CN113620866A - 一种氘代含氮杂环化合物的制备方法 - Google Patents

一种氘代含氮杂环化合物的制备方法 Download PDF

Info

Publication number
CN113620866A
CN113620866A CN202110985204.5A CN202110985204A CN113620866A CN 113620866 A CN113620866 A CN 113620866A CN 202110985204 A CN202110985204 A CN 202110985204A CN 113620866 A CN113620866 A CN 113620866A
Authority
CN
China
Prior art keywords
deuterated
containing heterocyclic
nitrogen
heterocyclic compound
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110985204.5A
Other languages
English (en)
Inventor
高章华
江之江
吴涛
李岩
陈佳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ningbo Cuiying Chemical Technology Co ltd
Zhejiang University of Science and Technology ZUST
Original Assignee
Ningbo Cuiying Chemical Technology Co ltd
Zhejiang University of Science and Technology ZUST
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ningbo Cuiying Chemical Technology Co ltd, Zhejiang University of Science and Technology ZUST filed Critical Ningbo Cuiying Chemical Technology Co ltd
Priority to CN202110985204.5A priority Critical patent/CN113620866A/zh
Publication of CN113620866A publication Critical patent/CN113620866A/zh
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/127—Preparation from compounds containing pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/02—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with only hydrogen, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

本发明公开了一种氘代含氮杂环化合物的制备方法，以式1至式5其中之一所示的含氮杂环化合物为原料，在氘源试剂及惰性气体的存在下，无机碱作为催化剂，60‑120℃下进行氘代反应，控制反应时间，获得式1a至式5a其中之一所示的氘代含氮杂环化合物或式1b至式5b其中之一所示的氘代含氮杂环化合物。本发明具有反应条件温和，操作简便，氘代效果好，收率高的优点。

