CN106946875B - A kind of preparation method for the imidazole heterocyclic compounds that C-3 oxygen replaces - Google Patents
A kind of preparation method for the imidazole heterocyclic compounds that C-3 oxygen replaces Download PDFInfo
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
The present invention relates to one kind such as formula (1) or formula (2) or the synthetic methods of formula (3) compound represented, specially adjacent amino azacycle compound, 2- oxygroup acetophenone derivs, transition metal salt catalyst are placed in organic solvent, reaction is heated under oxygen-containing atmosphere, after reaction, reaction solution is post-treated obtains formula (1) or formula (2) or formula (3) compound represented；The 2- amino-heterocyclic compounds are 2-aminopyridine class compound or 2- amino benzo [d] thiazole compound or 1- aminoisoquinoline.Synthetic method of the present invention, easy to operate, reaction condition is mild, and by-product is only water, and reaction yield is high, has been up to 97%, two kinds of heterocycle compounds of synthesis all have pharmacological, can be used as the important as precursors of drug.
Description
Technical field
The present invention relates to a kind of preparation methods for the imidazole heterocyclic compounds that C-3 oxygen replaces, and in particular to C-3 oxygen take
Imidazo [1,2-a] pyridine in generation and the synthetic method of benzo [d] imidazo [2,1-b] thiazole heterocycle class compound.
Background technique
In recent years, imidazo [1,2-a] pyridine and benzo [d] imidazo [2,1-b] thiazole are because it is in the wide of different field
General application and cause the concern of chemist.Imidazo [1,2-a] pyridine is a kind of important nitrogen-containing heterocycle compound, the structure
It is one of most common nitrogen-containing heterocycle in natural products and biologically active drug molecule, while it also has in materials science field
Extensive purposes.Two kinds of main synthetic methods are reported at present, one is passing through oxidative amination or series connection with 2-aminopyridine
Reaction is cyclized.The second is based on imidazo [1,2-a] pyridine the position C-3 nucleophilicity, using transition-metal catalyst come
The position the C-3 C-H bond for activating imidazo [1,2-a] pyridine, imidazo [1, the 2-a] pyridine for finally obtaining C-3 position functional produce
Object, available includes selenizing, amination, the product of vulcanization and arylation.But the position C-3 about imidazo [1,2-a] pyridine
Direct oxidation there is not yet report.The pharmacological activity of these heterocycles is often depending on the property of imidazoles ring substituents, therefore, closes
There is very high researching value at different functionalized imidazo [1,2-a] pyridines.Likewise, benzo [d] imidazo [2,1-b]
Thiazole is that another important sulfur-bearing and nitrogenous condensed bis-heterocyclic compounds, research are found: this substance has excellent life
Object activity is in antitumor, application value with higher in terms of the preparation of antibacterial and kinase inhibition drug.About C-3 alkoxies
Imidazo [1,2-a] pyridine and benzo [d] imidazo [2,1-b] thiazolium compounds replaced with phenoxy group all has not been reported
's.
Not only quantity is very limited for the synthetic method for the imidazolium compounds that the known C-3 oxygen replaces, the substrate scope of application
It is narrow, and poisonous and hazardous by-product is generated mostly, do not meet environmental-friendly requirement.Currently, more efficient method is micro-
Three component reactions using 2-aminopyridine and boric acid under the conditions of wave, but obtained product is the miaow that 3- hydroxyl replaces
Azoles heterocycle (Tetrahedron Letters 2014,55,1281-1284).The imidazoles replaced about 3- alkoxy or phenoxy group
There is not been reported for the efficient synthesis of heterocycle.Therefore, using raw material simple and easy to get, develop and directly efficiently, greenly prepare
The synthetic method of functionalized imidazo [1,2-a] pyridine and benzo [d] imidazo [2,1-b] thiazole heterocycle class compound is ten
Divide necessary.
Summary of the invention
The purpose of the present invention is to provide a kind of imidazo [1,2-a] pyridines and benzo for being effectively synthesized the substitution of 3-oxygen
The synthetic method of [d] imidazo [2,1-b] thiazole heterocycle class compound.
To achieve the above object, the present invention is that synthesis formula (1) or formula (2) or formula (3) compound represented use following skill
Art scheme:
Adjacent amino azacycle compound, 2- oxygroup acetophenone derivs, transition metal salt catalyst are placed in organic solvent
In, reaction is heated under oxygen-containing atmosphere, after reaction, reaction solution is post-treated to obtain formula (1) corresponding with reactant, formula
(2) or formula (3) compound represented；The 2- amino-heterocyclic compounds are 2-aminopyridine class compound or 2- amino benzo
[d] thiazole compound or 1- aminoisoquinoline；
In formula (1), R1For hydrogen, C1~3Alkyl, cyano, carbonyl, C1~3Alkoxy or halogen；R2For C1~5Alkyl, phenyl,
C1~3Alkyl-substituted C6~10The C that aromatic radical, cyano replace6~10Aromatic radical, C1~3The C that alkoxy replaces6~10Aromatic radical, carbonyl
Substituted C6~10The C that aromatic radical or halogen replace6~10Aromatic radical；R3For C1~5The C that alkyl, phenyl, cyano replace6~10Fragrance
Base, C1~3The C that alkoxy replaces6~10The C that aromatic radical or halogen replace6~10Aromatic radical；R in formula (2)4For hydrogen, C1~3Alkyl, cyanogen
Base, carbonyl, C1~3Alkoxy or halogen；R5For phenyl, C1~3Alkyl-substituted C6~10The C that aromatic radical, cyano replace6~10Fragrance
Base, C1~3The C that alkoxy replaces6~10The C that aromatic radical, carbonyl replace6~10The C that aromatic radical or halogen replace6~10Aromatic radical；R6For
Phenyl, C1~3Alkyl-substituted C6~10The C that aromatic radical, 3,4- methylene-dioxy replace6~10The C that aromatic radical, cyano replace6~10Virtue
The C that perfume base, carbonyl replace6~10Aromatic radical, C1~3The C that alkoxy replaces6~10The C that aromatic radical or halogen replace6~10Aromatic radical.
