CN116354959A - 一种N-N桥连噻唑单元的β-咔啉衍生物及其制备方法、应用 - Google Patents
一种N-N桥连噻唑单元的β-咔啉衍生物及其制备方法、应用 Download PDFInfo
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- CN116354959A CN116354959A CN202310228786.1A CN202310228786A CN116354959A CN 116354959 A CN116354959 A CN 116354959A CN 202310228786 A CN202310228786 A CN 202310228786A CN 116354959 A CN116354959 A CN 116354959A
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- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 9
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 9
- -1 4-phenyl-2- (((E) - (9-methyl- β -carbolin-3-yl) methylene) hydrazino) -2, 3-dihydrothiazole Chemical compound 0.000 claims description 147
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- 238000006243 chemical reaction Methods 0.000 claims description 47
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- 238000000034 method Methods 0.000 claims description 36
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- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
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- 238000001308 synthesis method Methods 0.000 claims description 4
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- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004344 phenylpropyl group Chemical group 0.000 claims description 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 150000007979 thiazole derivatives Chemical class 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000012544 monitoring process Methods 0.000 description 8
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- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
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Classifications
-
- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明为一种N‑N桥连噻唑单元的β‑咔啉衍生物及其制备方法、应用。本发明公开了一类新的化合物—N‑N桥连噻唑单元的β‑咔啉衍生物,及N‑N桥连噻唑单元的β‑咔啉衍生物的制备方法、在制备抗肿瘤药物中的应用。本发明的N‑N桥连噻唑单元的β‑咔啉衍生物为一种新的化合物,是将β‑咔啉与噻唑衍生物连接得到,具有较好的抗肿瘤活性,可应用于抗肿瘤药物中。
Description
技术领域
本发明属于医药化学领域,具体涉及一种N-N桥连噻唑单元的β-咔啉衍生物及其制备方法、应用。
背景技术
β-咔啉衍生物是一大类天然和合成的吲哚生物碱,具有广泛的生物化学和药理学性质,如抗焦虑、抗抑郁、镇静、止痛以及抗肿瘤、抗疟疾等。近些年,现有技术研究了在β-咔啉的1、2、3、7和9位具有不同取代基的β-咔啉衍生物的体外和体内制备及其抗肿瘤活性,构效关系表明:(1)β-咔啉部分的抗肿瘤活性在药物设计中非常重要;(2)在β-咔啉的1、3和9位(如下所示)引入合适的取代基可以进一步增强它们的抗肿瘤功效。
杂环化合物是具有出色的生物学和药理特性的一类常见且重要的有机化合物。在许多含氮杂环化合物中,噻唑环是一种具有广泛生物活性的特殊结构,它在临床研究中也有广泛的用途,除了低细胞毒性外,它还具有抗真菌特性和抗增殖活性,前期研究发现C2-位和C4-位取代的1,3-噻唑具有非凡的抗肿瘤和免疫调节活性。
有鉴于此,本发明提出一种新的β-咔啉衍生物——N-N桥连噻唑单元的β-咔啉衍生物,对于抗肿瘤药物的合成及发现具有重要的意义。
发明内容
本发明的目的在于提供一种N-N桥连噻唑单元的β-咔啉衍生物,其是一种结构新颖的β-咔啉衍生物,对于抗肿瘤药物的合成及发现具有重要的意义。
为了实现上述目的,所采用的技术方案为:
一种N-N桥连噻唑单元的β-咔啉衍生物,其化学结构通式为:
进一步的,所述的β-咔啉衍生物的化学结构通式中,R1为氢、甲基、异丙基、2-氯苯基中的一种;
R3为苯基、4-氟苯基、4-甲氧基苯基、4-溴苯基、3-溴苯基中的一种;
R9为氢、甲基、正丁基、异丁基、苄基、4-氟苄基、3-氯苄基、苯丙基中的一种。
再进一步的,所述的β-咔啉衍生物,为下列任一化合物:
4-苯基-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑:
4-(4-甲氧基苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(3-溴苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-甲氧基苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(3-溴苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-甲氧基苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(3-溴苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-甲氧基苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-甲氧基苯基)-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-甲氧基苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(3-溴苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
