WO2019020026A1 - 二氟甲氧基取代的二苯乙烷及反式二苯乙烯衍生物及其制备方法和应用 - Google Patents

二氟甲氧基取代的二苯乙烷及反式二苯乙烯衍生物及其制备方法和应用 Download PDF

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WO2019020026A1
WO2019020026A1 PCT/CN2018/096862 CN2018096862W WO2019020026A1 WO 2019020026 A1 WO2019020026 A1 WO 2019020026A1 CN 2018096862 W CN2018096862 W CN 2018096862W WO 2019020026 A1 WO2019020026 A1 WO 2019020026A1
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difluoromethoxydiphenylethane
preparation
difluoromethoxy
trans
stilbene derivative
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PCT/CN2018/096862
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English (en)
French (fr)
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吴范宏
马仲林
开振鹏
黄磊磊
李丹丹
黄金文
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上海华理生物医药股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds

Definitions

  • the invention relates to the technical field of pharmaceutical synthesis, in particular to the synthesis of anti-cancer drugs of difluoromethoxy-substituted diphenylethane and derivatives.
  • Maolansu chemical name 3,4,5-trimethoxy-3'-hydroxy-4'-methoxydiphenylethane (code: MLS) is a natural extract from the valuable Chinese herbal medicine Dendrobium Diphenylethane active ingredient has anti-tumor effect.
  • Lanolin is structurally identical to the stilbene natural product Combretastatin A-4 (codename CA4, also known as pinionin), which has a common AB ring structure, and the lanolin is equivalent to a vinyl bridge hydrogenated.
  • CA4 lanolin is also a tubulin inhibitor with strong tumor vascular targeting disruption, acting on the colchicine binding site.
  • Fluorine-containing drugs account for a large proportion in clinical therapeutic drugs.
  • the introduction of fluorine atoms or fluorine-containing groups in small-molecule drugs is one of the important strategies for improving drug activity.
  • the introduction of a fluorine atom or a fluorine-containing group into a small molecule drug has little effect on its molecular volume, but its physical and chemical properties include electronic effects and steric effects, biological activity, pharmacokinetic properties, metabolic stability, and ligands.
  • the interaction with the target protein and selectivity may have a significant effect, and may also enhance the lipophilicity of the small molecule, making it easier to penetrate the cell membrane, thereby increasing biological activity.
  • stilbene fluoro modifiers mostly monofluoro and trifluoromethyl substitutions, but not reported for difluoromethoxy substituted diphenylethane and trans diethylene derivatives.
  • the present invention provides a difluoromethoxydiphenylethane and a trans stilbene derivative, the structure of which is as shown in the general formula (I):
  • R is hydrogen, hydroxy, nitro, amino, benzyloxy, phosphate, sulfate, phosphorylcholine, or an amino acid side chain and its water-soluble ammonium salt.
  • R is hydrogen, hydroxy, nitro, amino, benzyloxy, -OPO 3 Na 2 , -NHCOCH 2 NH 2 , or -NHCOCH(NH 2 )CH 2 OH.
  • the invention also provides a preparation method of the 4'-difluoromethoxy group and the trans stilbene derivative in the above difluoromethoxydiphenylethane compound, and the specific steps are as follows:
  • R functional group in the formula (1) is a sodium phosphate salt
  • it is prepared by reacting the corresponding phenolic hydroxyl group with phosphorus oxychloride and neutralizing with a base.
  • the reaction equation is as follows:
  • R functional group in the formula (I) is an amino acid side chain, it is prepared by condensing the corresponding amino compound with a Boc-amino acid and then deprotecting with an acid.
  • the reaction equation is as follows:
  • the present invention further provides an application of the above-mentioned difluoromethoxydiphenylethane and trans-stilbene derivatives in the preparation of a medicament for anti-tumor vascular disrupting agent having vascular targeting effects on various tumors.
  • the various tumors mainly include: lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, gastric cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical Cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchial carcinoma, osteocyte carcinoma , epithelial cancer, cholangiocarcinoma, choriocarcinoma, embryo, carcinoma, spermatoma,
  • the present invention also provides the use of the above-mentioned difluoromethoxydiphenylethane and a medicament for preparing a disease caused by abnormal neovascularization, the diseases mainly including: rheumatoid arthritis, diabetic retinopathy, precocious retina Disease, retinal vein occlusion, psoriasis, rosacea, Kaposi's sarcoma, specific reactive keratitis, epidemic keratoconjunctivitis, neovascular glaucoma, bacterial ulcer, fungal ulcer, simple herpes infection, band Herpes zoster infection, protozoal infection, mycobacterial infection, polyarteritis, sarcoidosis, scleritis, flushing, dry mouth and arthritis syndrome, systemic lupus erythematosus, AIDS syndrome, syphilis.
  • the diseases mainly including: rheumatoid arthritis, diabetic retinopathy, precoc
  • the pharmaceutical preparation of the difluoromethoxydiphenylethane and the stilbene derivative of the present invention is selected from the following dosage forms: lyophilized powder for administration by intravenous injection, powder, injection, liposome, emulsion, micro A sac, suspension or solution; granules, tablets, capsules or syrups for oral administration; or suppositories.
  • the present invention has the beneficial effects that the present invention chemically modifies the 4' position of the diphenylethane B aromatic ring with a difluoromethoxy group, and simultaneously converts its 3' position into a nitro group.
  • a substituent such as an amino group or a hydroxyl group
  • the difluoromethoxydiphenylethane and the trans-stilbene derivative obtained by the present invention have strong antitumor activity in vitro, and the introduction of difluoromethyl group changes the physical and chemical properties of the compound. And biological properties, have a significant inhibitory effect on tumor cells.
