CN109608394A - 氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物 - Google Patents

氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物 Download PDF

Info

Publication number
CN109608394A
CN109608394A CN201811466352.0A CN201811466352A CN109608394A CN 109608394 A CN109608394 A CN 109608394A CN 201811466352 A CN201811466352 A CN 201811466352A CN 109608394 A CN109608394 A CN 109608394A
Authority
CN
China
Prior art keywords
ring
substituted
unsubstituted
formula
compound
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
CN201811466352.0A
Other languages
English (en)
Inventor
王雪强
谭蔚泓
王霞
龙城宇
黄思捷
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.)
Hunan University
Original Assignee
Hunan University
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 Hunan University filed Critical Hunan University
Priority to CN201811466352.0A priority Critical patent/CN109608394A/zh
Publication of CN109608394A publication Critical patent/CN109608394A/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
    • C07D213/72—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
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides 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
    • C07D215/16—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 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
    • 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
    • C07D215/16—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 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供一种式(I)所示氮杂芳胺类化合物的合成方法，包括：在碱存在以及加热的条件下，使式(Ⅱ)所示氮杂芳烃化合物与式(Ⅲ)所示胺类化合物反应，使所述式(Ⅱ)化合物的A环上的u个X取代基分别被式(Ⅲ)化合物中的NR1R2取代，得到式(I)化合物；其中，A为氮杂六元或五元芳环，其为独立单环或与B环稠和；Xn是指A环上至少具有n个X取代基，各个X取代基独立选自：F、Cl、Br、I、CN、C1～6烷氧基或C1～4烷硫基，其中，n为1～5的正整数；所述碱选自tBuOK、tBuONa、tBuONa、KHMDS、NaHMDS、LiHMDS中的一种或多种的混合。本发明提供的合成方法无需使用过渡金属催化剂，操作简便、经济实用、环境友好。此外，本发明还提供由上述方法制备得到的氮杂芳胺类化合物。