本发明的另一个目的在于提供上述的β-咔啉衍生物的制备方法,通过亲核加成-缩合反应将β-咔啉与噻唑衍生物连接,得到了一系列新颖结构的β-咔啉衍生物。且该制备方法具有较好的收率。
为了实现上述目的,所采用的技术方案为:
上述的β-咔啉衍生物的制备方法,所述的制备方法的化学反应式为:
进一步的,(1)向相应的1-取代-9-取代-3-甲酰基-β-咔啉、氨基硫脲中加入无水乙醇,95℃加热回流,至反应完全后,冷却至室温,抽滤得黄色固体,用无水乙醇重结晶,得中间体Z1;
(2)向所述的中间体Z1、相应的2-溴-取代-乙酮中加入无水乙醇,95℃加热回流,至反应完全后,冷却至室温,抽滤得黄色固体,用甲醇重结晶,得所述的β-咔啉衍生物。
进一步的,所述的步骤(1)中,氨基硫脲与相应的1-取代-9-取代-3-甲酰基-β-咔啉的摩尔比为1:1
所述的步骤(2)中,中间产物Z1与相应的2-溴-取代-乙酮的摩尔比为1:1。
再进一步的,所述的步骤(2)中,1-取代-9-取代-3-甲酰基-β-咔啉的合成方法的化学反应式为:
再进一步的,所述的步骤(2)中,1-取代-9-取代-3-甲酰基-β-咔啉的合成方法具体包括以下步骤:
a:将L-色氨酸与NaOH溶解于水中后,加入40%的HCHO溶液,室温下搅拌反应3.5h后,120℃加热回流,至反应完全后,冷却、调节pH、冷藏、抽滤,经水洗、丙酮冲洗,得中间体1;
b:将所述的中间体1溶解于无水乙醇中,加SOCl2,加热回流至反应完全后,冷却至室温,减压浓缩得砖红色固体;将所述的砖红色固体溶于水,用NaHCO3调节pH后,用乙酸乙酯萃取有机相,再用饱和NaCl洗涤、减压浓缩,得白色固体的中间体2;
c:将所述的中间体2溶解于二甲苯中,缓慢加入S8,150℃加热回流至反应完全后,冷却至室温,冷藏、抽滤,经二甲苯、石油醚冲洗,再脱色脱硫,得白色固体的中间体3;
d:将所述的中间体3溶解于DMF中,缓慢加入60%NaH,搅拌,缓慢滴加CH3I,搅拌反应至完全后,倒入冰水中淬灭NaH,再用乙酸乙酯萃取有机相,后用饱和NaCl洗涤,并加入有机相体积1/2的无水乙醇;再用HCl调节pH 3,减压浓缩得淡黄色固体,进行重结晶后,溶于水中,用NaHCO3调节pH 9,用乙酸乙酯萃取,减压浓缩,得淡黄色纯产品的中间体4;
e:将所述的中间体4溶解于THF溶剂中,缓慢加入LiBH4,搅拌反应至完全后,冷却,用HCl调节pH 3,室温搅拌4h,再用NaOH调节pH 9,用乙酸乙酯萃取,减压浓缩后,用丙酮重结晶,抽滤得白色固体的中间体5;
f:将所述的中间体5溶解于乙腈中,缓慢加入MnO2,90℃加热回流至反应完全后,过薄层色谱硅胶短柱子,用乙酸乙酯洗脱,减压浓缩后,用丙酮重结晶,抽滤得白色固体的1-取代-9-取代-3-甲酰基-β-咔啉。
再进一步的,所述的步骤a中,L-色氨酸、NaOH、HCHO的摩尔比为1:1:1;
所述的步骤d中,中间体3、NaH的摩尔比为1:3;
所述的步骤e中,中间体4、LiBH4的摩尔比为1:3;
所述的步骤f中,中间体5、MnO2的摩尔比为1:3。
本发明还有一个目的在于提供上述的β-咔啉衍生物在制备抗肿瘤药物中的应用。
与现有技术相比,本发明的有益效果在于:
本发明在借鉴β-咔啉环含有吡啶环的结构特点,通过构效关系进行修饰,使β-咔啉环1,9-位同时具有取代基。具体的,通过亲核加成-缩合反应将β-咔啉与噻唑衍生物连接,得到了一系列新颖结构的β-咔啉衍生物,具有较好的抗肿瘤活性,可应用于抗肿瘤药物中,对于抗肿瘤药物的合成及发现具有重要的意义。
具体实施方式
为了进一步阐述本发明一种N-N桥连噻唑单元的β-咔啉衍生物及其制备方法、应用,达到预期发明目的,以下结合较佳实施例,对依据本发明提出的一种N-N桥连噻唑单元的β-咔啉衍生物及其制备方法、应用,其具体实施方式、结构、特征及其功效,详细说明如后。在下述说明中,不同的“一实施例”或“实施例”指的不一定是同一实施例。此外,一或多个实施例中的特定特征、结构或特点可由任何合适形式组合。
下面将结合具体的实施例,对本发明一种N-N桥连噻唑单元的β-咔啉衍生物及其制备方法、应用做进一步的详细介绍:
实施例1.
中间体:1-取代-9-取代-3-甲酰基-β-咔啉的合成,采用以下反应:
化合物1a-1d的合成:以1a为例,称取L-色氨酸(51.05g,250mmol)与NaOH(10g,250mmol)投入到1000mL圆底烧瓶中,再加入溶剂H2O(500mL),充分搅拌溶解均匀,得到橙红色溶液,随后向其中加入40%的HCHO溶液(19mL,250mmol),室温搅拌3.5h,溶液颜色逐渐加深,120℃加热回流2.5h;TLC监测反应进程;待反应完全后,将反应液冷却至室温倒入冰水(400mL)中,用HCl调节pH 6左右,伴有淡黄色固体出现,冷藏过夜,析出更多固体,抽滤,经水洗、丙酮冲洗滤饼,得黄色固体即为产品2a,收率:97%。
化合物2a-2d的合成:以2a为例,称取化合物1a(43.25g,200mmol)与无水EtOH(600mL)投入到1000mL三颈烧瓶中,充分搅拌溶解均匀,得到黄色溶液,随后向反应液中缓慢滴加SOCl2(40mL),溶液颜色逐渐变为砖红色,加热回流5h;TLC监测反应进程;待反应完全后,将反应液冷却至室温,减压浓缩得砖红色固体,溶于水,用NaHCO3调节pH 9,用乙酸乙酯萃取,后用饱和盐水洗涤有机相,减压浓缩有机相得白色固体即为产品2a收率:94%。
化合物3a-3d的合成:以3a为例,称取化合物2a(24.4g,100mL)投入到500mL圆底烧瓶中,并加入溶剂二甲苯使其溶解,随后缓慢加入S8(16g,500mmol),150℃加热回流7h。(此反应有H2S气体产生,需要尾气处理装置);TLC监测反应进程;待反应完全后,将反应液冷却至室温,放入冰箱冷藏过夜,次日,抽滤,滤饼用少量二甲苯冲洗,石油醚洗,得到浅红色的粗产品;将粗产品进行脱色脱硫,得白色固体即为产品3a,收率:96%。
化合物4a’-4h’的合成:以4a’为例,称取化合物3a(2.4g,10mmol)投入到250mL茄形瓶中,加入溶剂DMF使其完全溶解,随后缓慢加入60%NaH(1.2g,30mmol),搅拌5min,再缓慢滴加CH3I(1.28mL),充分搅拌;TLC监测反应进程;待反应完全后,将反应液倒入冰水中淬灭反应,随后用乙酸乙酯萃取,后用饱和盐水洗涤有机相,合并有机相,并加入有机相体积1/2的无水乙醇,用HCl调节pH 3,减压浓缩得淡黄色固体,用丙酮重结晶,抽滤得滤饼,将其用水溶解,用NaHCO3调节pH 9,随后用乙酸乙酯萃取,减压浓缩得淡黄色纯产品4a’,收率:92%。
化合物5a’-5h’的合成:以5a’为例,称取化合物4a’(3.48g,10mmol)投入到250mL茄形瓶中,加入溶剂THF使其完全溶解,随后缓慢加入LiBH4(0.65g,30mmol),室温搅拌10h;TLC监测反应进程;待反应完全后,将反应液倒入冰水中,用HCl调节pH 3,室温搅拌4h,随后再用NaOH调节pH 9,用乙酸乙酯萃取,减压浓缩后,用丙酮重结晶,抽滤得白色固体即为纯产品5a’,产率:91%。
化合物6a’-6h’的合成:以6a’为例,称取化合物5a’(1.53g,5mmol)投入到250mL茄形瓶中,加入溶剂乙腈使其完全溶解,随后缓慢加入MnO2(1.31g,15mmol),90℃加热回流2h;TLC监测反应进程;待反应完全后,趁热过薄层色谱硅胶短柱子,用乙酸乙酯洗脱,减压浓缩后,用丙酮重结晶,抽滤得白色固体即为纯产品6a’,收率:92%。
实施例2.
