CN116478160A - 恶唑酮类苦参碱衍生物及其制备方法与应用 - Google Patents
恶唑酮类苦参碱衍生物及其制备方法与应用 Download PDFInfo
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- -1 Oxazolone matrine derivative Chemical class 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 4
- 229940079593 drug Drugs 0.000 claims abstract description 3
- 239000000543 intermediate Substances 0.000 claims description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 19
- ZSBXGIUJOOQZMP-JLNYLFASSA-N Matrine Chemical compound C1CC[C@H]2CN3C(=O)CCC[C@@H]3[C@@H]3[C@H]2N1CCC3 ZSBXGIUJOOQZMP-JLNYLFASSA-N 0.000 claims description 19
- 238000010992 reflux Methods 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- ZSBXGIUJOOQZMP-UHFFFAOYSA-N Isomatrine Natural products C1CCC2CN3C(=O)CCCC3C3C2N1CCC3 ZSBXGIUJOOQZMP-UHFFFAOYSA-N 0.000 claims description 16
- 229930014456 matrine Natural products 0.000 claims description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
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- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
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- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 4
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
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- CIJQGPVMMRXSQW-UHFFFAOYSA-M sodium;2-aminoacetic acid;hydroxide Chemical compound O.[Na+].NCC([O-])=O CIJQGPVMMRXSQW-UHFFFAOYSA-M 0.000 claims description 3
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- 238000000967 suction filtration Methods 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
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- 239000000843 powder Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
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- 229910052760 oxygen Inorganic materials 0.000 description 3
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- OAVCWZUKQIEFGG-UHFFFAOYSA-O 2-(5-methyl-2H-tetrazol-1-ium-1-yl)-1,3-thiazole Chemical compound CC1=NN=N[NH+]1C1=NC=CS1 OAVCWZUKQIEFGG-UHFFFAOYSA-O 0.000 description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- YXVRNKHCEGDYKT-UHFFFAOYSA-N COC(=O)Cl.C1=CC=CC=2C3=CC=CC=C3CC12 Chemical compound COC(=O)Cl.C1=CC=CC=2C3=CC=CC=C3CC12 YXVRNKHCEGDYKT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- HPNSNYBUADCFDR-UHFFFAOYSA-N chromafenozide Chemical compound CC1=CC(C)=CC(C(=O)N(NC(=O)C=2C(=C3CCCOC3=CC=2)C)C(C)(C)C)=C1 HPNSNYBUADCFDR-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/16—Peri-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明公开了一种恶唑酮类苦参碱衍生物及其制备方法与应用,属于化学医药技术领域。所述恶唑酮类苦参碱衍生物可以制备抗肿瘤药物,原料易得、操作简单、精简了合成步骤、反应条件温和、产物收率高,通过体外抗肿瘤活性研究,表明该类化合物是具有发展前景的抗肿瘤药物,该类化合物可使用于临床上肿瘤的治疗。
