CN116478215A - 一种含二茂铁结构的化合物及其应用 - Google Patents
一种含二茂铁结构的化合物及其应用 Download PDFInfo
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- CN116478215A CN116478215A CN202310270333.5A CN202310270333A CN116478215A CN 116478215 A CN116478215 A CN 116478215A CN 202310270333 A CN202310270333 A CN 202310270333A CN 116478215 A CN116478215 A CN 116478215A
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- alkyl
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- 400mhz
- acetone
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 123
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 title claims abstract description 33
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 40
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 21
- 230000034994 death Effects 0.000 claims abstract description 21
- 229910052742 iron Inorganic materials 0.000 claims abstract description 20
- 102100023410 Phospholipid hydroperoxide glutathione peroxidase Human genes 0.000 claims abstract description 18
- 101000829725 Homo sapiens Phospholipid hydroperoxide glutathione peroxidase Proteins 0.000 claims abstract description 16
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- 230000000694 effects Effects 0.000 claims abstract description 10
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- 230000004083 survival effect Effects 0.000 claims abstract description 5
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 4
- 201000008808 Fibrosarcoma Diseases 0.000 claims abstract description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims abstract description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 4
- 206010038389 Renal cancer Diseases 0.000 claims abstract description 4
- 201000010982 kidney cancer Diseases 0.000 claims abstract description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 4
- 201000008968 osteosarcoma Diseases 0.000 claims abstract 2
- 238000002360 preparation method Methods 0.000 claims description 31
- -1 amino, mercapto, hydroxy Chemical group 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 4
- 239000000411 inducer Substances 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000002489 hematologic effect Effects 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 142
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- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 54
- 230000015572 biosynthetic process Effects 0.000 description 54
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- 238000006243 chemical reaction Methods 0.000 description 32
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000007787 solid Substances 0.000 description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 22
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
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- 238000001035 drying Methods 0.000 description 14
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 13
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- UJHBVMHOBZBWMX-UHFFFAOYSA-N ferrostatin-1 Chemical compound NC1=CC(C(=O)OCC)=CC=C1NC1CCCCC1 UJHBVMHOBZBWMX-UHFFFAOYSA-N 0.000 description 6
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- 101100173542 Caenorhabditis elegans fer-1 gene Proteins 0.000 description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
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- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- XNFNGGQRDXFYMM-UHFFFAOYSA-N hydron;methyl 2-amino-3-(1h-indol-3-yl)propanoate;chloride Chemical compound [Cl-].C1=CC=C2C(CC([NH3+])C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- XGIBLEBJVMIPPF-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-1,3-dien-1-ylmethanamine iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.NCc1ccc[cH-]1 XGIBLEBJVMIPPF-UHFFFAOYSA-N 0.000 description 3
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明公开了一种含二茂铁结构的化合物及其应用。所述化合物的结构如式I、或者式II、或者式III所示。本发明经过实验验证，所述的含二茂铁结构的化合物具有很好的抑制多种肿瘤细胞活性的作用，且为GPX4抑制剂，即通过抑制GPX4，引发铁死亡，从而抑制肿瘤细胞的存活，达到抗肿瘤的作用。因此，所述化合物对骨肉瘤、纤维肉瘤、乳腺癌、肾癌、非小细胞肺癌、胰腺癌、血液癌等铁死亡性肿瘤的治疗具有很好的应用价值。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种含二茂铁结构的化合物及其应用。
技术背景
恶性肿瘤是一种严重威胁人类健康的常见病和多发病，以细胞或变异细胞异常增殖和向周围组织转移为特点，人类因恶性肿瘤而引起的死亡居于所有疾病死亡率的第二位，仅次于心脑血管疾病。研制具有新作用机制和新结构的抗肿瘤药物一直是全球药业公司和各国政府重点关注和发展的领域。目前的癌症主要治疗手段包括手术、放疗、化疗以及分子靶向治疗，在这其中术后的复发和转移，尤其是抗癌药物的耐药性问题严重影响治疗效果。纵观整个肿瘤治疗历史，耐药已经成为癌症治疗失败的主要原因之一，极大地限制了癌症药物的选择和使用。
铁死亡(ferroptosis)是近年来新发现的一种铁依赖的氧化损伤而诱发的调节性细胞死亡类型，受细胞内信号通路的严密调节。它与其他细胞死亡方式如细胞凋亡和坏死等不同，其主要特征在于广泛的脂质过氧化，细胞内活性氧(reactive oxygen species，ROS)累积，谷胱甘肽(glutathione，GSH)耗竭，多不饱和脂肪酸释放增加等。已报道有多种物质和外界刺激可引发铁死亡，其中负责清除脂质过氧化物的谷胱甘肽过氧化酶4(GPX4)被证实在铁死亡中起着关键作用，GPX4为含硒蛋白，其催化核心含有硒代半胱氨酸。抑制GPX4的活性可以促进癌细胞发生铁死亡。
二茂铁作为非常重要的有机金属官能团，具备稳定性高、亲脂、低毒、独特的三明治夹心结构及可参与氧化还原的特性，在药物化学中应用广泛。二茂铁在抗肿瘤药物化学领域的应用主要涉及两个方面：一是利用二茂铁独特的立体空间构象将其作为结构单元引入小分子药物设计中，扩展设计抗肿瘤相关分子的化学空间结构；二是基于二茂铁可以参与氧化还原的特性，研究证实特定结构取代的二茂铁衍生物可通过芬顿/类芬顿反应产生具有细胞毒性的活性氧自由基，进而杀伤肿瘤细胞。因此，筛选及合成含有二茂铁结构的化合物并用于促进铁死亡的发生，对于肿瘤的治疗具有重大的意义。
发明内容
本发明的一个目的是提供了一种含二茂铁结构的新型化合物。
本发明的另一目的是提供了所述含二茂铁结构的化合物的制备方法。
本发明的另一目的是提供了所述含二茂铁结构的化合物在医药领域的用途，即作为靶向GPX4的铁死亡诱导剂用于肿瘤的治疗。
为实现上述发明目的，本发明采用以下技术方案予以实现：
本发明提供了一种含二茂铁结构的化合物，其结构如式I、或者式II、或者式III所示：
式中，L选自直接键、C1-C6烷基或含1-3个独立取代基的C1-C6烷基、C2-C6烯基或含1-3个独立取代基的C2-C6烯基、(C0-C6烷基)-(C3-C6环烷基)-(C0-C6烷基)或含1-3个独立取代基的(C0-C6烷基)-(C3-C6环烷基)-(C0-C6烷基)、(C0-C6烷基)-Z-(C0-C6烷基)或含1-3个独立取代基的(C0-C6烷基)-Z-(C0-C6烷基)；其中，Z选自N(Ra)、-SO2-、OC(＝O)或者C(＝O)O；所述取代基选自C1-C6烷基、C1-C6烷氧基、C1-C6烷基、C3-C8环烷基、卤素、氨基、巯基、羟基、-CF3、-CN、-NO2、-NRaRb、-NRaCORb、-NRaCOORb、-NRaSO2Rb、-COORb、-CORb、-CONRaRb、-SO2Rb、-SO2NRaRb、-ORa和-OCORb；
M选自C1-C2卤烷基或含1-2个甲基取代的卤烷基、C2-C3烯基或含1-2个甲基取代的C2-C3卤基烯基、C2炔基或含1个甲基取代的C2炔基、-CH2OS(O)2-苯基或含1个甲基取代的苯基、或者4-硝基-5-烷基异噁唑；
X选自N、O、或者S；
R1、R2、R3、R4、R5和R6选自至少含有1个未取代或被1-3个取代基取代的二茂铁基团；所述取代基选自C1-C6烷基、C1-C6烷氧基、C1-C6烷基、杂环基、杂环基羰基、C1-C6烷基杂环基、C6-C10芳基、C3-C8环烷基、卤素、巯基、羟基、-CF3、-CN、-NO2、-NRaRb、-NRaCORb、-NRaCOORb、-NRaSO2Rb、-COORb、-CORb、-CONRaRb、-SO2Rb、-SO2NRaRb、-ORa、或者-OCORb，且NRaRb能够共同组成环胺；所述杂环包括1-3个选自N、O和S中的杂原子；
R7选自氢、卤素、羟基、巯基、-CF3、-CN、-NO2、或者未取代或被1-3个取代基取代的C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C3-C8环烷氧基、氨基、苯基、苄基、萘基、C5-C10芳香性杂环基或C3-C7饱和杂环基；所述取代基选自C1-C6烷基、C1-C6烷氧基C1-C6烷基、杂环基、杂环基羰基、C1-C6烷基杂环基、C6-C10芳基、C3-C8环烷基、卤素、巯基、羟基、-CF3、-CN、-NO2、-NRaRb、-NRaCORb、-NRaCOORb、-NRaSO2Rb、-COORb、-CORb、-CONRaRb、-SO2Rb、-SO2NRaRb、-ORa、或者-OCORb，且NRaRb能够共同组成环胺；所述杂环包括1-3个选自N、O和S中的杂原子；
Ra、Rb为R1、R2、R3、R4、R5、R6、R7中的一种。
进一步的，所述化合物具体为化合物I-1～I-29，其结构具体如下：
进一步的，所述化合物具体为化合物II-1～II-36，其结构具体如下：
进一步的，所述化合物具体为化合物III-1～III-10，其结构具体如下：
进一步的，所述结构如式I所示的化合物通过以下方法制备：
进一步的，所述结构如式II所示的化合物通过以下方法制备：
所述化合物通过以二茂铁为原料，经过傅克酰基化、还原、取代或者还原胺化、酰胺缩合等反应合成以及市售的含有NH或NH2结构的二茂铁中间体，再与相应的酸或者酰氯缩合得到目标产物；
反应试剂和反应条件：(a)NaBH4,THF-MeOH＝1:1；(b)乙酸酐，吡啶；(c)哌嗪或乙二胺,CH3CN；(d)相应的酰氯底物,Et3N,DCM或者相应的酸,HBTU,DIPEA,DCM；(e)相应的酰氯底物，三氯化铝，DCM；(f)NaBH(OAc)3,THF；(g)i:NaOH,盐酸羟胺,EtOH；ii:LiAlH4,THF；(h)i:草酰氯，DCM；ii:哌嗪，三乙胺。
进一步的，所述结构如式III所示的化合物通过以下方法制备：
其中，化合物III-1，III-2,III-3,III-4是通过L-或D-色氨酸甲酯盐酸盐脱盐酸，然后与二茂铁甲醛通过Pictet Spengler反应得到相应中间体，进一步和氯乙酰反应制备得到；III-5是1S3R构型中间体与丙烯酰氯制得，III-6是1S3R构型中间体与丙炔酸制得；III-7,III-8,III-9先通过酰胺缩合或者酯缩合合成前体，后采用同样方法制得终产物；III-10,III-11以D-色氨酸为起始原料，经过Boc保护、酰胺缩合、脱保护基得到前体，后通过PS反应制备；III-12、III-13以对氟苯腈为原料，经取代、还原得中间体，然后制得终产物；
具体反应路线和条件如下：(a)三乙胺,二氯甲烷；(b)二茂铁甲醛，三氟乙酸,二氯甲烷；(c)NaHCO3,二氯甲烷，氯乙酰氯；(d)丙烯酰氯，DIPEA,DMAP,二氯甲烷；(e)CMPI,二氯甲烷；(f)HBTU,DIPEA,DMF；(g)2,三氟乙酸，二氯甲烷；(h)EDCI,HOBt,DIPEA,DMAP,DMF；(i)碳酸钾，DMF；(j)DIBAL-H,四氢呋喃；(k)(Boc)2O,三乙胺，甲醇；(l)氨基二茂铁，HBTU,DIPEA,DCM；(m)三氟乙酸，二氯甲烷；(n)对甲酰基苯甲酸甲酯，三氟乙酸，二氯甲烷；(o)二茂铁甲胺,HBTU,DIPEA,DCM。
本发明还提供了一种组合物，其作为GPX4抑制剂，其中包含所述的含二茂铁结构的化合物。
本发明还提供了所述的化合物或者所述的组合物在制备铁死亡诱导剂中的应用。
本发明还提供了所述的化合物或者所述的组合物在制备抗肿瘤的药物中的应用。
进一步的，所述肿瘤为铁死亡性肿瘤，具体包括乳腺癌、肺癌、胰腺癌、纤维肉瘤、肾癌、骨肉瘤、血液癌。
进一步的，所述化合物通过抑制GPX4，来引发铁死亡，从而抑制肿瘤细胞的存活，达到抗肿瘤的作用。
进一步的，所述药物中还添加有药物学上可接受的载体或助剂。
进一步的，用所述化合物治疗的肿瘤是以间充质特征或间充质表型为特征，在一些癌症中，间充质特征的增加与癌症的迁移(例如血管内渗)和侵袭性相关；间充质特征尤其包括增强的迁移能力、侵袭性、升高的对细胞凋亡的抗性和增加的细胞外基质(ECM)组分的产生。
进一步的，用所述化合物治疗的癌症被鉴别为具有或确定具有活化或致癌性RAS突变；RAS可以是K-RAS、H-RAS或N-RAS。
进一步的，所述化合物能够用于治疗难以用一种或多种其它化学治疗剂，包括但不限于细胞毒性化学治疗剂治疗的癌症；或治疗对放射治疗具有抗性的癌症。
与现有技术相比，本发明具有的优点和有益效果是：
本发明通过多种合成手段获得了能够靶向谷胱甘肽过氧化酶4(GPX4)的含二茂铁结构的新型化合物，丰富了二茂铁类化合物的种类，且其可以作为铁死亡诱导剂。本发明还经过实验验证，所述的含二茂铁结构的化合物具有很好的抑制多种肿瘤细胞活性的作用，且为GPX4抑制剂，即通过抑制GPX4，引发铁死亡，从而抑制肿瘤细胞的存活，达到抗肿瘤的作用。因此，所述化合物对铁死亡性肿瘤的治疗具有很好的应用价值。
具体实施方式
结合以下具体实例对本发明的技术方案作进一步详细的说明。
下述实施例中，如无特殊说明，所使用的实验方法均为常规方法，所用材料、试剂等均可从生物或化学试剂公司购买。
实施例1：含二茂铁结构的化合物的制备
化合物的1H-NMR光谱数据测量使用VJEOL400MHz或Bruker AVENCE NEO 400MHz核磁共振，质谱EI-MS用Finnigan MAT 95质谱仪，ESI-MS使用Finnigan LCQ Deca质谱仪测定。快速柱层析在硅胶H(10-40μM)上进行。
一、如通式I所示的含二茂铁结构的化合物的制备：
I-1的合成：称取二茂铁甲醛(0.1958g，0.9148mmol，1.2eq)和3-氯-4-甲氧基苯胺(0.1442g，0.9148mmol，1.2eq)溶于甲醇(3mL)中，于室温搅拌30min。随后加入氯乙酸(0.0720g，0.7623mmol 1eq)和2-苯代乙基异腈(0.10mL，0.7623mmol，1eq)，继续室温搅拌。TLC检测反应完全，减压蒸干，经柱层析纯化，得产物0.3535g，红色固体，产率80.05％。1HNMR(400MHz,Acetone-d6)δ7.63(s,1H),7.37–7.30(m,5H),7.23(td,J＝6.0,3.2Hz,1H),6.91(s,1H),5.88(s,1H),4.19(s,1H),4.13(s,6H),4.04(s,1H),3.98(s,1H),3.86(d,J＝4.5Hz,5H),3.74–3.65(m,1H),3.56(td,J＝13.4,5.9Hz,1H),2.96(h,J＝6.7Hz,2H)13C NMR(400MHz,ACETONE-D6)δ168.35,165.44,155.02,139.66,132.36,131.14,130.73,129.45,128.50,126.30,81.21,69.99,69.75,68.87,68.15,59.83,55.75,42.68,40.93,35.75.
