CN118047710A - N-取代马来酰亚胺类化合物及其制备方法和在抗肿瘤药物中的应用 - Google Patents
N-取代马来酰亚胺类化合物及其制备方法和在抗肿瘤药物中的应用 Download PDFInfo
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- CN118047710A CN118047710A CN202410179622.9A CN202410179622A CN118047710A CN 118047710 A CN118047710 A CN 118047710A CN 202410179622 A CN202410179622 A CN 202410179622A CN 118047710 A CN118047710 A CN 118047710A
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- Prior art keywords
- reaction
- substituted maleimide
- alkynylamide
- alkyl
- maleimide compound
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- -1 N-substituted maleimide compound Chemical class 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 8
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 19
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 19
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 8
- 201000007270 liver cancer Diseases 0.000 claims abstract description 7
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 6
- 239000001257 hydrogen Chemical group 0.000 claims abstract description 6
- 229910052739 hydrogen Chemical group 0.000 claims abstract description 6
- 201000005202 lung cancer Diseases 0.000 claims abstract description 6
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 60
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
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- 230000000171 quenching effect Effects 0.000 claims description 5
- IAVUPMFITXYVAF-HTRCEHHLSA-N (4r,6r)-4-(ethylamino)-6-methyl-7,7-dioxo-5,6-dihydro-4h-thieno[2,3-b]thiopyran-2-sulfonamide Chemical compound CCN[C@@H]1C[C@@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-HTRCEHHLSA-N 0.000 claims description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 4
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- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 claims description 4
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
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Abstract
本发明属有机化学合成领域，公开了一种N‑取代马来酰亚胺类化合物及其制备方法和在抗肿瘤药物中的应用。其为如下通式结构，其中，R选自C1‑6烷基、氢；R1选自C1‑6烷基、苄基、烯丙基；R2选自苯基或被C1‑3烷基、卤素、甲氧基、三氟甲基单取代的苯基。本发明在非金属催化下，通过炔酰胺和炔基亚砜发生环合反应，得到一系列N‑取代马来酰亚胺类化合物。该制备方法具有原料易得，后处理简单，对环境友好，底物普适性广和官能团耐受性良好等优点。该N‑取代马来酰亚胺类化合物具有抑制人子宫颈癌细胞C33A、人宫颈癌细胞Hela、人肺癌细胞A549、人乳腺癌细胞MCF‑7和人肝癌细胞Hep G2的活性，将其应用于抗肿瘤药物的制备。
