CN114591298A - 一种苯并氮杂䓬化合物及其合成方法 - Google Patents

一种苯并氮杂䓬化合物及其合成方法 Download PDF

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CN114591298A
CN114591298A CN202210342897.0A CN202210342897A CN114591298A CN 114591298 A CN114591298 A CN 114591298A CN 202210342897 A CN202210342897 A CN 202210342897A CN 114591298 A CN114591298 A CN 114591298A
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周庆发
朱晋
吴添枝
王碧川
汤玉姜
郝思远
韩芳
吴可
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China Pharmaceutical University
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Abstract

本发明属于有机化学领域，具体涉及一种苯并氮杂䓬化合物及其合成方法。本方法将靛红偶氮次甲基亚胺和联烯酸酯或炔酸酯、炔酮溶于二甲亚砜溶剂中，以廉价易得的三苯基膦为催化剂，反应8小时，得到一种苯并氮杂䓬化合物，该类化合物具有潜在的药学应用价值。本发明合成方法具有底物适用面广，操作简便、反应温和、后处理方便、原料和催化剂简单易得等优点。

Description

一种苯并氮杂䓬化合物及其合成方法
技术领域
本发明涉及一种苯并氮杂
Figure BDA0003575530990000014
化合物及其合成方法，属于有机化学合成方法学领域。
背景技术
苯并氮杂
Figure BDA0003575530990000015
骨架广泛存在于多种生物活性分子，已上市药物中已至少有25种药物以苯并氮杂
Figure BDA0003575530990000016
为核心骨架。不仅如此，该类化物还易于通过取代反应引入各种官能团，并且可参与多种交叉偶联反应。虽然苯并氮杂
Figure BDA0003575530990000017
化合物具有广泛的用途，但根据文献调研，该类化合物的卓有成效的合成方法较少，几乎所有的方法都采用金属催化剂。
近年来，Fujita团队曾报道过利用铑催化氨基醇的内酰胺化方法得到苯并氮杂
Figure BDA0003575530990000018
化合物，但是该方法的空间选择性及立体选择性较为一般。Driver团队报道了基于铑催化通过开环-扩环的途径，生成具有优异的区域和立体选择性的苯并氮杂卓衍生物。随后，该团队又使用1-(2-氨基苯基)环丁-1-醇为底物，通过苯胺氧化的策略生成亲电性N-芳基亚硝基中间体，参与C-N键的形成，从而构建官能化的苯并氮杂
Figure BDA00035755309900000113
尽管上述方法均可成功合成苯并氮杂
Figure BDA00035755309900000110
化合物，但大部分的方法使用的原料制备需要多步过程，操作复杂。且多需使用过渡金属催化剂，金属催化剂的使用需保证反应体系无水无氧，且易造成重金属离子残留。因此，开发一种操作简便、条件温和的苯并氮杂
Figure BDA00035755309900000111
的合成方法具有重要的研究意义。
因此我们首次实现了膦催化下偶氮次甲基亚胺与联烯酸酯的新型[5+2]环加成，在温和条件下，通过吲哚骨架C-C键断裂、联烯酸酯碳插入扩环的方式一步获得了药物优势骨架苯并氮杂
Figure BDA00035755309900000114
更重要的是，该反应具有优秀的化学选择性，可通过改变溶剂，获得单一反应类型的产物。
a)Previous work
Figure BDA0003575530990000011
b)This work
Figure BDA0003575530990000012
发明内容
发明目的：本发明提供一种苯并氮杂
Figure BDA0003575530990000023
化合物合成的新方法。
技术方案：
下述通式3化合物和其药学上可接受的盐：
Figure BDA0003575530990000021
R1为甲基、苄基或苯基；
R2为甲基、氟、氯或溴，R3为3位或4位单取代苄基，R4为H、甲基、乙基、苯基或噻吩。
所述的化合物，其特征在于，所述化合物如下任意一种：
Figure BDA0003575530990000022
Figure BDA0003575530990000031