I-2的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.47(d,J＝5.0Hz,1H),7.29(p,J＝7.4Hz,5H),7.20(t,J＝7.2Hz,1H),7.05–7.01(m,1H),6.80(s,1H),6.26(s,1H),4.61(s,1H),4.35(s,1H),4.30(s,6H),4.25(s,1H),4.14–4.01(m,2H),3.56(dq,J＝13.2,6.6,6.0Hz,1H),3.44(dt,J＝12.9,6.6Hz,1H),2.83–2.81(m,2H).13C NMR(400MHz,ACETONE-D6)δ167.38,166.16,139.69,138.93,128.93,128.56,128.51,127.13,126.23,126.07,103.40,69.65,66.49,66.16,65.88,65.31,42.40,41.25,35.52.
I-3的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.52(d,J＝4.5Hz,1H),7.30–7.26(m,2H),7.21(d,J＝6.7Hz,4H),7.12(s,1H),7.06(s,1H),6.10(s,1H),4.61(s,1H),4.49(d,J＝15.7Hz,1H),4.33(s,2H),4.23(s,1H),4.08(s,7H),4.00(s,1H),3.69(s,1H),3.45(d,J＝24.8Hz,2H),2.84(s,2H).13C NMR(400MHz,ACETONE-D6)δ205.18,166.46,128.87,128.44,127.33,126.60,126.24,68.80,45.52,42.59,40.90,35.39.
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I-4的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.51(s,1H),7.36(d,J＝4.9Hz,1H),7.06–6.92(m,3H),6.89–6.86(m,1H),6.32(s,1H),4.12(s,5H),4.03(d,J＝4.9Hz,4H),3.98–3.96(m,2H),3.87(s,3H),3.40(dq,J＝13.3,6.8Hz,2H),3.03(s,2H).13CNMR(400MHz,ACETONE-D6)δ167.74,165.95,155.27,136.19,132.34,131.43,130.77,130.09,127.86,126.82,121.43,111.84,86.02,68.51,68.23,67.31,59.79,55.87,42.73,40.70.
I-5的合成路线与I-1相同。1H NMR(400MHz,Chloroform-d)δ7.40–7.29(m,2H),7.05–6.92(m,3H),6.83(dt,J＝13.5,7.0Hz,1H),6.21–6.16(m,1H),6.05(s,1H),4.15(dd,J＝4.7,1.9Hz,3H),4.10(t,J＝2.0Hz,3H),4.02(s,5H),3.90(s,3H),3.87(s,2H).13C NMR(400MHz,ACETONE-D6)δ168.27,166.03,155.29,136.19,131.65,130.69,130.19,128.02,126.44,111.70,85.79,68.45,67.70,67.53,60.09,55.86,42.19,39.11.
I-6的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ8.88(s,1H),7.38(d,J＝4.8Hz,1H),7.13–6.86(m,5H),6.30(s,1H),4.78(d,J＝30.1Hz,2H),4.17(s,5H),4.00(d,J＝11.9Hz,4H),3.88(s,3H)13C NMR(400MHz,ACETONE-D6)δ167.15,166.09,155.27,135.39,131.22,130.31,128.19,126.58,121.43,111.80,95.31,68.96,64.07,61.01,60.58,60.13,55.85,42.64.
I-7的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.77(s,1H),7.21(d,J＝28.4Hz,1H),6.92(s,1H),5.88(s,1H),4.25–4.07(m,18H),3.87(d,J＝10.0Hz,5H),3.54(d,J＝25.6Hz,2H),2.68(s,2H).13C NMR(400MHz,ACETONE-D6)δ204.88,165.63,132.40,130.69,111.35,86.10,81.28,70.00,69.82,68.92,68.50,68.23,67.38,67.28,59.98,56.82,46.13,42.69,40.92.
I-8的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.68(s,1H),7.32(d,J＝6.4Hz,4H),7.25–7.16(m,2H),7.01(d,J＝6.4Hz,1H),6.90(d,J＝8.8Hz,1H),5.85(s,1H),4.21(s,1H),4.14(s,6H),4.07(s,1H),3.99(s,1H),3.85(s,3H),3.73–3.64(m,1H),3.60(s,1H),3.55(dd,J＝12.6,7.3Hz,1H),2.95(q,J＝6.6Hz,2H).13C NMR(400MHz,ACETONE-D6)δ168.03,154.93,152.70,139.59,132.48,131.82,131.01,128.94,128.54,126.30,120.48,111.00,81.50,80.93,76.47,69.92,69.72,68.91,68.31,68.20,59.46,55.71,41.04,35.68.
I-9的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.72(s,1H),7.36–7.26(m,5H),7.20(t,J＝6.9Hz,1H),6.90(s,1H),6.25(dd,J＝16.8,2.4Hz,1H),5.99(s,1H),5.85(dd,J＝16.7,10.2Hz,1H),5.52(dd,J＝10.3,2.4Hz,1H),4.18(s,1H),4.11(d,J＝5.8Hz,7H),3.97(s,1H),3.85(s,3H),3.70–3.54(m,2H),2.94(dt,J＝12.4,6.0Hz,2H).13CNMR(400MHz,ACETONE-D6)δ168.72,164.74,154.65,139.66,132.24,132.00,130.74,129.09,128.94,128.51,127.25,126.25,111.34,81.62,70.11,69.75,68.84,68.08,59.22,55.75,40.92,35.73.
I-10的合成路线与I-1相同。1H NMR(400MHz,Chloroform-d)δ7.35–7.23(m,6H),7.00(dt,J＝9.6,5.4Hz,1H),6.57(s,1H),6.09(s,1H),4.26(d,J＝34.8Hz,2H),4.04(d,J＝12.1Hz,7H),3.78(s,3H),3.75–3.63(m,2H),2.98(t,J＝7.1Hz,2H),2.69(s,3H).13C NMR(101MHz,CDCl3)δ167.59,155.46,153.71,134.74,131.99,130.36,129.95,128.45,126.76,122.15,111.34,81.40,69.22,69.12,68.80,68.79,68.16,60.22,58.63,56.33,45.79,41.37.
I-11的合成路线与I-1相同。1H NMR(400MHz,Chloroform-d)δ7.48(s,1H),7.00(s,1H),6.70(d,J＝77.5Hz,2H),5.88(s,1H),4.29(d,J＝13.8Hz,4H),4.19(s,6H),4.14(s,4H),4.03(s,6H),3.85(s,3H),3.76(s,2H).13C NMR(400MHz,ACETONE-D6)δ166.37,165.52,154.19,130.81,129.65,128.64,82.88,79.03,68.98,68.61,67.98,67.65,67.59,67.47,55.19,41.19,38.37.
I-12的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)7.79(d,J＝6.1Hz,2H),7.32(dt,J＝14.9,7.5Hz,10H),7.20(t,J＝7.1Hz,4H),5.75(s,2H),4.06(s,4H),3.97(s,2H),3.87(s,2H),3.81(d,J＝4.0Hz,4H),3.77(s,6H),3.69(dd,J＝13.6,6.8Hz,2H),3.49(dd,J＝13.1,6.5Hz,2H),2.88(t,J＝7.6Hz,4H).13C NMR(400MHz,ACETONE-D6)δ207.18,191.03,155.09,138.94,132.29,130.70,129.08,128.46,126.29,102.52,85.58,83.99,81.94,71.40,70.94,68.89,68.62,58.97,55.77,42.70,40.82,35.85.
I-13的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.98(d,J＝55.1Hz,1H),7.28(q,J＝7.7,7.0Hz,5H),7.20(d,J＝8.2Hz,1H),7.01(s,1H),6.91(s,1H),5.72(d,J＝189.5Hz,1H),4.86–4.61(m,2H),4.56(t,J＝6.8Hz,1H),4.46(d,J＝13.9Hz,1H),4.17–4.11(m,7H),4.10–4.05(m,2H),3.73–3.48(m,2H),2.91(d,J＝8.3Hz,2H).13C NMR(400MHz,Acetone)δ170.01,169.79,168.71,168.39,144.82,144.29,141.17,136.29,136.25,135.38,130.53,130.25,128.51,128.29,128.12,128.01,127.93,127.90,127.52,126.75,83.08,71.62,71.27,70.75,70.68,70.46,70.34,70.24,70.13,61.85,58.52,48.65,48.41,43.91,42.58,42.49,37.26,36.96.
I-14的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.93(d,J＝43.6Hz,1H),7.29(q,J＝5.1,3.7Hz,4H),7.22–7.07(m,3H),6.97(dd,J＝25.1,16.8Hz,2H),6.03–5.44(m,1H),4.81–4.40(m,4H),4.20–4.11(m,7H),4.09(s,2H),3.68(s,2H),2.95–2.87(m,2H).13C NMR(400MHz,Acetone)δ170.04,168.71,142.49,141.22,135.56,131.69,130.87,130.55,130.23,129.18,128.62,128.00,127.91,126.40,83.22,71.59,71.28,70.69,70.30,70.12,62.14,58.70,48.94,44.04,42.56,37.26,36.84.
I-15的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.63(s,1H),7.37–7.30(m,2H),7.23(td,J＝6.0,3.2Hz,1H),6.91(s,1H),5.88(s,1H),4.19(s,1H),4.13(s,6H),4.04(s,1H),3.98(s,1H),3.86(d,J＝4.5Hz,3H),3.74–3.65(m,1H),3.56(td,J＝13.4,5.9Hz,1H),2.96(h,J＝6.7Hz,6H),1.32–1.27(m,6H).13C NMR(400MHz,ACETONE-D6)δ168.35,165.44,139.66,132.36,131.14,130.73,129.45,128.50,81.21,69.99,69.75,68.87,68.15,59.83,55.75,42.68,40.93,35.75,33.39,21.76,15.03.
I-16的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)7.57(s,1H),7.31(d,J＝2.1Hz,4H),7.29(d,J＝0.9Hz,1H),7.20(ddd,J＝9.1,7.0,5.0Hz,4H),5.88(s,1H),4.16(dt,J＝2.6,1.3Hz,1H),4.08(d,J＝1.0Hz,5H),4.06(td,J＝2.5,1.3Hz,1H),4.02(dt,J＝2.6,1.3Hz,1H),3.90(td,J＝2.5,1.3Hz,1H),3.81–3.72(m,2H),3.70–3.61(m,1H),3.56–3.50(m,1H),2.93(dp,J＝8.0,6.7Hz,2H).13C NMR(400MHz,ACETONE-D6)δ175.24,164.11,140.90,130.72,128.97,128.49,126.23,93.35,79.73,70.12,69.81,68.82,68.08,60.05,42.54,40.95,35.69.
