CN106397430A - Poly-substituted indolinone preparation method - Google Patents

Poly-substituted indolinone preparation method Download PDF

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CN106397430A
CN106397430A CN201510449497.XA CN201510449497A CN106397430A CN 106397430 A CN106397430 A CN 106397430A CN 201510449497 A CN201510449497 A CN 201510449497A CN 106397430 A CN106397430 A CN 106397430A
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alkyl
compound shown
reaction
aryl
heteroaryl
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CN106397430B (en
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唐亚林
王立霞
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Institute of Chemistry CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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Abstract

The present invention provides a poly-substituted indolinone preparation method, which comprises that a compound represented by a formula II reacts with a compound represented by a formula III to obtain a compound represented by a formula I, wherein R', R" and R are defined in the specification. With the method of the present invention, the poly-substituted indolinone can be effectively prepared through the one-pot method, and the method is simple and efficient. The formulas I, II and III are defined in the specification.

Description

The method preparing polysubstituted indolinone
Technical field
The present invention relates to organic synthesis field, in particular it relates to the method preparing polysubstituted indolinone.
Background technology
Polysubstituted indolinone (compound shown in Formulas I) is a class very important multicomponent heterocycle structure, containing this skeleton Derivant is demonstrated by significant biological activity and pharmaceutical active.The synthetic method of this series compound relevant of document report is all From the alkynyl alcohol containing 2- substituted pyridines, and the alkynyl alcohol of 2- substituted pyridines cannot directly obtain from commercial channel it is necessary to Preparation is participated in by lithium reagent or tetrabutyl ammonium fluoride, and condition is harsher, such as two methods are required for anhydrous, lithium Reagent also needs to stringent low-temperature.Not only complex steps, and due to strict reaction condition, be difficult to realize, and relatively costly.
Thus, still have much room for improvement currently, with respect to the method preparing polysubstituted indolinone.
Content of the invention
It is contemplated that at least solving one of technical problem in correlation technique to a certain extent.For this reason, the one of the present invention Purpose is to propose the method that one kind efficiently can prepare polysubstituted indolinone by " one kettle way ".
The invention provides a kind of method preparing polysubstituted indolinone.According to embodiments of the invention, the method includes： Compound shown in Formula II is made to react with compound shown in formula III, to obtain compound shown in Formulas I,
Wherein, R ' is any one in haloalkyl, alkyl, cycloalkyl, optionally substituted aryl, heteroaryl,
R " be selected from hydrogen, alkyl, haloalkyl, alkoxyl, alkylamino, nitro, hydroxyl, amino, cyano group, carboxyl, Halogen, hydroxy alkoxy base, hydroxy alkyl, aminoalkoxy, halogenated alkoxy, aryl, aryl alkyl, heteroaryl, miscellaneous Any one in aryl alkyl, heterocyclic radical, cycloheteroalkylalkyl, cycloalkyl or cycloalkyl-alkyl,
R is any one in alkyl, haloalkyl, optionally substituted aryl, heteroaryl.
Inventor find, using the method according to embodiments of the present invention, can effectively pass through " one kettle way " prepare many Substituted Indolinyl ketone, and the method, with pyridone and end alkynes as initiation material, can avoid the alkynyl alcohol of 2- substituted pyridines Preparation, from the reaction condition harsh without anhydrous, stringent low-temperature etc., not only step is simple, easily operation, and cost Relatively low.
The method preparing polysubstituted indolinone according to an embodiment of the invention, can also have following additional technical feature：
According to embodiments of the invention, R ' is selected from C1-6Haloalkyl, C1-6Alkyl, C3-10Cycloalkyl, optionally substituted C6-10Aryl, C1-9At least one in heteroaryl,
R " is selected from hydrogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6Alkylamino, nitro, hydroxyl, amino, Cyano group, carboxyl, halogen, hydroxyl C1-6Alkoxyl, hydroxyl C1-6Alkyl, amino C1-6Alkoxyl, halo C1-6Alkoxyl, C6-10Aryl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical, C2-10Heterocycle Base C1-6Alkyl, C3-10Cycloalkyl or C3-10Cycloalkyl C1-6Any one in alkyl,
R is selected from C1-6Alkyl, C1-6Haloalkyl, optionally substituted C6-10Aryl, C1-9Any one in heteroaryl.
According to embodiments of the invention, R ' is selected from C1-6Haloalkyl, C1-6Alkyl, C3-10Cycloalkyl, optionally substituted pyrrole At least one in piperidinyl, thienyl, furyl,
R " is selected from hydrogen, C1-6Any one in alkyl,
R is any one in optionally substituted phenyl, naphthyl, pyridine radicals, thienyl, furyl.
According to embodiments of the invention, R ' is in 2- pyridine radicals, 4- pyridine radicals, 4- methyl -2- pyridine radicals, trifluoromethyl Any one,
R " is any one in hydrogen, methyl,
R be selected from phenyl, p-methylphenyl, Chloro-O-Phenyl, a chlorphenyl, rubigan, p-bromophenyl, to methoxyl group Phenyl, p-nitrophenyl, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 4- xenyl, naphthyl, cyclohexyl, 4- phenyl fourth Any one in base, n-hexyl.
According to embodiments of the invention, in a solvent, compound shown in Formula II is made to react with compound shown in formula III, wherein, Solvent can be at least in dioxane, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, toluene, water Kind, preferably dioxane.
According to embodiments of the invention, compound shown in Formula II and formula III can be made under conditions of catalyst and alkali exist Shown compound reaction, wherein, catalyst can be mantoquita, preferably Schweinfurt green, and alkali is inorganic base or organic base, at this In some embodiments of invention, inorganic base can be at least one in potassium carbonate, sodium carbonate, sodium bicarbonate, at this Invention other embodiments in, organic base can be in triethylamine, three-ethylenediamine, two-isopropyl-ethamine at least One kind is it is preferable that alkali can be triethylamine.
According to embodiments of the invention, in 110-140 degree Celsius, it is preferable under 110 degrees celsius, make Formula II shownization Compound reacts 1-96 hour with compound shown in formula III.
