CN102295644A - Method for synthesizing 1-halo-2-aryl indolizine compound - Google Patents

Method for synthesizing 1-halo-2-aryl indolizine compound Download PDF

Info

Publication number
CN102295644A
CN102295644A CN 201110136164 CN201110136164A CN102295644A CN 102295644 A CN102295644 A CN 102295644A CN 201110136164 CN201110136164 CN 201110136164 CN 201110136164 A CN201110136164 A CN 201110136164A CN 102295644 A CN102295644 A CN 102295644A
Authority
CN
China
Prior art keywords
aryl
indolizine
ethoxy carbonyl
halogen
salt
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
CN 201110136164
Other languages
Chinese (zh)
Other versions
CN102295644B (en
Inventor
匡春香
杨义文
金辉
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.)
Tongji University
Original Assignee
Tongji 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 Tongji University filed Critical Tongji University
Priority to CN 201110136164 priority Critical patent/CN102295644B/en
Publication of CN102295644A publication Critical patent/CN102295644A/en
Application granted granted Critical
Publication of CN102295644B publication Critical patent/CN102295644B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to a method for synthesizing a 1-halo-2-aryl indolizine compound. According to the method, the 1-halo-2-aryl indolizine compound can be conveniently and effectively synthesized by using brominated N-ethyoxyl carbonyl methyl pyridinium salt (or chlorinated N-cyan methyl pyridinium salt) and 1,1-dibromo-2-arylethylene (or 1-halo-2-arylacetylene) as substrates under the action of alkali. Compared with the existing methods, the method provided by the invention has the advantages that the range of adaptable substrates is wide, reaction conditions are mild, no catalyst is needed, and reaction efficiency is high and is simple to operate, thus the method has an important application value.

