CN111303148B - 一类1-取代β-咔啉衍生物及其应用 - Google Patents

一类1-取代β-咔啉衍生物及其应用 Download PDF

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CN111303148B
CN111303148B CN202010089835.4A CN202010089835A CN111303148B CN 111303148 B CN111303148 B CN 111303148B CN 202010089835 A CN202010089835 A CN 202010089835A CN 111303148 B CN111303148 B CN 111303148B
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盛涛
伍辉军
顾沁
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Abstract

本发明公开了一类1‑取代β‑咔啉衍生物及其应用。本发明专利以β‑咔啉为母核，主要在1号位置引入烷基和吸电子基团,合成了一些列1取代β‑咔啉衍生物，选取农业上重要的植物病原真菌和细菌，测试化合物对真菌细菌的抑制活性，抑菌活性测试结果显示，1‑取代β‑咔啉衍生物对多种植物致病菌均有抑制活性。

Description

一类1-取代β-咔啉衍生物及其应用
技术领域
本发明涉及一类1-取代β-咔啉衍生物及其应用。
背景技术
使用杀菌剂防治植物病害是保证农作物高产、稳产的重要措施之一。20世纪70年代前使用的杀菌剂几乎都是传统的保护性杀菌剂，作用位点多，不易引发病原菌产生抗药性。直至60年代末70年代初，随着高效、内吸、选择性强的现代杀菌剂被开发和广泛应用，杀菌剂抗性越来越严重和普遍，常导致植物病害化学防治失败，农业生产遭受巨大损失。(参见：祁之秋,王建新,陈长军,周明国.现代杀菌剂抗性研究进展[J].农药.2006(10))。由此可见，不断开发新的杀菌剂品种的解决主流杀菌剂抗药性问题，是当今农药研究的一个重要方向。
咔啉类生物碱是吲哚类生物碱中的一大类，拥有一个共同的吡啶并吲哚三环结构。β-咔啉类生物碱是在自然界分布最广，数量最多，研究最为深入的咔啉类生物碱。β-咔啉具有抗肿瘤、抗病毒、抗菌、抗氧化等多种生活性，目前研究较多的主要是其抗癌活性，在农用杀菌活性方面鲜有报道。
发明内容
本发明的目的在于提供一类新型1-取代β-咔啉衍生物作为农用杀菌剂。
本发明的技术方案如下：
一类式(I)所示的1-取代β-咔啉衍生物，
Figure BDA0002383296940000011
当C＝1,2,3,6-四氢吡啶时，
R2选自羧甲基,R1选自羧基，氢，C1-4烷基，N-丙基，异丙基，N-辛基，苯基，羧甲基，2-吡啶基，3-噻吩基，4-Br-苯基中的任意一种；
或者，R2＝甲基,R1＝羧基
当C＝1,2-二氢吡啶时，
R2选自氢,R1为氨甲酰基
当C＝吡啶时,
R2＝羧甲基,R1选自氢，C1-4烷基，N-丙基，N-辛基，苯基，乙酮基，羧甲基，羟甲基，2-吡啶基，3-噻吩基，4-Br-苯基，氨甲酰基，甲醛基，羟基，N-甲基甲酰胺基中的任意一种；
或者，R2＝羧基,R1选自氢，甲基，乙基，N-丙基，异丙基，N-辛基，苯基，乙酮基，羧基，2-吡啶基，3-噻吩基，4-Br-苯基，氨甲酰基，羟基，羟甲基中的任意一种；
或者，R2＝氢R1＝羧甲基、氨甲酰基中的任意一种；
或者，R2＝氨甲酰基R1＝氢，乙基，异丙基，氨甲酰基，乙酮基，N-甲基甲酰胺基中的任意一种。
本发明所述的式(I)所示的1-取代β-咔啉衍生物，优选，
当C＝1,2,3,6-四氢吡啶时，
R2选自羧甲基,R1选自羧基，C1-4烷基；
当C＝1,2-二氢吡啶时，
R2选自氢,R1为氨甲酰基
当C＝吡啶时,
R2＝羧甲基,R1选自C1-4烷基，氨甲酰基，羧基、羟甲基中的任意一种；
或者，R2＝羧基,R1选自羟甲基中的任意一种；
或者，R2＝氢R1＝氨甲酰基。
作为本发明的一种优选实施方式，所述的式(I)所示的1-取代β-咔啉衍生物，选自以下任意一种化合物：
Figure BDA0002383296940000021
本发明所述的式(I)所示的1-取代β-咔啉衍生物或其可接受的盐在制备抑制植物病原真菌的制剂中的应用。
所述的植物病原真菌优选自以下任意一种或多种：灰葡萄孢(Botrytis cinerea)常引起草莓灰霉病、禾顶囊壳小麦变种(Gaeumannomyces graminis)常引起小麦全蚀病、核盘菌(Sclerotinia sclerotiorum)常引起油菜菌核病、尖镰孢(Fusarium oxysporum)常引起瓜类枯萎病、瓜亡革菌(Thanatephorus cucumeris)常引起水稻纹枯病、禾谷镰孢(Fusarium graminearum)常引起小麦赤霉病、辣椒疫霉(Phytophthora capsici)常引起辣椒疫病、刺盘孢菌(Cladosporium orbiculare)常引起黄瓜炭疽病、串珠镰孢(Fusariummoniliforme)常引起水稻恶苗病。
本发明所述的式(I)所示的1-取代β-咔啉衍生物或其可接受的盐在制备抑制植物病原细菌的制剂中的应用。
所述的植物病原细菌优选自以下任意一种或多种：丁香假单胞菌大豆致病变种(Pseudomonas syringae pv.glycinea)常引起大豆细菌性斑点病，稻黄单胞菌稻生致病变种(Xanthomonasoryzae oryzae pv.oryzae)常引起水稻白叶枯病，稻黄单胞菌稻生致病变种(Xanthomonasoryzae oryzae pv.oryzicola oryzae)常引起水稻细菌性条斑病。此外，选择了非致病的革兰氏阳性菌枯草芽胞杆菌(Bacillus subtilis)。
有益效果：
本发明专利以β-咔啉环为母核，主要在1号位置引入烷基和吸电子基团,合成了一系列1取代β-咔啉衍生物，选取农业上重要的植物病原真菌和细菌，测试化合物对真菌细菌的抑制活性，抑菌活性测试结果显示，1-取代β-咔啉衍生物对多种农业植物致病菌均有抑制活性。
具体实施方式
制备本发明所述的1-取代β-咔啉衍生物的方法，它由下列步骤组成：
路线1(以化合物18合成为例)：
步骤1-1.(1S,3S)-1-Methyl-2,3,4,9-tetrahydro-1H-pyrido-[3,4-b]indole-3-carboxylic acid的合成：在50mL水中依次加入0.5mL浓H2SO4和40％的乙醛水溶液(3.5mL，24.5mmol，1.0当量)然后加入L-色氨酸(5.0g，24.5mmol，1.0当量)。混合物在室温搅拌过夜，用1mol/L氢氧化钠调节至pH＝6-7，有白色固体析出。过滤白色浆液，并将滤饼用水洗三遍得到白色固体(5.1g，91％)。
步骤1-2.(1S,3S)-1-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(化合物7)的合成：将(1S,3S)-1-Methyl-2,3,4,9-tetrahydro-1H-pyrido-[3,4-b]indole-3-carboxylic acid(5.0g，21.7mmol，1.0eqiv)溶解在在150mL甲醇中，冰浴条件下加入SOCl2(3.15mL，43.4mmol，2.0equiv)。将混合物在室温下搅拌30分钟，回流5小时。反应结束后，蒸干溶剂，将残余物溶于水(100mL)中。用饱和NaHCO3水溶液将混合物的调节至pH＝9再用乙酸乙酯(150mL×3)萃取水层，合并的有机相用饱和NaCl溶液洗涤，并用无水Na2SO4干燥，然后将混合物真空浓缩，柱色谱纯化得到浅黄色固体状的化合物7(4.56g，86％)
步骤1-3.Ethyl 1-Methyl-9H-pyrido[3,4-b]indole-3-car-boxylate(18)的合成。将化合物7(4g，16.4mmol，1.0equiv)溶解在150mL DMF中，冰浴条件下分批少量加入高锰酸钾(5.20g，32.8mmol，2.0当量)。将反应室温搅拌24小时后加入亚硫酸氢钠还原过量的高锰酸钾，并通过硅藻土过滤。然后将滤液浓缩至干，残余物进行柱色谱纯化，得到褐色固体的化合物18(2.3g，60％)
步骤1-4.1-methyl-9H-pyrido[3,4-b]indole-3-carboxylic acid(34)的合成。将化合物18(0.30g，1.25mmol)溶解在甲醇(20mL)中和1mol/L NaOH(20mL)的混合溶液中，加热回流2h。反应完成后，冷却至室温后，用1mol/L HCl溶液将混合物的pH调节至8。然后过滤出沉淀物，并将残余物从热甲醇中重结晶得到白色固体34(0.25g，90％)。