According to embodiments of the invention, compound shown in Formula II is 1 with the mol ratio of compound shown in formula III：1-1：10, excellent Select 1：2.
According to embodiments of the invention, the method preparing polysubstituted indolinone further includes：By silica gel column chromatography method, The step that compound of formula I is isolated and purified.In some embodiments of the invention, silica gel column chromatography method is adopted The granularity of silica gel is 100-200 mesh, and eluant is volume ratio 5：1-0：1 normal hexane and the mixed solution of ethyl acetate.
According to embodiments of the invention, by " one kettle way ", compound shown in Formula II is reacted with compound shown in formula III, with Just obtain compound shown in Formulas I.
Specific embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining the present invention, And be not considered as limiting the invention.Unreceipted particular technique or condition in embodiment, according to document in the art Described technology or condition or carry out according to product description.Agents useful for same or the unreceipted production firm person of instrument, are Can by city available from conventional products.
The invention provides a kind of method preparing polysubstituted indolinone.According to embodiments of the invention, the method includes： Compound shown in Formula II is made to react with compound shown in formula III, to obtain compound shown in Formulas I,
Wherein, R ' can be any one in haloalkyl, alkyl, cycloalkyl, optionally substituted aryl, heteroaryl Kind,
R " can be selected from hydrogen, alkyl, haloalkyl, alkoxyl, alkylamino, nitro, hydroxyl, amino, cyano group, carboxylic Base, halogen, hydroxy alkoxy base, hydroxy alkyl, aminoalkoxy, halogenated alkoxy, aryl, aryl alkyl, heteroaryl, Any one in heteroaryl alkyl, heterocyclic radical, cycloheteroalkylalkyl, cycloalkyl or cycloalkyl-alkyl,
R can be any one in alkyl, haloalkyl, optionally substituted aryl, heteroaryl.
According to some embodiments of the present invention, R ' can be selected from C1-6Haloalkyl, C1-6Alkyl, C3-10Cycloalkyl, optionally The C replacing6-10Aryl, C1-9At least one in heteroaryl,
R " can be selected from hydrogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6Alkylamino, nitro, hydroxyl, Amino, cyano group, carboxyl, halogen, hydroxyl C1-6Alkoxyl, hydroxyl C1-6Alkyl, amino C1-6Alkoxyl, halo C1-6 Alkoxyl, C6-10Aryl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl or C3-10Cycloalkyl C1-6Any one in alkyl,
R can be selected from C1-6Alkyl, C1-6Haloalkyl, optionally substituted C6-10Aryl, C1-9Any one in heteroaryl Kind.
According to some currently preferred embodiments of the present invention, R ' can be selected from C1-6Haloalkyl, C1-6Alkyl, C3-10Cycloalkyl, At least one in optionally substituted pyridine radicals, thienyl, furyl,
R " can be selected from hydrogen, C1-6Any one in alkyl,
R can be any one in optionally substituted phenyl, naphthyl, pyridine radicals, thienyl, furyl.
According to some specific examples of the present invention, R ' can be selected from 2- pyridine radicals, 4- pyridine radicals, 4- methyl -2- pyridine radicals -, Any one in trifluoromethyl,
R " can be any one in hydrogen, methyl,
R can be selected from phenyl, p-methylphenyl, Chloro-O-Phenyl, a chlorphenyl, rubigan, p-bromophenyl, to first Phenyl, p-nitrophenyl, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 4- xenyl, naphthyl, cyclohexyl, 4- benzene Any one in base butyl, n-hexyl.
According to embodiments of the invention, compound shown in Formula II can be made to react with compound shown in formula III in a solvent, its In, solvent can be in dioxane, dimethyl sulfoxide, acetonitrile, DMF, toluene, water extremely Few one kind, provides suitable reaction environment thereby, it is possible to the reaction between compound shown in compound shown in Formula II and formula III, Be conducive to improving reaction rate and yield.According to a preferred embodiment of the present invention, solvent can be dioxane.Thus, Reaction rate is very fast, and yield is higher.
According to embodiments of the invention, compound shown in Formula II and formula III can be made under conditions of catalyst and alkali exist Shown compound reaction.Thereby, it is possible to make reaction carry out under the conditions of optimal such that it is able to improve reaction further Speed and yield.
According to some embodiments of the present invention, the catalyst of employing can be mantoquita, according to a preferred embodiment of the invention, urges Agent can be Schweinfurt green.Carry out thereby, it is possible to effectively facilitate reaction, greatly improve reaction rate, shorten the response time.
According to embodiments of the invention, the alkali of employing can be inorganic base or organic base.In some embodiments of the invention, Inorganic base can be at least one in potassium carbonate, sodium carbonate, sodium bicarbonate, in other embodiments of the present invention, Organic base can be at least one in triethylamine, three-ethylenediamine, two-isopropyl-ethamine.One in the present invention excellent Select in embodiment, the alkali of employing can be triethylamine.Thereby, it is possible to provide suitable reaction condition for reaction, reduce secondary anti- Should occur, be conducive to improving the yield of reaction rate and target product.
According to embodiments of the invention, can make shown in compound shown in Formula II and formula III under 110-140 degrees celsius Compound reacts 1-96 hour.Thereby, it is possible to be reacted under optimal temperature conditionss, ensureing the same of reaction rate When, can effectively reduce side reaction and occur such that it is able to improve the yield of target product.Inventor is through lot of experiment validation Find, if reaction temperature is too high, be susceptible to side reaction, lead to target product yield to reduce, and increase target product to divide From the difficulty of purification, if temperature is too low, reaction is not susceptible to, or reaction rate is excessively slow, and the response time is long；If anti- Too short between seasonable, then react insufficient, target product yield is low, and the waste of reaction raw materials can be caused, if the response time Long, then the extent of reaction and target product yield do not have significant change, and economy is poor.One in the present invention is preferable to carry out In example, under 110 degrees celsius, compound shown in Formula II is made to react 1-96 hour with compound shown in formula III.Thus, Reaction rate is very fast, can effectively reduce side reaction and occur, target product yield is higher.