所述化合物的合成方法：以联烯酸酯或者炔酸酯或炔基酮和靛红偶氮次甲基亚胺为原料，以廉价易得的三苯基膦为催化剂，二甲亚砜溶剂中反应8小时，得到苯并氮杂
Figure BDA0003575530990000033
化合物III，其反应式如下：
Figure BDA0003575530990000032
其中化合物I为靛红偶氮次甲基亚胺，R1为甲基、苄基、苯基等取代基团，R2为甲基、氟、氯、溴等。化合物II为联烯酸酯类衍生物，R3为苄基(3位或4位单取代)、正丁基等，R4为H或甲基、乙基、苯基、噻吩等，R5为H、甲氧基、乙氧基、甲基等，R6为H、甲基等。
本发明的较佳反应条件为：
(1)催化剂为三苯基膦；
(2)靛红偶氮次甲基亚胺类化合物、联烯酸酯或者炔酸酯或炔基酮、三苯基膦用量的摩尔比为1：1.2：0.2；
(3)溶剂为二甲亚砜；
(4)反应温度为室温；
(5)反应时间为8小时；
(6)本发明中的化合物III可以用上述或类似上述的制备方法制备得到，根据取代基的不同和取代基位置的不同选用相应的原料即可。
有益效果
本发明是全新的化合物，同时本发明提供该化合物的合成方法，该反应起始原料易得，条件温和，合成路线简短、操作方便，成本较低。该反应具有较好的化学选择性，产率高，并且可将该反应进行规模放大生产，因此在有机合成中具有较高的实用性。通过此法合成的苯并氮杂
Figure BDA0003575530990000041
III具有潜在的生物活性，酯基水解酸化为相应的羧酸且羟基可以进行多种衍生化，在新药研发领域有较好的应用前景。
具体实施方式
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
实施例1：(3-羟基-1H-吡唑基)-4-甲基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000042
3-羧酸苄酯(III-1)
在25mL圆底烧瓶中加入二甲亚砜(2.0mL)靛红偶氮次甲基亚胺(0.1mmol，21.5mg)、联烯酸酯(0.12mmol，20.9mg)和三苯基膦(0.02mmol，5.25mg)。搅拌反应8h。向反应液中加入50mL饱和氯化钠溶液，使用乙酸乙酯萃取。合并有机相，无水硫酸钠干燥，将有机相浓缩，经以石油醚：乙酸乙酯体积比为1：1的混合溶剂作为洗脱剂柱层析洗脱，分离得到白色固体III-1 29.5mg,收率77％。
1H NMR(400MHz,DMSO-d6)δ10.69(d,J＝1.5Hz,1H),10.03(s,1H),7.45(d,J＝2.4Hz,1H),7.31(d,J＝1.6Hz,1H),7.33–7.23(m,3H),7.13–7.05(m,3H),6.99(ddd,J＝8.2,7.1,1.2Hz,1H),6.55–6.48(m,1H),5.72(d,J＝2.4Hz,1H),4.75(d,J＝12.5Hz,1H),4.68(d,J＝12.8Hz,1H),4.43(s,1H),1.98(s,3H).HRMS(ESI+)m/z 390.4188[M+H]+。
Figure BDA0003575530990000051
实施例2：1-甲基(3-羟基-1H-吡唑基)-4-甲基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000054
3-羧酸苄酯(III-2)
以1-甲基靛红偶氮次甲基亚胺(22.92mg,0.1mmol)为原料，操作方法同III-2，得淡黄色固体III-2 27.4mg，收率79％。
1H NMR(300MHz,DMSO-d6)δ10.06(s,1H),7.53(d,J＝2.5Hz,1H),7.49–7.40(m,2H),7.35(d,J＝3.1Hz,5H),7.23–7.05(m,2H),5.60(d,J＝2.5Hz,1H),5.49(q,J＝1.2Hz,1H),5.10(s,2H),3.22(s,3H),2.08(d,J＝1.3Hz,3H).HRMS(ESI+)m/z 404.4457[M+H]+。
Figure BDA0003575530990000052
实施例3：1-苄基(3-羟基-1H-吡唑基)-4-甲基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000055
3-羧酸苄酯(III-3)
以1-苄基靛红偶氮次甲基亚胺(30.53mg,0.1mmol)为原料，操作方法同III-1，得黄色油状液体III-3 44.6mg，收率93％。
1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),7.57(d,J＝2.5Hz,1H),7.48(dd,J＝7.5,1.2Hz,1H),7.42–7.21(m,11H),7.17–7.03(m,2H),5.65(d,J＝2.5Hz,1H),5.52(d,J＝1.4Hz,1H),5.11(d,J＝1.5Hz,2H),5.05–4.89(m,2H),2.10(d,J＝1.3Hz,3H).HRMS(ESI+)m/z 480.5342[M+H]+。