路线2(以化合物29合成为例)：
化合物methyl 1-carbamoyl-9H-pyrido[3,4-b]indole-3-carboxylate(29)的合成。将化合物17(0.34g，1.5mmol)加入到50mL甲酰胺的溶液中，然后加入1mL浓硫酸。搅拌混合物并冷却至10–15℃，在10分钟内持续并同时加入FeSO4·7H2O和H2O2的饱和溶液(30％水溶液)，TLC监测反应进行直到没有原料为止。反应完成后，将反应混合物倒入水(150mL)中，然后用碳酸钠饱和溶液中和并用乙酸乙酯(3×100mL)萃取。合并的有机层用饱和NaCl(1×100mL)洗涤，用MgSO4干燥并蒸干溶剂。残留物通过柱层析纯化得到淡黄色固体29(0.22g，55％)。
路线3(以化合物5合成为例)：
步骤3-1.9H-pyrido[3,4-b]indole-1-carboxamide(5)的合成。将化合物3(1g，4.42mmol)溶解在到甲醇(40mL)和氨水(40mL)的混合溶液中，加热回流搅拌过夜。反应结束后过滤混合物，蒸干甲醇并用1mol/L HCl溶液调节滤液pH＝8，用乙酸乙酯(1×100mL)萃取。合并的有机层用饱和NaCl洗涤，MgSO4干燥。蒸干溶剂，残留物通过柱层析纯化，得到黄色固体化合物5(0.75g，80％)。
实施例1：3-(methoxycarbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylic acid(1)的制备
Figure BDA0002383296940000041
制备方法同步骤1-1和1-2。用乙醛酸代替乙醛，L-色氨酸甲酯盐酸盐代替L-色氨酸，得到3-(methoxycarbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylic acid为白色粉末，产率93％。M.p.143-145(℃).1H NMR(400MHz,DMSO-d6)δH10.83(s,1H),7.52–7.43(m,2H),7.09(ddd,1H,J＝8.2,7.0,1.2),7.00(ddd,1H,J＝8.0,7.0,1.1),5.19(s,1H),4.48(dd,1H,J＝11.7,5.1),3.82(s,3H),3.21(ddd,1H,J＝15.5,5.1,1.6),3.12–2.97(m,1H).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C13H13N2O4,261.09,Found:261.24.
实施例2：methyl 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-carboxylate(2)的制备
Figure BDA0002383296940000051
制备方法同步骤1-1和1-2。用乙醛酸代替乙醛，色胺代替L-色氨酸，得到methyl2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-carboxylate为白色固体，产率89％。1H NMR(500MHz,CDCl3)δH 8.47(br,1H),7.50(d,J＝7.5,1H),7.29(d,J＝7.5,1H),7.08-7.17(m,2H),3.83-3.87(m,2H),3.72(s,3H),3.61(dd,J＝13.5,4.5,1H),3.30-3.36(m,1H),3.23(dd,J＝13.5,3,1H),2.90-3.00(m,3H).
实施例3：methyl 9H-pyrido[3,4-b]indole-3-carboxylate(3)的制备
Figure BDA0002383296940000052
制备方法同步骤1-3，用化合物2代替化合物7，得到methyl 9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率75％。M.p.143-145(℃).1H NMR(400MHz,DMSO-d6)δH 11.68(s,1H),8.50(d,1H,J＝4.9),8.43(dd,1H,J＝4.9,0.7),8.34–8.29(m,1H),7.80(dt,1H,J＝8.3,0.9),7.62(ddd,1H,J＝8.3,7.1,1.2),7.31(ddd,1H,J＝8.0,7.1,1.0),4.03(s,3H).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C13H11N2O2,227.08,Found:227.24.；Calcd.for[M+Na]+,C13H10N2NaO2,249.06,Found:249.22.
实施例4：2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxamide(4)的制备
Figure BDA0002383296940000053
制备方法同步骤3-1，用化合物2代替化合物5，得到2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxamide为黄色固体，产率82％。M.p.233.2-234.9(℃).1HNMR(400MHz,DMSO-d6)δH 11.15(s,1H),7.99–7.87(m,1H),7.65–7.61(m,1H),7.57(dd,2H,J＝9.5,8.1),7.20(ddd,1H,J＝8.2,6.9,1.2),7.04(ddd,1H,J＝8.0,6.9,1.0),4.01–3.89(m,2H),2.93–2.78(m,2H).13C NMR(125MHz DMSO-d6)δC 166.60,152.70,137.56,126.46,124.48,124.47,119.94,119.86,116.82,113.74,48.41,18.96.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C12H12N3O,214.10,Found:214.16；Calcd.for[M+Na]+,C12H11N3NaO,236.08,Found:236.12.
实施例5：9H-pyrido[3,4-b]indole-1-carboxamide(5)的制备
Figure BDA0002383296940000061
制备方法同步骤3-1，得到9H-pyrido[3,4-b]indole-1-carboxamide为黄色固体，产率71％。M.p.223.7-224.1(℃).1H NMR(400MHz,DMSO-d6)δH 11.67(s,1H),8.40(d,J＝5.0,1H),8.35(d,J＝5.0,1H),8.28(d,J＝8.0,2H),7.82(dt,J＝8.3,0.9,1H),7.79–7.76(m,1H),7.57(ddd,J＝8.3,7.1,1.2,1H),7.27(ddd,J＝7.9,7.1,1.0,1H).13C NMR(125MHzDMSO-d6)δC 168.42,141.99,137.14,134.98,133.13,131.03,129.15,122.19,120.32,120.17,118.41,113.48.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C12H9N3O,211.07,Found:212.28.
实施例6：methyl 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(6)的制备
Figure BDA0002383296940000062
制备方法同步骤1-1和1-2。用甲醛代替乙醛，得到methyl2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate为黄色固体，产率91％。M.p.188.9-190.3(℃).1H NMR(400MHz,DMSO-d6)δH 10.73(s,1H),7.37(dd,J＝7.7,1.2,1H),7.26(dt,J＝8.0,1.0,1H),7.01(ddd,J＝8.1,7.0,1.3,1H),6.93(ddd,J＝8.0,7.0,1.1,1H),4.04–3.87(m,2H),3.73(dd,J＝8.8,4.8,1H),3.68(s,3H),2.97–2.89(m,1H),2.74(ddt,J＝15.0,8.7,1.8,1H).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C13H15N2O2,231.11,Found:231.19；Calcd.for[M+Na]+,C19H14N2NaO2,325.10,Found:325.27.
