CN106008477B - 3-(2-芳基-1h-吲哚-3-基)-4-羟基呋喃-2(5h)-酮及其合成方法 - Google Patents
3-(2-芳基-1h-吲哚-3-基)-4-羟基呋喃-2(5h)-酮及其合成方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种3‑(2‑芳基‑1H‑吲哚‑3‑基)‑4‑羟基呋喃‑2(5H)‑酮的合成方法，该合成方法是以取代苯甲酰甲醛、取代苯胺和季酮酸为原料，以醇、醚、腈、水、二甲亚砜、N,N‑二甲基甲酰胺、醋酸或芳香烃化合物为溶剂，在不使用催化剂，或以无机碱、无机酸、有机酸或有机小分子化合物为催化剂的情况下，在微波辐射下利用多组分反应，将这三种原料通过“一锅煮”的方法合成了一种同时具有呋喃‑2(5H)‑酮和吲哚两种骨架的新型化合物。本发明的合成方法具有反应时间较短，条件较为简单，高产率，高原子经济性，收敛性以及易操作等优点。
Description
技术领域
本发明属于有机化合成领域，具体而言，涉及一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮及其合成方法。
背景技术
呋喃-2(5H)-酮是一种重要的呋喃类杂环化合物，它广泛存在自然界中，维生素C(结构式1)和青霉酸(结构式2)是人们最为熟悉的呋喃-2(5H)-酮衍生物。4,5-二甲基-3-羟基呋喃-2(5H)-酮(结构式3)是一种具有香味的物质(R.Kazlauskas,P.T.Murphy,R.J.Quinn,R.J.Wells,Tetrahedron Lett.,1977,18,37)。某些重要中药的有效成分，也含有呋喃-2(5H)-酮结构的化合物，例如：威灵仙中的白头翁素(结构式4)等(吕丹，海峡药学，1999,11,7)。
呋喃-2(5H)-酮结构的化合物具有广泛的生物和药理学活性，例如：抗真菌、抗炎、抗病毒、抗癌等等((a)G.Grossmann,M.Poncioni,M.Bornand,B.Jolivet,M.Neuburger,U.Sequin,Tetrahedron,2003,59,3237.)。近几年又发现该类骨架的化合物具有抑制细菌群体效应的活性((a)M.Hentzer,K.Riedel,T.B.Rasmussen,A.Heydorn,J.B.Andersen,M.R.Parsen,S.A.Rice,L.Eberl,S.Molin,N.Hoiby,S.Kjelleberg,M.Givskov,Microbiology,2002,148,87；(b)D.Ren,R.Zuo,T.K.Wood,Applied Microbiology andBiotechnology,2005,66,689.)。一些具有呋喃-2(5H)-酮结构的化合物研究应用于药物和农药中，例如：新型非甾体抗炎药物罗昔布(rofecoxib,MK 966)(结构式5)(嵇汝运，国外医药合成药，生化药，制剂分册，1999,20,258.)和农药杀螨剂螺螨酯(结构式6)(R.Fischer,T.Bretschneider,B.W.Krueger,DE,4216814,1993.01.21.)及螺虫酯(结构式7)(U.Wachendorff-Neumann,WO,20000042850,2000.07.27.)都具有呋喃-2(5H)-酮骨架。
吲哚类化合物是自然界中分布最广的杂环化合物，作为医药、农药、染料和其它精细化工产品的中间体，其应用越来越广。首先，吲哚环在许多药物中是一个重要的骨架，比如治疗成年人和儿童哮喘的新药顺尔宁(Singulair)，以及治疗偏头痛药物(Maxalt)；同样，针对结肠、乳腺癌细胞具有高选择性的抗肿瘤活性的吲哚-醌醇化合物，其结构式为(A.J.McCarroll,T.D.Bradshaw,A.D.Westwell,C.S.Matthews,M.F.G.Stevens.J.Med.Chem.,2007,50,1707)；吲哚衍生物可作为神经保护药物，高效阿片受体兴奋剂，治疗骨质疏松症药物PPAR-c，治疗周围神经病变以及神经退化疾病的药物，葡萄糖激酶活化剂，细胞毒性抗生素CC-1065和它的前体药物，以及治疗心血管疾病催化剂PPAR-delta(G.Bratulescu,Tetrahedron Lett.,2008,49,984)。
多组分反应就是一种符合环境友好型的合成方法学，多组分反应是将三个或者三个以上的原料通过“一锅煮”的方法合成包含所有组分主要结构片段的新化合物的过程。多组分具有高产率、高原子经济性、收敛性以及易操作等优点。通过多组分反应可以利用一些简单易得的原料，方便、高效地构建具有结构多样性和复杂性的化合物，该方法已经广泛应用于各种杂环化合物的合成。
发明内容
基于呋喃-2(5H)-酮骨架和吲哚骨架所具有的重要的生物和药理学活性，本发明的目的是利用多组分反应的合成方法，一步合成一种同时具有呋喃-2(5H)-酮和吲哚两种骨架的新型化合物，该种新型化合物具有潜在应用价值。