I-17的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.95(d,J＝55.0Hz,1H),7.27(dq,J＝7.6,4.5,3.9Hz,4H),7.18(ddt,J＝8.2,6.3,2.8Hz,2H),6.95(ddd,J＝14.9,6.2,2.1Hz,2H),5.90(dd,J＝62.5,4.4Hz,1H),4.93–4.76(m,1H),4.68–4.40(m,2H),4.17–4.08(m,7H),3.61–3.44(m,2H),2.88(dhept,J＝14.3,7.0Hz,3H).13C NMR(400MHz,CDCl3)δ167.65,167.33,154.42,153.65,140.59,140.45,138.51,138.43,134.36,134.13,128.92,128.82,128.77,126.93,126.90,126.83,126.70,126.51,125.40,80.40,80.24,78.99,75.52,70.41,69.96,69.86,69.36,69.20,69.11,69.03,68.88,68.74,62.35,56.69,49.17,46.05,40.81,35.63,35.36.
I-18的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.74(d,J＝19.9Hz,1H),7.45-7.28(m,5H),7.25-7.13(m,2H),6.80-6.68(m,2H),5.70-5.61(m,1H),4.15(s,2H),4.14-3.93(m,7H),3.92-3.76(m,2H),3.75-3.51(m,2H),3.34(s,1H),2.99-2.92(m,2H),1.32–1.27(m,3H).
I-19的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.67(s,1H),7.54(d,J＝8.5Hz,2H),7.31–7.26(m,4H),7.19(tt,J＝5.5,2.7Hz,1H),6.89(d,J＝8.1Hz,2H),5.72(d,J＝98.9Hz,1H),4.17(dt,J＝2.6,1.3Hz,1H),4.11(s,5H),4.09(dt,J＝3.7,1.8Hz,1H),4.04(dt,J＝2.6,1.3Hz,1H),3.96(dt,J＝3.7,1.7Hz,1H),3.71–3.61(m,1H),3.58(s,1H),3.53(ddd,J＝13.2,7.9,4.1Hz,1H),2.92(dt,J＝8.0,6.2Hz,2H).13C NMR(400MHz,ACETONE-D6)δ167.92,152.28,139.59,138.96,137.18,133.24,128.94,128.54,126.30,93.63,81.61,80.83,76.34,69.99,69.74,68.92,68.36,68.20,59.47,41.04,35.66.
I-20的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.12(d,J＝87.4Hz,3H),6.87(d,J＝8.6Hz,1H),5.75(s,1H),4.19(s,4H),4.16(d,J＝2.5Hz,2H),4.08(d,J＝2.2Hz,1H),3.98(q,J＝2.2Hz,1H),3.82(s,3H),3.56(s,1H),1.44(s,9H).13C NMR(400MHz,Acetone)δ169.11,156.57,154.31,134.18,133.51,132.69,122.12,112.63,83.09,82.97,78.20,71.47,71.38,70.59,69.82,69.76,61.55,57.39,52.72.
I-21的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.59(s,1H),7.24(s,1H),7.04(d,J＝8.8Hz,1H),6.86(d,J＝8.7Hz,1H),5.78(s,1H),4.19–4.18(m,1H),4.16(s,5H),4.10(ddt,J＝3.8,2.4,1.3Hz,2H),3.97(td,J＝2.5,1.3Hz,1H),3.81(s,3H),3.56(s,1H),3.34(dtd,J＝8.5,7.0,5.7Hz,2H),1.60(td,J＝7.1,3.2Hz,2H),1.43(q,J＝7.5Hz,2H),0.93(t,J＝7.4Hz,3H).13C NMR(400MHz,Acetone)δ169.77,156.60,154.32,134.25,133.58,132.77,122.15,112.67,83.06,82.77,78.18,71.65,71.46,70.61,70.53,69.96,69.85,61.24,57.41,40.81,33.39,21.76,15.03.
I-22的合成路线与I-1相同。1H NMR(400MHz,Chloroform-d)δ7.89(t,J＝1.8Hz,1H),7.83(dt,J＝7.9,1.5Hz,1H),7.58(d,J＝7.8Hz,1H),7.40(t,J＝7.9Hz,1H),7.36–7.27(m,5H),7.25–7.20(m,1H),7.10(t,J＝6.0Hz,1H),6.65(s,1H),6.53(d,J＝8.4Hz,1H),6.08(s,1H),4.18(d,J＝4.9Hz,2H),4.03(s,6H),3.96(s,1H),3.75(d,J＝2.5Hz,3H),3.74–3.61(m,2H),2.97(h,J＝7.0Hz,2H).13C NMR(101MHz,Acetone)δ207.62,170.26,168.98,156.01,141.32,140.52,137.26,134.84,134.03,132.58,131.67,130.64,130.51,130.23,129.74,128.02,122.56,112.84,82.93,71.67,70.65,70.05,69.85,62.46,57.40,42.71,37.33,33.50,24.20,15.24.
I-23的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ8.14(s,1H),7.45(d,J＝7.9Hz,2H),7.28(dt,J＝35.6,7.3Hz,4H),7.07(d,J＝9.0Hz,1H),6.86(d,J＝8.7Hz,1H),5.86(d,J＝6.1Hz,1H),4.55(ddt,J＝37.6,9.8,6.0Hz,2H),4.22–4.15(m,1H),4.10–4.04(m,7H),3.95(tt,J＝4.8,2.3Hz,1H),3.84–3.79(m,3H),3.63–3.54(m,1H).13C NMR(400MHz,CDCl3)δ167.34,155.05,153.47,137.75,132.17,131.11,130.07,128.90,128.20,127.78,121.48,110.81,81.12,79.86,75.79,70.07,69.65,69.03,68.95,68.68,59.54,56.11,44.11.
I-24的合成路线与I-1相同。1H NMR(400MHz,Chloroform-d)δ7.35–7.30(m,4H),7.25–7.20(m,1H),6.96(t,J＝5.9Hz,1H),6.76(s,1H),6.60(s,1H),5.89(s,1H),4.34(q,J＝1.6Hz,1H),4.21(q,J＝1.6Hz,1H),4.12(d,J＝8.7Hz,2H),4.06(q,J＝1.8Hz,3H),3.99(s,1H),3.84(s,3H),3.82(s,1H),3.75(d,J＝4.8Hz,2H),3.56(dtd,J＝13.6,7.0,5.0Hz,1H),2.99–2.92(m,2H),2.70(s,1H).13C NMR(101MHz,CDCl3)δ167.84,154.88,153.38,138.75,132.12,131.08,130.02,128.98,128.68,126.54,110.65,81.06,80.95,77.32,77.00,76.68,75.20,72.61,72.54,71.34,71.14,70.62,70.48,69.73,69.50,64.59,58.85,56.03,40.90.
I-25的合成路线与I-1相同。1H NMR(400MHz,Chloroform-d)δ7.34(d,J＝7.5Hz,1H),7.32–7.28(m,3H),7.25–7.20(m,1H),7.04(s,1H),6.89(q,J＝7.4,6.3Hz,1H),6.67(d,J＝8.7Hz,1H),5.85(s,1H),4.33(q,J＝1.6Hz,1H),4.22(q,J＝1.7Hz,1H),4.16(p,J＝1.7Hz,1H),4.12–4.08(m,2H),4.06(t,J＝2.0Hz,2H),4.01(t,J＝2.1Hz,1H),3.89–3.84(m,1H),3.83(s,3H),3.54(dtd,J＝12.2,7.0,5.1Hz,1H),2.94(td,J＝6.9,2.0Hz,2H),2.87(s,1H),2.63(s,1H).13C NMR(101MHz,CDCl3)δ168.00,155.04,153.54,138.91,132.28,131.24,130.18,129.14,128.84,126.70,121.50,110.81,81.97,81.22,81.11,76.01,75.36,72.77,72.70,71.50,71.30,70.78,70.64,69.89,69.66,64.75,59.01,56.19,41.06,35.87.
I-26的合成路线与I-1相同。1H NMR(400MHz,Chloroform-d)δ7.33(dd,J＝5.1,1.2Hz,1H),7.16(d,J＝8.8Hz,1H),7.03(t,J＝2.2Hz,1H),6.96(dd,J＝5.2,3.5Hz,1H),6.81(d,J＝8.7Hz,1H),6.22(t,J＝5.2Hz,1H),6.13(s,1H),4.17(d,J＝5.2Hz,1H),4.14(d,J＝4.8Hz,2H),4.12–4.09(m,3H),4.03(s,5H),3.90(s,3H),2.91(s,1H).13C NMR(101MHz,CDCl3)δ167.09,155.46,153.65,135.04,132.30,131.77,130.42,129.72,128.62,126.92,122.22,111.44,81.45,75.81,68.61,68.31,68.25,67.96,67.70,60.79,56.33,39.27.
I-27的合成路线与I-1相同。1H NMR(400MHz,Chloroform-d)δ7.04(q,J＝18.8,14.0Hz,2H),6.72(d,J＝8.6Hz,1H),5.89(s,1H),4.28(d,J＝14.5Hz,4H),4.19(s,6H),4.15(s,3H),4.07(d,J＝9.4Hz,2H),4.03(s,5H),3.85(s,3H),2.87(s,1H).13C NMR(101MHz,CDCl3)δ167.03,155.08,153.50,132.17,131.34,130.08,121.53,110.89,83.95,81.28,79.95,75.87,70.05,69.66,69.10,69.07,69.02,68.72,68.55,68.39,59.80,56.22,39.43.
I-28的合成路线与I-1相同。1H NMR(400MHz,Chloroform-d)δ7.20(s,1H),7.10(d,J＝8.9Hz,1H),6.93(d,J＝3.7Hz,1H),6.90(t,J＝4.4Hz,1H),6.78(d,J＝8.8Hz,1H),6.10(s,1H),6.04(t,J＝6.3Hz,1H),4.10(s,5H),4.06(s,2H),4.03(s,1H),3.99(s,1H),3.89(s,3H),3.40(p,J＝6.6Hz,2H),3.11(s,2H),2.89(s,1H).13C NMR(101MHz,CDCl3)δ167.59,155.46,153.71,134.74,131.99,130.36,129.95,128.45,126.76,122.15,111.34,81.40,75.89,69.22,69.12,68.80,68.79,68.20,68.16,60.22,58.63,56.33,45.79,41.37.
I-29的合成路线与I-1相同。1H NMR(400MHz,Acetone-d6)δ7.81(t,J＝5.5Hz,2H),7.41–7.25(m,10H),7.20(dp,J＝7.0,2.0Hz,3H),6.84(d,J＝7.8Hz,3H),5.71(d,J＝2.5Hz,2H),4.10–4.01(m,8H),3.76(d,J＝4.5Hz,6H),3.72–3.66(m,2H),3.61(d,J＝2.4Hz,2H),3.50(dt,J＝11.0,3.6Hz,2H),2.88(t,J＝7.2Hz,4H).13C NMR(101MHz,Acetone)δ170.10,170.02,156.72,154.31,141.26,134.29,133.20,132.85,130.73,130.21,130.11,127.99,122.18,112.67,83.39,83.00,78.10,73.04,72.64,70.69,70.52,61.52,60.20,57.41,42.69,42.56,37.21.
二、如通式II所示的含二茂铁结构的化合物的制备：
合成路线A：合成化合物II-1、II-4
称取KOH(1.070g 1.5eq)加入H2SO4(3mL)，称取异噁唑1(0.9g 1eq)，加入H2SO4和KOH的混合溶液，搅拌4h。取样TLC，反应完全。加入NaHCO3中和，EA萃取3次，干燥，过滤，旋干。产物m＝0.7481g，产率61.4％。称取中间体2(0.7481g 1eq)溶于DCM(15mL)中，滴加草酰氯(0.725mL 2eq)，再加一滴DMF，搅拌。旋干，加入氯仿3*2mL继续旋干。得产物m＝0.2546g，产率＝92.15％。称取硝基异噁唑2(0.05g0.29mmol 1eq)，溶于DCM(2mL)，加入三乙胺(0.08mL 0.58mmol 2eq)，氨基二茂铁(0.0583g 0.29mmol 1eq)搅拌0.5h。加入饱和碳酸氢钠，DCM萃取。柱色谱分离得黄色固体II-1(43mg 41.8％)1H NMR(400MHz,Acetone-d6)δ9.54(s,1H),4.78(t,J＝1.9Hz,2H),4.24(s,5H),4.08(t,J＝1.9Hz,2H),2.89(d,J＝0.9Hz,3H).13C NMR(101MHz,Acetone-d6)δ172.44,154.65,154.00,65.16,61.68,12.63.m/z[M]+:356.15(calcd.:356.13)
II-4合成路线与II-1相同。1H NMR(400MHz,Chloroform-d)δ6.76(t,J＝5.8Hz,1H),4.15(s,7H),4.11(s,2H),3.56(d,J＝6.5Hz,2H),2.80(s,3H),2.64(t,J＝7.0Hz,2H).13C NMR(101MHz,Chloroform-d)δ172.07,156.39,153.12,85.04,68.94,68.51,68.00,41.24,29.22,13.45.