Description

氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物
技术领域
本发明属于有机合成化学技术领域，具体涉及氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物。
背景技术
氮杂芳烃化合物是众多药物分子的母核结构，例如，在美国FDA批准的药物分子中，吡啶，嘧啶，喹唑啉、喹啉、吡嗪是最常用的5类六元杂环芳烃化合物。因而，基于杂环芳烃化合物的合成，发展绿色、高效、经济、便于后阶段衍生化的合成方法在药物合成化学中具有重要意义，获得了巨大关注，其中，氮杂芳烃和胺类化合物反应构建分子间碳-氮键得到新的氮杂芳胺类化合物是现代药物化学中最重要的反应之一，并已经取得巨大进展，例如在过去几十年，布赫瓦尔德-哈特维希反应(Buchwald–Hartwig)、乌尔曼反应(Ullmann)和陈-林反应(Chan-Lam)已经发展成为三大相关应用最广的反应技术，这些反应因常面临严重的金属污染等问题，在药物合成中的应用将被受到限制。现代药物化学合成中所应用的反应需满足的条件主要包括：1)商业易得；2)容易操作；3)安全经济，具体涉及基于产品层面的毒性、重金属控制；基于操作层面的操作简便、条件温和、安全可控，基于效益层面的原料易得，适于工业化制备收率等问题的考虑，仅有少量有机反应能被用在药物及其原料或生物活性化合物的合成中。因此发展满足上述条件的实用合成方法充满挑战，也潜藏着巨大的经济价值和社会效益。
发明内容
为了克服上述问题，本发明的目的在于提供一种操作简便、经济实用、环境友好的氮杂芳胺类化合物的合成方法，反应中无需使用过渡金属催化剂即可能实现氮杂芳环上碳-氮键的高效构建。
术语定义
如无特别限定，在本发明中，
所述的不同碳原子数的“杂烷基”“杂环烷基”“杂芳基”“脂杂环”中含有的杂原子为一个或多个，优选地，为1～6个，更优选地，为1～3个，包括但不限于选自氧、氮或硫原子的一或几种，当所述杂原子为多个时，所述的多个杂原子相同或不同。
所述的取代或未取代的氨基、取代未或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或取代的杂芳基、取代或未取代的烷氧基中所述的取代是指被下列一个或者多个取代基取代：氟、氯、溴、碘、羟基、氧、氨基、伯胺基、仲胺基、亚胺基、硝基、亚硝基、氰基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的环烷基，取代或未取代的杂环烷基，取代或未取代的芳基，取代或未取代的杂芳基；其中，当取代基为氧时，是指氧与相连的碳形成羰基；当取代基为亚胺基时，是指亚胺基与相连的碳形成亚胺；其中，优选取代或未取代的C1～C20烷基、取代或未取代的C1～C20烷氧基、取代或未取代的C3～C20环烷基，取代或未取代的C2～C20杂环烷基，取代或未取代的C6～C20芳基，取代或未取代的C4～C20杂芳基。
为了实现本发明的目的，本发明一方面提供一种式(I)所示氮杂芳胺类化合物的合成方法，包括：在碱存在以及加热的条件下，使式(Ⅱ)所示氮杂芳烃化合物与式(Ⅲ)所示胺类化合物反应，得到式(I)化合物；
其中，A为氮杂六元或五元芳环，其为独立单环或与B环稠和，所述B环为取代或未取代的5-8元的芳环、杂芳环、脂环、脂杂环或其任意组合形成的稠环；
其中，
Xn是指A环上至少具有n个X取代基，各个X取代基独立选自：F、Cl、Br、I、CN、C1～6烷氧基或C1～4烷硫基，其中，n为1～5的正整数；
(NR1R2)u是指A环上具有u个NR1R2取代基，其中，u为小于或等于n的正整数，R1和R2分别独立地为：H、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂芳基，且R1和R2不同时为H，当R1和R2均不为氢时，R1和R2可以相连并与N形成5-8元环；
其中，所述使式(Ⅱ)所示氮杂芳烃化合物与式(Ⅲ)所示胺类化合物反应是指使所述式(Ⅱ)化合物的A环上的u个X取代基分别被式(Ⅲ)化合物中的NR1R2取代；
X(n-u)是指未被NR1R2取代的X取代基；
所述碱选自tBuOK、tBuONa、tBuOLi、KHMDS、NaHMDS、LiHMDS中的一种或多种的混合。
在一些实施例中，A为一氮杂或二氮杂的六元芳环或五元芳环；在一些实施例中，A为吡啶环、哒嗪环、嘧啶环、吡嗪环或咪唑环。
在一些实施例中，n为1或2，各个X取代基独立地为F、Cl、Br、I、CN、甲氧基、乙氧基、丙氧基、正丁氧基或甲硫基。
在一些实施例中，A环上还具有m个Y取代基，各个Y取代基独立选自：三氟甲基、硝基、亚硝基、羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基，其中，m为0～4的整数，优选0或1或2。
值得一提的是，上述Y取代基在本发明反应的特定条件下为非活性取代基。
在一些实施例中，B为杂芳环，且所述杂芳环中的杂原子为O、S、N的至少之一，且当所述杂原子为N时，该N原子在杂芳环中参与共轭的电子为孤对电子。
在一些实施例中，B为取代或未取代的苯环、萘环、蒽环、菲环、吡咯环、呋喃环、噻唑环、吡唑环、恶唑环、异恶唑环、吲哚环、苯并噻唑环、苯并恶唑环、苯并异恶唑环、哌啶环、噻吩环、吗啉环、四氢吡咯环、四氢呋喃环、环己烷、环戊烷、环庚烷或环辛烷。
在一些实施例中，B环上含一个或多个取代基，这些取代基分别独立地选自：F、Cl、Br、I、CN、三氟甲基、硝基、亚硝基、羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基。
在一些实施例中，A环与B环稠和，参与稠和的A环和B环分别独立地为1个或多个，优选1个或2个。
在一些实施例中，所述A环与B环稠和形成喹啉、异喹啉、喹唑啉、喹喔啉、嘌呤、苯并咪唑、蝶啶、吖啶、菲啶、菲啰啉环的稠杂环结构。
在一些实施例中，R1为取代或未取代的芳基或取代或未取代的杂芳基，R2为H、取代或未取代的烷基或取代或未取代的芳基。
在本发明中，所述取代或未取代的氨基中所述的取代是指被下列基团的至少之一进一步取代形成1°氨基、2°氨基：三氟甲基、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基。
在本发明中，所述取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基中所述的取代是指被下列基团的至少之一进一步取代：F、Cl、Br、I、CN、三氟甲基、硝基、亚硝基、三甲基硅基、羟基、氨基、1°氨基、2°氨基、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基。
在一些实施例中，当R1为芳基或杂芳基时，所述芳基或杂芳基的芳环为苯环、萘环、蒽环、菲环、吡咯环、呋喃环、噻吩环、噻唑环、吡唑环、恶唑环、异恶唑环、吲哚环、苯并噻唑环、苯并噻吩环、苯并恶唑环、苯并异恶唑环、喹啉环、异喹啉环、喹唑啉环、喹喔啉环、嘌呤环、苯并咪唑环、蝶啶环、吖啶环、菲啶环、菲啰啉环。
在一些实施例中，R1和R2相连并与它们共同取代的N原子形成哌啶环、吗啉环或四氢吡咯环。
在一些实施例中，所述胺类化合物选自下列结构：
在一些实施例中，所述加热条件下的反应温度为40-150℃；优选60～120℃，进一步优选为80±5℃、85℃、90±5℃、95℃、100±5℃、105℃、110±5℃或120±5℃。
在一些实施例中，所述反应在有机溶剂中或者在无溶剂条件下进行，所述溶剂选自醚类溶剂或芳烃类溶剂或其混合溶剂，在一些实施例中，所述醚类溶剂选自THF、1,4-二氧六环、甲基叔丁基醚中的一种或多种，所述芳烃类溶剂选自苯、甲苯、二甲苯、氯苯、二氯苯中的一种或多种。
在一些实施例中，所述反应操作在干燥条件下进行，所用反应溶剂为无水溶剂，其中，所述无水溶剂水含量≤200ppm，进一步地，所述无水溶剂水含量≤100ppm或≤50ppm。
在一些实施例中，所述碱相对于式(Ⅱ)化合物的投料摩尔比为1.5:2.0～2.5:1.0，优选1.0:1.0～2.0:1.0。
在一些实施例中，式(Ⅲ)化合物与式(Ⅱ)化合物的投料摩尔比为1.0:2.0～2.0:1.0，优选1.0:1.5～1.5:1.0。
在一些实施例中，所述碱预先用所述溶剂溶解后再加入反应体系中。
在一些实施例中，所述反应在干燥空气或惰性气氛下进行，所述惰性气氛包括但不限于氮气、氩气、二氧化氮气充气保护下的气氛。
为了实现本发明的目的，本发明还提供一种由前面所述方法制备得到的式(I)所示氮杂芳胺类化合物。
在一些实施例中，所述氮杂芳胺类化合物选自下列所示结构及其衍生物：
在一些实施例中，所述氮杂芳胺类化合物为选自下列所示结构的化合物、其衍生物、及可用于制备下列所示结构化合物的前体化合物：
本发明的有益效果
本发明提供的氮杂芳胺类化合物的合成方法，在商用易得的碱存在以及常规加热的条件下，即可实现式(Ⅱ)所示氮杂芳烃化合物与式(Ⅲ)所示胺类化合物反应，高手率地得到式(I)化合物，反应中无需使用过渡金属催化剂即可能实现氮杂芳环上C-N键的构建，该方法操作简便、成本经济、方法实用、环境友好；并且本发明提供的氮杂芳胺类化合物的合成方法官能团兼容性强，具有广泛的底物适用性，容易衍生化，适合复杂分子的合成与修饰，特别是过渡金属催化转化，例如偶联；并且能适用大规模制备，合成得到的氮杂芳胺类化合物广泛存在于天然产物、药物以及生物活性化合物中，利用本发明提供的方法，由于断裂化学键的位置不同，引发药物合成方法的改变，为许多药物及其中间体合成和衍生化提供新的方法和途径。
具体实施方式
为了使本发明清楚和易于理解，首先提供本发明实施例涉及英文简写的中文对照，具体如下：
下面具体介绍本发明提供的氮杂芳胺类化合物的合成方法，值得说明的是，以下是说明本发明的实施方案的实施例，不应将这些实施例视为限制性的。如无特别限定，所有物料百分比均以重量计，所有溶剂混合物比例均以体积计。
实施例1(反应条件筛选)
N2氛下，向反应管中依次加入4-甲氧基吡啶2a(0.5mmol)，苯胺3a(0.75mmol)，预先以1.0M浓度溶解于THF的碱(0.75mmol)和溶剂(0.5ml)得到的混合物，加热至T℃,下搅拌反应约16h至原料转化完毕，降至室温，向反应混合物中加入THF(3ml)稀释，硅胶或硅藻土过滤，THF洗涤，粗产物经真空浓缩后进行硅胶柱层析从而得到相应产物1aa。
实施例2(不同氮杂芳烃底物拓展)
N2氛下，向反应管中依次加入2x(0.5mmol),3b(0.75mmol)和预先以1.0M溶解于THF的KHMDS(0.75mmol)得到的混合物，加热至100℃,下搅拌反应约16h至原料转化完毕，降至室温，向反应混合物中加入THF(3ml)稀释，硅胶或硅藻土过滤，THF洗涤，粗产物经真空浓缩后进行硅胶柱层析从而得到相应产物1xb，如下式所示，其中，列出了使用不同2x作原料时分离得到的1xb的收率，例如使用2f’时，产物1f’b的收率为88％。