  • the compound of the present invention can be prepared by using a suitable substance as a raw material according to the general scheme described below, and is specifically exemplified by the following examples. Of course, various known and reasonable variations in the conditions and methods of the exemplary compound preparation steps of the examples can also be used to prepare these compounds.
  • Analytical test equipment and conditions Unless otherwise stated: HRMS high resolution mass spectrometry is SolanX-70 FT-MS from Switzerland Bruker, H-NMR nuclear magnetic resonance spectrum Volance III 500M or Agilent 400 NMR or Bruker AMX-400 nuclear magnetic The test solvent was CDCl 3 as determined by a resonator.
  • 4-difluoromethoxybenzaldehyde (1.47 g, 8.54 mmol) was added to a single-necked flask, and mixed acid sulfuric acid (4.8 mL) + nitric acid (0.6 mL) was slowly added dropwise at 0 ° C, and the mixture was added to the residue.
  • the reaction was carried out at room temperature. After 1 h, the reaction was terminated by TLC. Aq. NaHCO 3 was added to remove the unreacted acid, and the mixture was extracted with EA. The organic phase was combined, dried over anhydrous Na 2 SO 4 , filtered, concentrated, and then purified by column chromatography. 40, a yellow liquid of 0.60 g was obtained, and the yield was 30%.
  • the cells were cultured in RPMI 1640 medium containing 200 mL/L fetal bovine serum, and the cells were kept in logarithmic growth phase, inoculated into 96-well plates at a density of 4-8 ⁇ 10 4 /ml, 37 ° C, pre-culture for 24 hours.
  • the drug is set at 6 concentrations, and each drug is set to 3 duplicate wells for 48 hours.
  • the culture solution is air-dried, and each well is ice-cold 500g/L trichloroacetic acid 50 ⁇ L (final concentration is 100g/L) for 60min.
  • Cells with a ratio of viable cells of more than 90% were tested.
  • the cells were digested, counted, and prepared into a cell suspension at a concentration of 1 ⁇ 10 5 /mL. 100 ⁇ L of cell suspension (1 ⁇ 10 4 cells per well) was added to each well of a 96-well plate; 96-well plates were placed at 37 ° C.
  • the cells were cultured for 24 hours in a 5% CO 2 incubator; 100 ⁇ L of the corresponding drug-containing medium was added to each well, and a negative control group, a vehicle control group, and a positive control group, 5 replicate wells per group; 96-well plates were placed at 37.
  • the positive control for the antitumor activity test of the compound of the above formula (I) is (Z)-3,4,5-trimethoxy-3'-hydroxy-4'-methoxydiphenylethylene (CA- 4)
  • CA- 4 The results of the evaluation of the efficacy of the drug are summarized as follows: The antitumor activity of the tumor cells cultured in vitro is evaluated. The results indicate that the CA-4 fluoro analog has broad inhibitory activity against Hela cells, and the activity values of these compounds are compared with the control drug CA-4.
  • the activity values are not much different, especially the IC 50 value of compound VIc-E is 0.069 ⁇ mol/mL less than the IC 50 value of CA-4 (0.27 ⁇ mol/mL), indicating the introduction of two fluorine atoms in the CA-4 structure B ring.
  • the antitumor activity of the compound is effectively improved.
  • the cis structure activity is greater than the trans structure, such as the compounds VIc-Z and VIc-E.
  • the IC 50 values of the compounds VIa-Z and VIa-E being 0.24 and 0.069 ⁇ mol/mL, respectively.
  • the compound VIb-Z did not detect its IC 50 value, and the trans structural activity was greater than the cis structure activity. This demonstrates that the anti-tumor activity in vitro cannot be judged from the cis-trans configuration of the compound alone.
  • the activity of the diphenylethane compound after reduction of the double bond did not change significantly, but the structure of the compound was relatively stable. Meanwhile, by comparing the activities of the compounds VIa-Z with VIc-Z and Ib, it can be seen that when the nitro group, the amino group or the hydroxyl group is substituted at the 3' position of the B ring, the activity of the compound is also improved.
  • the inhibitory activity of the compound against various tumor cell lines such as SW579, HepG2, A549, MCG-803, MDA-MB-231 was further evaluated by CCK-8.