According to embodiments of the invention, during the course of the reaction, reality can be carried out to reaction process by thin layer chromatography (TLC) When monitoring.
According to embodiments of the invention, compound shown in Formula II is 1 with the mol ratio of compound shown in formula III：1-1：10.By This, be conducive to reaction fully to carry out, improve the yield of target product.Inventor finds through many experiments, if ratio mistake Height, can cause reaction raw materials significantly excessive, cause wastage of material, if ratio is too low, be unfavorable for that reaction is fully carried out. In a preferred embodiment of the invention, compound shown in Formula II and the mol ratio of compound shown in formula III are 1：2.By This, enable to reaction and carry out relatively fully, and better economy simultaneously.
The according to embodiments of the present invention method preparing polysubstituted indolinone may further include：By silica gel column chromatography side Method, the step that compound shown in Formulas I is isolated and purified.Specifically, after detecting that reaction terminates by TLC, obtain Reaction mixture, then, reaction mixture is filtered, and gained filtrate isolates and purifies acquisition by silica gel column chromatography method Compound shown in Formulas I.In some embodiments of the invention, before carrying out silica gel column chromatography, can also include solvent Reduce pressure filtrate obtained by filtering the step being spin-dried for.In some embodiments of the invention, silica gel column chromatography method is adopted The granularity of silica gel is 100-200 mesh, and eluant is volume ratio 5：1-0：1 normal hexane and the mixed solution of ethyl acetate. Obtain compound shown in Formulas I thereby, it is possible to fast and efficiently separate, and the product purity obtaining is higher.
According to embodiments of the invention, by " one kettle way ", compound shown in Formula II can be reacted with compound shown in formula III, So that compound shown in acquisition Formulas I.It is thereby, it is possible to fast and efficiently prepare compound shown in Formulas I and simple to operate, Convenient and swift, reaction condition is gentle, suitable industrialized production.
Embodiments of the invention are described below in detail.
Embodiment 1
By two -2- pyridinyl methanones (55mg, 0.3mmol), phenylacetylene (61mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03 ), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL) mmol.Obtained mixed system is added , to 110 DEG C, after reaction 4h, TLC monitoring reaction is complete for heat.Stopped reaction, filters, crude on silica gel column chromatography (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 82mg, yield is 95%.
1H NMR(300MHz,CDCl3) δ 8.60 (d, J=4.3Hz, 1H), 7.68 (t, J=4.8Hz, 3H), 7.58 7.46 (m, 4H), 7.19 (dd, J=7.0,5.1Hz, 1H), 6.73 (d, J=7.2Hz, 1H), 6.45 (d, J=9.2Hz, 1H), 6.12 (dd, J=9.2,5.5Hz, 1H), 5.39 5.29 (m, 1H), 5.21 (s, 1H)；13C NMR(75MHz,CDCl3)δ199.22, 175.24,158.66,149.50,136.83,131.18,129.49,129.07,128.20,124.58,123.50,122.72,122.03, 120.24,108.80,99.51,73.78.HRMS(ESI):Exact mass calcd for C19H14N2O+[M+Na]+309.0996, found 309.0998.
Embodiment 2
By two -2- pyridinyl methanones (55mg, 0.3mmol), to methyl phenylacetylene (69mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 4h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post layer Analysis (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 90mg, yield is 100%.
1H NMR(300MHz,CDCl3) δ 8.59 (d, J=4.7Hz, 1H), 7.66 (td, J=7.9,1.7Hz, 1H), 7.55 (d, J=8.1Hz, 2H), 7.49 (d, J=8.0Hz, 1H), 7.34 (d, J=8.0Hz, 2H), 7.20 7.13 (m, 1H), 6.74 (d, J=7.3Hz, 1H), 6.44 (d, J=9.2Hz, 1H), 6.10 (dd, J=9.2,5.5Hz, 1H), 5.37 5.29 (m, 1H), 5.18(s,1H),2.44(s,3H)；13C NMR(75MHz,CDCl3)δ199.1,175.4,158.8,149.5,141.7,136.7, 129.7,128.1,126.6,124.7,123.4,122.7,122.1,120.1,108.7,99.2,73.8,21.7.HRMS(ESI): Exact mass calcd for C20H16N2O+[M+Na]+323.1152,found 323.1155.
Embodiment 3
By two -2- pyridinyl methanones (55mg, 0.3mmol), to Methoxy-phenylacetylene (79mg, 0.6mmol), Schweinfurt green (5.4 Mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).Obtained is mixed Fit system is heated to 110 DEG C, and after reaction 24h, TLC monitoring reaction is complete.Stopped reaction, filters, crude product is through silicon Plastic column chromatography (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 81mg, yield is 85%.
1H NMR(300MHz,CDCl3) δ 8.58 (d, J=4.1Hz, 1H), 7.70 7.54 (m, 3H), 7.48 (d, J=8.0 Hz, 1H), 7.17 (dd, J=6.7,5.0Hz, 1H), 7.04 (d, J=8.8Hz, 2H), 6.77 (d, J=7.2Hz, 1H), 6.44 (d, J=9.2Hz, 1H), 6.10 (dd, J=9.2,5.4Hz, 1H), 5.39 5.27 (m, 1H), 5.16 (s, 1H), 3.88 (s, 3H)；13C NMR(75MHz,CDCl3)δ198.98,175.11,161.93,158.86,149.48,136.74,129.90,124.79, 123.39,122.64,122.16,121.65,120.21,114.49,108.71,98.85,73.81,55.51.HRMS(ESI):Exact mass calcd for C20H16N2O+[M+Na]+339.1101,found 339.1104.
Embodiment 4
By two -2- pyridinyl methanones (55mg, 0.3mmol), p-nitrophenylacetylene (88mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 24h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post Chromatography (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 77mg, yield is 78%.
