CN116462624A - 一种环丁烯衍生物的制备方法 - Google Patents
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
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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
本发明公开了一种环丁烯衍生物的制备方法,在廉价易得的金属离子催化剂作用下,共轭的乙酰酸酯在催化剂存在下,与吲哚类化合物发生反应,可以在吲哚类化合物的3‑位上生成环丁烯衍生物。环丁烯衍生物可以通过各种还原方法,很容易制得环丁烷衍生物。本发明提出了不同于现有技术的反应原料底物,拓宽了通过交叉耦合制备四元环化合物的种类的选择范围。
Description
技术领域
本发明属于有机化合物工艺应用技术领域,更具体地,涉及一种四元环衍生物,尤其是环丁烯衍生物的制备方法。
背景技术
四元环化合物,如环丁烷、环丁烯衍生物是广泛存在于各类药物分子中的基本结构骨架,这类衍生物大都具有良好的药性及其它生物活性。同时,由于四元环化合物的张力能较大(如环丁烷的张力能为26.3kal/mol),较容易在过渡金属催化下进行C-C键断裂,发生开环反应合成其它化合物[Chemical Reviews.2015,115,9410]。因此,四元环化合物的合成受到了越来越多研究者的关注。
四元环衍生物的合成一直是小环有机化学领域中的热点。在这一领域中,制备高区域、高立体选择性的四元环化合物一直以来都面临着巨大的挑战。目前,比较常用的合成方法有:[2+2]环加成反应、扩环反应、和缩环反应。其中,[2+2]环加成反应更为普遍。环加成反应是经典有机反应,在加热条件下,烯烃的[4+2]环加成反应就可以发生,而相比较而言,[2+2]环加成反应则需在光照、酸或过渡金属作用下才能进行,其中,光照作用下的[2+2]环加成反应是人们得到四元环类化合物最直接有效的方法[Chemical Reviews 2016,116,7330]。同时,环丁烯衍生物可以通过各种还原方法,很容易制得环丁烷衍生物。
但目前的合成方法均存在不足:原料在自然界中并非广泛存在,需要事先制备,成本昂贵;反应步骤冗长,操作步骤复杂;原子利用率低,产物产率低,且有些试剂对人体伤害较大。因此迫切需要开发一种更简洁的方法。
发明内容
针对现有技术的以上缺陷或改进需求,本发明提供了一种四元环衍生物的制备方法,特别是一种环丁烯衍生物的制备方法。环丁烯衍生物可以通过各种还原方法,很容易制得环丁烷衍生物。本发明的目的在于提供一种新型的四元环衍生物的制备技术,并解决现有技术存在的原料成本昂贵、制备步骤复杂、试剂危害大等问题。
本发明发现,共轭的乙酰酸酯在催化剂存在下,与吲哚类衍生物发生反应,可以生成环丁烯衍生物,其化学反应式如下:
其中,R1为芳香烃或脂肪烃;
R2为氢、羟基、卤素、C1-C10的脂肪烃、C6-C13芳香烃、C1-C10脂肪烃氧基、C6-C13芳香烃氧基,其取代位置可以为吲哚环的4,5,6,7-位的任意位置;
R3为氢、C1-C10的脂肪烃、C1-C10脂肪烃氧基、C6-C13芳香烃、C6-C13芳香烃氧基。
进一步的,所述共轭的乙酰酸酯为R1为C1-C5的脂肪烃,R2为5-位取代的羟基、C6-C13芳香烃氧基;
所述催化剂为有机金属催化剂,包括三氯化铟、氯化铁、氯化锡。
更进一步的,所述共轭的乙酰酸酯为乙酰乙酸甲酯、乙酰乙酸乙酯、乙酰乙酸丁酯;
所述催化剂为三氯化铟。
本发明所用的原料与反应为有机化学领域常用,且有文献报道:在同样的原料与反应条件下,得到与本发明完全不一样的反应产物。如在文献[J Enzyme Inhib Med Chem,2009,24(5):1148-1153]中,作者在意图将1-甲基-5-羟基吲哚(1)与乙酰乙酸乙酯(EAA)通过von Pechmann反应来制备pyranoindole(2),但是却根据乙酰乙酸乙酯用量的多少而意外地得到了MIBE(3)或者产物(4)。
