2),4. 02 ~3. 88 (m, 2H, 0CH2),3. 80 (s, 3H, 0CH3), 3. 78 (s, 3H, 0CH3), 3. 72 (s, 6H, 2 X 0CH3), 3. 35 (m, 2H, NCH2), 2. 92 (m, 2H, NCH2). [0101] The 1-2 (.. 0 10g, 0 19mmol) was dissolved in 2mL of dichloromethane, saturated HC1 in ether was added dropwise, and stirred for 5 minutes, the precipitated white solid was suction filtered to give 1_2 * 11 (: 10.08 8, yield 74.77%, 1114.128 ~ 13〇1:? .11 billion ', u cm-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. Che NMR (300MHz, CDC13) 8 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, 1H, ArH), 7 . 14 (m, 1H, ArH), 6. 90 (d, J = 8. 4Hz, 1H, ArH), 6. 52 (s, 2H, ArH), 6. 47 (s, 2 H, ArH), 4. 30 (s, 2H, PhCH2), 4. 27 (m, 2H, 0CH2), 4. 02 ~ 3. 88 (m, 2H, 0CH2), 3. 80 (s, 3H, 0CH3), 3. 78 (s, 3H, 0CH3), 3. 72 (s, 6H, 2 X 0CH3), 3. 35 (m, 2H, NCH2), 2. 92 (m, 2H, NCH2).

[0102] 实施例17 [0102] Example 17

[0103] 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(1-3)盐酸盐 [0103] 4- (piperidin-1-ylmethyl) benzoic acid - (Z) -2- methoxy-5- (3,4,5-trimethoxy styryl) phenyl ester (1-3) hydrochloride

[0104] 在装有回流冷凝管的25mL爺型瓶中加入7c (255. lmg, 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。 [0104] 25mL equipped with a reflux condenser Lord type flask 7c (255. lmg, 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. Ommol) 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. Ommol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant-type flask, was added triethylamine (0. 20g, 0. 28mL, 2 . Ommol), 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 until the aqueous layer no product, the ethyl acetate layer was washed with water three times, saturated brine washed with water 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%,mp 100 ~102C。 Filtration, the filtrate was spin-dried, the residue was column chromatographed (dichloromethane: methanol = 200: 1) separation and purification to give 1-3 as a white solid 0 • 21g, yield 40. 62%, mp 100 ~ 102 C. 将1-3(0. 10g, 0• 193mmol) 溶于2mL二氯甲烷中,滴加饱和HC1的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-3 • 抝10.09,收率84.11%,111.?.132~1351:。 The 1-3 (0. 10g, 0 • 193mmol) was dissolved in 2mL of dichloromethane, diethyl ether was added dropwise saturated HC1 and stirred for 5 minutes to precipitate a white solid, filtration, was 1-3 • bend 10.09, income rate of 84.11%, 111? 132 ~ 1351 :. 11?(11',。〇11- 1):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.屮匪R(300MHz, CDC13) S 12. 47(s, 1H), 8. 22(d, J = 3. 6Hz, 2H, ArH), 7. 92 - 7. 76 (m, 2H, ArH), 7. 19 (dd, J = 8. 4, 1. 8Hz, 1H, ArH), 7. 14 (d, J = 1. 9Hz, 1H, ArH), 6. 91 (d, J = 8. 5 Hz, 1H, ArH), 6. 54 (s, 2H, ArH), 6. 48 (s, 2H, ArH), 4. 22 ( s, 2H, PhCH2), 3. 82 (s, 3H, OCH3), 3. 80 (s, 3H, OCH3), 3. 74 (s, 6H, 2 X OCH3), 2. 64 (m, 2H, NCH2) ,2. 34 (m, 2H, NCH2),1. 99 (m, 2H, C迅CH2CH2),1. 89 (m, 2H, CH2CH2C$),1. 88 ~1. 77 (m, 2H, CH 2C$CH2). 13C NMR(75MHz,CDC13) S 163. 23, 152. 45, 149. 78, 138. 80, 133. 02, 131. 98, 131. 3 8, 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 C31H36N06, 5 1 8 . 2 5 3 7). ? 11 (1 1 ', 〇11- 1): 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. Che bandit R (300MHz, CDC13) S 12. 47 (s, 1H), 8. 22 (d, J = 3. 6Hz, 2H , ArH), 7. 92 - 7. 76 (m, 2H, ArH), 7. 19 (dd, J = 8. 4, 1. 8Hz, 1H, ArH), 7. 14 (d, J = 1. 9Hz, 1H, ArH), 6. 91 (d, J = 8. 5 Hz, 1H, ArH), 6. 54 (s, 2H, ArH), 6. 48 (s, 2H, ArH), 4. 22 (s, 2H, PhCH2), 3. 82 (s, 3H, OCH3), 3. 80 (s, 3H, OCH3), 3. 74 (s, 6H, 2 X OCH3), 2. 64 (m, 2H , NCH2), 2. 34 (m, 2H, NCH2), 1. 99 (m, 2H, C fast CH2CH2), 1. 89 (m, 2H, CH2CH2C $), 1. 88 ~ 1. 77 (m, 2H, CH 2C $ CH2). 13C NMR (75MHz, CDC13) S 163. 23, 152. 45, 149. 78, 138. 80, 133. 02, 131. 98, 131. 3 8, 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 C31H36N06, 5 1 8. 2 5 3 7).