  • the difluoroethane-modified diphenylethane and stilbene derivatives have strong anti-tumor activity, which is significantly better than the positive control drug CA4, and has good application development prospects.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

本发明公开了一种二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物及其制备方法和应用。本发明在二苯乙烷/烯的B芳环的4'位用二氟甲氧基进行化学结构修饰，同时将其3'位改造成硝基、氨基或羟基等取代基；本发明得到的二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物具有较强的体外抗肿瘤活性，二氟甲基的引入改变了化合物的物理、化学和生物性质，对肿瘤细胞具有明显的抑制作用。

Description

二氟甲氧基取代的二苯乙烷及反式二苯乙烯衍生物及其制备方法和应用 技术领域
本发明涉及药物合成技术领域，尤其涉及二氟甲氧基取代的二苯乙烷及衍生物抗癌药物的合成。
背景技术
毛兰素，化学名为3,4,5-三甲氧基-3’-羟基-4’-甲氧基二苯乙烷(代号：MLS)是一种从名贵中药材石斛中提取出来的天然二苯乙烷类活性成分，具有抗肿瘤作用。毛兰素在结构上与二苯乙烯类天然产物Combretastatin A-4(代号CA4，又称风车子素)具有共同的结构特征，具有共同的AB环结构，毛兰素相当于是乙烯基桥被氢化了的CA4。与CA4一样，毛兰素也是一种微管蛋白抑制剂且具有较强的肿瘤血管靶向破化作用，作用于秋水仙碱结合位点。此外有文献报道毛兰素的抗肿瘤作用还可能通过作用于端粒酶而诱导肿瘤细胞凋亡有关。此前我们发现将毛兰素B环4-位的甲氧基替换为乙氧基后得到一种4-乙氧基毛兰素(EBT)，其抗肿瘤活性与毛兰素和CA4相比有显著提高(吴范宏等，一种乙氧基二苯乙烷衍生物及其制备方法和用途，国际公布号US2012/0046492A1)，通过分子对接技术模拟确定其与微观蛋白秋水碱结合位点作用更好。由于不存在顺反式异构体的变化，相关理化性质比CA4更稳定，化合物的制备工艺更加简便，合成收率显著提高，而原料损耗和单位合成成本大大降低(一种3,4,5-三甲氧基-3’-羟基-4’-烷氧基二苯乙烷的制备方法CN103539642)。
含氟药物在临床治疗药物中占有很大的比重，在小分子药物中引入氟原子或含氟基团，是改善药物活性的重要策略之一。在小分子药物中引入氟原子或含氟基团后，对其分子体积几乎没有影响，但是对其理化性质包括电子效应和立体效应、生物活性、药代动力学性质、代谢稳定性和配体与靶标蛋白的相互作用力以及选择性等可能产生显著影响，而且还可以增强小分子的亲脂性，使其更容易透过细胞膜，进而提高生物活性。二苯乙烯类氟代修饰物已有较多报道，多为单氟取代和三氟甲基取代，而对于二氟甲氧基取代二苯乙烷和反式二本乙烯衍生物未见报道。
发明内容
本发明的目的在于提供一种二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物 及其制备方法和应用。
本发明的技术方案具体介绍如下。
本发明提供一种二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物，其结构如通式(I)所示：
Figure PCTCN2018096862-appb-000001
其中：
虚线---表示键或不存在；R为氢、羟基、硝基、氨基、苄氧基、磷酸盐、硫酸盐、磷酸胆碱、或是氨基酸侧链及其水溶性铵盐。优选的，R为氢、羟基、硝基、氨基、苄氧基、-OPO 3Na 2、-NHCOCH 2NH 2、或-NHCOCH(NH 2)CH 2OH。
本发明还提供的一种上述二氟甲氧基二苯乙烷化合物中4'-二氟甲氧基及反式二苯乙烯衍生物的制备方法，具体步骤如下：
(1)将3位R基取代的4-羟基苯甲醛和溴氟甲基膦酸二乙酯发生二氟甲醚化反应得到3位R基取代的4-二氟甲氧基苯甲醛；
(2)3,4,5-三甲氧基苄溴三苯基溴化磷和3位R基取代的4-二氟甲氧基苯甲醛在碱作用下进行Wittig反应，得到二氟甲氧基二苯乙烯类衍生物；
(3)将二氟甲氧基二苯乙烯类衍生物进行还原，使双键氢化得到3,4,5-三甲氧基-3'-R-4'-二氟甲氧基二苯乙烷。
Figure PCTCN2018096862-appb-000002
当通式(1)中的R官能团为磷酸酯钠盐时，其制备方法为由相应的酚羟基与三氯氧磷反应，再用碱中和得到。反应方程如下所示：
Figure PCTCN2018096862-appb-000003
当通式(I)中的R官能团为氨基酸侧链时，其制备方法为由相应的氨基化合物与Boc-氨基酸缩合，再用酸脱保护制到。反应方程如下所示：
Figure PCTCN2018096862-appb-000004
本发明进一步提供一种上述二氟甲氧基二苯乙烷和反式二苯乙烯类衍生物在制备作为抗肿瘤血管破坏剂，对各种肿瘤具有血管靶向作用的药物中的应用。所述各种肿瘤主要包括有：肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列腺癌、睾丸癌、结肠癌、卵巢癌、膀胧癌、子宫颈癌、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊性腺癌、囊性癌、髓状癌、支气管癌、骨细胞癌、上皮癌、胆管癌、绒毛膜癌、胚癌、精原细胞癌、维尔姆斯癌、胶质细胞癌、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血细胞瘤、声带神经瘤、脑膜瘤、成神经细胞瘤、成视神经细胞瘤、成视网膜细胞瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、纤维腺瘤、纤维软骨瘤、纤维囊瘤、纤维粘液瘤、纤维骨瘤、纤维粘液肉瘤、纤维乳头状瘤、粘液肉瘤、粘液囊瘤、粘液软骨瘤、粘液软骨肉瘤、粘液软骨纤维肉瘤、粘液腺瘤、成粘液细胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂细胞瘤、脂肪软骨瘤、脂肪纤维瘤、脂肪血管瘤、粘液脂瘤、软骨肉瘤、软骨瘤、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、骨软骨瘤、骨囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管软骨瘤、成血管细胞瘤、血管角质瘤、血管神经胶质瘤、血管内皮瘤、血管纤维瘤、血管肌 瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神经瘤、血管粘液瘤、血管网状内皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纤维瘤、淋巴细胞瘤、淋巴上皮瘤、成淋巴细胞瘤、内皮瘤、成内皮细胞瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纤维瘤、横纹肌瘤、横纹肌肉瘤、横纹肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病细胞、红细胞增多症、淋巴瘤、多发性骨髓瘤。
本发明还提供一种上述二氟甲氧基二苯乙烷和制备治疗非正常新生血管引起的疾病的药物中的应用，所述疾病主要包括有：风湿性关节炎、糖尿病视网膜病、早熟视网膜病、视网膜静脉闭塞、牛皮癣、红斑痤疮、卡波济肉瘤、特异性反应性角膜炎、流行性角膜结膜炎、新生血管性青光眼、细菌性溃疡、真菌性溃疡、单纯性疤疹感染、带状疤疹感染、原生动物感染、分支杆菌感染、多动脉炎、肉样瘤、巩膜炎、潮红、口干眼燥关节炎综合症、全身性红斑狼疮、艾滋病综合症、梅毒。
本发明的二氟甲氧基二苯乙烷和二苯乙烯类衍生物的药物制剂，选自包括以下剂型：静脉注射形式给药的冻干粉剂、粉剂、注射剂、脂质体、乳剂、微囊、悬浮液或溶液；口服形式给药的颗粒剂、片剂、胶囊或糖浆；或是栓剂。
和现有技术相比，本发明的有益效果在于，本发明在二苯乙烷B芳环的4'位用二氟甲氧基进行化学结构修饰，同时将其3'位改造成硝基、氨基、羟基等取代基；本发明得到的二氟甲氧基二苯乙烷及反式二苯乙烯衍生物具有较强的体外抗肿瘤活性，二氟甲基的引入改变了化合物的物理、化学和生物性质，对肿瘤细胞具有明显的抑制作用。
具体实施方式
下列实例仅仅为了说明方案的实施过程，包括但不限于其中的条件。本发明的化合物能根据以下所述的一般方案使用适当的物质作为原料来制备，并且通过后面的实施例来具体举例说明。当然，实施例中的举例化合物制备步骤的条件和方法的各种已知合理的变化也能用于制备这些化合物。所述的分析测试仪器和条件除非另有说明，否则：HRMS高分辨质谱为瑞士布鲁克公司的SolanX-70 FT-MS，H-NMR核磁氢谱VolanceⅢ 500M或Agilent 400 NMR或Bruker  AMX-400型核磁共振仪测定，测试溶剂为CDCl 3。
实施例1 4-二氟甲氧基苯甲醛(IIa)的制备
将4-羟基苯甲醛(1.00g,8.20mmol)，KOH(9.20g,164mmol)，CH 3CN-H 2O(50mL,1:1)混合至密封管中，-78℃下缓慢滴加溴氟甲基膦酸二乙酯(3mL,16.40mmol)，然后升至室温反应，室温反应20min后，TLC检测反应结束，加入饱和NaHCO 3溶液，用乙酸乙酯萃取，合并有机相，用无水Na 2SO 4干燥，过滤，浓缩，柱层析分离(EA:PE＝1:70)，得到1.01g固体，产率72％。Mp:184.9-185.5℃. 1H NMR(CDCl 3,500MHz):δ6.63(t,1H,J＝73.0Hz),7.27(s,1H),7.92(d,2H,J＝9.0Hz),8.02(d,1H,J＝8.5Hz),9.98(s,1H). 13C NMR(CDCl 3,125MHz):δ190.2,155.7 132.2,131.7,119.1,117.3,115.2,113.2. 19F NMR(CDCl 3,470MHz):δ-82.15(d,J＝115.6Hz).MS(m/z):172(M +).ESI-HRMS(m/z):calculated for C 8H 6F 2O 2(M+K) +:210.9973,found:211.2084.
实施例2 (Z/E)-3,4,5-三甲氧基-4'-二氟甲氧基二苯乙烯(IVa)的制备
Figure PCTCN2018096862-appb-000005
N 2保护下，将3,4,5-三甲氧基苄溴三苯基溴化磷(3.04g，5.8mmol)悬浮于40mL无水THF溶液中，-30℃下缓慢滴加正丁基锂(4.40mL，7.0mmol，1.2eq)，然后反应1h，接着缓慢滴加4-二氟甲氧基苯甲醛(1.00g，5.8mmol)的THF溶液(10mL)至反应体系中，升至室温过夜反应12h。反应结束后将体系冷却至-5℃以下，加入饱和NaCl水溶液，EA萃取，合并有机相，无水Na 2SO 4干燥，过滤，浓缩后柱层析分离EA:PE＝1:25，得到0.84g无色油状物为顺反混合物，产率44％(Z:E＝4:1)。进一步柱层析分离得到纯的顺反异构体。
(Z)-3,4,5-三甲氧基-4'-二氟甲氧基二苯乙烯(IVa-Z)
无色油状物，Z-isomer: 1H NMR(CDCl 3,500MHz):δ3.68(s,6H),3.85(s,3H),6.46(s,2H),6.51(m,1H),6.53(d,1H,J＝12.0Hz),6.56(d,1H,J＝12.0Hz),7.03(d,2H,J＝8.5Hz),7.30(d,2H,J＝8.5Hz). 13C NMR(CDCl 3,125MHz):δ153.0,149.9,137.5,134.8,132.2,130.6,130.4,128.6,119.4,117.9,115.8,113.7,106.2,60.8,55.8. 19F NMR(CDCl 3,470MHz):δ-81.06.MS(m/z):336(M +).ESI-HRMS(m/z):calculated for C 18H 18F 2O 4(M+K) +:375.0810,found:375.0802.
