阅读说明：本技术 一类多并杂环螺羟吲哚类化合物的合成方法 (Synthesis method of polyatomic heterocyclic spiro oxindole compound ) 是由 任海 潘卫东 宋俊蓉 李志遥 于 2019-10-10 设计创作，主要内容包括：本发明涉及一类多并杂环螺羟吲哚类化合物的合成方法。该类化合物在有机溶剂中,在绿色环保、廉价的铁催化剂作用下一步反应得到。得到的部分化合物是临床二期开发药物NITD609及其类似物或者重要的药物中间体。同时本发明的制备方法反应收率高,催化剂绿色环保,催化剂用量少,水是唯一副产物,绿色无污染,适用取代基范围广,操作简单,有望实现工业化应用前景。(The invention relates to a synthesis method of a polyatomic heterocyclic spiro oxindole compound. The compound is obtained by one-step reaction in an organic solvent under the action of a green, environment-friendly and cheap iron catalyst. The obtained partial compound is a clinical second-stage development medicament NITD609 and analogues thereof or important medicament intermediates. Meanwhile, the preparation method disclosed by the invention is high in reaction yield, the catalyst is green and environment-friendly, the using amount of the catalyst is small, water is the only byproduct, the preparation method is green and pollution-free, the applicable substituent range is wide, the operation is simple, and the industrial application prospect is expected to be realized.)

一类多并杂环螺羟吲哚类化合物的合成方法

技术领域

本发明属于药物及药物中间体的生成工艺领域，尤其涉及一类多并杂环螺羟吲哚类化合物的合成方法。

背景技术

多并杂环螺羟吲哚作为一类重要的核心结构单元，广泛地存在于天然产物和众多具有生物活性分子中(a)Peddibhotla,S.Curr.Bioact.Compd.2009,5,20.(b)Trost,B.M.；Brennan,M. K.Synthesis 2009,2009,3003.(c)Christensen,M.K.；Erichsen,K.D.；Trojel-Hansen,C.； Tjornelund,J.；Nielsen,S.J.；Frydenvang,K.；Johansen,T.N.；Nielsen,B.；Sehested,M.；Jensen,P. B.；Ikaunieks,M.；Zaichenko,A.；Loza,E.；Kalvinsh,I.；Bjorkling,F.J.Med.Chem.2010,53,7140. (d)Sharma,I.；Tan,D.S.Nat.Chem.2013,5,157.(e)Cao,Z.-Y.；Zhou,F.；Zhou,J.Acc.Chem. Res.2018,51,1443.如何高效构多并杂环螺羟吲哚结构衍生物一直是有机合成领域的研究热点难点。

2010年Diagana等人在Top期刊Science上报道了四氢-β-咔啉螺羟吲哚分子NITD609(式 1)，数据表明该分子具有优异的抗疟活性(IC50＝0.9nM)。更值得注意的是，该分子不同于现有抗疟药物美氟喹(mefloquine)和青蒿素(artemisinin)的作用机制，其通过调节P型ATP 酶(PfATP4)从而迅速抑制寄生虫中蛋白质的合成。该研究为当前抗疟药物严峻的耐药性问题提供一条全新的缓解途径。目前诺华公司正在对其开展临床Ⅱ期试验研究。2014年,McLeod 等人现化合物NITD609除具有抗疟原虫活性外，对弓形虫速殖子也表现出较好的药理活性，在体外细胞实验中其IC₅₀值为1μM。此外该化合物安全性高，即使用药量在大于10μM，对人体正常细胞也无损害。(a)Rottmann,M.；McNamara,C.；Yeung,B.K.；Lee,M.C.；Zou,B.； Russell,B.；Seitz,P.；Plouffe,D.M.；Dharia,N.V.；Tan,J.；Cohen,S.B.；Spencer,K.R.； Gonzalez-Paez,G.E.；Lakshminarayana,S.B.；Goh,A.；Suwanarusk,R.；Jegla,T.；Schmitt,E.K.； Beck,H.P.；Brun,R.；Nosten,F.；Renia,L.；Dartois,V.；Keller,T.H.；Fidock,D.A.；Winzeler,E.A.； Diagana,T.T.Science 2010,329,1175.

式1：抗疟疾药物分子NITD609

由于极具应用价值和前景。以NITD609母核四氢-β-咔啉螺羟吲哚骨架结构的合成为例，科学家进行了大量的研究并取得了系列重要的研究成果(a)Zheng,H.；Liu,X.；Xu,C.；Xia,Y.；Lin,L.；Feng,X.Angew.Chem.Int.Ed.2015,54,10958.(b)Yeung,B.K.S.；Zou,B.；Rottmann, M.；Lakshminarayana,S.B.；Ang,S.H.；Leong,S.Y.；Tan,J.；Wong,J.；Keller-Maerki,S.；Fischli, C.；Goh,A.；Schmitt,E.K.；Krastel,P.；Francotte,E.；Kuhen,K.；Plouffe,D.；Henson,K.；Wagner, T.；Winzeler,E.A.；Petersen,F.；Brun,R.；Dartois,V.；Diagana,T.T.；Keller,T.H.J.Med.Chem. 2010,53,5155.(c)冯小明，郑海丰，刘小华，林丽丽.中国专利：CN104926813A。一直以来，通过文献调研，发现含有氧杂环螺羟吲哚和硫杂环螺羟吲哚等结构单元、且与四氢-β-咔啉螺羟吲哚母核相对应的螺环结构衍生物一直未见报道(式2)。值得一提的是，通过已报道的策略和方法都无法实现对该类结构的合成。