实施例3(不同胺类底物拓展)
N2氛下，向反应管中依次加入2a或2f(0.5mmol),3y(0.75mmol)和预先以1.0M溶解于THF的KHMDS(0.75mmol)得到的混合物，加热至100℃,下搅拌反应约16h至原料转化完毕，降至室温，向反应混合物中加入THF(3ml)稀释，硅胶或硅藻土过滤，THF洗涤，粗产物经真空浓缩后进行硅胶柱层析从而得到相应产物1ay或1fy。
实施例4(不同氮杂芳烃底物与不同胺类底物拓展)
N2氛下，向反应管中依次加入2x或2f(0.5mmol),3y(0.75mmol)和预先以1.0M溶解于THF的KHMDS(0.75mmol)得到的混合物，加热至100℃,下搅拌反应约16h至原料转化完毕，降至室温，向反应混合物中加入THF(3ml)稀释，硅胶或硅藻土过滤，THF洗涤，粗产物经真空浓缩后进行硅胶柱层析从而得到相应产物1ay或1fy。
实施例5(克级规模反应)
N2氛下，向25ml反应管中依次加入2g(1.58g,10mmol),3b(1.875g,15mmol)和预先以1.0M溶解于THF的KHMDS(15ml,15mmol)得到的混合物，加热至100℃搅拌反应约16h至原料转化完毕，降至室温，向反应混合物中加入THF(30ml)稀释，硅胶过滤，THF洗涤，粗产物经真空浓缩后进行硅胶柱层析从而得到相应产物1gb 1.48g，收率73％。
1f’b:(97.0mg,收率96％)黄色油状液体(层析条件:正己烷/乙酸乙酯(正己烷/EtOAc)＝40/1).1H NMR(400MHz,CDCl3)δ8.24(d,J＝4.9Hz,1H),7.75(d,J＝8.0Hz,1H),7.50(m,J＝7.8Hz,1H),7.03–6.95(m,1H),6.92(s,1H),6.77(t,J＝9.1Hz,3H),2.33(s,3H)ppm.13C NMR(101MHz,CDCl3)δ156.60,153.26,150.87,137.69,134.01,133.97,128.52,128.42,123.15,123.08,121.72,121.70,115.37,115.08,114.88,109.27,21.15ppm.19FNMR(376MHz,CDCl3)δ-134.10ppm.
1bb:(88.9mg,收率88％)黄色油状液体(层析条件:正己烷/EtOAc＝1/1).1HNMR(400MHz,CDCl3)δ8.31(d,J＝5.5Hz,2H),7.19(d,J＝7.8Hz,1H),7.10–6.94(m,1H),6.94–6.83(m,1H),6.81(d,J＝5.3Hz,2H),6.23(s,1H),2.32(s,3H)ppm.13C NMR(101MHz,CDCl3)δ154.55,152.15,150.54,150.24,134.33,134.29,127.46,127.34,125.30,125.23,123.14,116.04,115.85,109.96,21.04ppm.19F NMR(376MHz,CDCl3)δ-131.97ppm.
1jb:(90.3mg,收率89％)白色固体(层析条件:正己烷/EtOAc＝10/1).1HNMR(400MHz,CDCl3)δ8.20(s,1H),8.11(s,1H),7.98(s,1H),7.84(d,J＝7.8Hz,1H),7.16(s,1H),6.97(t,J＝9.6Hz,1H),6.87–6.65(m,1H),2.31(s,3H)ppm.13C NMR(101MHz,CDCl3)δ153.14,152.00,150.74,141.66,135.03,134.16,134.14,133.72,127.21,127.16,123.94,123.90,121.78,116.06,114.97,21.10ppm.19F NMR(376MHz,CDCl3)δ-133.88ppm.
1aa:(83.3mg,收率98％)黄色固体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.18(d,J＝5.2Hz,2H),7.34(t,J＝7.4Hz,2H),7.19(d,J＝7.9Hz,2H),7.02(t,J＝7.5Hz,1H),6.89(d,J＝5.3Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ150.09,150.05,140.47,129.34,122.49,120.02,109.15ppm.
1ac:(74.4mg,收率60％)黄色固体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.20(d,J＝5.1Hz,2H),7.48(d,J＝7.9Hz,2H),7.15(d,J＝7.9Hz,2H),6.90(d,J＝5.1Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ150.18,149.47,140.01,132.06,121.56,113.55,109.51ppm.
1ad:(97.4mg,收率95％)黄色固体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.20(d,J＝5.2Hz,2H),7.36(d,J＝7.9Hz,2H),7.20(d,J＝8.0Hz,2H),6.90(d,J＝5.2Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ150.18,149.61,139.57,129.19,125.79,121.28,109.43ppm.
1ae:(97.0mg,收率97％)黄色固体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.10(d,J＝5.3Hz,2H),7.12(d,J＝8.4Hz,2H),6.94(d,J＝8.4Hz,2H),6.72(d,J＝5.3Hz,2H),3.74(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ155.49,151.28,149.90,133.00,123.26,114.60,108.22,55.22ppm.3
1af:(96.8mg,收率94％)黄色固体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.16(d,J＝5.2Hz,2H),7.32(q,J＝6.9Hz,1H),7.22(t,J＝8.2Hz,2H),6.56(d,J＝5.2Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ158.94,158.89,156.48,156.43,150.90,149.78,126.74,126.64,126.54,116.63,116.37,116.21,112.54,112.49,112.36,112.31,108.71ppm.19F NMR(376MHz,DMSO-d6)δ-118.32ppm.
1ag:(102.8mg,收率91％)黄色固体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,CDCl3)δ8.11(d,J＝5.7Hz,2H),7.31–7.21(m,1H),7.16(d,J＝7.4Hz,2H),6.68(s,1H),6.33(s,1H),2.54(q,J＝7.5Hz,4H),1.12(t,J＝7.6Hz,6H)ppm.13C NMR(101MHz,CDCl3)δ153.66,149.62,142.88,134.65,127.78,126.90,107.93,24.69,14.76ppm.
1ah:(61.8mg,收率60％)黄色固体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.28(d,J＝5.2Hz,2H),7.01(d,J＝5.2Hz,2H),6.90–6.60(m,3H)ppm.13C NMR(101MHz,DMSO-d6)δ164.40,164.25,161.98,161.82,150.41,148.48,143.80,143.67,143.67,110.61,101.47,101.39,101.27,101.19,96.95,96.68,96.42ppm.19F NMR(376MHz,DMSO-d6)δ-109.13ppm.
1ai:(92.7mg,收率87％)红色固体(层析条件：正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.15(d,J＝5.5Hz,2H),7.13(t,J＝8.0Hz,1H),6.88(d,J＝5.1Hz,2H),6.52(d,J＝7.8Hz,1H),6.47(s,1H),6.42(d,J＝8.4Hz,1H),2.88(s,6H)ppm.13C NMR(101MHz,DMSO-d6)δ151.35,150.45,149.96,141.06,129.58,109.18,108.22,107.34,104.34,40.07ppm.
1aj:(86.9mg,收率79％)红色固体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.14(d,J＝5.3Hz,2H),8.01(d,J＝7.8Hz,1H),7.96(d,J＝7.8Hz,1H),7.77(d,J＝8.0Hz,1H),7.62–7.43(m,4H),6.74(d,J＝5.3Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ152.11,149.91,135.94,134.35,128.61,128.30,126.34,126.01,125.91,124.83,122.83,120.19,109.02ppm.
1pa:(79.6mg,收率78％)黄色固体(层析条件：正己烷/EtOAc＝40/1).1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.14(d,J＝2.3Hz,1H),7.62(d,J＝7.8Hz,3H),7.26(t,J＝7.8Hz,2H),6.91(t,J＝7.3Hz,1H),6.85(d,J＝8.9Hz,1H)ppm.13C NMR(101MHz,DMSO-d6)δ154.42,145.13,141.10,137.00,128.59,120.83,119.90,118.14,112.06ppm.