(E)-3,4,5-三甲氧基-4'-二氟甲氧基二苯乙烯(IVa-E)
白色固体，E-isomer:Mp:100.4-100.9℃. 1H NMR(CDCl 3,500MHz):δ3.87(s,3H),3.92(s,6H),6.50(m,1H),6.73(s,2H),6.98(s,2H),7.11(d,2H,J＝8.5Hz),7.49(d,2H,J＝8.5Hz). 13C NMR(CDCl 3,125MHz):δ153.5,150.5,138.2,134.7,132.8,129.0,127.7,126.8,119.8,118.0,115.9,113.8,103.7,61.0,56.2. 19F NMR(CDCl 3,470MHz):δ-80.71.MS(m/z):336(M +).ESI-HRMS(m/z):calculated for C 18H 18F 2O 4(M+K) +:375.0810,found:375.0802.
实施例3 3,4,5-三甲氧基-4'-二氟甲氧基二苯乙烷(Ia)的制备
Figure PCTCN2018096862-appb-000006
将3,4,5-三甲氧基-4'-二氟甲氧基二苯乙烯(1.15g，3.42mmol)溶于50mL乙醇中，加入Pd/C(0.10g,0.90mmol)，H 2过量室温搅拌过夜，反应结束后将Pd/C过滤除去，将溶剂旋干得到白色固体1.10g，产率95％。Mp:71.2-71.7℃. 1H NMR(CDCl 3,500MHz):δ2.84(m,2H),2.90(m,2H),3.82(d,9H,J＝9Hz),6.34(s,2H),6.48(m,1H),7.03(d,2H,J＝8.5Hz),7.15(d,2H,J＝8.5Hz). 13C NMR(CDCl 3,125MHz):δ153.1,149.4,138.9,137.1,136.3,129.8,119.6,118.1,116.0,114.0,105.5,60.9,56.0,38.3,37.2. 19F NMR(CDCl 3,470MHz):δ-80.58.MS(m/z):338(M +).ESI-HRMS(m/z):calculated for C 18H 20F 2O 4(M+K) +:377.0967,found:377.0955.
实施例4 4-二氟甲氧基-3-苄氧基苯甲醛(IIb)的制备
Figure PCTCN2018096862-appb-000007
将4-羟基-3-苄氧基苯甲醛(1.00g,4.38mmol)，KOH(5.00g,87.6mmol)，CH 3CN-H 2O(50mL,1:1)混合至密封管中，-78℃下缓慢滴加溴氟甲基膦酸二乙酯(1.5mL,8.76mmol)，然后升至室温反应，室温反应30min后，TLC检测反应结束，加入饱和NaHCO 3溶液，用乙酸乙酯萃取，合并有机相，用无水Na 2SO 4干燥，过滤，浓缩，柱层析分离(EA:PE＝1:40)，得到1.00g白色固体，产率82％。Mp:51.6-52.1℃. 1H NMR(CDCl 3,500MHz):δ5.23(s,2H),6.61(t,1H,J＝74.0Hz),7.13(d,1H,J＝8.0Hz),7.38(m,5H),7.70(d,2H,J＝8.0Hz),9.86(s,1H). 13C NMR(CDCl 3,125MHz):δ189.9,155.5,140.6,135.3,130.3,129.6,128.8,128.5,127.2,122.8,117.9,115.8,113.8,71.1. 19F NMR(CDCl 3,470MHz):δ-81.72.MS(m/z):278(M +).ESI-HRMS(m/z):calculated for C 15H 12F 2O 3(M+H) +:279.0833, found:279.0832.
实施例5 (Z/E)-3,4,5-三甲氧基-4'-二氟甲氧基-3'-苄氧基二苯乙烯(IVb)的制备
Figure PCTCN2018096862-appb-000008
N 2保护下，将3,4,5-三甲氧基苄溴三苯基溴化磷(1.88g，3.59mmol)悬浮于40mL无水THF溶液中，-30℃下缓慢滴加正丁基锂(2.7mL，4.31mmol，1.2eq)，然后反应1h，接着缓慢滴加4-二氟甲氧基-3-苄氧基苯甲醛(1.00g，3.59mmol)的THF溶液(10mL)至反应体系中，升至室温过夜反应12h。反应结束后将体系冷却至-5℃以下，加入饱和NaCl水溶液，EA萃取，合并有机相，无水Na 2SO 4干燥，过滤，浓缩后柱层析分离EA:PE＝1:20，得到1.40g白色固体顺反混合物(Z:E＝1:1.5)，产率88％(Z:E＝1.5:1)。进一步柱层析分离得到纯的顺反异构体。
(Z)-3,4,5-三甲氧基-4'-二氟甲氧基-3'-苄氧基二苯乙烯(IVb-Z)
无色液体，Z-isomer: 1H NMR(CDCl 3,500MHz):δ3.67(s,6H),3.87(s,3H),5.10(s,2H),6.45(d,1H,J＝12.0Hz),6.51(s,3H),6.55(m,1H),6.90(d,1H,J＝8.0Hz),7.12(m,2H),7.35(m,5H). 13C NMR(CDCl 3,125MHz):δ153.1,149.2,139.9,137.5,136.4,132.4,130.8,130.1,128.7,128.4,128.1,127.4,127.2,123.1,118.3,116.2,114.1,106.0,70.8,60.8,55.8. 19F NMR(CDCl 3,470MHz):δ-81.23.MS(m/z):442(M +).ESI-HRMS(m/z):calculated for C 25H 24F 2O 5(M+H) +:443.1670,found:443.1652.
