CN112645871A - N-cf2h-1,2-二氢吡啶-2-酮化合物的合成方法 - Google Patents

N-cf2h-1,2-二氢吡啶-2-酮化合物的合成方法 Download PDF

Info

Publication number
CN112645871A
CN112645871A CN202011637271.XA CN202011637271A CN112645871A CN 112645871 A CN112645871 A CN 112645871A CN 202011637271 A CN202011637271 A CN 202011637271A CN 112645871 A CN112645871 A CN 112645871A
Authority
CN
China
Prior art keywords
compound
dihydropyridine
dihydropyridin
synthesizing
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.)
Granted
Application number
CN202011637271.XA
Other languages
English (en)
Other versions
CN112645871B (zh
Inventor
王光伟
周森
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.)
Tianjin University
Original Assignee
Tianjin 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 Tianjin University filed Critical Tianjin University
Priority to CN202011637271.XA priority Critical patent/CN112645871B/zh
Publication of CN112645871A publication Critical patent/CN112645871A/zh
Application granted granted Critical
Publication of CN112645871B publication Critical patent/CN112645871B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • 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
    • 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
    • C07D215/16—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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • 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
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明属于有机合成领域，具体涉及一种N‑CF2H‑1,2‑二氢吡啶‑2‑酮化合物的合成方法，采用下式(III)进行；
Figure DDA0002878849090000011
其中，化合物1的母体骨架为未活化的吡啶、喹啉或者异喹啉，R为任何取代基。本发明实现了一种新的合成N‑CF2H‑1,2‑二氢吡啶‑2‑酮类化合物的方法。该方法对底物适用性广，收率高，不需要对吡啶类化合物进行预活化，极大地促进了N‑CF2H‑1,2‑二氢吡啶‑2‑酮类化合物的规模化生产和应用。