Description

The method of a kind of synthetic 1-halogen-2-aryl indolizine compound
Technical field
The invention belongs to organic and technical field of medicine synthesis, be specifically related to the method for a kind of synthetic 1-halogen-2-aryl indolizine compound.
Background technology
Indolizine (indolizine) is the indoles isomer that a class has 10 πDian Zi systems.Its parent nucleus extensively is present in and manyly has in the active natural product molecule of important biomolecule, such as tabersonine (Tabersonine), brucine (Strychnine), vinealeucoblastine(VLB) (+Vinblastine) etc. in.The biological activity of indolizine is very extensive, mainly contain antitumor, antibiotic, antiviral, hide worm, anti-inflammatory, anti-arrhythmia, hypertension etc. from extremely.Discovered in recent years is that the compound of parent nucleus all has certain curative effect to mental disorder, anti-inflammatory, pain relieving, hypoglycemia and adult's respiratory tract disease etc. with the indolizine.Synthetic and naturally occurring indolizine nuclear all may have the nervus centralis of inhibition, the calcium element stops, treats effects such as cardiovascular diseases.In addition, indolizine also can be used as photosensitizers, and is used for synthetic novel dyestuff etc.
Indolizine is the important heterogeneous ring compound of a class, and its derivative is at biological, agricultural chemicals and pharmaceutically all have been widely used, for example: can be used as pigment, weedicide, potential inhibitor of phospholipase enzymes, anti-Leishmania and antiviral etc.; But also can show antimycobacterial activity.In addition, they still syntheticly have an alkaloidal key intermediate of important physiologically active.
Forming the five-ring in the indolizine structure, is the synthetic the most general method of indolizine.Wherein, utilize 1, the pentacyclic method that the 3-Dipolar Cycloaddition forms indolizine be study at present method the most widely.This method uses pyridine ylide and dipolarophile alkynes or alkene to take place 1, the 3-Dipolar Cycloaddition, and last dehydroaromatizationof obtains indolizine.Huisgen has proposed 1 from nineteen fifty-seven, and after the notion of 3-dipole cycloaddition, this method is applied in synthesizing of indolizine very soon.1961, Boekelheide etc. utilized pyridine ylide and dimethyl butyn to take place 1, the 3-Dipolar Cycloaddition, and dehydroaromatizationof has synthesized the indolizine derivative again.
But because alkynes costs an arm and a leg, be not easy to obtain, therefore under the oxygenant effect, active olefin is studied more extensively as the method for the synthetic indolizine of dipolarophile body.WangBing Xiang etc. have reported that pyridine compounds and their and acrylonitrile reaction obtain salt, again at alkali and oxygenant [CoPy 4(HCrO 4) 2] (TpCD) effect down and electron deficiency alkene carry out 1, the 3-Dipolar Cycloaddition can obtain indolizine-3-amides.Hu Yuefei etc. have reported that carboxylic pyridine quaternary ammonium salt obtains the pyridine ylide under the effect of alkali, take place 1 with active olefin again, and the cycloaddition of 3-dipole obtains the tetrahydrochysene indolizine, then by MnO 2Oxidation dehydrogenation and decarboxylation obtain indolizine, pyrroles [1,5- a] quinoline and pyrroles [1,5- a] derivative of isoquinoline 99.9.Though this method productive rate is higher, synthesis step is more.
Nitroolefin is to make up nitrogen-containing heterocycle compound intermediate .Weaver commonly used etc. to utilize 1 first, 1-dinitrobenzene-2,2-acetylene diiodide and pyridine or isoquinoline 99.9 ylide generation 1, the cycloaddition of 3-dipole, cancellation HI and HNO immediately again 2, aromizing form indolizine and pyrroles [1,5- a] isoquinoline 99.9, but productive rate is lower.Chen Qingyun group is dissolved in polyfluoro ethene among the DMF, respectively with the quaternary ammonium salt of pyridine, quinoline, isoquinoline 99.9 at K 2CO 3/ Et 3Under the N condition, in 70 ℃ of reactions 24 hours, by 1, the cycloaddition of 3-dipole obtained a series of fluorine-containing indolizine and benzo indolizine derivative, and productive rate is between 11-91%.This method reaction times is longer, and productive rate changes greatly.
M ü ller etc. utilizes the derivative of the synthetic indolizine of ternary one kettle way and two indolizine recently. and at first the active alkynes of Sonogashira coupling formation takes place in acyl chlorides and terminal alkyne, it takes place 1 with pyridine or dipyridyl ylide immediately, the cycloaddition of 3-dipole, simultaneous oxidation obtains indolizine and two indolizine derivative of high fluorescence, and productive rate is respectively 41%～59% and 18%～28%.This reaction yield is lower, and will use transition-metal catalyst and associated ligands, and reaction cost is higher relatively.