Description
技术领域
本发明属于医药化学技术领域,具体涉及一种恶唑酮类苦参碱衍生物及其制备方法与应用。
背景技术
癌症的危害不可小窥,世界各地都在努力与癌症作斗争,努力研发新的抗肿瘤药物,并取得了显著进展。
苦参碱(matrine)是从苦参、苦豆子等植物中分离得到的一类喹诺里西啶类生物碱,化学分子式为C15H24N2O,相对分子质量为248.58,在强碱性条件下可以水解开环生成苦参酸。苦参碱具有抗肿瘤、抗病毒、神经保护、杀虫等多种生物活性。苦参碱具有可药用优势,如特殊的化学骨架,灵活的结构,高溶解性和良好的安全性,使其成为一种较好的结构改造的前体,目前已有的改造包括苦参碱的C-13、C-14、C-15羰基的改造、D环的开环、形成离子配合物等。苦参碱结构如下:
在药物化学领域,含氮、硫和氧的杂环化合物家族在五元环和六元环结构中发挥着重要作用。恶唑酮是一种含氧和氮的五元杂环化合物。取代恶唑衍生物在药物开发中与多种生物活性和重要药效团有关,含有恶唑酮这种骨架结构的化合物具有广谱活性,如抗炎、抗凝血、抗肿瘤等。此外,研究表明,含有氮氧硫元素的苦参碱衍生物抗肿瘤活性会有一定程度的提升。
发明内容
本发明的目的在于克服现有技术的不足,提供一种恶唑酮类苦参碱衍生物及其制备方法与应用,所述恶唑酮类苦参碱衍生物具备较强抗肿瘤活性。
为实现上述目的,本发明提供了如下技术方案:
本发明技术方案之一:一种恶唑酮类苦参碱衍生物,具有如通式Ⅰ、通式Ⅱ或通式Ⅲ所示的结构:
通式Ⅰ中,R1=H、9-芴基甲氧基羰基(Fmoc)、对叔丁基苯磺酰基、叔丁氧羰基(Boc),R2=α-萘环、β-萘环、蒽环、3-吲哚基、N,N-二甲基苯基、3,5-二氯苯基、2-氯喹啉基;
通式Ⅱ中,R1=H、叔丁氧羰基,R2=N,N-二甲基苯基、3-吲哚基;
通式Ⅲ中,R1=H,R2=α-萘环、蒽环。
本发明技术方案之二:一种上述恶唑酮类苦参碱衍生物的制备方法,当制备具有通式Ⅰ、Ⅱ、Ⅲ结构的恶唑酮类苦参碱衍生物时,以苦参碱为起始原料,经过苦参碱D环酰胺键水解得到苦参酸钾盐,与MeOH/SOCl2反应得到苦参酸甲酯,再与R1Cl、K2CO3反应后酸化得到中间体;该中间体再与SOCl2反应得到酰氯,与甘氨酸在10%氢氧化钠溶液中反应,甘氨酸氨基上的孤对电子作为亲核试剂,攻击酰氯的羰基,生成醇酸中间体,中间体基团在失去氯的情况下重排生成N-乙酰甘氨酸,得到具有通式Ⅰ、Ⅱ、Ⅲ结构的恶唑酮类苦参碱衍生物,其化学反应式为:
制备方法包括以下步骤:
1)将苦参碱与氢氧化钾溶液混合,搅拌回流,反应结束后冷却至室温,调节至pH=7~8,抽滤,干燥,得到白色固体;将白色固体溶于甲醇,过滤,滤液减压浓缩后用丙酮沉淀,得到中间体1苦参酸钾盐,无须纯化直接用于下一步反应;所述中间体1的结构式如下:
2)将步骤1)得到的中间体1和SOCl2置于甲醇中,在氮气保护下回流,之后减压除去溶剂,得到中间体2苦参酸甲酯;所述中间体2的结构式如下:
3)将步骤2)得到的中间体2和K2CO3溶于无水乙腈中,并加入取代酰基、磺酰或卤化苄,搅拌反应;反应结束后过滤,滤液经浓缩,萃取,有机相干燥,得到残渣;残渣经洗脱,纯化得到中间体3;所述中间体3的结构式如下:其中,R1=9-芴基甲氧基羰基、对叔丁基苯磺酰基或叔丁氧羰基;
4)将步骤3)得到的中间体3置于HCl溶液中,回流,反应结束后冷却至室温,调节至pH=5~6,之后萃取,有机相干燥,得到残渣;残渣经洗脱,纯化得到中间体4;所述中间体4的结构式如下:
5)将步骤4)得到的中间体4溶于二氯甲烷中,并加入二氯亚砜和二甲基甲酰胺,反应结束后真空除去溶剂,得到中间体5;所述中间体5的结构式如下:
6)将步骤5)得到的中间体5分次加入甘氨酸的氢氧化钠溶液中,搅拌后冷却,酸化,得到白色固体,白色固体经洗涤,干燥,重结晶,得到中间体6;所述中间体6的结构式如下:
7)将步骤6)得到的中间体6与醛、无水乙酸钠、乙酸酐混合,回流反应,过滤,洗涤,重结晶,得到目标产物7,即所述具有通式Ⅰ、Ⅱ、Ⅲ结构的恶唑酮类苦参碱衍生物。
进一步地,当中间体6中的n=1时,目标产物7为具有通式Ⅰ结构的恶唑酮类苦参碱衍生物;当中间体6中的n=2时,目标产物7为具有通式Ⅱ结构的恶唑酮类苦参碱衍生物;当中间体6中的n=3时,目标产物7为具有通式Ⅲ结构的恶唑酮类苦参碱衍生物。
进一步地,步骤1)中,所述氢氧化钾溶液的质量分数为10%,所述苦参碱与氢氧化钾溶液的料液比为10mmol∶40mL;所述搅拌回流的温度为120℃,时间为8h;所述调节pH在冰浴条件下进行。
进一步地,步骤2)中,所述中间体1、SOCl2和甲醇的料液比为10mmol∶2.4mL∶30mL;所述回流的时间为3h。
进一步地,步骤3)中,所述中间体2、K2CO3、无水乙腈和酰基、磺酰或卤化苄的料液比为10mmol∶35mmol∶30mL∶10mmol;所述萃取的萃取剂为乙酸乙酯和水按体积比为2∶1混合;所述干燥的干燥剂为Na2SO4;所述洗脱的洗脱剂为CH2Cl2和CH3OH按体积比为40∶1混合;所述纯化为硅胶柱层析纯化。
进一步地,步骤4)中所述HCl溶液的浓度为3mol/L,所述中间体3和HCl溶液的料液比为10mmol∶20mL;所述回流的温度为70℃,时间为3h;所述萃取的萃取剂为乙酸乙酯和水按体积比为2∶1混合;所述干燥的干燥剂为Na2SO4;所述洗脱的洗脱剂为CH2Cl2和CH3OH按体积比为40∶1混合;所述纯化为硅胶柱层析纯化。
进一步地,步骤5)中,所述中间体4、二氯甲烷、二氯亚砜和二甲基甲酰胺的料液比为50mmol∶50mL∶75mmol∶0.05mmol;所述反应的时间为1h。