Description

N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法
技术领域
本发明属于有机合成领域，具体涉及一种N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法。
背景技术
近年来，在化合物中引入含氟官能团一直是合成化学的研究热点之一。有研究发现，在药物分子中引入含氟官能团能够有效改善药物的代谢稳定性，亲脂性，膜通透性等。在含氟官能团中，二氟甲基(CF2H)受到了极大关注，这是因为它是羟甲基结构(CH2OH)的电子等排体。除此之外，它还可以通过微弱的氢键作用作为氢供体。因此通过引入二氟甲基官能团是改善生物活性分子以及药物分子特性的有利手段。目前有研究表明N-CF2H-1,2-二氢吡啶-2-酮是一种新的提高靶受体结合亲和力的重要结构单元，而且N-CF2H-1,2-二氢吡啶-2-酮结构单元也是双重COX/5-LOX抑制剂的药效基团，例如塞来昔布类似物，以及1,2-二芳基乙炔类5-LOX抑制剂等。
尽管N-CF2H-1,2-二氢吡啶-2-酮结构单元在药物分子等方面有很重要的应用前景，但是目前关于N-CF2H-1,2-二氢吡啶-2-酮化合物的合成却很少被报道。例如，2006年Ando课题组报道了从2-乙酰胺基吡啶两步合成N-CF2H-1,2-二氢吡啶-2-酮化合物(如式(I)示出)。该反应中吡啶类化合物在ClCF2CO2Na做氟源，18-crown-6作相转移催化剂的条件下，在乙腈中回流反应完成N-二氟甲基化，然后经过水解得到目标产物。2010年Knaus课题组也报道了该类反应(如式(II)示出)。2-氯吡啶类化合物在FSO2CF2CO2H做氟源，在碳酸氢钠做碱的条件下，在乙腈中回流反应得到目标产物。从上述两个反应中，我们可以发现，吡啶类化合物在吡啶环的邻位均需要预活化，Ando课题组所用的吡啶类化合物，在吡啶环的邻位需要构建酰胺结构，而Knaus课题组则需要利用2-氯吡啶类化合物作为原料进行反应，极大地限制了这些方法的大规模应用。因此，发展更实用、更高效的合成N-CF2-1,2-二氢吡啶-2-酮骨架的方法仍然是很重要和迫切的。
Figure BDA0002878849080000011
Figure BDA0002878849080000021
发明内容
本发明的目的在于提供一种N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法。
为实现上述目的，本发明采用的技术方案为：
一种N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,采用下式(III)进行；
Figure BDA0002878849080000022
其中，化合物1的母体骨架为未活化的吡啶、喹啉或者异喹啉，R为任何取代基。
所述的R为H,吸电子基团，或者供电子基团。
所述的R为吸电子基团。
所述的吸电子基团为酰基，醛基，酯基，酰胺基，氰基，磺酰基，含氟烷基，或者卤素中的一种或者多种。
化合物1的母体骨架为未活化的吡啶时，R取代基的位置为2位，3位，4位，5位和6位；化合物1的母体骨架为未活化喹啉时，R取代基的位置可以是任意位置。
化合物1的母体骨架为未活化的吡啶时，R取代基的位置为3位或者5位；化合物1的母体骨架为未活化喹啉时，R取代基的位置为4位、5位、或者6位。
具体的包括下述步骤：化合物1作为原料，加入二氟试剂、碱，以及氧化剂,在溶剂中反应生成目标产物。
化合物1：二氟试剂：碱：氧化剂的摩尔比为1：(1.5-2.5)：(1.2-1.5)：(2-4)。
化合物1：二氟试剂：碱：氧化剂的摩尔比为1：2：1.5：2。
所述的二氟试剂为BrCF2CO2Et,BrCF2CO2H,BrCF2CO2Na,ClCF2CO2Na,BrCF2P(O)(OEt)2,FSO2CF2CO2H中的一种。
所述的碱为1,8-二氮杂二环十一碳-7-烯(DBU),Et3N,iPrNEt2,NaOH,CH3ONa,tBuONa,K2CO3,Cs2CO3,Na2CO3中的一种。
所述的氧化剂为过氧化叔丁醇(TBHP),H2O2,二叔丁基过氧化物(DTBP),间氯过氧苯甲酸(MCPBA)，过氧乙酸中的一种。
所述的溶剂为MeCN,1,2-二氯乙烷(DCE),N,N-二甲基甲酰胺(DMF),二甲基亚砜(DMSO),Dioxane,Toluene,四氢呋喃(THF)中的一种。
与现有技术相比，本发明的有益效果是：
本发明实现了一种新的合成N-CF2H-1,2-二氢吡啶-2-酮类化合物的方法。该方法对底物适用性广，收率高，不需要对吡啶类化合物进行预活化，极大地促进了N-CF2H-1,2-二氢吡啶-2-酮类化合物的规模化生产和应用。
具体实施方式
为了使本技术领域的技术人员更好地理解本发明的技术方案，下面结合最佳实施例对本发明作进一步的详细说明。
实施例1：5-乙酰基-N-CF2H-1,2-二氢吡啶-2-酮化合物(3a)的合成：(BrCF2CO2Et作为二氟试剂用于吡啶酮3a的合成)。
Figure BDA0002878849080000031