Happy Gui Zhou etc. have developed the novel method of liquid phase organic synthesis three replacement indolizine and benzo indolizine compound library, and overall yield is respectively 70%～94% and 50%～84%.They change the connection base subsequently, by ester bond the 4-pyridine carboxylic acid are bonded on the PEG, obtain quaternary indolizine compound with alkene or alkynes reaction high yield again.Though this method productive rate is higher, the synthetic difficulty of raw material.
The method of above-mentioned synthetic indolizine compound exists all that synthesis step is many, productive rate is low, can fit that substrate is few, raw material is expensive or synthetic difficulty, some reaction also need be with shortcomings such as transition-metal catalyst catalysis.
Reference:
1、Mehta?L?K，Parrick?J.?The?synthesis?of?three?indolizine?derivatives?of?interest?as?non-isomerizable?analogues?of?tamoxifen[J].?J.?Heterocycl.?Chem.,?1995,?32(2):
391-394.
2、Lins?C?L?K，Block?J?H，Doerge?R?F.?Nitro-?Para-?and?meta-?substituted?2-Phenylindolizines?as?potential?antimicrobial?agents?[J].?J.?Pharm.?Sci.1982,?71(5):556-561.
3、Ignatenko?A?G,?YUtilov?Yu?M，Mikhailova?L?E，etal.?2,3-dimethyl-8-(p-bromophenyl)?-imidazo[4,5-g]indolizine?exhibiting?acaricide?activity?:?Russia,SU879946A1[P].1998-05-27。
4, Hagishita S, Yamada M, Shirahase K etal. Potent inhibitors of secretory phospholipase A2:Synthesis and inhibitory activities of indolizine and indene derivatives [J] .J. Med. Chem., 1996,39 (19): 3,636 1 3658.
5、Clive?D.?L.?J，Coltart?D.?M，Zhou?Y?.Synthesis?of?the?angiotensin-converting?enzyme?inhibitors?(-)-A58365A?and?(-)-A58365B?from?a?common?intermediate?[J].J.?Org.?Chem.,?1999,?64(5):1447-1454.）。
6、L?pez,?S.;?Rodríguez,?V.; Montenegro,?J.;?Saá,?C.;?Alvarez,R.;?L?pez,?S.?S.;?Lera,?A.?R.;?Sim?n,?R.;?Lazarova,?T.;Padr?s,?E.? ChemBioChem? 2005,? 6,?2078.
7.?Smith,?S.?C.;?Clarke,?E.?D.;?Ridley,?S.?M.;?Bartlett,?D.;Greenhow,?D.?T.;?Glithro,?H.;?Klong,?A.?Y.;?Mitchell?G.;Mullier,?G.?W.? Pest?Manag.? Sci.? 2005,? 61,?16.
8.?Hagishita,?S.;?Yamada,?M.;?Shirahase,?K.;?Okada,?T.;?Murakami,Y.;?Ito,?Y.;?Matsuura,?T.;?Wada,?M.;?Kato,?T.;?Ueno,M.;?Chikazawa,?Y.;?Yamada,?K.;?Ono,?T.;?Teshirogi,?I.;Ohtani,?M.? J.? Med.? Chem.? 1996,? 39,?3636.
9.?Bolle,?L.?D.;?Andrei,?G.;?Snoeck,?R.;?Zhang,?Y.;?Lommel,?A.?V.;?Otto,?M.;?Bousseau,?A.;?Roy,?C.;?Clercq,?E.?D.;?Naesens,?L.? Biochem.? Pharmacol.? 2004,? 67,?325.
10.?Medda,?S.;?Jaisankar,?P.;?Manna,?R.?K.;?Pal,?B.;?Giri,?V.?S.;?Basu,?M.?K.? J.? Drug?Targeting? 2003,? 11,?123.
11.?Gundersen,?L.-L.;?Negussie,?A.?H.;?Ostbly,?O.?B.? Arch.? Pharm.? 2003,? 336,?191.
12.?Poissonnet,?G.;?Theret-Bettiol,?M.-H.;?Dodd,?R.?H.? J.? Org. Chem.? 1996,? 61,?2273.）.
13、Uchida?T，Matsurnoto?K.?M.?Methods?for?the?construetion?of?the?indolizine?nucleus?[J].Synthesis,1976,(4):209-236.
14、Boekelheide,V.;Fahrenholtz,K.The?Formation?of?Pyrrocolines?by?the?Reaction?of?Dimethyl?Acetylenedicarboxylate?with?Heterocyclic?Zwitterions[J]J.Am.Chem.Soc.1961,83,458-462.
15、Swinbourne?F?J,?Hunt?J?H,?Klinkert?G.?Advances?in?indolizine?chemistry[J].Adv.?Heterocycl. Chem.?1979?,?23:103-170.
16、g?B,?Zhang?X,?Hu?Y,?etal.?Preparation?of?indolizine-3-carboxamides?and?indolizine-3-carbonitriles?by?l,3-dipolar?cycloaddition?of?N-(cyanomethyl)pyridinium?ylides?to?alkenes?in?the?presence?of?tetrakispyridinecobalt(Ⅱ)?dichromate?or?manganese?(IV)?oxide[J].?J.?Chem.?Soc.，Perkin?Trans.?1,?1999,?(11):?1571?-1575.)。
17、ang,?L.-D.;?Liang,?F.;?Sun,?L.;?Hu,?Y.-F.;?Hu,?H.-W.? Synthesis， 2000,?1733.
18、ultadakis,?E.;?Chung,?B.;?Elsegood,?M.?R.?J.;?Weaver,?G.W.? Synlett， 2002,?1547.
19、K.;?Chen,?Q.-Y.? Synthesis? 2003,?35。
20、taru,?A.?V.;?Druta,?I.?D.;?Oeser,?T.;?M?ller,?T.?J.?J.? Helv. Chim.? Acta? 2005,? 88,?1798.
21、hen,?Z.;?Yue,?G.;?Lu,?C.;?Yang,?G.? Synlett， 2004,?1231。
22、Yue,?G.;?Wan,?Y.;?Song,?S.;?Yang,?G.;?Chen,?Z.? Bioorg. Med.? Chem.? Lett.? 2005,? 15,?453.
23、Yue,?G.;?Yang,?G.;?Chen,?Z.? J.? Heterocycl.? Chem.? 2006,? 43,?781。
Summary of the invention
The object of the present invention is to provide the method for a kind of synthetic 1-halogen-2-aryl indolizine compound.
The present invention utilizes bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt and 1, and 1-dibromo (chlorine)-2-aryl ethylene (or 1-halogen-2-aryl ethane) synthesizes the method for 1-halogen-2-aryl-3-ethoxy carbonyl (cyano group) indolizine compound.
The method of a kind of synthetic 1-halogen-2-aryl indolizine compound that the present invention proposes, its reaction principle is as follows:
Figure 619022DEST_PATH_IMAGE001
EWG is CO 2Et or CN; X is Br or Cl;
Ar is
In any one.
 