进一步地,步骤6)中,所述甘氨酸的氢氧化钠溶液的制备方法为:将10mmol甘氨酸溶解于30mL质量分数为10%的NaOH溶液中;所述甘氨酸与中间体5的质量比为1∶2;所述搅拌的时间为1h;所述重结晶是从乙醇中重结晶。
进一步地,步骤7)中,所述中间体6、醛、无水乙酸钠和乙酸酐的料液比为10mmol∶20mmol∶10mmol∶30mmol;所述回流反应的时间为2h,温度为95~100℃;所述重结晶是从乙醇中重结晶。
本发明技术方案之三:上述恶唑酮类苦参碱衍生物在制备肝癌、肺癌、宫颈癌和乳腺癌药物中的应用。
与现有技术相比,本发明具有以下有益效果:
本发明恶唑酮类苦参碱衍生物的制备方法,反应原料易得、操作简单、反应条件温和且产物收率高。通过实验表明本发明的恶唑酮类苦参碱衍生物对多种癌细胞增殖具有较强的抑制作用,该类化合物可使用于临床上肿瘤的治疗。
具体实施方式
现详细说明本发明的多种示例性实施方式,该详细说明不应认为是对本发明的限制,而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。应理解本发明中所述的术语仅仅是为描述特别的实施方式,并非用于限制本发明。
另外,对于本发明中的数值范围,应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明,否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料,但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入,用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时,以本说明书的内容为准。
在不背离本发明的范围或精神的情况下,可对本发明说明书的具体实施方式做多种改进和变化,这对本领域技术人员而言是显而易见的。由本发明的说明书得到的其他实施方式对技术人员而言是显而易见的。本发明说明书和实施例仅是示例性的。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等,均为开放性的用语,即意指包含但不限于。
以下实施例中,所述室温为25±2℃。
以下实施例中,恶唑酮类苦参碱衍生物的设计如下:
实施例1
目标化合物G1的制备:
1)将10mmol苦参碱置于250mL烧瓶中,并加入40mL质量分数为10%的KOH溶液,于120℃下搅拌回流8h;反应结束后冷却至室温,冰浴条件下滴加质量分数为20%的H2SO4调节至pH=7,真空抽滤,干燥,得到白色固体;将白色固体溶于甲醇中,过滤,滤液减压浓缩后用丙酮沉淀,得到中间体1苦参酸钾盐,无须纯化直接用于下一步反应;
2)将10mmol步骤1)得到的中间体1和2.4mL SOCl2置于30mL甲醇中,在氮气保护下回流3h,之后减压除去溶剂,得到中间体2苦参酸甲酯;
3)将10mmol步骤2)得到中间体2和35mmol K2CO3溶于30mL无水乙腈中,并加入10mmol芴甲氧羰酰氯,室温下搅拌过夜;TLC监测反应完全后过滤,滤液经浓缩,乙酸乙酯-水萃取(乙酸乙酯∶水=2∶1(v∶v)),Na2SO4干燥乙酸乙酯相,得到残渣;残渣经CH2Cl2∶CH3OH=40∶1(v∶v)的洗脱剂洗脱,硅胶柱层析纯化,得到中间体3;
4)将10mmol步骤3)得到的中间体3置于20mL 3mol/L的HCl溶液中,70℃下回流3h;反应结束后冷却至室温,滴加3mol/L的KOH溶液调节至pH=5,之后乙酸乙酯-水萃取(乙酸乙酯∶水=2∶1(v∶v)),Na2SO4干燥乙酸乙酯相,得到残渣;残渣经CH2Cl2∶CH3OH=40∶1(v∶v)的洗脱剂洗脱,硅胶柱层析纯化,得到中间体4;
5)将50mmol步骤4)得到的中间体4溶于50mL无水DCM(二氯甲烷)中,并缓慢加入75mmol 1.5eq二氯亚砜和0.05mmol二甲基甲酰胺,室温搅拌反应1h,真空除去溶剂,得到中间体5;
6)将10mmol甘氨酸溶解于30mL质量分数为10%的NaOH溶液中,得到甘氨酸的氢氧化钠溶液,之后将20mmol的步骤5)得到的中间体5分次与甘氨酸的氢氧化钠溶液混合,连续搅拌1h;之后加入碎冰使溶液冷却并加入15mL质量分数为30%的盐酸酸化,过滤,得到白色固体,白色固体经冰水冲洗,干燥,从乙醇中重结晶,得到中间体6;
7)将10mmol步骤6)得到的中间体6与20mmolα-萘甲醛、10mmol无水乙酸钠、30mmol乙酸酐混合,于98℃下回流反应2h,过滤,洗涤,从乙醇中重结晶,得到目标产物7;经计算,目标产物7(G1)的产率为78%。
G1-Chemical Formula:C43H43N3O4
淡黄色粉末,收率65%,1H NMR(500MHz,CDCl3)δ8.19(dd,1H),8.03(s,1H),7.97(tt,1H),7.94–7.86(m,5H),7.71(ddd,1H),7.64(dd,2H),7.45(ddd,1H),7.34(ddd,2H),7.24(ddd,2H),5.00(d,2H),4.02(dd,1H),3.63(t,1H),3.42(m,J=33.0Hz,2H),2.59(m,J=17.7Hz,2H),2.32(t,2H),2.18(m,J=17.2Hz,3H),2.04(t,1H),1.82(m,J=5.9Hz,2H),1.67–1.52(m,6H),1.42(m,J=8.2Hz,4H),1.27(m,1H).13C NMR(126MHz,CDCl3)δ174.13(s),169.48(s),155.79(s),154.55(s),147.49(s),145.84(s),144.35(d,J=17.5Hz),143.32(s),141.53(d,J=15.0Hz),140.11(s),139.41(s),139.03(s),137.99(s),137.25(s),134.71(s),134.12(s),129.08(s),128.73(s),127.16–126.98(s),124.30(s),120.99(s),120.32(s),119.72(s),117.76(s),107.78(s),63.65(d,J=26.7Hz),57.20(d,J=8.6Hz),53.15(s),43.18(s),41.43(s),35.31(s),32.79(s),27.71(s),27.11(s),26.40(s),21.06(d,J=14.2Hz),20.70(s),18.93(s).m/z:665.3912(M+1)。