取磁子于25mL Schlenk瓶中，在双排管上用氩气置换三次，然后加入MeCN(3.0mL),接下来加入3-乙酰基吡啶(1a,110μL,1.0mmol,1.0equiv)。搅拌条件下，加入BrCF2CO2Et(2a,256μL,2.0mmol,2.0equiv),然后加入DBU(224μL,1.5mmol,1.5equiv),最后加入70％过氧叔丁醇水溶液(290μL,2.0mmol,2.0equiv),于80℃下回流12小时。待反应完全后，将反应液转移至圆底烧瓶中，旋蒸除去乙腈溶剂，然后加入5mL水，用10mL乙酸乙酯萃取，水相用乙酸乙酯(5mL x 3)萃取三次，合并有机相，有机相分别用10mL水，饱和氯化钠水溶液(10mL x 2)洗涤，然后用无水MgSO4干燥，过滤，将过滤后的有机相旋蒸，旋蒸后的浓缩液转移至硅胶柱中，通过柱层析(PE/EA＝3/1)得到纯产物148.8mg(黄色液体)。产率:81％yield。1H NMR(400MHz,CDCl3)δ8.17(d,J＝2.5Hz,1H),7.90(ddd,J＝9.8Hz,2.6Hz,1.3Hz,1H),7.63(t,J＝60.0Hz,1H),6.53(d,J＝10.1Hz,1H),2.45(s,3H).13C NMR(101MHz,CDCl3)δ192.5,160.4,138.8,134.5(t,J＝3.3Hz),121.3,119.1,107.5(t,J＝254.0Hz),25.6.19FNMR(376MHz,CDCl3)δ-103.66(d,2JFH＝59.9Hz).HRMS(ESI):m/z calcd.for C8H8F2NO2 +[M+H+]:188.0518,found:188.0521。
实施例2：5-乙酰基-N-CF2H-1,2-二氢吡啶-2-酮化合物(3a)的合成：(ClCF2CO2Na作为二氟试剂用于吡啶酮3a的合成)。
Figure BDA0002878849080000041
取磁子于25mL Schlenk瓶中，加入ClCF2CO2Na(2b,305mg,2.0mmol,2.0equiv),在双排管上用氩气置换三次，然后加入MeCN(3.0mL),接下来加入3-乙酰基吡啶(1a,110μL,1.0mmol,1.0equiv)。搅拌条件下加入DBU(224μL,1.5mmol,1.5equiv),最后加入70％过氧叔丁醇水溶液(290μL,2.0mmol,2.0equiv),于80℃下回流12小时。待反应完全后，将反应液转移至圆底烧瓶中，旋蒸除去乙腈溶剂，然后加入5mL水，用10mL乙酸乙酯萃取，水相用乙酸乙酯(5mL x 3)萃取三次，合并有机相，有机相分别用10mL水，饱和氯化钠水溶液(10mL x2)洗涤，然后用无水MgSO4干燥，过滤，将过滤后的有机相旋蒸，旋蒸后的浓缩液转移至硅胶柱中，通过柱层析(PE/EA＝3/1)得到纯产物145.2mg(黄色液体)。产率:78％yield。
实施例3：5-乙酰基-N-CF2H-1,2-二氢吡啶-2-酮化合物(3a)的合成：(BrCF2P(O)(OEt)2作为二氟试剂用于吡啶酮3a的合成)。
Figure BDA0002878849080000042
取磁子于25mL Schlenk瓶中，在双排管上用氩气置换三次，然后加入MeCN(3.0mL),接下来加入3-乙酰基吡啶(1a,110μL,1.0mmol,1.0equiv)。搅拌条件下加入BrCF2P(O)(OEt)2(2c,356μL,2.0mmol,2.0equiv),然后加入DBU(224μL,1.5mmol,1.5equiv),最后加入70％过氧叔丁醇水溶液(290μL,2.0mmol,2.0equiv),于80℃下回流12小时。待反应完全后，将反应液转移至圆底烧瓶中，旋蒸除去乙腈溶剂，然后加入5mL水，用10mL乙酸乙酯萃取，水相用乙酸乙酯(5mL x 3)萃取三次，合并有机相，有机相分别用10mL水，饱和氯化钠水溶液(10mL x 2)洗涤，然后用无水MgSO4干燥，过滤，将过滤后的有机相旋蒸，旋蒸后的浓缩液转移至硅胶柱中，通过柱层析(PE/EA＝3/1)得到纯产物134.1mg(黄色液体)。产率:72％yield。
实施例4：5-乙酰基-N-CF2H-1,2-二氢吡啶-2-酮化合物(3a)的合成：(H2O2作氧化剂用于吡啶酮3a的合成)。
Figure BDA0002878849080000051
取磁子于25mL Schlenk瓶中，在双排管上用氩气置换三次，然后加入MeCN(3.0mL),接下来加入3-乙酰基吡啶(1a,110μL,1.0mmol,1.0equiv)。搅拌条件下，加入BrCF2CO2Et(2a,256μL,2.0mmol,2.0equiv),然后加入DBU(224μL,1.5mmol,1.5equiv),最后加入35％过氧化氢水溶液(172μL,2.0mmol,2.0equiv),于80℃下回流12小时。待反应完全后，将反应液转移至圆底烧瓶中，旋蒸除去乙腈溶剂，然后加入5mL水，用10mL乙酸乙酯萃取，水相用乙酸乙酯(5mL x 3)萃取三次，合并有机相，有机相分别用10mL水，饱和氯化钠水溶液(10mL x 2)洗涤，然后用无水MgSO4干燥，过滤，将过滤后的有机相旋蒸，旋蒸后的浓缩液转移至硅胶柱中，通过柱层析(PE/EA＝3/1)得到纯产物104.5mg(黄色液体)。产率:29％yield。
实施例5：5-乙酰基-N-CF2H-1,2-二氢吡啶-2-酮化合物(3a)的合成(Et3N作碱用于吡啶酮3a的合成)