Description
技术领域
本发明涉及有机化学合成领域，具体涉及一种N-取代马来酰亚胺类化合物及其制备方法和在抗肿瘤药物中的应用。
背景技术
马来酰亚胺是一类重要的药物活性优势骨架，官能团骨架是2,5-吡咯烷二酮及其衍生物，是许多海洋天然生物碱和生物活性分子的母核，广泛存在于许多药物活性化合物和天然产物中。另外，其作为有机合成中的重要骨架，是合成多种天然产物、药物的关键前体。因此，开发简便高效的此类化合物的合成方法也是目前的研究热点之一。
针对N-取代马来酰亚胺类化合物的合成，早期文献报道的合成方法十分有限，且大多具有步骤繁琐、后处理复杂、条件苛刻等缺点。2015年，Dyson课题组使用钯催化剂Pd(xantphos)Cl2有效地实现了p-TsOH存在下的炔烃与CO和胺的羰基化反应，制备了一系列N-取代马来酰亚胺类化合物。然而，CO难以处理和运输，而且毒性很大(J.Org.Chem.2015,80,386-391)。2019年，Wu课题组报道了二(乙酰丙酮)钯催化硝基芳烃和炔烃在对氯苯磺酸、DMF的存在下合成N-取代马来酰亚胺，但需要同时使用1,3-双(二苯基膦丙烷)作为配体与金属钯结合起到促进反应发生(J.Catal.2019,379,519-523)。此外，近年来报道的其他合成方法同样涉及使用有毒的CO气体和价格昂贵的过渡金属催化剂，且过渡金属的使用会对环境有一定污染；反应条件比较苛刻：大多需要在高温下进行且需要配体或额外的添加剂来促进反应发生。
发明内容
为了克服上述技术缺陷，本发明目的在于提供一种N-取代马来酰亚胺类化合物的合成新方法；另一目的在于提供对抗肿瘤活性好的N-取代马来酰亚胺类化合物。
为实现本发明目的，本发明采用非金属催化剂催化炔酰胺和炔基亚砜发生环合反应得到N-取代马来酰亚胺类化合物。
具体技术方案如下：
本发明所述N-取代马来酰亚胺类化合物，其结构通式为：
其中，R选自烷基、芳基、杂芳基、氢；R1选自烷基、芳基、烯基；R2选自烷基、芳基。
优选：R选自C1-6烷基、氢；R1选自C1-6烷基、烯丙基；R2选自苯基或被C1-3烷基、卤素、甲氧基、三氟甲基单取代的苯基。
更优选：R选自氢；R1选自C1-4烷基、烯丙基；R2选自苯基或被C1-3烷基、卤素、甲氧基、三氟甲基单取代的苯基。
上述N-取代马来酰亚胺类化合物的制备方法，合成路线如下：
具体合成步骤如下：
在氧气保护下，向干燥的反应管内依次加入炔酰胺1或1'、炔基亚砜2、甲苯和三氟甲磺酸三甲基硅脂，保持氧气球与反应管相连，置于油浴中搅拌；薄层色谱法监测反应进程，待反应完全后，将反应液冷却至室温，抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到一系列N-取代马来酰亚胺类化合物3。
进一步地，在上述技术方案中，所述原料炔酰胺1的合成路线如下：
具体合成步骤如下：
1)在氮气保护下，将炔基溴化物4、磺酰胺5、1,10-菲咯啉、磷酸钾、五水硫酸铜和甲苯置于反应瓶中，加热搅拌；薄层色谱法监测反应进程，待反应完全后，将反应液冷却至室温，抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料炔基末端为TIPS取代的磺酰基炔酰胺6。
2)在氮气保护下，将TIPS取代的磺酰基炔酰胺6置于反应瓶中，加入无水四氢呋喃，缓慢滴加正四丁基氟化铵，随后转移至室温进行反应；薄层色谱法监测反应进程，至反应完全，淬灭，萃取，合并有机相，经干燥，抽滤，减压蒸馏除去溶剂后，所得粗产物经硅胶柱层析分离得到原料炔酰胺1。
所述步骤中炔基溴化物4、磺酰胺5、1,10-菲咯啉、磷酸钾和五水硫酸铜的摩尔比为1:1.2:0.3:2:0.15；TIPS取代的炔酰胺6和正四丁基氟化铵的摩尔比为1:1.5。
进一步地，在上述技术方案中，所述原料炔酰胺1'的合成路线如下：
具体合成步骤如下：
在氮气保护下，将炔酰胺1置于反应瓶中，加入无水四氢呋喃，缓慢滴加双(三甲硅基)氨基锂，随后缓慢升温并搅拌，然后缓慢滴加碘代烷化合物，缓慢升至室温；薄层色谱法监测反应进程，待反应完全后，加水淬灭，经萃取，合并有机相，干燥，抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料炔酰胺1'。
所述步骤中炔酰胺1、双(三甲硅基)氨基锂和碘代烷化合物的摩尔比为1:1.5:2。
进一步地，在上述技术方案中，所述原料炔基亚砜2的合成路线如下：
具体合成步骤如下：
在氮气保护下，将炔基硫醚7和二氯甲烷置于反应瓶中，加入3-氯过氧苯甲酸8，搅拌反应；薄层色谱法监测反应进程，待反应完全后，经淬灭，萃取，合并有机相，洗涤有机相，经干燥，抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料炔基亚砜2。
所述步骤中炔基硫醚7和3-氯过氧苯甲酸8的摩尔比为1:1。
所述N-取代马来酰亚胺类化合物在抗肿瘤药物中的应用，其显示出抑制C33A、Hela、A549、MCF-7和Hep G2细胞的活性，可将其应用于治疗子宫颈癌、宫颈癌、肺癌、乳腺癌和肝癌药物的制备。