1H NMR(300MHz,CDCl3) δ 8.57 (d, J=4.3Hz, 1H), 8.47 8.35 (m, 2H), 7.89 (d, J=8.7 Hz, 2H), 7.69 (dd, J=7.7,1.4Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 7.26 (s, 1H), 7.22 (dd, J=7.0, 5.3Hz, 1H), 6.59 (d, J=7.2Hz, 1H), 6.42 (d, J=9.2Hz, 1H), 6.15 (dd, J=9.2,5.5Hz, 1H), 5.44–5.33(m,1H),5.27(s,1H)；13C NMR(75MHz,CDCl3)δ199.13,172.30,158.25,149.34, 137.04,135.69,129.42,124.28,123.92,123.79,122.97,121.72,120.89,109.43,100.56,73.92. HRMS(ESI):Exact mass calcd for C19H13N3O3 +[M+Na]+354.0842,found 354.0849.
Embodiment 5
By two -2- pyridinyl methanones (55mg, 0.3mmol), 4- chlorobenzene acetylene (82mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 24h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post Chromatography (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 89mg, yield is 93%.
1H NMR(300MHz,CDCl3) δ 8.58 (d, J=4.1Hz, 1H), 7.74 7.56 (m, 3H), 7.56 7.44 (m, 3H), 7.19 (dd, J=6.6,5.0Hz, 1H), 6.66 (d, J=7.2Hz, 1H), 6.42 (d, J=9.2Hz, 1H), 6.12 (dd, J =9.2,5.5Hz, 1H), 5.41 5.30 (m, 1H), 5.19 (s, 1H)；13C NMR(75MHz,CDCl3)δ199.1,173.9, 158.5,149.4,137.4,136.9,129.6,129.4,127.9,124.3,123.6,122.8,121.9,120.5,109.0,99.6, 73.8.HRMS(ESI):Exact mass calcd for C19H13ClN2O+[M+Na]+343.0605,found 343.0609.
Embodiment 6
By two -2- pyridinyl methanones (55mg, 0.3mmol), 3- chlorobenzene acetylene (82mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 4h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post layer Analysis (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 89mg, yield is 93%.
1H NMR(300MHz,CDCl3) δ 8.59 (d, J=4.2Hz, 1H), 7.74 7.62 (m, 2H), 7.61 7.42 (m, 4H), 7.20 (dd, J=6.8,5.1Hz, 1H), 6.67 (d, J=7.2Hz, 1H), 6.43 (d, J=9.2Hz, 1H), 6.13 (dd, J =9.2,5.4Hz, 1H), 5.43 5.31 (m, 1H), 5.21 (s, 1H)；13C NMR(75MHz,CDCl3)δ190.2,173.5, 158.5,149.5,136.9,135.2,131.2,130.4,128.2,126.4,124.3,123.6,122.8,121.9,120.5,109.1, 88.8,73.8.HRMS(ESI):Exact mass calcd for C19H13ClN2O+[M+Na]+343.0605,found 343.0609.
Embodiment 7
By two -2- pyridinyl methanones (55mg, 0.3mmol), 2- chlorobenzene acetylene (82mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 4h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post layer Analysis (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 92mg, yield is 96%.
1H NMR(300MHz,CDCl3) δ 8.63 (d, J=4.4Hz, 1H), 7.67 (td, J=7.7,1.7Hz, 1H), 7.60 7.51 (m, 3H), 7.45 (dtd, J=14.4,7.3,1.7Hz, 2H), 7.19 (ddd, J=7.2,4.8,1.0Hz, 1H), 6.48 (d, J =9.2Hz, 1H), 6.30 (d, J=7.2Hz, 1H), 6.11 (dd, J=9.2,5.5Hz, 1H), 5.35 (t, J=6.1Hz, 1H), 5.19(s,1H)；13C NMR(75MHz,CDCl3)δ199.3,171.9,158.3,149.7,136.7,132.5,131.9,130.7, 130.4,128.8,127.3,124.2,123.4,122.7,122.5,119.9,109.4,100.5,73.4.HRMS(ESI):Exact mass calcd for C19H13ClN2O+[M+Na]+343.0605,found 343.0609.
Embodiment 8
By two -2- pyridinyl methanones (55mg, 0.3mmol), 4- bromobenzene acetylene (108mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 24h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post Chromatography (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 100mg, yield is 91%.
1H NMR(300MHz,CDCl3) δ 8.57 (d, J=4.2Hz, 1H), 7.67 (dd, J=10.9,5.0Hz, 3H), 7.52 (dd, J=15.4,8.2Hz, 3H), 7.19 (dd, J=6.9,5.4Hz, 1H), 6.65 (d, J=7.2Hz, 1H), 6.42 (d, J= 9.2Hz, 1H), 6.12 (dd, J=9.2,5.5Hz, 1H), 5.40 5.29 (m, 1H), 5.19 (s, 1H)；13C NMR(75MHz, CDCl3)δ199.1,173.9,158.5,149.4,136.9,132.4,129.7,128.4,125.7,124.3,123.6,122.8, 121.9,120.5,109.0,99.6,73.8.HRMS(ESI):Exact mass calcd for C19H13BrN2O+[M+Na]+ 387.0097,found 387.0104.
Embodiment 9
By two -2- pyridinyl methanones (55mg, 0.3mmol), 4- pyridine acetylene (62mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 130 DEG C, and after reaction 24h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post Chromatography (100-200 mesh, normal hexane：Ethyl acetate=1：2) process, obtain target product 56mg, yield is 64%.
1H NMR(400MHz,CDCl3) δ 8.83 (d, J=5.7Hz, 2H), 8.57 (d, J=4.1Hz, 1H), 7.69 (td, J =7.9,1.6Hz, 1H), 7.60 7.54 (m, 2H), 7.51 (d, J=8.0Hz, 1H), 7.21 (dd, J=6.9,5.3Hz, 1H), 6.61 (d, J=7.2Hz, 1H), 6.42 (d, J=9.2Hz, 1H), 6.13 (dd, J=9.2,5.5Hz, 1H), 5.39 (t, J=6.3 Hz,1H),5.26(s,1H)；13C NMR(75MHz,CDCl3)δ199.23,171.99,158.20,150.77,149.39, 137.22,136.98,123.92,123.72,122.92,122.26,121.79,120.69,109.39,100.23,73.84.HRMS (ESI):Exact mass calcd for C18H13N3O+[M+Na]+310.0949,found 310.0951.