Figure BDA0002878849080000052
取磁子于25mL Schlenk瓶中，在双排管上用氩气置换三次，然后加入MeCN(3.0mL),接下来加入3-乙酰基吡啶(1a,110μL,1.0mmol,1.0equiv)。搅拌条件下，加入BrCF2CO2Et(2a,256μL,2.0mmol,2.0equiv),然后加入Et3N(278μL,1.5mmol,1.5equiv),最后加入70％过氧叔丁醇水溶液(290μL,2.0mmol,2.0equiv),于80℃下回流12小时。待反应完全后，将反应液转移至圆底烧瓶中，旋蒸除去乙腈溶剂，然后加入5mL水，用10mL乙酸乙酯萃取，水相用乙酸乙酯(5mL x 3)萃取三次，合并有机相，有机相分别用10mL水，饱和氯化钠水溶液(10mL x 2)洗涤，然后用无水MgSO4干燥，过滤，将过滤后的有机相旋蒸，旋蒸后的浓缩液转移至硅胶柱中，通过柱层析(PE/EA＝3/1)得到纯产物143.6mg(黄色液体)。产率:77％yield。
实施例6：5-乙酰基-N-CF2H-1,2-二氢吡啶-2-酮化合物(3a)的合成(K2CO3作碱用于吡啶酮3a的合成)
Figure BDA0002878849080000061
取磁子于25mL Schlenk瓶中，加入K2CO3(207mg,1.5mmol,1.5equiv),在双排管上用氩气置换三次，然后加入MeCN(3.0mL),接下来加入3-乙酰基吡啶(1a,110μL,1.0mmol,1.0equiv)。搅拌条件下加入BrCF2CO2Et(2a,256μL,2.0mmol,2.0equiv),最后加入70％过氧叔丁醇水溶液(290μL,2.0mmol,2.0equiv),于80℃下回流12小时。待反应完全后，将反应液转移至圆底烧瓶中，旋蒸除去乙腈溶剂，然后加入5mL水，用10mL乙酸乙酯萃取，水相用乙酸乙酯(5mL x 3)萃取三次，合并有机相，有机相分别用10mL水，饱和氯化钠水溶液(10mL x2)洗涤，然后用无水MgSO4干燥，过滤，将过滤后的有机相旋蒸，旋蒸后的浓缩液转移至硅胶柱中，通过柱层析(PE/EA＝3/1)得到纯产物55.4mg(黄色液体)。产率:30％yield。
实施例7：5-乙酰基-N-CF2H-1,2-二氢吡啶-2-酮化合物(3a)的合成(DCE作溶剂用于吡啶酮3a的合成)
Figure BDA0002878849080000071
取磁子于25mL Schlenk瓶中，在双排管上用氩气置换三次，然后加入DCE(3.0mL),接下来加入3-乙酰基吡啶(1a,110μL,1.0mmol,1.0equiv)。搅拌条件下，加入BrCF2CO2Et(2a,256μL,2.0mmol,2.0equiv),然后加入DBU(224μL,1.5mmol,1.5equiv),最后加入70％过氧叔丁醇水溶液(290μL,2.0mmol,2.0equiv),于80℃下回流12小时。待反应完全后，将反应液转移至圆底烧瓶中，旋蒸除去乙腈溶剂，然后加入5mL水，用10mL乙酸乙酯萃取，水相用乙酸乙酯(5mL x 3)萃取三次，合并有机相，有机相分别用10mL水，饱和氯化钠水溶液(10mLx 2)洗涤，然后用无水MgSO4干燥，过滤，将过滤后的有机相旋蒸，旋蒸后的浓缩液转移至硅胶柱中，通过柱层析(PE/EA＝3/1)得到纯产物153.2mg(黄色液体)。产率:82％yield。
实施例8：5-乙酰基-N-CF2H-1,2-二氢吡啶-2-酮化合物(3a)的合成(DMF作溶剂用于吡啶酮3a的合成)
Figure BDA0002878849080000072
取磁子于25mL Schlenk瓶中，在双排管上用氩气置换三次，然后加入DMF(3.0mL),接下来加入3-乙酰基吡啶(1a,110μL,1.0mmol,1equiv)。搅拌条件下，加入BrCF2CO2Et(2a,256μL,2.0mmol,2.0equiv),然后加入DBU(224μL,1.5mmol,1.5equiv),最后加入70％过氧叔丁醇水溶液(290μL,2.0mmol,2.0equiv),于80℃下回流12小时。待反应完全后，将反应液转移至圆底烧瓶中，旋蒸除去乙腈溶剂，然后加入5mL水，用10mL乙酸乙酯萃取，水相用乙酸乙酯(5mL x 3)萃取三次，合并有机相，有机相分别用10mL水，饱和氯化钠水溶液(10mL x2)洗涤，然后用无水MgSO4干燥，过滤，将过滤后的有机相旋蒸，旋蒸后的浓缩液转移至硅胶柱中，通过柱层析(PE/EA＝3/1)得到纯产物136.1mg(黄色液体)。产率:73％yield。
实施例9：5-酰胺基-N-CF2H-1,2-二氢吡啶-2-酮化合物(3b)的合成
Figure BDA0002878849080000081