与现有技术相比，本发明提供的N-取代马来酰亚胺类化合物，具有如下优势：1、该类化合物具有抑制人子宫颈癌细胞C33A、人宫颈癌细胞Hela、人肺癌细胞A549、人乳腺癌细胞MCF-7和人肝癌细胞Hep G2的活性，将其应用于抗肿瘤药物的制备，具有良好的应用前景。2、本发明合成方法在非金属条件下进行，原料易得，后处理简单，对环境友好，具有良好的底物普适性和官能团耐受性。
具体实施方式
下面通过具体实施方式，对本发明的技术方案做进一步的详细描述，但本发明的保护范围并不局限于此。若未特别指明，以下实施例中所用的技术手段为本领域技术人员所熟知的常规手段，如没有特别说明，均为质量百分比。
主要仪器与化学试剂
核磁共振波谱仪：Bruker AscendTM 400；高分辨质谱仪：Bruker MicrOTOF-Q II质谱仪；红外光谱仪：知微Smart傅立叶变换红外光谱仪(天津港东科技股份有限公司)；三用紫外线分析仪：ZF-6型(上海高鹏科技有限公司)；测定用熔点仪：XT4A显微熔点测定仪(北京科仪电光仪器厂)。
本发明实施过程中所用的原料、溶剂均为商业途径购进。
实施例1：原料炔酰胺1和1'的合成
1.1原料炔酰胺1的合成
以炔酰胺1a具体合成步骤为例，具体合成步骤如下：
1)在氮气保护下，向100mL圆底烧瓶中依次加入炔基溴化物4a(8.69g,4.8mmol)、磺酰胺5(1.05g,4.0mmol)、磷酸钾(1.70g,8.0mmol)、五水硫酸铜(149.81mg,0.6mmol)、1,10-菲咯啉(216.25mg,1.2mmol)和甲苯(30mL)，80℃下加热搅拌12h；薄层色谱法监测反应进程，待反应完全后，将反应液冷却至室温，砂芯漏斗铺硅胶和硅藻土抽滤，减压蒸馏除去溶剂，所得粗产物以石油醚/乙酸乙酯/二氯甲烷(20:1:3)加3％Et3N为洗脱剂经硅胶柱层析分离得到末端为TIPS取代的磺酰基炔酰胺6a(1.67g,3.76mmol)，为白色固体，产率为94％。
2)在氮气保护下，向50mL圆底烧瓶中加入6a(1.77g,4.0mmol)，加入无水四氢呋喃(20.0mL)进行溶解，在0℃下缓慢滴入正四丁基氟化铵(6.0mL,1.0M四氢呋喃溶液)，移至室温下搅拌0.5h；薄层色谱法监测反应进程，待反应完全后，加饱和氯化铵溶液淬灭，乙酸乙酯萃取(3×10.0mL)，合并有机相，无水硫酸钠干燥，抽滤，减压蒸馏除去溶剂，所得粗产物以石油醚/乙酸乙酯/二氯甲烷(20:1:4)加3％Et3N为洗脱剂柱层析分离得到白色固体产物1a(1.10g,3.84mmol)，产率为96％。
将对应的末端为TIPS取代的磺酰基炔酰胺6b-6d分别按本实施例中上述方法制备化合物1，对应得到化合物1b-1d。
化合物1a：白色固体，96％产率，1H NMR(400MHz,CDCl3)δ7.76(d,2H,J＝8.3Hz),7.34-7.23(m,7H),4.49(s,2H),2.68(s,1H),2.45(s,3H).
化合物1b：白色固体，64％产率，1H NMR(400MHz,CDCl3)δ7.81(d,2H,J＝8.1Hz),7.38(d,2H,J＝8.0Hz),3.07(s,3H),2.69(s,1H),2.47(s,3H).
化合物1c：白色固体，83％产率，1H NMR(400MHz,CDCl3)δ7.81(d,2H,J＝8.3Hz),7.36(d,2H,J＝8.1Hz),5.78-5.68(m,1H),5.28-5.21(m,2H),3.96(dt,2H,J＝6.3,1.3Hz),2.73(s,1H),2.46(s,3H).
化合物1d：白色固体，93％产率，1H NMR(400MHz,CDCl3)δ7.80(d,2H,J＝8.4Hz),7.35(d,2H,J＝8.1Hz),3.30(t,2H,J＝7.2Hz),2.73(s,1H),2.45(s,3H),1.68-1.57(m,2H),1.39-1.29(m,2H),0.91(t,3H,J＝7.4Hz).
1.2原料炔酰胺1'的合成
以炔酰胺1'a具体合成步骤为例，具体合成步骤如下：
在氮气保护下，向100mL圆底烧瓶中加入炔酰胺1a(1.14g,4.00mmol)，加入无水四氢呋喃(31.0mL)进行溶解，在-78℃下缓慢滴入双(三甲硅基)氨基锂(6.00mL,1.0M四氢呋喃溶液)，搅拌并缓慢升温至-60℃后，在-60℃下搅拌1.0h，然后缓慢滴入碘甲烷(0.50mL,8.00mmol)，升至室温搅拌12h；薄层色谱法监测反应进程，待反应完全后，加水淬灭，乙酸乙酯萃取(3×10.0mL)，合并有机相，无水硫酸钠干燥，抽滤，减压蒸馏除去溶剂，所得粗产物以石油醚/乙酸乙酯/二氯甲烷(100:3:5～100:5:5)加3％Et3N为洗脱剂，硅胶柱层析分离得到白色固体产物1'a(1.19g,3.96mmol)，产率为99％。
将对应的炔酰胺1b-1d按本实施例中上述方法步骤分别制备炔酰胺1'b-1'd。
化合物1'a：白色固体，99％产率，1H NMR(400MHz,CDCl3)δ7.74(d,2H,J＝8.3Hz),7.36-7.27(m,7H),4.44(s,2H),2.44(s,3H),1.81(s,3H).
化合物1'b：白色固体，85％产率，1H NMR(400MHz,CDCl3)δ7.78(d,2H,J＝8.4Hz),7.36(d,2H,J＝7.9Hz),3.01(s,3H),2.46(s,3H),1.88(s,3H).