式2：抗疟疾药物分子类似结构

综上所述，本领域尚缺乏一种反应操作简便、合成步骤短、适用取代基范围广、能工业化系统合成包括NITD609母核在内的多种类型的并杂环螺羟吲哚的合成方法，该现状亟待解决。

发明内容

本发明意在提供一种多类型多并杂环螺羟吲哚的合成方法，以解决现有技术合成方法中反应产物类型单一，底物兼容性有限，以及催化剂昂贵等问题。

众所周知，自然界铁资源丰富，不仅如此，铁也是人体微量元素之一。铁催化具有廉价、安全和环保等显著优点，比如FeCl₃是一种常用的污水废水处理剂。将铁催化剂运用于具有药理活性化合物的高效构建并实现其工业化生产具有重要的价值和意义。

本发明提供的一种多并杂环螺羟吲哚的合成方法，于惰性溶剂中，在微量的铁盐催化下，将式1化合物与式2化合物进行反应，从而形成式A化合物，化学式如下：

上述各式中，R¹、R²、R³和R⁴各自独立的为H、取代或未取代的C₁-C₁₅的烷基、卤素、取代或未取代的C₆-C₁₅芳基、烷氧基或苄氧基；

R⁵为H、取代或未取代的C₁-C₁₅的烷基，取代或未取代的C₆-C₁₅芳基，酰基；

R⁶和R⁷各自独立的为H、取代或未取代的C₁-C₁₅的烷基、卤素、取代或未取代的C₆-C₁₅芳基、烷氧基或苄氧基或连接关环形成结构(B)所示的芳香体系，其中R¹⁰、R¹¹、R¹²和 R¹³各自独立的为H、取代或未取代的C₁-C₁₅的烷基、卤素、取代或未取代的C₆-C₁₅芳基、烷氧基或苄氧基。

R⁸、R⁹各自独立的为H、取代或未取代的C₁-C₁₅的烷基、卤素、烷氧基或苄氧基；

X、Y各自独立的为O,S,NR¹⁴,其中R¹⁴为H、取代或未取代的C₁-C₁₅的烷基，取代或未取代的C₆-C₁₅芳基，酰基；

式1化合物和2化合物的摩尔比例为1:1-1:1.5；

优选的，催化剂铁盐为FeCl₃，Fe(ClO₄)₃.6H₂O，Fe(OTf)₃，FeCl₂；

优选的，催化剂铁盐的用量为0.01％—1％；

优选的，反应温度在25℃-60℃下进行，进一步优选的，所述的反应温度在30℃-50℃下进行。

优选的，惰性溶剂选自，N,N-二甲基酰胺、二甲基亚砜、四氢呋喃或其组合。

本发明的工作原理：本发明的发明人通过长期深入系统的研究，发现了一种全新的多并杂环螺羟吲哚的合成方法，于惰性溶剂中，在微量铁盐的催化下，将式1化合物与式2化合物进行反应，从而得到结构多样的多并杂环螺羟吲哚类化合物。该方法具有原料简单，易得，催化剂绿色环保，底物适用范围广，操作简便，反应效率高，水是唯一副产物，绿色少污染等优点。在此基础上，发明人完成了本发明。本发明制得的多并杂环螺羟吲哚类化合物在抗疟疾、抗菌等生物医药领域有着十分重要的应用前景。

具体实施方式

下面结合具体实施，进一步阐明本发明。应理解，这些实施例仅用于说明本发明而不限制与本发明的范围。下列实施例子中为注明具体条件的实验方法，通常按照常规条件，或按照制造商所建议的条件，若未注明反应温度，均表示该反应在室温条件下进行。除非另有说明，否则百分比和份数胺重量计算。

以下实施例子中均采用本领域常规的后处理方法进行纯化。

实施例1

实施例1将1-1(2mmol)，2-1(2mmol)，FeCl₃(0.02mmol)加入到25mL反应管中，抽换氮气，在氮气保护下加入5mL四氢呋喃，随后升至40℃搅拌28h，TLC跟踪至原料2-1消失。制得产物A-1，产率为90％。

制备得到的A-1的核磁共振(¹H NMR和¹³C NMR)、红外和高分辨质谱检测数据为：white solid,28h,574.0mg,90％yield.¹H NMR(600MHz,CDCl₃)δ7.59(d,J＝8.0Hz,1H),7.39(td, J＝7.8,1.0Hz,1H),7.23-7.10(m,4H),7.05(t,J＝7.6Hz,1H),6.93(d,J＝8.0Hz,1H),4.74- 4.70(m,1H),4.23-4.19(m,1H),3.30(s,3H),3.17-3.10(m,1H),3.03(s,3H),3.00-2.97(m, 1H).¹³C NMR(150MHz,CDCl₃)δ174.2,144.0,137.6,130.8,130.1,128.7,126.2,125.5,123.5, 122.2,119.2,118.6,111.2,108.9,108.7,76.1,62.2,29.4,26.4,22.0.IR(KBr):2917.7,2838.7, 2360.3,1716.5,1610.2,1469.3,1369.0,1299.8,1242.0,1181.9,10153.3,1096.2,1048.39,996.31. HRMS-ESI:Exact mass calcd.forC₂₀H₁₈N₂O₂Na⁺[M+Na]⁺:341.1260；Found:341.1263.