Further, in formula (1), R1Preferably hydrogen, C1~3Alkyl, cyano, carbonyl, C1~3Alkoxy or halogen；R2Preferably
C1~5Alkyl, phenyl, C1~3Phenyl, the C that alkyl-substituted phenyl, cyano replace1~3Phenyl, the carbonyl of alkoxy substitution replace
The phenyl that phenyl or halogen replace；R3Preferably C1~5Phenyl, the C that alkyl, phenyl, cyano replace1~3The phenyl that alkoxy replaces
Or the phenyl that halogen replaces；R in formula (2)4Preferably hydrogen, C1~3Alkyl, cyano, carbonyl, C1~3Alkoxy or halogen；R5Preferably
Phenyl, C1~3Phenyl, the C that alkyl-substituted phenyl, cyano replace1~3The phenyl or halogen of phenyl, carbonyl substitution that alkoxy replaces
The phenyl that element replaces；R6Preferably phenyl, C1~3Alkyl-substituted phenyl, the phenyl of 3,4- methylene-dioxy substitution, cyano replace
Phenyl, carbonyl replace phenyl, C1~3The phenyl that the phenyl or halogen that alkoxy replaces replace.
Further, in formula (1), R1More preferably hydrogen, cyano, methyl, carbomethoxy, F, Cl or Br；R2More preferably benzene
The phenyl that base, methoxy-substituted phenyl or F replace；R3More preferably phenyl, methyl, isopentyl, methoxy-substituted phenyl,
The phenyl that the phenyl or I that Br replaces replace；In formula (2), R4More preferably H；R5More preferably phenyl or methoxy-substituted benzene
Base；R6More preferably phenyl, methoxy-substituted phenyl, 3,4- the methylene-dioxy phenyl replaced or the phenyl of Cl substitution.
The present invention under relatively mild conditions, using simple transition metal salt as catalyst, oxygen as oxidant,
The nitrogenous of C-3 oxygen substitutions is prepared from simple raw material 2-aminopyridine or 2- amino benzo [d] thiazole or 1- aminoisoquinoline
Heterocyclic compound, reaction equation are as follows:
Further, 2- amino-heterocyclic compounds of the present invention: 2- oxygroup acetophenone derivs: transition metal salt catalyst
The ratio between the amount of substance be 0.2~0.6:0.2:0.01~0.4.
Further, the organic solvent is toluene, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, 1,2- dichloroethanes, ethyl alcohol or two
Ethyl Methyl Ether,.
Further, the bright transition metal salt catalyst of this law is mantoquita, molysite or ruthenium salt.
Further, transition metal salt catalyst of the present invention is preferably iron chloride, ruthenic chloride, copper bromide or iodate
It is cuprous.
In general, the volumetric usage of organic solvent of the present invention is calculated as with the amount of the substance of 2- metaphenoxy acetophenone derivative
2~5L/mol.
Further, heating reaction temperature of the present invention is 80~120 DEG C, the reaction time 16~24 hours.
Further, post-processing of the present invention are as follows: reaction solution is filled into column, residual reaction liquid methylene chloride solution transfer,
Column chromatography for separation is carried out with 300 mesh silica gel, the ethyl acetate and petroleum ether mixed liquor that eluant, eluent is volume ratio 1:4 are collected and contains mesh
The eluent of compound is marked, concentrate drying obtains respective objects product.
More specifically, the heterocycle compound is one of following: 3- phenoxy group -2- phenylimidazole is simultaneously [1,2-a]
Pyridine, 3- phenoxy group -2- (4- methoxyphenyl) imidazo [1,2-a] pyridine, 3- phenoxy group -2- (4- fluorophenyl) imidazo
[1,2-a] pyridine, 2- (4- bromobenzene oxygroup) phenylimidazole simultaneously [1,2-a] pyridine, 2- (4- iodobenzene oxygroup)-phenylimidazole simultaneously [1,
2-a] pyridine, 3- (2- methoxyphenoxy) -2- (4- methoxyphenyl)-imidazo [1,2-a] pyridine, 3- methoxyl group -2- benzene
Base imidazo [1,2-a] pyridine, 3- (4- methoxyphenoxy) -2- isopentyl imidazo [1,2-a] pyridine, 3- phenoxy group -2-
Phenyl -7- cyanoimidazole simultaneously [1,2-a] pyridine, 3- phenoxy group -2- phenyl -7- methylimidazole simultaneously [1,2-a] pyridine, 3- benzene oxygen
Base -2- phenylimidazole simultaneously [1,2-a] pyridine-7-carboxylic acid methyl esters, 3- (2- methoxyphenoxy) -2- (4- methoxyphenyl) -6-
Bromine imidazo [1,2-a] pyridine, 3- (2- methoxyphenoxy) -2- (4- methoxyphenyl) -7- methylimidazole simultaneously [1,2-a] pyrrole
Pyridine, 3- (2- methoxyphenoxy) -2- (4- methoxyphenyl) -6- flumizole simultaneously [1,2-a] pyridine, 3- (2- methoxybenzene oxygen
Base) -2- (4- methoxyphenyl) -6- chlorine imidazo [1,2-a] pyridine, 3- (2- methoxyphenoxy) -2- (4- methoxybenzene
Base) imidazo [2,1-a] isoquinolin, 3- phenoxy group -2- phenyl benzo [d] imidazo [2,1-b] thiazole, 3- is (between 1,3- benzo
Dioxole -5- oxygroup) -2- (4- methoxyphenyl) benzo [d] imidazo [2,1-b] thiazole, 3- (4- methoxybenzene oxygen
Base) -2- (4- chlorphenyl) benzo [d] imidazo [2,1-b] thiazole, 3- (4- methoxyphenoxy) -2- (4- methoxyphenyl)
Benzo [d] imidazo [2,1-b] thiazole, 3- (4- methoxyphenoxy) -2- phenyl benzo [d] imidazo [2,1-b] thiazole.
Two kinds of heterocycle compounds that the present invention is prepared all have a pharmacological, and the latter also has antibiotic property, antitumor
With the bioactivity such as kinase inhibition, the important as precursors of drug can be used as.
Compared with prior art, beneficial effect of the present invention is mainly reflected in:
(1) the present invention provides a kind of imidazole heterocyclic compounds for efficiently synthesizing -3 phenoxy group of novel C or alkoxy and replacing
Method, obtained product is all completely new and has not been reported.
(2) synthetic method of the invention, easy to operate, reaction condition is mild, and by-product is only water, and reaction yield is high, most
Up to 97%.
(3) C-3 functionalization occurs for the nucleophilicity that imidazo [1,2-a] pyridine is avoided relying in synthetic method of the invention
Limitation, while also without the participation of precious metal, O2Environmentally friendly as oxidant, economic benefit is higher, production environmental protection
Pressure is smaller.
(4) inventive substrate is applied widely, and yield is higher (49~97%), has wide range of applications, and it is very good to have
Economic value.