合成路线B：合成化合物II-2
称取二茂铁甲醛4(1g 4.67mmol 1eq)、氢氧化钠(1.10g 27.5mmol 6eq)、盐酸羟胺(0.65g 9.3mmol 2eq)，溶于无水乙醇(50mL)，回流0.5h，TLC检测反应完全。冷却，加水，DCM萃取旋干，得红色固体(0.987g，92.3％)。称取氢化铝锂(0.8652g22.799mmol 5.3eq)溶于THF(25mL)，滴加到将上一步产物(0.987g 4.318mmol 1eq)的THF(25mL)溶液中，回流0.5h，TLC检测反应完全。冷却，滴加水，EA萃取得中间体5(0.849g，91.4％)。1H NMR(400MHz,Chloroform-d)δ4.16(t,J＝1.9Hz,2H),4.14(s,5H),4.11(d,J＝1.9Hz,2H),3.55(s,2H).
合成II-2与II-1反应相同，将中间体3换成5。1H NMR(500MHz,Chloroform-d)δ6.68(s,1H),4.34(d,J＝5.1Hz,2H),4.29(s,2H),4.23(s,5H),4.21(s,2H),2.83(s,3H).13CNMR(101MHz,Chloroform-d)δ172.25,155.84,153.06,83.69,68.89,68.60,68.43,39.53,13.52.m/z[M]+:370.16(calcd.:370.16)
合成路线C：合成化合物II-3
称取二茂铁甲胺5(0.5g 2.325mmol 1eq)、二茂铁甲醛4(0.498g 2.325mmol 1eq)溶于DCM(30mL)，加入三乙酰氧硼氢化钠(0.739g 3.488mmol 1.5eq)，搅拌2h。加入水，EA萃取3次，饱和食盐水洗，无水硫酸钠干燥，柱色谱分离，得中间体6(0.39g40.7％)1H NMR(400MHz,Chloroform-d)δ4.21(dt,J＝3.8,1.8Hz,4H),4.16–4.03(m,14H),3.55(d,J＝5.0Hz,4H).
合成II-3与II-1反应相同，将中间体3换成6。1H NMR(400MHz,Acetone-d6)δ4.47(s,2H),4.36(t,J＝1.9Hz,2H),4.21(d,J＝3.1Hz,7H),4.18(q,J＝1.4Hz,3H),4.14(q,J＝1.5Hz,3H),4.09(s,1H),4.04(s,4H),2.90(s,3H).13C NMR(101MHz,Acetone-d6)δ172.69,157.29,153.78,82.32,81.95,69.68,69.51,68.64,68.25,68.11,46.66,42.66,13.54.
合成路线D：合成化合物II-5
称取二茂铁甲酸4(0.5g 2.174mmol)，溶于DCM(8mL)，加入草酰氯(0.37mL4.35mmol)，1滴DMF，溶液橙黄浑浊变成酒红色，搅拌4h，旋干，氯仿带3次。将哌嗪(1.872g 21.74mmol)溶于DCM(22mL)中，再逐滴滴加二茂铁甲酰氯5，1d三乙胺，搅拌过夜。再加入DCM，饱和碳酸氢钠洗3次，DCM:MeOH柱色谱分离，得中间体6(0.22g，34％)。1H NMR(400MHz,Chloroform-d)δ4.57–4.51(m,2H),4.32–4.28(m,2H),4.24(s,5H),3.74(s,1H),3.70(t,J＝5.0Hz,4H),2.86(t,J＝4.9Hz,4H).
合成II-5与II-1反应相同，将中间体3换成6。1H NMR(400MHz,Acetone-d6)δ4.60(t,J＝1.9Hz,2H),4.36(t,J＝1.9Hz,2H),4.24(s,5H),3.90(d,J＝5.9Hz,2H),3.84(dd,J＝6.7,3.7Hz,2H),3.72(s,2H),3.54–3.46(m,2H),2.90(s,3H).13C NMR(101MHz,Acetone-d6)δ173.05,169.06,156.88,153.45,78.11,70.39,69.66,69.40,46.52,42.10,12.87.
合成路线E：合成化合物II-6
称取二茂铁甲醛4(0.5g 2.336mmol 1eq)、哌嗪(1.006g 11.68mmol 5eq)、三乙酰氧硼氢化钠(1.238g 5.84mmol 2eq)，加入THF(25mL)，搅拌过夜，旋干THF，加入1M氢氧化钠(50mL)，EA萃取3次，旋干，以DCM和MeOH进行柱色谱分离，得中间体8(0.545g，82％)。1H NMR(400MHz,Chloroform-d)δ4.17(t,J＝1.8Hz,2H),4.11(d,J＝1.9Hz,7H),3.35(s,2H),2.84(t,J＝4.9Hz,4H),2.37(s,4H).
合成II-6与II-1反应相同，将中间体3换成8。1H NMR(400MHz,Acetone-d6)δ4.18(t,J＝1.9Hz,2H),4.11(d,J＝5.8Hz,7H),3.72–3.64(m,2H),3.43(s,2H),3.35–3.28(m,2H),2.87(s,3H),2.48(t,J＝5.1Hz,2H),2.33(t,J＝5.1Hz,2H).13C NMR(101MHz,Acetone-d6)δ172.91,156.42,153.55,82.72,70.14,68.45,67.89,57.73,52.32,51.69,46.45,41.77,12.86.
合成路线F：合成化合物II-7～II-18、II-27～II-29
称取化合物9(0.15g 0.516mmol 1eq)溶于THF(3mL)和甲醇(3mL)混合溶液，0℃搅拌，加入硼氢化钠(0.0195g 0.516mmol 1eq)，搅拌2h，滴加盐酸，加入，水洗3次，饱和食盐水洗，无水硫酸钠干燥，得中间体10(0.305g，101％)。1H NMR(400MHz,Acetone-d6)δ7.42(d,J＝7.6Hz,2H),7.30(t,J＝7.5Hz,2H),7.26–7.14(m,1H),5.55(d,J＝4.2Hz,1H),4.28(s,1H),4.17(s,5H),4.11(s,1H),4.08(s,2H).
将中间体10溶于吡啶(2mL)中，加入乙酸酐(1.9mL)，搅拌过夜，将吡啶旋干。溶于CH3CN(30mL),加入哌嗪(0.887g 10.3mmol 10eq)，回流过夜，旋干乙腈，加入EA，水洗3次，饱和食盐水洗，无水硫酸钠干燥，柱色谱分离得中间体11(0.323g，87％)。1H NMR(400MHz,Chloroform-d)δ7.51–7.46(m,2H),7.39(t,J＝7.5Hz,2H),7.34–7.29(m,1H),4.17–4.07(m,4H),3.90(s,1H),3.71(s,5H),2.87(d,J＝6.1Hz,4H),2.35(s,4H).
合成II-7与II-1反应相同，将中间体3换成11。1H NMR(400MHz,Acetone-d6)δ7.58(ddd,J＝6.8,3.4,1.4Hz,2H),7.43(ddt,J＝9.3,7.0,3.4Hz,2H),7.35–7.27(m,1H),4.26(q,J＝2.0Hz,1H),4.16(ddd,J＝4.6,3.0,1.5Hz,1H),4.12(dt,J＝3.0,1.9Hz,2H),4.08(d,J＝3.5Hz,1H),3.78–3.71(m,5H),3.62(dq,J＝8.4,4.5Hz,2H),3.27(dt,J＝6.0,3.8Hz,2H),2.85(s,3H),2.42–2.33(m,2H),2.28–2.13(m,2H).13C NMR(101MHz,Acetone-d6)δ173.59,157.07,154.23,143.77,129.51,128.80,127.95,90.14,71.28,71.10,69.44,69.31,68.08,67.36,52.47,51.77,47.34,42.69,13.55.
合成II-10与II-7反应相同，将中间体2换成氯乙酰氯。1H NMR(400MHz,Acetone-d6)δ7.57(d,J＝7.6Hz,2H),7.43(t,J＝7.5Hz,2H),7.33(t,J＝7.3Hz,1H),4.26(d,J＝2.4Hz,1H),4.19(s,2H),4.17(d,J＝3.1Hz,1H),4.14(p,J＝2.5,2.0Hz,2H),4.07(s,1H),3.76(s,5H),3.42(d,J＝5.8Hz,4H),2.37–2.19(m,4H).13C NMR(101MHz,Acetone-d6)δ164.34,143.04,128.83,128.04,127.18,89.51,70.53,70.49,68.70,68.53,67.41,66.63,51.84,51.28,46.05,41.97,41.25.
合成II-13与II-7反应相同，将中间体2换成丙烯酰氯。1H NMR(400MHz,Acetone-d6)δ7.57–7.52(m,2H),7.40(dd,J＝8.3,6.8Hz,2H),7.33–7.26(m,1H),6.65(dd,J＝16.7,10.5Hz,1H),6.09(dd,J＝16.7,2.5Hz,1H),5.56(dd,J＝10.5,2.5Hz,1H),4.26–4.21(m,1H),4.16–4.12(m,1H),4.11(p,J＝2.1,1.7Hz,2H),4.03(s,1H),3.73(s,5H),3.45(s,4H),2.29–2.15(m,4H).13C NMR(101MHz,Acetone-d6)δ165.20,144.16,129.88,129.13,129.08,128.21,127.52,90.60,71.61,69.75,69.58,68.45,67.65,53.28,52.56,46.59,42.85.
将丙炔酸(0.01mL 0.149mmol 1.2eq)溶于DCM(1mL)中，加入HBTU(0.06997g0.1845mmol 1.5eq)，DIPEA(0.033mL 0.1845mmol 1.5eq)，搅拌0.5h，加入中间体11(0.056g 0.1418mmol 1eq)，搅拌0.5h，水洗2次，饱和食盐水洗，无水硫酸钠干燥，柱色谱分离得产物II-16(0.003g，6％)。1H NMR(400MHz,Acetone-d6)δ7.57(d,J＝7.5Hz,2H),7.43(t,J＝7.6Hz,2H),7.32(dd,J＝13.8,6.5Hz,1H),4.30–4.25(m,1H),4.17(s,1H),4.13(dt,J＝4.3,1.9Hz,2H),4.10(s,1H),3.83(s,1H),3.76(s,4H),3.73–3.59(m,2H),3.44(dd,J＝6.2,4.1Hz,2H),2.73(s,1H),2.37–2.27(m,2H),2.25(ddd,J＝8.2,5.8,3.6Hz,2H).13CNMR(101MHz,Acetone-d6)δ151.77,143.64,129.57,128.78,128.59,127.95,90.13,80.42,76.32,71.28,71.13,69.45,69.28,68.17,67.41,52.61,51.80,47.56,41.98.
称取二茂铁12(5.73g,30.8mmol,1.1eq)溶于二氯甲烷，加入无水氯化铝(4.1g,30.8mmol,1.1eq)，溶解后，冰水浴中滴加4-氯苯甲酰氯13(4.1g,30.8mmol,1.1eq)，搅拌过夜，加水淬灭，二氯甲烷萃取，浓缩后柱色谱分离，得中间体14(5.6g 79.7％)。1H NMR(400MHz,Acetone-d6)δ8.00-7.89(m,2H),7.57-7.51(m,2H),4.89–4.80(m,2H),4.69-4.59(m,2H),4.22(s,5H).
合成II-8与II-7反应相同，将中间体9换成10。1H NMR(400MHz,Acetone-d6)δ7.62(d,J＝8.5Hz,2H),7.53–7.40(m,2H),4.27(d,J＝1.6Hz,1H),4.18(dd,J＝2.5,1.4Hz,1H),4.16–4.12(m,2H),4.08(dd,J＝2.5,1.3Hz,1H),3.79(d,J＝0.9Hz,5H),3.72–3.53(m,2H),3.27(td,J＝6.0,3.9Hz,2H),2.85(s,3H),2.37(t,J＝5.2Hz,2H),2.27–2.16(m,2H).13CNMR(101MHz,Acetone-d6)δ172.87,156.36,153.48,141.87,132.25,130.47,128.09,88.66,70.53,69.46,68.75,67.21,66.88,51.62,50.94,46.58,41.93,13.54.
合成II-11与II-7反应相同，将中间体2换成氯乙酰氯。1H NMR(400MHz,Acetone-d6)δ7.61(d,J＝8.4Hz,2H),7.49–7.44(m,2H),4.27(dt,J＝2.6,1.4Hz,1H),4.19(s,3H),4.16(dq,J＝2.5,1.2Hz,1H),4.13(s,1H),4.11–4.06(m,1H),3.80(s,5H),3.43(t,J＝5.9Hz,4H),2.34–2.19(m,4H).13C NMR(101MHz,Acetone-d6)δ164.37,141.85,132.22,130.52,128.09,88.76,70.51,69.58,68.76,68.69,67.28,66.88,51.71,51.17,46.03,41.96,41.25.