N-N桥连噻唑单元的β-咔啉衍生物的合成采用以下反应式:
具体操作步骤如下:
(1)化合物Z1a的合成:称取化合物6a’(相应的1,9-二取代-3-甲酰基-β-咔啉,采用实施例1的方法制备而成,420.48mg,2mmol)与氨基硫脲(182.26mg,2mmol)投入250mL茄形瓶中,加入溶剂无水乙醇,95℃加热回流12h,伴有土黄色固体生成;TLC监测反应进程;待反应完全后,将反应液冷却至室温,抽滤得黄色固体,用无水乙醇重结晶,得纯产品Z1a,无需进一步处理可投下一步,收率:88.2%。
(2)目标化合物Z2a的合成:以称取化合物Z1a(283.35mg,1mmol)与2-溴苯乙酮(199.05mg,1mmol)投入100mL茄形瓶中,加入溶剂无水乙醇,95℃加热回流约1.5h,反应液逐渐由土黄色变为橙黄色,且伴有土黄色固体生成;TLC监测反应进程;待反应完全后,将反应液冷却至室温,更多固体产生,抽滤得土黄色固体,用甲醇对其进行重结晶,得纯产品Z2a。
4-苯基-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2a):灰绿色固体,产率80.4%。m.p.250.2~250.5℃.1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),9.04(s,1H),8.61(s,1H),8.41(d,J=7.6Hz,1H),8.30(s,1H),7.88(d,J=7.6Hz,2H),7.73(d,J=8.4Hz,1H),7.67(t,J=7.6Hz,1H),7.45–7.38(m,3H),7.32(q,J=8.0Hz,2H),4.01(s,3H).13C NMR(100MHz,DMSO-d6)δ168.06,150.60,143.24,142.74,142.04,136.65,134.71,132.02,128.74,128.61,127.93,127.52,125.51,122.26,120.39,119.86,110.36,110.24,103.63,29.44.
实施例3.
实施例3的操作步骤与实施例2相同,其中,R9为甲基,R1为氢,R3为4-氟苯基,得到的产物为4-(4-氟苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-氟苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2b):灰绿色固体,产率73.6%。m.p.269.1~269.5℃.1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),9.03(s,1H),8.60(s,1H),8.40(d,J=8.0Hz,1H),8.30(s,1H),7.92(dd,J=8.4,5.6Hz,2H),7.72(d,J=8.4Hz,1H),7.66(t,J=7.6Hz,1H),7.36(s,1H),7.33(t,J=7.6Hz,1H),7.25(t,J=8.8Hz,2H),4.00(s,3H).13C NMR(100MHz,DMSO-d6)δ168.19,160.39(d,J=242.8Hz),149.54,143.47,142.81,142.14,136.68,132.11,131.35(d,J=2.5Hz),128.71,127.87,127.53(d,J=7.9Hz),122.24,120.41,119.84,115.35(d,J=21.3Hz),110.33,110.24,103.37,29.43.
实施例4.
实施例4的操作步骤与实施例2相同,其中,R9为甲基,R1为氢,R3为4-甲氧基苯基,得到的产物为4-(4-甲氧基苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-甲氧基苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2c):土黄色固体,产率69.8%。m.p.285.1~285.4℃.1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),9.04(s,1H),8.61(s,1H),8.41(d,J=8.0Hz,1H),8.29(s,1H),7.82(d,J=8.8Hz,2H),7.73(d,J=8.4Hz,1H),7.69–7.63(m,1H),7.34(t,J=7.2Hz,1H),7.20(s,1H),6.99(d,J=8.8Hz,2H),4.01(s,3H),3.80(s,3H).13C NMR(100MHz,DMSO-d6)δ168.43,159.26,143.65,143.30,142.51,137.13,132.52,129.21,128.40,128.08,127.32,122.73,120.88,120.33,114.45,110.78,110.72,101.94,55.60,29.92.
实施例5.
实施例5的操作步骤与实施例2相同,其中,R9为甲基,R1为氢,R3为4-溴苯基,得到的产物为4-(4-溴苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-溴苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2d):黄色固体,产率84.7%。m.p.309.1~309.3℃.1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),9.34(s,1H),8.99(s,1H),8.60(d,J=8.0Hz,1H),8.38(s,1H),8.05–7.74(m,4H),7.73–7.54(m,3H),7.50(t,J=7.2Hz,1H),4.13(s,3H).13C NMR(100MHz,DMSO-d6)δ167.84,149.92,145.10,136.35,135.97,134.59,134.01,133.06,132.32,132.06,128.00,126.67,124.22,122.12,121.18,120.04,114.63,111.66,106.32,30.89.
实施例6.
实施例6的操作步骤与实施例2相同,其中,R1为氢,R9为甲基,R3为3-溴苯基,得到的产物为4-(3-溴苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(3-溴苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2e):灰绿色固体,产率82.6%。m.p.270.3~270.9℃.1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),9.04(s,1H),8.61(s,1H),8.41(d,J=8.0Hz,1H),8.30(s,1H),8.08(s,1H),7.89(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.67(t,J=7.6Hz,1H),7.54(s,1H),7.50(d,J=7.6Hz,1H),7.39(t,J=8.0Hz,1H),7.33(t,J=7.2Hz,1H),4.01(s,3H).13C NMR(100MHz,DMSO-d6)δ168.69,149.33,144.09,143.23,142.49,137.44,137.18,132.62,131.31,130.59,129.20,128.61,128.35,124.87,122.72,122.57,120.89,120.33,110.87,110.73,105.73,29.92.
实施例7.
实施例7的操作步骤与实施例2相同,其中,R1为氢,R9为苄基,R3为苯基,得到的产物为4-苯基-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-苯基-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2f):橙黄色固体,产率90.3%。m.p.189.5~189.9℃.1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),9.44(s,1H),9.05(s,1H),8.64(d,J=8.0Hz,1H),8.39(s,1H),7.94–7.80(m,4H),8.08–7.19(m,10H),5.97(s,2H).13C NMR(100MHz,DMSO-d6)δ167.75,144.42,137.40,136.90,135.86,134.83,133.41,132.36,129.29,129.26,129.18,128.31,128.23,127.45,126.96,126.02,124.41,122.34,120.47,114.81,112.07,105.42,47.20.
实施例8.
实施例8的操作步骤与实施例2相同,其中,R1为氢,R9为苄基,R3为4-氟苯基,得到的产物为4-(4-氟苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-氟苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2g):黄色固体,产率87.4%。m.p.183.2~183.5℃.1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),9.45(s,1H),9.04(s,1H),8.63(d,J=8.0Hz,1H),8.40(s,1H),7.99–7.77(m,4H),7.52–7.47(m,2H),7.35–7.24(m,7H),5.97(s,2H).13C NMR(100MHz,DMSO-d6)δ167.34,162.91(d,J=243.3Hz),149.56,144.01,136.66,136.40,135.33,134.06(d,J=2.9Hz),133.06,131.96,130.98,128.82,127.84,127.59(d,J=8.1Hz),126.99,126.27,123.96,121.90,119.96,115.64(d,J=21.5Hz),114.41,111.61,104.76,46.75.
实施例9.