2-20的具体实施方式，参考实施例1，部分代表性化合物的核磁共振(¹H NMR和¹³CNMR)、红外和高分辨质谱检测数据如下：

实施例2：

A-2yellow solid,12h,515mg,95％yield.¹H NMR(600MHz,CDCl₃)δ7.39(td,J＝7.8,1.2Hz, 1H),7.24-7.20(m,2H),7.08(td,J＝7.8,1.2Hz,1H),6.90(dd,J＝8.4,6.6Hz,2H),4.94(ddd,J ＝11.4,10.2,3.6Hz,1H),4.18(ddd,J＝11.4,5.4,2.4Hz,1H),3.24(s,3H),3.08(ddd,J＝16.2, 10.2,5.4Hz,1H),2.86(ddd,J＝16.2,3.6,2.4Hz,1H).¹³C NMR(150MHz,CDCl₃)δ175.2, 143.6,136.2,131.7,131.1,130.5,127.0,125.1,124.7,123.4,108.5,61.4,26.4,25.6.IR(KBr): 2953.2,2359.6,1725.3,1610.9,1492.4,1468.9,1346.3,1224.5,1103.4,1049.9,990.7.HRMS-ESI: Exact mass calcd.for C₁₅H₁₃NO₂SNa⁺[M+Na]⁺:294.0565；Found:294.0557.

实施例3：

A-3yellow solid,12h,391mg,65％yield.¹H NMR(600MHz,CDCl₃)δ7.58(d,J＝2.7Hz,2H), 7.39(td,J＝7.8,0.9Hz,1H),7.20(d,J＝7.2Hz,1H),7.14-7.09(m,3H),7.06(t,J＝7.5Hz,1H), 6.94(d,J＝7.8Hz,1H),3.89-3.79(m,1H),3.34(dt,J＝13.1,5.4Hz,1H),3.25(s,3H),2.98(t,J ＝5.7Hz,2H).¹³C NMR(150MHz,DMSO)δ176.6,143.5,136.1,131.4,130.0,129.8,127.1, 124.6,123.3,122.4,119.5,118.4,112.4,111.0,108.7,61.4,39.9,26.5,22.0.IR(KBr):3450.5, 2938.1,1715.2,1610.6,1469.8,1369.9,1346.0,1236.2,1088.4,751.7,538.3.HRMS-ESI:Exact mass calcd.for HRMS-ESI:Exactmass calcd.for C₁₉H₁₈N₃O⁺[M+H]⁺:304.1444；Found: 304.1444.

实施例4：

A-4yellow solid,23h,224mg,37％yield.¹H NMR(600MHz,DMSO)δ10.75(s,1H),8.49(s, 1H),7.54(d,J＝7.8Hz,1H),7.48(d,J＝8.0Hz,1H),7.26-7.22(m,3H),7.16-7.10(m,2H), 7.09-7.06(m,1H),3.81(d,J＝20.8Hz,1H),3.71(d,J＝20.8Hz,1H),3.26(s,3H).¹³C NMR (150MHz,DMSO)δ173.9,169.5,143.8,137.2,130.0,129.9,127.4,125.4,124.3,122.9,122.1, 118.9,118.3,111.3,109.4,106.7,62.7,28.5,26.7.IR(KBr):3244.0,2923.8,2359.8,1703.1, 1612.9,1660.6,1468.2,1367.0,1227.1,1084.9,1055.8.HRMS-ESI:Exact mass calcd.for HRMS-ESI:Exact mass calcd.for C₁₉H₁₆N₃O₂ ⁺[M+H]⁺:318.1243；Found:318.1231.

实施例5：

A-5yellow solid,15h,191mg,35％yield.¹H NMR(600MHz,CDCl₃)δ7.59(d,J＝7.8Hz,1H), 7.39(td,J＝7.8,1.2Hz,1H),7.25-7.19(m,2H),7.17-7.11(m,2H),7.08(td,J＝7.2,0.8Hz, 1H),6.96(d,J＝7.8Hz,1H),3.90(ddd,J＝13.6,11.4,3.6Hz,1H),3.40-3.36(m,1H),3.35(s, 3H),3.28(ddd,J＝15.6,11.4,4.8Hz,1H),2.95(s,3H),2.91(ddd,J＝13.6,4.6,3.0Hz,1H).¹³C NMR(150MHz,CDCl₃)δ176.1,143.0,136.8,129.7,129.3,126.8,124.9,123.4,122.5,119.1, 118.4,114.5,108.7,108.7,70.3,47.6,29.9,26.8,25.4,24.0.IR(KBr):3441.9,2900.3,2923.5, 2360.4,1702.5,1606.6,1491.8,1472.9,1342.3,1366.0,1239.7,1084.9,1126.0.HRMS-ESI:Exact mass calcd.for C₂₀H₂₁N₂OS⁺[M+H]⁺:335.1218；Found:335.1252.