Figure BDA0003575530990000053
实施例4：(3-羟基-1H-吡唑基)-4-甲基-2，3-二氢-1H-7-氯苯并氮杂
Figure BDA0003575530990000056
3-羧酸苄酯(III-4)
以5-氯靛红偶氮次甲基亚胺(24.96mg,0.1mmol)为原料，操作方法同III-1，得无色液体III-4 29.6mg，收率70％。
1H NMR(300MHz,DMSO-d6)δ10.79(s,1H),10.04(s,1H),7.47(d,J＝2.4Hz,1H),7.41–7.18(m,4H),7.13–6.94(m,4H),6.46(d,J＝8.6Hz,1H),5.73(d,J＝2.4Hz,1H),4.80(s,2H),4.51(s,1H),1.97(s,3H).HRMS(ESI+)m/z 424.8607[M+H]+。
Figure BDA0003575530990000061
实施例5：(3-羟基-1H-吡唑基)-4-甲基-2，3-二氢-1H-8-氯苯并氮杂
Figure BDA0003575530990000064
3-羧酸苄酯(III-5)
以6-氯靛红偶氮次甲基亚胺(24.96mg,0.1mmol)为原料，操作方法同III-1，得无色液体III-5 27.1mg，收率64％。
1H NMR(300MHz,DMSO-d6)δ11.01(s,1H),10.04(s,1H),7.53(d,J＝2.5Hz,1H),7.42–7.24(m,11H),6.92(dd,J＝8.2,4.6Hz,1H),5.59(t,J＝2.5Hz,1H),5.43(s,1H),5.17(s,1H),5.12(d,J＝3.8Hz,1H),5.01(s,2H),3.39(d,J＝7.0Hz,3H).HRMS(ESI+)m/z424.8607[M+H]+。
Figure BDA0003575530990000062
实施例6：(3-羟基-1H-吡唑基)-4-甲基-2，3-二氢-1H-9-氟苯并氮杂
Figure BDA0003575530990000065
3-羧酸苄酯(III-6)
以7-氟靛红偶氮次甲基亚胺(23.32mg,0.1mmol)为原料，操作方法同III-1，得无色液体III-6 30.1mg，收率74％。
1H NMR(300MHz,DMSO-d6)δ10.79(s,1H),10.04(s,1H),7.47(d,J＝2.4Hz,1H),7.41–7.18(m,4H),7.13–6.94(m,4H),6.46(d,J＝8.6Hz,1H),5.73(d,J＝2.4Hz,1H),4.80(s,2H),4.51(s,1H),1.97(s,3H).HRMS(ESI+)m/z 424.8607[M+H]+。
Figure BDA0003575530990000063
实施例7：(3-羟基-1H-吡唑基)-4-甲基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000073
3-羧酸丁酯(III-7)
以联烯酸丁酯(16.82mg,0.12mmol)为原料，操作方法同III-1，得无色液体III-730.9mg，收率87％。
1H NMR(300MHz,DMSO-d6)δ10.83(s,1H),9.98(s,1H),7.48(d,J＝2.5Hz,1H),7.33–7.18(m,2H),7.00(td,J＝7.6,1.1Hz,1H),6.90(d,J＝7.7Hz,1H),5.57(d,J＝2.5Hz,1H),5.38(s,1H),5.14(s,1H),3.93(t,J＝6.6Hz,2H),3.34–3.01(m,2H),1.49(m,J＝8.4,6.4Hz,2H),1.28(m,J＝9.5,7.2Hz,2H),0.87(t,J＝7.3Hz,3H).HRMS(ESI+)m/z 356.4012[M+H]+。
Figure BDA0003575530990000071
实施例8：(3-羟基-1H-吡唑基)-4-甲基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000074
3-羧酸-(3-溴)苄酯(III-8)
以联烯酸-3-溴苄酯(30.37mg,0.12mmol)为原料，操作方法同III-1，得黄色油状液体III-8 31.3mg，收率67％。
1H NMR(300MHz,DMSO-d6)δ10.68(d,J＝1.5Hz,1H),10.02(s,1H),7.53–7.42(m,3H),7.24(ddd,J＝8.4,7.1,1.5Hz,1H),7.12–6.90(m,4H),6.48(d,J＝8.0Hz,1H),5.72(d,J＝2.4Hz,1H),4.83–4.61(m,2H),4.43(s,1H),1.97(s,3H).HRMS(ESI+)m/z 469.3144[M+H]+。