Concrete synthesis step is as follows:
In reactor, add bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt, 1,1-two bromo-2-aryl ethylenes, 1, among 1-two chloro-2-aryl ethylenes or the 1-halogen-2-aryl ethane three any, tetrahydrofuran (THF) and alkali, 60 ℃ of-100 ℃ of lower magnetic force stirring and refluxing reactions 1-20 hour, after finishing, reaction is chilled to room temperature, the pressure reducing and steaming solvents tetrahydrofurane, residue is that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with the ethyl acetate/petroleum ether, wherein, bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt and 1,1-two bromo-2-aryl ethylenes, 1, the mol ratio of any among 1-two chloro-2-aryl ethylenes or the 1-halogen-2-aryl ethane three is 1:1-1:5; The mol ratio of alkali and bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt is 1:1-10:1.
Among the present invention, described alkali can be one among cesium carbonate, salt of wormwood or the DBU (1,8-diazabicylo [5.4.0] 11 carbon-7-alkene) to several, preferred DBU.
Among the present invention, described temperature of reaction is 85-90 ℃.
Among the present invention, the described reaction times is 10 hours-12 hours.
Among the present invention, bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt and 1,1-two bromo-2-aryl ethylenes, 1, the mol ratio of any among 1-two chloro-2-aryl ethylenes or the 1-halogen-2-aryl ethane three is 1:1.5-1:2.
Among the present invention, the mol ratio of described alkali and bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt is 4:1-5:1.
The present invention adopts bromination N-ethoxy carbonyl picoline salt cheap and easy to get (or chlorination N-cyano-methyl pyridine salt) and 1,1-dibromo (chlorine)-2-aryl ethylene (or 1-halogen-2-aryl ethane) is a substrate, after the alkali effect, can synthesize 1-halogen-2-aryl-3-ethoxy carbonyl (cyano group) indolizine compound easily and effectively.Compare with existing method, this method can fit that the substrate scope is wide, and the reaction conditions gentleness need not catalyzer, and is easy and simple to handle, and the reaction efficiency height, is a kind of method with potential using value.
Embodiment
Further specify the present invention below by embodiment, but can not limit content of the present invention.
Synthesizing of embodiment 1:1-bromo-2-p-nitrophenyl-3-ethoxy carbonyl indolizine
Figure 188074DEST_PATH_IMAGE003
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-p-nitrophenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow solid, yield 95%.
1H?NMR(400MHz,?CDCl 3):?δ?=?9.60(d,? J?=?7.2?Hz,?1H),?8.37(d,? J?=?8.4?Hz,?2H),7.73(d,? J?=?8.0?Hz,?2H),?7.53(d,? J?=?9.6?Hz,?1H),?7.16(t,? J?=?7.8?Hz,?1H),?6.93(t,? J?=?7.0?Hz,?1H),?4.50(q,? J?=?7.0,?7.2Hz,?2H),?1.50(t,? J?=?7.0?Hz,?3H).
Embodiment 2:1-bromo-2-is synthetic to fluorophenyl-3-ethoxy carbonyl indolizine
Figure 804869DEST_PATH_IMAGE004
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-are to fluorophenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is the yellow-green colour solid, yield 63%.
1H?NMR(400MHz,?CDCl 3):?δ?=?9.45?(d,? J?=?7.2?Hz,?1H),?7.40-7.35?(m,?3H),?7.10?(t,? J?=?8.4Hz,?2H),?6.97(t,? J?=?7.8?Hz,?1H),?6.76(t,? J?=?7.0?Hz,?1H),?4.39(q,? J?=?7.2,?6.8?Hz,?2H),?1.39(t,? J?=?7.2?Hz,?3H).
Synthesizing of embodiment 3:1-bromo-2-rubigan-3-ethoxy carbonyl indolizine
Figure 672593DEST_PATH_IMAGE005
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-rubigan ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a faint yellow solid, yield 85%.
1H?NMR(400MHz,?CDCl 3):?δ=9.46(d,? J?=?7.2?Hz,?1H),?7.40-7.35(m,?5H),?6.98(t,? J?=?7.8?Hz,?1H),?6.77(t,? J?=?6.8?Hz,?1H),?4.39(q,? J?=?7.0,?7.2?Hz,?2H),?1.40(t,? J?=7.2?Hz,?3H).
Synthesizing of embodiment 4:1-bromo-2-Chloro-O-Phenyl-3-ethoxy carbonyl indolizine
Figure 636132DEST_PATH_IMAGE006
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-Chloro-O-Phenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is pale brown look oily matter, yield 44%.. 1H?NMR(400MHz,?CDCl 3):?δ=9.57(d,? J?=?7.2?Hz,?1H),?7.57(d,? J?=?4.0?Hz,?1H),7.40?(s,?3H),7.19(d,? J?=?8.8?Hz,?1H),?7.06(t,? J?=?7.2?Hz,?1H),?6.87(t,? J?=?6.4?Hz,?1H),?4.48(q,? J?=?6.4,?6.8?Hz,?2H),?1.49(t,? J?=?7.0?Hz,?3H).
