CN116283931A - 一种(z)-氮杂环烯基氯化合物及其制备方法和应用 - Google Patents
一种(z)-氮杂环烯基氯化合物及其制备方法和应用 Download PDFInfo
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- 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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Abstract
Description
技术领域
本发明涉及有机合成技术领域,具体涉及一种(Z)-氮杂环烯基氯化合物及其制备方法和应用。
背景技术
烯基氯化合物是一类重要的合成中间体,广泛用于合成多样性重要分子骨架,并广泛存在于多种天然产物与生物活性分子中。与此同时,烯基氯化物结构也能较方便转化为不同的C-C与C-杂键。但目前高立体选择性三键的氢氯化反应构建烯基氯化合物的例子仍然十分有限,最近,Engle课题组通过导向基实现了Pd催化下三键的不对称氢氯化反应(J.Am.Chem.Soc.,2017,139,5183-5193),贵金属Pd的使用以及导向基的后续脱除都限制了这一反应的进一步应用。发展更高效,更实用的氢氯化过程具有重要的研究意义。自从第一例含氘药物分子deutetrabenazine(SD-809,J.Med.Chem.,2014,57,3595)开发以来,氘代药物的研发近期受到药物学家的广泛关注,在药物分子中定点引入氘,对分子进行选择性修饰,能够显著改变药物分子的药理活性。并且能够通过同位素的放射性定点监测药物分子的作用效果,同时也可为临床上探索药物分子的作用机制提供相应的探索监测,因而开发有效简便的方法在分子结构中定点引入氘元素具有重要研究意义。
烯炔化合物的氢官能化环化反应是构建杂环化合物的重要手段。目前已经发展了众多金属催化烯炔化合物的氢官能化环化反应,所使用的催化剂往往都是贵金属催化剂Ru,Rh,Pd等。通过一些廉价,无毒,来源广泛的丰产金属催化剂实现烯炔化合物的环化反应具有重要研究意义。当前通过廉价金属盐催化剂实现烯炔化合物的氢官能化的例子仍然很有限,开发绿色高效,简单的廉价金属盐催化合成(Z)-氮杂环烯基氯化合物具有重要意义。以氘水作为原料,在分子结构中选择性引入氘,合成含氘药物分子,具有重要的研究意义。目前以氘水为原料在分子结构中引入氘元素的例子仍然很有限,开发绿色高效,简单的催化体系(以氘水为原料引入氘)合成氘取代杂环化合物具有重要意义。
发明内容
本发明所要解决的技术问题在于提供了一种(Z)-氮杂环烯基氯化合物及其制备方法,所述制备方法简单、高效,得到的化合物为单一Z-式结构,能用于杂环药物分子的开发。
本发明通过以下技术手段实现解决上述技术问题:
一种(Z)-氮杂环烯基氯化合物,其结构式为如下式I、式II中的任一种:
其中,式I和式II中,R1为氢原子、烷基取代基和芳基取代基中的至少一种;R2为氢原子、烷基取代基、芳基取代基、烯丙基、炔丙基中的至少一种;n1为1-5的整数,n2为1-5的整数。
优选地,R1、R2为碳原子数为3~8之间整数的环烷基。
优选地,R1和R2中,所述烷基取代基为C1-C10的烷基;所述芳基取代基为苯基、对氟苯基、对氯苯基、对溴苯基、对羟甲基苯基、对甲基苯基、对叔丁基苯基、对联苯基、对三氟甲基苯基、对硼酸频那醇酯苯基、对甲氧基苯基、间氟苯基、间氯苯基、间溴苯基、间甲氧基苯基、间三氟甲基苯基、邻氟苯基、α-萘基、β-萘基、2-噻吩基、
优选地,所述烷基取代基为甲基、乙基、正丁基中的一种。
优选地,式I和式II中,R1为苯基、对甲基苯基、对氟苯基、对氯苯基、对溴苯基、对叔丁基苯基、对羟甲基苯基、对联苯基、对三氟甲基苯基、对硼酸频那醇酯苯基、间甲氧基苯基、间氟苯基、间氯苯基、间溴苯基、间三氟甲基苯基、邻氟苯基、α-萘基、β-萘基、2-噻吩基、乙基、正丁基、氢、 中的一种;R2为甲基、苯基中的一种。
本发明还提出一种所述的(Z)-氮杂环烯基氯化合物的制备方法,包括以下步骤:将烯炔化合物与金属铁盐催化剂混合,再加入水或重水的二氯甲烷溶液以及Cl-试剂,加热反应,得到所述(Z)-氮杂环烯基氯化合物。
优选地,所述烯炔化合物的结构式中,R1和R2中,烷基取代基为碳原子数1~10的烷基;所述芳基取代基为苯基、对氟苯基、对氯苯基、对溴苯基、对羟甲基苯基、对甲基苯基、对叔丁基苯基、对联苯基、对三氟甲基苯基、对硼酸频那醇酯苯基、对甲氧基苯基、间氟苯基、间氯苯基、间溴苯基、间甲氧基苯基、间三氟甲基苯基、邻氟苯基、α-萘基、β-萘基、2-噻吩基、 中的至少一种。
优选地,所述烯炔化合物的结构式中,R1为苯基、对甲基苯基、对氟苯基、对氯苯基、对溴苯基、对叔丁基苯基、对羟甲基苯基、对联苯基、对三氟甲基苯基、对硼酸频那醇酯苯基、间甲氧基苯基、间氟苯基、间氯苯基、间溴苯基、间三氟甲基苯基、邻氟苯基、α-萘基、β-萘基、2-噻吩基、乙基、正丁基、氢、 中的一种;R2为甲基、苯基中的一种。