Figure BDA0003575530990000072
实施例9：(3-羟基-1H-吡唑基)-4-甲基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000075
3-羧酸苯乙酯(III-9)
以联烯酸苯乙酯(22.58mg,0.12mmol)为原料，操作方法同III-1，得淡黄色液体III-9 37.1mg，收率92％。
1H NMR(300MHz,DMSO-d6)δ10.84(s,1H),10.01(s,1H),7.43(d,J＝2.5Hz,1H),7.33–7.13(m,9H),6.98(td,J＝7.6,1.1Hz,1H),6.91(d,J＝7.7Hz,1H),5.56(d,J＝2.5Hz,1H),5.31(s,1H),5.10(s,1H),4.13(t,J＝6.9Hz,3H),3.21(s,2H),2.82(t,J＝6.9Hz,2H).HRMS(ESI+)m/z 404.4457[M+H]+。
Figure BDA0003575530990000081
实施例10：(3-羟基-1H-吡唑基)-4-苄基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000084
3-羧酸苄酯(III-10)
以γ-苯基联烯酸苄酯(30.03mg,0.12mmol)为原料，操作方法同III-1，得无色液体I-10 40.9mg，收率88％。
1H NMR(300MHz,DMSO-d6)δ10.88(s,1H),10.00(s,1H),7.64(d,J＝2.5Hz,1H),7.41–7.22(m,12H),7.07–6.87(m,2H),6.72(s,1H),5.60(d,J＝2.5Hz,1H),4.88(s,2H),3.58(d,J＝17.4Hz,1H),1.09(t,J＝7.0Hz,1H).HRMS(ESI+)m/z 466.5169[M+H]+。
Figure BDA0003575530990000082
实施例11：(3-羟基-1H-吡唑基)-4-乙基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000085
3-羧酸苄酯(III-11)
以γ-甲基联烯酸苄酯(22.58mg,0.12mmol)为原料，操作方法同III-1，得黄色油状物III-11 37.1mg，收率92％。
1H NMR(300MHz,DMSO-d6)δ10.71(s,1H),9.92(s,1H),7.48(d,J＝2.5Hz,1H),7.42–7.20(m,6H),7.09(dd,J＝7.6,1.3Hz,1H),7.01–6.80(m,2H),5.72(q,J＝6.8Hz,1H),5.54(d,J＝2.5Hz,1H),5.02(d,J＝2.2Hz,2H),1.61(d,J＝6.9Hz,3H).HRMS(ESI+)m/z404.4457[M+H]+。
Figure BDA0003575530990000083
实施例12：(3-羟基-1H-吡唑基)-4-丁基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000086
3-羧酸苄酯(III-12)
以γ-丙基联烯酸苄酯(25.95mg,0.12mmol)为原料，操作方法同III-1，得白色固体III-12 35.3mg，收率82％。
1H NMR(300MHz,DMSO-d6)δ10.72(s,1H),9.94(s,1H),7.49(d,J＝2.5Hz,1H),7.42–7.20(m,6H),7.09(dd,J＝7.5,1.3Hz,1H),7.01–6.83(m,2H),5.65–5.51(m,2H),5.00(d,J＝1.9Hz,2H),3.51(d,J＝17.5Hz,1H),3.32(d,J＝17.5Hz,1H),2.02(m,J＝17.9,15.0,7.5Hz,2H),0.85(t,J＝7.5Hz,3H).HRMS(ESI+)m/z 432.4994[M+H]+。
Figure BDA0003575530990000091
实施例13：(3-羟基-1H-吡唑基)-4-戊基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000093
3-羧酸苄酯(III-13)
以γ-丁基联烯酸苄酯(27.63mg,0.12mmol)为原料，操作方法同III-1，得无色液体III-13 37.8mg，收率85％。
