CN105884670B - 一类2,3,4-三取代吡咯类化合物及其合成方法和应用 - Google Patents
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- C07—ORGANIC CHEMISTRY
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及一类2,3,4‑三取代吡咯类化合物及其合成方法和应用，具体是在较温和条件下，铜催化异腈和联烯发生环化反应，开拓了较为简单的合成多取代吡咯的方法。该类化合物结构通式如下式所示，其中R1,R2为给电子的烷基或者芳基；R3为烷基或卤素。本申请首次运用该方法合成出了一系列3位含有芳基砜官能团的2,3,4‑三取代吡咯类化合物，在建立该类化合物库的合成应用方面具有广阔的前景。本申请在合成的一系列3位含有芳基砜官能团的2,3,4‑三取代吡咯类化合物中选取两个进行了体外肿瘤细胞抑制活性的测试，对人白血病细胞(HL‑60)有抑制活性。
Description
技术领域
本发明涉及有机合成领域，特别是涉及铜催化的联烯和异腈发生环化反应合成多取代吡咯化合物的有机合成方法，尤其是一种2,3,4-三取代吡咯类化合物及其合成方法。
技术背景
多取代吡咯化合物是一类重要的杂环化合物，是许多天然产物的重要结构单元，也是许多药物和材料结构的重要中间体。因此，开发多取代吡咯合成的方法受到许多化学家的关注。
吡咯环的合成有多种合成方法。传统的吡咯及其衍生物的合成方法包括Paal.Knorr合成法，Knorr合成法，Hantzsch合成法，Van-Leusen合成法和Barton-Zard合成法等。近年来化学家们还发展了铜，银或者有机膦催化的异腈和炔的1,3-偶极环加成反应来合成吡咯。虽然合成吡咯的方法很多，但合成三取代吡咯的方法并不多，这就为后续开发三取代吡咯合成的新方法留下了巨大的空间。
发明内容
本发明的目的是提供一类2,3,4-三取代吡咯类化合物及其合成方法和应用，本方法在铜的催化下，异腈和联烯发生环化反应合成多取代吡咯化合物的方法，本方法条件温和，方法简单。
本发明的目的是通过以下技术方案实现的：
一类新型3位含有芳基砜官能团的2,3,4-三取代吡咯类化合物，结构式通式如下：
而且，所述的R1,为给电子的烷基或者芳基。
而且，所述的R2为给电子的烷基或者芳基。
而且，所述的R3为烷基或卤素。
一类新型3位含有芳基砜官能团的2,3,4-三取代吡咯类化合物的合成方法，其特征在于：合成路线如下：
所用的溶剂为1,4-二氧六环和水。反应温度为50℃。反应时长为1小时。
已合成的多取代吡咯化合物的命名与结构如下表所示：
表1 3位含有芳基砜官能团的2,3,4-三取代吡咯类化合物的命名与结构
一类新型3位含有芳基砜官能团的2,3,4-三取代吡咯类化合物16作为制备治疗抗肿瘤药物中的作用。所述抗肿瘤药物为治疗白血病的药物。
本发明的优点和积极效果：
1、本发明采用现有的原料和催化剂，来源广泛，便宜易得，生产成本低。
2、本发明的反应条件温和，无高温高压反应，反应条件安全，适合大规模生产和开发。
3、本反应能合成三取代的多取代吡咯化合物，可以按照本发明的原理进行推广使用，适用于多种取代基。
4、本发明涉及的化合物具有抑制或者杀灭肿瘤的作用，可用作制备治疗人白血病的药物，经过实际检测发现，化合物16对人白血病细胞IC50(μm)<100，对其有抑制作用。
附图说明
图1-1和图1-2为ethyl 4-(tosylmethyl)-1H-pyrrole-3-carboxylate化合物1的核磁谱图，图1-1为氢谱，图1-2为碳谱。
图2-1和图2-2为ethyl 4-(2,2-dimethyl-1-tosylpropyl)-1H-pyrrole-3-carboxylate化合物4的核磁共振谱图，图2-1为氢谱，图2-2为碳谱。
图3-1和图3-2ethyl 5-methyl-4-(tosylmethyl)-1H-pyrrole-3-carboxylate化合物9的核磁共振谱图，图3-1为氢谱，图3-2为碳谱。
图4-1和图4-2为ethyl 5-ethyl-4-(((4-fluorophenyl)sulfonyl)methyl)-1H-pyrrole-3-carboxylate化合物16的核磁共振谱图，图4-1为氢谱，图4-2为碳谱。
具体的实施方式
为了理解本发明，下面结合实施例对本发明作进一步说明：下述实施例是说明性的，不是限定性的，不能以下述实施例来限定本发明的保护范围。
本发明所述的多取代吡咯化合物结构通式如下式所示
具体命名与结构如上表1所示。
以上多取代吡咯化合物均是通过以下合成通法合成的：
在15mL耐压管中依次加入苯并呋喃衍生物(1mmol)、联烯(0.6mmol)、氧化亚铜(0.025mmol)和1,10-菲罗啉(0.05mmol)，加入1,4-二氧六环(1mL)，水(0.1ml)。然后加热至50℃反应，1h后点板检测反应完全后，石油醚：乙酸乙酯＝5:0-7.5:1作为流动相，柱层析得到表1所示各化合物，产率43-84％。
下面通过实施例具体说明。
实施例1
化合物1的合成。
实施例1的合成方法同上述合成通法。
ethyl 4-(tosylmethyl)-1H-pyrrole-3-carboxylate
收率：43％；白色固体；熔点：137-137.7℃。
1H NMR(400MHz,CDCl3)δ8.83(s,1H),7.60(d,J＝8.2Hz,2H),7.30(t,J＝5.2Hz,1H),7.24(d,J＝8.0Hz,2H),6.90(s,1H),4.72(s,2H),4.05(q,J＝7.2Hz,2H),2.41(s,3H),1.23(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ164.30,144.25,135.68,129.30,128.55,124.52,121.48,114.77,110.66,77.32,77.00,76.68,59.48,53.33,21.54,14.27.HRMS(ESI)m/e calcd for C15H18O4NS(M+H)+308.0951,found308.0946.