实施例6：

A-6yellow solid,22h,227mg,74％yield.¹H NMR(600MHz,CDCl₃)δ7.56(dd,J＝8.0,5.0Hz, 1H),7.38(d,J＝7.8Hz,1H),7.33(dd,J＝7.8,5.2Hz,1H),7.24(dd,J＝6.6,3.0Hz,2H),7.18(d, J＝7.2Hz,1H),7.06(d,J＝7.2Hz,1H),6.91(d,J＝7.8Hz,1H),4.91-4.87(m,1H),4.26(ddd,J ＝11.4,5.4,2.4Hz,1H),3.26(s,3H),3.13(ddd,J＝15.6,9.6,5.4Hz,1H),2.94-2.89(m,1H).¹³C NMR(150MHz,CDCl₃)δ173.9,154.9,148.0,144.4,130.9,127.5,127.3,125.1,124.5,123.3, 122.9,119.3,114.8,111.6,108.8,75.9,62.1,26.5,21.9.IR(KBr):3430.9,2966.1,2931.2,2360.4, 2341.1,1722.9,1599.3,1493.0,1461.1,1356.5,1289.3,1235.6,1025.9.HRMS-ESI:Exact mass calcd.for C₁₉H₁₅NO₃Na⁺[M+Na]⁺:328.0944；Found:328.0944.

实施例7：

A-7yellow solid,22h,305mg,48％yield.¹H NMR(600MHz,CDCl₃)δ7.73(t,J＝8.0Hz,2H), 7.43(td,J＝8.0,3.6Hz,2H),7.36-7.33(m,1H),7.25(dd,J＝7.2,0.6Hz,1H),7.10(td,J＝7.8, 0.6Hz,1H),6.93(d,J＝7.8Hz,1H),5.08(ddd,J＝11.2,10.2,3.6Hz,1H),4.34(ddd,J＝11.4, 6.0,2.4Hz,1H),3.27(s,3H),3.20(ddd,J＝10.2,7.8,3.6Hz,1H),3.05(ddd,J＝15.6,3.6,2.4Hz, 1H).¹³C NMR(150MHz,CDCl₃)δ173.9,154.9,148.0,144.4,130.9,127.5,127.3,125.1,124.5, 123.3,122.8,119.2,114.7,111.6,108.8,75.9,62.1,26.4,21.9.IR(KBr):3401.8,2927.0,2360.1, 1709.8,1612.2,1494.7,1469.3,1345.2,1238.5,1157.1,1095.0,1044.0,1017.9,986.0,924.2. HRMS-ESI:Exactmass calcd.for C₁₉H₁₅NO₂SNa⁺[M+Na]⁺:344.0718；Found:344.0718.

实施例8：

A-8yellow solid,23h,406.1mg,61％yield.¹H NMR(600MHz,CDCl₃)δ7.58(d,J＝7.8Hz, 1H),7.19(ddd,J＝13.8,10.2,4.2Hz,2H),7.13-7.10(m,1H),7.05(d,J＝8.0Hz,1H),6.50(dd, J＝10.8,2.4Hz,2H),4.70(ddd,J＝11.2,9.2,4.0Hz,1H),4.19(ddd,J＝11.1,5.0,3.6Hz,1H), 3.83(s,3H),3.26(s,3H),3.11(ddd,J＝14.4,9.0,5.4Hz,1H),3.04(s,3H),2.97(dt,J＝15.6,3.6 Hz,1H).¹³C NMR(150MHz,CDCl₃)δ174.7,162.1,145.4,137.5,130.3,126.3,126.1,122.0, 120.5,119.1,118.5,111.0,108.8,106.8,96.9,75.8,62.1,55.6,29.3,26.4,22.0.IR(KBr):2934.3, 2883.0,2359.3,1726.1,1618.1,1621.0,1419.4,1349.6,1245.8,1103.9,995.1.HRMS-ESI:Exact mass calcd.for C₂₁H₂₀N₂O₂Na⁺[M+Na]⁺:355.1417；Found:355.1416.

实施例9：

A-9yellow solid,17h,604.1mg,87％yield.¹H NMR(600MHz,CDCl₃)δ7.60(d,J＝7.8Hz, 1H),7.24-7.18(m,2H),7.16-7.10(m,1H),6.92(s,1H),6.79(s,1H),4.73(ddd,J＝11.2,9.8, 3.8Hz,1H),4.21(ddd,J＝11.1,5.2,3.0Hz,1H),3.55(s,3H),3.16(ddd,J＝15.2,8.9,4.0Hz,1H), 3.07(s,3H),2.97(dt,J＝15.5,3.4Hz,1H),2.58(s,3H),2.19(s,3H).¹³C NMR(150MHz,CDCl₃) δ175.0,139.1,137.5,134.9,133.1,130.6,129.3,126.1,124.1,122.0,120.0,119.2,118.65,111.0, 108.9,75.5,62.1,29.8,29.4,22.1,20.6,18.8.IR(KBr):2915.7,2364.3,1713.8,1463.5,1342.3, 1039.38,1104.7,1078.4.HRMS-ESI:Exact mass calcd.for C₂₂H₂₂N₂O₂Na⁺[M+Na]⁺:369.1579；Found:369.1570.