优选地,所述Cl-试剂为乙酰氯、苯甲酰氯、三甲基氯硅烷TMSCl中的至少一种;所述金属铁盐催化剂为Fe(acac)2、Fe(OAc)2、FeCl2、FeCl3、Fe2(SO4)3、Fe(acac)3中的一种或多种的混合物;所述烯炔化合物、Cl-试剂与水或重水的摩尔比为1:1~5:1~5;所述金属铁盐催化剂与所述烯炔化合物的摩尔比为0.5~30:100;所述反应的温度为20℃~100℃,时间为0.1-1小时。
优选地,所述烯炔化合物、Cl-试剂与水或重水的摩尔比为1:1.5:1.5;所述金属铁盐催化剂与所述烯炔化合物的摩尔比为0.5~5:100。
优选地,所述金属铁盐催化剂与所述烯炔化合物的摩尔比为5~30:100。
优选地,所述金属铁盐催化剂与所述烯炔化合物的摩尔比为1~20:100。
优选地,所述金属铁盐催化剂与所述烯炔化合物的摩尔比为1:100。
优选地,所述反应的温度为80℃。
优选地,所述反应的时间为10分钟。
优选地,所述制备方法中,还包括将加热反应后的产物分离提纯的步骤;所述分离提纯的方法包括柱层析、减压蒸馏和重结晶中的至少一种。
本发明还提出一种所述的(Z)-氮杂环烯基氯化合物在制备杂环药物分子中的应用。
本发明结构式中,Ts为对甲苯磺酰基。
本发明的优点在于:
1、本发明所使用的催化剂廉价易得,来源广泛,毒性低、易于操作;
2、本发明制备方法反应迅速,大大降低了合成成本和合成周期;
3、本发明所涉及的合成方法所用催化剂的量能降低到1mol%,催化效率高、对映选择性好;
4、本发明采用合成方法绿色环保;
5、本发明所涉及的方法易于大规模生产,而且放大后产率和选择性都能够保持;
6、本发明合成的化合物为单一Z-式结构的产物,能用于杂环药物分子的开发;
7、本发明通过开发新型有机化学反应,在分子特定活性位点选择性引入氘元素。
附图说明
图1为本发明实施例2制备的产物的核磁氢谱图;
图2为本发明实施例2制备的产物的核磁碳谱图;
图3为本发明实施例3制备的产物的核磁氢谱图;
图4为本发明实施例3制备的产物的核磁碳谱图;
图5为本发明实施例4制备的产物的核磁氢谱图;
图6为本发明实施例4制备的产物的核磁碳谱图;
图7为本发明实施例5制备的产物的核磁氢谱图;
图8为本发明实施例5制备的产物的核磁碳谱图;
图9为本发明实施例6制备的产物的核磁氢谱图;
图10为本发明实施例6制备的产物的核磁碳谱图;
图11为本发明实施例7制备的产物的核磁氢谱图;
图12为本发明实施例7制备的产物的核磁碳谱图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
下述实施例中所用的试验材料和试剂等,如无特殊说明,均可从商业途径获得。
实施例中未注明具体技术或条件者,均可以按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。
实施例1
烯炔化合物的制备
参照文献已报道方法合成烯炔化合物(Angew.Chem.Int.Ed..2010,49,5138;Adv.Synth.Catal.2015,357,3069),相关实验步骤与文献报道方法基本一致;其中,的制备方法包括以下步骤:
在0℃的冰水浴下,向Ts(对甲苯磺酰基)保护的炔丙胺(25.0mmol)的丙酮(25mL)溶液中加入K2CO3(38.0mmol)与烯丙基溴(40.0mmol),混合物加热回流24小时后。旋蒸除去溶剂,所得固体溶于乙酸乙酯,水洗,萃取,干燥,得到粗产品直接用于下一步。氮气气氛中,向所得粗产品(10.0mmol)的Et3N(20mL)溶液中,加入碘苯(11.0mmol),Pd(PPh3)2Cl2(0.2mmol),CuI(0.2mmol)。混合物在氮气气氛中搅拌16小时,所得产物经水洗,干燥,柱层析分离得到最终产物。
本发明实施例中用到的其他烯炔化合物均参照上述方法制备而成。
实施例2
(Z)-氮杂环烯基氯化合物的制备
按照如下所示的反应方程式进行制备:
将1,6-烯炔(50mmol)与Fe(acac)3(0.5mmol)加入反应器中,再将H2O(75mmol)用10ml二氯甲烷溶解后加入反应器中,0℃冰水浴下滴入三甲基氯硅烷(75mmol),加热至80℃,搅拌10分钟后反应完成,柱色谱分离得到目标产物(Z)-氮杂环烯基氯化合物,产率为91%。
(Z)-氮杂环烯基氯化合物结构确证的核磁谱图如图1和图2所示,数据如下:1HNMR(600MHz,CDCl3)δ7.75(d,J=8.3Hz,2H),7.40–7.37(m,2H),7.35–7.31(m,3H),7.25–7.21(m,2H),4.05(s,2H),3.00(s,2H),2.47(s,3H),0.91(s,6H).13C NMR(151MHz,CDCl3)δ144.0,141.9,137.9,132.2,129.9,129.2,129.0,128.4,128.2,125.3,63.1,54.0,43.3,26.2,21.8.