参考化合物G1的制备方法制备化合物G2~G15,G2~G15的结构鉴定数据如下:
G2-Chemical Formula:C43H43N3O4
红棕色粉末,收率66%。1H NMR(500MHz,CDCl3)δ7.88(dd,2H),7.84–7.80(m,3H),7.76(m,J=10.0Hz,2H),7.67(dd,2H),7.65(s,1H),7.49(dd,1H),7.43(ddd,1H),7.32(ddd,2H),7.22(ddd,2H),4.79(d,2H),4.10(dd,1H),3.54(t,1H),3.31(dd,J=18.0Hz,2H),2.59(m,J=15.9Hz,2H),2.32(m,2H),2.27–2.09(m,3H),2.03(t,1H),1.83(m,J=23.5Hz,2H),1.68–1.57(m,5H),1.53(m,3H),1.41(m,J=11.0Hz,2H),1.31(m,1H).13C NMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ167.79(s),167.35(s),157.50(s),144.14(s),139.48(s),135.23(s),134.90(d,J=5.7Hz),131.00(s),129.77(d,J=12.3Hz),127.81(s),127.63(s),127.36(s),126.65(d,J=4.1Hz),126.28(s),125.95(s),125.14(s),121.89(s),120.96(s),67.50(s),64.79(s),55.58(s),53.09(s),48.11(s),46.35(s),40.68(s),36.68(s),30.86(s),28.37(d,J=6.9Hz),26.39(s),23.42(s),23.23(s),21.39(s).m/z:665.4532(M+1)。
G3-Chemical Formula:C47H45N3O4
淡黄色粉末,收率58%。1H NMR(500MHz,CDCl3)δ8.64(t,1H),8.32(m,2H),8.20(s,1H),8.00(m,2H),7.90(dd,2H),7.47(m,J=15.0Hz,4H),7.34(ddd,2H),7.24(ddd,2H),7.11(dd,2H),5.06(d,2H),3.84(dd,1H),3.70(q,1H),3.34–3.13(m,2H),2.64(m,J=18.1Hz,2H),2.32(t,2H),2.28–2.11(m,3H),2.06(q,J=16.4Hz,2H),1.85(m,J=57.1Hz,2H),1.62(m,2H),1.53(m,J=1.2Hz,4H),1.43(m,2H),1.37(m,J=9.8Hz,2H).13C NMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ170.10(s),167.35(s),157.50(s),144.14(s),139.48(s),132.79(d,J=14.7Hz),129.20(s),128.35(d,J=9.3Hz),127.63(s),126.86(s),126.28(s),125.90(s),125.69(s),125.14(s),120.96(s),120.42(s),119.38(s),67.50(s),64.79(s),55.58(s),53.09(s),48.11(s),46.35(s),40.68(s),36.68(s),30.86(s),28.37(d,J=6.9Hz),26.39(s),23.42(s),23.23(s),21.39(s).m/z:715.3341(M+1)。
G4-Chemical Formula:C39H39Cl2N3O4
淡黄色粉末,收率70%。1H NMR(500MHz,CDCl3)δ7.89(dd,2H),7.71(t,1H),7.45(d,2H),7.40(ddd,2H),7.34(dd,2H),7.24(ddd,2H),7.04(s,1H),5.10(d,2H),4.40(dd,1H),3.91(t,1H),3.29(dd,1H),2.95(q,1H),2.64(m,J=2.2Hz,2H),2.39–2.16(m,5H),2.04(t,1H),1.89(m,J=45.5Hz,2H),1.76–1.59(m,5H),1.48(m,J=50.0Hz,4H),1.38(m,J=35.5Hz,2H).13C NMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ167.79(s),167.35(s),157.50(s),144.14(s),139.48(s),136.08(s),134.84(s),134.00(s),127.85(s),127.63(s),126.49(s),126.28(s),125.14(s),122.00(s),120.96(s),67.50(s),64.79(s),55.58(s),53.09(s),48.11(s),46.35(s),40.68(s),36.68(s),30.86(s),28.37(d,J=6.9Hz),26.39(s),23.42(s),23.23(s),21.39(s).m/z:683.4344(M+1)。