[0105] 实施例18 [0105] Example 18

[0106] 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)盐酸盐 [0106] 4- (pyrrolidin-1-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爺型瓶中加入7d(241. lmg, 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] 25mL equipped with a reflux condenser Lord type flask 7d (241. Lmg, 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. Ommol) 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. Ommol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant-type flask, was added triethylamine (0. 20g, 0. 28mL, 2 . Ommol), 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 until the aqueous layer no product, the ethyl acetate layer was washed with water three times, saturated brine washed with water 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0.2(^,收率39.76%,111邛.98~1001:。11?(诎1',。〇11-1):3434, u cnT1) : 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. 10g, 0• 199mmol)溶于2mL 二氯甲烷中,滴加饱和HC1的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-4 • HC1 0. 08g,收率74. 76%,mp 110 ~112C。 Filtration, the filtrate was spin-dry the residue by column chromatography (dichloromethane: methanol = 500: 1) separation and purification, to obtain a white solid 0.2 1_4 (^, yield 39.76%, 111 Qiong .98 ~ 1001: .11 (? . bend 1 ', 〇11-1): 3434, u cnT1): 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. 10g, 0 • 199mmol) was dissolved in 2mL of dichloromethane, saturated HC1 in ether was added dropwise, and stirred for 5 minutes, the precipitated white solid was suction filtered give 1-4 • HC1 0. 08g, yield 74. 76%, mp 110 ~ 112 C. IR(KBr,u cm-1) : 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. :H NMR(300MHz, CDC13) 8 12. 86 (s, 1H), 8. 22 (d, J =7. 5Hz, 2H, ArH) , 7. 84 (d, J = 7. 6Hz, 2H, ArH) , 7. 19 (dd, J:= 8. 4, J 2 = 2. 0Hz, 1H, ArH), 7. 14 (d, J = 2. 0Hz, 1H, ArH), 6. 91 (d, J = 8. 5Hz, 1H, ArH), 6. 54 (s, 2H, Ar H), 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, 2 X 0CH3),3. 70 ~3. 68 (m, 2H, NCH2),2. 88 (m, 2H, NCH2),2. 27 (m, 2H, CH2),2. 08 (m ,2H,CH2).13CNMR(75MHz,CDC13)S 163.25,152.43,149.77,138.83,136.46,134.65,131. 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 C30H34N06, 504. 2 381). IR (KBr, u cm-1): 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.: H NMR (300MHz, CDC13) 8 12. 86 (s, 1H), 8. 22 (d, J = 7 5Hz, 2H, ArH.) , 7. 84 (d, J = 7. 6Hz, 2H, ArH), 7. 19 (dd, J: = 8. 4, J 2 = 2. 0Hz, 1H, ArH), 7. 14 (d, J = 2. 0Hz, 1H, ArH), 6. 91 (d, J = 8. 5Hz, 1H, ArH), 6. 54 (s, 2H, Ar H), 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, 2 X 0CH3 ), 3. 70 ~ 3. 68 (m, 2H, NCH2), 2. 88 (m, 2H, NCH2), 2. 27 (m, 2H, CH2), 2. 08 (m, 2H, CH2). 13CNMR (75MHz, CDC13) S 163.25,152.43,149.77,138.83,136.46,134.65,131. 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 C30H34N06, 504. 2 381).