(5) synthesis material of the invention is economical and easily available, and it is more complicated with special bioactivity chemical combination to be suitable for structure
The efficient preparation of object, is with a wide range of applications, and is a kind of effectively supplement in preparation method.
Specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in
This.
Column chromatography for separation described in following embodiment all uses 300 mesh silica gel to carry out column chromatography for separation, and eluant, eluent is volume
Ethyl acetate and petroleum ether mixed liquor than 1:4, collect the eluent containing target compound, and concentrate drying obtains formula (1) or formula
(2) compound represented.
The preparation of embodiment 1:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes (1.0mL), the lower 100 DEG C of heating of oxygen
After reaction 16 hours, reaction solution obtains target product (44.0mg, yield 77%) after direct column chromatography for separation.White solid,
m.p.:145-146℃.1H NMR(400MHz,CDCl3): δ=8.07 (d, J=7.6Hz, 2H), 7.75 (d, J=6.8Hz,
1H), 7.66 (d, J=9.2Hz, 1H), 7.41 (t, J=7.2Hz, 2H), 7.28-7.35 (m, 3H), 7.20 (t, J=7.6Hz,
1H), 7.12 (t, J=7.2Hz, 1H), 6.97 (d, J=8.0Hz, 2H), 6.77 (t, J=6.8Hz, 1H)13C NMR
(100MHz,CDCl3): δ=156.1,139.9,132.5,131.1,130.2,128.7,127.8,126.5,124.4,
123.7,121.6,117.9,115.0,112.3.FTIR(NaCl,cm-1):3053.3,2985.8,1647.2,1495.6,
1421.5,1390.1,1362.2,1265.3,1201.7,895.0,738.7,706.0.HR-MS(ESI):m/z
calculated for C19H14N2O[M+H]+:287.1184；found 287.1184.
The preparation of embodiment 2:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes (1.0mL), the lower 80 DEG C of heating of oxygen
After reaction 16 hours, reaction solution obtains target product (40.0mg, yield 70%) after direct column chromatography for separation.
The preparation of embodiment 3:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes (1.0mL), the lower 120 DEG C of heating of oxygen
After reaction 16 hours, reaction solution obtains target product (37.8mg, yield 66%) after direct column chromatography for separation.
The preparation of embodiment 4:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), tetrahydrofuran (1.0mL), the lower 100 DEG C of heating reaction of oxygen
After 16 hours, reaction solution obtains target product (37.0mg, yield 65%) after direct column chromatography for separation.
The preparation of embodiment 5:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), dimethoxy-ethane (1.0mL), the lower 100 DEG C of heating of oxygen
After reaction 16 hours, reaction solution obtains target product (28.0mg, yield 49%) after direct column chromatography for separation.
The preparation of embodiment 6:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), toluene (1.0mL), the lower 100 DEG C of heating reaction 16 of oxygen are small
Shi Hou, reaction solution obtain target product (33.7mg, yield 59%) after direct column chromatography for separation.
The preparation of embodiment 7:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), toluene (1.0mL), the lower 100 DEG C of heating reaction 16 of oxygen are small
Shi Hou, reaction solution obtain target product (40.6mg, yield 71%) after direct column chromatography for separation.
The preparation of embodiment 8:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), ethyl alcohol (1.0mL), the lower 100 DEG C of heating reaction 16 of oxygen are small
Shi Hou, reaction solution obtain target product (24.0mg, yield 42%) after direct column chromatography for separation.
The preparation of embodiment 9:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), copper bromide (0.4mmol), 1,2- dichloroethanes (1.0mL), the lower 100 DEG C of heating of air are anti-
After answering 16 hours, reaction solution obtains target product (46.3mg, yield 81%) after direct column chromatography for separation.
The preparation of embodiment 10:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), iron chloride (0.01mmol), 1,2- dichloroethanes (1.0mL), the lower 100 DEG C of heating of oxygen are anti-
After answering 16 hours, reaction solution obtains target product (6.3mg, yield 11%) after direct column chromatography for separation.
The preparation of embodiment 11:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (56.5mg, 0.6mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), ruthenic chloride (0.01mmol), 1,2- dichloroethanes (1.0mL), the lower 100 DEG C of heating of oxygen are anti-
After answering 16 hours, reaction solution obtains target product (13.7mg, yield 24%) after direct column chromatography for separation.
The preparation of embodiment 12:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine
Clean reaction flask is taken, small magneton is added, is dried, 2-aminopyridine (18.8mg, 0.2mmol), 2- phenoxy group is added
Acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes (1.0mL), the lower 100 DEG C of heating of oxygen
After reaction 16 hours, reaction solution obtains target product (26.3mg, yield 46%) after direct column chromatography for separation.
The preparation of embodiment 13:3- phenoxy group -2- (4- methoxyphenyl) imidazo [1,2-a] pyridine
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2-aminopyridine (56.5mg,
0.6mmol), 2- phenoxy group-(4- methoxyl group) acetophenone (48.4mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- bis-
Chloroethanes (1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 16 hours, reaction solution obtains target production after direct column chromatography for separation
Object (54.0mg, yield 86%).White solid, m.p.:145-147 DEG C1H NMR(400MHz,CDCl3): δ=7.99-8.01
(m, 2H), 7.71-7.74 (dt, J=1.2Hz, J=6.8Hz, 1H), 7.61-7.64 (dt, J=1.2Hz, J=9.2Hz, 1H),
7.28-7.33 (m, 2H), 7.09-7.19 (m, 2H), 6.93-6.97 (m, 4H), 6.72-6.75 (td, J=6.8Hz, J=
0.8Hz,1H),3.82(s,3H).13C NMR(100MHz,CDCl3): δ=159.3,156.2,139.8,131.2,130.2,
129.3,127.8,125.2,124.1,123.6,121.5,117.6,115.0,114.1,112.1,55.2.FTIR(NaCl,
cm-1):3053.3,2985.8,1707.0,1568.1,1506.4,1421.5,1359.8,1265.3,1201.7,1032.0,
895.0,837.1,738.7,706.0.HR-MS(ESI):m/z calculated for C20H16N2O2[M+H]+:
317.1290；found 317.1188.