Embodiment 10
By two -2- pyridinyl methanones (55mg, 0.3mmol), 3- pyridine acetylene (62mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 72h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post Chromatography (100-200 mesh, normal hexane：Ethyl acetate=1：2) process, obtain target product 68mg, yield is 79%.
1H NMR(300MHz,CDCl3) δ 8.93 (s, 1H), 8.78 (d, J=3.7Hz, 1H), 8.56 (d, J=4.7Hz, 1H), 8.06 7.93 (m, 1H), 7.67 (td, J=7.8,1.7Hz, 1H), 7.48 (dd, J=7.9,4.1Hz, 2H), 7.23 7.14 (m, 1H), 6.63 (t, J=5.7Hz, 1H), 6.42 (d, J=9.2Hz, 1H), 6.13 (dd, J=9.2,5.3Hz, 1H), 5.45 5.32 (m, 1H), 5.25 (d, J=4.5Hz, 1H)；13C NMR(75MHz,CDCl3)δ199.1,171.6,158.3, 152.1,149.4,148.8,136.9,135.7,125.8,124.0,123.7,122.9,121.9,120.7,109.4,100.2,73.8. HRMS(ESI):Exact mass calcd for C18H13N3O+[M+Na]+310.0949,found 310.0951.
Embodiment 11
By two -2- pyridinyl methanones (55mg, 0.3mmol), 2- pyridine acetylene (62mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 130 DEG C, and after reaction 18h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post Chromatography (100-200 mesh, normal hexane：Ethyl acetate=1：2) process, obtain target product 53mg, yield is 61%.
1H NMR(300MHz,CDCl3) δ 8.83 (d, J=4.6Hz, 1H), 8.62 (d, J=4.2Hz, 1H), 7.88 (td, J =7.8,1.6Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 7.65 (td, J=7.8,1.7Hz, 1H), 7.55 (t, J=8.3Hz, 2H), 7.45 (dd, J=6.5,5.0Hz, 1H), 7.17 (dd, J=6.5,5.0Hz, 1H), 6.51 (d, J=9.2Hz, 1H), 6.11 (dd, J=9.2,5.4Hz, 1H), 5.44 (s, 1H), 5.42 5.34 (m, 1H)；13C NMR(75MHz,CDCl3)δ199.4, 171.5,158.5,149.8,149.7,149.1,137.3,136.8,126.1,125.4,125.2,123.5,122.7,122.5,119.9, 109.2,99.5,74.2.HRMS(ESI):Exact mass calcd for C18H13N3O+[M+Na]+310.0949,found 310.0951.
Embodiment 12
By two -2- pyridinyl methanones (55mg, 0.3mmol), 2- naphthyl acetylene (91mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).Mixed system by gained It is heated to 130 DEG C, after reaction 5h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel column chromatography (100-200 mesh, normal hexane：Ethyl acetate=1：2) process, obtain target product 100mg, yield is 100%.
1H NMR(400MHz,CDCl3) δ 8.64 (d, J=4.0Hz, 1H), 8.19 (s, 1H), 8.00 (d, J=8.5Hz, 1H), 7.98 7.89 (m, 2H), 7.76 7.65 (m, 2H), 7.65 7.53 (m, 3H), 7.21 (dd, J=6.7,5.3Hz, 1H), 6.81 (d, J=7.2Hz, 1H), 6.47 (d, J=9.2Hz, 1H), 6.14 (dd, J=9.2,5.5Hz, 1H), 5.36 (t, J=6.3 Hz,1H),5.32(s,1H)；13C NMR(75MHz,CDCl3)δ199.26,175.36,158.78,149.54,136.84, 134.36,132.86,128.98,128.66,128.48,127.96,127.91,127.21,126.81,124.78,124.69,123.52, 122.74,122.05,120.34,108.83,99.79,73.91.HRMS(ESI):Exact mass calcd for C23H16N2O+ [M+Na]+359.1150,found 359.1155.
Embodiment 13
By two -2- pyridinyl methanones (55mg, 0.3mmol), 4- diphenylethyne (107mg, 0.6mmol), Schweinfurt green (5.4 Mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).Obtained is mixed Fit system is heated to 130 DEG C, and after reaction 1h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel Column chromatography (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 100mg, yield is 92%.
1H NMR (300MHz, CDCl3) δ 8.61 (d, J=4.0Hz, 1H), 7.76 (d, J=2.8Hz, 4H), 7.72 7.61 (m, 3H), 7.55 7.38 (m, 4H), 7.23 7.15 (m, 1H), 6.81 (d, J=7.3Hz, 1H), 6.47 (d, J=9.2Hz, 1H), 6.13 (dd, J=9.2,5.4Hz, 1H), 5.38 (dd, J=9.3,3.4Hz, 1H), 5.26 (s, 1H)；13C NMR(75 MHz,CDCl3)δ199.16,174.94,158.72,149.49,144.16,139.86,136.83,129.05,128.73,128.26, 128.21,127.71,127.20,124.70,123.50,122.73,122.08,120.29,108.84,99.48,73.87.HRMS (ESI):Exact mass calcd for C25H18N2O+[M+Na]+385.1306,found 385.1311.
Embodiment 14
By two -2- pyridinyl methanones (55mg, 0.3mmol), cyclohexyl-acetylene (65mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 1h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post layer Analysis (100-200 mesh, normal hexane：Ethyl acetate=2：1) process, obtain target product 79mg, yield is 90%.
1H NMR(300MHz,CDCl3) δ 8.54 (d, J=4.6Hz, 1H), 7.61 (t, J=7.7Hz, 1H), 7.34 (d, J= 7.9Hz, 1H), 7.21 7.09 (m, 1H), 6.67 (d, J=7.1Hz, 1H), 6.41 (d, J=9.1Hz, 1H), 6.07 (dd, J= 9.2,5.2Hz,1H),5.44–5.39(m,1H),4.93(s,1H),2.67-2.63(m,1H),2.21-1.32(m,10H)；13C NMR(75MHz,CDCl3)δ199.3,182.6,158.5,149.3,136.6,123.4,123.0,122.5,119.9,109.3, 95.4,72.9,36.4,31.5,30.7,26.1,25.9,25.8.HRMS(ESI):Exact mass calcd for C19H20N2O+ [M+Na]+315.1464,found 315.1468.