实施例9的操作步骤与实施例2相同,其中,R1为氢,R9为苄基,R3为4-甲氧基苯基,得到的产物为4-(4-甲氧基苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-甲氧基苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2h):黑棕色固体,产率85.1%。m.p.170.3~170.7℃.1H NMR(400MHz,DMSO-d6)δ13.04(s,1H),9.47(s,1H),9.05(s,1H),8.63(d,J=8.0Hz,1H),8.39(s,1H),7.92–7.72(m,4H),7.49(t,J=7.6Hz,1H),7.34–7.26(m,6H),6.98(d,J=8.4Hz,2H),5.97(s,2H),3.79(s,3H).13C NMR(100MHz,DMSO-d6)δ167.60,159.41,150.79,144.63,136.84,135.73,133.82,132.61,130.49,129.93,129.71,129.30,128.33,127.61,127.48,127.38,126.37,124.52,122.47,120.40,115.19,115.05,114.52,114.32,114.24,112.13,103.35,55.64,47.27.
实施例10.
实施例10的操作步骤与实施例2相同,其中,R1为氢,R9为苄基,R3为4-溴苯基,得到的产物为4-(4-溴苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-溴苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2i):橙黄色固体,产率91.4%。m.p.243.3~243.6℃.1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),9.45(s,1H),9.04(s,1H),8.63(d,J=8.0Hz,1H),8.40(s,1H),7.89–7.79(m,4H),7.68–7.55(m,3H),7.49(t,J=7.6Hz,1H),7.35–7.27(m,5H),5.97(s,2H).13C NMR(100MHz,DMSO-d6)δ167.85,149.92,144.49,137.09,136.87,135.81,134.62,134.03,133.54,132.45,132.08,129.29,128.31,128.03,127.47,126.74,124.44,122.39,121.21,120.43,114.92,112.10,106.38,47.23.
实施例11.
实施例11的操作步骤与实施例2相同,其中,R1为氢,R9为苄基,R3为3-溴苯基,得到的产物为4-(3-溴苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(3-溴苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2j):黄色固体,产率77.6%。m.p.224.3~224.8℃.1H NMR(400MHz,DMSO-d6)δ12.89(s,1H),9.43(s,1H),8.98(s,1H),8.58(d,J=8.0Hz,1H),8.38(s,1H),8.04(s,1H),7.84(d,J=8.4Hz,2H),7.78(t,J=7.6Hz,1H),7.63(s,1H),7.49–7.43(m,2H),7.38(d,J=7.8Hz,1H),7.29(q,J=6.8Hz,5H),5.95(s,2H).13C NMR(100MHz,DMSO-d6)δ167.85,149.39,144.45,137.17,137.07,136.89,135.84,134.83,133.45,132.41,131.37,130.79,129.29,128.61,128.31,127.46,126.85,124.90,124.41,122.62,122.37,120.45,114.88,112.09,107.06,47.22
实施例12.
实施例12的操作步骤与实施例2相同,其中,R1为氢,R9为4-氟苄基,R3为苯基,得到的产物为4-苯基-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-苯基-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2k):橙黄色固体,产率91.0%。m.p.170.1~170.6℃.1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),9.46(s,1H),9.05(s,1H),8.64(d,J=8.0Hz,1H),8.40(s,1H),7.91–7.80(m,4H),7.61–7.27(m,6H),7.17(t,J=8.4Hz,2H),5.96(s,2H).13C NMR(100MHz,DMSO-d6)δ167.75,160.92(d,J=242.3Hz),150.95,144.32,137.29,135.77,134.82,133.54,133.13(d,J=3.0Hz),132.40,129.65(d,J=8.2Hz),129.18,128.22,127.02126.81,126.03,124.44,122.39,120.51,116.21(d,J=21.4Hz),114.82,112.04,105.44,46.49.
实施例13.
实施例13的操作步骤与实施例2相同,其中,R1为氢,R9为4-氟苄基,R3为4-氟苄基,得到的产物为4-(4-氟苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-氟苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2l):橙黄色固体,产率86.7%。m.p.184.6~185.0℃.1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),9.44(s,1H),9.04(s,1H),8.63(d,J=8.0Hz,1H),8.39(s,1H),8.06–7.72(m,4H),7.61–7.43(m,2H),7.52–7.34(m,2H),7.27(t,J=8.8Hz,1H),7.16(t,J=8.8Hz,2H),5.95(s,2H).13C NMR(100MHz,DMSO-d6)δ167.83,163.39(d,J=243.2Hz),163.34(d,J=242.4Hz),150.04,144.32,137.31,135.75,134.70,133.51,133.12(d,J=3.0Hz),132.42,131.46(d,J=2.8Hz),129.74(d,J=8.2Hz),128.07(d,J=8.2Hz),126.88,124.44,122.39,120.49,116.21(d,J=21.3Hz),116.12(d,J=21.4Hz),114.84,112.04,105.21,46.51.
实施例14.
实施例14的操作步骤与实施例2相同,其中,R1为氢,R9为4-氟苄基,R3为4-甲氧基苯基,得到的产物为4-(4-甲氧基苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-甲氧基苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2m):橙红色固体,产率80.1%。m.p.176.3~176.8℃.1HNMR(400MHz,DMSO-d6)δ12.86(s,1H),9.44(d,J=3.6Hz,1H),9.03(s,1H),8.63(d,J=8.0Hz,1H),8.38(d,J=2.0Hz,1H),8.05–7.71(m,4H),7.50(t,J=7.6Hz,1H),7.44–7.24(m,3H),7.20–7.14(m,2H),7.00(d,J=8.4Hz,2H),5.95(s,2H),3.80(s,3H).13C NMR(100MHz,DMSO-d6)δ167.68,163.34(d,J=242.3Hz),159.41,150.97,144.24,137.71,135.79,134.84,133.36,133.15(d,J=3.1Hz),132.32,129.73(d,J=8.3Hz),127.67,127.38,127.10,124.39,122.33,120.53,116.21(d,J=21.4Hz),114.67,114.53,112.01,103.22,55.63,46.46.
实施例15.
实施例15的操作步骤与实施例2相同,其中,R1为氢,R9为4-氟苄基,R3为4-溴苯基,得到的产物为4-(4-溴苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-溴苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2n):橙黄色固体,产率84.3%。m.p.210.6~210.9℃.1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),9.46(s,1H),9.04(s,1H),8.63(d,J=8.0Hz,1H),8.40(s,1H),7.91–7.80(m,4H),7.74–7.55(m,3H),7.50(t,J=7.6Hz,1H),7.36(dd,J=8.4,5.6Hz,2H),7.17(t,J=8.8Hz,2H),5.96(s,2H).13CNMR(100MHz,DMSO-d6)δ167.88,163.34(d,J=242.4Hz),149.93,144.28,137.36,135.77,134.92,134.05,133.44,133.13(d,J=3.0Hz),132.38,132.09,129.74(d,J=8.3Hz),128.03,126.97,124.41,122.38,121.21,120.50,116.21(d,J=21.3Hz),114.81,112.04,106.35,46.50.