Embodiment 5:1-bromo-2-is synthetic to bromophenyl-3-ethoxy carbonyl indolizine
Figure 47914DEST_PATH_IMAGE007
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-are to bromophenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow solid, yield 76%.
1H?NMR?(400MHz,?CDCl 3)?:?δ?=?9.55(d,? J?=?7.2?Hz,?1H),?7.63(d,? J?=?8.4?Hz,?2H),7.46(d,? J?=?9.2?Hz,?1H),?7.40(d,? J?=?8.4?Hz,?2H),?7.08(t,? J?=?7.8?Hz,?1H),?6.87(t,? J?=?6.4?Hz,?1H),?4.48(q,? J?=?7.0,?7.2?Hz,?2H),?1.49(t,? J?=?7.0?Hz,?3H).
Synthesizing of bromophenyl between embodiment 6:1-bromo-2--3-ethoxy carbonyl indolizine
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1, bromophenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU between 1-two bromo-2-, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is pale brown look solid, yield 72%.
1H?NMR?(400MHz,?CDCl 3)?:?δ?=?9.46?(d,? J?=?7.2?Hz,?1H),?7.58(s,?1H),?7.45(d,? J?=?8.0?Hz,?1H),?7.38(t,? J?=?9.8?Hz,?2H),?7.28(t,? J?=?7.8?Hz,?1H),?7.00(t,? J?=?7.8?Hz,?1H),?6.78(t,? J?=?6.8?Hz,?1H),?4.39(q,? J?=?7.2,?6.8?Hz,?2H),?1.40(t,? J?=?7.0?Hz,?3H).
Synthesizing of embodiment 7:1-bromo-2-p-trifluoromethyl phenyl-3-ethoxy carbonyl indolizine
Figure 862734DEST_PATH_IMAGE009
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-p-trifluoromethyl phenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is the yellow-green colour solid, yield 62%. 1H?NMR?(400MHz,?CDCl 3):?δ?=?9.48(d,? J?=?7.2?Hz,?1H),?7.67(d,? J?=?8.0?Hz,?2H),?7.56(d,? J?=?8.0?Hz,?2H),?7.40(d,? J?=?8.8?Hz,?1H),?7.01(t,? J?=?7.8?Hz,?1H),?6.79(t,? J?=?6.8?Hz,?1H),?4.40(q,? J?=?7.0,?7.2?Hz,?2H),?1.40(t,? J?=?7.0?Hz,?3H).
Embodiment 8:1-bromo-2-is synthetic to cyano-phenyl-3-ethoxy carbonyl indolizine
Figure 692281DEST_PATH_IMAGE010
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-are to cyano-phenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow solid, yield 54%.
1H?NMR?(400MHz,?CDCl 3):?δ?=?9.58(d,? J?=?7.2?Hz,?1H),?7.79(d,? J?=?8.4?Hz,?2H),?7.66(d,? J?=?8.0?Hz,?2H),?7.49(d,? J?=?8.8?Hz,?1H),?7.13(t,? J?=?7.8?Hz,?1H),?6.91(t,? J?=?7.0?Hz,?1H),?4.49(q,? J?=?7.2,?6.8?Hz,?2H),?1.49(t,? J?=?7.0?Hz,?3H).
Embodiment 9:1-bromo-2-is synthetic to methoxycarbonyl phenyl-3-ethoxy carbonyl indolizine
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-are to methoxycarbonyl phenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow solid, yield 46%. 1H?NMR?(400MHz,?CDCl 3):?δ=9.57(d,? J?=?7.2?Hz,?1H),?8.17(d,? J?=?7.6?Hz,?2H),?7.62(d,? J?=?8.0?Hz,?2H),?7.51(d,? J?=?8.8?Hz,?1H),?7.10(t,? J?=?7.6?Hz,?1H),?6.88(t,? J?=?7.0?Hz,?1H),?4.49(q,? J?=?7.2,?6.8?Hz,?2H),?3.98(s,?3H),1.49(t,? J?=?7.0?Hz,?3H).
Synthesizing of embodiment 10:1-bromo-2-phenyl-3-ethoxy carbonyl indolizine
Figure 774955DEST_PATH_IMAGE012
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-phenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow-green colour oily matter, yield 40%. 1H?NMR?(400MHz,?CDCl 3):?δ?=?9.55(d,? J?=?7.2?Hz,?1H),?7.54-7.49?(m,?5H),?7.42(d,? J?=?6.8?Hz,?1H),?7.06(t,? J?=?7.8?Hz,?1H),?6.85(t,? J?=?6.8?Hz,?1H),?4.49(q,? J?=?7.0,?7.2?Hz,?2H),?1.49(t,? J?=?7.0?Hz,?3H).
Synthesizing of embodiment 11:1-bromo-2-p-methylphenyl-3-ethoxy carbonyl indolizine
Figure 408149DEST_PATH_IMAGE013
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-p-methylphenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow-green colour oily matter, yield 36%. 1H?NMR?(400MHz,?CDCl 3):?δ=9.45(d,? J?=?7.2?Hz,?1H),?7.40(d,? J?=?9.2?Hz,?1H),?7.32(d,? J?=?8.0?Hz,?2H),?7.22(d,? J?=?8.0?Hz,?2H),?6.94(t,? J?=?7.4?Hz,?1H),?6.74(t,? J?=?7.0?Hz,?1H),?4.38(q,? J?=?7.0,?7.2?Hz,?2H),?2.36(s,?3H),1.39(t,? J?=?7.0?Hz,?3H).
Synthesizing of embodiment 12:1-bromo-2-p-methoxyphenyl-3-ethoxy carbonyl indolizine
Figure 415288DEST_PATH_IMAGE014
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-p-methoxyphenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow-green colour oily matter, yield 31%. 1H?NMR?(400MHz,?CDCl 3):?δ=9.44(d,? J?=?7.2?Hz,?1H),?7.38(d,? J?=?9.2?Hz,?1H),?7.34(d,? J?=?8.8?Hz,?2H),?6.94(t,? J?=?7.8?Hz,?3H),?6.74(t,? J?=?6.8?Hz,?1H),?4.38(q,? J?=?7.0,?7.2?Hz,?2H),?3.80(s,?3H),1.39(t,? J?=?7.0?Hz,?3H).