1H NMR(300MHz,DMSO-d6)δ10.71(s,1H),9.93(s,1H),7.48(d,J＝2.5Hz,1H),7.41–7.20(m,6H),7.08(dd,J＝7.6,1.3Hz,1H),7.00–6.84(m,2H),5.62(t,J＝7.1Hz,1H),5.55(d,J＝2.5Hz,1H),5.00(d,J＝1.9Hz,2H),3.50(d,J＝17.5Hz,1H),3.31(d,J＝17.5Hz,1H),1.99(dd,J＝19.1,15.0,7.5Hz,2H),1.28(h,J＝7.3Hz,2H),0.78(t,J＝7.4Hz,3H).HRMS(ESI+)m/z 446.5267[M+H]+。
Figure BDA0003575530990000092
实施例14：(3-羟基-1H-吡唑基)-4-噻吩基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000094
3-羧酸苄酯(III-14)
以γ-噻吩基联烯酸苄酯(30.75mg,0.12mmol)为原料，操作方法同III-1，得黄色油状液体III-14 22.1mg，收率47％。
1H NMR(300MHz,DMSO-d6)δ10.86(s,1H),10.00(d,J＝4.2Hz,1H),7.66–7.60(m,1H),7.57(dd,J＝4.9,2.5Hz,1H),7.41–7.26(m,6H),7.22(dd,J＝7.7,1.2Hz,1H),7.17–7.11(m,1H),7.11–6.97(m,2H),6.96–6.89(m,1H),6.73(d,J＝55.4Hz,1H),5.57(d,J＝2.5Hz,1H),4.98(d,J＝18.2Hz,2H),3.85–3.49(m,2H).HRMS(ESI+)m/z 472.5383[M+H]+。
Figure BDA0003575530990000101
实施例15：(3-羟基-1H-吡唑基)-4-癸基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000104
3-羧酸苄酯(III-15)
以γ-壬基联烯酸苄酯(34.36mg,0.12mmol)为原料，操作方法同III-1，得无色液体III-15 34.5mg，收率67％。
1H NMR(300MHz,DMSO-d6)δ10.71(s,1H),9.93(s,1H),7.48(d,J＝2.5Hz,1H),7.41–7.20(m,6H),7.07(dd,J＝7.5,1.3Hz,1H),7.00–6.84(m,2H),5.61(t,J＝7.1Hz,1H),5.54(d,J＝2.4Hz,1H),4.99(d,J＝1.5Hz,2H),3.49(d,J＝17.5Hz,1H),3.31(d,J＝17.4Hz,1H),1.98(dq,J＝18.3,7.4Hz,2H),1.39–1.03(m,13H),0.85(t,J＝6.8Hz,3H).HRMS(ESI+)m/z 516.6612[M+H]+。
Figure BDA0003575530990000102
实施例16：(3-羟基-1H-吡唑基)-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000105
3-羧酸甲酯(III-16)
以丙炔酸甲酯(10.09mg,0.12mmol)为原料，操作方法同III-1，得白色固体III-1619.15mg，收率64％。
1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),10.23(s,1H),7.55(d,J＝2.6Hz,1H),7.48(ddd,J＝8.5,6.4,2.3Hz,1H),7.37–7.13(m,4H),6.26(d,J＝6.6Hz,1H),5.75(d,J＝2.5Hz,1H),3.70(s,3H).HRMS(ESI+)m/z 300.2931[M+H]+。
Figure BDA0003575530990000103
实施例17：1-甲基(3-羟基-1H-吡唑基)-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000106
3-羧酸甲酯(III-17)
以1-甲基靛红偶氮次甲基亚胺(22.92mg,0.1mmol)为原料，操作方法同III-16，得淡黄色固体III-17 25.4mg，收率81％。
1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),7.55(d,J＝2.5Hz,1H),7.44(td,J＝7.8,1.3Hz,1H),7.35(dd,J＝7.4,1.2Hz,1H),7.29(s,1H),7.25(s,1H),7.18–7.12(m,2H),5.83(d,J＝15.8Hz,1H),5.59(d,J＝2.5Hz,1H),3.69(s,3H),3.21(s,3H).HRMS(ESI+)m/z314.3202[M+H]+。