Description

一种氘代含氮杂环化合物的制备方法
技术领域
本发明涉及有机合成技术领域，特别涉及一种氘代含氮杂环化合物的制备方法。
背景技术
氘元素是一种氢的同位素，自发现以来，由于其独特的性质，被广泛应用于核能、军事、分析检测、医学检验、高分子材料合成改性、制药等各个领域。如在药物化学领域中，在药物分子的非代谢位点和非作用位点引入氘，采用同位素示踪法，可以在不影响药物作用的情况下对药物分子的吸收、分布、代谢和排泄等进行研究；在材料研究领域中，由于C-D键的稳定性优于C-H键，可以在不影响材料其他性能的情况下将设备寿命延长。
含氮杂环化合物是一类含有氮杂原子的杂环化合物，是杂环化合物中应用开发最广泛的化合物之一，其作为化学工业，特别是精细化工的重要原料，应用范围极广，如3-甲基吡啶可用于合成烟酸或烟酰胺，可作血管扩张治疗药，用于治疗视神经萎缩，视网膜病变，也可用于合成农用化学品—除草剂。以含氮杂环化合物的氘代产物作为中间体，合成药物，农用化学品，饲料，香料，日化用品等，可以改良性能，产品更优。
目前含氮杂环化合物的氘代研究仍处于起步阶段，现有氘代方法主要为化学合成法，多采用含Ir、Pd、Ru、Fe等过渡金属元素化合物作为催化剂进行合成，需要多种助剂参与反应，实验繁琐，操作复杂，产率较低。
发明内容
本发明的目的在于提供一种氘代含氮杂环化合物的制备方法，该方法以安全低毒的含氮杂环化合物为原料，在惰性气体存在下，通过一锅法一步反应，完成氘代含氮杂环化合物的合成，具有反应条件温和，操作简便，氘代效果好，收率高的优点。
本发明解决其技术问题所采用的技术方案是：
一种氘代含氮杂环化合物的制备方法，以式1至式5其中之一所示的含氮杂环化合物为原料，在氘源试剂及惰性气体的存在下，无机碱作为催化剂，60-120℃下进行氘代反应，控制反应时间，获得式1a至式5a其中之一所示的氘代含氮杂环化合物或式1b至式5b其中之一所示的氘代含氮杂环化合物；
Figure BDA0003229043380000021
所述无机碱选自叔丁醇钾、叔丁醇钠、叔丁醇锂、氢化钠、碳酸钾、磷酸钾、醋酸钾、氢氧化钾中的一种。
所述氘源试剂为氘代二甲基亚砜。
反应中各物料的摩尔用量比为含氮杂环化合物：无机碱：氘源试剂＝1:0.1-2.5:5.0-60。
所述惰性气氛为氮气或氩气所构成的惰性气体环境。
控制反应时间为4-6小时，获得式1a至式5a其中之一所示的氘代含氮杂环化合物。
控制反应时间为12-48小时，式1b至式5b其中之一所示的氘代含氮杂环化合物。
所述R基为氢原子、溴原子、甲基、叔丁基、苯基、对甲苯基、3-联苯基、氰基、氨基、二甲氨基、甲氧基中的一种或几种。
本发明的有益效果是：
1、本发明可以进行选择性氘代，选择性体现在吡啶环的氘代上，在短时间反应后可以得到部分位点氘代的产物，继续延长时间，能把剩下的位点进行氘代。
2、所采用技术路线在常规实验室条件下完成，一步一锅法反应无需中途替换溶剂，无需增加氘源用量，且反应时间短，氘代效果好，产率高，对反应操作简单。
3、方法普适性好，可用于多种含氮杂环化合物氘代产物的制备。
具体实施方式
下面通过具体实施例，对本发明的技术方案作进一步的具体说明。
本发明中，若非特指，所采用的原料和设备等均可从市场购得或是本领域常用的。下述实施例中的方法，如无特别说明，均为本领域的常规方法。
总实施方案
一种氘代含氮杂环化合物的制备方法，以式1至式5其中之一所示的含氮杂环化合物为原料，在氘源试剂及惰性气体的存在下，无机碱作为催化剂，60-120℃下进行氘代反应，控制反应时间，获得式1a至式5a其中之一所示的氘代含氮杂环化合物或式1b至式5b其中之一所示的氘代含氮杂环化合物；
Figure BDA0003229043380000031
所述无机碱选自叔丁醇钾、叔丁醇钠、叔丁醇锂、氢化钠、碳酸钾、磷酸钾、醋酸钾、氢氧化钾中的一种。无机碱优选叔丁醇钾。所述氘源试剂为氘代二甲基亚砜。
反应中各物料的摩尔用量比为含氮杂环化合物：无机碱：氘源试剂＝1:0.1-2.5:5.0-60。
所述惰性气氛为高纯氮气或氩气所构成的惰性气体环境。
控制反应时间为4-6小时，获得式1a至式5a其中之一所示的氘代含氮杂环化合物。
控制反应时间为12-48小时，式1b至式5b其中之一所示的氘代含氮杂环化合物。
所述R基为氢原子、溴原子、甲基、叔丁基、苯基、对甲苯基、3-联苯基、氰基、氨基、二甲氨基、甲氧基中的一种或几种。
实施例1含氮杂环化合物的选择性氘代
于15mL干燥的耐压瓶中，称取2-溴吡啶(95μL,1.0mmol,1eq)，叔丁醇钾(112.2mg,1.0mmol)，随后加入氘代二甲基亚砜(2mL)，用氮气置换反应体系中气体，100℃下搅拌反应4小时。
反应结束后，二氯甲烷萃取，有机相饱和食盐水洗涤，经Na2SO4干燥后浓缩，随后通过硅胶柱纯化(PE:EA＝30:1,Rf＝0.5)得106.7mg无色液体，氘代度151％D，产率67％。1HNMR(399MHz,DMSO-d6)δ8.38(dt,J＝4.8,1.1Hz,1H),7.46–7.40(m,1H).MS(EI)159.6。