Synthesizing of embodiment 13:1-bromo-2-(3-pyridyl)-3-ethoxy carbonyl indolizine
Figure 456188DEST_PATH_IMAGE015
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-(3-pyridyl) ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is the yellow-green colour solid, yield 45%.
1H?NMR?(400MHz,?CDCl 3):?δ?=?9.50(d,? J?=?7.2?Hz,?1H),?8.72(s,?1H),?8.58(d,? J?=?2.8?Hz,?1H),?7.92(d,? J?=?7.6?Hz,?1H),?7.47(q,? J?=?5.2,?2.4?Hz,?1H),?7.40(d,? J?=?9.2?Hz,?1H),?7.05(t,? J?=?7.6?Hz,?1H),?6.83(t,? J?=?6.8?Hz,?1H),?4.40(q,? J?=?7.2,?6.8?Hz,?2H),?1.41(t,? J?=?7.2?Hz,?3H).
Synthesizing of embodiment 14:1-bromo-2-(2-naphthyl)-3-ethoxy carbonyl indolizine
Figure 523370DEST_PATH_IMAGE016
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two bromo-2-(2-naphthyl) ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow-green colour oily matter, yield 35%. 1H?NMR?(400MHz,?CDCl 3):?δ=9.48(d,? J?=?7.2?Hz,?1H),?7.87(d,? J?=?7.2?Hz,?2H),?7.82(q,? J?=?5.8,?3.2?Hz,?2H),?7.56(d,? J?=?8.8?Hz,?1H),?7.47-7.43?(m,?3H),?6.97(t,? J?=?7.8?Hz,?1H),?6.77(t,? J?=?7.0?Hz,?1H),?4.40(q,? J?=?7.0,?7.2?Hz,?2H),?1.41(t,? J?=?7.2?Hz,?3H).
Synthesizing of embodiment 15:1-chloro-2-p-nitrophenyl-3-ethoxy carbonyl indolizine
Figure 587403DEST_PATH_IMAGE017
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1,1-two chloro-2-p-nitrophenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow solid, yield 72%.
1H?NMR?(400MHz,?CDCl 3):?δ=9.59(d,? J?=?6.8?Hz,?1H),?8.37(d,? J?=?8.0?Hz,?2H),7.75(d,? J?=?8.0?Hz,?2H),?7.57(d,? J?=?8.8?Hz,?1H),?7.19(t,? J?=?7.6?Hz,?1H),?6.95(t,? J?=?6.4?Hz,?1H),?4.49(q,? J?=?6.6,?7.2?Hz,?2H),?1.49(t,? J?=?6.8?Hz,?3H).
Synthesizing of embodiment 16:1-bromo-2-p-nitrophenyl-3-cyano group indolizine
Figure 132654DEST_PATH_IMAGE018
In the 25mL round-bottomed flask, add 0.3mmol chlorination N-cyano-methyl pyridine salt, 0.6mmol 1,1-two bromo-2-p-nitrophenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is the reddish-brown solid, yield 80%. 1H?NMR?(400MHz,?CDCl 3):?δ=8.30(d,? J?=?6.8?Hz,?1H),?8.25(d,? J?=?8.0?Hz,?2H),7.79(d,? J?=?9.2?Hz,?1H),?7.63(d,? J?=?8.0?Hz,?2H),?7.15(t,? J?=?8.0?Hz,?1H),?6.92(t,? J?=?6.2?Hz,?1H).
Synthesizing of embodiment 17:1-chloro-2-p-nitrophenyl-3-cyano group indolizine
Figure 169005DEST_PATH_IMAGE019
In the 25mL round-bottomed flask, add 0.3mmol chlorination N-cyano-methyl pyridine salt, 0.6mmol 1,1-two chloro-2-p-nitrophenyl ethene, 5mL tetrahydrofuran (THF), 1.35mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow solid, yield 67%. 1H?NMR?(400MHz,?CDCl 3):?δ?=?8.38(d,? J?=?8.4?Hz,?2H),?8.30(d,? J?=?6.8?Hz,?1H),?7.75(d,? J?=?8.4?Hz,?2H),?7.65(d,? J?=?8.8?Hz,?1H),?7.23(t,? J?=?7.8?Hz,?1H),?7.02(t,? J?=?6.6?Hz,?1H).
Synthesizing of embodiment 18:1-bromo-2-p-nitrophenyl-3-ethoxy carbonyl indolizine
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1-bromo-2-p-nitrophenyl ethyl-acetylene, 5mL tetrahydrofuran (THF), 0.45mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow solid, yield 96%. 1H?NMR(400MHz,?CDCl 3):?δ?=?9.60(d,? J?=?7.2?Hz,?1H),?8.37(d,? J?=?8.4?Hz,?2H),7.73(d,? J?=?8.0?Hz,?2H),?7.53(d,? J?=?9.6?Hz,?1H),?7.16(t,? J?=?7.8?Hz,?1H),?6.93(t,? J?=?7.0?Hz,?1H),?4.50(q,? J?=?7.0,?7.2Hz,?2H),?1.50(t,? J?=?7.0?Hz,?3H).
Synthesizing of embodiment 19:1-bromo-2-phenyl-3-ethoxy carbonyl indolizine
In the 25mL round-bottomed flask, add 0.3mmol bromination N-ethoxy carbonyl picoline salt, 0.6mmol 1-bromo-2-phenylacetylene, 5mL tetrahydrofuran (THF), 0.45mmol DBU, reaction solution was 90 ℃ of lower magnetic force stirring and refluxing reactions 12 hours then, after finishing, reaction is chilled to room temperature, pressure reducing and steaming solvent, residue are that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with ethyl acetate/petroleum ether=1:10 (v/v).Product is a yellow-green colour oily matter, yield 45%. 1H?NMR?(400MHz,?CDCl 3):?δ?=?9.55(d,? J?=?7.2?Hz,?1H),?7.54-7.49?(m,?5H),?7.42(d,? J?=?6.8?Hz,?1H),?7.06(t,? J?=?7.8?Hz,?1H),?6.85(t,? J?=?6.8?Hz,?1H),?4.49(q,? J?=?7.0,?7.2?Hz,?2H),?1.49(t,? J?=?7.0?Hz,?3H).