1up:(93.2mg,69％yield)黄色固体(层析条件：正己烷/EtOAc＝10/1).1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.04(d,J＝2.6Hz,1H),7.66(d,J＝1.9Hz,1H),7.61–7.52(m,3H),7.45(t,J＝7.6Hz,2H),7.33(t,J＝7.0Hz,1H),6.67(d,J＝8.8Hz,1H),6.43(s,1H)ppm.13C NMR(101MHz,DMSO-d6)δ154.90,145.73,139.80,138.91,138.52,137.38,128.96,127.05,123.47,120.51,110.15,101.60ppm.1ak:(83.7mg,收率91％)黄色油状液体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,CDCl3)δ8.18(d,J＝5.3Hz,2H),7.50–7.36(m,2H),7.31–7.23(m,1H),7.20(d,J＝7.8Hz,2H),6.61–6.47(m,2H),3.30(s,3H)ppm.13C NMR(101MHz,CDCl3)δ153.73,149.60,129.92,126.61,126.36,108.21,39.33ppm.
1al:(97.0mg,收率98％)黄色油状液体(层析条件：正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝5.5Hz,2H),7.25(d,J＝7.6Hz,2H),7.12(d,J＝7.6Hz,2H),6.53(d,J＝5.7Hz,2H),3.23(s,3H),2.31(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ153.82,149.93,143.74,136.02,130.91,126.75,108.44,39.63,21.04ppm.I
1am:(96.4mg,收率98％)黄色油状液体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝5.5Hz,2H),7.37(d,J＝8.1Hz,1H),7.24(d,J＝7.3Hz,1H),7.14(q,J＝11.0,6.5Hz,3H),6.87(t,J＝7.4Hz,1H),3.96(t,J＝8.4Hz,2H),3.12(t,J＝8.5Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ150.08,148.64,143.98,132.42,127.09,125.39,120.81,110.35,110.03,50.49,27.14ppm.IR(neat,cm-1):702,766,827,997,1510,1640,2250.HRMS(ESI)calculated for C13H12N2:[M+H+]:197.1073,found:197.1072.
1an:(88.2mg,收率84％)黄色油状液体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,CDCl3)δ8.30(d,J＝5.6Hz,2H),7.27(d,J＝7.9Hz,1H),7.18–7.06(m,2H),7.04–6.91(m,3H),3.63(t,J＝6.3Hz,2H),2.72(t,J＝6.4Hz,2H),2.00(p,J＝6.3Hz,2H)ppm.13CNMR(101MHz,CDCl3δ153.50,150.13,140.32,131.11,129.14,126.32,122.66,120.74,112.15,47.73,27.31,24.08ppm.
1fo:(43.3mg,收率42％)黄色油状液体(层析条件:正己烷/EtOAc＝40/1).1H NMR(400MHz,CDCl3)δ8.13(d,J＝4.9Hz,1H),7.37(t,J＝7.8Hz,1H),6.44(dd,J＝15.0,7.6Hz,2H),3.57–3.31(m,4H),1.58(q,J＝7.6Hz,4H),1.36(q,J＝7.3Hz,4H),0.95(t,J＝7.3Hz,6H)ppm.13C NMR(101MHz,CDCl3)δ158.07,148.17,136.93,110.75,105.61,48.50,29.94,20.46,14.15ppm.
1la:(99.2mg,收率82％)黄色固体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.70(s,1H),7.14(t,J＝7.5Hz,2H),6.72(t,J＝7.3Hz,1H),6.52(d,J＝7.9Hz,2H),4.49(s,2H),3.27(s,3H),2.09(d,J＝12.0Hz,6H)ppm.13C NMR(101MHz,DMSO-d6)δ154.52,147.55,146.73,144.72,128.94,127.96,127.70,118.42,114.40,74.98,57.56,15.36,13.08ppm.
1ma:(115.8mg,收率99％)黄色固体(层析条件:正己烷/EtOAc＝1/1).1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.32(d,J＝8.3Hz,1H),7.79(d,J＝8.3Hz,1H),7.64(t,J＝7.5Hz,1H),7.41(q,J＝17.1,7.7Hz,5H),7.13(t,J＝7.0Hz,1H),6.84(s,1H),2.44(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ158.69,148.65,147.70,140.73,129.35,129.15,128.47,123.76,123.47,122.33,121.88,118.41,101.44,25.17ppm.
1fa:(81.6mg,收率96％)黄色固体(层析条件:正己烷/EtOAc＝40/1).1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.14(d,J＝4.7Hz,1H),7.68(d,J＝7.9Hz,2H),7.54(t,J＝7.7Hz,1H),7.25(t,J＝7.4Hz,2H),6.94–6.77(m,2H),6.72(t,J＝5.9Hz,1H)ppm.13C NMR(101MHz,DMSO-d6)δ155.89,147.21,141.72,137.17,128.56,120.30,117.94,114.19,110.64ppm.
1na:(90.2mg,收率98％)黄色油状液体(层析条件:正己烷/EtOAc＝40/1).1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.00(d,J＝5.1Hz,1H),7.65(d,J＝8.2Hz,2H),7.23(t,J＝7.8Hz,2H),6.86(t,J＝7.3Hz,1H),6.64(s,1H),6.58(d,J＝5.1Hz,1H),2.22(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ156.03,147.43,146.93,141.82,128.47,120.13,117.95,115.70,110.44,20.60ppm.
34:(66mg,收率66％)黄色油状液体(层析条件:正己烷/EtOAc＝40/1).1H NMR(400MHz,CDCl3)δ7.86(d,J＝4.9Hz,1H),7.75(d,J＝7.9Hz,2H),7.35(t,J＝7.5Hz,2H),7.07(s,1H),7.01(t,J＝7.3Hz,1H),6.95(d,J＝7.8Hz,1H),6.80–6.64(m,1H),3.88(s,3H)ppm.13C NMR(101MHz,CDCl3)δ146.56,142.34,140.61,138.30,128.92,121.52,118.76,114.63,114.02,55.40ppm.
1qa:(86mg,收率86％)黄色油状液体(层析条件:正己烷/EtOAc＝40/1).1H NMR(400MHz,CDCl3)δ7.41(d,J＝9.8Hz,3H),7.34(t,J＝7.5Hz,2H),7.05(t,J＝7.2Hz,1H),6.48(s,1H),6.41(d,J＝7.8Hz,1H),6.24(d,J＝7.9Hz,1H),3.94(s,3H)ppm.13C NMR(101MHz,CDCl3)δ163.63,154.40,140.73,140.21,129.19,122.33,119.86,100.17,99.84,53.48ppm.
1ra:(88.3mg,收率96％)黄色油状(层析条件:正己烷/EtOAc＝40/1).1H NMR(400MHz,CDCl3)δ7.30(t,J＝7.8Hz,1H),7.23(s,4H),7.01–6.92(m,1H),6.81(s,1H),6.65(d,J＝8.3Hz,1H),6.52(d,J＝7.3Hz,1H),2.37(s,3H)ppm.13C NMR(101MHz,CDCl3)δ157.29,155.57,140.75,138.05,129.25,122.60,120.30,114.37,104.88,24.27ppm.
1sa:(90.4mg,收率69％)黄色固体(层析条件:正己烷/EtOAc＝40/1).1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),9.15(s,1H),8.02(d,J＝5.6Hz,1H),7.73(q,J＝12.1,8.4Hz,4H),7.27(q,J＝27.9,7.3Hz,4H),7.00(t,J＝7.2Hz,1H),6.91(t,J＝7.2Hz,1H),6.23(d,J＝5.6Hz,1H)ppm.13C NMR(101MHz,DMSO-d6)δ160.46,159.54,155.97,140.88,140.05,128.62,128.26,122.04,120.93,119.98,119.13,98.77ppm.