[0108] 实施例19 [0108] Example 19

[0109] 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)盐酸盐 [0109] 4- (diethylamino-1-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爺型瓶中加入7e (243. lmg, 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。 [0110] 25mL equipped with a reflux condenser Lord type flask 7e (243. lmg, 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. Ommol) 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. Ommol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant-type flask, was added triethylamine (0. 20g, 0. 28mL, 2 . Ommol), 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 until the aqueous layer no product, the ethyl acetate layer was washed with water three times, saturated brine washed with water 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 0.25,收率49.50%。 Filtration, the filtrate was spin-dry the residue by column chromatography (dichloromethane: methanol = 500: 1) separation and purification, as a white solid 1-5 0.25, a yield of 49.50%. 将1-5(0.1(^,0.198臟〇1) 溶于2mL二氯甲烷中,滴加饱和HC1的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-5_11(:10.09 8,收率84.11%,111.口.115~118 1:。111匪1?(3001抱,0)(:13) 8 12. 66 (s, 1H), 8. 26 (d, J = 7. 5Hz, 2H, ArH), 7. 83 (d, J = 7. 6Hz, 2H, ArH), 7. 21 (dd, J:= 8. 4, J2= 2. 0Hz, 1H, ArH), 7. 16 (d, J = 2. 0Hz, 1H, ArH), 6. 90 (d, J = 8. 5Hz, 1H, 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 (CH2CH3) 2). 13C NMR(75MHz,CDC13)S 163.49,152.15,146.88,136.40,135.96,132.35,132.03,131.04,129. 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 C30H36N06, 506 . 2 5 3 7). The 1-5 (0.1 (^, 0.198 dirty 〇1) was dissolved in 2mL of dichloromethane, saturated HC1 in ether was added dropwise, and stirred for 5 minutes, the precipitated white solid was suction filtered to give 1-5_11 (: 8 10.09, Yield 84.11%, 111 mouth .115 ~ 1181: .111 bandit 1 (3001 holds, 0)? (: 13) 8 12. 66 (s, 1H), 8. 26 (d, J = 7. 5Hz , 2H, ArH), 7. 83 (d, J = 7. 6Hz, 2H, ArH), 7. 21 (dd, J: = 8. 4, J2 = 2. 0Hz, 1H, ArH), 7. 16 (d, J = 2. 0Hz, 1H, ArH), 6. 90 (d, J = 8. 5Hz, 1H, 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 (CH2CH3) 2). 13C NMR (75MHz, CDC13) S 163.49, 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 C30H36N06, 506. 2 5 3 7 ).

[0111] 实施例20 [0111] Example 20

[0112] 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)盐酸盐 [0112] 4 - ((4-methyl-piperazin-1-yl) methyl) -3-nitrobenzoic acid _ (Z) -2- methoxy-5- (3, 4, 5- trimethoxy styryl) phenyl ester (1-6) hydrochloride