该反应步骤和实施例1中反应步骤相类似,通过柱层析(PE/EA＝3/1)得到纯产物199.3.8mg(黄色液体)。产率:78％yield。1H NMR(400MHz,CDCl3)δ7.66(d,J＝2.6Hz,1H),7.63(t,J＝59.8Hz,1H),7.42(dd,J＝9.8Hz,2.5Hz,1H),6.52(d,J＝9.6Hz,1H),3.63-3.37(m,4H),1.76-1.63(m,2H),1.62-1.45(m,4H).13C NMR(101MHz,CDCl3)δ165.6,160.3,140.3,130.7(t,J＝3.6Hz),121.2,116.3,107.4(t,J＝253.1Hz),26.1,24.4.19F NMR(376MHz,CDCl3)δ-103.62(d,2JFH＝60.2Hz,2F).HRMS(ESI):m/z calcd.for C12H15F2N2O2 +[M+H+]:257.1096,found:257.1106.
实施例10：5-Ts-N-CF2H-1,2-二氢吡啶-2-酮化合物(3c)的合成
Figure BDA0002878849080000082
该反应步骤和实施例1中反应步骤相类似,通过柱层析(PE/EA＝3/1)得到纯产物175.5mg(淡黄色液体)。产率:59％yield。1H NMR(400MHz,CDCl3)δ8.29(d,J＝2.6Hz,1H),7.79(d,J＝8.4Hz,2H),7.59(t,J＝59.8Hz,1H),7.57(dd,J＝9.9Hz,2.6Hz,1H),7.35(d,J＝8.1Hz,2H),6.55(d,J＝9.9Hz,1H),2.42(s,3H).13C NMR(101MHz,CDCl3)δ159.6,145.4,137.3,137.2,133.8(t,J＝3.9Hz),130.5,127.8,123.3,122.5,107.4(t,J＝255.5Hz),21.7.19F NMR(376MHz,CDCl3)δ-103.61(d,2JFH＝59.9Hz,2F).HRMS(ESI):m/z calcd.forC13H12F2NO3S+[M+H+]:300.0500,found:300.0507.
实施例11：6-Br-N-CF2H-1,2-二氢喹啉-2-酮类化合物(3d)的合成
Figure BDA0002878849080000083
该反应步骤和实施例1中反应步骤相类似,通过柱层析(PE/EA＝3/1)得到纯产物144.3mg(黄色固体)。产率:53％yield。m.p.124-127℃.1H NMR(600MHz,CDCl3)δ8.08(t,J＝58.5Hz,1H),7.67(dt,J＝9.1Hz,2.9Hz,1H),7.65(d,J＝2.3Hz,1H),7.60(dd,J＝9.1Hz,2.3Hz,1H),7.58(d,J＝9.7Hz,1H),6.59(d,J＝9.6Hz,1H).13C NMR(151MHz,CDCl3)δ161.2,140.7,134.0,133.7,131.4,122.3,122.1,118.1(t,J＝6.6Hz),117.0,109.8(t,J＝250.5Hz).19F NMR(565MHz,CDCl3)δ-106.13(d,2JFH＝58.5Hz,2F).HRMS(ESI):m/zcalcd.for C10H7BrF2NO+[M+H+]:273.9674,found:273.9677.
实施例12：5-酯基-N-CF2H-1,2-二氢吡啶-2-酮类化合物(3e)的合成
Figure BDA0002878849080000091
该反应步骤和实施例1中反应步骤相类似,通过柱层析(PE/EA＝3/1)得到纯产物316.8mg(黄色液体)。产率:72％yield。1H NMR(400MHz,CDCl3)δ8.47(d,J＝2.5Hz,1H),7.97(dd,J＝9.8Hz,2.5Hz,1H),7.67(t,J＝59.9Hz,1H),7.30(d,J＝8.5Hz,1H),6.92(dd,J＝8.4Hz,2.7Hz,1H),6.90-6.85(m,1H),6.59(d,J＝9.8Hz,1H),3.02-2.81(m,2H),2.48(dd,J＝18.7Hz,8.6Hz,1H),2.43-2.32(m,1H),2.34-2.21(m,1H),2.19-1.86(m,4H),1.72-1.54(m,2H),1.53-1.38(m,2H),0.89(s,3H).13C NMR(101MHz,CDCl3)δ162.2,160.4,148.1,139.9,138.3,137.9,136.0(t,J＝3.4Hz),126.6,121.4,121.1,118.6,111.0,107.4(t,J＝254.5Hz),50.4,47.9,44.1,37.9,35.8,31.5,29.4,26.3,25.7,21.6,13.8.19F NMR(376MHz,CDCl3)δ-103.57(d,2JFH＝59.9Hz,2F).HRMS(ESI):m/z calcd.for C25H26F2NO4 +[M+H+]:442.1824,found:442.1825.
其他N-CF2H-1,2-二氢吡啶-2-酮类化合物的制备方法同实施例1类似，产物及其收率如表1示出。
表1
Figure BDA0002878849080000101
有多种实施产物可以看出本发明实现了一种新的合成N-CF2H-1,2-二氢吡啶-2-酮类化合物的方法。该方法对底物适用性广，收率高，不需要对吡啶类化合物进行预活化，极大地促进了N-CF2H-1,2-二氢吡啶-2-酮类化合物的规模化生产和应用。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

