CN113173899B - 异苯并呋喃-1（3h）-酮类化合物的合成方法 - Google Patents

异苯并呋喃-1（3h）-酮类化合物的合成方法 Download PDF

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CN113173899B
CN113173899B CN202110455026.5A CN202110455026A CN113173899B CN 113173899 B CN113173899 B CN 113173899B CN 202110455026 A CN202110455026 A CN 202110455026A CN 113173899 B CN113173899 B CN 113173899B
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郑子圣
杨文谦
王雷
曾海强
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Du Chuang Shanghai Pharmaceutical Development Co ltd
Du Chuang Shanghai Medical Technology Co ltd
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Abstract

本发明公开了异苯并呋喃‑1(3H)‑酮类化合物的合成方法，该方法包括如下步骤：将原料2‑(1‑苯基乙烯)苯甲酸类化合物II溶于甲醇中，再加入二乙酰氧基碘苯，进行反应，得到异苯并呋喃‑1(3H)‑酮类化合物I；反应式如下：

Description

异苯并呋喃-1(3H)-酮类化合物的合成方法
技术领域
本发明涉及异苯并呋喃-1(3H)-酮类化合物的合成方法。
背景技术
异苯并呋喃-1(3H)-酮类化合物是一类重要的天然产物，具有多种生物学特性1。一些天然的化合物如灯盏花素2、褐藻素3、(±)-海藻蛋白B4、芦丁内酯A5、倍内酯6和花冠孢子素7，其化学结构中均包含异苯并呋喃-1(3H)-酮结构。这些生物活性物质已经表示出良好的抗细菌、抗炎、抗肿瘤、抗微生物、抗癌和抗HIV活性。
2-(5-苯基噻唑-4-基)苯甲酸被认为是潜在的植物生长调节剂，在水芹幼苗试验中已经证实它具有向地作用活性。8已有的文献报道了该化合物可以通过市售的3-亚苄基苯酞制备，在甲酰胺和五硫化磷或硫脲的混合物处理下形成噻唑酯，再经过水解提供了上述苯甲酸。其中，3-苄基-3-甲氧基异苯并呋喃-1(3H)-酮是上述转化中的重要中间体。9
由于异苯并呋喃-1(3H)-酮骨架表现出了重要的药用价值，相关合成方法策略的发展也受到越来越多的关注。在已有的对于3-苄基-3-甲氧基异苯并呋喃-1(3H)-酮的合成报道中，具有反应时间过长，产率不高等缺点。并未见在二乙酰氧基碘苯和甲醇的共同作用下形成3-苄基-3-甲氧基异苯并呋喃-1(3H)-酮的报道。
式III为灯盏花素；式IV为褐藻素；式V为(±)-海藻蛋白；式VI为芦丁内酯A；式VII为倍内酯；式VIII为花冠孢子素。
参考文献：
(1)(a)Chen,Z.J.；Zhang,C.；Gao,F.；Fu,Q.；Fu,C.M.；He,Y.；Zhang,J.M.Asystematic review on the rhizome of Ligusticum chuanxiong Hort.(Chuanxiong).Food Chem.Toxicol.2018,119,309-325；(b)Cragg,G.M.；Newman,D.J.；Snader,K.M.Natural Products in Drug Discovery and Development.J.Nat.Prod.1997,60,52-60.
(2)(a)Khan,K.M.；Hayat,S.；Zia,U.；Atta ur,R.；Choudhary,M.I.；Maharvi,G.M.；Bayer,E.An alternative method for the synthesis of gamma-lactones byusing cesium fluoride-celite/acetonitrile combination.Synth.Commun.2003,33,3435-3453；(b)Kumar,M.；Zhao,X.；Wang,X.W.Molecular carcinogenesis ofhepatocellular carcinoma and intrahepatic cholangiocarcinoma:one step closerto personalized medicine？Cell Biosci.2011,1,5-13.
(3)Yoganathan,K.；Rossant,C.；Ng,S.；Huang,Y.C.；Butler,M.S.；Buss,A.D.10-methoxydihydrofuscin,fuscinarin,and fuscin,novel antagonists of the humanCCR5 receptor from Oidiodendron griseum.J.Nat.Prod.2003,66,1116-1117.