[0113] 在装有回流冷凝管的25mL茄型瓶中加入7f (0. 32g,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。 [0113] 25mL equipped with a reflux condenser, an eggplant-shaped flask 7f (0. 32g, 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. Ommol) 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. Ommol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant-type flask, was added triethylamine (0. 20g, 0. 28mL, 2 . Ommol), 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 until the aqueous layer no product, the ethyl acetate layer was washed with water three times, saturated brine washed with water 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%,mp 70 ~72C。 Filtration, the filtrate was spin-dry the residue by column chromatography (dichloromethane: methanol = 200: 1) separation and purification to give 1-6 as a white solid 0 • 23g, yield 39. 86%, mp 70 ~ 72 C. IR(KBr, u cm-1) :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.屮匪R (300MHz,CDC13) S 8. 57 (d,J = 1. 3Hz, 1H, ArH), 8. 29 (dd, J = 8. 0, 1. 5Hz, 1H, ArH), 7. 74 (d, J = 8. 0Hz, 1H, ArH), 7. 19 (dd, J =8. 5, 1. 9Hz, 1H, ArH), 7. 12 (d, J = 1. 9Hz, 1H, ArH), 6. 91 (d, J = 8. 5Hz, 1H, ArH), 6. 52 (s, 1H, ArH), 6. 49 (s, 1H, HC = CH), 3. 87 (s, 2H, PhC^N), 3. 82 (s, 3H, 0CH3), 3. 80 (s, 3H, 0CH3), 3. 73 (s, 6H, 2 X 0CH3), 2. 70 - 2. 38 (m, 8H,哌嗪氢),2. 33 (s, 3H, NCH3) • 13C NMR (75MHz, CDC13) 8 162. 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. 4 4, 54. 40, 52. 32, 45. 27. HR-ESIMS m/z 578. 2488 [M+H] + (calcd for C31H36N3〇8, 578. 2497). IR (KBr, u cm-1): 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. Che bandit R (300MHz, CDC13) S 8. 57 (d, J = 1. 3Hz, 1H, ArH), 8. 29 (dd, J = 8. 0, 1. 5Hz, 1H, ArH), 7. 74 (d, J = 8. 0Hz, 1H, ArH), 7. 19 (dd, J = 8. 5, 1. 9Hz, 1H, ArH), 7 . 12 (d, J = 1. 9Hz, 1H, ArH), 6. 91 (d, J = 8. 5Hz, 1H, ArH), 6. 52 (s, 1H, ArH), 6. 49 (s, 1H, HC = CH), 3. 87 (s, 2H, PhC ^ N), 3. 82 (s, 3H, 0CH3), 3. 80 (s, 3H, 0CH3), 3. 73 (s, 6H, 2 X 0CH3), 2. 70 -. 2. 38 (m, 8H, piperazine hydrogen), 2 33 (s, 3H, NCH3) • 13C NMR (75MHz, CDC13) 8 162. 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. 4 4, 54. 40, 52. 32, 45. 27. HR-ESIMS m / z 578. 2488 [M + H] + (calcd for C31H36N3〇8, 578.2497).