实施例7：methyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(7)的制备
Figure BDA0002383296940000063
制备方法同步骤1-1和1-2。得到methyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate为黄色油状，产率82％。M.p.65.2-66.6(℃).1H NMR(400MHz,DMSO-d6)δH 10.80(s,1H),7.38(d,1H,J＝7.7),7.29(dt,1H,J＝8.0,0.9),7.02(ddd,1H,J＝8.2,7.0,1.3),6.94(ddd,1H,J＝8.0,7.0,1.1),4.11(dt,1H,J＝6.8,2.1),4.03(q,1H,J＝7.1),3.72(s,3H),2.92(ddd,1H,J＝14.8,4.3,1.8),2.65(ddd,1H,J＝14.8,11.1,2.4),1.41(d,3H,J＝6.6).13C NMR(125MHz DMSO-d6)δC 173.72,138.18,136.28,127.21,120.96,118.83,117.90,111.39,106.04,56.62,52.15,48.71,26.04,20.52.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H17N2O2,245.13,Found:245.27.
实施例8：methyl 1-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(8)的制备
Figure BDA0002383296940000071
制备方法同步骤1-1和1-2。用正丙醛代替乙醛，得到methyl 1-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate为黄色油状，产率86％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C15H19N2O2,259.14,Found:259.13；Calcd.for[M+Na]+,C15H18N2NaO2,281.13,Found:281.12.
实施例9：methyl 1-propyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(9)的制备
Figure BDA0002383296940000072
制备方法同步骤1-1和1-2。用正丁醛代替乙醛，得到methyl 1-propyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate为黄色油状，产率81％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C16H21N2O2,273.16,Found:273.26.
实施例10：methyl 1-isopropyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(10)的制备
Figure BDA0002383296940000073
制备方法同步骤1-1和1-2。用异丁醛代替乙醛，得到methyl 1-isopropyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate为黄色油状，产率82％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C16H21N2O2,273.16,Found:273.24；Calcd.for[M+Na]+,C16H20N2NaO2,295.14,Found:295.24.
实施例11：methyl 1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(11)的制备
Figure BDA0002383296940000081
制备方法同步骤1-1和1-2。用正戊醛代替乙醛，得到methyl 1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate为黄色油状，产率89％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C21H31N2O2,343.24,Found:343.39.
实施例12：methyl 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(12)的制备
Figure BDA0002383296940000082
制备方法同步骤1-1和1-2。用苯甲醛代替乙醛，得到methyl 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率88％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C19H19N2O2,307.4,Found:307.28.
实施例13：Dimethyl 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1,3-dicarboxylate(13)的制备
Figure BDA0002383296940000083
制备方法同步骤1-1和1-2。用乙醛酸代替乙醛，得到Dimethyl 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1,3-dicarboxylate为黄色油状，产率85％。1H NMR(400MHz,DMSO-d6)δH 11.11(s,1H),7.48(m,2H),7.15(t,1H),7.04(t,1H),5.78(s,1H),4.74(dd,1H),3.94(s,3H)，3.85(s,3H),3.28(dd,1H),3.15(m,1H).13C NMR(125MHz DMSO-d6)δC 165.90,165.68,142.24,137.41,136.55,131.71,130.05,129.81,122.81,121.42,121.20,120.91,113.66,52.89,52.72.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C15H17N2O4,289.12,Found:289.25.
实施例14：methyl 1-(pyridin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(14)的制备
Figure BDA0002383296940000091
制备方法同步骤1-1和1-2。用2-吡啶甲醛代替乙醛，得到methyl 1-(pyridin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率78％。M.p.213.1-214.1(℃).1HNMR(400MHz,DMSO-d6)δH 10.46(s,1H),8.59(dd,J＝2.2,0.8,1H),8.54(dd,J＝4.8,1.7,1H),7.68(dt,J＝7.9,2.0,1H),7.48–7.43(m,1H),7.38(ddd,J＝7.8,4.8,0.9,1H),7.20(dt,J＝8.1,1.0,1H),6.99(dtd,J＝19.8,7.0,1.2,2H),5.28(d,J＝2.0,1H),3.90(dd,J＝11.0,4.1,1H),3.71(s,3H),3.06(ddd,J＝14.8,4.1,1.8,2H),2.86(ddd,J＝14.8,11.0,2.4,1H).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C18H18N3O2,308.14,Found:308.36.
实施例15：methyl 1-(thiophen-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(15)的制备
Figure BDA0002383296940000092
制备方法同步骤1-1和1-2。用3-噻吩甲醛代替乙醛，得到methyl 1-(thiophen-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate为黄色油状，产率85％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C17H17N2O2S,313.10,Found:313.22；Calcd.for[M+Na]+,C17H16N2NaO2S,335.08,Found:335.23.
实施例16：methyl 1-(4-bromophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(16)的制备
Figure BDA0002383296940000101
制备方法同步骤1-1和1-2。用4-溴苯甲醛代替乙醛，得到methyl 1-(4-bromophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate为黄色固体，产率71％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C19H18BrN2O2,385.26,Found:385.48.
实施例17：methyl 9H-pyrido[3,4-b]indole-3-carboxylate(17)的制备
Figure BDA0002383296940000102
制备方法同步骤1-3，用化合物6代替化合物7，得到methyl 9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率79％。M.p.248.5-249.2(℃).1H NMR(400MHz,DMSO-d6)δH 12.08(1H,s),8.98(1H,d,J＝1.0),8.94(1H,s),8.42(1H,d,J＝7.9),7.68(1H,d,J＝8.2),7.61(1H,ddd,J＝8.2,7.0,1.2),7.33(1H,ddd,J＝8.0,7.0,1.1),3.92(3H,s).13C NMR(125MHz DMSO-d6)δC 166.26,141.78,138.20,138.18,133.35,129.55,128.52,122.87,121.71,121.46,117.93,111.56,74.23,56.25,52.55.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C13H11N2O2,227.08,Found:227.20.
实施例18：methyl 1-methyl-9H-pyrido[3,4-b]indole-3-carboxylate(18)的制备
Figure BDA0002383296940000103
制备方法同步骤1-3。得到methyl 1-methyl-9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率85％。M.p.239.2-241.1(℃).1H NMR(400MHz,DMSO-d6)δH12.06(s,1H),8.78(s,1H),8.37(d,1H,J＝7.9),7.66(dt,1H,J＝8.2,1.0),7.61(dd,1H,J＝7.0,1.2),7.31(ddd,1H,J＝7.9,7.0,1.1),3.90(s,3H),2.82(s,3H).13C NMR(125MHzDMSO-d6)δC 166.61,142.65,141.18,136.63,136.36,128.84,127.24,122.60,121.80,120.62,116.45,112.77,52.33,20.85.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H13N2O2,241.10,Found:241.24.
实施例19：methyl 1-ethyl-9H-pyrido[3,4-b]indole-3-carboxylate(19)的制备
Figure BDA0002383296940000111
制备方法同步骤1-3，用化合物8代替化合物7，得到methyl 1-ethyl-9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率85％。M.p.161.7-163.1(℃).1H NMR(400MHz,DMSO-d6)δH 12.03(s,1H),8.79(s,1H),8.37(d,J＝7.9,1H),7.67(dt,J＝8.2,0.9,1H),7.60(ddd,J＝8.3,7.0,1.2,1H),7.31(ddd,J＝8.0,7.0,1.1,1H),3.92(s,3H),3.76–3.65(m,1H),1.41(d,J＝6.8,6H).13C NMR(125MHz DMSO-d6)δC 166.66,147.41,141.19,136.47,135.87,128.83,127.55,122.52,121.81,120.58,116.49,112.76,52.35,27.26,13.24.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C15H15N2O2,255.11,Found:255.22.