实施例3
(Z)-氮杂环烯基氯化合物的制备
按照如下所示的反应方程式进行制备:
将1,7-烯炔(50mmol)与FeCl3(0.5mmol)加入反应器中,再将H2O(75mmol)用10ml二氯甲烷溶解后加入反应器中,0℃冰水浴下滴入乙酰氯(75mmol),加热至40℃,搅拌10分钟后反应完成,柱色谱分离得到目标产物(Z)-氮杂环烯基氯化合物,产率为64%,(Z)-氮杂环烯基氯化合物结构确证的核磁谱图如图3和图4所示。
实施例4
将1,6-烯炔(50mmol)与Fe(OAc)2(0.5mmol)加入反应器中,再将H2O(75mmol)用10ml二氯甲烷溶解后加入反应器中,0℃冰水浴下滴入苯甲酰氯(75mmol),加热至50℃,搅拌10分钟后反应完成,将反应升温至100℃,继续反应10分钟,反应后得到酯基与氯交换产物,柱色谱分离得到目标产物四取代内烯化合物,产率为70%;相应的产物核磁谱图如图5和图6所示,数据如下:1H NMR(600MHz,CDCl3)δ7.91(dd,J=7.7,1.0Hz,1H),7.80(d,J=8.0Hz,1H),7.74–7.71(m,3H),7.54(t,J=7.5Hz,1H),7.37(d,J=8.0Hz,2H),4.18(s,2H),3.12(s,2H),2.44(s,3H),1.50(s,6H).13C NMR(151MHz,CDCl3)δ166.0,144.2,140.1,136.3,134.4,131.1,130.2,129.9,129.6,128.4,126.12,126.06,124.1,63.8,53.1,41.3,25.1,21.7.
实施例5
(Z)-氮杂环烯基氯化合物的制备
按照如下所示的反应方程式进行制备:
将1,6-烯炔(50mmol)与Fe(acac)3(0.5mmol)加入反应器中,再将D2O(75mmol)用10ml二氯甲烷溶解,0℃冰水浴下滴入苯甲酰氯(75mmol),加热至80℃,搅拌10分钟后反应完成,柱色谱分离得到目标产物氘取代杂环化合物,即所述(Z)-氮杂环烯基氯化合物;产率为83%。
氘取代杂环化合物结构确证的核磁谱图如图7和图8所示,数据如下:1H NMR(600MHz,CDCl3)δ7.74(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),7.33(t,J=3.3Hz,3H),7.25–7.20(m,2H),4.04(s,2H),2.99(s,2H),2.47(s,3H),0.91(s,5H).13C NMR(151MHz,CDCl3)δ144.0,141.9,137.8,132.0,129.9,129.2,129.0,128.4,128.2,125.3,63.1,54.0,43.3,26.2,26.1,21.8.
实施例6
将1,6-烯炔(50mmol)与Fe(OAc)2(0.5mmol)加入反应器中,再将D2O(75mmol)用10ml二氯甲烷溶解后加入反应器中,0℃冰水浴下滴入苯甲酰氯(75mmol),加热至50℃,搅拌10分钟后反应完成,将反应升温至100℃,继续反应10分钟,反应后得到酯基与氯交换产物,柱色谱分离得到目标产物四取代内烯化合物,产率为72%。
相应的产物核磁谱图如图9和图10所示,数据如下:1H NMR(600MHz,CDCl3)δ7.91(d,J=7.6Hz,1H),7.80(d,J=8.0Hz,1H),7.74–7.70(m,3H),7.54(t,J=7.5Hz,1H),7.37(d,J=7.9Hz,2H),4.17(s,2H),3.11(s,2H),2.44(s,3H),1.49(d,J=10.7Hz,5H).13C NMR(151MHz,CDCl3)δ166.0,144.2,140.1,136.3,134.4,131.0,130.2,129.9,129.6,128.4,126.1,126.0,124.0,63.8,63.8,53.1,41.25,41.17,25.1,25.0,21.7.
实施例7
氮气保护气氛下,将实施例2的产物(50mmol)与[Pd(allyl)Cl]2(1mmol)加入反应器中,再将配体(ligand,0.5mmol),Cs2CO3(75mmol)用10ml甲苯溶解后加入反应器中,再加入氘代二苯甲醇(75mmol),加热至90℃,搅拌24小时后反应完成,反应后得到D取代氯的产物,柱色谱分离得到目标产物,产率为95%。
相应的产物核磁谱图如图11和12所示,数据如下:1H NMR(600MHz,CDCl3)δ7.73(d,J=7.9Hz,2H),7.36(d,J=7.9Hz,2H),7.28–7.24(m,3H),7.24–7.19(m,1H),7.13–7.09(m,2H),3.99(s,2H),2.99(s,2H),2.46(s,3H),1.02(s,6H).13C NMR(151MHz,CDCl3)δ144.8,143.7,136.9,132.7,129.8,129.0,128.0,127.9,127.0,122.5,63.1,54.3,42.3,26.1,21.7.
同样的方法合成如下1-37的化合物:
采用结构式为R为对甲基苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为67%。其结构确证的核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=8.3Hz,2H),7.38(d,J=7.8Hz,2H),7.13(t,J=6.2Hz,4H),4.04(s,2H),2.99(s,2H),2.46(s,3H),2.34(s,3H),0.92(s,6H).13C NMR(151MHz,CDCl3)δ143.9,141.7,139.0,135.0,132.2,129.9,129.1,129.0,128.2,125.5,63.1,54.0,43.3,26.2,21.7,21.4.