The preparation of embodiment 14:3- phenoxy group -2- (4- fluorophenyl) imidazo [1,2-a] pyridine
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2-aminopyridine (56.5mg,
0.6mmol), 2- phenoxy group-(4- fluorine) acetophenone (46.0mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- bis- chloroethene
Alkane (1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 16 hours, reaction solution obtains target product after direct column chromatography for separation
(33.0mg, yield 55%).White solid, m.p.:114-115 DEG C of1H NMR(400MHz,CDCl3): δ=8.02-8.05 (m,
2H), 7.74-7.76 (dt, J=6.8Hz, J=1.2Hz, 1H), 7.62-7.64 (dt, J=9.2Hz, J=1.2Hz, 1H),
7.28-7.35 (m, 2H), 7.18-7.22 (qd, J=6.8Hz, J=1.2Hz, 1H), 7.07-7.15 (m, 3H), 6.95-6.97
(m, 2H), 6.75-6.79 (td, J=6.8Hz, J=0.8Hz, 1H)13C NMR(100MHz,CDCl3): δ=162.4 (J=
246Hz), 156.0,139.9,130.3 (J=16Hz), 128.8,128.7,128.2 (J=8Hz), 124.4,123.8,
(121.6,117.8,115.6 J=21Hz), 115.0,112.4.FTIR (NaCl, cm-1):3053.3,2985.8,1574.2,
1504.5,1489.1,1421.5,1392.6,1359.8,1265.3,1201.7,1159.2,895.0,842.5,738.7,
704.5.HR-MS(ESI):m/z calculated for C19H13FN2O[M+H]+:305.1090；found 305.1088.
The preparation of embodiment 15:3- (4- bromobenzene oxygroup) -2- phenylimidazole simultaneously [1,2-a] pyridine
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2-aminopyridine (56.5mg,
0.6mmol), 2- (4- bromine) metaphenoxy acetophenone (58.2mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes
(1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 16 hours, reaction solution obtains target product after direct column chromatography for separation
(49.0mg, yield 67%).Red liquid,1H NMR(400MHz,CDCl3): δ=7.98-8.00 (m, 2H), 7.69 (d, J=
6.8Hz, 1H), 7.62 (d, J=9.2Hz, 1H), 7.35-7.40 (m, 4H), 7.25-7.29 (m, 1H), 7.16-7.20 (m,
1H), 6.81-6.84 (m, 2H), 6.74-6.78 (td, J=0.8Hz, J=6.8Hz, 1H)13C NMR(100MHz,CDCl3):δ
=155.3,140.0,133.1,132.2,131.3,128.7,127.9,126.5,124.5,12 1.4,118.0,116.8,
116.2,112.5.FTIR(NaCl,cm-1):3053.3,2985.8,1481.3,1421.5,1362.6,1265.3,1201.7,
1159.2,895.0,738.7,706.2.HR-MS(ESI):m/z calculated for C19H13BrN2O[M+H]+:
365.0290,367.0271；found365.0288,368.0302.
The preparation of embodiment 16:3- (4- iodobenzene oxygroup) -2- phenylimidazole simultaneously [1,2-a] pyridine
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2-aminopyridine (56.5mg,
0.6mmol), 2- (4- iodine) metaphenoxy acetophenone (67.6mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes
(1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 16 hours, reaction solution obtains target product after direct column chromatography for separation
(47.0mg, yield 57%).White solid, m.p.:138-140 DEG C of1H NMR(400MHz,CDCl3): δ=7.98 (d, J=
8.4Hz, 2H), 7.69 (d, J=6.8Hz, 1H), 7.62 (d, J=9.2Hz, 1H), 7.56-7.58 (dd, J=2.4Hz, J=
6.8Hz, 2H), 7.37 (t, J=8.0Hz, 2H), 7.25-7.29 (dd, J=7.6Hz, J=10.8Hz, 2H), 7.16-7.20
(m,1H),6.70-6.77(m,3H).13C NMR(100MHz,CDCl3): δ=156.1,139.1,132.2,128.9,128.7,
127.9,127.2,126.5,124.5,121.4,118.0,117.3,112.5,86.5.FTIR(NaCl,cm-1):3942.5,
3689.8,3053.3,2985.8,2684.9,1684.2,1645.2,1577.8,1562.3,1506.4,1479.4,1433.1,
1421.5,1390.7,1363.7,1265.3,1203.6,1161.2,1149.6,1004.9,895.0,823.6,752.2,
727.2,706.0.HR-MS(ESI):m/z calculated for C19H13IN2O[M+H]+:413.0151；
found413.0153.
The preparation of embodiment 17:3- (2- methoxyphenoxy) -2- (4- methoxyphenyl)-imidazo [1,2-a] pyridine
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2-aminopyridine (56.5mg,
0.6mmol), 2- (2- methoxyphenoxy) -1- (4- methoxyl group) acetophenone (54.5mg, 0.2mmol), cuprous iodide
(0.01mmol), 1,2- dichloroethanes (1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 16 hours, reaction solution is chromatographed through direct column
Target product (66.0mg, yield 95%) is obtained after separation.White solid, m.p.:121-122 DEG C of1H NMR(400MHz,
CDCl3): δ=8.02-8.04 (dd, J=2.0Hz, J=6.8Hz, 2H), 7.79 (d, J=6.8Hz, 1H), 7.59 (d, J=
8.0Hz, 1H), 7.14-7.18 (m, 1H), 7.05-7.07 (m, 2H), 6.93-6.95 (dd, J=2.0Hz, J=6.8Hz, 2H),
6.70-6.76 (m, 2H), 6.55 (d, J=7.6Hz, 1H)13C NMR(100MHz,CDCl3): δ=159.3,149.0,
145.1,139.7,131.3,129.7,127.8,125.3,124.2,124.1,121.5,121.1,117.5,114.7,
114.1,112.8,112.1,56.2,55.2.FTIR(NaCl,cm-1):3053.3,2986.8,1701.2,1614.4,
1568.1,1498.7,1456.3,1421.5,1394.5,1361.7,1265.3,1251.8,1199.7,1174.7,1114.9,
1030.0,895.0,837.2,738.7,704.0.HR-MS(ESI):m/z calculated for C21H18N2O3[M+H]+:
347.1396；found 347.1393.
The preparation of embodiment 18:3- methoxyl group -2- phenylimidazole simultaneously [1,2-a] pyridine
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2-aminopyridine (56.5mg,
0.6mmol), 2- methoxyacetophenone (30.0mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes
After (1.0mL), oxygen or the lower 100 DEG C of heating of air are reacted 16 hours, reaction solution obtains target after direct column chromatography for separation
Product (32.0mg, yield 71%).Red liquid.1H NMR(400MHz,CDCl3): δ=8.12 (d, J=8.0Hz, 2H),
7.98 (d, J=6.8Hz, 1H), 7.56 (d, J=9.2Hz, 1H), 7.49 (t, J=7.6Hz, 2H), 7.34 (t, J=7.6Hz,
1H), 7.12-7.16 (m, 1H), 6.83 (t, J=6.8Hz, 1H)13C NMR(100MHz,CDCl3): δ=139.0,133.4,
113.5,128.7,127.4,126.4,123.7,121.3,117.9,113.2,112.0,61.1.FTIR(NaCl,cm-1):
2985.8,1707.0,1587.4,1568.1,1501.2,1421.6,1386.8,1359.8,1265.3,1207.8,968.3,
896.0,748.4,706.0.HR-MS(ESI):m/z calculated forC14H12N2O[M+H]+:225.1028；found
225.1029.