1ta:(82.0mg,收率96％)黄色油状液体(层析条件:正己烷/EtOAc＝40/1).1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.23(s,1H),8.11(s,1H),7.91(d,J＝2.6Hz,1H),7.69(d,J＝8.2Hz,2H),7.30(t,J＝7.7Hz,2H),6.95(t,J＝7.3Hz,1H)ppm.13C NMR(101MHz,DMSO-d6)δ152.31,140.93,140.55,134.93,133.45,128.69,121.33,118.27ppm.
1va:(101.6mg,收率80％)as a黄色固体(层析条件:正己烷/EtOAc＝10/1).1HNMR(400MHz,DMSO-d6)δ9.09(s,1H),8.54–8.35(m,2H),7.90(s,1H),7.57(d,J＝8.7Hz,1H),7.48–7.31(m,4H),7.17(d,J＝7.4Hz,1H),6.91(d,J＝5.0Hz,1H)ppm.13C NMR(101MHz,DMSO-d6)δ189.58,187.23,185.63,177.78,171.53,167.04,165.30,162.52,162.07,161.68,160.29,139.38ppm.
1wa:(103.5mg,收率87％)黄色固体(层析条件:正己烷/EtOAc＝10/1).1H NMR(400MHz,CDCl3)δ8.51(d,J＝5.1Hz,1H),8.06–7.96(m,1H),7.60(d,J＝9.8Hz,1H),7.40(q,J＝7.4Hz,3H),7.27(d,J＝7.7Hz,2H),7.17(t,J＝7.3Hz,1H),6.98(d,J＝5.1Hz,1H),6.83(s,1H)ppm.13C NMR(101MHz,CDCl3)δ161.33,158.87,150.26,150.23,147.53,147.48,146.21,139.86,132.56,132.47,129.84,124.82,122.73,120.53,120.45,119.54,119.29,104.36,104.12,102.83ppm.19F NMR(376MHz,CDCl3)δ-113.99ppm.
1a’a:(134.1mg,收率90％)黄色固体(层析条件:正己烷/EtOAc＝10/1).1H NMR(400MHz,CDCl3)δ8.55(d,J＝5.3Hz,1H),8.13(d,J＝2.0Hz,1H),7.90(d,J＝9.0Hz,1H),7.73(dd,J＝9.0,2.0Hz,1H),7.42(t,J＝7.8Hz,2H),7.29(d,J＝7.6Hz,2H),7.21(t,J＝7.4Hz,1H),6.98(d,J＝5.3Hz,1H),6.76(s,1H)ppm.13C NMR(101MHz,CDCl3)δ151.22,147.70,147.15,139.62,132.86,131.72,129.86,125.03,122.92,122.84,121.17,119.19,102.89ppm.
1b’a:(116.6mg,收率81％)as黄色固体(层析条件:正己烷/EtOAc＝10/1).1H NMR(400MHz,CDCl3)δ8.18(d,J＝8.5Hz,1H),8.00(d,J＝8.4Hz,1H),7.79(t,J＝8.1Hz,1H),7.63(t,J＝7.4Hz,1H),7.50(t,J＝7.8Hz,2H),7.36(d,J＝7.6Hz,2H),7.33–7.28(m,1H),7.26(s,1H),6.98(s,1H)ppm.13C NMR(101MHz,CDCl3)δ149.61,149.04,148.71,148.28,138.90,130.87,130.62,130.11,127.14,125.84,123.48,123.23,120.49,119.67,119.63,97.41ppm.
1c’a:(111.0mg,收率79％)红色固体(层析条件:正己烷/EtOAc＝2/1).1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.01(s,1H),7.61(d,J＝8.0Hz,2H),7.32(t,J＝7.6Hz,2H),7.20(d,J＝18.6Hz,2H),7.08(d,J＝7.5Hz,1H),3.87(d,J＝19.4Hz,6H)ppm.13C NMR(101MHz,CDCl3)δ156.85,154.77,153.72,149.46,147.44,138.71,129.05,124.47,122.39,109.32,107.64,100.14,56.23ppm.
1d’q:(126.2mg,收率99％)黄色固体(层析条件:正己烷/EtOAc＝6/1).1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.51(d,J＝8.3Hz,1H).8.64(s,1H),8.09(s,1H),7.81(q,J＝15.9,7.9Hz,3H),7.61(t,J＝7.3Hz,1H),7.38(t,J＝8.1Hz,1H),7.13(d,J＝7.8Hz,1H)ppm.13C NMR(101MHz,DMSO-d6)δ157.68,154.33,149.73,140.87,133.28,132.90,130.13,127.91,126.56,123.27,123.00,121.56,120.46,115.24ppm.9
1fr:(71.4mg,收率51％)黄色固体(层析条件:正己烷/EtOAc＝8/1).1H NMR(400MHz,CDCl3)δ8.92(s,1H),8.22(d,J＝4.4Hz,1H),7.55(t,J＝7.8Hz,1H),7.48(d,J＝7.7Hz,2H),7.28(t,J＝7.7Hz,2H),7.08(t,J＝7.3Hz,1H),6.78(t,J＝5.9Hz,1H),6.46(d,J＝8.4Hz,1H),5.52(d,J＝13.2Hz,1H),5.38(d,J＝13.3Hz,1H),5.13(s,1H),2.27(s,3H)ppm.13C NMR(101MHz,CDCl3)δ168.83,166.37,155.87,148.35,138.36,137.37,129.08,124.73,120.03,115.24,107.90,78.30,73.00,17.93ppm.
1fs:(183.4mg,收率83％)黄色油状液体(层析条件:正己烷/EtOAc＝40/1).1HNMR(400MHz,CDCl3)δ9.23(s,1H),8.86(d,J＝7.7Hz,1H),8.79(s,1H),8.38(d,J＝4.6Hz,1H),8.10(d,J＝8.2Hz,1H),7.55(t,J＝7.8Hz,2H),7.39(q,J＝7.8,3.8Hz,1H),7.33(d,J＝8.1Hz,1H),6.98(d,J＝8.3Hz,1H),6.80(t,J＝5.9Hz,1H)ppm.13C NMR(101MHz,CDCl3)δ155.36,147.84,147.41,138.59,137.30,137.26,136.34,128.37,127.71,121.40,118.16,115.24,112.97,111.82ppm.
1e’t:(144.5mg,收率89％)黄色固体(层析条件：正己烷/EtOAc＝1/1).1H NMR(400MHz,CDCl3)δ8.60(s,1H),8.40(d,J＝5.2Hz,1H),8.03–7.95(m,2H),7.88(s,1H),7.43(d,J＝5.3Hz,3H),7.27(d,J＝9.6Hz,2H),7.19(d,J＝6.3Hz,2H),7.11(d,J＝5.2Hz,1H),6.93(d,J＝8.0Hz,1H),2.31(s,3H)ppm.13C NMR(101MHz,CDCl3)δ164.86,159.99,158.57,139.03,136.69,135.81,135.56,131.18,130.99,130.01,128.82,126.94,125.45,118.19,114.64,112.93,108.85,17.56ppm.
实施例6(药物合成)
2-(2-氯-5,6-二甲基嘧啶-4-基)-1-甲基-1,2,3,4-四氢异喹啉(S1):取250ml的反应管，放入一颗磁子，加入反应物1-甲基-四氢异喹啉(1.47g,10.0mmol)，三乙胺(2.02g,20.0mmol)，溶剂二甲基亚砜(20mL)，最后加入2,4-二氯-5,6-二甲基嘧啶，盖好反应管盖子，在75℃下反应12h。反应结束后，将反应冷却到室温，加入50mL水淬灭反应，然后用乙酸乙酯萃取反应液(50mL x 3)。有机相用无水NaSO4干燥，用旋转蒸发仪将溶剂除去，最后通过层析柱分离产物，层析条件为:CH2Cl2/MeOH(60:1v/v)，产物是黄色固体，产率80％。(Song,W.；Zhang,X.；Li,S.；Xu,W.Chem Biol Dru Des.2015,85,306-314.)1H NMR(400MHz,CDCl3)δ7.19–6.98(m,4H),5.10(q,J＝6.5Hz,1H),4.00(d,J＝13.5Hz,1H),3.48(t,J＝12.8Hz,1H),3.22(t,J＝11.3Hz,1H),2.77(d,J＝16.4Hz,1H),2.35(s,3H),2.17(s,3H),1.55(d,J＝6.7Hz,3H)ppm.13C NMR(101MHz,CDCl3)δ167.29,165.98,138.77,133.42,129.05,126.71,126.37,125.91,112.84,53.79,40.35,28.37,22.37,21.56,15.05ppm.熔点：68.8℃.IR(neat,cm-1):758,910,1110,120,1430,1560.HRMS(ESI)calculated forC16H18ClN3:[M+H+]:288.1262,found:288.1264.
5-(1H-咪唑-1-基)-2-甲基苯胺(S2):取250ml的反应管，放入一颗磁子，加入反应物5-溴-2-甲基苯胺(920mg,5.0mmol)，咪唑(510mg,7.5mmol)，将反应管转移到氮气氛围下，依次加入CuI(190mg,1mmol)，Cs2CO3(3.26g,10mmol)，最后加入溶剂N,N-二甲基甲酰胺(20mL)，在110℃下反应12h。反应结束后，将反应冷却到室温，加入30ml乙酸乙酯，用水洗反应液(30mL x 3)。有机相用无水NaSO4干燥，用旋转蒸发仪将溶剂除去，最后通过层析柱分离产物，层析条件为:正己烷/EtOAc(1:1v/v)，产物是白色固体，产率70％。(Cheng,H.；Yuan,R.；Lü,C.；Lang,J.Inorg.Chem.Com.2014,40,138-142.)1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.19(s,1H),7.14(s,1H),7.08(d,J＝7.8Hz,1H),6.66(dd,J＝10.5,2.6Hz,2H),3.71(s,2H),2.17(s,3H)ppm.13C NMR(101MHz,CDCl3)δ145.93,136.45,135.66,131.49,129.96,121.50,118.44,111.20,107.62,17.00ppm.熔点：157.6℃.IR(neat,cm-1):737,816,1310,1590,1630,2920.HRMS(ESI)calculated for C10H11N3:[M+H+]:174.1026,found:174.1021.