G5-Chemical Formula:C42H43ClN4O4
淡黄色粉末,收率73%。1H NMR(500MHz,DMSO)δ7.88(dd,2H),7.56(ddd,2H),7.32(ddt,J=3.5Hz,3H),7.26–7.21(m,4H),7.19(m,1H),7.04(m,1H),5.25(d,2H),4.43(dd,1H),4.05(q,1H),3.80(t,1H),3.37(dd,1H),2.91(q,1H),2.63(m,J=7.0Hz,2H),2.46(dd,1H),2.36–2.18(m,5H),2.08(m,J=48.6Hz,2H),1.89(m,J=30.7Hz,2H),1.66(m,J=4.4Hz,4H),1.53(m,2H),1.43(m,J=3.0Hz,3H),1.33(m,2H).13C NMR(125MHz,DMSO)δ173.10(s),166.62(s),157.50(s),144.14(s),140.01(s),139.48(s),136.87(s),129.04(s),128.64(s),127.63(s),126.89(s),126.28(s),125.70(s),125.14(s),123.14(s),121.69(s),120.96(s),67.50(s),64.79(s),55.58(s),53.09(s),48.11(s),46.35(s),40.74(d,J=16.0Hz),36.68(s),36.02(s),30.86(s),28.37(d,J=6.9Hz),26.39(s),23.42(s),23.23(s),21.39(s).m/z:702.8647(M+1)。
G6-Chemical Formula:C41H46N4O4
红棕色油状物,收率74%。1H NMR(500MHz,CDCl3)δ7.91(m,J=10.0Hz,4H),7.57(dd,2H),7.34(ddd,2H),7.27(s,1H),7.24dd,2H),6.99(tt,2H),5.43(d,2H),4.00(t,1H),3.83(m,1H),3.51(dd,1H),3.20(m,1H),3.02(s,6H),2.62(m,J=3.9Hz,2H),2.37–2.14(m,4H),2.06(m,J=24.5Hz,2H),1.85(m,J=47.1Hz,2H),1.63(m,J=12.7Hz,5H),1.48(m,J=50.0Hz,4H),1.35(m,J=28.4Hz,2H).13C NMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ167.79(s),167.35(s),157.50(s),152.56(s),144.14(s),139.48(s),134.16(s),129.62(s),127.63(s),126.28(s),125.14(s),122.86(d,J=4.8Hz),120.96(s),113.39(s),67.50(s),64.79(s),55.58(s),53.09(s),48.11(s),46.35(s),41.92(s),40.68(s),36.68(s),30.86(s),28.37(d,J=6.9Hz),26.39(s),23.42(s),23.23(s),21.39(s).m/z:658.2937(M+1)。
G7-Chemical Formula:C33H41N3O4
白色粉末,收率66%。1H NMR(500MHz,CDCl3)δ8.18(dd,1H),7.96(tt,1H),7.90(m,J=6.0,4.0Hz,4H),7.70(ddd,1H),7.44(ddd,1H),,4.02(dd,1H),3.32(m,J=4.8Hz,2H),2.62(m,J=3.6Hz,2H),2.32(q,2H),2.23(m,J=0.7Hz,2H),2.07(m,J=34.4Hz,2H),1.85(m,J=33.1Hz,2H),1.66(m,1H),1.61(m,J=7.0Hz,4H),1.53(t,2H),1.50–1.44(m,2H),1.42(s,9H),1.36(m,J=32.7Hz,2H).13CNMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ167.79(s),167.35(s),157.27(s),135.12(d,J=16.3Hz),133.47(s),130.39(s),128.84(s),128.44(s),127.83(s),126.77(d,J=19.9Hz),126.35(s),126.09(s),122.46(s),81.20(s),64.79(s),55.58(s),53.09(s),46.35(s),40.68(s),36.68(s),30.86(s),28.36(t,J=4.0Hz),26.39(s),23.42(s),23.23(s),21.39(s).m/z:543.2743(M+1)。
G8-Chemical Formula:C26H32N4O2
红棕色油状物,收率69%。1H NMR(500MHz,CDCl3)δ8.10(s,1H),7.78(s,1H),7.65(dd,1H),7.62(s,1H),7.19(m,1H),7.11(d,1H),7.08(q,1H),3.05(dd,1H),2.60(m,J=24.1Hz,3H),2.32(t,2H),2.23(m,J=10.0Hz,2H),2.09(m,1H),2.04(d,1H),1.92–1.73(m,3H),1.72–1.50(m,6H),1.49(s,1H),1.46(m,J=25.4Hz,3H),1.37(m,J=12.8Hz,2H).13CNMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ173.50(s),167.84(s),135.68(s),132.78(s),129.22(s),127.16(s),122.80(s),120.35(d,J=9.1Hz),119.96(s),112.56(s),107.91(s),65.58(s),57.82(s),53.09(s),48.20(s),41.73(s),35.91(s),32.21(s),28.41(d,J=16.6Hz),26.47(s),23.42(s),23.23(s),20.44(s).m/z:432.2810(M+1)。