The preparation of embodiment 19:3- (4- methoxyphenoxy) -2- isopentyl imidazo [1,2-a] pyridine
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2-aminopyridine (56.5mg,
0.6mmol), 1- (4- methoxyphenoxy) -5- methyl hex- 2- ketone (47.3mg, 0.2mmol), cuprous iodide (0.01mmol),
After 1,2- dichloroethanes (1.0mL), oxygen or the lower 100 DEG C of heating of air are reacted 16 hours, reaction solution is through direct column chromatography point
Target product (38.0mg, yield 61%) is obtained from after.Colourless liquid.1H NMR(400MHz,CDCl3): δ=7.69 (d, J=
6.8Hz, 1H), 7.50 (d, J=9.2Hz, 1H), 7.06-7.10 (m, 1H), 6.80 (s, 4H), 6.67-6.71 (m, 1H), 3.75
(s, 3H), 2.66 (t, J=8.0Hz, 2H), 1.53-1.63 (m, 3H), 0.86 (d, J=6.4Hz, 6H)13C NMR(100MHz,
CDCl3): δ=155.6,151.1,139.4,133.6,131.7,123.2,121.3,117.4,115.7,11 4.9,111.7,
55.7,37.9,27.9,24.6,22.4.FTIR(NaCl,cm-1):3053.3,2985.8,1562.2,1502.6,1421.5,
1265.3,1198.05,1031.9,895.0,831.2,738.7,706.0.HR-MS(ESI):m/z calculated for
C19H22N2O2[M+H]+:311.1760；found 311.1756.
The preparation of embodiment 20:3- phenoxy group -2- phenyl -7- cyanoimidazole simultaneously [1,2-a] pyridine
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, the addition different nicotinic acid nitrile of 2- amino (71.5mg,
0.6mmol), 2- metaphenoxy acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes
(1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 16 hours, reaction solution obtains target product after direct column chromatography for separation
(42.0mg, yield 67%).White solid, m.p.:204-206 DEG C of1H NMR(400MHz,CDCl3): δ=7.98-8.03 (m,
3H), 7.78-7.80 (dd, J=1.2Hz, J=7.2Hz, 1H), 7.29-7.41 (m, 5H), 7.12 (t, J=7.2Hz, 1H),
6.90-6.92 (m, 2H), 6.86-6.88 (dd, J=1.6Hz, J=6.8Hz, 1H)13C NMR(100MHz,CDCl3): δ=
155.5,137.4,135.0,131.7,131.4,130.4,128.9,128.7,126.8,124.3,124.0,122.2,
117.7,115.0,112.6,106.7.FTIR(NaCl,cm-1):3053.3,3009.1,2304.9,2227.8,1556.6,
1485.2,1421.5,1361.7,1265.3,1203.6,1159.2,895.0,746.5,704.0.HR-MS(ESI):m/z
calculated for C20H13N3O[M+H]+:312.1137；found 312.1138.
The preparation of embodiment 21:3- phenoxy group -2- phenyl -7- methylimidazole simultaneously [1,2-a] pyridine
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 4- methyl-2-amino pyridine (64.9mg,
0.6mmol), 2- metaphenoxy acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes
(1.0mL), after the lower 100 DEG C of heating of air are reacted 16 hours, reaction solution obtains target product after direct column chromatography for separation
(39.0mg, yield 65%).White solid, m.p.:158-160 DEG C of1H NMR(400MHz,CDCl3): δ=8.03-8.06 (m,
2H), 7.63 (d, J=6.8Hz, 1H), 7.26-7.41 (m, 6H), 7.09-7.13 (t, J=7.6Hz, 1H), 6.96-6.98 (m,
2H), 6.58-6.60 (dd, J=1.2Hz, J=6.8Hz, 1H), 2.42 (s, 3H)13C NMR(100MHz,CDCl3): δ=
156.3,140.4,135.2,132.7,130.7,130.2,128.9,128.6,127.5,126.4,123.6,120.9,
116.2,115.0,114.9,21.4.FTIR(NaCl,cm-1):3053.3,2985.8,2924.1,1643.4,1583.6,
1568.1,1489.1,1446.6,1421.5,1394.5,1363.7,1265.3,1201.7,1159.2,1072.4,1026.1,
895.0,731.0,704.0.HR-MS(ESI):m/z calculated for C20H16N2O[M+H]+:301.1341；
found301.1345.
The preparation of embodiment 22:3- phenoxy group -2- phenylimidazole simultaneously [1,2-a] pyridine-7-carboxylic acid methyl esters
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2- aminoisonicotinic acid methyl esters (91.3mg,
0.6mmol), 2- metaphenoxy acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes
(1.0mL), after the lower 100 DEG C of heating of air are reacted 16 hours, reaction solution obtains target product after direct column chromatography for separation
(53.0mg, yield 77%).White solid, m.p.:132-134 DEG C of1H NMR(400MHz,CDCl3): δ=8.35-8.36
(dd, J=0.8Hz, J=1.6Hz, 1H), 8.03-8.05 (m, 2H), 7.73-7.75 (dd, J=0.8Hz, J=7.2Hz, 1H),
7.25-7.40 (m, 6H), 7.08-7.12 (td, J=8.0Hz, J=0.8Hz, 1H), 6.90-6.93 (m, 2H), 3.94 (s,
3H).13C NMR(100MHz,CDCl3): δ=165.7,155.8,138.6,134.2,132.0,131.3,130.3,128.7,
128.3,126.7,125.6,124.0,121.1,120.7,115.0,111.7,52.6.FTIR(NaCl,cm-1):3053.3,
3004.5,2304.9,1718.6,1556.6,1487.1,1404.2,1367.5,1334.7,1265.3,1232.5,1203.6,
1159.2,1091.7,895.0,738.7,704.0.HR-MS(ESI):m/z calculated for C21H16N2O3[M+H]+:
345.1239；found 345.1238.