4-(3-((4-氯-7-甲氧基喹唑啉-6-基)氧)丙基)吗啡啉(S3):取100ml的圆底烧瓶，放入一颗磁子，加入反应物7-甲氧基-6-(3-吗啉-4-基丙氧基)喹唑啉-4(3H)-酮(957mg,3mmol)，加入溶剂乙腈(20mL)，将反应管放在冰浴下搅拌，用注射器缓慢滴加三氯氧磷(689g,4.5mmol)，滴加完之后，将反应管放在100℃下反应12h。反应结束后，将反应冷却到室温，加入30ml水淬灭反应，用二氯甲烷萃取反应液(30mL x 3)。有机相用无水NaSO4干燥，用旋转蒸发仪将溶剂除去，最后通过层析柱分离产物，层析条件为:EtOAc/MeOH(50:1v/v)，产物是白色固体，产率80％。(W.；Lüth,A.J.Heterocyclic Chem.2008,45,703-708.)1H NMR(400MHz,CDCl3)δ8.80(s,1H),7.32(s,1H),7.26(s,1H),4.22(t,J＝6.4Hz,2H),4.00(s,3H),3.75–3.59(m,4H),2.55(t,J＝7.0Hz,2H),2.45(s,4H),2.09(p,J＝6.7Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ158.92,157.07,152.42,150.93,148.99,119.53,106.92,103.47,67.60,67.01,56.56,55.35,53.80,26.02ppm.
A)的合成
N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉丙氧基)喹唑啉-4-胺(吉非替尼)：取10ml反应管，放入一颗磁子，反应管中依次加入7-甲氧基-6-(3-吗啉-4-基丙氧基)喹唑啉(0.5mmol),3-氯-4-氟苯胺(0.75mmol)，用油泵将反应管抽充氮气三次，最后在氮气氛围下加入KHMDS溶液(0.75ml,1M in THF)，得到的混合物加热至100℃,搅拌反应约16h至原料转化完毕，降至室温，向反应混合物中加入THF(3ml)稀释，硅胶或硅藻土过滤，THF洗涤，粗产物经真空浓缩后进行硅胶柱层析从而得到目标产物A(137.6mg,70％yield),黄色固体(层析条件:DCM/MeOH＝50/1).172mg,77％yield，黄色固体(层析条件:EA/MeOH＝10/1).1HNMR(400MHz,DMSO-d6)δ9.49(s,1H),8.48(s,1H),8.11(d,J＝6.7Hz,1H),7.85–7.67(m,2H),7.40(t,J＝9.0Hz,1H),7.16(s,1H),4.15(t,J＝6.0Hz,2H),3.92(s,3H),3.57(s,4H),2.46(t,J＝6.9Hz,2H),2.37(s,4H),1.97(p,J＝6.0Hz,2H)ppm.13C NMR(101MHz,DMSO-d6)δ155.96,154.47,154.31,152.53,151.90,148.32,146.94,136.85,136.82,123.40,122.24,122.18,118.84,118.66,116.50,116.29,108.78,107.22,102.49,67.13,66.19,55.80,54.97,53.43,25.90.19F NMR(376MHz,DMSO-d6)δ-123.39.
B)的合成
N-(3-乙炔苯基)-6,7-双(2-甲氧乙氧基)-4-喹啉胺(厄洛替尼):取10ml反应管，放入一颗磁子，向反应管中依次加入4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉(0.5mmol),3-乙炔基苯胺(0.75mmol)，用油泵将反应管抽充氮气三次，最后在氮气氛围下加入KHMDS溶液(0.75ml,1M in THF)，加热至100℃,下搅拌反应约16h至原料转化完毕，降至室温，向反应混合物中加入THF(3ml)稀释，硅胶或硅藻土过滤，THF洗涤，粗产物经真空浓缩后进行硅胶柱层析从而得到产物B(137.6mg,70％yield),黄色固体(层析条件:DCM/MeOH＝50/1).1HNMR(400MHz,CDCl3)δ8.56(s,1H),7.87(s,1H),7.78(s,1H),7.67(d,J＝8.0Hz,1H),7.23(d,J＝8.1Hz,2H),7.17(d,J＝7.5Hz,1H),7.06(s,1H),4.10(q,J＝5.5Hz,4H),3.76–3.61(m,4H),3.33(d,J＝2.3Hz,6H),3.02(s,1H)ppm.13C NMR(101MHz,CDCl3)δ166.64,154.49,153.66,148.78,147.56,139.06,129.02,127.78,125.30,122.82,122.56,109.35,108.63,102.71,77.53,77.36,70.97,70.46,69.03,68.30,59.31,59.24.
C)的合成
4-【3，4-二氢-1-甲基-2(1H)-异喹啉基】-N-(4-氟苯基)-5，6-二甲基-2-嘧啶胺:取10ml反应管，放入一颗磁子，向反应管中依次加入N-(2-氯-5,6-二甲基嘧啶)-1-甲基-四氢异喹啉(0.5mmol),4-氟苯胺(0.75mmol)，用油泵将反应管抽充氮气三次，最后在氮气氛围下加入KHMDS溶液(0.75ml,1M in THF)，加热至100℃,下搅拌反应约16h至原料转化完毕，降至室温，向反应混合物中加入THF(3ml)稀释，硅胶或硅藻土过滤，THF洗涤，粗产物经真空浓缩后进行硅胶柱层析从而得到产物C(109.5mg,61％yield)，黄色油状液体(层析条件：正己烷/EtOAc＝5/1).1H NMR(400MHz,CDCl3)δ7.49(dd,J＝8.8,4.8Hz,2H),7.33(s,1H),7.17(dq,J＝16.0,7.4Hz,4H),6.95(t,J＝8.7Hz,2H),5.14(q,J＝6.7Hz,1H),3.93(dd,J＝13.6,5.5Hz,1H),3.67–3.42(m,1H),3.24–3.03(m,1H),2.74(d,J＝16.2Hz,1H),2.33(s,3H),2.16(s,3H),1.56(d,J＝6.8Hz,3H)ppm.13C NMR(101MHz,CDCl3)δ166.15,165.60,159.01,156.68,156.62,139.79,136.78,134.04,136.76,129.18,126.99,126.28,125.90,120.08,120.04,116.05,115.24,115.23,115.01,106.84,77.48,77.16,76.84,53.60,40.75,28.32,22.45,22.12,14.64ppm.19F NMR(376MHz,CDCl3)δ-122.46ppm.IR(neat,cm-1):758,831,1210,1410,1510,1560.HRMS(ESI)calculated for C22H23FN4:[M+H+]:363.1980,found:363.1984.
实施例7(药物或生物活性分子的衍生化)
N-(1-((3r,5r,7r)金刚烷-1-基)乙基)吡啶-2-胺(金刚乙胺衍生物):(48.5mg,收率：38％)黄色油状液体，(层析条件：正己烷/EtOAc＝20/1).1H NMR(400MHz,CDCl3)δ8.02(d,J＝4.8Hz,1H),7.36(t,J＝7.7Hz,1H),6.53–6.43(m,1H),6.35(d,J＝8.5Hz,1H),4.44(d,J＝9.4Hz,1H),3.41(q,J＝13.4,6.7Hz,1H),1.98(s,3H),1.72–1.60(m,9H),1.53(d,J＝11.9Hz,3H),1.08(d,J＝6.7Hz,3H)ppm.13C NMR(101MHz,CDCl3)δ159.16,148.22,137.46,112.12,106.59,55.73,38.77,37.29,36.48,28.57,14.75ppm.IR(neat,cm-1):768,1450,1510,1600,2850,2900.HRMS(ESI)calculated for C17H24N2:[M+H+]:257.2012,found:257.2011.
N-甲基-N-(3-苯基-3-(4-(三氟甲基)苯氧)丙基)吡啶-2-胺(氟西汀衍生物):(60mg,收率：31％)黄色油状液体，(层析条件：正己烷/EtOAc＝20/1).1H NMR(400MHz,CDCl3)δ8.10(q,J＝5.0,1.9Hz,1H),7.43(d,J＝8.5Hz,2H),7.40–7.30(m,5H),7.26(s,1H),6.90(d,J＝8.5Hz,2H),6.50(q,J＝7.0,5.0Hz,1H),6.46(d,J＝8.6Hz,1H),5.23(q,J＝8.4,4.6Hz,1H),3.92–3.60(m,2H),3.04(s,3H),2.29–2.15(m,2H)ppm.13C NMR(101MHz,CDCl3)δ160.64,158.62,148.07,141.1,137.25,128.91,127.96,126.91,126.87,126.84,126.80,125.84,123.18,123.08,122.76,115.86,111.69,105.81,78.32,47.03,36.75,36.72,29.84 ppm.19F NMR(376 MHz,CDCl3)δ-61.55 ppm.IR(neat,cm-1):692,756,1310,1380,1440,1490,1600,1670,2920.HRMS(ESI)calculated for C22H21F3N2O:[M+H+]:387.1679,found:387.1674.