为实现上述技术目的，达到上述技术效果，本发明通过以下技术方案实现：
一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮，其结构如下所示：
其中，R1为H、4-CH3或4-Br中的任意一种；R2为5-Br、5-CH3、5-(CH3)3C、5,6-OCH2O或4-Cl中的任意一种。
一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法，是以取代苯甲酰甲醛(式I)、取代苯胺(式II)和季酮酸(式III)为原料，以醇、醚、腈、水、二甲亚砜、N,N-二甲基甲酰胺、醋酸或芳香烃化合物为溶剂，在不使用催化剂，或以无机碱、无机酸、有机酸或有机小分子化合物为催化剂的情况下，在微波辐射下经过三组分反应，一步合成得到目标化合物，一步合成得到目标化合物，即3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮衍生物(式IV)：
其反应式如下：
进一步的，所述溶剂为甲醇、乙醇、1,4-二氧六环、四氢呋喃、乙腈、N,N-二甲基甲酰胺、二甲亚砜、醋酸、甲苯、水或水与乙醇的混合溶剂中的任意一种。
进一步的，所述催化剂为碳酸钠、碳酸钾、盐酸、硫酸、醋酸、三氟乙酸、对甲苯磺酸或L-脯氨酸中的任意一种。
进一步的，所述取代苯甲酰甲醛、所述取代苯胺、所述季酮酸和所述催化剂的摩尔比为1:1:1:0.1～1:1:1:0.3。
进一步的，该反应的反应时间为20～50分钟。
进一步的，该反应的反应温度为60～100℃。
经过多次反应条件的筛选，并考虑到反应的效果和绿色化学的原则，作为优选，确定以水和乙醇组成(体积比为1:1)的混合溶剂作为溶剂，以三氟乙酸作为催化剂，将取代苯甲酰甲醛、取代苯胺、季酮酸和三氟乙酸按照1:1:1:0.2的摩尔比，在反应温度为90℃的条件下反应40分钟，得到的目标产物的收率最高。
本发明的有益效果是：
本发明的合成方法利用多组分反应，将三种原料通过“一锅煮”的方法合成了一种同时具有呋喃-2(5H)-酮和吲哚两种骨架的新型化合物，该种新型化合物具有的重要的生物和药理学活性，以及具有潜在应用价值。与现有技术相比，本发明的合成方法具有反应时间较短，条件较为简单，高产率，高原子经济性，收敛性以及易操作等优点。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例详细说明。本发明的具体实施方式由以下实施例详细给出。
具体实施方式
下面将结合实施例，来详细说明本发明。
一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮，其结构如下所示：
其中，R1为H、4-CH3或4-Br中的任意一种；R2为5-Br、5-CH3、5-(CH3)3C、5,6-OCH2O或4-Cl中的任意一种。
一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法，是以取代苯甲酰甲醛(式I)、取代苯胺(式II)和季酮酸(式III)为原料，以醇、醚、腈、水、二甲亚砜、N,N-二甲基甲酰胺、醋酸或芳香烃化合物为溶剂，在不使用催化剂，或以无机碱、无机酸、有机酸或有机小分子化合物为催化剂的情况下，在微波辐射下经过三组分反应，一步合成得到目标化合物，一步合成得到目标化合物，即3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮衍生物(式IV)：
其反应式如下：
本发明的合成方法，是由取代苯甲酰甲醛、取代苯胺、季酮酸、催化剂和适当溶剂所组成的反应体系在微波辐射下进行的。其中，所述取代苯甲酰甲醛、所述取代苯胺、所述季酮酸和所述催化剂的摩尔比为1:1:1:0.1～1:1:1:0.3。
本发明的合成方法中所使用的溶剂为甲醇、乙醇、1,4-二氧六环、四氢呋喃、乙腈、N,N-二甲基甲酰胺、二甲亚砜、醋酸、甲苯、水或水与乙醇的混合溶剂中的任意一种。
本发明的合成方法中所使用的催化剂为碳酸钠、碳酸钾、盐酸、硫酸、醋酸、三氟乙酸、对甲苯磺酸或L-脯氨酸中的任意一种。
本发明的合成方法的反应时间为20～50分钟。
本发明的合成方法的反应温度为60～100℃。
经过多次反应条件的筛选，并考虑到反应的效果和绿色化学的原则，作为优选，确定以水和乙醇组成(体积比为1:1)的混合溶剂作为溶剂，以三氟乙酸作为催化剂，将取代苯甲酰甲醛、取代苯胺、季酮酸和三氟乙酸按照1:1:1:0.2的摩尔比，在反应温度为90℃的条件下反应40分钟，得到的目标产物的收率最高。
下面由以下实施例对该种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法进行详细举例和说明：
实施例1