实施例2
化合物4的合成。
实施例2的合成方法同上述合成通法。
ethyl 4-(2,2-dimethyl-1-tosylpropyl)-1H-pyrrole-3-carboxylate
收率：55％；白色固体；熔点：141.3-141.5℃
1H NMR(400MHz,CDCl3)δ8.71(s,1H),7.42(d,J＝8.0Hz,2H),7.17(dt,J＝5.1,2.2Hz,2H),7.05(d,J＝8.0Hz,2H),5.47(s,1H),4.16–3.99(m,2H),2.31(s,3H),1.27(s,9H),1.22(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ164.35,143.03,138.33,128.67,128.02,123.63,120.86,116.28,115.27,77.32,77.00,76.68,68.52,59.27, 36.95,29.29,21.43,14.30.HRMS(ESI)m/e calcd for C19H26O4NS(M+H)+364.1577,found364.1573.
实施例3
化合物9的合成。
实施例3的合成方法同上述合成通法。
ethyl 5-methyl-4-(tosylmethyl)-1H-pyrrole-3-carboxylate
收率：62％；黄色固体；熔点：112.1-127.6℃；
1H NMR(400MHz,CDCl3)δ8.44(s,1H),7.58(d,J＝8.2Hz,2H),7.23(d,J＝8.0Hz,2H),7.18(d,J＝3.0Hz,1H),4.65(s,2H),4.00(q,J＝7.1Hz,2H),2.40(s,3H),2.23(s,3H),1.21(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ164.47,144.14,135.80,130.91,129.22,128.63,122.95,114.79,106.36,77.32,77.00,76.68,59.29,52.99,21.52,14.25,11.16.HRMS(ESI)m/e calcd for C16H20O4NS(M+H)+322.1108,found322.1104.
实施例4
化合物16的合成。
实施例4的合成方法同上述合成通法。
ethyl 5-ethyl-4-(((4-fluorophenyl)sulfonyl)methyl)-1H-pyrrole-3-carboxylate
产率：84％；黄色油状物；
1H NMR(400MHz,CDCl3)δ9.19(s,1H),7.70(dd,J＝8.4,5.2Hz,2H),7.19(d,J＝2.4Hz,1H),7.11(t,J＝8.5Hz,2H),4.72(s,2H),4.01(q,J＝7.1Hz,2H),2.63(q,J＝7.5Hz,2H),1.21(dd,J＝15.6,7.6Hz,6H).13C NMR(100MHz,CDCl3)δ166.87,164.44,164.33,136.69,134.47(d,J＝3.0Hz),131.58(d,J＝9.5Hz),123.21,115.78,115.55,114.26,105.33,77.32,77.00,76.68,59.28,52.86,18.61,14.18,13.25.HRMS(ESI)m/e calcd forC16H19FNO4S(M+H)+340.10133,found 340.10184.
化合物1和化合物16的抗肿瘤活性测定
取处于对数生长期的细胞，确定细胞密度为5×104cell/mL接种于96孔板上，每孔加入细胞悬液100μL，同时设置空白孔和对照孔。于37℃、5％CO2培养箱中培养一定时间(悬浮细胞培养2h，贴壁细胞培养24h)，分别加入终浓度为0.01，0.1，1，10，100μM的化合物，每孔0.5μL，每个药物浓度设置3个复孔。空白孔为完全培养基孔(即不含有细胞、DMSO及化合物)；对照孔为细胞悬液中仅加入含相同浓度DMSO。置于37℃，5％CO2恒温培养箱中，孵育48h后，每孔加入5mg/mL的MTT溶液20μL(用PBS配制，0.22μm滤膜过滤除菌)，置于37℃，5％CO2恒温培养箱中继续孵育4h，终止培养。贴壁细胞处理方式小心移除孔内培养上清液，每孔加入100μL DMSO；悬浮细胞处理方式就是在每孔中继续加入100μL盐酸-异丙醇溶液后反复吹打混匀，37℃放置10min后，使紫色结晶物甲瓒充分溶解，用酶标仪(490nm,630nm或570nm,630nm)测定各孔的吸光度(OD)值，按以下公式计算细胞抑制率。细胞存活率(％)＝(实验组OD-空白组OD)/(对照组OD-空白组OD)×100％IC50：即细胞存活率为50％时的药物浓度，又称半数有效抑制浓度。根据MTT结果求直线回归方程，并计算每个时间点的IC50值。
表1化合物1和化合物16的抗肿瘤活性测试结果
注：悬浮细胞为K562/HL-60人白血病细胞
贴壁细胞为NCI-H1299人肺癌细胞、HT-29人结直肠癌、MCF-7人乳腺癌细胞
本发明所涉及的化合物16可以抑制或者杀灭肿瘤细胞，具有抗肿瘤活性，可以在治疗肿瘤的药物中应用。
Claims (2)
1.新型3位含有芳基砜官能团的2,3,4-三取代吡咯类化合物，其特征在于：结构式如下：
2.一类新型3位含有芳基砜官能团的2,3,4-三取代吡咯类化合物的合成方法，其特征在于：合成路线如下：
R1为H,R2为乙基，R3为F；
所用的溶剂为1,4-二氧六环和水；
反应温度为50℃，反应时长为1小时。
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