同样条件下，从各吡啶类化合物出发，在上述条件下得到氘代产物，其结果如下表所示：
化合物编号 氘代度(％D) 产率(％)
1 297 94
2 360 98
3 644 39
4 595 65
5 670 10
6 620 97
7 714 78
8 430 42
9 95 29
10 478 59
11 157 55
12 589 67
13 389 32
14 94 32
15 142 95
。
氘代2-苯基吡啶2-phenylpyridine-d(1).1H NMR(399MHz,Chloroform-d)δ8.71(s,1H),8.03–7.96(m,2H),7.52–7.45(m,2H),7.45–7.39(m,1H)。
氘代5-甲基-2-苯基吡啶5-methyl-2-phenylpyridine-d(2).1H NMR(399MHz,DMSO-d6)δ8.48(q,J＝1.1Hz,1H),8.06–8.00(m,2H),7.86–7.81(m,1H),7.71–7.64(m,1H),7.50–7.42(m,2H),7.42–7.35(m,1H).
氘代2,5-二甲基吡啶2,5-dimethylpyridine-d(3).1H NMR(399MHz,DMSO-d6)δ8.25(t,J＝1.2Hz,1H),7.11(ddd,J＝4.5,3.3,0.9Hz,1H)。
氘代3,4-二甲基吡啶3,4-dimethylpyridine-d(4).1H NMR(399MHz,DMSO-d6)δ8.26(d,J＝0.7Hz,1H),8.25–8.21(m,1H),7.13(dd,J＝4.8,0.7Hz,1H)。
氘代2,3-二甲基吡啶2,3-dimethylpyridine-d(5).1H NMR(399MHz,DMSO-d6)δ8.26–8.19(m,1H)。
氘代2,6-二甲基吡啶2,6-dimethylpyridine-d(6).1H NMR(399MHz,DMSO-d6)δ8.07(s,1H),7.07–6.93(m,1H),3.89(s,1H)。
氘代5-甲基-2-(4-甲苯基)吡啶5-methyl-2-(p-tolyl)pyridine-d(7).1H NMR(399MHz,DMSO-d6)δ8.49–8.42(m,1H),7.97–7.90(m,2H),7.79(d,J＝8.1Hz,1H),7.67–7.60(m,1H),7.26(d,J＝7.9Hz,2H),2.32(d,J＝12.5Hz,6H)。
氘代2-溴吡啶2-bromopyridine-d(8).1H NMR(399MHz,DMSO-d6)δ8.24–8.18(m,1H),7.57(dt,J＝2.2,0.9Hz,1H)。
氘代2-溴-5-苯基吡啶2-bromo-5-phenylpyridine-d(9).1H NMR(399MHz,DMSO-d6)δ8.77–8.61(m,1H),8.07–8.00(m,1H),7.75–7.68(m,2H),7.59–7.34(m,3H)。
氘代3-氨基-6-溴吡啶6-bromopyridin-3-amine-d(10).1H NMR(399MHz,DMSO-d6)δ7.06(s,1H),6.91–6.77(m,1H),5.21(s,39H),2.18(p,J＝2.3Hz,2H)。
氘代3-氰基-6-溴吡啶6-bromonicotinonitrile-d(11).1H NMR(399MHz,DMSO-d6)δ8.87(d,J＝1.0Hz,1H),7.94–7.89(m,1H)。
氘代2-溴-3,5-二甲基吡啶2-bromo-3,5-dimethylpyridine-d(12).1H NMR(399MHz,DMSO-d6)δ8.04–7.99(m,1H),7.56(dd,J＝2.4,0.5Hz,1H)。
氘代2-溴-3-氟-6-甲基吡啶2-bromo-3-fluoro-6-methylpyridine-d(13).1HNMR(399MHz,DMSO-d6)δ7.36(d,J＝3.7Hz,1H)。
氘代2-溴-3-甲氧基吡啶2-bromo-3-methoxypyridine-d(14).1H NMR(399MHz,DMSO-d6)δ7.98–7.92(m,1H),7.40(d,J＝4.6Hz,1H),3.91–3.85(m,2H)。
氘代4-二甲氨基吡啶N,N-dimethylpyridin-4-amine-d(15).1H NMR(399MHz,DMSO-d6)δ8.10(d,J＝2.9Hz,1H),2.95(s,3H)。
同样条件下，从联苯类、嘧啶类，吲哚类，氮杂蒽等化合物出发，从上述条件下得到氘代产物，其结果如下表所示：
Figure BDA0003229043380000051
Figure BDA0003229043380000061
。