合成II-14与II-7反应相同，将中间体2换成丙烯酰氯。1H NMR(400MHz,Acetone-d6)δ7.64–7.58(m,2H),7.49–7.43(m,2H),6.68(dd,J＝16.7,10.5Hz,1H),6.12(dd,J＝16.7,2.5Hz,1H),5.59(dd,J＝10.5,2.5Hz,1H),4.27(dt,J＝2.7,1.4Hz,1H),4.22–4.14(m,2H),4.14–4.07(m,2H),3.80(s,5H),3.48(s,4H),2.32–2.18(m,4H).13C NMR(101MHz,Acetone-d6)δ164.14,141.82,132.22,130.52,128.07,126.51,88.82,70.65,69.66,68.86,67.38,66.95,52.09,51.39,45.48,41.74,29.77,29.57.
合成II-17与II-16反应相同。1H NMR(400MHz,Acetone-d6)δ7.61(d,J＝8.3Hz,2H),7.46(d,J＝8.1Hz,2H),4.28(s,1H),4.24–4.12(m,3H),4.09(s,1H),3.86(s,1H),3.80(s,4H),3.71–3.56(m,2H),3.44(t,J＝5.1Hz,2H),2.73(s,1H),2.30(dt,J＝9.8,5.2Hz,2H),2.24(q,J＝5.1Hz,2H).13C NMR(101MHz,Acetone-d6)δ151.97,142.62,133.15,131.42,129.01,89.50,80.79,76.43,71.44,70.39,69.67,68.19,67.83,52.65,51.85,47.68,42.11,38.84.
合成路线G：合成化合物II-19～II-23
称取二茂铁12(0.93g 5mmol 1eq)、AlCl3(0.665g 5mmol 1eq)溶于DCM(10mL)，-78℃搅拌，将丙烯酰氯(0.4mL 5mmol 1eq)溶于DCM(1.5mL)，滴加到二茂铁溶液中，15min滴加完，搅拌过夜，将反应液立即投入冰水中，DCM萃取。柱色谱分离，得中间体17(0.434g34.8％)。1H NMR(400MHz,Chloroform-d)δ4.83(t,J＝2.1Hz,2H),4.60(d,J＝1.9Hz,2H),4.37(t,J＝2.0Hz,2H),4.02(d,J＝1.9Hz,2H),2.95(d,J＝2.1Hz,4H).
合成II-9与II-7反应相同，将中间体9换成17。1H NMR(400MHz,Acetone-d6)δ4.23(d,J＝2.4Hz,1H),4.13(t,J＝1.9Hz,2H),4.10–4.03(m,2H),4.00(dt,J＝11.3,2.4Hz,2H),3.86(q,J＝2.0Hz,1H),3.79–3.59(m,2H),3.32(q,J＝5.3Hz,2H),3.06(dd,J＝11.1,2.3Hz,1H),2.81(s,3H),2.57(t,J＝5.2Hz,2H),2.46(t,J＝3.5Hz,1H),2.41(t,J＝5.2Hz,2H),2.34–2.18(m,1H),2.13(ddt,J＝13.0,4.8,2.6Hz,1H),1.98(d,J＝2.8Hz,1H).13C NMR(101MHz,Acetone-d6)δ172.85,156.36,153.53,87.82,80.00,71.71,71.32,69.21,69.17,68.20,67.64,67.53,66.85,64.72,50.52,49.53,46.79,42.10,38.86,25.70,12.82.
合成II-12与II-10反应相同。1H NMR(400MHz,Acetone-d6)δ4.23(s,1H),4.18(s,2H),4.13(s,2H),4.07(d,J＝9.5Hz,2H),4.00(d,J＝10.7Hz,2H),3.86(s,1H),3.49(td,J＝14.4,13.5,8.7Hz,4H),3.07(d,J＝11.1Hz,1H),2.47(dd,J＝7.6,4.1Hz,3H),2.45–2.36(m,2H),2.36–2.21(m,1H),2.13(d,J＝13.1Hz,1H),1.97(dd,J＝13.7,2.8Hz,1H).13C NMR(101MHz,Acetone-d6)δ164.38,87.85,71.81,71.33,69.18,68.22,67.75,67.54,66.85,64.78,50.46,49.67,42.01,41.27,38.90,25.74.
合成II-15与II-13反应相同。1H NMR(400MHz,Acetone-d)δ6.68(dd,J＝16.8,10.5Hz,1H),6.09(dd,J＝16.7,2.6Hz,1H),5.63–5.51(m,1H),4.23(d,J＝2.5Hz,1H),4.12(d,J＝2.6Hz,2H),4.09–4.03(m,2H),3.99(dt,J＝12.3,2.4Hz,2H),3.86(d,J＝2.8Hz,1H),3.55(dt,J＝12.4,7.4Hz,4H),3.05(dd,J＝11.1,2.3Hz,1H),2.44(dq,J＝4.7,2.5Hz,5H),2.35–2.22(m,1H),2.14(ddt,J＝12.9,4.8,2.6Hz,1H),1.97(dd,J＝13.4,2.9Hz,1H).13C NMR(101MHz,Acetone-d)δ164.16,128.17,126.36,87.85,79.96,71.78,71.32,69.15,68.17,67.72,67.53,66.83,64.75,50.85,49.92,45.69,41.90,38.89,25.74.
合成II-18与II-16反应相同。1H NMR(400MHz,Acetone-d6)δ4.29–4.24(m,1H),4.14(d,J＝2.0Hz,2H),4.12–4.04(m,2H),4.01(ddd,J＝9.2,5.1,2.6Hz,2H),3.90-3.81(m,2H),3.72(q,J＝5.0Hz,2H),3.52(dddd,J＝18.4,13.2,9.1,5.5Hz,2H),3.12(dd,J＝11.2,2.2Hz,1H),2.53(t,J＝5.1Hz,2H),2.49–2.40(m,3H),2.37–2.22(m,1H),2.15(ddt,J＝12.9,4.8,2.5Hz,1H),2.01–1.94(m,1H).13C NMR(101MHz,Acetone-d)δ88.55,80.49,80.23,76.31,72.58,72.11,70.01,69.96,69.38,69.05,68.51,68.31,67.63,65.60,51.25,50.32,47.54,41.94,39.51,30.52,30.28,26.47.
称取中间体17(0.5g,2.083mmol,1eq)溶解于DCM中，冷却到-15℃，滴加三氟化硼乙醚(0.5mL,3.95mmol,2eq)和2M(三甲硅基)重氮甲烷(1.6mL,1.5eq)。反应1h，投入冰水中，DCM萃取，饱和食盐水洗，柱色谱分离得中间体20(0.05g,10％)。1H NMR(400MHz,Chloroform-d)δ4.69(t,J＝2.0Hz,2H),4.53(t,J＝2.0Hz,2H),4.14(t,J＝1.9Hz,2H),3.99(t,J＝1.9Hz,2H),2.63–2.57(m,2H),2.31–2.20(m,4H).
由中间体20合成化合物II-19的路线与合成路线F相同。
将中间体23(0.5g,2.19mmol 1eq)溶于DCM(10mL),将3-氯丙酰氯(0.314mL,3.29mmol 1.5eq)溶解于DCM(5mL)缓慢滴加，冰水浴下，缓慢加入三氯化铝(0.876g,6.57mmol 3eq)，冰水浴搅拌过夜。将反应物投入冰水中，DCM萃取,饱和食盐水洗,无水硫酸钠干燥,柱色谱分离得到中间体(0.6365g,91.4％)。1H NMR(400MHz,Chloroform-d)δ4.81(dt,J＝8.3,1.9Hz,4H),4.55(dd,J＝4.6,2.4Hz,4H),3.91(t,J＝6.3Hz,2H),3.12(t,J＝6.4Hz,2H),2.36(s,3H).称取中间体(1.273g,4.0mmol 1eq)溶解于甲醇MeOH(150mL).加入10％ NaOH(4mL,8.76mmol)，反应液搅拌回流30min.，冰水浴冷却，过滤,水洗,旋干柱色谱分离得到中间体24(0.982g,86.97％)。1H NMR(400MHz,Chloroform-d)δ4.80(t,J＝2.0Hz,4H),4.55(t,J＝2.0Hz,4H),2.58–2.44(m,6H).
将AlCl3(0.189g,1.42mmol 4eq)缓慢加入到无水的THF(2mL)，氮气保护，冰水浴搅拌30min。加入LiAlH4(0.040g,1.06mmol 3eq)，缓慢加入中间体24(0.1g,0.3546mmol1eq)，加热回流1h,。缓慢加入冰水，EA萃取，柱色谱分离得到中间体25(0.098g,93％)。1HNMR(400MHz,Acetone-d6)δ4.04(t,J＝1.8Hz,4H),3.96(t,J＝1.9Hz,4H),2.33–2.28(m,4H),2.04(s,2H),1.81(t,J＝6.3Hz,4H).
合成II-20与II-7反应相同，将中间体9换成26。1H NMR(400MHz,Chloroform-d)δ4.27–4.20(m,4H),4.16(dq,J＝5.7,2.9Hz,4H),4.12(d,J＝3.8Hz,4H),4.08(q,J＝2.7Hz,4H),4.03(s,2H),3.99(s,2H),3.96(s,2H),3.93(s,2H),2.85(s,3H).
合成II-21与II-10反应相同。1H NMR(400MHz,Chloroform-d)δ4.21(q,J＝2.2Hz,1H),4.10(ddt,J＝5.6,3.8,1.9Hz,3H),4.01(ddd,J＝6.4,2.7,1.4Hz,2H),3.98(s,3H),3.97(dd,J＝2.4,1.3Hz,1H),3.58(t,J＝5.2Hz,2H),3.45(td,J＝6.3,3.6Hz,2H),3.41–3.33(m,1H),2.45–2.38(m,2H),2.37–2.24(m,2H),2.19–2.02(m,4H),1.94–1.72(m,4H).13CNMR(101MHz,CDCl3)δ164.78,90.94,69.67,69.20,68.44,67.90,67.38,67.05,66.86,49.40,49.02,46.18,42.05,40.83,31.92,31.50,30.11,29.69,29.65,29.36,27.34,24.73,24.61,22.69,14.13.
合成II-22与II-16反应相同。1H NMR(400MHz,Acetone-d6)δ4.29–4.24(m,1H),4.14(d,J＝2.0Hz,2H),4.12–4.04(m,2H),4.01(ddd,J＝9.2,5.1,2.6Hz,2H),3.90-3.81(m,2H),3.72(q,J＝5.0Hz,2H),3.52(dddd,J＝18.4,13.2,9.1,5.5Hz,2H),3.12(dd,J＝11.2,2.2Hz,1H),2.53(t,J＝5.1Hz,2H),2.49–2.40(m,3H),2.37–2.22(m,1H),2.15(ddt,J＝12.9,4.8,2.5Hz,1H),2.01–1.94(m,1H).13C NMR(101MHz,Acetone-d)δ88.55,80.49,80.23,76.31,72.58,72.11,70.01,69.96,69.38,69.05,68.51,68.31,67.63,65.60,51.25,50.32,47.54,41.94,39.51,30.52,30.28,26.47.
合成II-23与II-7反应相同，将中间体9换成24。
合成路线H：合成化合物II-24
合成中间体31与14反应相同。1H NMR(400MHz,Acetone-d6)δ4.82(t,J＝1.9Hz,2H),4.54(t,J＝2.0Hz,2H),4.24(s,5H),3.73(t,J＝6.6Hz,2H),2.98(t,J＝7.0Hz,2H),2.13(p,J＝6.8Hz,2H).
合成II-24与II-6反应相同，将中间体4换成31。1H NMR(400MHz,Chloroform-d)δ4.79–4.72(m,2H),4.52–4.46(m,2H),4.18(s,5H),3.76(t,J＝5.2Hz,1H),3.32–3.27(m,2H),3.17(s,1H),2.97(s,1H),2.86(d,J＝3.0Hz,3H),2.74(t,J＝6.9Hz,2H),2.56(t,J＝5.2Hz,2H),2.48–2.39(m,4H),1.89(t,J＝7.0Hz,2H).13C NMR(101MHz,CDCl3)δ172.08,156.41,153.13,129.24,85.04,68.95,68.75,68.52,68.00,41.23,29.71,29.22,22.72,13.44.
合成路线I：合成化合物II-25、II-26
称取2-碘苯甲酸33(0.865g,3.5mmol 1eq)溶于DCM(5mL)，加入一滴DMF，草酰氯(0.39mL,4.55mmol)，形成白色浑浊溶液，室温搅拌至溶液澄清，旋干溶剂。溶于DCM中，加入DCM(4mL)和二茂铁(0.653g,3.5mmol 1eq)。将溶液冷却到0℃，将AlCl3(0.465g,3.5mmol1eq)分批加入，升至室温。TLC检测反应完全，将反应液投入冰水中，DCM萃取，饱和食盐水洗，无水硫酸钠干燥，柱色谱分离得到橙红色固体中间体34(1.207g,82.9％)。1H NMR(400MHz,Chloroform-d)δ7.92(d,J＝7.9Hz,1H),7.49(dd,J＝7.6,1.8Hz,1H),7.43(t,J＝7.5Hz,1H),7.15(td,J＝7.6,1.8Hz,1H),4.76–4.70(m,2H),4.60(t,J＝1.9Hz,2H),4.29(d,J＝7.5Hz,5H).