Embodiment 15
By two -2- pyridinyl methanones (55mg, 0.3mmol), 4- phenyl-ethyl acetylene (78mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 1h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post layer Analysis (100-200 mesh, normal hexane：Ethyl acetate=2：1) process, obtain target product 88mg, yield is 94%.
1H NMR(300MHz,CDCl3) δ 8.55 (d, J=4.1Hz, 1H), 7.62 (t, J=7.1Hz, 1H), 7.31 (dd, J =9.0,5.6Hz, 3H), 7.23 (dd, J=8.3,4.2Hz, 2H), 7.19 7.12 (m, 1H), 6.60 (d, J=7.1Hz, 1H), 6.39 (d, J=9.2Hz, 1H), 6.09 (dd, J=9.2,5.4Hz, 1H), 5.43 5.36 (m, 1H), 4.98 (s, 1H), 3.13 2.83(m,4H)；13C NMR(75MHz,CDCl3)δ199.3,177.0,158.4,149.3,139.7,136.7,128.7, 128.4,126.7,123.6,123.0,122.8,122.6,120.4,109.6,97.6,73.1,32.8,29.2.HRMS(ESI):Exact mass calcd for C21H18N2O+[M+Na]+337.1307,found 337.1311.
Embodiment 16
By two -2- pyridinyl methanones (55mg, 0.3mmol), 1- octyne (66mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03 ), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL) mmol.Obtained mixed system is added , to 110 DEG C, after reaction 1h, TLC monitoring reaction is complete for heat.Stopped reaction, filters, crude on silica gel column chromatography (100-200 mesh, normal hexane：Ethyl acetate=2：1) process, obtain target product 70mg, yield is 80%.
1H NMR(400MHz,CDCl3)δ8.58(s,1H),7.70(s,1H),7.45(s,1H),7.22(s,1H),6.71(s, 1H), 6.38 (d, J=9.1Hz, 1H), 6.11 (dd, J=9.0,5.5Hz, 1H), 5.44 (t, J=6.1Hz, 1H), 4.97 (s, 1H), 2.81–2.53(m,2H),1.89–0.75(m,13H).；13C NMR(75MHz,CDCl3)δ199.3,178.2,158.5, 149.3,136.6,123.5,123.1,122.8,122.6,120.3,109.3,97.5,73.1,31.45,29.0,27.4,26.7,22.5, 14.0.HRMS(ESI):Exact mass calcd for C19H22N2O+[M+Na]+317.1621,found 317.1624.
Embodiment 17
By two-(4- methyl -2- pyridine)-ketones (42mg, 0.2mmol), phenylacetylene (41mg, 0.4mmol), Schweinfurt green (3.6mg, 0.02mmol), and triethylamine (40mg, 0.4mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).Will be obtained Mixed system be heated to 110 DEG C, reaction 1h after TLC monitoring reaction complete.Stopped reaction, filters, crude product warp Silica gel column chromatography (100-200 mesh, normal hexane：Ethyl acetate=2：1) process, obtain target product 48mg, yield is 77%.
1H NMR(300MHz,CDCl3) δ 8.43 (d, J=4.9Hz, 1H), 7.73 7.62 (m, 2H), 7.59 7.49 (m, 3H), 7.31 (s, 1H), 6.99 (d, J=4.6Hz, 1H), 6.70 (d, J=7.2Hz, 1H), 6.12 (d, J=1.1Hz, 1H), 5.21(s,1H),5.20(s,1H),2.35(s,3H),1.84(s,3H)；13C NMR(75MHz,CDCl3)δ199.88, 175.04,158.91,149.03,147.88,132.05,131.06,129.67,129.00,128.23,124.07,123.67,121.33, 117.14,112.38,99.89,74.12,21.32,20.69.HRMS(ESI):Exact mass calcd for C21H19N2O+ [M+H]+315.1489,found 315.1492.
Embodiment 18
By two-(4- methyl -2- pyridine)-ketones (32mg, 0.15mmol), to Methoxy-phenylacetylene (40mg, 0.3mmol), Schweinfurt green (2.7mg, 0.015mmol), and triethylamine (30mg, 0.3mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (1.5mL). Obtained mixed system is heated to 110 DEG C, after reaction 24h, TLC monitoring reaction is complete.Stopped reaction, filters, Crude on silica gel column chromatography (100-200 mesh, normal hexane：Ethyl acetate=2：1) process, obtain target product 35mg, Yield is 68%.
1H NMR(400MHz,CDCl3) δ 8.42 (d, J=4.8Hz, 1H), 7.63 (d, J=8.4Hz, 2H), 7.30 (s, 1H), 7.03 (d, J=8.7Hz, 2H), 6.98 (d, J=4.4Hz, 1H), 6.74 (d, J=7.2Hz, 1H), 6.11 (s, 1H), 5.21 (d, J=7.3Hz, 1H), 5.17 (s, 1H), 3.88 (s, 3H), 2.34 (s, 3H), 1.83 (s, 3H)；13C NMR(75MHz, CDCl3)δ199.8,175.0,161.9,159.2,149.1,131.9,129.9,124.3,123.6,121.8,121.3,117.3,114.4, 112.3,99.2,74.2,55.5,21.3,20.7.HRMS(ESI):Exact mass calcd for C22H21N2O2 +[M+H]+ 345.1593,found 345.1598.
Embodiment 19
By two-(4- methyl -2- pyridine)-ketones (32mg, 0.15mmol), 2- naphthyl acetylene (45mg, 0.3mmol), vinegar Sour copper (2.7mg, 0.015mmol), and triethylamine (30mg, 0.3mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (1.5mL).Will Obtained mixed system is heated to 110 DEG C, and after reaction 24h, TLC monitoring reaction is complete.Stopped reaction, filters, Crude on silica gel column chromatography (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 45mg, Yield is 82%.