G9-Chemical Formula:C28H33N3O2
淡黄色油状物,收率79%。1H NMR(500MHz,CDCl3)δ8.19(dd,1H),7.97(tt,1H),7.94(s,1H),7.92(m,3H),7.90(ddd,J=5.0Hz,1H),7.71(ddd,1H),2.84(dd,1H),2.58(m,J=10.5Hz,2H),2.39(t,1H),2.32(q,2H),2.27–2.12(m,3H),2.04(t,1H),1.72(m,J=16.8Hz,3H),1.51(m,J=12.3Hz,6H),1.45–1.32(m,4H),1.31(s,1H),1.18(m,1H).13C NMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ170.10(s),167.35(s),135.12(d,J=16.3Hz),133.47(s),130.39(s),128.84(s),128.44(s),127.83(s),126.77(d,J=19.9Hz),126.35(s),126.09(s),122.46(s),65.58(s),57.82(s),53.09(s),48.20(s),41.73(s),35.91(s),32.21(s),28.41(d,J=16.6Hz),26.47(s),23.42(s),23.23(s),20.44(s).m/z:443.2460(M+1)。
G10-Chemical Formula:C38H45N3O4S
淡黄色油状物,收率72%。1H NMR(500MHz,CDCl3)δ8.19(dd,1H),7.99(s,1H),7.97(t,1H),7.94–7.87(m,3H),7.71(dd,1H),7.63(m,J=15.0Hz,4H),7.45(ddd,1H),3.29(dd,1H),2.91(dd,1H),2.52(m,J=14.6Hz,3H),2.37(m,J=43.8Hz,4H),1.82(m,J=40.9Hz,2H),1.69(m,2H),1.63–1.52(m,4H),1.52–1.42(m,5H),1.35(m,1H),1.33(s,9H),1.30(m,1H).13C NMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ167.79(s),167.35(s),154.65(s),135.37–134.95(m),133.47(s),130.39(s),128.85(d,J=2.5Hz),128.41(d,J=6.3Hz),127.83(s),126.77(d,J=19.9Hz),126.35(s),126.09(s),122.46(s),64.79(s),60.40(s),53.09(s),49.16(s),40.89(s),35.99(s),34.94(s),31.36(s),29.04(s),28.37(d,J=6.9Hz),26.39(s),23.42(s),23.23(s),21.39(s).m/z:639.4935(M+1)。
G11-Chemical Formula:C36H44N4O4S
淡黄色油状物,收率69%。1H NMR(500MHz,CDCl3)δ8.25(s,1H),7.89(s,1H),7.78(s,1H),7.64(m,J=15.0Hz,5H),7.19(ddd,1H),7.10(ddd,J=15.0Hz,2H),3.89(dd,1H),3.33(dd,1H),3.08(q,1H),2.55(m,J=1.2Hz,2H),2.32(t,2H),2.17(m,J=2.7Hz,2H),1.80(m,J=6.4Hz,2H),1.67(t,J=7.0Hz,1H),1.57(m,2H),1.51(m,J=19.3Hz,4H),1.43(m,3H),1.38(m,2H),1.33(d,J=2.5Hz,9H),1.32–1.25(m,1H).13C NMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ173.10(s),167.84(s),154.65(s),135.68(s),135.26(s),132.78(s),129.22(s),128.86(s),128.39(s),127.16(s),122.80(s),120.35(d,J=9.1Hz),119.96(s),112.56(s),107.91(s),64.79(s),60.40(s),53.09(s),49.16(s),40.89(s),35.99(s),34.94(s),31.36(s),29.04(s),28.37(d,J=6.9Hz),26.39(s),23.42(s),23.23(s),21.39(s).m/z:628.2868(M+1)。
G12-Chemical Formula:C32H46N4O4