(4)Loughlin,W.A.；Pierens,G.K.；Petersson,M.J.；Henderson,L.C.；Healy,P.C.Evaluation of novel Hyphodermin derivatives as Glycogen Phosphorylase ainhibitors.Bioorganic&Medicinal Chemistry 2008,16,6172-6178.
(5)Kimura,Y.；Yoshinari,T.；Koshino,H.；Fujioka,S.；Okada,K.；Shimada,A.Rubralactone,rubralides A,B and C,and rubramin produced by Penicillium rubrum.Biosci.Biotechnol.Biochem.2007,71,1896-1901.
(6)Bankova,V.；Koeva-Todorovska,J.；Stambolijska,T.；Ignatova-Groceva,M.D.；Todorova,D.；Popov,S.Polyphenols in Stachys and Betonica species(Lamiaceae).Z.Naturforsch.C.1999,54,876-880.
(7)(a)Mikolasch,A.；Hessel,S.；Salazar,M.G.；Neumann,H.；Manda,K.；Goerdes,D.；Schmidt,E.；Thurow,K.；Hammer,E.；Lindequist,U.；Beller,M.；Schauer,F.Synthesis of new N-analogous corollosporine derivatives with antibacterialactivity by laccase-catalyzed amination.Chem.Pharm.Bull.2008,56,781-786；(b)Liberra,K.；Jansen,R.；Lindequist,U.Corollosporine,a new phthalide derivativefrom the marine fungus Corollospora maritima Werderm.1069.Pharmazie 1998,53,578-581.
(8)TEITEI；Tsutomu The Synthesis and Anti-geotropic Activity of o-Arylethenylbenzoic Acids.Agricultural and biological chemistry 1981,45,1669-1674.
(9)Teitei The synthesis of 2-(5-Phenylthiazol-4-y1)benzoicacids.Australian Journal of Chemistry 1980,33,605-611.
发明内容
本发明的目的是克服现有技术的不足，提供一种简单实现分子内环化的异苯并呋喃-1(3H)-酮类化合物的合成方法。
本发明的技术方案概述如下：
异苯并呋喃-1(3H)-酮类化合物的合成方法，包括如下步骤：将原料2-(1-苯基乙烯)苯甲酸类化合物II溶于甲醇中，再加入二乙酰氧基碘苯，进行反应，得到异苯并呋喃-1(3H)-酮类化合物I；反应式如下：
其中：
R1为氢原子、氯原子、溴原子或甲基。
所述2-(1-苯基乙烯)苯甲酸类化合物II与二乙酰氧基碘苯的摩尔比为1:3。
本发明具有操作简单，原料价廉易得，反应条件温和，反应时间短，收率高等优点.
具体实施方式
实施例中所需要的反应原料，2-(1-苯基乙烯)苯甲酸化合物II，为参照文献方法制备。((1)Geary,G.C.；Hope,E.G.；Stuart,A.M.Intramolecular Fluorocyclizations ofUnsaturated Carboxylic Acids with a Stable Hypervalent FluoroiodaneReagent.Angew.Chem.Int.Ed.,2015,54,14911-14914.)
下面通过具体实施例对本发明作进一步的说明。
实施例1
3-苄基-3-甲氧基异苯并呋喃-1(3H)-酮l-a的合成方法，包括如下步骤：
将2-(1-苯基乙烯)苯甲酸ll-a(0.5mmol,112mg)溶于甲醇(5mL)中，再加入二乙酰氧基碘苯(1.5mmol,483mg)，在回流条件下进行反应直至TLC显示底物完全消耗(约20分钟)。将反应液中的溶剂通过旋蒸除去，用水(20mL)和二氯甲烷(20mL×3)萃取反应液，合并有机相，先用饱和食盐水洗涤有机相，再加入无水硫酸钠干燥，经柱层析(乙酸乙酯：石油醚＝5:95)分离得到白色固体112mg,收率为88％,熔点为93-94℃。1H NMR(400MHz,CDCl3)δ7.73(d,J＝7.6Hz,1H),7.64(t,J＝7.5Hz,1H),7.50(t,J＝7.5Hz,1H),7.25(d,J＝8.1Hz,1H),7.19–7.11(m,3H),7.07(dd,J＝6.4,3.1Hz,2H),3.44(d,J＝13.8Hz,1H),3.37(d,J＝13.8Hz,1H),3.07(s,3H).13C NMR(101MHz,CDCl3)δ167.8,145.6,134.1,133.5,130.8,130.6,128.2,128.0,127.1,125.4,123.2,110.2,51.4,44.8.HRMS(ESI)calcd forC16H14NaO3 +[M+Na+]277.0835,found 277.0832.为式I-a。