2-([1,1'-biphenyl]-3-yl)pyridine-d(16).1H NMR(399MHz,Chloroform-d)δ8.74(s,1H),8.28–8.22(m,1H),7.97(ddd,J＝7.7,1.8,1.1Hz,1H),7.72–7.68(m,2H),7.68–7.64(m,1H),7.59–7.53(m,1H),7.50–7.43(m,2H),7.40–7.34(m,1H)。
氘代2,9-二甲基-1,10-邻菲咯啉2,9-dimethyl-1,10-phenanthroline-d(17).1HNMR(399MHz,Chloroform-d)δ8.14–8.09(m,3H),7.96–7.88(m,1H),7.70(s,5H),7.52–7.46(m,3H),7.35(d,J＝1.1Hz,1H),2.92(p,J＝2.2Hz,2H)。
氘代4,7-二叔丁基-1,10-邻菲咯啉4,7-di-tert-butyl-1,10-phenanthroline-d(18).1H NMR(399MHz,Chloroform-d)δ8.61–8.56(m,2H),8.41(s,2H),7.31(dd,J＝5.2,2.0Hz,1H),1.41(s,15H)。
氘代2,2'-联吡啶2,2'-bipyridine-d(19).1H NMR(399MHz,DMSO-d6)δ8.67(d,J＝1.0Hz,9H),8.37(d,J＝1.0Hz,5H),7.95–7.90(m,1H),7.44(d,J＝4.7Hz,1H)。
氘代2,2'-联嘧啶2,2'-bipyrimidine-d(20).1H NMR(399MHz,DMSO-d6)δ9.02–8.95(m,3H),7.64(t,J＝4.9Hz,1H)。
氘代联喹啉2,2'-biquinoline-d(21).1H NMR(399MHz,Chloroform-d)δ8.93–8.77(m,1H),8.32(dt,J＝8.7,1.2Hz,1H),8.24(ddt,J＝8.5,4.6,1.0Hz,2H),8.05(ddd,J＝8.3,1.4,0.7Hz,1H),7.94–7.83(m,1H),7.76(ddp,J＝8.3,6.8,1.2Hz,2H),7.59(tdd,J＝8.0,6.8,1.2Hz,2H)。
氘代1H-吲哚1H-indole-d(22).1H NMR(399MHz,DMSO-d6)δ11.05(s,1H),7.53(dd,J＝7.9,1.0Hz,1H),7.39(dd,J＝8.1,1.0Hz,1H),7.32(t,J＝2.1Hz,1H),7.07(ddd,J＝8.1,6.9,1.2Hz,1H),6.97(ddd,J＝7.9,6.9,1.1Hz,1H)。
氘代异喹啉Isoquinoline-d(23).1H NMR(399MHz,DMSO-d6)δ7.94–7.89(m,1H),7.76(dddd,J＝10.7,8.1,6.9,1.3Hz,1H),7.66(tdd,J＝8.3,6.8,1.3Hz,1H)。
氘代吖啶Acridine-d(24).1H NMR(399MHz,DMSO-d6)δ8.20–8.13(m,4H),7.85(ddd,J＝8.8,6.6,1.4Hz,2H),7.61(ddd,J＝8.3,6.5,1.1Hz,2H)。
实施例2含氮杂环化合物的全氘代
方法同实施例1，不同之处是将反应时间延长至24小时。
化合物编号 氘代度(％D) 产率(％)
25 326 100
26 228 58
27 43 99
28 175 74
氘代2,5-二苯基吡啶2,5-diphenylpyridine-d(25).1H NMR(399MHz,DMSO-d6)δ8.99(s,1H),8.18–8.11(m,2H),7.83–7.76(m,2H),7.55–7.48(m,4H),7.47–7.40(m,2H)。
氘代1,10-邻菲咯啉1,10-phenanthroline-d(26).1H NMR(399MHz,DMSO-d6)δ9.10–9.05(m,1H),7.98(s,1H),7.79–7.72(m,1H)。
氘代2-甲基-1H-吲哚2-methyl-1H-indole-d(27).1H NMR(399MHz,DMSO-d6)δ10.86(s,1H),7.38(ddt,J＝7.6,1.5,0.8Hz,1H),7.25(dq,J＝7.9,1.0Hz,1H),6.97(ddd,J＝8.1,7.0,1.3Hz,1H),6.93–6.88(m,1H),6.10(dt,J＝2.0,1.0Hz,1H),2.38(d,J＝0.9Hz,3H)。
氘代喹啉Quinoline-d(28).1H NMR(399MHz,DMSO-d6)δ8.90(d,J＝1.3Hz,1H),8.02(ddd,J＝8.5,1.2,0.7Hz,1H),7.97(ddt,J＝8.1,1.7,0.8Hz,1H),7.75(ddd,J＝8.5,6.9,1.5Hz,1H),7.60(ddd,J＝8.1,6.8,1.2Hz,1H)。
以上所述的实施例只是本发明的一种较佳的方案，并非对本发明作任何形式上的限制，在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。