化合物1'c：浅黄色油状物，80％产率，1H NMR(400MHz,CDCl3)δ7.78(d,2H,J＝8.1Hz),7.34(d,2H,J＝8.1Hz),5.72(ddt,1H,J＝16.6,10.1,6.3Hz),5.34-5.11(m,2H),3.91(d,2H,J＝6.3Hz),2.45(s,3H),1.88(s,3H).
化合物1'd：白色固体，89％产率，1H NMR(400MHz,CDCl3)δ7.78(d,2H,J＝8.3Hz),7.34(d,2H,J＝8.1Hz),3.24(t,2H,J＝7.2Hz),2.45(s,3H),1.90(s,3H),1.63-1.56(m,2H),1.38-1.29(m,2H),0.90(t,3H,J＝7.4Hz).
实施例2：原料炔基亚砜的合成(J.Am.Chem.Soc.2014,136,16557-16562)
具体合成步骤如下：
在氮气保护下，向100mL圆底烧瓶中依次加入炔基硫醚7(444.7mg,3.0mmol)和二氯甲烷(60mL)，0℃下加入3-氯过氧苯甲酸8(517.7mg,3.0mmol)，随后在该温度下搅拌4.0h；薄层色谱法监测反应进程，待反应完全后，30％亚硫酸钠溶液淬灭，二氯甲烷(3×10.0mL)萃取，合并有机相，饱和碳酸氢钠溶液和饱和食盐水洗涤合并的有机相，无水硫酸钠干燥，抽滤，减压蒸馏除去溶剂，所得粗产物以石油醚/乙酸乙酯(4:1～2:1)为洗脱剂，经硅胶柱层析分离得到浅黄色油状物2(438.5mg,2.67mmol)，产率为89％。
以对应的炔基硫醚7a、7b、7c、7d、7e、7f和7g按本实施例中上述方法步骤分别制备炔基亚砜2a、2b、2c、2d、2e、2f和2g。
化合物2a：浅黄色油状物，89％产率，1H NMR(400MHz,CDCl3)δ7.54(d,2H,J＝7.0Hz),7.48-7.44(m,1H),7.41-7.37(m,2H),3.07(s,3H).
化合物2b：浅黄色油状物，75％产率，Rf＝0.21[石油醚/乙酸乙酯(2:1)]；1H NMR(400MHz,CDCl3)δ7.54(d,2H,J＝8.6Hz),7.40(d,2H,J＝8.6Hz),3.07(s,3H)；13C NMR(100MHz,CDCl3)δ132.3,130.8,128.7,119.7,101.6,86.4,43.5；IR(KBr)(cm-1)3447w,2167s,1485m,1055m,1010w,822s；HRMS(ESI):m/z calcd for C9H7BrOS[M+H]+:242.9474；found 242.9473.
化合物2c：浅黄色油状物，80％产率，1H NMR(400MHz,CDCl3)δ7.69-7.64(m,4H),3.11(s,3H).
化合物2d：浅黄色油状物，82％产率，Rf＝0.26[石油醚/乙酸乙酯(2:1)]；1H NMR(400MHz,CDCl3)δ7.43(d,2H,J＝8.2Hz),7.19(d,2H,J＝7.9Hz),3.06(s,3H),2.39(s,3H)；13C NMR(100MHz,CDCl3)δ141.5,132.4,129.6,116.7,102.2,85.9,43.6,21.9；IR(KBr)(cm-1)3474w,2162s,1604m,1507m,1409w,1069s；HRMS(ESI):m/z calcd for C10H10OS[M+H]+:179.0525；found 179.0520.
化合物2e：浅黄色油状物，80％产率，1H NMR(400MHz,CDCl3)δ7.49(d,2H,J＝8.8Hz,),6.90(d,2H,J＝8.6Hz),3.85(s,3H),3.05(s,3H).
化合物2f：浅黄色油状物，75％产率，Rf＝0.27[石油醚/乙酸乙酯(2:1)]；1H NMR(400MHz,CDCl3)δ7.55-7.37(m,4H),3.07(s,3H)；13C NMR(100MHz,CDCl3)δ132.4,130.8,128.8,119.8,101.7,86.4,43.6,其中在132.4和128.8ppm处有两个碳信号重叠；IR(KBr)(cm-1)3460w,2165m,1668s,1488s,1069m,961w；HRMS(ESI):m/z calcd for C9H7BrOS[M+H]+:242.9474；found 242.9473.