本发明用同样的原材料与反应条件,原意为了获得化合物3,但在产物的结构确证中发现与文献结果不一致。多次反应验证后,本发明通过二维核磁确定了反应产物的结构,并从中发现了一种新的环丁烯化合物的合成方法。环丁烯衍生物可以通过各种还原方法,很容易制得环丁烷衍生物。
本发明与现有技术相比,具有以下效果:
(1)本发明提出了一种在廉价易得的金属离子催化剂作用下,乙酰乙酸酯衍生物通过交叉耦合反应制备四元环化合物的制备方法,金属离子催化剂比如三价铟催化剂,廉价易得,对环境没有危害。反应操作非常简单,反应条件温和,产率中等。
(2)本发明提出的四元环化合物的制备方法,提出了不同于现有技术的反应原料底物,拓宽了通过交叉耦合制备四元环化合物的种类的选择范围。
(3)已报道的合成四元环化合物的方法一般原料复杂难得,并且条件苛刻难操作,对工业化应用造成很大的限制。本发明合成的四元环化合物广泛存在于各类药物分子中的基本结构骨架,这类衍生物大都具有良好的药性及其它生物活性,本发明创新设计的反应路线为合成这类化合物提供了了一个简便的制备方法。
附图说明
图1为化合物5的核磁共振氢谱(1H-NMR);
图2为化合物5的核磁共振碳谱(13C-NMR);
图3为化合物5的二级核磁共振碳谱(DEPT-135);
图4为化合物5的二级核磁共振谱(HSQC);
图5为化合物5的二级核磁共振谱图(H-H COSY);
图6为化合物5的二级核磁共振谱图(NOE);
图7为化合物5的二级核磁共振谱图(HMBC);
图8为化合物5的高分辨质谱(HRMS);
图9为化合物6的核磁共振氢谱(1H-NMR);
图10为化合物6的核磁共振氢谱(1H-NMR)局部放大图;
图11为化合物6的核磁共振碳谱(13C-NMR);
图12为化合物6的质谱(MS)。
具体实施方式
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实例和制备例的范围并不以任何方式限制本发明的范围。本发明的原料可以从商业途径获得或通过本领域已知的方法制备。
化合物的结构通过核磁共振(NMR)和质谱(MS)来确定,NMR测定是用ACF-400BRUK型核磁共振仪,测定溶剂为氘代氯仿(CDC13)或氘代二甲亚砜(DMSO-d6),TMS为内标。柱层析采用200-300目硅胶。
实施例1:化合物5的制备
在氮气下将氯化铟(III)(10mol%)加入到吲哚衍生物和乙酰乙酸乙酯的混合物中(过量,也用作溶剂)。将反应混合物在120℃加热2小时,然后将其冷却至室温。加入冰水,反应混合物用乙酸乙酯(EtOAc)萃取。收集有机层并用盐水洗涤,用MgSO4干燥并在减压下蒸发。将残余物在硅胶上进行柱色谱分离(己烷-EtOAc=6∶1的混合物作为洗脱剂),得到所需的产物化合物5:收率25%,白色晶体,mp 178-180℃.1H-NMR(d6-DMSO)δ:8.93(s,1H,Ar);7.33(d,1H,Ar,J7,6=8.8Hz);6.90(d,1H,Ar);6.81(dd,1H,Ar);6.05(s,1H,C=CH);4.13-4.12(q,2H,CH2);3.94-3.90(m,2H,CH2);3.78(s,3H,NCH3);3.75(d,1H,C=CH2);3.27(d,1H,C=CH2);2.75-2.63(dd,2H,CH2);1.44(s,3H,C-CH3);1.26-1.23(t,3H,CH3);0.97-0.95(t,3H,CH3).13C-NMR(d6-DMSO)δ:170.8,166.7,151.9,151.0,140.0,139.0,137.5,121.8,115.0,111.3,104.1,103.5,59.5,59.1,51.1,44.9,40.0,30.8,27.1,14.4,13.8.HRMS(ESI):calc for C21 H25 NO5[M+H]+372.1824,found372.1801.