Embodiment 23:3- (2- methoxyphenoxy) -2- (4- methoxyphenyl) -6- bromine imidazo [1,2-a] pyridine
Preparation
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2- amino -5- bromopyridine (103.8mg,
0.6mmol), 2- metaphenoxy acetophenone (42.5mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes
(1.0mL), after the lower 100 DEG C of heating of person's air are reacted 16 hours, reaction solution obtains target product after direct column chromatography for separation
(41.0mg, yield 57%).White solid, m.p.:159-161 DEG C of1H NMR(400MHz,CDCl3): δ=7.99-8.01 (m,
2H), 7.86-7.87 (dd, J=0.8Hz, J=1.6Hz, 1H), 7.49-7.51 (dd, J=0.8Hz, J=9.6Hz, 1H),
7.20-7.38(m,6H),7.09-7.13(m,1H),6.92-6.95(m,2H).13C NMR(100MHz,CDCl3): δ=
155.8,138.2,132.2,132.0,130.3,130.1,128.7,128.1,127.9,126.5,124.0,121.6,
118.6,115.0,107.3.FTIR(NaCl,cm-1):3053.3,3012.2,1596.3,1526.3,1489.1,1421.5,
1401.3,1325.1,1265.3,1199.7,1159.2,895.0,798.5,738.7,704.0.HR-MS(ESI):m/z
calculated for C19H13BrN2O[M+H]+:367.0251；found 367.0255.
Embodiment 24:3- (2- methoxyphenoxy) -2- (4- methoxyphenyl) -7- methylimidazole simultaneously [1,2-a] pyridine
Preparation
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 4- methyl 2-aminopyridine (64.9mg,
0.6mmol), 2- (2- methoxyphenoxy) -1- (4- methoxyl group) acetophenone (54.5mg, 0.2mmol), cuprous iodide
(0.01mmol), 1,2- dichloroethanes (1.0mL), after the lower 100 DEG C of heating of air are reacted 24 hours, reaction solution is chromatographed through direct column
Target product (67.0mg, yield 93%) is obtained after separation.White solid, m.p.:154-156 DEG C of1H NMR(400MHz,
CDCl3): δ=7.95-7.98 (dd, J=2.0Hz, J=6.8Hz, 2H), 7.63 (d, J=7.2Hz, 1H), 7.31 (d, J=
1.2Hz,1H),7.01-7.05(m,2H),6.87-6.90(m,2H),6.66-6.70(m,1H),6.50-6.54(m,2H),
4.03(s,3H),3.78(s,3H),2.36(s,3H).13C NMR(100MHz,CDCl3): δ=159.1,149.0,145.3,
140.2,135.0,130.7,129.3,127.7,125.5,124.1,121.1,120.8,115.9,114.7,114.6,
114.0,112.7,56.2,55.2,21.4.FTIR(NaCl,cm-1):3053.3,2983.9,2839.2,1695.4,1643.4,
1614.4,1570.1,1498.7,1456.3,1440.8,1421.5,1392.6,1361.7,1296.2,1265.3,1249.9,
1199.7,1170.8,1114.9,1030.0,895.0,837.1,738.7,704.0.HR-MS(ESI):m/z calculated
for C22H20N2O3[M+H]+:361.1552；found 361.1553.
Embodiment 25:3- (2- methoxyphenoxy) -2- (4- methoxyphenyl) -6- flumizole simultaneously [1,2-a] pyridine
Preparation
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2- amino-5-fluorine pyridine (67.3mg,
0.6mmol), 2- (2- methoxyphenoxy) -1- (4- methoxyl group) acetophenone (54.5mg, 0.2mmol), cuprous iodide
(0.01mmol), 1,2- dichloroethanes (1.0mL), after the lower 100 DEG C of heating of air are reacted 24 hours, reaction solution is chromatographed through direct column
Target product (48.0mg, yield 66%) is obtained after separation.White solid, m.p.:134-136 DEG C of1H NMR(400MHz,
CDCl3): δ=7.96-7.99 (m, 2H), 7.70-7.72 (m, 1H), 7.51-7.55 (m, 1H), 7.01-7.06 (m, 3H),
6.89-6.93 (m, 2H), 6.69-6.73 (m, 1H), 6.53 (d, J=7.6Hz, 1H)13C NMR(100MHz,CDCl3): δ=
(159.4,155.3 J=236Hz), 149.1,144.8,137.2,133.0,131.1,127.8,125.0,124.5,121.1,
118.1 (J=9Hz), 116.0 (J=26Hz), 114.9,114.1,112.9,108.2 (J=41Hz), 56.2,55.2.FTIR
(NaCl,cm-1):3053.3,2839.2,2304.9,1651.1,1564.3,1535.3,1500.6,1421.5,1421.5,
1369.5,1328.9,1298.1,1265.3,1251.8,1209.4,1180.4,1116.8,1208.1,839.0,810.1,
746.5,704.0.HR-MS(ESI):m/z calculated for C21H17FN2O3[M+H]+:365.1301；found
365.1302.
Embodiment 26:3- (2- methoxyphenoxy) -2- (4- methoxyphenyl) -6- chlorine imidazo [1,2-a] pyridine
Preparation
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2- amino -5- chloropyridine (77.1mg,
0.6mmol), 2- (2- methoxyphenoxy) -1- (4- methoxyl group) acetophenone (54.5mg, 0.2mmol), cuprous iodide
(0.01mmol), 1,2- dichloroethanes (1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 16 hours, reaction solution is chromatographed through direct column
Target product (53.0mg, yield 70%) is obtained after separation.White solid, m.p.:130-132 DEG C of1H NMR(400MHz,
CDCl3): δ=7.96-7.98 (dd, J=2.0Hz, J=6.8Hz, 2H), 7.82-7.83 (dd, J=0.8Hz, J=2.0Hz,
1H), 7.49-7.52 (dd, J=0.8Hz, J=9.6Hz, 1H), 7.05-7.10 (m, 3H), 6.90-6.92 (dd, J=2.0Hz,
J=6.8Hz, 2H), 6.69-6.74 (m, 1H), 6.52 (d, J=8.0Hz, 1H), 4.04 (s, 3H), 3.80 (s, 3H)13C NMR
(100MHz,CDCl3): δ=159.5,149.1,144.9,138.0,132.5,130.1,127.9,125.5,124.8,
124.5,121.2,120.5,119.4,117.9,114.8,114.2,112.9,56.2,55.3.FTIR(NaCl,cm-1):
3015.6,2839.2,1498.7,1419.6,1392.6,1325.1,1298.1,1265.3,1251.8,1199.7,1174.7,
1116.7,1028.1,895.0,837.1,798.5,738.7,704.0.HR-MS(ESI):m/z calculated for
C21H17ClN2O3[M+H]+:381.1006；found 381.1003.