化合物2g：浅黄色油状物，75％产率，Rf＝0.15[石油醚/乙酸乙酯(2:1)]；1H NMR(400MHz,CDCl3)δ7.40-7.32(m,2H),7.24(ddd,1H,J＝8.9,2.6,1.4Hz),7.22-7.15(m,1H),3.08(s,3H)；13C NMR(100MHz,CDCl3)δ162.2(d,1JC-F＝246.7Hz),130.6(d,3JC-F＝8.4Hz),128.3(d,4JC-F＝3.2Hz),121.5(d,3JC-F＝9.3Hz),119.1(d,2JC-F＝23.3Hz),118.3(d,2JC-F＝21.0Hz),100.0(d,4JC-F＝3.4Hz),87.2,43.5；19F NMR(376MHz,CDCl3)δ-111.5；IR(KBr)(cm-1)3446w,2924s,2854m,2165m,1581s,1363w；HRMS(ESI):m/zcalcd for C9H7FOS[M+H]+:183.0274；found 183.0269.
实施例3：N-取代马来酰亚胺类化合物3的合成
以化合物3a具体合成步骤为例，在氧气保护下，向干燥的反应管中依次加入炔酰胺1'a(119.8mg,0.40mmol)、炔基亚砜2a(98.5mg,0.60mmol)、甲苯(1.0mL)和三氟甲磺酸三甲基硅脂(36.2μL,0.20mmol)，保持氧气球与反应管相连，并在70℃油浴中搅拌2.0h；薄层色谱法监测反应进程，待反应完全后，将反应液冷却至室温，过硅胶抽滤，减压蒸馏除去溶剂，所得粗产物以石油醚/乙酸乙酯(40:1)为洗脱剂，经硅胶柱层析分离得到白色固体产物3a(66.6mg,0.24mmol)，产率为61％。
将实施例1中制备得到的炔酰胺1a、1b、1c和1d与实施例2中制备得到的炔基亚砜2a分别按本实施例中上述方法制备化合物3，对应得到N-取代马来酰亚胺类化合物3e、3f、3g和3h；将实施例1中制备得到的炔酰胺1'a、1'b、1'c和1'd与实施例2中制备得到的炔基亚砜2a，分别按本实施例中上述方法制备化合物3，对应得到N-取代马来酰亚胺类化合物3a、3b、3c和3d；将实施例1中制备得到的炔酰胺1a与实施例2中制备得到的炔基亚砜2b、2c、2d、2e、2f和2g分别按本实施例中上述方法制备化合物3，对应得到N-取代马来酰亚胺类化合物3i、3j、3k、3l、3m和3n。
化合物3a：白色固体，61％产率，Rf＝0.26[石油醚/乙酸乙酯(40:1)]；mp＝75–76℃；1H NMR(400MHz,CDCl3)δ7.59-7.56(m,2H),7.49-7.40(m,5H),7.35-7.27(m,3H),4.74(s,2H),2.20(s,3H)；13C NMR(100MHz,CDCl3)δ171.7,170.8,137.2,136.6,136.5,129.6,129.5,129.0,128.7,128.65,128.59,127.8,41.8,10.0；IR(neat)(cm-1)3440w,2940w,1701s,1434s,1350m,1124m；HRMS(ESI):m/z calcd for C18H16NO2[M+H]+:278.1176；found278.1176.
化合物3b：白色固体，42％产率，Rf＝0.21[石油醚/乙酸乙酯(40:1)]；mp＝73–75℃；1H NMR(400MHz,CDCl3)δ7.59-7.56(m,2H),7.50-7.41(m,3H),3.09(s,3H),2.21(s,3H)；13C NMR(100MHz,CDCl3)δ172.2,171.2,137.2,136.6,129.6,129.5,129.0,128.6,24.1,10.0；IR(neat)(cm-1)3448w,2923m,1706s,1770w,1439m,1384s；HRMS(ESI):m/z calcd forC12H12NO2[M+H]+:202.0863；found 202.0857.
化合物3c：白色固体，58％产率，Rf＝0.23[石油醚/乙酸乙酯(40:1)]；mp＝39–41℃；1H NMR(400MHz,CDCl3)δ7.61-7.57(m,2H),7.54-7.39(m,3H),5.91-5.81(m,1H),5.27-5.17(m,2H),4.19(dt,2H,J＝5.7,1.5Hz),2.22(s,3H)；13C NMR(100MHz,CDCl3)δ171.6,170.6,137.1,136.6,131.8,129.6,129.5,129.0,128.6,117.6,40.3,10.0；IR(neat)(cm-1)3451w,2923w,1706s,1435m,1398s,1126m；HRMS(ESI):m/z calcd for C14H14NO2[M+H]+:228.1019；found 228.1015.