实施例10：

A-10yellow solid,23h,627.5mg,90％yield.¹H NMR(600MHz,CDCl₃)δ7.63(d,J＝7.8Hz, 1H),7.26-7.21(m,2H),7.18-7.15(m,1H),7.11(t,J＝9.0Hz,1H),6.56(dd,J＝10.8,2.4Hz, 2H),4.77-4.73(m,1H),4.25-4.22(m,1H),3.88(s,3H),3.31(s,3H),3.19-3.14(m,1H),3.09(s, 3H),3.02(dt,J＝15.0,3.6Hz,1H).¹³C NMR(150MHz,CDCl₃)δ174.7,162.1,145.4,137.5, 130.3,126.3,126.1,122.0,120.4,119.1,118.5,111.1,108.8,106.8,96.9,75.8,62.1,55.6,29.3, 26.4,22.0.IR(KBr):2923.8,2360.2,1723.8,1608.0,1453.3,1354.4,1107.0,1054.1,993.2. HRMS-ESI:Exact mass calcd.forC₂₁H₂₀N₂O₃Na⁺[M+Na]⁺:371.1366；Found:371.1366.

实施例11：

A-11yellow solid,16h,398mg,59％yield.¹H NMR(600MHz,CDCl₃)δ7.59(d,J＝7.8Hz, 1H),7.24-7.21(m,1H),7.19(d,J＝8.4Hz,1H),7.13(dd,J＝10.8,3.6Hz,1H),7.10(td,J＝8.8, 2.4Hz,1H),6.92(dd,J＝7.2,2.4Hz,1H),6.86(dd,J＝8.8,3.6Hz,1H),4.71(ddd,J＝11.2,9.4, 3.6Hz,1H),4.21(ddd,J＝11.2,5.4,3.4Hz,1H),3.29(s,3H),3.14(ddd,J＝14.8,9.6,5.2Hz,1H), 3.06(s,3H),2.99(dt,J＝15.5,3.6Hz,1H).¹⁹F NMR(565MHz,CDCl₃)δ118.9.¹³C NMR(150 MHz,CDCl₃)δ174.0,160.4,158.8,139.9(d,J＝2.0Hz),137.6,130.3(d,J＝7.6Hz),129.4, 126.0,122.4,119.4,118.6,117.0(d,J＝23.6Hz),113.6(d,J＝24.9Hz),111.4,108.9(d,J＝7.9 Hz),76.1,62.3,29.4,26.7,22.0.IR(KBr):3045.0,2913.9,2852.2,2358.5,1711.3,1494.4,1265.0, 1103.1,1047.9.HRMS-ESI:Exact mass calcd.for C₂₀H₁₇N₂O₂FNa⁺[M+Na]⁺:359.116；Found:359.1166.

实施例12：

A-12yellow solid,18h,460.5mg,65％yield.¹H NMR(600MHz,CDCl₃)δ7.63(d,J＝7.8Hz, 1H),7.35(t,J＝8.0Hz,1H),7.26-7.22(m,2H),7.18-7.14(m,1H),7.03(d,J＝8.4Hz,1H), 6.85(d,J＝7.8Hz,1H),4.82(td,J＝11.2,3.6Hz,1H),4.30(ddd,J＝11.4,5.4,1.2Hz,1H),3.31 (s,3H),3.23(ddd,J＝16.2,11.4,5.4Hz,1H),3.12(s,3H),3.00-2.94(m,1H).¹³C NMR(150 MHz,CDCl₃)δ173.7,145.8,147.5,132.8,131.8,128.2,126.0,125.3,124.7,122.1,119.2,118.6, 112.2,108.9,107.0,76.0,62.5,29.3,26.6,21.8.IR(KBr):34223.0,2960.2,2925.2,2854.1,2359.5, 1719.7,1610.5,1460.5,13445.4,1261.7,1122.9,997.3,938.0.HRMS-ESI:Exact mass calcd.for C₂₀H₁₈N₂O₂Cl[M+H]⁺:353.1051；Found:353.1049.