白色粉末,收率77%。1H NMR(500MHz,CDCl3)δ7.63(d,2H),6.78(d,2H),5.64(t,1H),4.27(dd,1H),3.20(tt,J=14.9Hz,3H),3.02(s,6H),2.77(q,1H),2.62(m,J=1.8Hz,2H),2.34–2.20(m,4H),2.09(m,J=50.7Hz,2H),1.87(m,J=52.5Hz,2H),1.64(m,J=10.4Hz,5H),1.53(m,4H),1.42(s,9H),1.35(m,J=38.0Hz,2H).13C NMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ168.80(s),164.68(s),157.27(s),150.44(s),137.80(s),130.00(s),123.11(s),117.40(s),112.85(s),81.20(s),64.79(s),55.58(s),53.09(s),46.35(s),41.92(s),40.68(s),36.68(s),35.49(s),34.17(s),30.86(s),28.37(d,J=7.9Hz),26.39(s),23.42(s),23.23(s),21.39(s).m/z:550.3976(M+1)。
G13-Chemical Formula:C27H34N4O2
淡黄色油状物,收率65%。1H NMR(500MHz,CDCl3)δ8.39(s,1H),7.97(tt,1H),7.59(dd,1H),7.09(ddd,1H),6.97(ddd,1H),6.46(d,1H),6.21(t,1H),3.53(s,2H),3.01(dd,1H),2.67–2.39(m,3H),2.33–2.14(m,5H),2.04(t,1H),1.92–1.67(m,4H),1.66(s,J=0.6Hz,1H),1.54(m,J=12.6Hz,3H),1.45(m,J=25.5Hz,5H),1.31(m,J=53.7Hz,2H).13CNMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ168.80(s),162.49(s),138.07(s),136.55(s),132.45(s),127.64(s),121.59(d,J=1.5Hz),120.36(s),111.82(s),110.22(s),105.60(s),65.58(s),57.82(s),53.09(s),48.20(s),41.73(s),35.91(s),34.72(s),34.17(s),32.21(s),28.48(s),26.47(s),23.42(s),23.23(s),20.44(s).m/z:446.2595(M+1)。
G14-Chemical Formula:C34H39N3O2
淡黄色油状物,收率71%。1H NMR(500MHz,CDCl3)δ8.35(t,1H),8.28(m,2H),7.96(m,2H),7.44(m,J=14.9Hz,4H),6.75(t,1H),2.91(dd,1H),2.73–2.54(m,4H),2.48–2.33(m,5H),2.23(m,J=3.7Hz,2H),2.03(t,1H),1.85–1.61(m,3H),1.58–1.42(m,6H),1.41–1.21(m,5H),1.13(s,1H),1.11(m,1H).13C NMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ172.80(s),158.51(s),132.73(s),131.32(s),129.20(s),128.39(s),126.86(s),125.90(s),125.69(s),120.96(s),118.96(s),65.58(s),57.82(s),53.09(s),48.20(s),41.73(s),35.91(s),33.59(s),32.72(s),32.21(s),28.68(s),28.48(s),26.47(s),23.42(s),23.23(s),20.44(s).m/z:521.3733(M+1)。
G15-Chemical Formula:C30H37N3O2
黄褐色油状物,收率71%。1H NMR(500MHz,CDCl3)δ7.92(m,1H),7.90(m,J=5.0Hz,2H),7.75–7.65(m,3H),7.45(ddd,1H),6.34(t,1H),2.98(dd,1H),2.55(q,J=38.3Hz,3H),2.45(m,4H),2.43–2.36(m,4H),2.04(s,1H),1.84–1.65(m,3H),1.53(m,J=0.9Hz,4H),1.48–1.34(m,6H),1.20-109(m,J=1.0Hz,3H).13CNMR(126MHz,CDCl3)δ176.15(s),174.30(s),167.71(s),154.82(s),132.27(s),130.91(s),128.81(s),65.56(s),55.21(s),43.30(s),42.92(s),35.34(s),30.54(s),29.63(d,J=9.5Hz),25.55(s),25.02(s),22.21(s),19.16(s),14.72(s),13.71(s).δ172.80(s),158.51(s),135.42(s),135.18(s),133.47(s),129.20(s),128.84(s),127.83(s),126.78(s),126.35(s),126.09(s),125.05(s),123.32(s),65.58(s),57.82(s),53.09(s),48.20(s),41.73(s),35.91(s),33.59(s),32.72(s),32.21(s),28.68(s),28.48(s),26.47(s),23.42(s),23.23(s),20.44(s).m/z:471.1596(M+1)。
表1给出了恶唑酮类苦参碱衍生物的结构式。
表1恶唑酮类苦参碱衍生物的结构式
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实施例2
研究制备的恶唑酮类苦参碱衍生物的体外抗肿瘤活性,肿瘤细胞为肝癌细胞HepG2、肺癌细胞A549、宫颈癌细胞Hela、乳腺癌细胞MCF-7,均通过购买得到。