Claims (6)

1. the method for synthetic 1-halogen-2-aryl indolizine compound is characterized in that its synthetic route is as follows:
Figure 2011101361643100001DEST_PATH_IMAGE001
EWG is CO 2Et, or CN; X is Br or Cl;
Ar is
Figure 202664DEST_PATH_IMAGE002
In any;
Concrete steps are as follows:
In reactor, add bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt, 1,1-two bromo-2-aryl ethylenes, 1, among 1-two chloro-2-aryl ethylenes or the 1-halogen-2-aryl ethane three any, tetrahydrofuran (THF) and alkali, 60 ℃ of-100 ℃ of lower magnetic force stirring and refluxing reactions 1-20 hour, after finishing, reaction is chilled to room temperature, the pressure reducing and steaming solvents tetrahydrofurane, residue is that leacheate carries out column chromatography for separation and purifies and promptly to get desired product with the ethyl acetate/petroleum ether, wherein, bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt and 1,1-two bromo-2-aryl ethylenes, 1, the mol ratio of any among 1-two chloro-2-aryl ethylenes or the 1-halogen-2-aryl ethane three is 1:1-1:5; The mol ratio of alkali and bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt is 1:1-10:1.
2. the method for synthetic 1-halogen according to claim 1-2-aryl indolizine compound is characterized in that described alkali is cesium carbonate, salt of wormwood or 1, the one to multiple kind in 8-diazabicylo [5.4.0] 11 carbon-7-alkene.
3. according to the method for the described synthetic 1-halogen of claim 1-2-aryl indolizine compound, it is characterized in that described temperature of reaction is 85-90 ℃.
4. the method for synthetic 1-halogen according to claim 1-2-aryl indolizine compound is characterized in that, the described reaction times is 10 hours-12 hours.
5. the method for synthetic 1-halogen according to claim 1-2-aryl indolizine compound, it is characterized in that, described bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt and 1,1-two bromo-2-aryl ethylenes, 1, the mol ratio of any among 1-two chloro-2-aryl ethylenes or the 1-halogen-2-aryl ethane three is 1:1.5-1:2.
6. the method for synthetic 1-halogen according to claim 1-2-aryl indolizine compound is characterized in that, the mol ratio of described alkali and bromination N-ethoxy carbonyl picoline salt or chlorination N-cyano-methyl pyridine salt is 4:1-5:1.
CN 201110136164 2011-05-25 2011-05-25 Method for synthesizing 1-halo-2-aryl indolizine compound Expired - Fee Related CN102295644B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 201110136164 CN102295644B (en) 2011-05-25 2011-05-25 Method for synthesizing 1-halo-2-aryl indolizine compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 201110136164 CN102295644B (en) 2011-05-25 2011-05-25 Method for synthesizing 1-halo-2-aryl indolizine compound