实施例20：methyl 1-propyl-9H-pyrido[3,4-b]indole-3-carboxylate(20)的制备
Figure BDA0002383296940000112
制备方法同步骤1-3，用化合物9代替化合物7，得到methyl 1-propyl-9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率71％。M.p.165.8-166.9(℃).1H NMR(400MHz,DMSO-d6)δH 10.87(s,1H),7.51–7.45(m,1H),7.33(dt,J＝8.1,1.0,1H),7.12(d,J＝2.4,1H),7.06(ddd,J＝8.2,7.0,1.2,1H),6.97(ddd,J＝8.0,7.0,1.1,1H),3.64(t,J＝6.3,2H),3.55(s,3H),3.06–2.90(m,2H),1.90(s,3H).13C NMR(125MHz DMSO-d6)δC166.66,146.37,141.20,136.48,136.26,128.86,127.55,122.53,121.77,120.58,116.43,112.75,52.36,35.98,22.13,14.44.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C16H17N2O2,269.18,Found:269.22.
实施例21：methyl 1-isopropyl-9H-pyrido[3,4-b]indole-3-carboxylate(21)的制备
Figure BDA0002383296940000113
制备方法同步骤1-3，用化合物10代替化合物7，得到methyl 1-isopropyl-9H-pyrido[3,4-b]indole-3-carboxylatee为白色固体，产率85％。M.p.151.1-152.8(℃).1HNMR(400MHz,DMSO-d6)δH 12.03(s,1H),8.79(s,1H),8.37(d,J＝7.9,1H),7.67(dt,J＝8.2,0.9,1H),7.60(ddd,J＝8.3,7.0,1.2,1H),7.31(ddd,J＝8.0,7.0,1.1,1H),3.92(s,3H),3.76–3.65(m,1H),1.41(d,J＝6.8,6H).13C NMR(125MHz DMSO-d6)δC 166.70,150.72,141.16,136.48,135.22,128.81,127.70,122.44,121.82,120.56,116.46,112.77,52.39,31.58,21.75.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C16H17N2O2,269.13,Found:269.26.
实施例22：methyl 1-octyl-9H-pyrido[3,4-b]indole-3-carboxylate(22)的制备
Figure BDA0002383296940000121
制备方法同步骤1-3，用化合物11代替化合物7，得到methyl 1-octyl-9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率67％。M.p.163.1-164.5(℃).1H NMR(400MHz,DMSO-d6)δH 12.02(s,1H),8.78(s,1H),8.39–8.33(m,1H),7.66(d,J＝8.2,1H),7.60(dd,J＝7.0,1.2,1H),7.30(ddd,J＝8.1,7.0,1.1,1H),3.91(s,3H),3.20–3.06(m,2H),1.80(h,J＝6.7,5.9,2H),1.40(q,J＝7.5,7.0,2H),1.35–1.13(m,8H),0.92–0.75(m,3H).13C NMR(125MHz DMSO-d6)δC 166.67,146.55,141.19,136.50,136.18,128.83,127.54,122.51,121.79,120.57,116.38,112.75,52.35,34.10,31.73,29.55,29.39,29.16,28.77,22.54,14.41.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C21H27N2O2,339.21,Found:339.36.
实施例23：methyl 1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate(23)的制备
Figure BDA0002383296940000122
制备方法同步骤1-3，用化合物12代替化合物7，得到methyl 1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率75％。M.p.256.5-257.6(℃).1H NMR(400MHz,DMSO-d6)δH 11.97(s,1H),8.95(s,1H),8.45(d,1H,J＝7.9),8.12–7.97(m,2H),7.70–7.54(m,5H),7.35(t,1H,J＝7.5),3.96(s,3H).13C NMR(125MHz DMSO-d6)δC 166.53,142.56,141.93,137.99,137.12,135.04,129.63,129.46,129.26,129.15,129.09,122.49,121.59,120.88,117.18,113.24,52.53.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C19H15N2O2,303.11,Found:303.32；Calcd.for[M+Na]+,C19H14N2NaO2,325.10,Found:325.27.
实施例24：methyl 1-acetyl-9H-pyrido[3,4-b]indole-3-carboxylate(24)的制备
Figure BDA0002383296940000131
制备方法同步骤1-2，用化合物40代替(1S,3S)-1-Methyl-2,3,4,9-tetrahydro-1H-pyrido-[3,4-b]indole-3-carboxylic acid，得到methyl 1-acetyl-9H-pyrido[3,4-b]indole-3-carboxylate为黄色固体，产率61％。M.p.201.1-201.9(℃).1H NMR(400MHz,DMSO-d6):δH 12.26(s,1H),9.16–9.11(m,1H),8.44(d,J＝7.9,1H),7.88–7.81(m,1H),7.63(ddd,J＝8.2,7.1,1.2,1H),7.35(ddd,J＝8.0,7.1,1.0,1H),3.97(s,3H),2.82(s,3H).13CNMR(125MHz DMSO-d6)δC 25.7,52.8,112.4,121.0,121.3,121.7,122.1,129.8,131.9,135.3,136.5,136.9,141.4,166.1,203.2.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C15H13N2O3,269.08,Found:269.22.
实施例25：Dimethyl 9H-pyrido[3,4-b]indole-1,3-dicarboxylate(25)的制备
Figure BDA0002383296940000132
制备方法同步骤1-3，用化合物13代替化合物7，得到Dimethyl 9H-pyrido[3,4-b]indole-1,3-dicarboxylate为黄色固体，产率68％。M.p.229.7-230.5(℃).1H NMR(400MHz,DMSO-d6)δH 12.08(s,1H),9.15(s,1H),8.48(d,1H,J＝7.9),7.89–7.81(m,1H),7.67(ddd,1H,J＝8.3,7.1,1.2),7.37(ddd,1H,J＝8.0,7.1,1.0),4.06(s,3H),3.96(s,3H).13C NMR(125MHz DMSO-d6)δC 165.90,165.69,142.24,137.41,136.55,131.71,130.05,129.80,122.82,121.42,121.20,120.91,113.66,52.89,52.72.LC–MS(ESI-)m/z:Calcd.for[M-H]-,C15H11N2O4,283.07,Found:283.21.
实施例26：methyl 1-(pyridin-2-yl)-9H-pyrido[3,4-b]indole-3-carboxylate(26)的制备
Figure BDA0002383296940000133
制备方法同步骤1-3，用化合物14代替化合物7，得到methyl 1-(pyridin-2-yl)-9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率85％。M.p.172.2-174.0(℃).1H NMR(400MHz,DMSO-d6)δH12.15(s,1H),9.23(dd,1H,J＝2.3,0.9),8.98(s,1H),8.79(dd,1H,J＝4.8,1.7),8.46(d,1H,J＝7.9),8.40(dt,1H,J＝7.8,2.0),7.73–7.60(m,3H),7.36(td,1H,J＝7.4,6.9,1.0),3.96(s,3H).13C NMR(125MHz DMSO-d6)δC 166.36,150.30,149.64,142.00,139.79,137.31,136.70,135.27,133.74,129.87,129.37,124.38,122.61,121.49,121.03,117.65,113.22,52.60.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C18H14N3O2,304.11,Found:304.24.
实施例27：methyl 1-(thiophen-3-yl)-9H-pyrido[3,4-b]indole-3-carboxylate(27)的制备
Figure BDA0002383296940000141
制备方法同步骤1-3，用化合物15代替化合物7，得到methyl 1-(thiophen-3-yl)-9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率75％。M.p.213.3-215.4(℃).1H NMR(400MHz,DMSO-d6)δH 11.92(s,1H),8.89(s,1H),8.44(d,1H,J＝7.9),8.16(dd,1H,J＝3.7,1.0),7.83–7.77(m,2H),7.65(ddd,1H,J＝8.2,7.1,1.2),7.39–7.37(m,1H),7.37–7.34(m,1H),3.96(s,3H).13C NMR(125MHz DMSO-d6)δC 166.10,142.80,141.98,136.79,136.76,132.88,130.23,129.38,129.36,128.95,127.15,122.48,121.51,121.22,116.99,113.39,52.64.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C17H13N2O2S,309.07,Found:309.14.