称取中间体34(0.2g,0.48mmol 1eq)加入Cs2CO3(0.312g,0.96mmol 2eq),Pd(OAc)2(0.0022mg,0.0096mmol,0.02eq),(S)-BINAP(0.01195g,0.0192mmol,0.04eq)以及三甲基乙酸(0.0074g,0.072mmol,0.3eq)加入甲苯(2mL,0.25M)氮气保护，100℃加热过夜，硅藻土过滤，旋干，得到紫色中间体35(0.170g，99％)。1H NMR(400MHz,Chloroform-d)δ7.53–7.45(m,1H),7.35–7.28(m,1H),7.21–7.08(m,2H),4.98(d,J＝3.1Hz,1H),4.91–4.82(m,2H),4.12(d,J＝4.9Hz,5H).
合成II-25与II-7反应相同，将中间体9换成35。1H NMR(400MHz,Chloroform-d)δ7.48(dd,J＝41.1,8.1Hz,1H),7.35–7.29(m,1H),7.22(d,J＝7.4Hz,1H),7.15(t,J＝7.4Hz,1H),5.03(s,1H),4.53(dd,J＝17.3,2.3Hz,2H),4.27(t,J＝2.3Hz,1H),3.88(s,6H),3.73(s,1H),3.27(t,J＝5.1Hz,2H),2.83(s,3H),2.64(s,1H),2.54(d,J＝5.0Hz,1H),2.33(q,J＝11.4,9.3Hz,2H).
化合物II-26合成路线与II-25相同。1H NMR(400MHz,Chloroform-d)δ7.48(dd,J＝41.1,8.1Hz,1H),7.35–7.29(m,1H),7.22(d,J＝7.4Hz,1H),7.15(t,J＝7.4Hz,1H),5.03(s,1H),4.53(dd,J＝17.3,2.3Hz,2H),4.27(t,J＝2.3Hz,1H),3.88(s,6H),3.73(s,1H),3.27(t,J＝5.1Hz,2H),2.83(s,3H),2.64(s,1H),2.54(d,J＝5.0Hz,1H),2.33(q,J＝11.4,9.3Hz,2H).
合成路线J：合成化合物II-30～II-33
将二茂铁二甲醛44(0.030g,0.12mmol,1eq),4-氨基-1-叔丁氧羰基哌啶45(0.024g,0.12mmol,1eq)和NaBH(OAc)3(0.07g,0.36mmol,3eq)溶解在DCE(2mL)，搅拌过夜。加入水，DCM萃取，饱和食盐水洗，无水硫酸钠干燥，柱色谱分离得到中间体46(0.024g49％)。1H NMR(400MHz,Chloroform-d)δ4.07(t,J＝1.8Hz,4H),4.05(d,J＝1.8Hz,4H),3.01(s,4H),2.88(td,J＝11.3,5.5Hz,1H),2.70(d,J＝15.3Hz,2H),1.83(d,J＝12.7Hz,2H),1.70(s,2H),1.57(dd,J＝12.2,4.4Hz,2H),1.46(s,9H).
合成II-30与II-7反应相同，将中间体11换成47。1H NMR(400MHz,Chloroform-d)δ4.17(s,3H),4.12(s,5H),3.20–3.14(m,9H),2.89(d,J＝4.7Hz,3H),2.18(d,J＝10.6Hz,2H),2.11–1.98(m,2H).13C NMR(101MHz,CDCl3)δ171.89,156.61,153.15,77.37,77.05,76.73,70.03,48.99,46.31,31.94,31.52,31.44,30.19,29.71,29.67,29.37,28.84,28.62,22.71,14.14,13.56,8.65.
合成II-31与II-10反应相同。1H NMR(400MHz,Chloroform-d)δ4.68(d,J＝13.4Hz,1H),4.10(s,3H),4.07(d,J＝4.0Hz,5H),4.02–3.91(m,2H),3.16(d,J＝14.3Hz,1H),3.08(d,J＝30.2Hz,4H),2.65(td,J＝12.8,2.8Hz,1H),1.96(d,J＝13.7Hz,2H),1.81–1.55(m,4H).13C NMR(101MHz,CDCl3)δ163.93,76.33,76.02,75.70,68.83,68.28,67.32,66.76,47.91,45.30,41.30,40.11,30.91,28.34,21.67,13.11.
合成II-32与II-13反应。1H NMR(400MHz,Chloroform-d)δ6.60(dd,J＝16.8,10.6Hz,1H),6.27(dd,J＝16.8,1.9Hz,1H),5.68(dd,J＝10.5,1.9Hz,1H),4.78(d,J＝13.3Hz,1H),4.08(s,3H),4.06(d,J＝1.9Hz,5H),3.99(s,1H),3.11(s,2H),3.03(s,5H),2.64(t,J＝12.2Hz,2H),2.44–2.16(m,2H).13C NMR(101MHz,CDCl3)δ163.93,76.33,76.02,75.70,68.83,68.28,67.32,66.76,47.91,45.30,41.30,40.11,30.91,28.34,21.67,13.11.13C NMR(101MHz,CDCl3)δ165.40,127.64,124.37,77.34,77.23,77.03,76.71,68.35,67.80,53.43,31.93,31.51,31.44,30.19,30.13,30.04,29.70,29.66,29.51,29.37,22.70,14.13.
合成II-33与II-16反应相同。1H NMR(400MHz,Chloroform-d)δ4.68(dq,J＝10.8,2.3Hz,1H),4.50(ddd,J＝13.4,4.5,2.3Hz,1H),4.07(d,J＝6.5Hz,8H),3.13–3.09(m,1H),3.03(s,4H),2.68(td,J＝12.9,3.0Hz,1H),1.97(s,2H),1.70–1.61(m,4H).13C NMR(101MHz,CDCl3)δ151.68,77.34,77.22,77.02,76.70,69.79,69.19,53.43,49.01,31.93,31.51,30.18,29.70,29.66,29.37,22.70,14.13.
合成路线K：合成化合物II-34～II-36
称取化合物48(0.1g,0.424mmol,1.0eq.)、三甲基硅基乙炔(0.299mL,22.1mmol,5.0eq.)in加入Et3N(1mL)、Pd(PPh3)2Cl2(10.2mg,0.0221mmol,0.05eq.)、CuI(4.2mg,0.0221mmol,0.05eq.)，80℃反应6h。冷却至室温，加入水。乙醚萃取，无水硫酸钠干燥，柱色谱分离得中间体49(1.31g,90％)。1H NMR(400MHz,Chloroform-d)δ8.19(d,J＝0.9Hz,1H),4.44(qd,J＝7.2,1.0Hz,2H),3.51(d,J＝0.9Hz,1H),1.41(td,J＝7.1,1.0Hz,3H).
合成II-34与II-17反应相同，将丙炔酸换成中间体50。1H NMR(400MHz,Chloroform-d)δ7.87(s,1H),7.43(d,J＝8.1Hz,2H),7.35(d,J＝8.4Hz,2H),4.15–4.08(m,3H),4.04–4.00(m,1H),3.90(s,1H),3.73(s,7H),3.65–3.55(m,2H),3.47(s,1H),2.35–2.18(m,4H).13C NMR(101MHz,CDCl3)δ171.16,165.76,161.41,151.24,146.36,141.21,132.83,129.93,128.30,126.55,88.41,82.88,77.47,77.15,76.83,75.99,70.53,70.15,68.85,67.26,66.94,52.20,51.49,47.23,42.90,38.63.
化合物II-35合成路线与II-34相同。1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),4.17(s,1H),4.10(dd,J＝12.3,4.3Hz,5H),4.04(d,J＝4.0Hz,2H),3.92(d,J＝6.4Hz,3H),3.78(ddd,J＝44.8,13.6,7.9Hz,2H),3.50(s,1H),3.05(dd,J＝9.2,3.8Hz,1H),2.61(t,J＝5.2Hz,2H),2.54(dt,J＝7.5,3.3Hz,2H),2.27–2.16(m,2H),2.04–1.96(m,1H).13CNMR(101MHz,CDCl3)δ170.77,155.48,146.65,146.06,140.97,89.21,76.32,76.00,75.68,69.72,67.14,66.80,64.70,59.36,46.75,41.24,36.07,33.85,33.50,33.38.
化合物II-36合成路线与II-34相同。1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),4.17–4.14(m,2H),4.11(d,J＝3.5Hz,7H),3.87(s,2H),3.75(s,2H),3.50(s,1H),3.44(s,2H),2.53–2.48(m,2H),2.46(t,J＝4.9Hz,2H).13C NMR(101MHz,CDCl3)δ161.55,151.20,146.43,126.66,82.83,81.69,77.39,77.28,77.08,76.76,76.01,70.30,68.59,68.31,58.19,52.80,52.12,46.90,42.60,38.63.
三、如通式III所示的含二茂铁结构的化合物的制备：
1、化合物III-1的合成
中间体3(1S,3R)构型化合物的制备，将1.2eq的D-色氨酸甲酯盐酸盐(0.716g,2.81mmol)溶于二氯甲烷中，在室温条件下，加入1.3eq三乙胺(0.42ml,3.04mmol),混合物搅拌1小时，过滤，滤液为色氨酸甲酯清油，真空干燥30min。色氨酸甲酯以及几粒分子筛溶于无水二氯甲烷(20ml)中，将1eq的二茂铁甲醛(0.5g,2.34mmol)以及0.1eq的三氟乙酸(0.017ml,0.234mmol)加入反应液中，回流1小时。随后，3eq的TFA(0.52ml,7.02mmol)加入溶液中，回流过夜监测反应结束，溶液冷至室温，用30％的氢氧化钠猝灭，二氯甲烷萃取，盐洗，无水硫酸钠干燥。PE/EA为流动相通过柱层析纯化，得黄色固体，产率为17％。1H NMR(400MHz,Acetone-d6)δ9.51(s,1H),7.43(d,J＝7.5Hz,1H),7.27(d,J＝7.8Hz,1H),7.06–6.92(m,2H),5.20(s,1H),4.43(dd,J＝2.5,1.3Hz,1H),4.40–4.34(m,1H),4.26(s,5H),4.22–4.15(m,2H),4.14–4.08(m,1H),3.72(s,3H),3.07(d,J＝5.5Hz,2H).
化合物III-1的制备，将175mg(1S,3R)构型中间体3溶于无水二氯甲烷(10ml)中，加入1.1eq的碳酸氢钠(0.040g,0.46mmol),冰水浴条件下，向混合液中加入0.5eq的氯乙酰氯(0.017ml,0.21mmol),1h监测反应结束，反应液用DCM萃取，盐洗，无水硫酸钠干燥。粗品用PE/EA过柱纯化，得到(1S,3S)-RSL3-Fc产物68mg,黄色固体，产率为33.0％。1H NMR(400MHz,Acetone-d6)δ10.07(s,1H),7.55(d,J＝8.4Hz,1H),7.44(s,1H),7.14(t,J＝7.4Hz,1H),7.06(t,J＝7.5Hz,1H),6.26(s,1H),4.66(s,1H),4.54(s,1H),4.44(s,2H),4.36–4.23(m,2H),4.13(s,6H),3.70(s,3H),3.23(s,1H),3.04(s,1H).13C NMR(101MHz,Acetone)δ169.53,166.25,136.80,134.00,126.48,121.79,119.31,118.12,111.44,107.41,88.17,68.93,68.46,67.73,67.03,54.70,53.99,51.30,41.72,22.08.
2、化合物III-2的合成
中间体3(1R,3R)构型化合物的制备与中间体3(1S,3R)构型化合物的制备方法类似，使用D-色氨酸甲酯盐酸盐。黄色固体，产率为19％。1H NMR(400MHz,Acetone-d6)δ9.43(s,1H),7.43(dd,J＝6.8,1.9Hz,1H),7.28–7.21(m,1H),7.05–6.93(m,2H),5.00(s,1H),4.51(dq,J＝2.4,1.1Hz,1H),4.32–4.26(m,6H),4.24(td,J＝2.4,1.3Hz,1H),4.14(td,J＝2.3,1.1Hz,1H),3.95(dd,J＝11.3,3.9Hz,1H),3.85(d,J＝0.8Hz,3H),3.14–2.98(m,2H).