实施例16.
实施例16的操作步骤与实施例2相同,其中,R1为氢,R9为4-氟苄基,R3为3-溴苯基,得到的产物为4-(3-溴苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(3-溴苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2o):橙黄色固体,产率86.4%。m.p.232.3~232.6℃.1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),9.48(s,1H),9.04(s,1H),8.64(d,J=8.0Hz,1H),8.40(s,1H),8.08(s,1H),7.89(d,J=8.0Hz,2H),7.83(t,J=7.6Hz,1H),7.67(s,1H),7.58–7.46(m,2H),7.45–7.27(m,3H),7.17(t,J=8.8Hz,2H),5.96(s,2H).13C NMR(100MHz,DMSO-d6)δ167.85,163.34(d,J=242.3Hz),149.38,144.32,137.25,137.07,135.76,134.84,133.50,133.12(d,J=2.9Hz),132.42,131.37,130.79,129.74(d,J=8.3Hz),128.61,126.89,124.90,124.43,122.61,122.40,120.49,116.21(d,J=21.4Hz),114.86,112.05,107.06,46.51.
实施例17.
实施例17的操作步骤与实施例2相同,其中,R1为甲基,R9为甲基,R3为苯基,得到的产物为4-苯基-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-苯基-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2p):橙黄色固体,产率85.4%。m.p.229.6~230.1℃.1H NMR(400MHz,DMSO-d6)δ12.99(s,1H),8.87(s,1H),8.62(d,J=8.0Hz,1H),8.39(s,1H),7.97–7.82(m,4H),7.54–7.39(m,4H),7.37–7.31(m,1H),4.27(s,3H),3.30(s,3H).13C NMR(100MHz,DMSO-d6)δ167.77,145.28,139.56,136.17,134.81,134.35,132.83,132.15,129.17,129.11,128.22,126.16,125.99,124.02,122.09,119.82,111.67,111.63,105.40,32.95,18.66.
实施例18.
实施例18的操作步骤与实施例2相同,其中,R1为甲基,R9为甲基,R3为4-氟苯基,得到的产物为4-(4-氟苯基)-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-氟苯基)-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2q):黄色固体,产率82.3%。m.p.203.1~203.6℃.1H NMR(400MHz,DMSO-d6)δ12.97(s,1H),8.82(s,1H),8.59(d,J=8.0Hz,1H),8.38(s,1H),7.97–7.78(m,4H),7.48(s,2H),7.25(t,J=8.8Hz,2H),4.25(s,3H),3.29(s,3H).13C NMR(100MHz,DMSO)δ167.56,166.47,162.90(d,J=243.2Hz),149.50,146.90,144.58,144.33,133.68,133.39(d,J=2.9Hz),130.04,129.96,129.49,127.57(d,J=8.1Hz),123.39,115.63(d,J=21.6Hz),115.44,111.79,111.03,104.46,31.09,31.05.
实施例19.
实施例19的操作步骤与实施例2相同,其中,R1为甲基,R9为甲基,R3为4-溴苯基,得到的产物为4-(4-溴苯基)-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-溴苯基)-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2r):橙黄色固体,产率84.8%。m.p.214.3~214.7℃.1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),8.86(s,1H),8.62(d,J=8.0Hz,1H),8.37(s,1H),7.93(d,J=8.4Hz,1H),7.88–7.82(m,3H),7.72–7.54(m,3H),7.48(t,J=8.0Hz,1H),4.27(s,3H),3.29(s,3H).13CNMR(100MHz,DMSO)δ167.03,157.42,153.07,149.50,145.11,143.58,140.17,139.65,134.64,134.53,133.62,131.63,127.55,123.41,121.71,120.73,119.48,112.64,111.15,105.73,93.07,45.27,32.45.
实施例20.
实施例20的操作步骤与实施例2相同,其中,R1为异丙基,R9为苄基,R3为苯基,得到的产物为4-苯基-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-苯基-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2s):橙黄色固体,产率90.6%。m.p.187.3~187.8℃.1H NMR(400MHz,DMSO-d6)δ12.92(s,1H),8.88(s,1H),8.65(d,J=8.0Hz,1H),8.54(s,1H),7.89(d,J=8.0Hz,3H),7.79(t,J=8.0Hz,1H),7.52–7.40(m,4H),7.35–7.25(m,4H),7.01(d,J=7.6Hz,2H),6.01(s,2H),3.96–3.81(m,1H),1.29(d,J=6.8Hz,6H).13C NMR(100MHz,DMSO-d6)δ168.16,151.04,145.41,137.72,134.88,132.68,132.02,129.43,129.16,128.85,128.80,128.32,128.18,128.00,126.02,125.94,123.71,122.16,120.41,111.60,110.72,105.17,48.90,29.60,21.92.
实施例21.
实施例21的操作步骤与实施例2相同,其中,R1为异丙基,R9为苄基,R3为4-氟苯基,得到的产物为4-(4-氟苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-氟苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2t):橙黄色固体,产率90.1%。m.p.186.2~186.7℃.1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),8.88(s,1H),8.65(d,J=8.0Hz,1H),8.55(s,1H),7.95–7.88(m,3H),7.79(t,J=8.0Hz,1H),7.48(s,2H),7.35–7.23(m,5H),7.01(d,J=7.6Hz,2H),6.01(s,2H),3.94–3.85(m,1H),1.29(d,J=6.8Hz,6H).13C NMR(100MHz,DMSO-d6)δ168.28,163.36(d,J=243.2Hz),150.06,137.79,132.76,131.58(d,J=3.1Hz),130.91,130.83,130.53,130.45,129.41,128.05(d,J=8.0Hz),125.93,123.57,122.04,120.47,116.10(d,J=21.4Hz),115.69,115.45,111.55,104.85,48.85,29.72,22.01.
实施例22.
实施例22的操作步骤与实施例2相同,其中,R1为异丙基,R9为苄基,R3为4-甲氧基苯基,得到的产物为4-(4-甲氧基苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-甲氧基苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2u):橙黄色固体,产率92.3%。m.p.193.5~193.9℃.1HNMR(400MHz,DMSO-d6)δ12.82(s,1H),8.84(s,1H),8.64(d,J=8.0Hz,1H),8.48(s,1H),7.92–7.73(m,4H),7.47(t,J=7.6Hz,1H),7.35–7.25(m,4H),7.05–6.97(m,4H),6.00(s,2H),3.86–3.78(m,4H),1.27(d,J=6.8Hz,6H).13C NMR(100MHz,DMSO-d6)δ168.10,159.39,150.83,145.21,137.81,132.77,130.79,130.11,129.70,129.42,127.98,127.74,127.37,125.94,123.61,122.05,120.49,114.52,114.24,111.56,110.54,102.93,55.63,48.85,29.71,22.02.
实施例23.