化合物3d：黄色油状物，47％产率，Rf＝0.65[石油醚/乙酸乙酯(40:1)]；1H NMR(400MHz,CDCl3)δ7.52-7.48(m,2H),7.42-7.33(m,3H),3.50(t,2H,J＝7.2Hz),2.13(s,3H),1.58-1.50(m,2H),1.30-1.24(m,2H),0.87(t,3H,J＝7.4Hz)；13C NMR(100MHz,CDCl3)δ172.1,171.2,136.9,136.4,129.5,129.5,129.1,128.6,38.0,30.7,20.1,13.7,10.0；IR(neat)(cm-1)3452w,2903m,1704s,1442m,1405s,1186w；HRMS(ESI):m/z calcd forC15H18NO2[M+H]+:244.1332；found 244.1326.
化合物3e：白色固体，15％产率，Rf＝0.21[石油醚/乙酸乙酯(40:1)]；mp＝142–144℃；1H NMR(400MHz,CDCl3)δ7.94-7.90(m,2H),7.49-7.38(m,5H),7.35-7.26(m,3H),6.75(s,1H),4.74(s,2H)；13C NMR(100MHz,CDCl3)δ170.5,170.2,144.0,136.5,131.3,129.1,128.9,128.8,128.78,128.67,128.0,124.0,41.8.
化合物3f：黄色固体，38％产率，Rf＝0.15[石油醚/乙酸乙酯(40:1)]；mp＝146–148℃；1H NMR(400MHz,CDCl3)δ7.94-7.91(m,2H),7.47-7.44(m,3H),6.74(s,1H),3.09(s,3H)；13C NMR(100MHz,CDCl3)δ170.9,170.6,144.1,131.3,129.1,128.9,128.7,124.1,24.1.
化合物3g：黄色固体，26％产率，Rf＝0.17[石油醚/乙酸乙酯(40:1)]；mp＝78–80℃；1H NMR(400MHz,CDCl3)δ7.95-7.92(m,2H),7.48-7.44(m,3H),6.74(s,1H),5.90-5.81(m,1H),5.26-5.18(m,2H),4.20(d,2H,J＝5.6Hz)；13C NMR(100MHz,CDCl3)δ170.4,170.1,144.0,131.8,131.3,129.1,128.9,128.8,124.0,117.8,40.2；IR(neat)(cm-1)3441w,2957m,2924s,1701s,1492m,1431w；HRMS(ESI):m/z calcd for C13H12NO2[M+H]+:214.0863；found 214.0859.
化合物3h：黄色油状物，30％产率，Rf＝0.28[石油醚/乙酸乙酯(40:1)]；1H NMR(400MHz,CDCl3)δ7.87-7.83(m,2H),7.40-7.37(m,3H),6.65(s,1H),3.51(t,2H,J＝7.3Hz),1.56-1.50(m,2H),1.32-1.24(m,2H),0.87(t,3H,J＝7.4Hz)；13C NMR(100MHz,CDCl3)δ170.9,170.7,143.8,131.2,129.1,129.0,128.7,124.0,38.0,30.8,20.2,13.8；IR(neat)(cm-1)3064w,1731m,1668m,1497w,1141s,1029s；HRMS(ESI):m/z calcd forC14H16NO2[M+H]+:230.1176；found 230.1168.
化合物3i：黄色固体，18％产率，Rf＝0.28[石油醚/乙酸乙酯(40:1)]；1H NMR(400MHz,CDCl3)δ7.96-7.88(m,2H),7.51-7.27(m,7H),6.75(s,1H),4.75(s,2H)；IR(neat)(cm-1)3438w,2956m,2923s,1694s,1401m,1279w；HRMS(ESI):m/z calcd for C17H10BrNO2[M-H]+:339.9978；found 339.9985.
化合物3j：黄色固体，24％产率，Rf＝0.23[石油醚/乙酸乙酯(40:1)]；mp＝130–132℃；1H NMR(400MHz,CDCl3)δ8.03(d,2H,J＝8.1Hz),7.70(d,2H,J＝8.3Hz),7.41-7.39(m,2H),7.36-7.27(m,3H),6.85(s,1H),4.75(s,2H)；13C NMR(100MHz,CDCl3)δ170.0,169.6,142.5,136.2,132.7(q,2JC-F＝32.8Hz),132.1,129.1,128.9,128.7,128.1,126.1,126.0(q,3JC-F＝3.7Hz),123.8(q,1JC-F＝270.9Hz),41.9；19F NMR(376MHz,CDCl3)δ-63.1；IR(neat)(cm-1)3445w,2958m,2924s,1697s,1456m,1277w；HRMS(ESI):m/z calcd forC18H11F3NO2[M-H]+:330.0747；found 330.0750.