化合物III-2的制备，方法与化合物III-1的制备方法类似，原料替换为(1R,3R)构型中间体3,得黄色固体，产率为42％。1H NMR(400MHz,Acetone-d6)δ10.05(s,1H),7.52(d,J＝7.8Hz,1H),7.42(d,J＝8.1Hz,1H),7.10(t,J＝7.6Hz,1H),7.03(t,J＝7.4Hz,1H),6.23(s,1H),4.64(s,1H),4.57–4.45(m,1H),4.41(s,2H),4.25(d,J＝17.2Hz,2H),4.13(d,J＝21.1Hz,6H),3.68(d,J＝8.6Hz,3H),3.21(t,J＝13.7Hz,1H),3.08–2.93(m,1H).13C NMR(101MHz,Acetone)δ169.90,166.39,136.62,130.22,126.57,121.83,119.21,117.98,111.58,106.45,87.72,69.36,69.02,68.79,68.52,68.40,68.38,66.30,52.58,51.56,48.71,42.57,31.75,30.80,22.44,21.10.
3、化合物III-3的合成
中间体3(1R,3S)构型化合物制备方法与(1S,3S)构型相似。(1R,3S)构型化合物得192mg，黄色固体，产率为20.0％。1H NMR(400MHz,Acetone-d6)δ9.52(s,1H),7.43(ddd,J＝7.4,1.6,0.7Hz,1H),7.27(dt,J＝7.9,0.9Hz,1H),7.06–6.92(m,2H),5.20(d,J＝1.7Hz,1H),4.43(dt,J＝2.4,1.3Hz,1H),4.37(dd,J＝2.6,1.3Hz,1H),4.26(d,J＝0.6Hz,5H),4.22–4.15(m,2H),4.11(td,J＝2.5,1.3Hz,1H),3.72(s,3H),3.07(dd,J＝5.6,1.6Hz,2H).
化合物III-3的制备，方法与化合物III-1的制备方法类似,原料替换为(1R,3S)构型中间体3,得黄色固体，产率为64.2％。1H NMR(400MHz,Acetone-d6)δ10.08(s,1H),7.54(d,J＝7.8Hz,1H),7.44(d,J＝7.9Hz,1H),7.13(ddd,J＝8.1,7.0,1.3Hz,1H),7.10–7.03(m,1H),6.26(s,1H),4.67(s,1H),4.54(d,J＝9.7Hz,1H),4.44(s,2H),4.30(s,1H),4.26(s,1H),4.18(d,J＝4.3Hz,1H),4.16–4.06(m,5H),3.71(d,J＝8.3Hz,3H),3.24(t,J＝13.6Hz,1H),3.09–2.97(m,1H).13C NMR(101MHz,ACETONE-D6)δ170.43,167.16,137.66,134.87,127.30,122.60,120.12,118.93,118.53,112.31,111.86,108.13,89.05,69.76,69.29,68.52,67.85,55.52,54.86,52.17,42.54,22.90.
4、化合物III-4的制备
中间体3(1S,3S)构型化合物的制备与中间体3(1S,3R)的制备方法相同。以L-色氨酸甲酯盐酸盐为起始原料，得黄色固体，产率为18.1％，1H NMR(400MHz,Acetone-d6)δ9.45(s,1H),7.43(dd,J＝6.7,2.0Hz,1H),7.24(dd,J＝7.0,1.8Hz,1H),7.05–6.93(m,2H),5.00(s,1H),4.51(dd,J＝2.5,1.2Hz,1H),4.28(s,6H),4.24(td,J＝2.4,1.3Hz,1H),4.17–4.11(m,1H),3.95(dd,J＝11.7,3.2Hz,1H),3.85(s,3H),3.15–2.99(m,2H).
化合物III-4的制备，方法与化合物III-1的制备方法类似,原料替换为(1S,3S)构型中间体3,得黄色固体，产率为34％。1H NMR(400MHz,Acetone-d6)δ9.28(s,1H),7.55(dd,J＝8.1,3.2Hz,2H),7.21–7.13(m,1H),7.08(t,J＝7.5Hz,1H),6.88(s,1H),5.09(d,J＝7.0Hz,1H),4.72(d,J＝13.3Hz,1H),4.59(dt,J＝2.6,1.4Hz,1H),4.37(s,6H),4.20(q,J＝2.2Hz,1H),4.05(dd,J＝4.3,2.7Hz,1H),3.56–3.43(m,2H),3.17–3.11(m,1H),3.09(s,3H).13C NMR(101MHz,ACETONE-D6)δ170.81,167.34,137.49,131.07,127.41,122.69,120.07,118.84,112.48,107.26,88.53,69.88,69.67,69.39,69.36,69.20,67.16,53.42,52.46,49.59,43.44,21.92.
5、化合物III-5的合成
化合物III-5的制备，将(1S,3R)构型中间体3(70mg,0.17mmol,1.0eq)溶DCM,加入DIPEA(0.033ml,0.20mmol,1.2eq),在0℃条件下，滴加丙烯酰氯(0.016ml,0.20mmol,1.2eq),随后加入DMAP(10mg,0.10mmol,0.5eq)撤去冰水浴，TLC监测反应完全，饱和NaHCO3溶液和DCM萃取，盐洗，有机相用无水Na2SO4干燥，旋干溶液，柱层析，得黄色固体49mg,产率为61.5％。1H NMR(400MHz,Acetone-d6)δ10.03(s,1H),7.51(ddt,J＝7.8,1.4,0.8Hz,1H),7.39(d,J＝8.0Hz,1H),7.09(ddd,J＝8.2,7.1,1.3Hz,1H),7.02(ddd,J＝8.0,7.1,1.1Hz,1H),6.78(dd,J＝16.8,10.5Hz,1H),6.30–6.11(m,2H),5.71(d,J＝10.5Hz,1H),4.59(s,1H),4.53(dd,J＝10.9,4.3Hz,1H),4.38(s,1H),4.22(s,1H),4.19–4.14(m,1H),4.09(s,5H),3.69(d,J＝3.2Hz,3H),3.31–3.19(m,1H),3.06–2.97(m,1H).13C NMR(101MHz,Acetone)δ169.91,166.38,136.78,128.76,127.93,126.47,121.70,120.88,119.24,118.11,111.35,88.74,68.85,68.45,68.30,67.62,66.99,66.70,54.07,51.20,22.19.
6、化合物III-6的合成
化合物III-6的制备，将(1S,3R)构型中间体3(100mg,0.24mmol,1.0eq)溶于DCM,加入三乙胺(0.075ml,0.58mmol,2.4eq),室温搅拌5分钟，在0℃条件下，滴加丙炔酸(0.015ml,0.24mmol,1.0eq),随后加入CMPI(74mg,0.29mmol,1.2eq)撤去冰水浴，室温搅拌，TLC监测反应完全，饱和NaHCO3溶液和DCM萃取，盐洗，有机相用无水Na2SO4干燥，旋干溶液，柱层析，得黄色固体，产率为10.2％。1H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.54(d,J＝7.7Hz,1H),7.41(d,J＝8.1Hz,1H),7.22(s,1H),7.17(t,J＝7.5Hz,1H),6.67(s,1H),4.61(s,1H),4.38–4.25(m,5H),4.24–4.15(m,2H),4.04(d,J＝5.1Hz,1H),3.75(s,3H),3.55(s,1H),3.29(s,2H),3.09–3.00(m,1H).
7、化合物III-7的合成
化合物8的制备。在0℃的条件下，将化合物6(0.1g，0.67mmol，1.0eq)溶于DMF中，加入DIPEA(0.22ml,1.34mmol,2.0eq),HBTU(0.379g,1.0mmol,1.5eq),搅拌5分钟，加入化合物7(0.135g,0.67mmol,1.0eq),撤去冰水浴，室温搅拌，为深红色溶液。TLC监测反应完全，水洗，DCM萃取，盐洗，无水硫酸钠干燥，过滤，旋干，柱层析，得红色固体0.184g，产率为82.4％。1H NMR(400MHz,Chloroform-d)δ10.08(s,1H),7.96(d,J＝7.9Hz,2H),7.88(d,J＝7.9Hz,2H),5.31(s,1H),4.70(s,2H),4.54(s,5H).
化合物9的制备。将D-色氨酸甲酯盐酸盐(0.168g,0.66mmol,1.2eq)溶于二氯甲烷中，在室温条件下，加入三乙胺(0.10ml,3.04mmol,1.3eq),室温搅拌1小时，过滤，滤液为D-色氨酸甲酯清油，旋干，真空干燥30min。将D-色氨酸甲酯溶于无水二氯甲烷中，加入化合物8(0.0.184g,0.55mmol,)以及三氟乙酸(0.004ml,0.055mmol,0.1eq)于反应液中，回流1小时。随后，3eq的TFA(0.123ml,1.65mmol)加入溶液中，回流过夜，TLC监测反应结束，溶液冷至室温，用饱和的碳酸氢钠溶液猝灭，二氯甲烷萃取，盐洗，无水硫酸钠干燥。PE/EA为流动相通过柱层析纯化，得60mg，黄色固体，产率为20.5％。1H NMR(400MHz,Chloroform-d)δ7.75(d,J＝7.8Hz,2H),7.66(s,1H),7.57(d,J＝7.0Hz,1H),7.39(d,J＝7.8Hz,2H),7.16(pd,J＝7.0,1.3Hz,3H),5.48(s,1H),4.79(s,2H),4.21(s,5H),4.17–4.08(m,2H),3.96(t,J＝6.0Hz,1H),3.73(s,3H),3.33–3.11(m,2H).
化合物III-7的制备。方法与化合物III-1的制备方法类似，原料替换为化合物9。得黄色固体，产率为55.6％。1H NMR(400MHz,Chloroform-d)δ7.82(s,1H),7.53(d,J＝7.4Hz,3H),7.36(s,2H),7.22–7.07(m,4H),6.05(s,1H),5.22(t,J＝4.2Hz,1H),4.69(s,4H),4.04(s,1H),3.70(s,1H),3.65(s,3H),3.47(d,J＝11.6Hz,1H).
8、化合物III-8的合成
化合物11的制备。方法与化合物8的制备方法相似，将化合物7替换为化合物10。得黄色固体0.17g，产率为73.1％。1H NMR(400MHz,Chloroform-d)δ10.08(d,J＝3.6Hz,1H),8.06–7.85(m,4H),6.35(s,1H),4.42–4.12(m,11H).
化合物12的制备。方法与化合物9的制备方法相似，将化合物8替换为化合物11。得黄色固体，产率为14.6％。1H NMR(400MHz,Chloroform-d)δ7.82(s,1H),7.53(d,J＝7.4Hz,2H),7.36(s,2H),7.22–7.07(m,3H),6.05(s,1H),5.27–5.17(m,1H),4.69(s,4H),4.04(s,1H),3.69(s,1H),3.65(s,3H),3.48(s,1H),2.34(t,J＝6.7Hz,1H),1.92–1.80(m,1H).
化合物III-8的制备。方法与化合物III-1的制备方法相似,原料替换为化合物12。得黄色固体。产率为44.0％。1H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.65(s,2H),7.53(d,J＝6.8Hz,1H),7.38(s,2H),7.23(s,1H),7.12(q,J＝7.9,7.1Hz,2H),6.14(d,J＝43.0Hz,2H),5.23(d,J＝4.8Hz,1H),4.23(q,J＝11.8,10.6Hz,9H),3.70(s,2H),3.64(s,3H),3.26(d,J＝158.4Hz,2H).13C NMR(101MHz,DMSO)δ172.19,168.22,166.16,136.87,134.32,133.63,127.72,126.18,121.82,119.37,118.52,111.81,104.03,86.88,68.80,68.45,67.68,57.04,56.52,53.27,43.80,38.47,31.63,30.29,29.48,23.92.
9、化合物III-9的合成
化合物15的制备。将化合物13(0.1g,0.82mmol,1.0eq)溶于DCM中，依次加入化合物14(0.225g,0.98mmol,1.2eq)、DIPEA(0.41ml,2.46mmol,3eq)、DMAP(10mg,0.08mmol,0.1eq),随后加入HOBt(0.122g,0.90mmol,1.1eq)、EDCI(0.188g,0.98mmol,1.2eq),室温条件下搅拌反应液，溶液为深红色，TLC监测反应结束，DCM萃取，盐洗，无水硫酸钠干燥，过滤，旋干，柱层析分离，得黄色固体，产率为83.2％。1H NMR(400MHz,Chloroform-d)δ10.02(s,1H),7.97(d,J＝8.1Hz,2H),7.37(d,J＝8.1Hz,2H),4.98(s,2H),4.55(s,2H),4.32(s,5H).
化合物16的制备。方法与化合物9的制备方法相似，将化合物8替换为化合物15。1HNMR(400MHz,Chloroform-d)δ7.83(s,1H),7.57(d,J＝7.5Hz,1H),7.32(dd,J＝8.5,2.2Hz,2H),7.22–7.07(m,4H),5.40(s,1H),4.95(q,J＝2.0Hz,2H),4.51(q,J＝2.0Hz,2H),4.29(d,J＝2.3Hz,5H),4.04–3.91(m,1H),3.73(d,J＝2.2Hz,3H),3.34–3.08(m,2H).