(E)-3,4,5-三甲氧基-4'-二氟甲氧基-3'-苄氧基二苯乙烯(IVb-E)
白色固体，E-isomer:Mp:122.1-122.7℃. 1H NMR(CDCl 3,500MHz):δ3.88(d,9H,J＝16.0Hz),5.13(s,2H),6.61(m,1H),6.70(s,2H),6.90(s,2H),6.98(d,1H,J＝8.5Hz),7.25(m,1H),7.37(m,6H). 13C NMR(CDCl 3,125MHz):δ153.5,149.7,140.7,138.1,136.3,132.9,131.3,128.7,128.2,127.2,126.6,124.9,120.3,118.4,116.4,114.8,114.3,103.6,71.1,61.0,56.1. 19F NMR(CDCl 3,470MHz):δ-81.06.MS(m/z):442(M +).ESI-HRMS(m/z):calculated for C 25H 24F 2O 5(M+H) +:443.1670,found:443.1652.
实施例6 3,4,5-三甲氧基-4'-二氟甲氧基-3'-羟基二苯乙烷(Ib)的制备
Figure PCTCN2018096862-appb-000009
将3,4,5-三甲氧基-4'-二氟甲氧基-3'-苄氧基二苯乙烯(1.00g，2.26mmol)溶于50mL乙醇中，加入Pd/C(0.25g,2.25mmol)，H 2过量室温搅拌过夜，反应结束后将Pd/C过滤除去，将溶剂旋干得到棕色液体0.78g，产率97％。 1H NMR(CDCl 3,500MHz):δ2.82(m,4H),3.82(d,9H,J＝6.5Hz),5.58(s,1H),6.33(s,2H),6.48(t,1H,J＝73.5Hz),6.87(s,1H),6.92(s,2H). 13C NMR(CDCl 3,125MHz):δ153.0,145.9,138.0,137.3,136.1,134.1,126.7,120.8,118.5,116.8,116.4,114.3,105.6,60.8,56.0,38.3,37.0. 19F NMR(CDCl 3,470MHz):δ-80.54.MS(m/z):354(M +).ESI-HRMS(m/z):calculated for C 18H 20F 2O 5(M+Na) +:377.1176,found:377.0955.
实施例7 4-二氟甲氧基-3-硝基苯甲醛(IVc)的制备
Figure PCTCN2018096862-appb-000010
将3-硝基-4-羟基苯甲醛(1.00g,8.20mmol)，KOH(9.20g,164mmol)，CH 3CN-H 2O(50mL,1:1)混合至密封管中，-78℃下缓慢滴加溴氟甲基膦酸二乙酯(3mL,16.40mmol)，然后升至室温反应，室温反应20min后，TLC检测反应结束，加入饱和NaHCO 3溶液，用乙酸乙酯萃取，合并有机相，用无水Na 2SO 4干燥，过滤，浓缩，柱层析分离(EA:PE＝1:70)，得到1.01g固体，产率72％。
或，将4-二氟甲氧基苯甲醛(1.47g，8.54mmol)加入单口烧瓶中，0℃下缓慢滴加混酸浓硫酸(4.8mL)+硝酸(0.6mL)，滴加完毕后升至室温反应，1h后TLC检测反应结束，加入饱和NaHCO 3水溶液除去未反应的酸，EA萃取，合并有机相，无水Na 2SO 4干燥，过滤，浓缩后柱层析分离EA:PE＝1:40，得到黄色液体0.60g，产率30％。 1H NMR(CDCl 3,500MHz):δ6.75(t,1H,J＝72Hz),7.60(d,1H,J＝8.5Hz),8.17(d,1H,J＝8.5Hz),8.42(s,1H),10.05(s,1H). 13C NMR(CDCl 3,125MHz):δ188.5,147.2,142.6,134.4,133.6,126.7,122.6,117.3,115.2,113.0. 19F NMR(CDCl 3,470MHz):δ-82.62.MS(m/z):217(M +).ESI-HRMS(m/z):calculated for C 8H 5F 2O 4(M+Na) +:240.0084,found:240.0016.
实施例8 (Z/E)-3,4,5-三甲氧基-4'-二氟甲氧基-3'-硝基二苯乙烯(VIc)的制备
Figure PCTCN2018096862-appb-000011
N 2保护下，将3,4,5-三甲氧基苄溴三苯基溴化磷(2.41g，4.61mmol)悬浮于40mL无水THF溶液中，-30℃下缓慢滴加正丁基锂(3.5mL，5.53mmol，1.2eq)，然后反应1h，接着缓慢滴加4-二氟甲氧基-3-硝基苯甲醛(1.00g，4.61mmol)的THF溶液(10mL)至反应体系中，升至室温过夜反应12h。反应结束后将体系冷却至-5℃以下，加入饱和NaCl水溶液，EA萃取，合并有机相，无水Na 2SO 4干燥，过滤，浓缩后柱层析分离EA:PE＝1:20，得到0.76g黄色固体顺反混合物，产率43％(Z:E＝1:1.5)。进一步柱层析分离得到纯的顺反异构体。(Z)-3,4,5-三甲氧基-4'-二氟甲氧基-3'-硝基二苯乙烯(IVc-Z)
黄色固体，Z-isomer:Mp:76.8-77.4℃. 1H NMR(CDCl 3,500MHz):δ3.70(s,6H),3.85(s,3H),6.42(s,2H),6.50(d,1H,J＝12.0Hz),6.59(dd,1H,J＝72.5Hz,J＝73.0Hz),6.69(d,1H,J＝12.0Hz),7.26(d,1H,J＝8.5Hz),7.49(d,1H,J＝8.5Hz),7.83(s,1H). 13C NMR(CDCl 3,125MHz):δ153.3,142.8,141.2,138.2,136.2,134.3,133.4,131.0,126.0,125.7,123.3,117.6,115.5,113.3,106.1,61.0,56.0. 19F NMR(CDCl 3,470MHz):δ-82.21.MS(m/z):381(M +).ESI-HRMS(m/z):calculated for C 18H 17F 2O 6(M+H) +:382.1102,found:382.1833.