1.一种N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,其特征在于，采用下式(III)进行；
Figure FDA0002878849070000011
其中，化合物1的母体骨架为未活化的吡啶、喹啉或者异喹啉，R为任何取代基。
2.根据权利要求1所述的N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,其特征在于，所述的R为H,吸电子基团，或者供电子基团。
3.根据权利要求1所述的N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,其特征在于，所述的R为吸电子基团。
4.据权利要求3所述的N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,其特征在于，所述的吸电子基团为酰基，醛基，酯基，酰胺基，氰基，磺酰基,含氟烷基，或者卤素中的一种或者多种。
5.根据权利要求1所述的N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,其特征在于，化合物1的母体骨架为未活化的吡啶时，R取代基的位置为2位，3位，4位，5位和6位；化合物1的母体骨架为未活化喹啉时，R取代基的位置为任意位置。
6.根据权利要求1所述的N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,其特征在于，化合物1的母体骨架为未活化的吡啶时，R取代基的位置为3位或者5位；化合物1的母体骨架为未活化喹啉时，R取代基的位置为4位、5位、或者6位。
7.根据权利要求1所述的N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,其特征在于，具体的包括下述步骤：化合物1作为原料，加入二氟试剂、碱，以及氧化剂,在溶剂中反应生成目标产物。
8.根据权利要求1所述的N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,其特征在于，化合物1：二氟试剂：碱：氧化剂的摩尔比为1：(1.5-2.5)：(1.2-1.5)：(2-4)。
9.根据权利要求7所述的N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,其特征在于，所述的二氟试剂为BrCF2CO2Et,BrCF2CO2H,BrCF2CO2Na,ClCF2CO2Na,BrCF2P(O)(OEt)2,FSO2CF2CO2H中的一种。
10.根据权利要求7所述的N-CF2H-1,2-二氢吡啶-2-酮化合物的合成方法,其特征在于，所述的氧化剂为过氧化叔丁醇,H2O2,二叔丁基过氧化物,间氯过氧苯甲酸，过氧乙酸中的一种。
CN202011637271.XA 2020-12-31 2020-12-31 N-cf2h-1,2-二氢吡啶-2-酮化合物的合成方法 Active CN112645871B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011637271.XA CN112645871B (zh) 2020-12-31 2020-12-31 N-cf2h-1,2-二氢吡啶-2-酮化合物的合成方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011637271.XA CN112645871B (zh) 2020-12-31 2020-12-31 N-cf2h-1,2-二氢吡啶-2-酮化合物的合成方法