化合物III-9的制备。方法与化合物III-1的制备方法相似,原料替换为化合物16。1HNMR(400MHz,Chloroform-d)δ7.88(s,1H),7.54(d,J＝7.7Hz,1H),7.41(s,2H),7.21–7.06(m,4H),6.22(s,1H),5.22(t,J＝4.6Hz,1H),4.93(s,2H),4.50(s,2H),4.27(s,5H),4.18–4.09(m,2H),3.96(s,1H),3.66(s,3H),3.40(d,J＝52.3Hz,1H).13C NMR(101MHz,CDCl3)δ168.74,136.78,127.99,126.17,122.40,119.75,118.36,111.47,72.15,70.67,70.63,69.98,60.44,42.38,41.98,31.92,31.43,30.18,29.69,29.65,29.36,27.01,24.97,22.69,21.07,14.19,14.13.
10、化合物III-10的合成
将原料17(1.0g，5.0mol，1.0eq)溶于甲醇中，氮气置换，将(Boc)2(1.75ml，7.5mol，1.5eq)和三乙胺(1.05ml，7.5mol，1.5eq)连续加入反应液中，室温搅拌过夜，处理，30℃下旋干，EA萃取，得0.213g中间体18。在0℃条件下，将中间体18(0.213g，0.70mmol，1.0eq)溶于DCM中，加入DIPEA(0.231ml,1.40mmol,2.0eq)和HBTU(0.398g,1.05mmol,1.5eq),搅拌30分钟，二茂铁甲胺(0.15g，0.70mmol，1.0eq)溶于DCM滴加至反应液中，然后室温搅拌，TLC监测原料反应完全，DCM萃取，过滤旋干。脱Boc，将中间体19溶于DCM中，加入TFA(DCM:TFA＝6:1),TLC监测反应结束，DCM萃取，柱层析，得72mg中间体20。将中间体20(0.072g,0.18mmol,1.0eq)溶于二氯甲烷中，加入对甲酰基苯甲酸甲酯(0.036g,0.216mmol,1.2eq)以及三氟乙酸(0.002ml,0.018mmol,0.1eq)于反应液中，回流1小时。随后，3eq的TFA(0.062ml,0.54mmol)加入反应液中，回流过夜，TLC监测反应结束，溶液冷至室温，用饱和的碳酸氢钠溶液猝灭，二氯甲烷萃取，盐洗，无水硫酸钠干燥。PE/EA为流动相通过柱层析纯化，得72mg的中间体21，黄色固体。将中间体21(0.072g,0.13mmol,1.0eq)溶于无水二氯甲烷(4ml)中,加入碳酸氢钠(0.012g,0.14mmol，1.1eq),冰水浴条件下，向混合液中加入氯乙酰氯(0.010ml,0.13mmol，1.0eq),TLC监测反应结束，反应液用DCM萃取，盐洗，无水硫酸钠干燥。粗品用PE/EA过柱纯化，得40mg黄色固体，产率为48.6％。1H NMR(400MHz,Chloroform-d)δ7.96(d,J＝8.0Hz,2H),7.68–7.57(m,1H),7.46–7.36(m,2H),7.29(s,1H),7.24–7.11(m,2H),5.51(s,1H),4.25(d,J＝11.7Hz,2H),3.99(s,6H),3.92(s,4H),3.73(d,J＝15.8Hz,2H),3.15(s,1H).
实施例2：含二茂铁结构的化合物对癌症细胞株生长的影响
细胞株：人乳腺癌细胞株4T1，JMIT，MDA-MB-231；人肺癌细胞株A549，H358，H69AR；人胰腺癌细胞株PANC-1，ASPC-1，均购自中国科学院上海细胞库。
方法：磺酰罗单明B(sulforhodamine B，SRB)法，具体如下：将一定数量处于对数生长期的不同种类的肿瘤细胞分别接种于96孔培养板，37℃、5％ CO2培养24h细胞贴壁后，加入不同浓度的本发明的受试化合物，每个浓度设三复孔，并设定相应浓度的DMSO溶液对照孔。用药物处理细胞72h后，倾去培养液，加入100μL冰预冷的10％的三氯乙酸溶液，于4℃固定细胞1h，用蒸馏水洗涤5次，空气中自然干燥。然后加入100μl SRB(4mg/mL)(Sigma，StLouis,MO，USA)溶液，室温中避光染色15min，去染色液，用1％冰醋酸洗涤5次，空气干燥。最后加入150μL 10mM的Tris溶液(pH 10.5)，检测515nm波长下OD值。以下列公式计算药物对细胞生长的抑制率：抑制率(％)＝(OD对照-OD实验)/OD对照×100％，采用GraphPad Prism进行半数抑制浓度的计算(IC50)。
结果参见表1和表2，说明本发明的多种化合物能够明显抑制肿瘤细胞的生长，具有良好的抗肿瘤活性。
表1化合物对肿瘤细胞4T1生长的抑制活性
表中：“A”指示IC50≤0.1μM，“B”指示IC50>0.1μM且≤0.5μM，“C”指示IC50>0.5μM且≤2μM，“D”指示IC50>2μM且≤10μM，“E”指示IC50值>10μM。
表2化合物对多种肿瘤细胞生长的抑制活性
实施例3：含二茂铁结构的化合物对铁死亡关键酶GPX4活性影响
研究显示，亲脂性抗氧化剂，如Ferrostatin-1(fer-1)，可以挽救细胞免于GPX4抑制诱导的铁死亡。间充质状态GPX4-基因敲除细胞可以在fer-1存在下存活，但在无fer-1存在时，这些细胞会发生铁死亡。另外，GPX4抑制剂诱发的铁死亡也可以被其他小分子物质阻断，如脂质ROS清除剂Liproxstatin、铁螯合剂DFO等。因此，GPX4抑制剂诱导铁死亡性癌细胞死亡的能力可以通过添加fer-1逆转进行指示。
细胞株：人急性髓性白血病纤维肉瘤细胞株HT1080；人肾癌细胞株OS-RC-2，购自中国科学院上海细胞库。
方法：MTT法，具体如下：取对数生长期细胞消化后计数，对照组以4000个/孔种于96孔板内，每孔90μl体积；实验组以4000个/孔种于96孔板内，每孔90μl体积，细胞悬液中添加终浓度为1.5μM Fer-1。96孔板置于37℃、5％CO2条件的培养箱中培养过夜后，对照组和实验组分别加入浓度合适的待筛选化合物或溶剂对照，每孔10μl，置于37℃、5％CO2条件的培养箱中培养72h。每孔加入20μl MTT溶液(5mg/ml)，置于37℃作用1-2h，弃掉上清，每孔加入100μl DMSO，震荡至Formazan充分溶解，用酶标仪于570nm处测定OD值。以下列公式计算药物对细胞生长的抑制率：存活率(％)＝OD实验/OD对照×100％，采用GraphPad Prism进行半数抑制浓度的计算(IC50)。
结果如表3和表4所示，本发明的部分化合物在fer-1存在的情况下抑制活性明显减弱，因此是一种有效的GPX4抑制剂。
表3对肿瘤细胞HT1080生长的抑制活性
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表4对肿瘤细胞OS-RC-2生长的抑制活性
以上实施例仅用以说明本发明的技术方案，而非对其进行限制；尽管参照前述实施例对本发明进行了详细的说明，对于本领域的普通技术人员来说，依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或替换，并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。
Claims (10)
1.一种含二茂铁结构的化合物，其特征在于，所述化合物的结构如式I、或者式II、或者式III所示：
式中，L选自直接键、C1-C6烷基或含1-3个独立取代基的C1-C6烷基、C2-C6烯基或含1-3个独立取代基的C2-C6烯基、(C0-C6烷基)-(C3-C6环烷基)-(C0-C6烷基)或含1-3个独立取代基的(C0-C6烷基)-(C3-C6环烷基)-(C0-C6烷基)、(C0-C6烷基)-Z-(C0-C6烷基)或含1-3个独立取代基的(C0-C6烷基)-Z-(C0-C6烷基)；其中，Z选自N(Ra)、-SO2-、OC(＝O)或者C(＝O)O；所述取代基选自C1-C6烷基、C1-C6烷氧基、C1-C6烷基、C3-C8环烷基、卤素、氨基、巯基、羟基、-CF3、-CN、-NO2、-NRaRb、-NRaCORb、-NRaCOORb、-NRaSO2Rb、-COORb、-CORb、-CONRaRb、-SO2Rb、-SO2NRaRb、-ORa和-OCORb；
M选自C1-C2卤烷基或含1-2个甲基取代的卤烷基、C2-C3烯基或含1-2个甲基取代的C2-C3卤基烯基、C2炔基或含1个甲基取代的C2炔基、-CH2OS(O)2-苯基或含1个甲基取代的苯基、或者4-硝基-5-烷基异噁唑；
X选自N、O、或者S；
R1、R2、R3、R4、R5和R6选自至少含有1个未取代或被1-3个取代基取代的二茂铁基团；所述取代基选自C1-C6烷基、C1-C6烷氧基、C1-C6烷基、杂环基、杂环基羰基、C1-C6烷基杂环基、C6-C10芳基、C3-C8环烷基、卤素、巯基、羟基、-CF3、-CN、-NO2、-NRaRb、-NRaCORb、-NRaCOORb、-NRaSO2Rb、-COORb、-CORb、-CONRaRb、-SO2Rb、-SO2NRaRb、-ORa、或者-OCORb，且NRaRb能够共同组成环胺；所述杂环包括1-3个选自N、O和S中的杂原子；
R7选自氢、卤素、羟基、巯基、-CF3、-CN、-NO2、或者未取代或被1-3个取代基取代的C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C3-C8环烷氧基、氨基、苯基、苄基、萘基、C5-C10芳香性杂环基或C3-C7饱和杂环基；所述取代基选自C1-C6烷基、C1-C6烷氧基C1-C6烷基、杂环基、杂环基羰基、C1-C6烷基杂环基、C6-C10芳基、C3-C8环烷基、卤素、巯基、羟基、-CF3、-CN、-NO2、-NRaRb、-NRaCORb、-NRaCOORb、-NRaSO2Rb、-COORb、-CORb、-CONRaRb、-SO2Rb、-SO2NRaRb、-ORa、或者-OCORb，且NRaRb能够共同组成环胺；所述杂环包括1-3个选自N、O和S中的杂原子；
Ra、Rb为R1、R2、R3、R4、R5、R6、R7中的一种。
2.根据权利要求1所述的含二茂铁结构的化合物，其特征在于，所述化合物具体为化合物I-1～I-29，其结构具体如下：
3.根据权利要求1所述的含二茂铁结构的化合物，其特征在于，所述化合物具体为化合物II-1～II-36，其结构具体如下：
4.根据权利要求1所述的含二茂铁结构的化合物，其特征在于，所述化合物具体为化合物III-1～III-10，其结构具体如下：
5.一种组合物，其特征在于，所述组合物作为GPX4抑制剂，其中包含权利要求1所述的含二茂铁结构的化合物。
6.权利要求1所述的化合物或者权利要求4所述的组合物在制备铁死亡诱导剂中的应用。
7.权利要求1所述的化合物或者权利要求4所述的组合物在制备抗肿瘤的药物中的应用。
8.根据权利要求7中的应用，其特征用于，所述肿瘤为铁死亡性肿瘤，具体包括乳腺癌、肺癌、胰腺癌、纤维肉瘤、肾癌、骨肉瘤、血液癌。
9.根据权利要求7中的应用，其特征用于，所述化合物通过抑制GPX4，来引发铁死亡，从而抑制肿瘤细胞的存活，达到抗肿瘤的作用。
10.根据权利要求7中的应用，其特征用于，所述药物中还添加有药物学上可接受的载体或助剂。
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| CN117462696A (zh) * | 2023-08-29 | 2024-01-30 | 东华大学 | 一种靶向中性粒细胞的纳米免疫药物及制备方法及应用 |
| CN118206706A (zh) * | 2024-05-17 | 2024-06-18 | 山东第二医科大学 | 一种利用和改善感染微环境实现杀菌的抗菌材料及其制备方法和应用 |
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| CN105111244A (zh) * | 2015-08-17 | 2015-12-02 | 铱诺(武汉)药业有限公司 | 二茂铁氧桥双环-[2．2．1]-庚烯类化合物 |
| US20160318964A1 (en) * | 2013-12-20 | 2016-11-03 | The University Of Birmingham | Novel ferrocenyl compounds |
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| US20160318964A1 (en) * | 2013-12-20 | 2016-11-03 | The University Of Birmingham | Novel ferrocenyl compounds |
| CN105111244A (zh) * | 2015-08-17 | 2015-12-02 | 铱诺(武汉)药业有限公司 | 二茂铁氧桥双环-[2．2．1]-庚烯类化合物 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117462696A (zh) * | 2023-08-29 | 2024-01-30 | 东华大学 | 一种靶向中性粒细胞的纳米免疫药物及制备方法及应用 |
| CN117462696B (zh) * | 2023-08-29 | 2024-05-03 | 东华大学 | 一种靶向中性粒细胞的纳米免疫药物及制备方法及应用 |
| CN118206706A (zh) * | 2024-05-17 | 2024-06-18 | 山东第二医科大学 | 一种利用和改善感染微环境实现杀菌的抗菌材料及其制备方法和应用 |
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