Claims (10)

1.一种式(I)所示氮杂芳胺类化合物的合成方法，其特征在于，包括：在碱存在以及加热的条件下，使式(Ⅱ)所示氮杂芳烃化合物与式(Ⅲ)所示胺类化合物反应，得到式(I)化合物；
其中，A为氮杂六元或五元芳环，其为独立单环或与B环稠和，所述B环为取代或未取代的5-8元的芳环、杂芳环、脂环、脂杂环或其任意组合形成的稠环；
其中，
Xn是指A环上至少具有n个X取代基，各个X取代基独立选自：F、Cl、Br、I、CN、C1～6烷氧基或C1～4烷硫基，其中，n为1～5的正整数；
(NR1R2)u是指A环上具有u个NR1R2取代基，其中，u为小于或等于n的正整数，R1和R2分别独立地为：H、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂芳基，且R1和R2不同时为H，当R1和R2均不为氢时，R1和R2可以相连并与N形成5-8元环；
其中，所述使式(Ⅱ)所示氮杂芳烃化合物与式(Ⅲ)所示胺类化合物反应是指使所述式(Ⅱ)化合物的A环上的u个X取代基分别被式(Ⅲ)化合物中的NR1R2取代；
X(n-u)是指未被NR1R2取代的X取代基；
所述碱选自tBuOK、tBuONa、tBuOLi、KHMDS、NaHMDS、LiHMDS中的一种或多种的混合。
2.根据权利要求1所述氮杂芳胺类化合物的合成方法，其特征在于，
A为一氮杂或二氮杂的六元芳环或五元芳环；且/或，
A为吡啶环、哒嗪环、嘧啶环、吡嗪环或咪唑环；且/或，
n为1或2，各个X取代基独立地为F、Cl、Br、I、CN、甲氧基、乙氧基、丙氧基、正丁氧基或甲硫基；且/或,
A环上还具有m个Y取代基，各个Y取代基独立选自：三氟甲基、硝基、亚硝基、羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基，其中，m为0～4的整数。
3.根据权利要求1所述氮杂芳胺类化合物的合成方法，其特征在于，
B为杂芳环，且所述杂芳环中的杂原子为O、S、N的至少之一，且当所述杂原子为N时，该N原子在杂芳环中参与共轭的电子为孤对电子；且/或，
B为取代或未取代的苯环、萘环、蒽环、菲环、吡咯环、呋喃环、噻唑环、吡唑环、恶唑环、异恶唑环、吲哚环、苯并噻唑环、苯并恶唑环、苯并异恶唑环、哌啶环、噻吩环、吗啉环、四氢吡咯环、四氢呋喃环、环己烷、环戊烷、环庚烷或环辛烷；且/或，
B环上含一个或多个取代基，所述B环上的一个或多个取代基分别独立地选自：F、Cl、Br、I、CN、三氟甲基、硝基、亚硝基、羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基。
4.根据权利要求1所述氮杂芳胺类化合物的合成方法，其特征在于，
A环与B环稠和，参与稠和的A环和B环分别独立地为1个或多个；且/或,
参与稠和的A环和B环分别独立地为1个或2个；且/或，
所述A环与B环稠和形成喹啉、异喹啉、喹唑啉、喹喔啉、嘌呤、苯并咪唑、蝶啶、吖啶、菲啶、菲啰啉环的稠杂环结构。
5.根据权利要求1所述氮杂芳胺类化合物的合成方法，其特征在于，
R1为取代或未取代的芳基或取代或未取代的杂芳基，R2为H、取代或未取代的烷基或取代或未取代的芳基；且/或，
R1为芳基或杂芳基，所述芳基或杂芳基的芳环为苯环、萘环、蒽环、菲环、吡咯环、呋喃环、噻吩环、噻唑环、吡唑环、恶唑环、异恶唑环、吲哚环、苯并噻唑环、苯并噻吩环、苯并恶唑环、苯并异恶唑环、喹啉环、异喹啉环、喹唑啉环、喹喔啉环、嘌呤环、苯并咪唑环、蝶啶环、吖啶环、菲啶环、菲啰啉环；且/或，
R1和R2相连并与它们共同取代的N原子形成哌啶环、吗啉环或四氢吡咯环。
6.根据权利要求1所述氮杂芳胺类化合物的合成方法，其特征在于，
所述加热条件下的反应温度为40-150℃；且/或，
所述反应在有机溶剂中进行，所述溶剂选自醚类溶剂或芳烃类溶剂或其混合溶剂。
7.根据权利要求1所述氮杂芳胺类化合物的合成方法，其特征在于，
所述反应操作在干燥条件下进行，所用反应溶剂为无水溶剂，其中，所述无水溶剂水含量≤200ppm；且/或，
所述碱相对于式(Ⅱ)化合物的投料摩尔比为1.5:2.0～2.5:1.0；且/或
式(Ⅲ)化合物与式(Ⅱ)化合物的投料摩尔比为1.0:2.0～2.0:1.0；且/或，
所述碱预先用所述溶剂溶解后再加入反应体系中；且/或，
所述反应在惰性气氛下进行。
8.一种如权利要求1至7任一项所述方法制备得到的式(I)所示氮杂芳胺类化合物。
9.根据权利要求8所述的氮杂芳胺类化合物，其特征在于，所述氮杂芳胺类化合物选自下列所示结构的化合物及其衍生物：
10.根据权利要求8所述的氮杂芳胺类化合物，其特征在于，所述氮杂芳胺类化合物为选自下列所示结构的化合物、其衍生物、及可用于制备下列所示结构化合物的前体化合物：
CN201811466352.0A 2018-12-03 2018-12-03 氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物 Pending CN109608394A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811466352.0A CN109608394A (zh) 2018-12-03 2018-12-03 氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811466352.0A CN109608394A (zh) 2018-12-03 2018-12-03 氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物