实施例23的操作步骤与实施例2相同,其中,R1为异丙基,R9为苄基,R3为4-溴苯基,得到的产物为4-(4-溴苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-溴苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2v):橙黄色固体,产率93.8%。m.p.208.3~208.9℃.1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.86(s,1H),8.64(d,J=8.0Hz,1H),8.52(s,1H),7.88(d,J=8.4Hz,1H),7.84(d,J=8.4Hz,2H),7.78(t,J=8.0Hz,1H),7.62(d,J=8.0Hz,2H),7.57(s,1H),7.47(t,J=7.6Hz,1H),7.35–7.25(m,3H),7.01(d,J=7.6Hz,2H),6.01(s,2H),3.91–3.83(m,1H),1.28(d,J=6.8Hz,6H).13C NMR(100MHz,DMSO-d6)δ168.31,167.25,149.95,147.56,145.21,137.78,134.14,133.09,132.76,132.08,131.87,130.27,129.42,128.03,127.99,125.94,123.61,122.05,121.15,120.47,111.57,110.63,106.02,48.86,29.70,22.00.
实施例24.
实施例24的操作步骤与实施例2相同,其中,R1为异丙基,R9为4-氟苄基,R3为苯基,得到的产物为4-苯基-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-苯基-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2w):橙黄色固体,产率90.8%。m.p.212.3~212.6℃.1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),8.87(s,1H),8.64(d,J=8.0Hz,1H),8.54–8.47(m,1H),7.89(d,J=7.6Hz,3H),7.79(t,J=7.6Hz,1H),7.49–7.41(m,4H),7.32(t,J=7.2Hz,1H),7.16(t,J=8.4Hz,2H),7.08–7.04(m,2H),5.99(s,2H),3.88–3.84(m,1H),1.31–1.29(m,6H).13C NMR(100MHz,DMSO)δ167.70,166.76,162.64(d,J=241.8Hz),150.56,146.94,144.72,134.41,133.45(d,J=3.0Hz),132.16,131.50,128.69,128.39,127.85,127.71,127.64(d,J=8.1Hz),125.54,123.22,121.68,120.02,115.89(d,J=21.6Hz),111.07,110.20,104.67,47.77,29.17,21.52.
实施例25.
实施例25的操作步骤与实施例2相同,其中,R1为异丙基,R9为4-氟苄基,R3为4-氟苯基,得到的产物为4-(4-氟苯基)-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-氟苯基)-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2x):橙黄色固体,产率89.7%。m.p.185.4~185.7℃.1HNMR(400MHz,DMSO-d6)δ12.88(s,1H),8.85(s,1H),8.64(d,J=7.2Hz,1H),8.51(s,1H),7.98–7.87(m,3H),7.78(t,J=7.6Hz,1H),7.48(d,J=8.8Hz,2H),7.26(t,J=8.8Hz,2H),7.15(t,J=8.8Hz,2H),7.07–7.04(m,2H),5.99(s,2H),3.92–3.76(m,1H),1.29(d,J=6.8Hz,4H),1.05(t,J=6.8Hz,2H).13C NMR(100MHz,DMSO-d6)δ167.81,166.69,162.90(d,J=243.3Hz),162.64(d,J=241.9Hz),149.58,144.61,138.57,133.49,132.20,131.09(d,J=3.0Hz),130.07(d,J=2.9Hz),129.99,127.63(d,J=8.3Hz),127.58(d,J=8.1Hz),123.15,121.62,120.06,115.88(d,J=21.4Hz),115.64(d,J=21.4Hz),115.23,111.05,110.12,104.39,47.75,29.25,21.57.
实施例26.
实施例26的操作步骤与实施例2相同,其中,R1为异丙基,R9为4-氟苄基,R3为4-溴苯基,得到的产物为4-(4-溴苯基)-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-溴苯基)-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2y):橙黄色固体,产率92.4%。m.p.210.3~210.6℃.1HNMR(400MHz,DMSO-d6)δ12.90(s,1H),8.86(s,1H),8.64(d,J=8.0Hz,1H),8.53(s,1H),7.89-7.76(m,4H),7.62–7.56(m,3H),7.47(t,J=7.6Hz,1H),7.15(t,J=8.8Hz,2H),7.07–7.04(m,2H),5.99(s,2H),3.89–3.83(m,1H),1.30(d,J=6.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ167.84,166.77,162.63(d,J=241.9Hz),149.46,146.73,144.23,139.29,133.66,133.48,132.61,132.21,131.59(d,J=3.1Hz),129.78,127.63(d,J=8.2Hz),123.11,121.54,120.67,120.19,120.05,115.87(d,J=21.6Hz),111.04,110.11,105.51,47.74,29.25,21.58.
实施例27.
实施例27的操作步骤与实施例2相同,其中,R1为2-氯苯基,R9为氢,R3为苯基,得到的产物为4-苯基-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-苯基-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2z):橙黄色固体,产率89.3%。m.p.190.6~190.8℃.1H NMR(400MHz,DMSO-d6)δ12.76(s,1H),12.29(s,1H),9.01(s,1H),8.62(d,J=8.0Hz,1H),8.42–8.41(m,1H),7.90–7.83(m,4H),7.78–7.65(m,4H),749–7.41(m,4H),7.32(t,J=7.2Hz,1H).13C NMR(100MHz,DMSO-d6)δ167.57,150.53,144.08,143.95,138.85,137.95,136.30,134.44,133.68,132.89,132.47,132.22,131.09,130.96,130.01,128.69,128.39,127.85,127.75,127.70,125.54,123.40,121.05,120.32,112.72,111.80,104.55.
实施例28.
实施例28的操作步骤与实施例2相同,其中,R1为2-氯苯基,R9为氢,R3为4-氟苯基,得到的产物为4-(4-氟苯基)-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-氟苯基)-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2a’):黄色固体,产率89.6%。m.p.195.6~196.0℃.1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),12.29(s,1H),9.00(s,1H),8.62(d,J=8.0Hz,1H),8.42(s,1H),7.93(dd,J=8.4,5.6Hz,2H),7.84(d,J=7.2Hz,2H),7.79–7.64(m,4H),7.47(s,1H),7.43(t,J=7.6Hz,1H),7.27(t,J=8.4Hz,2H).13CNMR(100MHz,DMSO-d6)δ168.11,163.37(d,J=243.2Hz),150.03,144.15,139.07,137.24,134.15,133.39,132.97,132.83,131.56(d,J=2.9Hz),130.54,130.50,130.46,128.25,128.05(d,J=8.1Hz),123.93,121.59,120.77,116.12(d,J=21.5Hz),115.93,115.72,113.22,112.37,104.84.
实施例29.