将苯甲酰甲醛(1mmol)、对溴苯胺(1mmol)、季酮酸(1mmol)加入微波反应管，加入4mL EtOH/H2O(体积比为1:1)，稍加震荡使底物混合均匀，滴加(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-溴-2-苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVa)，收率为65％。化合物的结构通过核磁共振谱确定。熔点为280～282℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.19(s,1H,OH),11.76(s,1H,NH),7.67(d,J＝7.6Hz,2H,ArH),7.45(s,1H,ArH),7.44(t,J＝7.6Hz,2H,ArH),7.40-7.32(m,2H,ArH),7.25(d,J＝8.4Hz,1H,ArH),4.87(s,2H,CH2)。
实施例2
按照实施例1的方法，将对溴苯胺换成对甲苯胺，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-甲基-2-苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVb)，收率为57％，熔点为276～277℃。1H NMR(400MHz,DMSO-d6)δ(ppm):11.95(s,1H,OH),11.39(s,1H,NH),7.65(d,J＝7.6Hz,2H,ArH),7.42(t,J＝7.6Hz,2H,ArH),7.30(t,J＝8.4Hz,2H,ArH),7.09(s,1H,ArH),6.96(d,J＝8.4Hz,1H,ArH),4.85(s,2H,CH2),2.37(s,3H,CH3)。
实施例3
按照实施例1的方法，将对溴苯胺换成对叔丁基苯胺，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-叔丁基-2-苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVc)，收率为71％，熔点为250～251℃。1H NMR(400MHz,DMSO-d6)δ(ppm):11.53(s,1H,OH),11.38(s,1H,NH),7.65(d,J＝7.2Hz,2H,ArH),7.42(t,J＝7.6Hz,2H,ArH),7.35(d,J＝8.4Hz,1H,ArH),7.30(t,J＝7.2Hz,2H,ArH),7.24(d,J＝8.8Hz,1H,ArH),4.88(s,2H,CH2),1.33(s,9H,(CH3)3C)。
实施例4
按照实施例1的方法，将对溴苯胺换成3,4-亚甲二氧基苯胺(胡椒胺)，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5,6-亚甲二氧基-2-苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVd)，收率为72％，熔点为244～246℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.09(s,1H,OH),11.38(s,1H,NH),7.62(d,J＝7.6Hz,2H,ArH),7.40(t,J＝7.6Hz,2H,ArH),7.26(t,J＝7.2Hz,1H,ArH),6.94(s,1H,ArH),6.77(s,1H,ArH),5.96(s,2H,OCH2O),4.86(s,2H,CH2)。
实施例5
按照实施例1的方法，将苯甲酰甲醛换成对甲基苯甲酰甲醛，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-溴-2-对甲苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVe)，收率为64％，熔点为266～267℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.17(s,1H,OH),11.70(s,1H,NH),7.56(d,J＝8.0Hz,2H,ArH),7.47(s,1H,ArH),7.37(d,J＝8.4Hz,1H,ArH),7.26-7.22(m,3H,ArH),4.86(s,2H,CH2),2.34(s,3H,CH3)。
实施例6