Publications (1)

Publication Number Publication Date
CN109608394A true CN109608394A (zh) 2019-04-12

Family

ID=66006218

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811466352.0A Pending CN109608394A (zh) 2018-12-03 2018-12-03 氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物

Country Status (1)

Country Link
CN (1) CN109608394A (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110804013A (zh) * 2019-10-09 2020-02-18 南京工业大学 一种邻位二胺类化合物的合成方法
WO2020200209A1 (zh) * 2019-04-02 2020-10-08 成都海创药业有限公司 芳香胺类化合物及其在制备ar和brd4双重抑制剂和调控剂中的用途
US11466000B2 (en) 2019-03-19 2022-10-11 Voronoi Inc. Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017137047A1 (en) * 2016-02-08 2017-08-17 Aaa Chemistry Aps Arylation of aliphatic amines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017137047A1 (en) * 2016-02-08 2017-08-17 Aaa Chemistry Aps Arylation of aliphatic amines

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ACS，STN REGISTRY数据库: "1368257-71-9", 《ACS，STN REGISTRY数据库》 *
ACS，STN REGISTRY数据库: "35488-08-5", 《ACS，STN REGISTRY数据库》 *
ROBERT A. SINGER等: "Practical Amination of Nitropyridones by Silylation", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 *
RYAN P. TRUMP等: "Design and Synthesis of an Array of Selective Androgen Receptor Modulators", 《JOURNAL OF COMBINATORIAL CHEMISTRY》 *
SILVIA ROSCALES等: "Synthesis of Di(hetero)arylamines from Nitrosoarenes and Boronic Acids: A General, Mild, and Transition-Metal-Free Coupling", 《ORGANIC LETTERS》 *
李立冬，等: "C-N偶联反应制备芳胺研究进展", 《化学研究与应用》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11466000B2 (en) 2019-03-19 2022-10-11 Voronoi Inc. Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component
WO2020200209A1 (zh) * 2019-04-02 2020-10-08 成都海创药业有限公司 芳香胺类化合物及其在制备ar和brd4双重抑制剂和调控剂中的用途
CN110804013A (zh) * 2019-10-09 2020-02-18 南京工业大学 一种邻位二胺类化合物的合成方法
CN110804013B (zh) * 2019-10-09 2024-04-05 南京工业大学 一种邻位二胺类化合物的合成方法

Similar Documents

Publication Publication Date Title
CN111675662B (zh) 一种2-三氟甲基取代的喹唑啉酮化合物的制备方法
CN109608394A (zh) 氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物
CN105294536B (zh) 一种制备3-亚氨基异吲哚啉酮类化合物的方法
CN114105978A (zh) 一种氧化吲哚类化合物及其制备方法和应用
CN112239424B (zh) 一种马兜铃生物碱及其中间体的制备方法
CN109651333B (zh) 一种具有抗肿瘤活性的2-吲哚-3-基-喹啉类化合物及其制备方法和应用
CN116554262A (zh) 制备细胞毒性苯二氮䓬衍生物的方法
CN112480015B (zh) 一种多组分一锅法合成2-三氟甲基取代的喹唑啉酮的方法
CN110396094B (zh) 一种喹啉酮并杂芳环类化合物及其衍生物和合成方法
CN109651271B (zh) 一种3-叔丁基-n-甲基喹喔啉-2(1h)-酮化合物的合成方法
CN116947854A (zh) 一种咪唑并[2,1-a]异喹啉类化合物的制备方法
CN109384784B (zh) 磺酰胺类衍生物、其制备方法及其在医药上的用途
CN113845509B (zh) 吲哚基取代螺[环丁烷-1，1′-茚]类化合物的合成方法
CN115557900A (zh) 一种3-取代哒嗪衍生物的合成方法
CN113004215B (zh) 一种2,4,5-三取代噁唑类化合物的合成方法
CN115260205A (zh) 双芘基掺杂的扩展卟啉、其双钯金属络合物、其制备方法及其应用
CN115054599A (zh) 2-氨基吲哚类化合物在抗肿瘤药物中的应用
CN110563649B (zh) 一种2-甲基氮杂环类化合物的高选择氘代方法
CN111808072B (zh) 一种3-甲酰基吲哚衍生物的合成方法
CN108503578B (zh) 一种茚并-[1,2-b]吲哚-10(5H)-酮类化合物的合成方法
CN115785110B (zh) 吲哚啉并四氢吡喃类化合物、其制备方法及用途
CN116003312B (zh) 一种制备间位三氟甲硫基、二氟甲硫基或三氟甲基取代的吡啶化合物的方法
CN110746336B (zh) 一种n-甲基-2-氰基-3-芳基吡咯化合物的绿色制备方法
CN114315734B (zh) 一种苯并咪唑衍生物及其合成方法
CN113683563B (zh) 一种多取代3-磺酰胺喹啉化合物的合成方法

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

Application publication date: 20190412

RJ01 Rejection of invention patent application after publication