(E)-3,4,5-三甲氧基-4'-二氟甲氧基-3'-硝基二苯乙烯(IVc-E)
黄色固体，E-isomer:Mp:149.8-150.3℃. 1H NMR(CDCl 3,500MHz):δ3.91(d,9H,J＝21Hz),6.63(t,1H,J＝73.0Hz),6.75(s,2H),6.97(d,1H,J＝16.0Hz),7.09(d,1H,J＝16.0Hz),7.38(d,1H,J＝8.5Hz),7.69(d,1H,J＝8.5Hz),8.05(s,1H). 13C NMR(CDCl 3,125MHz):δ153.6,143.1,141.6,138.9,136.4,132.2,131.7,131.3,124.3,124.0,122.7,117.8,115.7,113.6,104.1,61.0,56.2. 19F NMR(CDCl 3,470MHz):δ-81.97.MS(m/z):381(M +).ESI-HRMS(m/z):calculated for C 18H 17F 2O 6(M+H) +:382.1102,found:382.1833.
实施例9 3,4,5-三甲氧基-4'-二氟甲氧基-3'-氨基二苯乙烷(Ic)的制备
Figure PCTCN2018096862-appb-000012
将(Z,E)-3,4,5-三甲氧基-4'-二氟甲氧基-3'-硝基二苯乙烯(0.50g,1.42mmol)溶于50mL乙醇中，加入Pd/C(0.10g,0.90mmol)，H 2过量室温搅拌过夜，反 应结束后将Pd/C过滤除去，将溶剂旋干得到0.41g，产率82％。 1H NMR(CDCl 3,500MHz):δ2.84(s,4H),3.83(s,9H),6.37(s,2H),6.41(t,1H,J＝74.5Hz),6.46(m,2H),6.92(d,1H,J＝8.5Hz). 13C NMR(CDCl 3,125MHz):δ153.1,140.2,137.5,136.6,119.3,119.0,116.9,116.1,114.9,111.9,105.5,60.9,56.1,38.3,38.1,37.9. 19F NMR(CDCl 3,470MHz):δ-79.21.MS(m/z):353(M +).ESI-HRMS(m/z):calculated for C 18H 21F 2O 4(M+H) +:354.1517,found:354.1516.
实施例10 3,4,5-三甲氧基-4'-二氟甲氧基-3'-二磷酸钠酯-二苯乙烷(Id)的制备
Figure PCTCN2018096862-appb-000013
将(Z,E)-3,4,5-三甲氧基-4'-二氟甲氧基-3'-羟基二苯乙烷(0.50g,1.42mmol)的二氯甲烷溶液(3mL)中，缓慢滴加入冰浴冷却的三氯氧磷(5mL)溶液中，加毕，自然升至室温搅拌2h，将反应液倒入冰水中，用二氯甲烷萃取3次，合并有机相，无水硫酸钠干燥，过滤浓缩，残渣重新溶解于95％乙醇中，加入计量的氢氧化钠中和至pH为7-8左右，再滴加入丙酮搅拌析晶，过滤干燥得到0.61g，产率87％。
实施例11 3,4,5-三甲氧基-4'-二氟甲氧基-3'-(盐酸氨基乙酰基)氨基二苯乙烷(Ie)的制备
Figure PCTCN2018096862-appb-000014
将(Z,E)-3,4,5-三甲氧基-4'-二氟甲氧基-3'-氨基二苯乙烯(0.50g,1.42mmol)和boc-甘氨酸(1.5mmol)溶于10mL无水二氯甲烷中，加入DCC(2.0mmol)，过量室温搅拌过夜，加水淬灭，用硅藻土过滤除去不溶物，滤液旋干，重新溶解于乙醚中，再加入2N氯化氢乙醚溶液脱保护，有固体析出，室温搅拌1h，TLC检测反应完毕，过滤得白色固体0.57g，产率90％。
实施例12 MTT法测试化合物对Hela细胞的抗肿瘤活性
1、试验方法
细胞以含200mL/L胎牛血清的RPMI 1640培养液培养，使细胞一直处于对数生长期，接种至96孔板，密度4～8×10 4/ml，37℃，预培养24小时加药，药物设6个浓度，每种药物设3个复孔，连续作用48小时，甩去培养液风干，每 孔加冰冷500g/L三氯醋酸50μL(终浓度为100g/L)固定60min后去离子水洗4～5次，干燥，每孔加4g/L SRB 100μL作用30min,10mL/L醋酸轻洗4次,甩干，每孔加10mmol Tris base 200μL摇动混匀，在平板振荡器上振荡5min,在酶联免疫检测仪测定A值，用空白对照调零，所用波长为490nm，抑瘤率(％)＝(无药细胞对照孔A值平均值-用药孔A值平均值)/无药细胞对照孔A值平均值×100％，阳性对照为CA-4，根据不同浓度下药物对细胞生长的抑制率，以Logit方法计算IC 50值。
2.试验结果
化合物编号 IC 50(μmol/L)
CA-4 0.27
VIa-Z 0.24
VIa-E 0.069
Ia 0.19
VIb-Z 0.53
VIb-E 0.26
Ib 0.18
VIc-Z 0.12
VIc-E 0.60
Ic 0.13
Id 0.11
Ie 0.07
实施例13 CCK-8法测试化合物对多种肿瘤细胞的抗肿瘤活性
1、试验方法