1H NMR(400MHz,CDCl3) δ 8.64 (d, J=4.0Hz, 1H), 8.19 (s, 1H), 8.00 (d, J=8.5Hz, 1H), 7.98 7.89 (m, 2H), 7.76 7.65 (m, 2H), 7.65 7.53 (m, 3H), 7.21 (dd, J=6.7,5.3Hz, 1H), 6.81 (d, J=7.2Hz, 1H), 6.47 (d, J=9.2Hz, 1H), 6.14 (dd, J=9.2,5.5Hz, 1H), 5.36 (t, J=6.3 Hz,1H),5.32(s,1H).；13C NMR(75MHz,CDCl3)δ200.0,175.2,159.1,149.1,148.3,134.3, 132.9,132.1,128.9,128.7,128.5,127.9,127.8,127.1,127.0,124.8,124.2,123.7,121.4,117.2, 112.4,100.2,74.3,21.3,20.7.HRMS(ESI):Exact mass calcd for C25H21N2O+[M+H]+365.1645, found 365.1648.
Embodiment 20
By two-(4- methyl -2- pyridine)-ketones (32mg, 0.15mmol), cyclohexyl-acetylene (32mg, 0.3mmol), Schweinfurt green (2.7mg, 0.015mmol), and triethylamine (30mg, 0.3mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (1.5mL). Obtained mixed system is heated to 110 DEG C, after reaction 1h, TLC monitoring reaction is complete.Stopped reaction, filters, Crude on silica gel column chromatography (100-200 mesh, normal hexane：Ethyl acetate=2：1) process, obtain target product 51mg, Yield is 80%.
1H NMR(400MHz,CDCl3) δ 8.36 (d, J=4.9Hz, 1H), 7.17 (s, 1H), 6.94 (d, J=4.0Hz, 1H), 6.64 (d, J=7.0Hz, 1H), 6.09 (s, 1H), 5.28 (d, J=7.2Hz, 1H), 4.93 (s, 1H), 2.65 2.61 (m, 1H),2.31(s,3H),2.20–1.27(m,10H),1.81(s,3H)；13C NMR(75MHz,CDCl3)δ200.1,182.3, 158.8,148.9,147.6,131.9,123.4,122.5,121.0,118.2,112.9,95.7,73.4,36.4,31.5,30.8,26.1, 25.9,25.8,21.3,20.6.HRMS(ESI):Exact mass calcd for C21H25N2O+[M+H]+321.1958,found 321.1961.
Embodiment 21
By three fluoro -1-Phenylethanone. (53mg, 0.3mmol), phenylacetylene (61mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03 ), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL) mmol.Obtained mixed system is added , to 110 DEG C, after reaction 20h, TLC monitoring reaction is complete for heat.Stopped reaction, filters, crude on silica gel column chromatography (100-200 mesh, normal hexane：Ethyl acetate=2：1) process, obtain target product 58mg, yield is 70%.
1H NMR(300MHz,CDCl3) δ 7.58 7.53 (m, 5H), 6.57 (dd, J=7.4,0.7Hz, 1H), 6.22 (dd, J =9.4,5.7Hz, 1H), 5.80 (d, J=9.4Hz, 1H), 5.37 (dd, J=7.2,1.0Hz, 1H), 5.35 (s, 1H)；13C NMR(100MHz,CDCl3)δ194.6,178.5,131.8,129.3,128.6,127.9,127.4,126.1,122.7(q,JC-F =288.0Hz, 1C), 113.3,108.3,101.8,101.8,69.6.HRMS (ESI):Exact mass calcd for C15H11F3NO+[M+H]+278.0786,found 278.0787.
Embodiment 22
By three fluoro -1-Phenylethanone. (53mg, 0.3mmol), 2- naphthyl acetylene (91mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 36h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post Chromatography (100-200 mesh, normal hexane：Ethyl acetate=12：1) process, obtain target product 56mg, yield is 57%.
1H NMR(300MHz,CDCl3)δ8.09(s,1H),8.04–7.86(m,3H),7.66–7.58(m,3H),6.65 (d, J=7.5Hz, 1H), 6.24 (dd, J=9.4,5.7Hz, 1H), 5.83 (d, J=9.4Hz, 1H), 5.47 (s, 1H), 5.38 (t, J=6.6Hz, 1H)；13C NMR(75MHz,CDCl3)δ194.6,178.6,134.6,132.8,129.3,128.7,128.5, 128.3,128.0,127.44,127.40,126.3,125.9,124.0,122.8(q,JC-F=288.0Hz, 1C), 113.4,108.3, 102.0,69.6(q,JC-F=28.5Hz, 1C) .HRMS (ESI):Exact mass calcd for C19H13F3NO+[M+H]+ 328.0942,found 328.0944.
Embodiment 23
By three fluoro -1-Phenylethanone. (53mg, 0.3mmol), cyclohexyl-acetylene (65mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 96h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post Chromatography (100-200 mesh, normal hexane：Ethyl acetate=12：1) process, obtain target product 45mg, yield is 53%.
1H NMR(300MHz,CDCl3) δ 6.54 (d, J=7.3Hz, 1H), 6.22 (dd, J=9.3,5.6Hz, 1H), 5.75 (d, J=9.3Hz, 1H), 5.50 (t, J=6.3Hz, 1H), 5.04 (s, 1H), 2.52 2.44 (m, 1H), 2.08-1.26 (m, 10H)；13C NMR(75MHz,CDCl3)δ195.0,185.5,127.5,124.2,122.7(q,JC-F=288.0Hz, 1C), 117.0,114.1,109.1,97.6,68.3(q,JC-F=28.5Hz, 1C), 36.3,31.4,30.3,26.0,25.70,25.67. HRMS(ESI):Exact mass calcd for C15H17F3NO+[M+H]+284.1257,found 284.1257.
Embodiment 24
By 2- pyridine -4- pyridine-ketone (55mg, 0.3mmol), phenylacetylene (61mg, 0.6mmol), Schweinfurt green (5.4mg, 0.03mmol), and triethylamine (60mg, 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL).By obtained mixture System is heated to 110 DEG C, and after reaction 63h, TLC monitoring reaction is complete.Stopped reaction, filters, crude on silica gel post Chromatography (100-200 mesh, normal hexane：Ethyl acetate=3：1) process, obtain target product 28mg, yield is 33%.