采用结构式为R为对氟苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为68%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=8.3Hz,2H),7.38(d,J=7.9Hz,2H),7.21(dd,J=8.7,5.3Hz,2H),7.02(t,J=8.6Hz,2H),4.04(s,2H),3.00(s,2H),2.47(s,3H),0.91(s,6H).13CNMR(151MHz,CDCl3)δ162.9(d,J=249.2Hz),144.0,142.7,134.0(d,J=3.5Hz),132.2,131.2(d,J=8.6Hz),129.9,128.2,124.3,115.5(d,J=21.9Hz),63.1,54.0,43.4,26.2,21.8.19F NMR(564MHz,CDCl3)δ-111.62(s,1F).
采用结构式为R为对氯苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为82%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=8.2Hz,2H),7.38(d,J=8.0Hz,2H),7.31(d,J=8.4Hz,2H),7.17(d,J=8.5Hz,2H),4.03(s,2H),3.00(s,2H),2.46(s,3H),0.92(s,6H).13CNMR(151MHz,CDCl3)δ144.0,142.8,136.3,135.1,132.1,130.6,129.9,128.7,128.2,124.0,63.1,54.0,43.4,26.3,21.8.
采用结构式为R为对溴苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为88%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=8.2Hz,2H),7.47(d,J=8.4Hz,2H),7.38(d,J=7.9Hz,2H),7.11(d,J=8.4Hz,2H),4.03(s,2H),3.00(s,2H),2.47(s,3H),0.92(s,6H).13CNMR(151MHz,CDCl3)δ144.0,142.9,136.8,132.2,131.7,130.9,129.9,128.2,124.0,123.3,63.1,54.0,43.4,26.3,21.8.
采用结构式为R为对叔丁基苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为71%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.75(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),7.35–7.32(m,2H),7.16–7.14(m,2H),4.04(s,2H),2.99(s,2H),2.47(s,3H),1.30(s,9H),0.92(s,6H).13C NMR(151MHz,CDCl3)δ152.2,143.9,141.7,134.9,132.2,129.9,128.8,128.2,125.6,125.2,63.2,54.0,43.3,34.8,31.4,26.2,21.8.
采用结构式为R为对羟甲基苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为67%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=8.2Hz,2H),7.38(d,J=8.0Hz,2H),7.36(d,J=8.1Hz,2H),7.23(d,J=8.2Hz,2H),4.57(s,2H),4.05(s,2H),3.00(s,2H),2.46(s,3H),0.91(s,6H).13C NMR(151MHz,CDCl3)δ144.0,142.4,138.3,137.9,132.2,129.9,129.6,128.5,128.1,124.5,63.1,54.0,45.6,43.3,26.2,21.7.
采用结构式为R为对联苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为42%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.76(d,J=8.0Hz,2H),7.58(dd,J=12.0,7.6Hz,4H),7.45(t,J=7.6Hz,2H),7.38(dd,J=14.4,7.6Hz,3H),7.31(d,J=8.0Hz,2H),4.07(s,2H),3.02(s,2H),2.48(s,3H),0.97(s,6H).13C NMR(151MHz,CDCl3)δ144.0,142.2,141.8,140.2,136.8,132.0,129.9,129.7,129.0,128.2,127.9,127.2,127.0,125.0,63.1,54.1,43.4,26.3,21.8.
采用结构式为R为/>的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为98%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ8.00(d,J=8.4Hz,2H),7.73(d,J=8.2Hz,2H),7.37(d,J=7.9Hz,2H),7.30(d,J=8.4Hz,2H),4.05(s,2H),3.90(s,3H),2.99(s,2H),2.45(s,3H),0.89(s,6H).13C NMR(151MHz,CDCl3)δ166.4,144.0,142.9,142.2,132.1,130.6,129.9,129.6,129.3,128.1,123.8,63.0,54.0,52.4,43.4,26.2,21.7.
采用结构式为R为对三氟甲基苯基的1,6-烯炔代替实施例2中的/>得到(Z)-氮杂环烯基氯化合物,产率为98%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.75(d,J=8.2Hz,2H),7.61(d,J=8.1Hz,2H),7.39(d,J=7.9Hz,2H),7.37(d,J=8.0Hz,2H),4.06(s,2H),3.01(s,2H),2.47(s,3H),0.92(s,6H).13CNMR(151MHz,CDCl3)δ143.7(d,J=118.5Hz),141.4,131.9,131.0(d,J=32.8Hz),129.9(d,J=7.0Hz),128.5,128.2,126.5,125.5(q,J=3.6Hz),123.8(q,J=273.3Hz),123.4,63.0,54.0,43.4,26.2,21.7.19F NMR(564MHz,CDCl3)δ-62.85(s,CF3).
采用结构式为R为对硼酸频那醇酯苯基的1,6-烯炔代替实施例2中的/>得到(Z)-氮杂环烯基氯化合物,产率为91%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.76(d,J=6.0Hz,2H),7.74(d,J=6.1Hz,2H),7.37(d,J=6.7Hz,2H),7.23(d,J=5.9Hz,2H),4.04(s,2H),2.99(s,2H),2.46(s,3H),1.33(s,12H),0.90(s,6H).13C NMR(151MHz,CDCl3)δ143.9,141.9,140.5,134.7,132.1,129.9,128.5,128.1,125.0,84.1,63.1,54.0,43.3,26.2,25.0,21.7.