Figure BDA0003575530990000111
实施例18：7-甲氧基(3-羟基-1H-吡唑基)-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000114
3-羧酸甲酯(III-18)
以5-甲氧基靛红偶氮次甲基亚胺(24.52mg,0.1mmol)为原料，操作方法同III-16，得无色液体III-18 14.2mg，收率43％。
1H NMR(400MHz,DMSO)δ10.49(s,1H),10.24(s,1H),7.59(d,J＝2.5Hz,1H),7.21(d,J＝8.9Hz,1H),7.12(dd,J＝9.0,2.9Hz,1H),6.70(d,J＝2.9Hz,1H),6.27(d,J＝6.6Hz,1H),5.75(d,J＝2.5Hz,1H),3.71(d,J＝3.6Hz,6H).HRMS(ESI+)m/z 330.3193[M+H]+。
Figure BDA0003575530990000112
实施例19：1-苄基(3-羟基-1H-吡唑基)-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000115
3-羧酸甲酯(III-19)
以1-苄基靛红偶氮次甲基亚胺(30.53mg,0.1mmol)为原料，操作方法同III-16，得无色液体III-19 33.9mg，收率87％。
1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),7.59(d,J＝2.5Hz,1H),7.39(dd,J＝7.5,1.2Hz,1H),7.38–7.32(m,6H),7.28(ddd,J＝8.5,3.6,1.9Hz,1H),7.12(td,J＝7.6,1.0Hz,1H),7.05(d,J＝7.7Hz,1H),5.87(d,J＝15.8Hz,1H),5.63(d,J＝2.5Hz,1H),4.98(d,J＝1.8Hz,2H),3.70(s,3H).HRMS(ESI+)m/z 390.4188[M+H]+。
Figure BDA0003575530990000113
实施例20：(3-羟基-1H-吡唑基)-2，3-二氢-1H-7-氟苯并氮杂
Figure BDA0003575530990000116
3-羧酸甲酯(III-20)
以7-氟靛红偶氮次甲基亚胺(23.32mg,0.1mmol)为原料，操作方法同III-16，得白色固体III-20 18.4mg，收率58％。
1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),10.31(s,1H),7.67–7.00(m,4H),6.33(d,J＝14.1Hz,1H),5.83–5.64(m,1H),3.74(s,3H).HRMS(ESI+)m/z 318.2837[M+H]+。
Figure BDA0003575530990000121
实施例21：(3-羟基-1H-吡唑基)-2，3-二氢-1H-7-氯苯并氮杂
Figure BDA0003575530990000124
3-羧酸甲酯(III-21)
以5-氯靛红偶氮次甲基亚胺(24.97mg,0.1mmol)为原料，操作方法同III-16，得白色固体III-21 20.7mg，收率62％。
1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),10.29(s,1H),7.70(d,J＝2.5Hz,1H),7.55(dd,J＝8.8,2.5Hz,1H),7.28(d,J＝8.7Hz,1H),7.17(d,J＝2.5Hz,1H),6.27(d,J＝6.6Hz,1H),5.77(s,1H),3.71(s,3H).HRMS(ESI+)m/z 334.7352[M+H]+。
Figure BDA0003575530990000122
实施例22：(3-羟基-1H-吡唑基)-2，3-二氢-1H-7-溴苯并氮杂
Figure BDA0003575530990000125
3-羧酸甲酯(III-22)
以5-溴靛红偶氮次甲基亚胺(29.41mg,0.1mmol)为原料，操作方法同III-16，得白色固体III-22 20.0mg，收率53％。
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),10.31(s,1H),7.74–7.61(m,2H),7.25(dd,J＝31.4,5.5Hz,2H),6.26(d,J＝6.7Hz,1H),5.78(d,J＝2.5Hz,1H),3.71(s,3H).HRMS(ESI+)m/z 379.1896[M+H]+。