一维、二维磁核图谱及HRMS见附图1-8。
实施例2:化合物6的制备
按实施例1的方法,用1-甲基-5-苄氧基吲哚代替1-甲基-5-羟基吲哚,得化合物6,收率30%,白色晶体,mp 162-163℃.1H-NMR(d6-DMSO)δ:7.48(d,2H,Ar);7.39(t,2H,Ar);7.32(t,1H,Ar);7.20(d,1H,Ar);7.11(d,1H,Ar);7.02(dd,1H,Ar);6.05(t,1H,C=CH);5.09(s,2H,Ar-CH2);4.25-4.15(q,2H,CH2);4.07-3.98(m,2H,CH2);3.91(dd,1H,CH);3.87(s,3H,NCH3);3.46-3.41(dd,2H,C=CH2);2.81-2.66(dd,2H,CH2);1.55(s,3H,C-CH3);1.35-1.31(t,3H,CH3);1.09-1.06(t,3H,CH3).13C-NMR(d6-DMSO)δ:171.5,167.6,153.2,152.1,140.8,140.1,138.5,137.3,128.6,128.0,127.6,122.2,115.5,110.8,105.1,103.4,71.0,60.2,60.0,51.7,45.7,40.5,31.1,27.3,14.5,14.1.MS(EI)m/z(%):461(M+,72.0),416.3(10.0),374.3(100),370.25(24.0),284.2(38.0),91.1(61.0).
磁核图谱及MS见附图9-12。
实施例3.肿瘤细胞的增殖抑制活性
取对数生长期的肿瘤细胞株(HepG2肝癌、MCF-7乳腺癌细胞、H1299人肺癌细胞、786-O人肾透明细胞癌细胞),按4000细胞/孔接种于96孔培养液,设置对照组(DMSO)及化合物处理组。化合物浓度最高为50μg/mL,5倍梯度稀释,总共5个浓度,每个浓度三个复孔。化合物作用细胞72小时后,弃去培养液,每孔加入预冷的10%三氯醋酸(TCA)溶液100微升固定细胞,4℃冰箱放置1小时,培养液各孔用去离子水洗涤五遍,去除三氯醋酸溶液,在空气中干燥后,每孔加入1%乙酸配制的SRB溶液(4mg/mL)50微升,室温下放置20分钟,弃去各孔内液体后用1%乙酸洗涤五遍,洗干净未结合的SRB染料后空气干燥,每孔加入pH=10.5的10mM的Tris-base(三羟甲基胺基甲烷)溶液100微升溶解,在平板振荡5分钟,酶标仪515nm波长下测定吸光度OD值。
MTT法测得化合物得IC50值如下表所示:
表.化合物IC50(μM)值
可见,用本发明提供的方法来合成得到的化合物具有较好的对肿瘤细胞的增殖抑制活性,并对不同的细胞株(HepG2肝癌、MCF-7乳腺癌细胞、H1299人肺癌细胞、786-O人肾透明细胞癌细胞)表现出一定的选择性,因而,可以在制备治疗、预防及缓解癌症的药物中有所应用。
Claims (5)
1.一种环丁烯衍生物的制备方法,其特征在于,共轭的乙酰酸酯在催化剂存在下,与吲哚类化合物发生反应,在吲哚类化合物的3-位上生成环丁烯衍生物,其化学反应式如下:
其中,R1为芳香烃或脂肪烃;
R2为氢、羟基、卤素、C1-C10的脂肪烃、C6-C13芳香烃、C1-C10脂肪烃氧基、C6-C13芳香烃氧基,其取代位置为吲哚环的4,5,6,7-位的任意位置;
R3为氢、C1-C10的脂肪烃、C1-C10脂肪烃氧基、C6-C13芳香烃、C6-C13芳香烃氧基。
2.如权利要求1所述的环丁烯衍生物的制备方法,其特征在于,R1为C1-C5的脂肪烃,R2为5-位取代的羟基、C6-C13芳香烃氧基。
3.如权利要求1所述的环丁烯衍生物的制备方法,其特征在于,所述共轭的乙酰酸酯为乙酰乙酸甲酯、乙酰乙酸乙酯或乙酰乙酸丁酯。
4.如权利要求1所述的环丁烯衍生物的制备方法,其特征在于,所述催化剂为有机金属催化剂。
5.如权利要求4所述的环丁烯衍生物的制备方法,其特征在于,所述有机金属催化剂为三氯化铟。
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