实施例13：

A-13yellow solid,18h,633.3mg,90％yield.¹H NMR(600MHz,CDCl₃)δ7.60(d,J＝7.8Hz, 1H),7.37(dd,J＝8.4,2.4Hz,1H),7.23-7.19(m,2H),7.15(dd,J＝6.6,1.8Hz,2H),6.86(d,J＝ 8.4Hz,1H),4.69(ddd,J＝11.4,9.6,4.0Hz,1H),4.21(ddd,J＝11.2,5.2,3.4Hz,1H),3.29(s,3H), 3.14(ddd,J＝14.7,9.2,5.2Hz,1H),3.06(s,3H),2.99(dt,J＝15.5,3.7Hz,1H).¹³C NMR(150 MHz,CDCl₃)δ173.9,142.5,137.6,130.7,130.4,129.3,129.1,126.0,125.9,122.4,119.4,118.7, 111.5,109.7,109.0,75.9,62.4,29.5,26.7,22.0.IR(KBr):3425.6,2924.6,1719.6,1612.8，1493.0, 1468.5,1375.2,1337.7,1261.3,1182.9,1101.2,1044.1.HRMS-ESI:Exact mass calcd.for C₂₀H₁₇N₂O₂ClNa⁺[M+Na]⁺:375.0871；Found:375.0872.

实施例14：

A-14yellow solid,22h,540mg,76％yield.¹H NMR(600MHz,CDCl₃)δ7.59(d,J＝7.8Hz, 1H),7.31(dd,J＝8.4,1.2Hz,1H),7.23-7.18(m,2H),7.15-7.12(m,1H),7.03(dd,J＝7.2,1.2 Hz,1H),6.95(t,J＝7.8Hz,1H),4.69(ddd,J＝11.4,9.6,3.6Hz,1H),4.19(ddd,J＝11.4,5.4,3.0 Hz,1H),3.66(s,3H),3.16-3.11(m,1H),3.07(s,3H),2.97(dt,J＝15.6,3.6Hz,1H).¹³C NMR (150MHz,CDCl₃)δ174.5,140.0,137.6,133.0,131.4,129.5,126.0,124.3,124.1,122.4,119.3, 118.6,116.1,111.4,109.8,75.4,62.2,39.9,29.5,22.0.IR(KBr):3423.0,2923.2,2840.6,2360.0, 1721.0,1608.7,1459.5,1356.7,1111.6,1056.8,963.3,944.6.HRMS-ESI:Exact mass calcd.for C₂₀H₁₇N₂O₂ClNa⁺[M+Na]⁺:375.0871；Found:375.0870.

实施例15：

A-9yellow solid,18h,419.1mg,65％yield.¹H NMR(600MHz,CDCl₃)δ7.59(d,J＝7.9Hz, 1H),7.31(dd,J＝8.2,1.1Hz,1H),7.23-7.20(m,1H),7.19(d,J＝8.0Hz,1H),7.15-7.12(m, 1H),7.03(dd,J＝7.3,1.1Hz,1H),6.96-6.93(m,1H),4.69(ddd,J＝11.2,9.7,3.9Hz,1H),4.19 (ddd,J＝11.2,5.3,3.0Hz,1H),3.66(s,3H),3.16-3.11(m,1H),3.09(s,3H),2.99-2.95(m,1H). ¹³C NMR(150MHz,CDCl₃)δ174.5,139.9,137.5,133.0,131.4,129.5,126.0,124.3,124.1,122.3, 119.3,118.6,116.1,111.4,108.9,75.4,62.2,29.9,29.5,22.0.IR(KBr):3434.6,2360.5,2342.7, 1725.5,1608.3,1459.8,1362.8,1259.2,112.1,1056.8.HRMS-ESI:Exact mass calcd.for C₂₀H₁₇N₂O₂ClNa⁺[M+Na]⁺:375.0871；Found:375.0870.

实施例15：

A-15yellow solid,48h,475.2mg,60％yield.¹H NMR(600MHz,CDCl₃)δ7.72(dd,J＝8.4,1.8 Hz,1H),7.60(d,J＝7.8Hz,1H),7.43(d,J＝1.8Hz,1H),7.25-7.19(m,2H),7.16-7.13(m,1H), 6.72(d,J＝8.2Hz,1H),4.68(ddd,J＝11.2,9.0,4.2Hz,1H),4.20(ddd,J＝11.2,5.4,3.6Hz,1H), 3.28(s,3H),3.14(ddd,J＝14.4,9.6,5.4Hz,1H),3.06(s,3H),2.99(dt,J＝15.6,3.6Hz,1H).¹³C NMR(150MHz,CDCl₃)δ173.6,143.7,139.6,137.6,134.1,130.9,129.3,126.0,122.4,119.4, 118.7,111.5,110.7,109.0,85.9,62.3,29.5,26.5,22.0.IR(KBr):2924.4,2360.5,1719.9,1606.9, 1455.6,1375.7,1253.1,1180.8,1112.6,1049.1,995.0,939.2.HRMS-ESI:Exact mass calcd.for C₂₀H₁₇N₂O₂BrNa⁺[M+Na]⁺:419.0363；Found:419.0363.