取活细胞比例达90％以上的细胞进行实验。细胞增殖抑制试验采用EnoGeneCell TM Counting Kit-8(CCK-8)细胞活力检测试剂盒。细胞消化、计数、制成浓度为1×10 5个/mL的细胞悬液，96孔板中每孔加入100μL细胞悬液(每孔1×10 4个细胞)；96孔板置于37℃，5％CO 2培养箱中培养24小时；每孔加入100μL相应的含药物的培养基，同时设阴性对照组，溶媒对照组，阳性对照组，每组5复孔；96孔板置于37℃，5％CO 2培养箱中培养72h后；每孔加入10μL CCK-8溶液,将培养板在培养箱内孵育4小时，用酶标仪测定在450nm处的OD值，计算目标化合物对人甲状腺癌细胞SW579、人肝癌细胞HepG2、人肺癌细胞A549、人胃癌细胞MGC-803、人乳腺癌细胞MDA-MB-231、等细胞的抑制率及IC 50值。
2、试验结果
Figure PCTCN2018096862-appb-000015
上述所述通式(I)上化合物抗肿瘤活性测试的阳性对照物为(Z)-3,4,5-三甲氧基-3'-羟基-4'-甲氧基二笨乙烯(CA-4)，药效评价结果综述如下：体外培养肿瘤细胞的抗肿瘤活性评价，结果表明CA-4含氟类似物对Hela细胞具有广泛的抑制活性，并且这些化合物的活性数值与对照药CA-4的活性数值相差不大，尤其化合物VIc-E的IC 50值为0.069μmol/mL小于CA-4的IC 50值(0.27μmol/mL)，说明在CA-4结构B环中引入两个氟原子有效地改善了化合物的抗肿瘤活性。对于二氟甲氧基取代的CA-4类似物，分析活性数据可以看到，顺式结构活性要大于反式结构，如化合物VIc-Z和VIc-E。但是也有例外如化合物VIa-Z和VIa-E的IC 50值分别为0.24和0.069μmol/mL，化合物VIb-Z没有测到其IC 50值，反式结构活性大于顺式结构活性。这说明了单独从化合物的顺反构型并不能判断其体外抗肿瘤活性。将双键还原后的二苯乙烷类化合物，活性并没有明显变化，但是化合物的结构比较稳定。同时，通过化合物VIa-Z与VIc-Z、Ib的活性比较，可以看到当在B环的3'位采用硝基、氨基或者羟基取代后，化合物的活性也有所改善。以化合物VIa-E为例，与CA4比较用CCK-8进一步评价了化合物对SW579、HepG2、A549、MCG-803、MDA-MB-231等多种肿瘤细胞株的抑制活性，总体而言，经偕二氟甲氧基修饰的二苯乙烷及二苯乙烯衍生物具有较强的抗肿瘤活性，显著优于阳性对照药CA4，具有较好的应用开发前景。
需要说明的是，以上实施例已对本发明创造的部分化合物进行了说明，但并不局限于所述实施例，熟悉本领域的技术人员在不违背发明创造精神的前提下，还可做出多种等同的改变和替换，这些等同的改变和替换应包括在本申请权利要求所限定的范围内。

Claims (8)

  1. 一种二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物，其特征在于，其结构如通式(I)所示：
    Figure PCTCN2018096862-appb-100001
    其中：
    虚线---表示键或不存在；
    R为氢、羟基、硝基、氨基、苄氧基、磷酸盐、硫酸盐、磷酸胆碱、或氨基酸侧链及其水溶性铵盐。
  2. 如权利要求1所述的二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物，其特征在于，R为H、OH、NH 2、NO 2、OPO 3Na 2、-NHCOCH 2NH 2、或-NHCOCH(NH 2)CH 2OH。
  3. 一种如权利要求1所述的二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物的制备方法，其特征在于，具体步骤如下：
    (1)将3位R基取代的4-羟基苯甲醛和溴氟甲基膦酸二乙酯发生二氟甲醚化反应得到3位R基取代的4-二氟甲氧基苯甲醛；
    (2)3,4,5-三甲氧基苄溴三苯基溴化磷和3位R基取代的4-二氟甲氧基苯甲醛在碱作用下进行Wittig反应，得到二氟甲氧基二苯乙烯类衍生物；
    (3)将二氟甲氧基二苯乙烯类衍生物进行还原，使双键氢化得到3,4,5-三甲氧基-3'-R-4'-二氟甲氧基二苯乙烷。
  4. 如权利要求3所述的二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物的制备方法，其特征在于，当R为如权利要求2所述的磷酸酯钠盐时，其制备方法为由相应的酚羟基与三氯氧磷反应，再用碱中和得到。
  5. 如权利要求3所述的二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物的制备方法，其特征在于，当R为如权利要求1所述的氨基酸侧链时，其制备方法为由相应的氨基化合物与Boc-氨基酸缩合，再用酸脱保护制得。
  6. 一种如权利要求1所述的二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物在制 备微管蛋白聚集抑制剂中的应用。
  7. 一种如权利要求1所述的二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物在制备抗肿瘤药物中的应用。
  8. 一种如权利要求1所述的二氟甲氧基二苯乙烷及反式二苯乙烯类衍生物在制备治疗非正常新生血管引起的疾病的药物中的应用。
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