Figure BDA0003575530990000123
实施例23：(3-羟基-1H-吡唑基)-2，3-二氢-1H-7-甲基苯并氮杂
Figure BDA0003575530990000126
3-羧酸甲酯(III-23)
以5-甲基靛红偶氮次甲基亚胺(22.92mg,0.1mmol)为原料，操作方法同III-16，得无色液体III-23 14.7mg，收率47％。
1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),10.26(s,1H),7.55(d,J＝2.5Hz,1H),7.30(dd,J＝8.5,2.0Hz,1H),7.16(d,J＝8.3Hz,1H),7.12–7.00(m,1H),6.23(d,J＝6.6Hz,1H),5.75(d,J＝2.6Hz,1H),3.77–3.62(m,3H),3.62(s,1H),2.28(s,3H).HRMS(ESI+)m/z314.3202[M+H]+。
Figure BDA0003575530990000131
实施例24：(3-羟基-1H-吡唑基)-2，3-二氢-1H-8-氯苯并氮杂
Figure BDA0003575530990000134
3-羧酸甲酯(III-24)
以6-氯靛红偶氮次甲基亚胺(22.92mg,0.1mmol)为原料，操作方法同III-16，得白色固体III-24 14.7mg，收率73％。
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),10.28(s,1H),7.63–7.57(m,1H),7.26(dd,J＝19.8,11.0Hz,3H),6.25(d,J＝6.7Hz,1H),5.75(d,J＝2.5Hz,1H),3.70(s,3H).HRMS(ESI+)m/z 334.7359[M+H]+。
Figure BDA0003575530990000132
实施例25：(3-羟基-1H-吡唑基)-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000135
3-羧酸乙酯(III-25)
以丙炔酸乙酯(11.77mg,0.12mmol)为原料，操作方法同III-16，得无色液体III-25 21.9mg，收率70％。
1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),10.25(s,1H),7.55(d,J＝2.6Hz,1H),7.48(ddd,J＝8.5,6.2,2.6Hz,1H),7.26(d,J＝8.3Hz,1H),7.22(d,J＝6.3Hz,3H),6.25(d,J＝6.8Hz,1H),5.75(d,J＝2.6Hz,1H),4.15(s,2H),1.26–1.14(m,3H).HRMS(ESI+)m/z314.3208[M+H]+。
Figure BDA0003575530990000133
实施例26：(3-羟基-1H-吡唑基)-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000136
3-羧酸乙酯(III-26)
以2-丁炔酸乙酯(13.98mg,0.12mmol)为原料，操作方法同III-16，得无色液体III-26 22.9mg，收率70％。
1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),10.03(s,1H),7.50(s,1H),7.29(t,J＝7.8Hz,1H),7.13(dd,J＝8.3,2.7Hz,1H),7.02(q,J＝5.3,2.7Hz,1H),6.57(d,J＝8.0Hz,1H),5.72(d,J＝2.7Hz,1H),4.31(s,1H),3.75–3.67(m,2H),1.96(d,J＝2.6Hz,3H),0.73(t,J＝7.2Hz,3H).HRMS(ESI+)m/z 314.3208[M+H]+。
Figure BDA0003575530990000141
实施例27：(3-羟基-1H-吡唑基)-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000144
3，4-二甲酸甲酯(III-27)
以丁炔二酸二甲酯(17.05mg,0.12mmol)为原料，操作方法同III-16，得白色固体III-27 26.1mg，收率73％。
1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),10.35(s,1H),7.56–7.39(m,2H),7.27–7.12(m,2H),6.90(d,J＝8.5Hz,1H),5.80(s,1H),3.56(s,6H).HRMS(ESI+)m/z 358.3292[M+H]+。