[0114] 将1-6(0. 10g,0. 173mmol)溶于2mL二氯甲烷中,滴加饱和HC1的乙醚溶液,搅拌5 分钟,析出白色固体,抽滤,得1_6*11(:10.08 8,收率75.47%,1114.144~1461:。11?〇1', u cnf1) : 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. [0114] The 1-6 (.. 0 10g, 0 173mmol) was dissolved in 2mL of dichloromethane, saturated HC1 in ether was added dropwise, and stirred for 5 minutes, the precipitated white solid was suction filtered to give 1_6 * 11 (: 10.08 8, yield 75.47%, 1114.144 ~ 1461:? .11 billion 1 ', u cnf1): 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爺型瓶中加入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] 25mL equipped with a reflux condenser Lord type flask 7g (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CA-4(0. 316g, 1. Ommol) 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. Ommol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant-type flask, was added triethylamine (0. 20g, 0. 28mL, 2 . Ommol), 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 until the aqueous layer no product, the ethyl acetate layer was washed with water three times, saturated brine washed with water 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0.23 8,收率40.78%,111.口.82~841:。 Filtration, the filtrate was spin-dry the residue by column chromatography (dichloromethane: methanol = 300: 1) separation and purification, as a white solid 0.23 8, the yield of 40.78%, 111 ~ 841 :. .82 mouth. 11?(诎1',。〇11-1):3467,2960, 2932, 2852, 1745, 1615, 1578, 1530, 1511,1451,1426, 1412, 1351,1339, 1322, 1269, 1243, 12 07, 1115, 1082, 1027, 1009, 913, 881,868, 841,803, 767, 740, 707, 582.屮NMR(300MHz,CDC13) 8 8. 58 (s, 1H, ArH), 8. 29 (d, J = 7. 1Hz, 1H, ArH), 7. 77 (d, J = 7. 4Hz, 1H, ArH), 7. 23 -7. 09 (m, 2H, ArH), 6. 91 (d, J = 7. 9Hz, 1H, ArH), 6. 52 (s, 2H, ArH), 6. 49 (s, 2H, HC = CH), 3 .86 (s, 2H, PhC^N), 3. 82 (s, 3H, 0CH3), 3. 80 (s, 3H, 0CH3), 3. 73 (s, 6H, 2 X 0CH3), 3. 68 (m, 4 H,0(CH2)2),2.46(m,4H,N(CH2)2). 13CNMR(75MHz,CDCl3)Sl61.94,152.50,149.64,149. 32, 138. 60, 138. 43, 133. 06, 131. 89, 130. 83, 129. 68, 129. 24, 129. 13, 127. 88, 127. 76, 12 5. 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 C3(lH33N209, 565. 2181). ? 11 (. Bend 1 ', 〇11-1): 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. Che NMR (300MHz, CDC13) 8 8. 58 (s, 1H, ArH), 8. 29 ( d, J = 7. 1Hz, 1H, ArH), 7. 77 (d, J = 7. 4Hz, 1H, ArH), 7. 23 -7. 09 (m, 2H, ArH), 6. 91 (d , J = 7. 9Hz, 1H, ArH), 6. 52 (s, 2H, ArH), 6. 49 (s, 2H, HC = CH), 3 .86 (s, 2H, PhC ^ N), 3 . 82 (s, 3H, 0CH3), 3. 80 (s, 3H, 0CH3), 3. 73 (s, 6H, 2 X 0CH3), 3. 68 (m, 4 H, 0 (CH2) 2), 2.46 (m, 4H, N (CH2) 2). 13CNMR (75MHz, CDCl3) Sl61.94,152.50,149.64,149. 32, 138. 60, 138. 43, 133. 06, 131. 89, 130. 83 , 129.68, 129.24, 129.13, 127.88, 127.76, 12 5.65, 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 C3 (lH33N209, 565. 2181).