实施例28：methyl 1-(4-bromophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate(28)的制备
Figure BDA0002383296940000142
制备方法同步骤1-3，用化合物16代替化合物7，得到methyl 1-(4-bromophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率51％。M.p.268.1-268.3(℃).1H NMR(400MHz,DMSO-d6)δH 12.00(s,1H),8.96(s,1H),8.45(d,J＝7.9,1H),8.05–7.94(m,2H),7.90–7.80(m,2H),7.74–7.66(m,1H),7.62(ddd,J＝8.2,7.0,1.2,1H),7.35(ddd,J＝8.0,6.9,1.1,1H),3.94(s,3H).13C NMR(125MHz DMSO-d6)δC 166.42,141.96,141.30,137.17,137.09,135.00,132.22,131.17,129.88,129.32,122.94,122.60,121.55,121.01,117.48,113.20,52.59.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C19H14BrN2O2,381.02,Found:381.09.
实施例29：methyl 1-carbamoyl-9H-pyrido[3,4-b]indole-3-carboxylate(29)的制备
Figure BDA0002383296940000151
制备方法同步骤2-1，得到methyl 1-carbamoyl-9H-pyrido[3,4-b]indole-3-carboxylate为黄色固体，产率55％。M.p.263.9-265.2(℃).1H NMR(400MHz,DMSO-d6)δH12.11(s,1H),9.11(s,1H),8.45(d,J＝7.9,1H),8.02(dd,J＝14.2,2.8,2H),7.87(dt,J＝8.3,1.0,1H),7.63(ddd,J＝8.2,7.1,1.1,1H),7.38–7.31(m,1H),3.96(s,3H).13C NMR(125MHz DMSO-d6)δC 167.54,165.85,142.47,136.11,135.39,132.67,131.38,129.72,122.66,121.13,120.72,120.55,113.89,52.74.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H12N3O3,270.09,Found:270.18；Calcd.for[M+Na]+,C14H11N3NaO3,292.07,Found:292.17.
实施例30：methyl 1-formyl-9H-pyrido[3,4-b]indole-3-carboxylate(30)的制备
Figure BDA0002383296940000152
制备方法同步骤2-1，用乙醛代替甲酰胺，得到methyl 1-formyl-9H-pyrido[3,4-b]indole-3-carbox ylate为白色固体，产率45％。M.p.242.4-244.5(℃).1H NMR(400MHz,DMSO-d6)δH 12.47(s,1H),10.27(s,1H),9.19(s,1H),8.48(d,J＝7.9,1H),7.83(d,J＝8.2,1H),7.71–7.61(m,1H),7.38(t,J＝7.6,1H),3.97(s,3H).13C NMR(125MHz DMSO-d6)δC194.76,165.77,142.90,137.07,135.80,135.19,132.00,130.11,122.92,121.95,121.77,120.60,113.89,52.79.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H11N2O3,255.08,Found:255.27.
实施例31：methyl 1-(hydroxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate(31)的制备
Figure BDA0002383296940000153
制备方法同步骤2-1，用乙醇代替甲酰胺，得到methyl 1-(hydroxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate为黄色固体，产率65％。M.p.251.9-253.1(℃).1HNMR(400MHz,DMSO-d6)δH 11.91(d,J＝94.6,1H),8.80(s,1H),8.32(d,J＝7.9,1H),7.68(d,J＝8.2,1H),7.53(ddd,J＝8.3,7.1,1.2,1H),7.25(ddd,J＝8.0,7.1,1.0,1H),5.64(t,J＝5.8,1H),4.95(d,J＝5.8,2H),3.86(d,J＝2.0,3H).13C NMR(125MHz DMSO-d6)δC 166.53,145.43,141.43,135.73,135.70,128.91,128.45,122.39,121.27,120.55,117.38,113.16,64.06,52.37.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H13N2O3,257.09,Found:257.21.
实施例32：methyl 1-(methylcarbamoyl)-9H-pyrido[3,4-b]indole-3-carboxylate(32)的制备
Figure BDA0002383296940000161
制备方法同步骤2-1，用N-甲基甲酰胺代替甲酰胺，得到methyl 1-(methylcarbamoyl)-9H-pyrido[3,4-b]indole-3-carboxylate为白色固体，产率65％。M.p.184.6–185.9(℃).1H NMR(400MHz,DMSO-d6)δH 12.14(s,1H),9.09(s,1H),8.66(q,J＝4.8,1H),8.44(d,J＝7.9,1H),7.85(dt,J＝8.4,1.0,1H),7.63(ddd,J＝8.3,7.1,1.2,1H),7.34(ddd,J＝8.0,7.1,1.0,1H),3.96(s,3H),2.98(d,J＝4.9,3H).13C NMR(125MHz DMSO-d6)δC 194.76,165.77,142.90,137.07,135.80,135.19,132.00,130.11,122.92,121.95,121.77,120.60,113.89,52.79.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C15H14N3O3,284.10,Found:284.24.
实施例33：9H-pyrido[3,4-b]indole-3-carboxylic acid(33)的制备
Figure BDA0002383296940000162
制备方法同步骤1-4，用化合物17代替化合物18，得到9H-pyrido[3,4-b]indole-3-carboxylic acid为白色固体，产率93％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C12H9N2O2,213.07,Found:213.08.
实施例34：1-methyl-9H-pyrido[3,4-b]indole-3-carboxylic acid(34)的制备
Figure BDA0002383296940000163
制备方法同步骤1-4，得到1-methyl-9H-pyrido[3,4-b]indole-3-carboxylicacid为白色固体，产率92％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C13H11N2O2,227.08,Found:227.18.
实施例35：1-ethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid(35)的制备
Figure BDA0002383296940000171
制备方法同步骤1-4，用化合物19代替化合物18，得到1-ethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid为白色固体，产率91％。M.p.203.9-204.1(℃).1H NMR(400MHz,DMSO-d6):δH 12.77(s,1H),9.02(s,1H),8.52(d,J＝8.0,1H),7.80(d,J＝8.3,1H),7.77–7.70(m,1H),7.43(t,J＝7.4,1H),3.40(q,J＝7.5,2H),3.22(s,1H),1.45(t,J＝7.5,3H).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H13N2O2,241.10,Found:241.21.
实施例36：1-propyl-9H-pyrido[3,4-b]indole-3-carboxylic acid(36)的制备
Figure BDA0002383296940000172
制备方法同步骤1-4，用化合物20代替化合物18，得到1-propyl-9H-pyrido[3,4-b]indole-3-carboxylic acid为白色固体，产率92％。M.p.171.5-171.9(℃).1H NMR(400MHz,DMSO-d6)δH 12.05(s,1H),8.79(s,1H),8.37(d,J＝7.8,1H),7.67(d,J＝8.2,1H),7.60(t,J＝7.6,1H),7.31(t,J＝7.4,1H),3.16(q,J＝7.4,2H),1.88(td,J＝16.6,15.0,9.0,2H),1.03(t,J＝7.3,3H).13C NMR(125MHz DMSO-d6)δC 167.36,145.93,141.29,137.08,136.24,128.86,127.84,122.55,121.79,120.52,115.96,112.73,35.85,22.03,14.46.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C15H15N2O2,255.11,Found:255.34；Calcd.for[M+Na]+,C15H14N2NaO2,277.10,Found:277.33.
实施例37：1-isopropyl-9H-pyrido[3,4-b]indole-3-carboxylic acid(37)的制备
Figure BDA0002383296940000173
制备方法同步骤1-4，用化合物21代替化合物18，得到1-isopropyl-9H-pyrido[3,4-b]indole-3-ca rboxylic acid为白色固体，产率93％。M.p.169.9-170.8(℃).1H NMR(400MHz,DMSO-d6)δH 12.03(s,1H),8.80(s,1H),8.37(d,1H,J＝7.9),7.68(d,1H,J＝8.2),7.61(t,1H,J＝7.6),7.31(t,1H,J＝7.4),3.72(p,1H,J＝6.8),1.44(d,6H,J＝6.7).13CNMR(125MHz DMSO-d6)δC 167.33,150.40,141.24,136.86,135.23,128.81,127.99,122.45,121.82,120.51,115.91,112.75,31.48,21.74.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C15H15N2O2,255.11,Found:255.17.