实施例29的操作步骤与实施例2相同,其中,R1为2-氯苯基,R9为氢,R3为4-甲氧基苯基,得到的产物为4-(4-甲氧基苯基)-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-甲氧基苯基)-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2b’):橙黄色固体,产率90.6%。m.p.194.6~194.9℃.1HNMR(400MHz,DMSO-d6)δ12.99(s,1H),12.27(s,1H),8.99(d,J=2Hz,1H),8.62(d,J=8.0Hz,1H),8.41(d,J=6.4Hz,1H),7.89–7.81(m,4H),7.79–7.65(m,4H),7.43(t,J=7.6Hz,1H),7.31(s,1H),7.00(d,J=6.8Hz,2H),3.80(s,3H).13C NMR(100MHz,DMSO-d6)δ167.45,158.92,156.26,154.68,150.15,146.03,143.67,138.29,136.14,133.65,132.92,132.50,132.14,131.12,130.03,127.77,127.25,126.89,123.49,121.12,120.29,114.05,113.77,112.74,111.87,102.44,101.62,55.16.
实施例30.
实施例30的操作步骤与实施例2相同,其中,R1为2-氯苯基,R9为4-氟苄基,R3为苯基,得到的产物为4-苯基-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-苯基-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2c’):橙黄色固体,产率92.4%。m.p.181.3~181.7℃.1HNMR(400MHz,DMSO-d6)δ12.80(s,1H),9.04(d,J=6.8Hz,1H),8.72(d,J=8.0Hz,1H),8.38(d,J=6.4Hz,1H),7.89(d,J=7.2Hz,2H),7.76(t,J=6.8Hz,2H),7.63(d,J=4.0Hz,2H),7.56(d,J=7.6Hz,1H),7.52–7.47(m,2H),7.46–7.40(m,3H),7.33(t,J=7.2Hz,1H),6.95(t,J=8.8Hz,2H),6.54(dd,J=8.8,5.6Hz,2H),5.29(dd,J=86.0,17.2Hz,2H).13C NMR(100MHz,DMSO-d6)δ168.05,167.02,162.98(d,J=241.5Hz),150.97,148.36,144.44,140.55,137.08,134.88,133.90,133.68(d,J=2.5Hz),133.00,132.65,131.72,129.86,129.16,128.86,128.32,128.18,127.71(d,J=8.3Hz),127.59,126.02,123.85,122.17,120.68,115.79(d,J=21.5Hz),112.03,111.66,105.05,46.87.
实施例31.
实施例31的操作步骤与实施例2相同,其中,R1为2-氯苯基,R9为4-氟苄基,R3为4-氟苯基,得到的产物为4-(4-氟苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-氟苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2d’):橙黄色固体,产率91.5%。m.p.182.3~182.7℃.1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),9.01(s,1H),8.69(d,J=6.8Hz,1H),8.35(s,1H),7.93(dd,J=8.8,5.6Hz,2H),7.73(s,2H),7.63–7.59(m,2H),7.53(d,J=8.0Hz,1H),7.51–7.36(m,3H),7.27(t,J=8.8Hz,2H),6.95(t,J=8.8Hz,2H),6.54(dd,J=8.4,5.6Hz,2H),5.40(d,J=17.4Hz,1H),5.16(d,J=17.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ168.18,163.37(d,J=243.0Hz),162.97(d,J=241.6Hz),150.01,144.19,140.82,137.67,133.85(d,J=2.9Hz),133.77(d,J=3.1Hz),133.08,132.60,131.58,131.45,130.54,130.45,129.83,128.05(d,J=8.0Hz),127.71(d,J=8.4Hz),127.57,123.73,122.06,120.76,116.11(d,J=21.4Hz),115.92,115.78(d,J=21.3Hz),115.71,111.87,111.62,104.72,46.82.
实施例32.
实施例32的操作步骤与实施例2相同,其中,R1为2-氯苯基,R9为4-氟苄基,R3为4-甲氧基苯基,得到的产物为4-(4-甲氧基苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
4-(4-甲氧基苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑(Z2e’):橙黄色固体,产率94.1%。m.p.181.4~181.9℃.1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),9.02(s,1H),8.70(d,J=8.0Hz,1H),8.36(s,1H),7.82(d,J=8.4Hz,2H),7.79–7.72(m,2H),7.63(d,J=4.4Hz,2H),7.56(d,J=7.6Hz,1H),7.51–7.47(m,1H),7.46–7.40(m,1H),7.30(s,1H),7.02–6.92(m,4H),6.54(dd,J=8.4,5.6Hz,2H),5.39(d,J=17.4Hz,1H),5.17(d,J=17.4Hz,1H),3.80(s,3H).13C NMR(100MHz,DMSO-d6)δ167.97,162.97(d,J=241.6Hz),159.39,150.71,144.36,140.76,137.26,133.88,133.70,133.05(d,J=2.9Hz),132.63,132.46,131.62,130.65,129.84,129.69,127.71(d,J=8.0Hz),127.58,127.37,123.79,122.11,120.71,115.79(d,J=21.4Hz),114.52,114.38,114.23,111.92,111.64,102.84,55.63,46.84.
实施例33.
实施例33的操作步骤与实施例2相同,其中,R1为2-氯苯基,R9为4-氟苄基,R3为4-溴苯基,得到的产物为4-(4-溴苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)亚肼基)-2,3-二氢噻唑。
4-(4-溴苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)亚肼基)-2,3-二氢噻唑(Z2f’):橙黄色固体,产率93.2%。m.p.183.2~183.6℃.1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),9.01(s,1H),8.69(d,J=8.0Hz,1H),8.36(s,1H),7.88–7.81(m,2H),7.78–7.72(m,2H),7.64–7.59(m,4H),7.55(d,J=8.8Hz,2H),7.51–7.46(m,1H),7.44–7.39(m,1H),6.94(t,J=8.8Hz,2H),6.53(dd,J=8.8,5.6Hz,2H),5.39(d,J=17.4Hz,1H),5.17(d,J=17.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ168.23,162.97(d,J=241.4Hz),149.90,144.26,140.83,137.49,134.16,133.86,133.75,133.12,133.08(d,J=3.1Hz),132.59,132.36,132.07,131.87,131.51,130.27,129.82,128.03,127.71(d,J=8.3Hz),127.56,123.71,122.06,121.15,120.74,115.78(d,J=21.4Hz),111.89,111.62,105.86,46.82.
实施例34.