化合物3k：黄色固体，17％产率，Rf＝0.29[石油醚/乙酸乙酯(40:1)]；mp＝117–120℃；1H NMR(400MHz,CDCl3)δ7.83(d,2H,J＝8.3Hz),7.40-7.37(m,2H),7.35-7.24(m,5H),6.69(s,1H),4.73(s,2H),2.39(s,3H)；13C NMR(100MHz,CDCl3)δ170.7,170.4,144.0,142.0,136.6,129.9,128.8,128.73,128.66,128.0,126.1,122.8,41.7,21.8；IR(neat)(cm-1)3441w,2919m,2849w,1692s,1611m,1402s；HRMS(ESI):m/z calcd for C18H16NO2[M+H]+:278.1176；found 278.1175.
化合物3l：黄色固体，13％产率，Rf＝0.16[石油醚/乙酸乙酯(40:1)]；mp＝124–126℃；1H NMR(400MHz,CDCl3)δ7.93(dt,2H,J＝9.0,3.0Hz),7.40-7.26(m,5H),6.95(dt,2H,J＝9.0,3.0Hz),6.61(s,1H),4.73(s,2H),3.86(s,3H)；13C NMR(100MHz,CDCl3)δ170.9,170.6,162.2,143.5,136.7,130.6,128.8,128.6,127.9,121.6,121.0,114.6,55.6,41.7；IR(neat)(cm-1)3439w,2957m,2923s,1697s,1604m,1434w；HRMS(ESI):m/z calcd forC18H16NO3[M+H]+:294.1125；found 294.1124.
化合物3m：白色固体，13％产率，Rf＝0.25[石油醚/乙酸乙酯(40:1)]；mp＝148–150℃；1H NMR(400MHz,CDCl3)δ7.93-7.90(m,2H),7.46-7.27(m,7H),6.74(s,1H),4.74(s,2H)；13C NMR(100MHz,CDCl3)δ170.5,170.2,144.0,136.5,131.3,129.1,128.9,128.8,128.7,128.0,124.1,41.8,其中在128.9,128.8和128.7ppm处有三个碳信号重叠；IR(neat)(cm-1)3439w,2920m,1759w,1703s,1397s,1176w；HRMS(ESI):m/z calcd for C17H13BrNO2[M+H]+:342.0124；found 342.0124.
化合物3n：黄色固体，20％产率，Rf＝0.22[石油醚/乙酸乙酯(40:1)]；mp＝126–128℃；1H NMR(400MHz,CDCl3)δ7.70-7.66(m,2H),7.44-7.39(m,3H),7.35-7.28(m,3H),7.16(tdd,J＝8.3,2.4,1.1Hz,1H),6.76(s,1H),4.74(s,2H)；13C NMR(100MHz,CDCl3)δ170.1,169.7,162.9(d,1JC-F＝245.7Hz),142.6(d,4JC-F＝2.9Hz),136.3,130.7(d,3JC-F＝8.0Hz),130.7(d,3JC-F＝8.2Hz),128.9,128.7,128.1,125.1,124.5(d,4JC-F＝3.1Hz),118.3(d,2JC-F＝21.1Hz),115.7(d,2JC-F＝23.3Hz),41.8；19F NMR(376MHz,CDCl3)δ-111.4；IR(neat)(cm-1)3409s,2922s,2851m,1708m,1434w,1400w；HRMS(ESI):m/z calcd forC17H12FNNaO2[M+H]+:304.0744；found 304.0742.
实施例4：本发明实施例3所合成的代表性化合物的抗肿瘤活性研究
化合物3抗肿瘤活性研究所用的细胞株、细胞培养试剂、实验仪器及来源见表1、表2和表3。
表1细胞株种类及来源
表2细胞培养试剂及生产厂家
表3实验仪器及生产厂家
化合物3的抗肿瘤细胞活性及细胞毒性检测：
以VCR(长春新碱)为阳性对照药，使用CCK-8法进行抗肿瘤活性实验步骤如下：取对数生长期的癌细胞计数，配制成浓度为5×104个/mL细胞悬液，震荡混匀后接种于96孔板，每孔加入细胞悬液100μL，37℃、体积百分比5％ CO2培养条件下培养4-8h；用新鲜的培养基配置含不同浓度化合物的培养液培养48h；48h后，甩掉96孔板孔内培养液，每孔加入10％ CCK8溶液100μL，继续培养1-4h，然后在450nm波长下检测吸光度。抑制率＝[(Ac-As)/(Ac-Ab)]×100％；As：实验孔吸光度(含细胞、培养基、CCK-8溶液，化合物培养液处理组)；Ac：对照孔吸光度(含细胞、培养基、CCK-8溶液，不含化合物培养液处理组)；Ab：空白孔吸光度(含培养基和CCK-8溶液，不含细胞和化合物)。以VCR(长春新碱)为阳性对照药，使用GraphPad Prism 9.0计算化合物的IC50见表4。