采用结构式为R为间甲氧基苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为71%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=8.2Hz,2H),7.38(d,J=7.9Hz,2H),7.25–7.22(m,1H),6.87(ddd,J=8.4,2.6,1.0Hz,1H),6.82(dt,J=7.5,1.3Hz,1H),6.76(dd,J=2.6,1.6Hz,1H),4.04(s,2H),3.78(s,3H),3.00(s,2H),2.47(s,3H),0.94(s,6H).13C NMR(151MHz,CDCl3)δ159.4,144.0,141.8,139.0,132.2,129.9,129.4,128.2,125.0,121.6,114.8,114.6,63.2,55.4,54.0,43.4,26.2,21.8.
采用结构式为R为间氟苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为83%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=7.8Hz,2H),7.38(d,J=7.9Hz,2H),7.30(q,J=7.6Hz,1H),7.02(t,J=6.2Hz,2H),6.94(d,J=9.2Hz,1H),4.04(s,2H),3.00(s,2H),2.46(s,3H),0.92(s,6H).13C NMR(151MHz,cdcl3)δ162.2(d,J=247.9Hz),144.0,142.7,139.6(d,J=8.0Hz),132.0,130.0(d,J=8.6Hz),129.9,128.1,125.1(d,J=3.0Hz),123.6(d,J=2.3Hz).,116.4,116.2(dd,J=35.2,21.4Hz),63.0,54.0,43.3,26.1,21.7.
采用结构式为R为间氯苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为91%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),7.33–7.30(m,1H),7.27(t,J=7.7Hz,2H),7.22(t,J=1.8Hz,1H),7.12(dt,J=7.5,1.4Hz,1H),4.03(s,2H),3.00(s,2H),2.46(s,3H),0.92(s,6H).13C NMR(151MHz,CDCl3)δ144.0,143.0,139.4,134.2,132.0,129.9,129.7,129.3,129.2,128.1,127.4,123.6,63.0,54.0,43.4,26.2,21.7.
采用结构式为R为间溴苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为76%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.73(d,J=7.9Hz,2H),7.47(d,J=7.9Hz,1H),7.38(d,J=8.4Hz,3H),7.21(t,J=7.8Hz,1H),7.17(d,J=7.7Hz,1H),4.03(s,2H),3.00(s,2H),2.46(s,3H),0.92(s,6H).13C NMR(151MHz,CDCl3)δ144.0,143.0,139.6,132.2,132.1,131.9,130.0,129.9,128.1,127.9,123.4,122.2,63.0,54.0,43.4,26.2,21.8.
采用结构式为R为间三氟甲基苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为66%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=8.2Hz,2H),7.60(d,J=7.5Hz,1H),7.51–7.46(m,2H),7.43(d,J=7.9Hz,1H),7.38(d,J=7.9Hz,2H),4.06(s,2H),3.01(s,2H),2.46(s,3H),0.90(s,6H).13C NMR(151MHz,CDCl3)δ143.8(d,J=85.0Hz),138.6,132.6,132.0,130.9(q,J=32.8Hz),130.0,129.1,128.2,126.2(q,J=3.7Hz),125.8(q,J=3.7Hz),123.7(q,J=273.3Hz),122.8,63.04,54.06,43.37,26.24,21.73.19F NMR(564MHz,CDCl3)δ-58.67(s,3F).
采用结构式为R为/>的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为79%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ8.03–7.99(m,1H),7.92(d,J=1.2Hz,1H),7.74(d,J=8.2Hz,2H),7.44–7.41(m,2H),7.38(d,J=7.9Hz,2H),4.05(s,2H),3.90(s,3H),3.00(s,2H),2.47(s,3H),0.90(s,6H).13C NMR(151MHz,CDCl3)δ166.4,144.0,142.9,138.1,133.5,132.0,130.4,130.1,129.9,128.6,128.1,124.0,63.1,54.0,52.4,43.4,26.3,21.7.
采用结构式为R为邻氟苯基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为79%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=7.8Hz,2H),7.38(d,J=8.0Hz,2H),7.35(t,J=6.9Hz,1H),7.23–7.19(m,1H),7.13(t,J=7.5Hz,1H),7.08–7.04(m,1H),4.18(d,J=15.8Hz,1H),3.95(d,J=15.6Hz,1H),3.13(d,J=8.9Hz,1H),2.90(d,J=8.9Hz,1H),2.47(s,3H),1.03(s,3H),0.79(s,3H).13C NMR(151MHz,CDCl3)δ159.6(d,J=249.3Hz),144.7,144.4(d,J=94.7Hz),132.0,131.5(d,J=2.3Hz),131.4(d,J=8.2Hz),130.0,128.1,125.4(d,J=16.2Hz),124.1,118.7,116.1(d,J=21.4Hz),53.9,43.4,26.9,23.9,21.7.