Claims (8)

1.一种氘代含氮杂环化合物的制备方法，其特征在于，以式1至式5其中之一所示的含氮杂环化合物为原料，在氘源试剂及惰性气体的存在下，无机碱作为催化剂，60-120℃下进行氘代反应，控制反应时间，获得式1a至式5a其中之一所示的氘代含氮杂环化合物或式1b至式5b其中之一所示的氘代含氮杂环化合物；
Figure FDA0003229043370000011
2.根据权利要求1所述的制备方法，其特征在于，所述无机碱选自叔丁醇钾、叔丁醇钠、叔丁醇锂、氢化钠、碳酸钾、磷酸钾、醋酸钾、氢氧化钾中的一种。
3.根据权利要求1所述的制备方法，其特征在于，所述氘源试剂为氘代二甲基亚砜。
4.根据权利要求1所述的制备方法，其特征在于，反应中各物料的摩尔用量比为含氮杂环化合物：无机碱：氘源试剂＝1:0.1-2.5:5.0-60。
5.根据权利要求1所述的制备方法，其特征在于，所述惰性气氛为氮气或氩气所构成的惰性气体环境。
6.根据权利要求1所述的制备方法，其特征在于，控制反应时间为4-6小时，获得式1a至式5a其中之一所示的氘代含氮杂环化合物。
7.根据权利要求1所述的制备方法，其特征在于，控制反应时间为12-48小时，式1b至式5b其中之一所示的氘代含氮杂环化合物。
8.根据权利要求1所述的制备方法，其特征在于，所述R基为氢原子、溴原子、甲基、叔丁基、苯基、对甲苯基、3-联苯基、氰基、氨基、二甲氨基、甲氧基中的一种或几种。
CN202110985204.5A 2021-08-25 2021-08-25 一种氘代含氮杂环化合物的制备方法 Pending CN113620866A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110985204.5A CN113620866A (zh) 2021-08-25 2021-08-25 一种氘代含氮杂环化合物的制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110985204.5A CN113620866A (zh) 2021-08-25 2021-08-25 一种氘代含氮杂环化合物的制备方法

Publications (1)

Publication Number Publication Date
CN113620866A true CN113620866A (zh) 2021-11-09

Family

ID=78387793

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110985204.5A Pending CN113620866A (zh) 2021-08-25 2021-08-25 一种氘代含氮杂环化合物的制备方法

Country Status (1)

Country Link
CN (1) CN113620866A (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894143A (zh) * 2022-10-31 2023-04-04 宁波萃英化学技术有限公司 氘代芳香化合物钯催化的双配体无导向制备方法
CN116425703A (zh) * 2023-03-27 2023-07-14 浙大宁波理工学院 一种饱和环醚类化合物c2位环外甲基氘代的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105979946A (zh) * 2014-01-24 2016-09-28 奥斯拜客斯制药有限公司 取代的n-芳基吡啶酮
CN106565600A (zh) * 2016-10-28 2017-04-19 湖南大学 一种氘代氮杂芳香化合物及其合成方法
WO2019143153A1 (ko) * 2018-01-17 2019-07-25 주식회사 엘지화학 신규한 화합물 및 이를 이용한 유기 발광 소자