实施例38：1-octyl-9H-pyrido[3,4-b]indole-3-carboxylic acid(38)的制备
Figure BDA0002383296940000181
制备方法同步骤1-4，用化合物22代替化合物18，得到1-octyl-9H-pyrido[3,4-b]indole-3-carboxylic acid为白色固体，产率85％。M.p.187.2-188.6(℃).1H NMR(400MHz,DMSO-d6)δH 12.00(s,1H),8.76(s,1H),8.36(d,J＝7.9,1H),7.66(d,J＝8.2,1H),7.59(t,J＝7.6,1H),7.30(t,J＝7.5,1H),3.15(t,J＝7.8,2H),1.83(p,J＝7.5,2H),1.46–1.31(m,2H),1.25(d,J＝10.7,8H),0.89–0.77(m,3H).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C20H25N2O2,325.19,Found:325.23.
实施例39：1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylic acid(39)的制备
Figure BDA0002383296940000182
制备方法同步骤1-4，用化合物23代替化合物18，得到1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylic acid为白色固体，产率93％。M.p.258.9-259.7(℃).1H NMR(400MHz,DMSO-d6)δH 12.74(s,1H),11.94(s,1H),8.93(s,1H),8.43(d,1H,J＝7.9),8.16–8.04(m,2H),7.81–7.50(m,5H),7.40–7.27(m,1H).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C18H13N2O2,289.10,Found:289.22.
实施例40：1-acetyl-β-carboline-3-carboxylic acid(40)的制备
Figure BDA0002383296940000183
制备方法同步骤1-1和1-2。用丙酮醛代替乙醛，得到1-acetyl-β-carboline-3-carboxylic acid为白色固体，产率95％。M.p.295.3-296.6(℃).1H NMR(400MHz,DMSO-d6)δH 13.02(s,1H),12.26(s,1H),9.17(s,1H),8.46(d,J＝7.9,1H),7.87(d,J＝8.2,1H),7.69–7.61(m,1H),7.37(t,J＝7.5,1H),2.88(s,3H).13C NMR(125MHz DMSO-d6)δC 201.59,166.78,142.72,136.89,135.52,135.45,131.94,129.75,122.65,121.48,121.39,120.69,113.85,26.25,14.54.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H11N2O3,255.08,Found:255.07；Calcd.for[M+Na]+,C14H10N2NaO3,277.06,Found:277.08.
实施例41：9H-pyrido[3,4-b]indole-1,3-dicarboxylic acid(41)的制备
Figure BDA0002383296940000191
制备方法同步骤1-4，用化合物25代替化合物18，得到9H-pyrido[3,4-b]indole-1,3-dicarboxylicacid为白色固体，产率85％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C13H9N2O4,257.06,Found:257.12；Calcd.for[M+Na]+,C13H8N2NaO4,279.04,Found:279.11
实施例42：1-(pyridin-2-yl)-9H-pyrido[3,4-b]indole-3-carboxylic acid(42)的制备
Figure BDA0002383296940000192
制备方法同步骤1-4，用化合物26代替化合物18，得到1-(pyridin-2-yl)-9H-pyrido[3,4-b]indole-3-carboxylic acid为白色固体，产率95％。M.p.271.2-275.6(℃).1H NMR(400MHz,DMSO-d6)δH11.96(s,1H),9.22(dd,J＝2.2,0.9,1H),8.86(s,1H),8.69(dd,J＝4.8,1.7,1H),8.43(dt,J＝7.9,2.0,1H),8.35(dt,J＝7.9,1.0,1H),7.67(dt,J＝8.2,1.0,1H),7.61–7.52(m,2H),7.29(ddd,J＝8.0,7.1,1.0,1H),1.89(s,1H,).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C17H12N3O2,290.09,Found:290.23.
实施例43：1-(thiophen-3-yl)-9H-pyrido[3,4-b]indole-3-carboxylic acid(43)的制备
Figure BDA0002383296940000201
制备方法同步骤1-4，用化合物27代替化合物18，得到1-(thiophen-3-yl)-9H-pyrido[3,4-b]indole-3-carboxylic acid为白色固体，产率95％。M.p.259.9-263.8(℃).1H NMR(400MHz,DMSO-d6)δH12.86(s,1H),11.90(s,1H),8.88(s,1H),8.43(d,J＝7.9,1H),8.17(dd,J＝3.7,1.0,1H),7.85–7.75(m,2H),7.65(ddd,J＝8.3,7.0,1.2,1H),7.42–7.33(m,2H).13C NMR(125MHz DMSO-d6)δC 167.03,142.91,142.01,137.66,136.56,132.81,130.33,129.31,129.28,128.91,127.07,122.44,121.55,121.13,116.79,113.37.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C16H11N2O2S,295.05,Found:295.20.
实施例44：1-(4-bromophenyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid(44)的制备
Figure BDA0002383296940000202
制备方法同步骤1-4，用化合物28代替化合物18，得到1-(4-bromophenyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid为白色固体，产率86％。M.p.288.6-289.4(℃).1HNMR(400MHz,DMSO-d6)δH11.73(s,1H),8.81(s,1H),8.34–8.13(m,1H),7.94(d,2H,J＝8.0),7.57(dd,4H,J＝37.1,7.9),7.21(t,1H,J＝7.6).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C18H12BrN2O2,367.01,Found:367.07.
实施例45：1-carbamoyl-9H-pyrido[3,4-b]indole-3-carboxylic acid(45)的制备
Figure BDA0002383296940000203
制备方法同步骤1-4，用化合物29代替化合物18，得到1-carbamoyl-9H-pyrido[3,4-b]indole-3-carboxylic acid为黄色固体，产率91％。LC–MS(ESI+)m/z:Calcd.for[M+H]+,C13H10N3O3,256.07,Found:256.20.
实施例46：1-(hydroxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid(46)的制备
Figure BDA0002383296940000211
制备方法同步骤1-4，用化合物31代替化合物18，得到1-(hydroxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid为白色固体，产率85％。M.p.293.1-295.6(℃).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H13N2O3,257.09,Found:257.21.
实施例47：9H-pyrido[3,4-b]indole-3-carboxamide(47)的制备
Figure BDA0002383296940000212
制备方法同步骤3-1，用化合物17代替化合物3，得到9H-pyrido[3,4-b]indole-3-carboxamide为白色固体，产率57％。M.p.234.4-235.9(℃).1H NMR(400MHz,DMSO-d6)δH11.96(s,1H),8.89(d,J＝8.5,2H),8.39(d,J＝7.8,1H),8.09(d,J＝3.3,1H),7.66(d,J＝8.2,1H),7.59(ddd,J＝8.2,6.9,1.2,1H),7.52(d,J＝3.2,1H),7.30(ddd,J＝7.9,6.9,1.1,1H).13C NMR(125MHz DMSO-d6)δC 167.44,141.49,140.38,137.60,132.73,129.05,128.60,122.66,121.44,120.43,114.57,112.71.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C12H10N3O,212.08,Found:212.18.
实施例48：1-ethyl-9H-pyrido[3,4-b]indole-3-carboxamide(48)的制备
Figure BDA0002383296940000213
制备方法同步骤3-1，用化合物19代替化合物3，得到1-ethyl-9H-pyrido[3,4-b]indole-3-carboxamide为黄色固体，产率73％。M.p.235.5-236.5(℃).1H NMR(400MHz,DMSO-d6)δH 11.92(s,1H),8.69(s,1H),8.34(d,1H,J＝7.8),7.99(d,1H,J＝3.6),7.67–7.62(m,1H),7.58(ddd,1H,J＝8.2,6.9,1.2),7.47(d,1H,J＝3.6),7.28(ddd,1H,J＝8.0,6.9,1.1),3.18(q,2H,J＝7.5),1.43(t,3H,J＝7.5).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H14N3O,240.11,Found:240.23.