实施例34的操作步骤与实施例2相同,其中,R1为2-氯苯基,R9为4-氟苄基,R3为3-溴苯基,得到的产物为4-(3-溴苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)亚肼基)-2,3-二氢噻唑。
4-(3-溴苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)亚肼基)-2,3-二氢噻唑(Z2g’):橙黄色固体,产率92.3%。m.p.185.3~185.8℃.1H NMR(400MHz,DMSO-d6)δ12.76(s,1H),9.02(d,J=6.0Hz,1H),8.70(d,J=8.4Hz,1H),8.36(d,J=5.2Hz,1H),8.08(s,1H),7.90(d,J=8.0Hz,1H),7.78–7.72(m,2H),7.69–7.61(m,3H),7.58–7.46(m,3H),7.45–7.37(m,2H),6.94(t,J=8.8Hz,2H),6.54(dd,J=8.4,5.6Hz,2H),5.39(d,J=17.2Hz,1H),5.17(d,J=17.2Hz,1H).13C NMR(100MHz,DMSO-d6)δ168.22,162.97(d,J=241.7Hz),149.37,144.25,140.86,137.20,136.12,133.85,133.78,133.08(d,J=2.8Hz),132.59,132.36,131.49,131.36,131.12,130.84,130.73,129.82,128.63,127.71(d,J=8.3Hz),127.56,127.07,124.88,123.70,122.61,122.09,120.87,120.75,115.78(d,J=21.5Hz),111.90,111.62,106.55,46.83.
实施例2-34制备的产物的化学结构式具体见表1。
表1目标化合物化学结构总表
实施例35:体外抗肿瘤活性研究
对实施例2-34合成的33个含有噻唑结构的β-咔啉衍生物,使用MTT法对目标化合物进行了体外抗肿瘤活性测试,测试以顺铂为阳性对照,其测试的结果如表2所示:
表2化合物Z2a-Z2g’的体外抗肿瘤活性(IC50,μmol·L-1)
各细胞系的半抑制浓度为IC50,是一种化合物的浓度,它使细胞的光密度比未处理的细胞降低了50%。该数据表示采用MTT法平行进行三个独立的实验测试实验数据,数据表示为平均值±SD(标准差)。
由上表可知,合成的含有噻唑结构的β-咔啉衍生物具有较好的抗肿瘤活性,可应用于抗肿瘤药物中。
以上所述,仅是本发明实施例的较佳实施例而已,并非对本发明实施例作任何形式上的限制,依据本发明实施例的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明实施例技术方案的范围内。
Claims (10)
2.根据权利要求1所述的β-咔啉衍生物,其特征在于,
所述的β-咔啉衍生物的化学结构通式中,R1为氢、甲基、异丙基、2-氯苯基中的一种;
R3为苯基、4-氟苯基、4-甲氧基苯基、4-溴苯基、3-溴苯基中的一种;
R9为氢、甲基、正丁基、异丁基、苄基、4-氟苄基、3-氯苄基、苯丙基中的一种。
3.根据权利要求1所述的β-咔啉衍生物,其特征在于,
所述的β-咔啉衍生物,为下列任一化合物:
4-苯基-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑:
4-(4-甲氧基苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(3-溴苯基)-2-(((E)-(9-甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-甲氧基苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(3-溴苯基)-2-(((E)-(9-苄基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-甲氧基苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(3-溴苯基)-2-(((E)-(9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(1,9-二甲基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-甲氧基苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(9-苄基-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(9-(4-氟苄基)-1-异丙基-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-甲氧基苯基)-2-(((E)-(1-(2-氯苯基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-苯基-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-氟苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-甲氧基苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(4-溴苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑;
4-(3-溴苯基)-2-(((E)-(1-(2-氯苯基)-9-(4-氟苄基)-β-咔啉-3-基)亚甲基)肼亚基)-2,3-二氢噻唑。
5.权利要求4所述的制备方法,其特征在于,具体包括以下步骤:
(1)向相应的1-取代-9-取代-3-甲酰基-β-咔啉、氨基硫脲中加入无水乙醇,95℃加热回流,至反应完全后,冷却至室温,抽滤得黄色固体,用无水乙醇重结晶,得中间体Z1;
(2)向所述的中间体Z1、相应的2-溴-取代-乙酮中加入无水乙醇,95℃加热回流,至反应完全后,冷却至室温,抽滤得黄色固体,用甲醇重结晶,得所述的β-咔啉衍生物。
6.根据权利要求5所述的制备方法,其特征在于,具体包括以下步骤:
所述的步骤(1)中,氨基硫脲与相应的1-取代-9-取代-3-甲酰基-β-咔啉的摩尔比为1:1
所述的步骤(2)中,中间产物Z1与相应的2-溴-取代-乙酮的摩尔比为1:1。
8.根据权利要求7所述的制备方法,其特征在于,具体包括以下步骤:
所述的步骤(2)中,1-取代-9-取代-3-甲酰基-β-咔啉的合成方法具体包括以下步骤:
a:将L-色氨酸与NaOH溶解于水中后,加入40%的HCHO溶液,室温下搅拌反应3.5h后,120℃加热回流,至反应完全后,冷却、调节pH、冷藏、抽滤,经水洗、丙酮冲洗,得中间体1;
b:将所述的中间体1溶解于无水乙醇中,加SOCl2,加热回流至反应完全后,冷却至室温,减压浓缩得砖红色固体;将所述的砖红色固体溶于水,用NaHCO3调节pH后,用乙酸乙酯萃取有机相,再用饱和盐水洗涤、减压浓缩,得白色固体的中间体2;
c:将所述的中间体2溶解于二甲苯中,缓慢加入S8,150℃加热回流至反应完全后,冷却至室温,冷藏、抽滤,经二甲苯、石油醚冲洗,再脱色脱硫,得白色固体的中间体3;
d:将所述的中间体3溶解于DMF中,缓慢加入60%NaH,搅拌,缓慢滴加CH3I,搅拌反应至完全后,倒入冰水中淬灭NaH,再用乙酸乙酯萃取有机相,后用饱和NaCl洗涤,并加入有机相体积1/2的无水乙醇;再用HCl调节pH 3,减压浓缩得淡黄色固体,进行重结晶后,溶于水中,用NaHCO3调节pH 9,用乙酸乙酯萃取,减压浓缩,得淡黄色纯产品的中间体4;
e:将所述的中间体4溶解于THF溶剂中,缓慢加入LiBH4,搅拌反应至完全后,冷却,用HCl调节pH 3,室温搅拌4h,再用NaOH调节pH 9,用乙酸乙酯萃取,减压浓缩后,用丙酮重结晶,抽滤得白色固体的中间体5;
f:将所述的中间体5溶解于乙腈中,缓慢加入MnO2,90℃加热回流至反应完全后,过薄层色谱硅胶短柱子,用乙酸乙酯洗脱,减压浓缩后,用丙酮重结晶,抽滤得白色固体的1-取代-9-取代-3-甲酰基-β-咔啉。
9.根据权利要求8所述的制备方法,其特征在于,具体包括以下步骤:
所述的步骤a中,L-色氨酸、NaOH、HCHO的摩尔比为1:1:1;
所述的步骤d中,中间体3、NaH的摩尔比为1:3;
所述的步骤e中,中间体4、LiBH4的摩尔比为1:3;
所述的步骤f中,中间体5、MnO2的摩尔比为1:3。
10.权利要求1所述的β-咔啉衍生物在制备抗肿瘤药物中的应用。
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