按照实施例4的方法，将对溴苯胺换成3,4-亚甲二氧基苯胺(胡椒胺)，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5,6-亚甲二氧基-2-对甲苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVf)，收率为78％，熔点为280～281℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.05(s,1H,OH),11.30(s,1H,NH),7.49(d,J＝7.6Hz,2H,ArH),7.20(d,J＝8.0Hz,2H,ArH),6.92(s,1H,ArH),6.74(s,1H,ArH),5.95(s,2H,OCH2O),4.84(s,2H,CH2),2.32(s,3H,CH3)。
实施例7
按照实施例4的方法，将3,4-亚甲二氧基苯胺(胡椒胺)换成对叔丁基苯胺，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-叔丁基-2-对甲苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVg)，收率为69％，熔点为268～270℃。1H NMR(400MHz,DMSO-d6)δ(ppm):11.82(s,1H,OH),11.32(s,1H,NH),7.53(d,J＝8.0Hz,2H,ArH),7.34(d,J＝8.4Hz,1H,ArH),7.26-7.21(m,4H,ArH),4.86(s,2H,CH2),2.33(s,3H,CH3),1.33(s,9H,(CH3)3C)。
实施例8
按照实施例4的方法，将苯甲酰甲醛换成对溴苯甲酰甲醛，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5,6-亚甲二氧基-2-对溴苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVh)，收率为73％，熔点为278～279℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.12(s,1H,OH),11.44(s,1H,NH),7.58(d,J＝8.8Hz,2H,ArH),7.53(d,J＝8.8Hz,2H,ArH),6.92(s,1H,ArH),6.77(s,1H,ArH),5.96(s,2H,OCH2O),4.84(s,2H,CH2)。
实施例9
按照实施例8的方法，将3,4-亚甲二氧基苯胺(胡椒胺)换成对氯苯胺，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-氯-2-对溴苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVi)，收率为61％，熔点为289～290℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.25(s,1H,OH),11.82(s,1H,NH),7.66-7.59(m,4H,ArH),7.43(d,J＝8.4Hz,1H,ArH),7.38(s,1H,ArH),7.16(d,J＝8.8Hz,1H,ArH),4.86(s,2H,CH2)。
上述实施例只是为了说明本发明的技术构思及特点，其目的是在于让本领域内的普通技术人员能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡是根据本发明内容的实质所作出的等效的变化或修饰，都应涵盖在本发明的保护范围内。
Claims (2)
1.一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法，所述的3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的结构如下所示：
其中，R1为4-CH3或4-Br中的任意一种；R2为5-CH3、5-(CH3)3C、5,6-OCH2O或4-Cl中的任意一种；
其特征在于，所述的3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法如下：
是以式I所示的取代苯甲酰甲醛、式II所示的取代苯胺和式III所示的季酮酸为原料，以甲醇、1,4-二氧六环、四氢呋喃、乙腈、N,N-二甲基甲酰胺、二甲亚砜、醋酸或甲苯中的任意一种为溶剂，在不使用催化剂，或以碳酸钠、碳酸钾、盐酸、硫酸、三氟乙酸或L-脯氨酸中的任意一种为催化剂的情况下，在90℃微波辐射下经过20～50分钟三组分反应，一步合成得到式IV所示的目标化合物，即3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮衍生物：
2.根据权利要求1所述的3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法，其特征在于：所述取代苯甲酰甲醛、所述取代苯胺、所述季酮酸和所述催化剂的摩尔比为1:1:1:0.1～1:1:1:0.3。
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