1H NMR(300MHz,CDCl3) δ 8.63 (s, 2H), 7.68 7.52 (m, 5H), 7.46 (s, 2H), 6.74 (d, J= 7.3Hz, 1H), 6.31 (d, J=9.2Hz, 1H), 6.08 (dd, J=9.2,5.5Hz, 1H), 5.46 5.33 (m, 1H), 5.22 (s, 1H).；13C NMR(75MHz,CDCl3) δ=198.83,175.13,149.83,149.19,131.55,129.28,129.00, 128.06,124.37,123.78,121.63,109.61,99.71,71.28.HRMS(ESI):Exact mass calcd for C19H15N2O+[M+H]+287.1181,found 287.1179.
In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " specific example ", Or the description of " some examples " etc. means specific features with reference to this embodiment or example description, structure, material or feature bag It is contained at least one embodiment or the example of the present invention.In this manual, to the schematic representation of above-mentioned term necessarily It is directed to identical embodiment or example.And, the specific features of description, structure, material or feature can be arbitrary Combine in an appropriate manner in individual or multiple embodiment or example.Additionally, in the case of not conflicting, the skill of this area The feature of the different embodiments described in this specification or example and different embodiment or example can be combined by art personnel And combination.
Although embodiments of the invention have been shown and described above it is to be understood that above-described embodiment is exemplary, It is not considered as limiting the invention, those of ordinary skill in the art within the scope of the invention can be to above-described embodiment It is changed, changes, replacing and modification.

Claims (10)

1. a kind of method preparing polysubstituted indolinone is it is characterised in that include：
Compound shown in Formula II is made to react with compound shown in formula III, to obtain compound shown in Formulas I,
Wherein, R ' is any one in haloalkyl, alkyl, cycloalkyl, optionally substituted aryl, heteroaryl,
R " be selected from hydrogen, alkyl, haloalkyl, alkoxyl, alkylamino, nitro, hydroxyl, amino, cyano group, carboxyl, Halogen, hydroxy alkoxy base, hydroxy alkyl, aminoalkoxy, halogenated alkoxy, aryl, aryl alkyl, heteroaryl, miscellaneous Any one in aryl alkyl, heterocyclic radical, cycloheteroalkylalkyl, cycloalkyl or cycloalkyl-alkyl,
R is any one in alkyl, haloalkyl, optionally substituted aryl, heteroaryl.
2. method according to claim 1 is it is characterised in that R ' is selected from C1-6Haloalkyl, C1-6Alkyl, C3-10 Cycloalkyl, optionally substituted C6-10Aryl, C1-9At least one in heteroaryl,
R " is selected from hydrogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6Alkylamino, nitro, hydroxyl, amino, Cyano group, carboxyl, halogen, hydroxyl C1-6Alkoxyl, hydroxyl C1-6Alkyl, amino C1-6Alkoxyl, halo C1-6Alkoxyl, C6-10Aryl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical, C2-10Heterocycle Base C1-6Alkyl, C3-10Cycloalkyl or C3-10Cycloalkyl C1-6Any one in alkyl,
R is selected from C1-6Alkyl, C1-6Haloalkyl, optionally substituted C6-10Aryl, C1-9Any one in heteroaryl.
3. method according to claim 2 is it is characterised in that R ' is selected from C1-6Haloalkyl, C1-6Alkyl, C3-10 At least one in cycloalkyl, optionally substituted pyridine radicals, thienyl, furyl,
R " is selected from hydrogen, C1-6Any one in alkyl,
R is any one in optionally substituted phenyl, naphthyl, pyridine radicals, thienyl, furyl.
4. method according to claim 3 is it is characterised in that R ' is selected from 2- pyridine radicals, 4- pyridine radicals, 4- methyl Any one in -2- pyridine radicals, trifluoromethyl,
R " is any one in hydrogen, methyl,
R be selected from phenyl, p-methylphenyl, Chloro-O-Phenyl, a chlorphenyl, rubigan, p-bromophenyl, to methoxyl group Phenyl, p-nitrophenyl, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 4- xenyl, naphthyl, cyclohexyl, 4- phenyl fourth Any one in base, n-hexyl.
5. method according to claim 1 it is characterised in that in a solvent, makes compound shown in described Formula II and institute State the reaction of compound shown in formula III, wherein, described solvent is selected from dioxane, dimethyl sulfoxide, acetonitrile, N, N- bis- At least one in methylformamide, toluene, water, preferably dioxane.
6. method according to claim 1 is it is characterised in that under conditions of catalyst and alkali exist, make described formula Compound shown in II is reacted with compound shown in described formula III,
Wherein,
Described catalyst is mantoquita, preferably Schweinfurt green,
Described alkali is inorganic base or organic base,
Optionally, described inorganic base is at least one in potassium carbonate, sodium carbonate, sodium bicarbonate, and described organic base is At least one in triethylamine, three-ethylenediamine, two-isopropyl-ethamine,
Preferably, described alkali is triethylamine.
7. method according to claim 1 is it is characterised in that in 110-140 degree Celsius, preferably 110 degrees Celsius bars Under part, compound shown in described Formula II and compound shown in described formula III is made to react 1-96 hour.
8. method according to claim 1 is it is characterised in that shown in compound shown in described Formula II and described formula III The mol ratio of compound is 1：1-1：10, preferably 1：2.
9. method according to claim 1 is it is characterised in that further include：
By silica gel column chromatography method, the step that described compound of formula I is isolated and purified,
Optionally, the granularity of the silica gel that described silica gel column chromatography method is adopted is 100-200 mesh, and eluant is volume ratio 5： 1-0：1 normal hexane and the mixed solution of ethyl acetate.
10. method according to claim 1 is it is characterised in that by " one kettle way " by chemical combination shown in described Formula II Thing is reacted with compound shown in described formula III, to obtain compound shown in described Formulas I.
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