The preparation of embodiment 27:3- (2- methoxyphenoxy) -2- (4- methoxyphenyl) imidazo [2,1-a] isoquinolin
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 1- aminoisoquinoline (86.5mg,
0.6mmol), 2- (2- methoxyphenoxy) -1- (4- methoxyl group) acetophenone (54.5mg, 0.2mmol), cuprous iodide
(0.01mmol), 1,2- dichloroethanes (1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 18 hours, reaction solution is chromatographed through direct column
Target product (39.0mg, yield 49%) is obtained after separation.White solid, m.p.:108-110 DEG C of1H NMR(400MHz,
CDCl3): δ=8.72 (d, J=8.0Hz, 1H), 8.03 (d, J=8.4Hz, 2H), 7.61-7.67 (m, 3H), 7.54 (t, J=
7.2Hz, 1H), 6.92-7.07 (m, 5H), 6.68-6.72 (m, 1H), 6.58 (d, J=8.0Hz, 1H), 4.05 (s, 3H), 3.81
(s,3H).13C NMR(100MHz,CDCl3): δ=159.0,149.0,145.7,129.3,128.2,128.1,127.6,
127.1,124.1,122.9,121.2,119.1,114.8,114.1,112.8,112.7,56.3,55.2.FTIR(NaCl,cm-1):3005.6,2839.2,1583.6,1578.6,1498.7,1454.3,1419.6,1377.2,1265.3,1251.8,
1199.7,1174.7,1026.1,895.0,792.7,738.7,704.0.HR-MS(ESI):m/z calculated for
C25H20N2O3[M+H]+:397.1552；found 397.1549.
The preparation of embodiment 28:3- phenoxy group -2- phenyl benzo [d] imidazo [2,1-b] thiazole
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2- amino benzo [d] thiazole (90.1mg,
0.6mmol), 2- metaphenoxy acetophenone (42.4mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2- dichloroethanes
(1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 16 hours, reaction solution obtains target product through direct column chromatography for separation
(58.0mg, yield 85%).White solid, m.p.:173-174 DEG C of1H NMR(500MHz,CDCl3): δ=7.82 (d, J=
8.0Hz,2H),7.51-7.56(m,1H),7.35-7.37(m,1H),7.24-7.27(m,4H),7.12-7.16(m,3H),
6.99-7.02(m,3H).13C NMR(125MHz,CDCl3): δ=155.5,141.2,132.6,131.4,131.1,130.6,
129.3,128.9,127.6,126.1,125.2,124.5,123.8,122.9,122.8,114.0,112.4.
The system of embodiment 29:3- (4- methoxyphenoxy) -2- (4- chlorphenyl) benzo [d] imidazo [2,1-b] thiazole
It is standby
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2- amino benzo [d] thiazole (90.1mg,
0.6mmol), 1- (4- chlorphenyl) -2- (4- methoxyphenoxy) second -1- ketone (55.2mg, 0.2mmol), cuprous iodide
(0.01mmol), 1,2- dichloroethanes (1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 16 hours, reaction solution is chromatographed through direct column
Isolated target product (70.0mg, yield 86%).White solid, m.p.:183-184 DEG C of1H NMR(500MHz,
CDCl3): δ=7.75 (brs, 2H), 7.52-7.54 (m, 1H), 7.36-7.37 (m, 1H), 7.16-7.21 (m, 4H), 6.88
(d, J=9.0Hz, 2H), 6.74 (d, J=9.0Hz, 2H), 3.64 (s, 3H)13C NMR(125MHz,CDCl3): δ=155.9,
150.3,132.9,132.7,131.6,131.2,129.9,129.3,129.2,128.8,126.7,126.3,124.9,
124.0,115.7,115.3,113.5,55.7.
Embodiment 30:3- (4- methoxyphenoxy) -2- (4- methoxyphenyl) benzo [d] imidazo [2,1-b] thiazole
Preparation
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2- amino benzo [d] thiazole (90.1mg,
0.6mmol), (4- methoxyphenoxy) -1- (4- methoxyphenyl) second -1- ketone (54.4mg, 0.2mmol), cuprous iodide
(0.01mmol), 1,2- dichloroethanes (1.0mL), after the lower 100 DEG C of heating of air are reacted 24 hours, reaction solution is chromatographed through direct column
Isolated target product (78.0mg, yield 97%).Yellow liquid.1H NMR(500MHz,CDCl3): δ=7.75 (d, J=
8.5Hz, 2H), 7.53 (t, J=4.0Hz, 1H), 7.37 (t, J=4.5Hz, 1H), 7.14-7.17 (m, 2H), 6.90 (d, J=
9.0Hz, 2H), 6.80 (d, J=8.0Hz, 2H), 6.74 (d, J=9.0Hz, 2H), 3.70 (s, 3H), 3.64 (s, 3H)13C
NMR(125MHz,CDCl3): δ=157.7,154.7,149.5,130.7,129.5,128.8,125.8,125.2,124.3,
123.6,122.9,114.9,114.7,114.2,113.6,113.0,112.3,54.5,54.2.
The preparation of embodiment 31:3- (4- methoxyphenoxy) -2- phenyl benzo [d] imidazo [2,1-b] thiazole
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2- amino benzo [d] thiazole (90.1mg,
0.6mmol), 2- (4- methoxyl group) phenoxy group -1- acetophenone (48.4mg, 0.2mmol), cuprous iodide (0.01mmol), 1,2-
Dichloroethanes (1.0mL), after the lower 100 DEG C of heating of oxygen are reacted 16 hours, the direct column chromatography for separation of reaction solution obtains target product
(71.0mg, yield 95%).Yellow liquid.1H NMR(500MHz,CDCl3): δ=7.82 (d, J=7.5Hz, 2H), 7.51-
7.53 (m, 1H), 7.36-7.38 (m, 1H), 7.25 (t, J=8.0Hz.2H), 7.11-7.16 (m, 3H), 6.90 (d, J=
9.0Hz, 2H), 6.73 (d, J=9.0Hz, 2H), 3.63 (s, 3H)13C NMR(125MHz,CDCl3): δ=154.7,149.4,
141.0,133.1,131.6,131.0,130.6,128.9,127.6,126.0,125.2,124.5,123.7,122.9,
114.7,114.2,112.4,54.6.