实施例16:

A-16yellow solid,48h,42.3mg,53％yield.¹H NMR(600MHz,CDCl₃)δ7.60(d,J＝7.8Hz, 1H),7.52(dd,J＝8.4,1.8Hz,1H),7.27(d,J＝1.8Hz,1H),7.24-7.18(m,2H),7.15-7.12(m, 1H),6.81(d,J＝8.4Hz,1H),4.68(ddd,J＝11.2,9.3,3.9Hz,1H),4.20(ddd,J＝11.2,5.4,3.6Hz, 1H),3.28(s,3H),3.16-3.11(m,1H),3.06(s,3H),2.99(dt,J＝15.5,3.6Hz,1H).¹³C NMR(150 MHz,CDCl₃)δ173.7,143.0,137.6,133.6,129.3,128.6,122.4,119.4,118.7,116.2,111.5,110.5, 110.1,109.0,75.9,62.4,29.5,26.5,22.0.IR(KBr):3442.0,2932.8,2360.7,1720.5,1609.4,1344.1, 1102.3,1046.9.HRMS-ESI:Exact masscalcd.for C₂₀H₁₇N₂O₂BrNa⁺[M+Na]⁺:419.0363；Found: 419.0363.

实施例17：

A-17yellow solid,13h,646.0mg,81％yield.¹H NMR(600MHz,CDCl₃)δ7.59(d,J＝7.8Hz, 1H),7.42(s,1H),7.23-7.17(m,3H),7.15-7.11(m,1H),7.09(d,J＝1.8Hz,1H),7.01(d,J＝7.8 Hz,1H),4.68(ddd,J＝11.2,9.0,3.6Hz,1H),4.19(ddd,J＝11.2,5.4,3.4Hz,1H),3.28(s,3H), 3.12(ddd,J＝14.4,9.6,5.2Hz,1H),3.05(s,3H),2.98(dt,J＝15.5,3.6Hz,1H).¹³C NMR(150 MHz,CDCl₃)δ174.1,145.3,137.6,129.4,127.6,126.7,126.3,126.1,124.6,122.4,119.4,118.6, 112.3,111.4,109.0,75.6,62.3,29.5,26.5,22.0.IR(KBr):3426.8,2941.6,2358.5,1723.0,1607.8, 1494.4,1469.6,1364.0,1240.2,1099.9,1058.6,991.3,939.4.HRMS-ESI:Exact mass calcd.for C₂₀H₁₇N₂O₂BrNa⁺[M+Na]⁺:419.0366；Found:419.0364.

实施例18：

A-18yellow solid,18h,483mg,61％yield.¹H NMR(600MHz,CDCl₃)δ7.59(d,J＝7.8Hz, 1H),7.49(dd,J＝8.4,0.6Hz,1H),7.20(dd,J＝18.0,7.8Hz,2H),7.13(t,J＝7.2Hz,1H),7.06(d, J＝7.2Hz,1H),6.88(t,J＝7.8Hz,1H),4.69(td,J＝10.2,3.8Hz,1H),4.19(ddd,J＝11.0,5.0, 2.4Hz,1H),3.67(s,3H),3.14(ddd,J＝15.0,9.6,5.2Hz,1H),3.06(s,3H),2.97(dt,J＝15.6,3.4 Hz,1H).¹³C NMR(150MHz,CDCl₃)δ174.7,141.3,137.6,136.3,131.7,129.5,126.0,124.6, 122.4,119.3,118.6,111.4,108.9,102.8,75.3,62.2,30.0,29.5,22.0.IR(KBr):2923.8,2848.3, 2360.2,2341.2，1723.8,1608.0,1580.6,1453.3,1354.4,1107.0,1054.6,993.2,944.2.HRMS-ESI: Exact mass calcd.forC₂₀H₁₈N₂O₂Br⁺[M+H]⁺:397.0552；Found:397.0544.

实施例19：

A-19yellow solid,19h,618mg,71％yield.¹H NMR(600MHz,CDCl₃)δ7.72(dd,J＝8.2,1.6 Hz,1H),7.60(d,J＝7.9Hz,1H),7.43(d,J＝1.6Hz,1H),7.24-7.19(m,2H),7.16-7.13(m,1H), 6.71(d,J＝8.2Hz,1H),4.68(ddd,J＝11.3,9.4,4.0Hz,1H),4.20(ddd,J＝11.1,5.1,3.4Hz,1H), 3.28(s,3H),3.17–3.12(m,1H),3.06(s,3H),2.99(dt,J＝15.5,3.6Hz,1H).¹³C NMR(150MHz, CDCl₃)δ173.6,143.7,139.6,137.6,134.1,130.9,129.4,126.0,122.4,119.4,118.7,111.5,110.7, 109.0,85.9,75.7,62.4,29.5,26.5,22.0.IR(KBr):3422.2,2912.8,2360.0,2339.2,1720.6,1605.8, 1465.4,1343.0,1242.2,1103.0,1049.3.HRMS-ESI:Exact mass calcd.for C₂₀H₁₇N₂O₂INa⁺ [M+Na]⁺:467.0227；Found:467.0230.