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105979946A (zh) * 2014-01-24 2016-09-28 奥斯拜客斯制药有限公司 取代的n-芳基吡啶酮
CN106565600A (zh) * 2016-10-28 2017-04-19 湖南大学 一种氘代氮杂芳香化合物及其合成方法
WO2019143153A1 (ko) * 2018-01-17 2019-07-25 주식회사 엘지화학 신규한 화합물 및 이를 이용한 유기 발광 소자

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RAKESH K. SAUNTHWAL ET AL.: "Regioselective Synthesis of C-3 Functionalized Quinolines via Hetero Diels-Alder Cycloaddition of Azadienes with Terminal Alkynes", 《THE JOURNAL OF ORGANIC CHEMISTRY》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894143A (zh) * 2022-10-31 2023-04-04 宁波萃英化学技术有限公司 氘代芳香化合物钯催化的双配体无导向制备方法
CN115894143B (zh) * 2022-10-31 2024-05-28 宁波萃英化学技术有限公司 氘代芳香化合物钯催化的双配体无导向制备方法
CN116425703A (zh) * 2023-03-27 2023-07-14 浙大宁波理工学院 一种饱和环醚类化合物c2位环外甲基氘代的方法
CN116425703B (zh) * 2023-03-27 2024-05-31 浙大宁波理工学院 一种饱和环醚类化合物c2位环外甲基氘代的方法

Similar Documents

Publication Publication Date Title
CN113620866A (zh) 一种氘代含氮杂环化合物的制备方法
CN109232363B (zh) 一种3-硒氰基吲哚化合物的合成方法
CN108117507A (zh) 一种氮杂螺环己二烯酮的合成方法和用途
CN111635300A (zh) 一种以重水为氘源制备氘代安息香的方法
CN106632043A (zh) 一类具抗肿瘤活性的甘草查尔酮a二氢吡唑类衍生物及其合成方法
CN111393438A (zh) 一种6-取代-β-咔啉碱类化合物及衍生物的制备方法、应用
CN108503552B (zh) 一种三氟甲基芳香胺的制备方法
Rajesh et al. Ultrasound-promoted synthesis of novel bipodal and tripodalpiperidin-4-ones and silica chloride mediated conversion to its piperidin-4-ols: Synthesis and structural confinements
CN101348502B (zh) 2-苯并咪唑-1,10-菲咯啉过渡金属配合物及其制备方法与应用
CN113307804B (zh) 含氟吲哚喹啉类化合物的合成方法及其应用
CN105859718B (zh) 一种铜催化的含氮多杂环化合物的制备方法
CN108440384B (zh) 异吲哚酮的三氟甲基羟基化衍生物的制备方法
CN114369085B (zh) 盐酸Asciminib的制备方法
CN113234015B (zh) 一种3-酰基二氢喹啉衍生物及其制备方法和应用
CN114773301A (zh) 一种从末端炔烃与碘叶立德出发合成呋喃类化合物的方法
CN110511233B (zh) 一种噻唑并[2,3-b]噁唑酮类化合物及其制备方法和用途
CN110551065B (zh) 氘代Lucitanib化合物及其用途
CN109180583B (zh) 含杂环砜基及n-氧化物的萘酰亚胺衍生物合成及应用
CN113461681A (zh) 一种铱催化的n-苯基-7氮杂吲哚衍生物及其制备方法
CN106279218A (zh) 具有阳离子骨架的镉化合物及其制备方法
Monte et al. Methods for controlling the regioselection in the reaction of 3‐amino‐5‐benzylthio‐1, 2, 4‐triazole with acetylacetaldehyde dimethyl acetal
CN114773252B (zh) 一种手性氨基吲哚啉衍生物及其制备方法和用途
CN105001163A (zh) 一种四取代咪唑的合成方法
Nelson et al. Six-membered ring phosphites in twist conformations. The methyl and phenyl trans-3', 5'-cyclic phosphites of thymidine
CN113248422B (zh) 一种手性α-氮杂芳烃四级碳中心类化合物、其制备方法及应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20211109