实施例49：1-isopropyl-9H-pyrido[3,4-b]indole-3-carboxamide(49)的制备
Figure BDA0002383296940000221
制备方法同步骤3-1，用化合物21代替化合物3，得到1-isopropyl-9H-pyrido[3,4-b]indole-3-car boxamide为黄色固体，产率81％。M.p.275.2-276.9(℃).1H NMR(400MHz,DMSO-d6)δH 11.94(s,1H),8.73(t,1H,J＝2.1),8.36(d,1H,J＝7.9),8.04(d,1H,J＝3.5),7.67(d,1H,J＝8.2),7.63–7.56(m,1H),7.55(d,1H,J＝4.4),7.34–7.23(m,1H),3.72(p,1H,J＝6.8),1.45(d,6H,J＝6.7).13C NMR(125MHz DMSO-d6)δC 167.60,149.39,141.23,139.58,134.90,128.67,128.34,122.40,121.95,120.28,112.63,112.49,31.20,21.82.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C15H16N3O,254.13,Found:254.24.
实施例50：9H-pyrido[3,4-b]indole-1,3-dicarboxamide(50)的制备
Figure BDA0002383296940000222
制备方法同步骤3-1，用化合物29代替化合物3，得到9H-pyrido[3,4-b]indole-1,3-dicarboxamide为白色固体，产率74％。M.p.259.1-261.0(℃).1H NMR(400MHz,DMSO-d6)δH 11.92(s,1H),8.69(s,1H),8.34(d,1H,J＝7.8),7.99(d,1H,J＝3.6),7.67–7.62(m,1H),7.58(ddd,1H,J＝8.2,6.9,1.2),7.47(d,1H,J＝3.6),7.28(ddd,1H,J＝8.0,6.9,1.1),3.18(q,2H,J＝7.5),1.43(t,3H,J＝7.5).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C13H11N4O2,255.09,Found:255.22；Calcd.for[M+Na]+,C13H10N4NaO2,277.07,Found:277.44.
实施例51：1-acetyl-9H-pyrido[3,4-b]indole-3-carboxamide(51)的制备
Figure BDA0002383296940000223
制备方法同步骤3-1，用化合物24代替化合物3，得到1-acetyl-9H-pyrido[3,4-b]indole-3-carboxamide为白色固体，产率68％。M.p.288.5-289.2(℃).1H NMR(400MHz,DMSO-d6)δH 12.17(s,1H),9.12(s,1H),8.44(d,1H,J＝7.6),8.26–8.19(m,1H),7.84(d,1H,J＝7.9),7.68(d,1H,J＝2.7),7.63(t,1H,J＝7.6),7.36(q,1H,J＝7.2),2.91(s,3H).13CNMR(125MHz DMSO-d6)δC 201.67,166.81,142.78,139.38,135.28,134.40,132.34,129.71,122.69,121.23,120.76,118.53,113.75,26.54.LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H12N3O2,254.09,Found:254.24.
实施例52：N1-methyl-9H-pyrido[3,4-b]indole-1,3-dicarboxamide(52)的制备
Figure BDA0002383296940000231
制备方法同步骤3-1，用化合物32代替化合物3，得到N1-methyl-9H-pyrido[3,4-b]indole-1,3-dicarboxamide为白色固体，产率59％。M.p.274.9–275.3(℃).1H NMR(400MHz,DMSO-d6)δH 12.01(s,1H),9.48(d,1H,J＝4.9),9.01(s,1H),8.85(d,1H,J＝2.7),8.41(d,1H,J＝7.9),7.99–7.73(m,1H),7.73–7.59(m,2H),7.31(ddd,1H,J＝8.0,7.1,1.0),2.97(d,3H,J＝4.7).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C14H13N4O2,269.10,Found:269.22.
实施例53：2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1,3-dicarboxylic(53)的制备
Figure BDA0002383296940000232
制备方法同步骤1-1。用乙醛酸代替乙醛，得到2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1,3-dicarboxylic为白色固体，产率95％。1H NMR(400MHz,DMSO-d6)δH11.06(d,1H,J＝2.4),7.57(d,1H,J＝7.8),7.35(d,1H,J＝8.1),7.24(d,1H,J＝2.3),7.06(ddd,1H,J＝8.1,6.9,1.2),7.00–6.91(m,1H),3.49(dd,1H,J＝8.7,4.2),3.32(dd,1H,J＝15.1,4.2),3.01(dd,1H,J＝15.1,8.7).LC–MS(ESI+)m/z:Calcd.for[M+H]+,C13H13N2O4,261.09,Found:261.24.
实施例54：1-取代β-咔啉衍生物抑制真菌活性测定
选取测试菌株于PDA平板进行活化，包括灰葡萄孢(Botrytis cinerea)常引起草莓灰霉病、禾顶囊壳小麦变种(Gaeumannomyces graminis)常引起小麦全蚀病、核盘菌(Sclerotinia sclerotiorum)常引起油菜菌核病、尖镰孢(Fusarium oxysporum)常引起瓜类枯萎病、瓜亡革菌(Thanatephorus cucumeris)常引起水稻纹枯病、禾谷镰孢(Fusariumgraminearum)常引起小麦赤霉病、辣椒疫霉(Phytophthora capsici)常引起辣椒疫病、刺盘孢菌(Cladosporium orbiculare)常引起黄瓜炭疽病、串珠镰孢(Fusariummoniliforme)常引起水稻恶苗病。将本发明化合物配制成系列梯度浓度的PDA含药平板，将测试菌株制成5mm直径菌饼置于含药培养皿中央，25℃恒温培养至空白对照皿的测试菌株长至培养皿边缘时，十字交叉法测量各含药平板的菌落直径，计算化合物对菌丝生长的抑制率。我们选择50μg·mL-1为初筛浓度，化合物在此浓度下对相应的病菌抑制率大于50％时再进一步设置不同浓度测试。然后以化合物浓度为横坐标，抑制率为纵坐标，作标准曲线，计算抑制率为50％时化合物的浓度(表1)，即EC50值。重复3次取平均值。以啶酰菌胺(boscalid)为阳性对照，各化合物对植物病原菌的EC50值(μg/mL)如表1所示。
表1化合物1-52在50μg·mL-1浓度下的菌丝生长抑制率
Figure BDA0002383296940000241
Figure BDA0002383296940000251
表2化合物1-52对多种植物病原真菌的菌丝生长抑制有效中浓度(EC50)
Figure BDA0002383296940000252
Figure BDA0002383296940000261
注：“>50”表示在50μg/mL的浓度下抑制率小于50％。
从表1中可以看出，1-取代β-咔啉衍生物对所测试的9种植物病原真菌有着很好的抑制作用，并对小麦全蚀病原菌禾顶囊壳(Gaeumannomyces graminis)表现出特别优异的抑制活性。从表2的EC50数据我们发现，当β-咔啉的C环是吡啶环并且R2位置是羧甲基时，化合物表现出比四氢吡啶作为C环和R2位置是羧基时的β-咔啉衍生物更高的活性。吡啶环上1位置的取代基的类型对小麦全蚀病原菌(Gaeumannomyces graminis)抑制活性有显著影响，其中当吡啶环上1位置取代基为氨甲酰基时(如化合物4,5,29等)化合物具有广谱的抑制真菌活性，并且对小麦全蚀病原菌(Gaeumannomyces graminis)表现出极强的抑制活性的EC50都在0.5μg/mL左右。
实施例55：1-取代β-咔啉衍生物抑制细菌活性测定