实验方法:取癌细胞株,复苏细胞并进行传代培养,24h后长至对数生长期,胰酶消化细胞,制成细胞悬液。以每孔100μL接种到96孔板中,设空白组、对照组以及给样组,每组设3个平行孔。将96孔细胞培养板至于37℃、5%CO2培养箱培养24h,吸出培养液,加入不同梯度化合物(将恶唑酮类苦参碱衍生物用二甲基亚砜(DMSO)溶解后用培养基稀释成所需溶液浓度)作用48h。每个孔加入10uL,5mg/mL MTT,培养箱孵育4h,弃上清液,加入100uLDMSO,振荡混匀,用酶标仪在490nm处测试每孔的吸收度,计算细胞抑制率。
上述实验重复3次,并且Blies法计算出IC50值。
实验结果:
表2目标化合物对HepG2细胞、A549细胞、Hela细胞和MCF-7细胞增殖的抑制
实验数据表明,合成的系列苦参碱衍生物大部分具有良好的抗肿瘤活性,在以苦参碱为对照药,与合成的目标化合物给药的情况下,对比它们的抑制率发现,化合物中的G4、G5、G6、G11对肿瘤细胞有较强的抑制作用,具有高效的抗肿瘤抑制活性。
以上,仅为本申请较佳的具体实施方式,但本申请的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本申请揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本申请的保护范围之内。因此,本申请的保护范围应该以权利要求的保护范围为准。
Claims (10)
1.一种恶唑酮类苦参碱衍生物,其特征在于,具有如通式Ⅰ、通式Ⅱ或通式Ⅲ所示的结构:
通式Ⅰ中,R1=H、9-芴基甲氧基羰基、对叔丁基苯磺酰基、叔丁氧羰基,R2=α-萘环、β-萘环、蒽环、3-吲哚基、N,N-二甲基苯基、3,5-二氯苯基、2-氯喹啉基;
通式Ⅱ中,R1=H、叔丁氧羰基,R2=N,N-二甲基苯基、3-吲哚基;
通式Ⅲ中,R1=H,R2=α-萘环、蒽环。
2.一种权利要求1所述恶唑酮类苦参碱衍生物的制备方法,其特征在于,具有通式Ⅰ、Ⅱ、Ⅲ结构的恶唑酮类苦参碱衍生物的制备方法,包括以下步骤:
1)将苦参碱与氢氧化钾溶液混合,搅拌回流,反应结束后冷却至室温,调节至pH=7~8,抽滤,干燥,得到白色固体;将白色固体溶于甲醇,过滤,滤液减压浓缩后用丙酮沉淀,得到中间体1苦参酸钾盐,无须纯化直接用于下一步反应;所述中间体1的结构式如下:
2)将步骤1)得到的中间体1和SOCl2置于甲醇中,在氮气保护下回流,之后减压除去溶剂,得到中间体2苦参酸甲酯;所述中间体2的结构式如下:
3)将所述中间体2和K2CO3溶于无水乙腈中,并加入取代酰基、磺酰或卤化苄,搅拌反应;反应结束后过滤,滤液经浓缩,萃取,有机相干燥,得到残渣;残渣经洗脱,纯化得到中间体3;所述中间体3的结构式如下:其中,R1=9-芴基甲氧基羰基、对叔丁基苯磺酰基或叔丁氧羰基;
4)将所述中间体3置于HCl溶液中,回流,反应结束后冷却至室温,调节至pH=5~6,之后萃取,有机相干燥,得到残渣;残渣经洗脱,纯化得到中间体4;所述中间体4的结构式如下:
5)将所述中间体4溶于二氯甲烷中,并加入二氯亚砜和二甲基甲酰胺,反应结束后真空除去溶剂,得到中间体5;所述中间体5的结构式如下:
6)将所述中间体5分次加入甘氨酸的氢氧化钠溶液中,搅拌后冷却,酸化,得到白色固体,白色固体经洗涤,干燥,重结晶,得到中间体6;所述中间体6的结构式如下:其中,n=1、2或3;
7)将所述中间体6与醛、无水乙酸钠、乙酸酐混合,回流反应,过滤,洗涤,重结晶,得到目标产物7,即所述具有通式Ⅰ、Ⅱ、Ⅲ结构的恶唑酮类苦参碱衍生物。
3.根据权利要求2所述的制备方法,其特征在于,步骤1)中,所述氢氧化钾溶液的质量分数为10%,所述苦参碱与氢氧化钾溶液的料液比为10mmol∶40mL;所述搅拌回流的温度为120℃,时间为8h;所述调节pH在冰浴条件下进行。
4.根据权利要求2所述的制备方法,其特征在于,步骤2)中,所述中间体1、SOCl2和甲醇的料液比为10mmol∶2.4mL∶30mL;所述回流的时间为3h。
5.根据权利要求2所述的制备方法,其特征在于,步骤3)中,所述中间体2、K2CO3、无水乙腈和取代酰基、磺酰或卤化苄的料液比为10mmol∶35mmol∶30mL∶10mmol;所述萃取的萃取剂为乙酸乙酯和水按体积比为2∶1混合;所述干燥的干燥剂为Na2SO4;所述洗脱的洗脱剂为CH2Cl2和CH3OH按体积比为40∶1混合;所述纯化为硅胶柱层析纯化。
6.根据权利要求2所述的制备方法,其特征在于,步骤4)中所述HCl溶液的浓度为3mol/L,所述中间体3和HCl溶液的料液比为10mmol∶20mL;所述回流的温度为70℃,时间为3h;所述萃取的萃取剂为乙酸乙酯和水按体积比为2∶1混合;所述干燥的干燥剂为Na2SO4;所述洗脱的洗脱剂为CH2Cl2和CH3OH按体积比为40∶1混合;所述纯化为硅胶柱层析纯化。
7.根据权利要求2所述的制备方法,其特征在于,步骤5)中,所述中间体4、二氯甲烷、二氯亚砜和二甲基甲酰胺的料液比为50mmol∶50mL∶75mmol∶0.05mmol;所述反应的时间为1h。
8.根据权利要求2所述的制备方法,其特征在于,步骤6)中,所述甘氨酸的氢氧化钠溶液的制备方法为:将10mmol甘氨酸溶解于30mL质量分数为10%的NaOH溶液中;所述甘氨酸与中间体5的质量比为1∶2;所述搅拌的时间为1h;所述重结晶是从乙醇中重结晶。
9.根据权利要求2所述的制备方法,其特征在于,步骤7)中,所述中间体6、醛、无水乙酸钠和乙酸酐的料液比为10mmol∶20mmol∶10mmol∶30mmol;所述回流反应的时间为2h,温度为95~100℃;所述重结晶是从乙醇中重结晶。
10.权利要求1所述恶唑酮类苦参碱衍生物在制备肝癌、肺癌、宫颈癌和乳腺癌药物中的应用。
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