[0118] 将1-7(0. 10g,0. 177mmol)溶于2mL二氯甲烷中,滴加饱和HC1的乙醚溶液,搅拌5 分钟,析出白色固体,抽滤,得I-7.HC1 0.08g,收率75.47%,mp216~219C。 [0118] The 1-7 (0. 10g, 0. 177mmol) was dissolved in 2mL of dichloromethane, saturated HC1 in ether was added dropwise, and stirred for 5 minutes, the precipitated white solid was suction filtered to give I-7.HC1 0.08 g, 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爺型瓶中加入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] 25mL equipped with a reflux condenser Lord type 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CA-4(0. 316g, 1. Ommol) 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. Ommol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant-type flask, was added triethylamine (0. 20g, 0. 28mL, 2 . Ommol), 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 until the aqueous layer no product, the ethyl acetate layer was washed with water three times, saturated brine washed with water 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0.19 8,收率33.80%,111.口.74~761:。 Filtration, the filtrate was spin-dry the residue by column chromatography (dichloromethane: methanol = 400: 1) separation and purification, as a white solid 0.19 8, the yield of 33.80%, 111 .74 ~ 761 :. mouth. 11?(诎1',。〇11-1):3467,3002, 2931,2853, 2782, 2747, 2335, 2330, 1745, 1615, 1578, 1528, 1512, 1464, 1447, 1424, 1412, 1 348, 1337, 1320, 1290, 1274, 1239, 1222, 1176, 1158, 1112, 1081,1027, 1012, 994, 978, 912, SSLSeTJAlJOSjeejAOJS〗.1!!匪R (300MHz, CDC13) S 8.58 (s,lH, ArH) ,8.29 (d,J = 7. 7Hz, 1H, ArH), 7. 83 (d, J = 7. 4Hz, 1H, ArH), 7. 19 (d, J = 8. 3Hz, 1H, ArH), 7. 13 (s, 1H, ArH),6. 91(d, J = 8. 4Hz, 1H, ArH), 6. 52 (s, 2H, ArH), 6. 48 (s, 2H, HC = CH),3. 81(d, J = 5. 9Hz, 8H, 2 X 0CH3and PhC^N), 3. 73 (s, 6H, 2 X 0CH3), 2. 28 - 2. 48 (m, 4H, N (C^) 2), 1. 38 -1. 49 (m, 4H, ,0• 97 - 0• 81 (m, 2H, CH2CH2CH2) • 13C NMR(75MHz,CDC13) S 162. 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 C31H35N208, 563. 2388). ? 11 (bend 1 ', 〇11-1.): 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, SSLSeTJAlJOSjeejAOJS〗 .1 !! bandits R (300MHz, CDC13) S 8.58 (s, lH , ArH), 8.29 (d, J = 7. 7Hz, 1H, ArH), 7. 83 (d, J = 7. 4Hz, 1H, ArH), 7. 19 (d, J = 8. 3Hz, 1H, ArH), 7. 13 (s, 1H, ArH), 6. 91 (d, J = 8. 4Hz, 1H, ArH), 6. 52 (s, 2H, ArH), 6. 48 (s, 2H, HC = CH), 3 81 (d, J = 5. 9Hz, 8H, 2 X 0CH3and PhC ^ N), 3. 73 (s, 6H, 2 X 0CH3), 2. 28 -. 2. 48 (m, 4H, N (C ^) 2), 1. 38 -1 49 (m, 4H,, 0 • 97 - 0 • 81 (m, 2H, CH2CH2CH2). • 13C NMR (75MHz, CDC13) S 162. 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 C31H35N208, 563. 2388).

[0122] 将1-8(0. 10g,0. 178mmol)溶于2mL二氯甲烷中,滴加饱和HC1的乙醚溶液,搅拌5 分钟,析出白色固体,抽滤,得I-8.HC1 0. 08g,收率75. 12%,mp 202~204C。 [0122] The 1-8 (0. 10g, 0. 178mmol) was dissolved in 2mL of dichloromethane, saturated HC1 in ether was added dropwise, and stirred for 5 minutes, the precipitated white solid was suction filtered to give I-8.HC1 0 . 08g, yield 75. 12%, mp 202 ~ 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(I1-9)盐酸盐 [0124] 4- (pyrrolidin-1-ylmethyl) -3-nitrobenzoic acid - (Z) -2- methoxy-5- (3, 4, 5- trimethoxy styryl) phenyl ester (I1-9) hydrochloride