选取测试菌株于LB平板进行活化，包括丁香假单胞菌大豆致病变种(Pseudomonassyringae pv.glycinea)常引起大豆斑点病，稻黄单胞菌水稻致病变种(Xanthomonasoryzae oryzae pv.oryzae)常引起水稻白叶枯病，稻黄单胞菌稻生致病变种(Xanthomonasoryzae oryzae pv.oryzicola)常引起水稻细菌性条斑病，以及非致病的革兰氏阳性菌枯草芽孢杆菌(Bacillus subtilis)。先将已灭菌的圆形滤纸片浸泡于浓度为1×104ug/mL的待测化合物溶液中，向100mL培养基中加入5mL菌液，充分混匀后倒平板。然后将含药滤纸片贴于平板上，置于28℃培养箱培养。最后测量抑菌圈直径并观察抑菌圈的透明度(表3)。能观察到抑菌圈的化合物，我们进一步采用Cck8法测定化合物对植物病原细菌的最小抑制浓度MIC值(表4)，硫酸链霉素(Streptomycin sulfate)为阳性对照。
表3化合物对4种植物病原细菌的抑制活性
Figure BDA0002383296940000271
注：“+表示仅能观察到抑菌圈，++可以清晰观察到抑菌圈，+++可以观察到清晰透明的抑菌圈；“--”表示无抑菌圈。
表4化合物对4种植物病原细菌的抑制活性的MIC值
Figure BDA0002383296940000272
Figure BDA0002383296940000281
表3数据表明，部分1-取代β-咔啉衍生物对所测试的植物病原细菌和革兰氏阳性菌均表现出抑制活性，当1号位置是短链的烷基(如化合物8,9,18)或者含有羟基(如化合物31,46)和羧基(如化合物1,53)化合物更容易表现出抑制细菌活性。表4的结果说明3号位置的羧基如(化合物46,53)对抑制细菌活性至关重要。化合物31,46,53对稻黄单胞菌水稻致病变种(Xanthomonasoryzae oryzae pv.oryzae)，稻黄单胞菌稻生致病变种(Xanthomonasoryzae oryzae pv.oryzicola)的MIC值要低于阳性对照硫酸链霉素。

Claims (3)

1.一类式(I)所示的1-取代β-咔啉衍生物或其可接受的盐在制备抑制植物病原真菌或细菌的制剂中的应用
Figure FDA0003596801480000011
C为吡啶,
R2＝羧甲基,R1选自氢，C1-4烷基，N-丙基，N-辛基，苯基，乙酮基，羧甲基，羟甲基，2-吡啶基，3-噻吩基，4-Br-苯基，氨甲酰基，甲醛基，羟基，N-甲基甲酰胺基中的任意一种；
或者，R2＝羧基,R1选自氢，甲基，乙基，N-丙基，异丙基，N-辛基，苯基，乙酮基，
羧基，2-吡啶基，3-噻吩基，4-Br-苯基，氨甲酰基，羟基，羟甲基中的任意一种；
或者，R2＝氢R1＝羧甲基、氨甲酰基中的任意一种；
或者，R2＝氨甲酰基R1＝氢，乙基，异丙基，氨甲酰基，乙酮基，N-甲基甲酰胺基中的任意一种；
所述的植物病原真菌为禾顶囊壳小麦变种(Gaeumannomyces graminis)；植物病原细菌选自以下任意一种或多种：丁香假单胞菌大豆致病变种(Pseudomonas syringaepv.glycinea)，稻黄单胞菌水稻致病变种(Xanthomonasoryzae oryzae pv.oryzae)，稻黄单胞菌稻生致病变种(Xanthomonasoryzae oryzae pv.oryzicola)，以及非致病的革兰氏阳性菌枯草芽孢杆菌(Bacillus subtilis)。
2.根据权利要求1所述的应用，其特征在于，
R2＝羧甲基,R1选自C1-4烷基，氨甲酰基，羧基、羟甲基中的任意一种；
或者，R2＝羧基,R1选自羟甲基中的任意一种；
或者，R2＝氢R1＝氨甲酰基。
3.根据权利要求1所述的应用，其特征在于，选自以下任意一种化合物：
Figure FDA0003596801480000012
Figure FDA0003596801480000021
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57169481A (en) * 1981-04-13 1982-10-19 Otsuka Pharmaceut Co Ltd Beta-carboline derivative
CN103070862A (zh) * 2011-10-25 2013-05-01 新疆华世丹药物研究有限责任公司 去氢骆驼蓬碱衍生物在制备抗菌药物中的应用
CN104744460A (zh) * 2013-12-30 2015-07-01 南开大学 β-咔啉,二氢-β-咔啉和四氢-β-咔啉生物碱衍生物及其制备方法和在防治植物病毒、杀菌、杀虫方面的应用
CN106977515A (zh) * 2017-04-13 2017-07-25 河北科技大学 β‑咔啉、γ‑咔啉衍生物、其制备方法及用途
CN107652296A (zh) * 2016-07-26 2018-02-02 南开大学 螺环氧化吲哚酰腙衍生物及其制备方法和在防治植物病毒、杀菌、杀虫方面的应用
CN108623585A (zh) * 2018-05-22 2018-10-09 中国人民解放军第二军医大学 β-四氢咔啉类抗真菌药物及其制备方法和应用
CN109575020A (zh) * 2018-12-27 2019-04-05 河北大学 β-咔啉衍生物及其制备方法和在制备抗肿瘤药物中的应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57169481A (en) * 1981-04-13 1982-10-19 Otsuka Pharmaceut Co Ltd Beta-carboline derivative
CN103070862A (zh) * 2011-10-25 2013-05-01 新疆华世丹药物研究有限责任公司 去氢骆驼蓬碱衍生物在制备抗菌药物中的应用
CN104744460A (zh) * 2013-12-30 2015-07-01 南开大学 β-咔啉,二氢-β-咔啉和四氢-β-咔啉生物碱衍生物及其制备方法和在防治植物病毒、杀菌、杀虫方面的应用
CN107652296A (zh) * 2016-07-26 2018-02-02 南开大学 螺环氧化吲哚酰腙衍生物及其制备方法和在防治植物病毒、杀菌、杀虫方面的应用
CN106977515A (zh) * 2017-04-13 2017-07-25 河北科技大学 β‑咔啉、γ‑咔啉衍生物、其制备方法及用途
CN108623585A (zh) * 2018-05-22 2018-10-09 中国人民解放军第二军医大学 β-四氢咔啉类抗真菌药物及其制备方法和应用
CN109575020A (zh) * 2018-12-27 2019-04-05 河北大学 β-咔啉衍生物及其制备方法和在制备抗肿瘤药物中的应用

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
Facile and efficient one-pot synthesis of β-carbolines;Tang, Jian-Guo等;《Synthetic Communications》;20101231;第40卷(第10期);第1413页表1，以及第1411页 *
RN:113247-36-2;ACS;《STN REGISTRY》;19880305 *
RN:1232142-81-2、1232142-82-3;ACS;《STN REGISTRY》;20100715 *
RN:123771-44-8;ACS;《STN REGISTRY》;19891117 *
RN:157341-07-6;ACS;《STN REGISTRY》;19940830 *
RN:158400-51-2;ACS;《STN REGISTRY》;19941019 *
RN:1609640-60-9;ACS;《STN REGISTRY》;20140605 *
RN:2067398-87-0;ACS;《STN REGISTRY》;20170207 *
RN:223690-90-2;ACS;《STN REGISTRY》;19990528 *
RN:321862-33-3;ACS;《STN REGISTRY》;20010215 *
RN:3464-66-2、16641-82-0、22329-38-0、33821-74-8、33821-76-0、38940-60-2、53399-63-6、53399-63-6、69954-48-9、73818-29-8、74214-63-4、75304-04-0、81677-50-1、81677-50-1;ACS;《STN REGISTRY》;19841116 *
RN:374710-96-0;ACS;《STN REGISTRY》;20011211 *
RN:94252-53-6;ACS;《STN REGISTRY》;19850112 *
RN:952200-73-6;ACS;《STN REGISTRY》;20071101 *

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