实施例20：

A-20yellow solid,23h,574mg,73％yield.¹H NMR(600MHz,CDCl₃)δ8.94(s,1H),7.61(d,J ＝7.8Hz,1H),7.28(dd,J＝7.8,1.2Hz,1H),7.21(dd,J＝12.8,4.2Hz,2H),7.14(dd,J＝10.4,4.0 Hz,2H),7.01(t,J＝7.2Hz,1H),6.92(d,J＝7.8Hz,1H),4.71(ddd,J＝11.4,8.8,4.2Hz,1H), 4.25(dt,J＝11.4,4.6Hz,1H),3.17-3.12(m,4H),3.03(dd,J＝11.4,4.2Hz,1H).¹³C NMR(150 MHz,CDCl₃)δ176.8,141.1,137.6,130.8,129.8,129.1,126.1,125.7,123.5,122.3,119.3,118.6, 111.2,110.8,109.1,62.2,29.7,29.4,22.0.IR(KBr):3214.4,2954.4,2923.8,2853.0,2360.2, 2339.2,1727.0,1618.5,1471.1,1374.4,1208.2,1181.4,1058.1,993.1,933.0.HRMS-ESI:Exact mass calcd.for C₁₉H₁₇N₂O₂ ⁺[M+H]⁺:305.1290；Found:305.1282.

实施例21：

A-21yellow solid,23h,580mg,87％yield.¹H NMR(600MHz,CDCl₃)δ7.47(d,J＝8.4Hz, 1H),7.38(td,J＝7.8,1.2Hz,1H),7.14(dd,J＝7.2,0.6Hz,1H),7.04(td,J＝7.8,0.6Hz,1H), 6.96(d,J＝7.2Hz,2H),6.92(d,J＝7.8Hz,1H),4.70(ddd,J＝11.2,9.2,3.6Hz,1H),4.20(ddd,J ＝11.2,5.4,3.6Hz,1H),3.30(s,3H),3.11(ddd,J＝14.6,9.0,5.4Hz,1H),2.99(s,3H),2.98-2.94 (m,1H),2.46(s,3H).¹³C NMR(150MHz,CDCl₃)δ174.3,144.0,138.0,132.0,130.7,129.4, 128.8,125.4,124.0,123.5,120.9,118.2,111.0,108.9,108.6,62.2,29.3,26.4,22.1,21.9.IR(KBr): 3406.9,2916.3,2846.4,1714.4,1609.8,1470.2,1365.0,1345.8,1243.7,1096.2,1046.5,995.2, 948.3.HRMS-ESI:Exactmass calcd.for C₂₁H₂₀N₂O₂Na⁺[M+Na]⁺:355.1417；Found:355.1414.

实施例22：

A-22yellow solid,23h,54.0mg,81％yield.¹H NMR(600MHz,CDCl₃)δ7.50(d,J＝8.6Hz, 1H),7.42(td,J＝7.8,1.2Hz,1H),7.17(dd,J＝7.3,0.7Hz,1H),7.07(td,J＝7.6,0.7Hz,1H), 6.99(d,J＝7.2Hz,2H),6.95(d,J＝7.8Hz,1H),4.74(ddd,J＝11.1,9.2,4.0Hz,1H),4.24(ddd,J ＝11.1,5.1,3.5Hz,1H),3.33(s,3H),3.15(ddd,J＝14.6,9.1,5.2Hz,1H),3.02(s,3H),3.02-2.98 (m,1H),2.50(s,3H).¹³C NMR(150MHz,CDCl₃)δ174.3,144.0,138.0,132.0,130.7,129.4, 128.8,125.4,124.0,123.5,120.9,118.2,111.0,108.9,108.6,76.1,62.2,29.3,26.4,22.1,21.9.IR (KBr):3416.5,2928.3,2854.1,2259.4,1712.7,1611.8,1468.3,1344.0,1096.7,1042.2,935.1. HRMS-ESI:Exact masscalcd.for C₂₁H₂₀N₂O₂Na⁺[M+Na]⁺:355.1417；Found:355.1416.

实施例23：

A-23yellow solid,23h,775mg,98％yield.¹H NMR(600MHz,CDCl₃)δ7.72-7.66(m,1H), 7.37(dd,J＝11.4,4.2Hz,1H),7.23-7.09(m,7H),6.99(t,J＝7.8Hz,1H),6.82(d,J＝7.8Hz, 1H),6.67-6.62(m,2H),4.98-4.85(m,2H),4.39(d,J＝18.0Hz,1H),4.25(ddd,J＝11.4,5.4, 2.4Hz,1H),3.27(ddd,J＝15.6,10.2,5.4Hz,1H),3.14-3.01(m,1H),2.80(s,3H).¹³C NMR (150MHz,CDCl₃)δ173.5,144.1,137.8,136.7,130.8,129.8,128.2,128.0,127.0,126.3,125.4, 125.3,123.3,122.6,119.6,118.6,111.9,109.4,108.4,75.8,61.7,46.6,25.7,22.0.IR(KBr): 3438.4,2806.2,2874.8,2360.1,1732.3,1609.0,1489.0,1465.7,1344.8,1241.2,1175.4,1090.1, 1054.2,994.4,929.8.HRMS-ESI:Exact masscalcd.for C₂₆H₂₂N₂O₂Na⁺[M+Na]⁺:417.1573； Found:417.1574.

本领域技术人员可对本发明做各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。应理解，本发明范围中，本发明的上述各技术特征和在下文(如实施例) 中具体描述的各种技术特征之间都可以互相组合，从而构成新的或优选的技术方案。