采用结构式为R为α-萘基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为40%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.85(t,J=8.2Hz,2H),7.83–7.80(m,1H),7.79(d,J=7.9Hz,2H),7.52–7.47(m,2H),7.44(d,J=7.4Hz,1H),7.41(d,J=8.2Hz,2H),7.37(d,J=6.9Hz,1H),4.30(d,J=15.5Hz,1H),4.16(d,J=15.6Hz,1H),3.14(d,J=9.0Hz,1H),2.93(d,J=9.0Hz,1H),2.49(s,3H),1.06(s,3H),0.52(s,3H).13C NMR(151MHz,CDCl3)δ144.0,143.8,134.7,133.7,132.5,131.2,130.0,129.8,128.5,128.2,127.9,126.8,126.4,125.6,125.0,123.8,63.0,53.9,43.6,27.2,24.2,21.8./>
采用结构式为R为β-萘基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为50%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.82(dd,J=11.5,8.8Hz,3H),7.77(d,J=7.9Hz,2H),7.72(d,J=1.6Hz,1H),7.51(tt,J=5.8,4.6Hz,2H),7.39(d,J=7.9Hz,2H),7.32(dd,J=8.5,1.7Hz,1H),4.12(s,2H),3.02(s,2H),2.48(s,3H),0.94(s,6H).13C NMR(151MHz,CDCl3)δ144.0,142.4,135.2,133.2,132.7,132.2,129.9,128.6,128.33,128.27,128.2,127.8,127.1,126.8,126.6,125.4,63.2,54.1,43.4,26.3,21.8.
采用结构式为R为2-噻吩基的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为43%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.73(d,J=7.9Hz,2H),7.37(d,J=7.9Hz,2H),7.28(td,J=2.9,1.4Hz,1H),7.22(dt,J=2.9,1.1Hz,1H),6.96(dt,J=5.0,1.2Hz,1H),4.01(s,2H),2.99(s,2H),2.46(s,3H),0.96(s,6H).13C NMR(151MHz,CDCl3)δ144.0,143.5,137.5,131.9,129.9,128.3,128.2,125.9,125.5,120.1,63.1,54.1,43.4,26.0,21.8.
采用结构式为的1,6-烯炔代替实施例2中的/>得到(Z)-氮杂环烯基氯化合物,产率为66%。相应的产物核磁数据如下:1H NMR(600MHz,CDCl3)δ7.71(d,J=8.2Hz,2H),7.36(d,J=7.9Hz,2H),7.19–7.13(m,3H),7.12–7.09(m,1H),7.05(dd,J=7.8,1.9Hz,2H),7.01(t,J=7.8Hz,2H),6.79(d,J=7.0Hz,2H),4.30–4.23(m,2H),3.47(d,J=9.3Hz,1H),3.24(d,J=9.3Hz,1H),2.47(s,3H),1.28(s,3H).13CNMR(151MHz,CDCl3)δ144.9,144.0,142.4,137.2,132.3,129.9,128.8,128.5,128.3,128.1,127.8,127.2,126.8,126.5,65.2,54.8,50.3,23.9,21.8.
采用结构式为R为-Et的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为41%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.70(d,J=8.3Hz,2H),7.35(d,J=7.8Hz,2H),3.83(s,2H),2.98(s,2H),2.44(s,3H),2.38(qt,J=7.3,1.3Hz,2H),1.24(s,6H),1.08(t,J=7.3Hz,3H).13C NMR(151MHz,CDCl3)δ143.9,138.8,131.8,130.7,129.8,128.2,63.4,54.1,42.5,28.7,26.2,21.7,12.8.
采用结构式为R为-nBu的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为60%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.70(d,J=7.9Hz,2H),7.35(d,J=7.9Hz,2H),3.83(s,2H),2.98(s,2H),2.45(s,3H),2.34(t,J=7.9Hz,2H),1.53–1.46(m,2H),1.33–1.27(m,2H),1.24(s,6H),0.90(t,J=7.3Hz,3H).13C NMR(151MHz,CDCl3)δ144.0,139.0,131.5,129.8,129.6,128.3,63.4,54.2,42.5,35.1,30.3,26.3,22.4,21.7,14.1./>
采用结构式为R为-H的1,6-烯炔代替实施例2中的/>得到(Z)-氮杂环烯基氯化合物,产率为64%。相应的产物核磁数据如下:1H NMR(600MHz,CDCl3)δ7.67(d,J=8.0Hz,2H),7.34(d,J=7.9Hz,2H),5.64(s,1H),3.59(s,2H),2.82(s,2H),2.44(s,3H),1.08(s,6H).13C NMR(151MHz,CDCl3)δ144.0,133.3,133.2,130.0,127.7,124.8,54.3,49.2,35.5,26.6,21.7.
采用结构式为的1,7-烯炔代替实施例3中的/>得到(Z)-氮杂环烯基氯化合物,产率为71%。相应的产物核磁数据如下:1H NMR(600MHz,CDCl3)δ7.78(d,J=7.9Hz,2H),7.37(d,J=7.9Hz,2H),7.30(dd,J=4.7,1.8Hz,3H),7.17–7.14(m,2H),4.23(s,2H),3.26(t,J=6.1Hz,2H),2.47(s,3H),1.47(t,J=6.1Hz,2H),0.74(s,6H).13C NMR(151MHz,CDCl3)δ143.6,140.7,136.8,134.4,129.8,129.0,128.8,128.5,128.2,127.8,46.9,42.3,39.6,36.3,29.0,21.7.
采用结构式为的烯炔代替实施例3中的/>得到(Z)-氮杂环烯基氯化合物,产率为90%。相应的产物核磁数据如下:1H NMR(600MHz,CDCl3)δ7.76–7.72(m,2H),7.39–7.35(m,2H),7.31–7.27(m,5H),3.45–3.42(m,2H),3.40(d,J=7.2Hz,2H),2.71(t,J=7.3Hz,2H),2.41(s,3H),2.11–2.07(m,2H),1.56(s,6H).13C NMR(151MHz,CDCl3)δ143.6,136.6,131.7,129.9,128.4,128.1,127.3,123.3,86.5,82.6,68.8,47.9,45.8,44.5,32.7,21.6,20.7.