[0125] 在装有回流冷凝管的25mL爺型瓶中加入7i (286. lmg, 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。 [0125] 25mL equipped with a reflux condenser Lord type flask 7i (286. lmg, 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. Ommol) 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. Ommol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant-type flask, was added triethylamine (0. 20g, 0. 28mL, 2 . Ommol), 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 until the aqueous layer no product, the ethyl acetate layer was washed with water three times, saturated brine washed with water 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.口.56~581:。11?(11',。〇11-〇:3447, 2935, 2835, 2362, 1746, 1618, 1579, 1535, 1508, 1460, 1426, 1350, 1328, 1265, 124 0, 1206, 1126, 1024, 1006, 915, 892, 854, 795, 739, 578.屮匪R(300MHz,CDC13) S 8. 63 (d,J =1. 5Hz, 1H, ArH), 8. 31 (d, J = 8. 1Hz, 1H, ArH), 7. 88 (d, J = 8. 1Hz, 1H, ArH), 7. 19 (dd, J =8. 5, 2. 1Hz, 1H, ArH), 7. 13(d, J = 2. 0Hz, 1H, ArH), 6. 91 (d, J = 8. 5Hz, 1H, ArH), 6. 53 (s, 2H, ArH), 6. 49 (s, 2H, ArH), 4. 01 (s, 2H, PhCH2N), 3. 82 (s, 3H, 0CH3), 3. 80 (s, 3H, 0CH3) ,3. 73(s, 6H, 2X0CH3), 2. 54(s, 4H N(CH2)2), 1. 80(s, 4H, Cfl2Cfl2). 13C 匪R(75MHz, CDC13) 8 162. 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 C30H33N208, 549. 2231). Filtration, the filtrate was spin-dry the residue by column chromatography (dichloromethane: methanol = 200: 1) separation and purification, as a white solid 1-9 0.2 (^, yield 36.50%, 111 ~ 581 :. .56 mouth. ? 11 (1 1 '〇11-square: 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. Che bandit R (300MHz, CDC13) S 8. 63 (d, J = 1. 5Hz, 1H, ArH), 8. 31 (d, J = 8 . 1Hz, 1H, ArH), 7. 88 (d, J = 8. 1Hz, 1H, ArH), 7. 19 (dd, J = 8. 5, 2. 1Hz, 1H, ArH), 7. 13 ( d, J = 2. 0Hz, 1H, ArH), 6. 91 (d, J = 8. 5Hz, 1H, ArH), 6. 53 (s, 2H, ArH), 6. 49 (s, 2H, ArH ), 4. 01 (s, 2H, PhCH2N), 3. 82 (s, 3H, 0CH3), 3. 80 (s, 3H, 0CH3), 3. 73 (s, 6H, 2X0CH3), 2. 54 ( s, 4H N (CH2) 2), 1. 80 (s, 4H, Cfl2Cfl2). 13C bandit R (75MHz, CDC13) 8 162. 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 C30H33N208, 549.2231).