实施例2
3-(4-氯苄基)-3-甲氧基异苯并呋喃-1(3H)-酮l-b的合成方法，包括如下步骤：
将2-(1-(4-氯苯基)乙烯基)苯甲酸ll-b(0.5mmol,129mg)溶于甲醇(5mL)中，再加入二乙酰氧基碘苯(1.5mmol,483mg)，在回流条件下进行反应直至TLC显示底物完全消耗(约20分钟)。将反应液中的溶剂通过旋蒸除去，用水(20mL)和二氯甲烷(20mL×3)萃取反应液，合并有机相，先用饱和食盐水洗涤有机相，再加入无水硫酸钠干燥，经柱层析(乙酸乙酯：石油醚＝5:95)分离得到白色固体118mg,收率为82％,熔点为102-104℃。1H NMR(400MHz,CDCl3)δ7.76(dt,J＝7.6,0.9Hz,1H),7.66(td,J＝7.5,1.1Hz,1H),7.53(td,J＝7.5,0.9Hz,1H),7.26(dt,J＝7.6,0.8Hz,1H),7.16–7.10(m,2H),7.06–6.98(m,2H),3.38(d,J＝13.9Hz,1H),3.33(d,J＝13.9Hz,1H),3.06(s,3H).13C NMR(101MHz,CDCl3)δ167.6,145.4,134.2,133.1,132.1,130.8,128.2,125.6,123.0,109.8,51.4,44.2.HRMS(ESI)calcd for C16H13ClNaO3 +[M+Na+]311.0445,found 311.0448.为式I-b。
实施例3
3-(4-溴苄基)-3-甲氧基异苯并呋喃-1(3H)-酮l-c的合成方法，包括如下步骤：
将2-(1-(4-溴苯基)乙烯基)苯甲酸ll-c(0.5mmol,151mg)溶于甲醇(5mL)中，再加入二乙酰氧基碘苯(1.5mmol,483mg)，在回流条件下进行反应直至TLC显示底物完全消耗(约20分钟)。将反应液中的溶剂通过旋蒸除去，用水(20mL)和二氯甲烷(20mL×3)萃取反应液，合并有机相，先用饱和食盐水洗涤有机相，再加入无水硫酸钠干燥，经柱层析(乙酸乙酯：石油醚＝5:95)分离得到白色固体148mg,收率为89％,熔点为67-68℃。1H NMR(400MHz,CDCl3)δ7.77(d,J＝7.6Hz,1H),7.66(td,J＝7.5,1.0Hz,1H),7.54(td,J＝7.5,0.9Hz,1H),7.32–7.28(m,2H),7.26(d,J＝7.6Hz,1H),7.00–6.93(m,2H),3.37(d,J＝13.9Hz,1H),3.32(d,J＝13.9Hz,1H),3.06(s,3H).13C NMR(101MHz,CDCl3)δ167.6,145.4,134.2,132.6,132.4,131.2,130.8,128.2,125.6,123.0,121.3,109.7,51.4,44.3.HRMS(ESI)calcd forC16H13BrNaO3 +[M+Na+]354.9940,found 354.9942.为式I-c。
实施例4
3-甲氧基-3-(4-甲基苄基)异苯并呋喃-1(3H)-酮l-d的合成方法，包括如下步骤：
将2-(1-(对甲苯基)乙烯基)苯甲酸ll-d(0.5mmol,119mg)溶于甲醇(5mL)中，再加入二乙酰氧基碘苯(1.5mmol,483mg)，在回流条件下进行反应直至TLC显示底物完全消耗(约20分钟)。将反应液中的溶剂通过旋蒸除去，用水(20mL)和二氯甲烷(20mL×3)萃取反应液，合并有机相，先用饱和食盐水洗涤有机相，再加入无水硫酸钠干燥，经柱层析(乙酸乙酯：石油醚＝5:95)分离得到白色固体125mg,收率为93％,熔点为51-53℃。1H NMR(400MHz,CDCl3)δ7.74(dt,J＝7.6,0.8Hz,1H),7.64(td,J＝7.5,1.1Hz,1H),7.51(td,J＝7.5,0.9Hz,1H),7.26(t,J＝3.8Hz,1H),6.98–6.92(m,4H),3.40(d,J＝13.9Hz,1H),3.33(d,J＝13.9Hz,1H),3.07(s,3H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ167.9,145.7,136.6,134.0,130.6,130.5,130.4,128.7,128.3,125.4,123.1,110.3,51.4,44.4,21.1.HRMS(ESI)calcd for C17H16NaO3 +[M+Na+]291.0992,found 291.0995.为式I-d。
以上所述，仅是本发明的部分实施例而已，并非对本发明做任何形式上的限制，凡是依据本发明的技术实质对上述实施例作的任何简单的修改，等同变化与修饰，均属于本发明技术方案范围内。

Claims (2)

1.异苯并呋喃-1(3H)-酮类化合物的合成方法，其特征是包括如下步骤：将原料2-(1-苯基乙烯)苯甲酸类化合物(II)溶于甲醇中，再加入二乙酰氧基碘苯，进行反应，得到异苯并呋喃-1(3H)-酮类化合物(I)；反应式如下：
其中：
R1为氢原子、氯原子、溴原子或甲基。
2.根据权利要求1所述的方法，其特征是所述2-(1-苯基乙烯)苯甲酸类化合物(II)与二乙酰氧基碘苯的摩尔比为1:3。
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