采用结构式为R为/>的1,6-烯炔代替实施例2中的/>得到(Z)-氮杂环烯基氯化合物,产率为32%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ8.20(dd,J=7.9,1.7Hz,1H),7.76(d,J=8.4Hz,2H),7.68–7.65(m,1H),7.41–7.38(m,1H),7.30–7.27(m,2H),7.19–7.17(m,1H),7.08–7.04(m,4H),4.67(s,2H),3.58(s,2H),2.36(s,3H),2.30(s,3H),1.72(s,6H).13C NMR(151MHz,CDCl3)δ169.7,162.6,151.2,150.4,143.8,136.1,134.8,132.8,132.1,129.6,127.9,126.2,124.1,122.2,121.6,120.1,85.1,82.1,69.9,57.6,39.6,30.9,21.4,21.0.
采用结构式为R为/>的1,6-烯炔代替实施例2中的得到(Z)-氮杂环烯基氯化合物,产率为63%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ10.39(s,1H),7.75(d,J=8.2Hz,2H),7.55(ddd,J=8.6,7.2,1.7Hz,1H),7.39(d,J=8.0Hz,2H),7.32(d,J=8.6Hz,2H),7.21(d,J=8.6Hz,2H),7.04(dd,J=8.4,1.1Hz,1H),6.97(ddd,J=8.2,7.2,1.2Hz,1H),4.06(s,2H),3.02(s,2H),2.47(s,3H),0.96(s,6H).13C NMR(151MHz,CDCl3)δ168.6,162.4,150.4,144.0,142.9,136.8,136.0,132.2,130.7,130.4,129.9,128.2,124.2,121.8,119.7,118.0,111.7,63.1,54.1,43.4,26.3,21.8.
采用结构式为R为/>的1,6-烯炔代替实施例2中的/>得到(Z)-氮杂环烯基氯化合物,产率为77%。相应的产物核磁数据如下:1HNMR(400MHz,CDCl3)δ8.03(d,J=8.1Hz,2H),7.76(d,J=8.0Hz,2H),7.39(d,J=8.1Hz,2H),7.33(d,J=8.1Hz,2H),4.95(td,J=10.9,4.4Hz,1H),4.08(s,2H),3.03(s,2H),2.46(s,3H),2.11(d,J=12.3Hz,1H),1.96(td,J=6.9,2.7Hz,1H),1.79–1.69(m,2H),1.56(tt,J=8.0,3.3Hz,2H),1.28(d,J=8.3Hz,1H),1.12(t,J=11.7Hz,2H),0.93(dd,J=7.7,5.8Hz,12H),0.80(d,J=7.0Hz,3H).13C NMR(151MHz,CDCl3)δ165.2,143.8,142.7,141.9,131.9,131.1,129.8,129.5,129.2,128.0,123.8,75.1,62.9,53.9,47.1,43.2,40.9,34.2,31.4,26.4,26.1,26.0,23.5,22.0,21.6,20.8,16.4.
采用结构式为R为对氟苯基的1,6-烯炔代替实施例5中的制备得到氘取代杂环化合物,产率为77%。其结构确证的核磁数据如下:1HNMR(600MHz,CDCl3)δ7.74(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),7.21(dd,J=8.5,5.4Hz,2H),7.02(t,J=8.6Hz,2H),4.03(s,2H),2.99(s,2H),2.46(s,3H),0.90(d,J=10.4Hz,5H).13C NMR(151MHz,cdcl3)δ162.8(d,J=249.2Hz),142.7,133.9(d,J=3.5Hz),132.0,131.2(d,J=8.5Hz),129.9,128.2,124.2,115.5(d,J=21.8Hz),63.0,54.0,43.2,26.20,26.18,21.7.19F NMR(564MHz,CDCl3)δ-111.57(s,1F).
采用结构式为R为对羟甲基苯基的1,6-烯炔代替实施例5中的制备得到氘取代杂环化合物,产率为70%。相应的产物核磁数据如下:1H NMR(600MHz,CDCl3)δ7.74(d,J=8.2Hz,2H),7.37(dd,J=13.2,8.0Hz,4H),7.23(d,J=8.2Hz,2H),4.57(s,2H),4.04(s,2H),2.99(s,2H),2.46(s,3H),0.90(d,J=10.6Hz,5H).13C NMR(151MHz,CDCl3)δ144.0,142.4,138.3,137.9,132.0,129.9,129.6,128.5,128.1,124.5,63.0,54.0,45.6,43.3,26.2,26.2,21.7.
采用结构式为R为对三氟甲基苯基的1,6-烯炔代替实施例5中的/>制备得到氘取代杂环化合物,产率为89%。相应的产物核磁数据如下:1H NMR(600MHz,CDCl3)δ7.74(d,J=8.2Hz,2H),7.61(d,J=7.3Hz,2H),7.37(dd,J=13.2,7.9Hz,4H),4.05(s,2H),3.00(s,2H),2.46(s,3H),0.90(d,J=10.0Hz,5H).13C NMR(151MHz,CDCl3)δ143.7(d,J=118.5Hz),141.4,131.9,131.0(d,J=32.8Hz),129.9(d,J=7.0Hz),128.5,128.2,126.5,125.5(q,J=3.6Hz),123.8(q,J=273.3Hz),123.4,122.9,110.1,63.0,54.0,43.3,26.3,26.2,21.8.19F NMR(564MHz,CDCl3)δ-62.80(s,1F).