Publications (2)

Publication Number Publication Date
CN102295644A true CN102295644A (en) 2011-12-28
CN102295644B CN102295644B (en) 2012-12-05

Family

ID=45356344

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 201110136164 Expired - Fee Related CN102295644B (en) 2011-05-25 2011-05-25 Method for synthesizing 1-halo-2-aryl indolizine compound

Country Status (1)

Country Link
CN (1) CN102295644B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801576A (en) * 2016-04-12 2016-07-27 湖北科技学院 Synthetic method of indolizine compounds
CN113582989A (en) * 2021-08-17 2021-11-02 广东药科大学 Preparation method of cyanized or thiocyanized indolizine and derivatives thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106380469A (en) * 2016-09-08 2017-02-08 河南师范大学 Synthesis method of 1-aromatic carbonyl-2-aryl-3-ester imidazolone compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101094852A (en) * 2004-11-01 2007-12-26 惠氏公司 Substituted indolizines and derivatives as cns agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101094852A (en) * 2004-11-01 2007-12-26 惠氏公司 Substituted indolizines and derivatives as cns agents

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
《Tetrahedron Letters》 20090929 Yongjia Shang et al New route synthesis of indolizines via 1,3-dipolar cycloaddition of pyridiniums and alkynes 6981-6984 1-6 第50卷, 第50期 *
《有机化学》 20061231 王炳祥等 吡啶叶立德与查尔酮1,3-偶极环加成反应制备2-苯基-3-乙酰基中氮茚 1587-1589 1-6 第26卷, 第11期 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801576A (en) * 2016-04-12 2016-07-27 湖北科技学院 Synthetic method of indolizine compounds
CN113582989A (en) * 2021-08-17 2021-11-02 广东药科大学 Preparation method of cyanized or thiocyanized indolizine and derivatives thereof

Also Published As

Publication number Publication date
CN102295644B (en) 2012-12-05

Similar Documents

Publication Publication Date Title
Kaila et al. Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists
Thapa et al. 1, 2-Disubstituted benzimidazoles by the iron catalyzed cross-dehydrogenative coupling of isomeric o-phenylenediamine substrates
US9630969B2 (en) N-alkyl tryptanthrin derivative, preparation method for same, and application thereof
Meng et al. Copper-catalyzed cascade cyclization of 1, 7-enynes toward trifluoromethyl-substituted 1′ H-spiro [azirine-2, 4′-quinolin]-2′(3′ H)-ones
Samineni et al. Spiroannulation of Oxindoles via Aryne and Alkyne Incorporation: Substituent-Diverted, Transition-Metal-Free, One-Pot Access to Spirooxindoles
Zou et al. Synthesis and evaluation of N-heteroaromatic ring-based analogs of piperlongumine as potent anticancer agents
Chandrashekharappa et al. One-pot microwave assisted synthesis and structural elucidation of novel ethyl 3-substituted-7-methylindolizine-1-carboxylates with larvicidal activity against Anopheles arabiensis
KR20120102688A (en) Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobezoquinoline
Liang et al. Silver-catalyzed cascade cyclization reaction of isocyanides with sulfoxonium ylides: synthesis of 3-aminofurans and 4-aminoquinolines
Minić et al. Design and synthesis of novel ferrocene-quinoline conjugates and evaluation of their electrochemical and antiplasmodium properties
Hédouin et al. Palladium-catalyzed domino allenamide carbopalladation/direct C–H allylation of heteroarenes: Synthesis of primprinine and papaverine analogues
Maiereanu et al. A novel amino-benzosuberone derivative is a picomolar inhibitor of mammalian aminopeptidase N/CD13
CN104470898A (en) Cycloalkyl Acid Derivative, Preparation Method Thereof, And Pharmaceutical Application Thereof
Pal Palladium-catalyzed alkynylation of aryl and hetaryl halides: a journey from conventional palladium complexes or salts to palladium/carbon
Zhang et al. Synthesis of Indeno [1′, 2′: 4, 5] imidazo [1, 2-a] pyridin-11-ones and Chromeno [4′, 3′: 4, 5] imidazo [1, 2-a] pyridin-6-ones through Palladium-Catalyzed Cascade Reactions of 2-(2-Bromophenyl) imidazo [1, 2-a] pyridines
KR20130119939A (en) Crystalline forms of hydrochloride salt of (4a-r,9a-s)-1-(1h-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1h-indeno[2,1-b]pyridine-6-carbonitrile and their use as hsd 1 inhibitors
Ren et al. Isocyano (triphenylphosphoranylidene) acetates: Key to the One-Pot Synthesis of Oxazolo [4, 5-c] quinoline Derivatives via a Sequential Ugi/Wittig/aza-Wittig Cyclization Process
CN110372598A (en) A kind of new method synthesizing deuterated amide and deuterated sulfonamide
Zhou et al. Access to 2-aroylthienothiazoles via C–H/N–O bond functionalization of oximes
CN102295644B (en) Method for synthesizing 1-halo-2-aryl indolizine compound
Deng et al. Novel complex crystal structure of prolyl hydroxylase domain-containing protein 2 (PHD2): 2, 8-Diazaspiro [4.5] decan-1-ones as potent, orally bioavailable PHD2 inhibitors
Huang et al. Palladium-catalyzed imidoylation-triggered [2+ 2+ 1] cyclization of internal alkyne with isocyanides
CN102548993B (en) Cyclic (aza)indolizinecarboxamides, their preparation and their use as pharmaceuticals
Wang et al. Regioselective synthesis of 2, 4-diaryl-6-trifluoromethylated pyridines through copper-catalyzed cyclization of CF3-ynones and vinyl azides
Liu et al. Chemo-and Diastereoselective Acylfluorination of Nonactivated Olefins to Access Benzo [b] azepines

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20121205

Termination date: 20150525

EXPY Termination of patent right or utility model