[0126] 将1-9(0. 10g,0. 182mmol)溶于2mL二氯甲烷中,滴加饱和HC1的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-9,11(:10.08 8,收率75.47%,1114.106~1081:。11? (KBr,u cnf1) : 3426, 2938, 2837, 2564, 1748, 1624, 1578, 1541,1508, 1454, 1426, 1412, 134 5, 1327, 1258, 1207, 1125, 1006, 856, 797, 771,747, 581,461. 4 匪R(300MHz, CDC13) S 12 ,93(s, 1H, ArH), 8.73 (m,2H, ArH), 8.51 (d,J = 6. 3Hz, 1H, ArH), 7. 18 (dd, J:= 8. 4, J2 = 1. 4Hz, 1H, ArH), 7. 11 (d, J = 1. 4Hz, 1H, ArH), 6. 90 (d, J = 8. 4Hz, 1H, ArH), 6. 50 (s, 2H, ArH) ,6. 47 (s, 2H, ArH),4. 73 (s, 2H, PhCI^N),3. 84 ~3. 66 (m, 14H, 4 X 0CH3, NCH2),3. 17 ~2. 94 (m, 2H,NCH2),2. 21 (m, 4H, CH2CH2) • [0126] The 1-9 (0. 10g, 0. 182mmol) was dissolved in 2mL of dichloromethane, saturated HC1 in ether was added dropwise, and stirred for 5 minutes, the precipitated white solid was suction filtered to give 1-9,11 ( : 10.08 8, yield 75.47%, 1114.106 ~ 1081:? .11 (KBr, u cnf1): 3426, 2938, 2837, 2564, 1748, 1624, 1578, 1541,1508, 1454, 1426, 1412, 134 5, 1327, 1258, 1207, 1125, 1006, 856, 797, 771,747, 581,461. 4 bandit R (300MHz, CDC13) S 12, 93 (s, 1H, ArH), 8.73 (m, 2H, ArH) , 8.51 (d, J = 6. 3Hz, 1H, ArH), 7. 18 (dd, J: = 8. 4, J2 = 1. 4Hz, 1H, ArH), 7. 11 (d, J = 1. 4Hz, 1H, ArH), 6. 90 (d, J = 8. 4Hz, 1H, ArH), 6. 50 (s, 2H, ArH), 6. 47 (s, 2H, ArH), 4. 73 ( s, 2H, PhCI ^ N), 3. 84 ~ 3. 66 (m, 14H, 4 X 0CH3, NCH2), 3. 17 ~ 2. 94 (m, 2H, NCH2), 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爺型瓶中加入7 j (288. lmg, 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。 [0129] 25mL equipped with a reflux condenser Lord type flask 7 j (288. lmg, 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. Ommol) 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. Ommol) was dissolved in 5mL of dichloromethane, then poured into a freshly prepared above acid chloride containing eggplant-type flask, was added triethylamine (0. 20g, 0. 28mL, 2 . Ommol), 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 until the aqueous layer no product, the ethyl acetate layer was washed with water three times, saturated brine washed with water 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i-io 〇• 23g,收率41. 82%,mp 96 ~98C。 Filtration, the filtrate was spin-dry the residue by column chromatography (dichloromethane: methanol = 200: 1) separation and purification, as a white solid i-io billion • 23g, yield 41. 82%, mp 96 ~ 98 C. 将1-10(0. 10g,0• 182mmol) 溶于2mL二氯甲烷中,滴加饱和HC1的乙醚溶液,搅拌5分钟,析出白色固体,抽滤,得1-10.抝10.08,收率75.05 %,111.?.104~1061:。 The 1-10 (0. 10g, 0 • 182mmol) was dissolved in 2mL of dichloromethane, diethyl ether was added dropwise saturated HC1 and stirred for 5 minutes to precipitate a white solid, leaching, was 1-10. Bend 10.08, income rate of 75.05%, 111? 104 ~ 1061 :. 11?(11',。〇11-1):3431,2939,2838,2 561,1748, 1624, 1578, 1541,1508, 1463, 1426, 1346, 1327, 1295, 1260, 1205, 1125, 1009, 857 NMR(300MHz,CDC13)S 12.89 (s,lH),8.92 (d,J = 5. lHz,lH,ArH),8 .76 (s, 1H, ArH), 8. 54 (d, J = 6. 1Hz, 1H, ArH), 7. 21 (dd, J = 8. 5, 1. 8Hz, 1H, ArH), 7. 13 (d, J =1. 8Hz, 1H, ArH), 6. 92 (d, J = 8. 5Hz, 1H, 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, OCH3), 3. 73 (s, 6H, 2 X OCH3), 3. 22 (s, 4H, N (CH2CH3)2), 1.47(s,6H,N(CH2CH3)2).13C NMR (75MHz,CDC13)S161.18,152.49,149.47,149. 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 C30H35N208, 551. 2388). ? 11 (1 1 ', 〇11-1.): 3431,2939,2838,2 561,1748, 1624, 1578, 1541,1508, 1463, 1426, 1346, 1327, 1295, 1260, 1205, 1125, 1009, 857 NMR (300MHz, CDC13) S 12.89 (s, lH), 8.92 (d, J = 5. lHz, lH, ArH), 8 .76 (s, 1H, ArH), 8. 54 (d, J = 6. 1Hz, 1H, ArH), 7. 21 (dd, J = 8. 5, 1. 8Hz, 1H, ArH), 7. 13 (d, J = 1. 8Hz, 1H, ArH), 6. 92 (d, J = 8. 5Hz, 1H, 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, OCH3), 3. 73 (s, 6H, 2 X OCH3), 3. 22 (s, 4H, N (CH2CH3) 2), 1.47 (s, 6H, N (CH2CH3) 2) .13C NMR (75MHz, CDC13) S161.18,152.49,149.47,149. 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 C30H35N208, 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. Og混合,用适量30%乙醇作湿润剂,制粒,压片。 [0132] the compound obtained in Example 20 taken implemented 0. 5g, starch 2. Og, dextrin 1. Og mixed with an appropriate amount of 30% ethanol as wetting agents, granulating, tabletting.

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Classifications
International ClassificationA61P29/00, C07D295/155, C07C227/18, A61K31/5375, A61P35/00, A61K31/4453, A61K31/495, C07C229/38, A61K31/40, A61K31/24
Cooperative ClassificationC07D295/155, C07C229/38
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