Embodiment 32:3- (3,4- methylene-dioxy phenoxy group) -2- (4- methoxyphenyl) benzo [d] imidazo [2,1-
B] thiazole preparation
The closed micro-reaction bottle of clean 8mL is taken, small magneton is added, is dried, addition 2- amino benzo [d] thiazole (90.1mg,
0.6mmol), 2- (benzo [d] [1,3] dioxole -5- base oxygroup) -1- (4- methoxyl group) acetophenone (57.2mg,
0.2mmol), cuprous iodide (0.01mmol), solvent (1.0mL), under oxygen after heating reaction 16 hours, reaction solution is directly filled
Column is eluant, eluent with ethyl acetate/petroleum ether system, target product (72.0mg, the yield that column chromatography for separation purifies
86%).Dark red oil.1H NMR(500MHz,CDCl3): δ=7.83 (d, J=8.0Hz, 2H), 7.62 (d, J=
8.0Hz, 1H), 7.47 (d, J=7.5Hz, 1H), 7.23-7.28 (m, 2H), 6.89 (d, J=8.0Hz, 2H), 6.64-6.68
(m, 2H), 6.48 (dd, J=2.0Hz, J=8.0Hz, 1H), 5.92 (s, 2H), 3.79 (s, 3H)13C NMR(125MHz,
CDCl3): δ=158.8,151.9,148.9,143.8,142.0,131.7,130.5,129.9,126.8,12 6.3,125.3,
124.7,124.0,114.1,114.0,113.3,108.5,106.6,101.8,97.8,55.3.
Claims (8)
1. one kind is such as formula (1) or formula (2) or the synthetic method of formula (3) compound represented, it is characterised in that the synthetic method
Are as follows:
Adjacent amino azacycle compound, methyl ketone derivatives, transition metal salt catalyst are placed in organic solvent, in oxygen-containing atmosphere
Lower heating reaction is enclosed, after reaction, reaction solution is post-treated to obtain formula (1) corresponding with reactant, formula (2) or formula (3) institute
The compound shown；Neighbour's amino azacycle compound is 2-aminopyridine class compound or 2- amino benzo [d] thiazoles
Close object or 1- aminoisoquinoline；The methyl ketone derivatives are that 1- phenoxymethyl ketone derivative or 1- alkoxy methyl ketone are derivative
Object；
In formula (1), R1For hydrogen, C1~3Alkyl, cyano, ester group, C1~3Alkoxy or halogen；R2For C1~5Alkyl, phenyl, C1~3Alkyl
Substituted C6~10The C that aromatic radical, cyano replace6~10Aromatic radical, C1~3The C that alkoxy replaces6~10Aromatic radical, ester group replace
C6~10The C that aromatic radical or halogen replace6~10Aromatic radical；R3For C1~5The C that alkyl, phenyl, cyano replace6~10Aromatic radical, C1~3Alkane
The C that oxygroup replaces6~10The C that aromatic radical or halogen replace6~10Aromatic radical；R in formula (2)4For hydrogen, C1~3Alkyl, cyano, ester group,
C1~3Alkoxy or halogen；R5For phenyl, C1~3Alkyl-substituted C6~10The C that aromatic radical, cyano replace6~10Aromatic radical, C1~3Alkane
The C that oxygroup replaces6~10The C that aromatic radical, ester group replace6~10The C that aromatic radical or halogen replace6~10Aromatic radical；R6For phenyl, C1~3
Alkyl-substituted C6~10The C that aromatic radical, 3,4- methylene-dioxy replace6~10The C that aromatic radical, cyano replace6~10Aromatic radical, ester group
Substituted C6~10Aromatic radical, C1~3The C that alkoxy replaces6~10The C that aromatic radical or halogen replace6~10Aromatic radical, the transition metal
Salt catalyst is iron chloride, ruthenic chloride, copper bromide or cuprous iodide.
2. synthetic method as described in claim 1, it is characterised in that: in formula (1), R1For hydrogen, C1~3Alkyl, cyano, ester group,
C1~3Alkoxy or halogen；R2For C1~5Alkyl, phenyl, C1~3Phenyl, the C that alkyl-substituted phenyl, cyano replace1~3Alkoxy
Substituted phenyl, the phenyl that ester group replaces or the phenyl of halogen substitution；R3For C1~5Alkyl, phenyl, cyano replace phenyl,
C1~3The phenyl that the phenyl or halogen that alkoxy replaces replace；R in formula (2)4For hydrogen, C1~3Alkyl, cyano, ester group, C1~3Alcoxyl
Base or halogen；R5For phenyl, C1~3Phenyl, the C that alkyl-substituted phenyl, cyano replace1~3Phenyl, the ester group of alkoxy substitution take
The phenyl that the phenyl or halogen in generation replace；R6For phenyl, C1~3Alkyl-substituted phenyl, 3,4- methylene-dioxy replace phenyl,
Phenyl, the C of phenyl, ester group substitution that cyano replaces1~3The phenyl that the phenyl or halogen that alkoxy replaces replace.
3. synthetic method as described in claim 1, it is characterised in that: in formula (1), R1For hydrogen, cyano, methyl, carbomethoxy, F,
Cl or Br；R2The phenyl replaced for phenyl, methoxy-substituted phenyl or F；R3For phenyl, methyl, isopentyl, methoxy substitution
Phenyl, Br replace phenyl or I replace phenyl；In formula (2), R4For H；R5For phenyl or methoxy-substituted phenyl；R6For
The phenyl that the phenyl or Cl that phenyl, methoxy-substituted phenyl, 3,4- methylene-dioxy replace replace.
4. synthetic method as described in claim 1, it is characterised in that: neighbour's amino azacycle compound: methyl ketone is derivative
Object: the ratio between amount of substance of transition metal salt catalyst is 0.2~0.6:0.2:0.01~0.4.
5. synthetic method as described in claim 1, it is characterised in that: the organic solvent is toluene, tetrahydrofuran, Isosorbide-5-Nitrae-two
Six ring of oxygen, 1,2- dichloroethanes, ethyl alcohol or dimethoxy-ethane.
6. synthetic method as described in claim 1, it is characterised in that: the volumetric usage of the organic solvent is derivative with methyl ketone
The amount of the substance of object is calculated as 2~5L/mol.
7. synthetic method as described in claim 1, it is characterised in that: the heating reaction temperature is 80~120 DEG C, when reaction
Between 16~24 hours.
8. synthetic method as described in claim 1, it is characterised in that: for reaction solution is filled column, residue is reacted for the post-processing
Liquid methylene chloride solution transfer carries out column chromatography for separation with 300 mesh silica gel, the ethyl acetate that eluant, eluent is volume ratio 1:4 with
Petroleum ether mixed liquor, collects the eluent containing target compound, and concentrate drying obtains target product.
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