Figure BDA0003575530990000142
实施例28：(3-羟基-1H-吡唑基)-3-乙酰基-2，3-二氢-1H-苯并氮杂
Figure BDA0003575530990000145
(III-28)
以3-丁炔-2-酮(8.17mg,0.12mmol)为原料，操作方法同III-16，得无色液体III-28 18.1mg，收率64％。
1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),10.23(s,1H),7.56–7.16(m,5H),6.34(d,J＝6.8Hz,1H),5.74(s,1H),3.95(s,1H),2.21(s,3H).HRMS(ESI+)m/z 284.2497[M+H]+。
Figure BDA0003575530990000143

Claims (4)

1.下述通式3化合物和其药学上可接受的盐：
Figure FDA0003575530980000011
R1为甲基、苄基或苯基；R2为甲基、氟、氯或溴，R3为3位或4位单取代苄基，R4为H、甲基、乙基、苯基或噻吩。
2.根据权利要求1所述的化合物，其特征在于，所述化合物如下化合物任意一种：
Figure FDA0003575530980000012
Figure FDA0003575530980000021
3.一种如权利要求1所述的化合物的合成方法，其特征在于以靛红偶氮次甲基亚胺和联烯酸酯或炔酸酯、炔酮为原料，以三苯基膦为催化剂，二甲亚砜溶剂中反应8小时，得到苯并氮杂
Figure FDA0003575530980000023
化合物；
其反应式如下：
Figure FDA0003575530980000022
R1为甲基、苄基或苯基；
R2为甲基、氟、氯或溴，R3为3位或4位单取代苄基，R4为H、甲基、乙基、苯基或噻吩，R5为H、甲氧基、乙氧基、甲基、乙基、苯基，R6为氢或甲基。
4.根据权利要求3所述的合成方法，其特征在于：将靛红偶氮次甲基亚胺类化合物和联烯酸酯或者炔酸酯或炔基酮溶于二甲亚砜中，最后加入三苯基膦，于室温下反应，向反应液中加入饱和氯化钠溶液，乙酸乙酯萃取，合并有机相，再使用饱和氯化钠溶液洗涤；收集有机相，使用无水硫酸钠干燥；随后浓缩，经以石油醚：乙酸乙酯体积比为1：1混合溶剂作为洗脱剂柱层析梯度洗脱，收集检测到的所有产物的洗脱液部分，旋蒸除溶剂后得到苯并氮杂
Figure FDA0003575530980000031
化合物；其中所述的靛红偶氮次甲基亚胺类化合物、联烯酸酯或者炔酸酯或炔基酮、三苯基膦的摩尔比为1：1.2：0.2。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021216378A1 (en) * 2020-04-23 2021-10-28 The Schepens Eye Research Institute, Inc. Methods and materials for treatment of fibrosis
CN113717176A (zh) * 2021-10-09 2021-11-30 上海再启生物技术有限公司 一种制备瑞马唑仑的方法
CN114014839A (zh) * 2021-12-16 2022-02-08 上海再启生物技术有限公司 一种制备瑞马唑仑关键中间体的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021216378A1 (en) * 2020-04-23 2021-10-28 The Schepens Eye Research Institute, Inc. Methods and materials for treatment of fibrosis
CN113717176A (zh) * 2021-10-09 2021-11-30 上海再启生物技术有限公司 一种制备瑞马唑仑的方法
CN114014839A (zh) * 2021-12-16 2022-02-08 上海再启生物技术有限公司 一种制备瑞马唑仑关键中间体的方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115806559A (zh) * 2023-01-06 2023-03-17 天津理工大学 一种苯并硫氮桥环化合物及其制备方法

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Application publication date: 20220607

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