采用结构式为R为对硼酸频那醇酯苯基的1,6-烯炔代替实施例5中的/>制备得到氘取代杂环化合物,产率为65%。相应的产物核磁数据如下:1HNMR(600MHz,CDCl3)δ7.75(dd,J=15.6,7.8Hz,4H),7.38(d,J=7.9Hz,2H),7.23(d,J=7.7Hz,2H),4.04(s,2H),2.98(s,2H),2.46(s,3H),1.33(s,12H),0.89(d,J=10.6Hz,5H).13C NMR(151MHz,CDCl3)δ144.0,141.9,140.5,135.0,134.7,132.0,129.9,128.5,128.2,125.0,84.2,63.1,54.0,43.3,43.3,26.20,26.18,25.0,21.8.
采用结构式为R为间甲氧基苯基的1,6-烯炔代替实施例5中的制备得到氘取代杂环化合物,产率为72%。相应的产物核磁数据如下:1H NMR(600MHz,CDCl3)δ7.74(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),7.24(t,J=8.0Hz,1H),6.87(dd,J=8.4,2.5Hz,1H),6.83–6.80(m,1H),6.76(s,1H),4.03(s,2H),3.78(s,3H),2.99(s,2H),2.46(s,3H),0.93(d,J=10.5Hz,5H).13C NMR(151MHz,CDCl3)δ159.3,143.9,141.8,139.0,132.1,129.9,129.4,128.1,125.0,121.6,114.7,114.6,63.1,55.4,54.0,43.3,26.12,26.09,21.7./>
采用结构式为R为/>的1,6-烯炔代替实施例5中的制备得到氘取代杂环化合物,产率为74%。相应的产物核磁数据如下:1H NMR(600MHz,CDCl3)δ8.01(td,J=4.7,1.7Hz,1H),7.91(s,1H),7.73(d,J=8.1Hz,2H),7.44–7.41(m,2H),7.38(d,J=7.9Hz,2H),4.05(s,2H),3.90(s,3H),2.99(s,2H),2.46(s,3H),0.89(d,J=10.4Hz,5H).13C NMR(151MHz,CDCl3)δ166.4,144.3,144.0,142.9,138.1,133.5,131.9,130.4,130.1,129.9,128.6,128.1,124.0,63.0,54.0,52.4,43.2,26.3,26.2,21.7.
采用结构式为的1,6-烯炔代替实施例5中的/>制备得到氘取代杂环化合物,产率为65%。相应的产物核磁数据如下:1H NMR(600MHz,CDCl3)δ7.71(d,J=7.9Hz,2H),7.36(d,J=7.9Hz,2H),7.16(d,J=7.4Hz,3H),7.11(t,J=7.6Hz,1H),7.07–7.04(m,2H),7.02(t,J=7.6Hz,2H),6.80(d,J=7.7Hz,2H),4.31–4.23(m,2H),3.48(d,J=9.3Hz,1H),3.24(d,J=9.3Hz,1H),2.47(s,3H),1.27(s,2H).13CNMR(151MHz,CDCl3)δ144.9,144.0,142.3,137.1,132.1,129.9,128.7,128.5,128.3,128.1,127.8,127.2,126.8,126.4,65.2,54.8,50.1,23.8,21.7.
采用结构式为的烯炔代替实施例5中的/>制备得到氘取代杂环化合物,产率为69%。相应的产物核磁数据如下:1H NMR(600MHz,CDCl3)δ7.78(d,J=8.3Hz,2H),7.37(d,J=8.0Hz,2H),7.30(dd,J=5.0,1.9Hz,3H),7.17–7.14(m,2H),4.23(s,2H),3.27–3.24(m,2H),2.47(s,3H),1.46(t,J=6.1Hz,2H),0.73(d,J=12.7Hz,5H).13C NMR(151MHz,CDCl3)δ143.6,140.7,136.7,134.3,129.8,128.9,128.8,128.5,128.2,127.8,46.8,42.3,39.5,36.3,36.2,29.0,28.9,21.7.
以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (10)
4.一种如权利要求1-3中任一项所述的(Z)-氮杂环烯基氯化合物的制备方法,其特征在于:包括以下步骤:将烯炔化合物与金属铁盐催化剂混合,再加入水或重水的二氯甲烷溶液以及Cl-试剂,加热反应,得到所述(Z)-氮杂环烯基氯化合物。
8.根据权利要求4-7中任一项所述的(Z)-氮杂环烯基氯化合物的制备方法,其特征在于:所述Cl-试剂为乙酰氯、苯甲酰氯、三甲基氯硅烷TMSCl中的至少一种;所述金属铁盐催化剂为Fe(acac)2、Fe(OAc)2、FeCl2、FeCl3、Fe2(SO4)3、Fe(acac)3中的一种或多种的混合物;所述烯炔化合物、Cl-试剂与水或重水的摩尔比为1:1~5:1~5;所述金属铁盐催化剂与所述烯炔化合物的摩尔比为0.5~30:100;所述反应的温度为20℃~100℃,时间为0.1-1小时。
9.一种如权利要求1-3中任一项所述的(Z)-氮杂环烯基氯化合物在制备杂环药物分子中的应用。
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