表4化合物3对部分癌细胞的抗肿瘤活性
本试验采用本领域技术人员熟知的方法进行，利用5种癌细胞株评价本发明所制备的N-取代马来酰亚胺类化合物3的抗肿瘤活性及细胞毒性。实验结果表明：1.所检测的目标化合物3e-3n对所测的癌细胞株(人子宫颈癌细胞C33A、人宫颈癌细胞Hela、人肝癌细胞Hep G2、人肺癌细胞A549和人乳腺癌细胞MCF-7)均具有很好的抑制活性；2.其中，所检测的目标化合物3e-3n对人子宫颈癌细胞C33A和人宫颈癌细胞Hela均具有很强的抑制活性；3.具体到各个化合物与阳性对照药VCR(长春新碱)相比，3e、3j和3m对人子宫颈癌细胞C33A、人宫颈癌细胞Hela、人肝癌细胞Hep G2和人乳腺癌细胞MCF-7具有很好的抑制活性；3f对人子宫颈癌细胞C33A、人宫颈癌细胞Hela和人乳腺癌细胞MCF-7具有很好的抑制活性；3g、3h和3l对人子宫颈癌细胞C33A和人宫颈癌细胞Hela具有很好的抑制活性；3i对人子宫颈癌细胞C33A具有很好的抑制活性；3k和3n对人子宫颈癌细胞C33A、人宫颈癌细胞Hela、人肝癌细胞Hep G2、人肺癌细胞A549和人乳腺癌细胞MCF-7具有很好的抑制活性。可以看出，本发明所述化合物具有很好的抗肿瘤活性，将其应用于抗肿瘤药物的制备，具有很好的开发前景。
Claims (8)
1.一种N-取代马来酰亚胺类化合物，其特征在于，其结构通式如下：
R选自C1-6烷基、氢；R1选自C1-6烷基、烯丙基；R2选自苯基或被C1-3烷基、卤素、甲氧基、三氟甲基单取代的苯基。
2.如权利要求1所述N-取代马来酰亚胺类化合物，其特征在于，R选自氢；R1选自C1-4烷基、烯丙基；R2选自苯基或被C1-3烷基、卤素、甲氧基、三氟甲基单取代的苯基。
3.如权利要求1所述N-取代马来酰亚胺类化合物，其特征在于，选自如下化合物：
4.制备如权利要求1所述N-取代马来酰亚胺类化合物的方法，其特征在于，通过如下方法实现：
在氧气保护下，向干燥的反应管内依次加入炔酰胺1或1'、炔基亚砜2、甲苯和三氟甲磺酸三甲基硅脂，保持氧气球与反应管相连，置于油浴中搅拌反应；薄层色谱法监测反应进程，待反应完全后，将反应液冷却至室温，抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到一系列N-取代马来酰亚胺类化合物3。
5.根据权利要求4所述N-取代马来酰亚胺类化合物的制备方法，其特征在于，原料炔酰胺1通过如下方法实现：
1)在氮气保护下，将炔基溴化物4、磺酰胺5、1,10-菲咯啉、磷酸钾、五水硫酸铜、甲苯置于反应瓶中，加热搅拌反应；薄层色谱法监测反应进程，待反应完全后，将反应液冷却至室温，抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料炔基末端为TIPS取代的磺酰基炔酰胺6；
2)在氮气保护下，将TIPS取代的磺酰基炔酰胺6置于反应瓶中，加入无水四氢呋喃，缓慢滴加正四丁基氟化铵，随后转移至室温进行反应；薄层色谱法监测反应进程，至反应完全，经淬灭，萃取，合并有机相，干燥，抽滤，减压浓缩除去溶剂后，所得粗产物经硅胶柱层析分离得到原料炔酰胺1。
6.根据权利要求4所述N-取代马来酰亚胺类化合物的制备方法，其特征在于，原料炔酰胺1'通过如下方法实现：
在氮气保护下，将炔酰胺1置于反应瓶中，加入无水四氢呋喃，缓慢滴加双(三甲硅基)氨基锂，随后缓慢升温，缓慢滴加碘代烷化合物，缓慢升至室温；薄层色谱法监测反应进程，待反应完全后，淬灭，萃取，合并有机相，经干燥，抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料炔酰胺1'。
7.根据权利要求4所述N-取代马来酰亚胺类化合物的制备方法，其特征在于，原料炔基亚砜2通过如下方法实现：
在氮气保护下，将炔基硫醚7和二氯甲烷置于反应瓶中，加入3-氯过氧苯甲酸8，搅拌反应；薄层色谱法监测反应进程，待反应完全后，淬灭，萃取，合并有机相，洗涤合并的有机相，经干燥，抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料炔基亚砜2。
8.根据权利要求1、2或3所述N-取代马来酰亚胺类化合物在制备抗肿瘤药物中的应用，其特征在于，以其为活性成分，将其应用于制备治疗子宫颈癌、宫颈癌、肝癌、肺癌或乳腺癌的药物。
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