Publications (2)

Publication Number Publication Date
CN112645871A true CN112645871A (zh) 2021-04-13
CN112645871B CN112645871B (zh) 2022-09-16

Family

ID=75367140

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011637271.XA Active CN112645871B (zh) 2020-12-31 2020-12-31 N-cf2h-1,2-二氢吡啶-2-酮化合物的合成方法

Country Status (1)

Country Link
CN (1) CN112645871B (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113200812A (zh) * 2021-04-27 2021-08-03 天津大学 1,3,5-三取代芳基化合物的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6350740B1 (en) * 2000-09-05 2002-02-26 Virginia Commonwealth University Transplatinum complexes as cytotoxic and anticancer agents
JP2016204322A (ja) * 2015-04-25 2016-12-08 国立大学法人 千葉大学 光学活性なペルオキシド付加体およびその製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6350740B1 (en) * 2000-09-05 2002-02-26 Virginia Commonwealth University Transplatinum complexes as cytotoxic and anticancer agents
JP2016204322A (ja) * 2015-04-25 2016-12-08 国立大学法人 千葉大学 光学活性なペルオキシド付加体およびその製造方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113200812A (zh) * 2021-04-27 2021-08-03 天津大学 1,3,5-三取代芳基化合物的合成方法

Also Published As

Publication number Publication date
CN112645871B (zh) 2022-09-16

Similar Documents

Publication Publication Date Title
CN110204486B (zh) 一种喹啉衍生物的合成方法
CN111960997B (zh) 一种羟烷基取代的喹啉类衍生物的合成方法
CN111690947B (zh) 三氟甲基化芳基酰胺衍生物的电化学合成方法
CN112645871B (zh) N-cf2h-1,2-二氢吡啶-2-酮化合物的合成方法
CN112794782B (zh) 一种含氟羧酸类化合物及其制备方法
CN103483255B (zh) 氟代异喹啉类化合物及其制备方法
CN102863371B (zh) 氟代二氢吡咯或氟代吡咯
WO2008024953A2 (en) Transition metal-catalyzed alkylation of c-h bonds with organoboron reagents
CN105693632A (zh) 一种多取代喹喔啉衍生物的制备方法
CN109734705A (zh) 一种经脱卤烷基化制备n-杂环芳烃衍生物的方法
CN106543081B (zh) 一种1-二氟烷基异喹啉的制备方法
CN115010753A (zh) 一种水相中制备磷酸化偕二氟二烯烃化合物的方法
CN111004164B (zh) 一种多取代2-芳基吲哚衍生物的制备方法
CN104447519B (zh) 一种制备3-取代-2-溴-6-三氟甲基吡啶的方法
CN105859620B (zh) 一类6-三氯甲基菲啶类化合物及其制备方法和应用
CN112174949A (zh) 一种喹嗪酮类化合物及其制备方法
CN112174877B (zh) 一种2,4-二芳基-6-三氟甲基吡啶衍生物的制备方法
CN113636968B (zh) 一种3-酰基吡咯类化合物的合成方法
CN112375036B (zh) 一种2-芳硫基吡啶-n-氧化物及其衍生物的制备方法
CN112079693B (zh) 选择性制备对苯二酚单醚类化合物或醌醇类化合物的方法
CN109180564A (zh) 一种哌啶及其衍生物的制备方法
CN111747874B (zh) 一种艾瑞昔布中间体及其制备方法和用途
CN113387837B (zh) 光氧化还原催化方法
CN107011219B (zh) 溴二氟甲硫氧基类化合物、中间体，及其制备方法和应用
CN109096181B (zh) 一种超声辅助绿色合成2-磺酰基吡啶衍生物的方法

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
GR01 Patent grant
GR01 Patent grant