CN104610255B - Method for synthesizing [1,2-a] imidazopyridine derivative containing isoxazole skeleton - Google Patents
Method for synthesizing [1,2-a] imidazopyridine derivative containing isoxazole skeleton Download PDFInfo
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- 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
Abstract
The invention relates to a method for synthesizing a [1,2-a] imidazopyridine derivative containing an isoxazole skeleton. The derivative has a structure as shown in the specification, wherein R1=H, Cl, CH3; and R2=H, CH3. The technical scheme of the invention is as follows: three components are adopted for synthesizing an intermediate by using a 'one-pot' method firstly, and then carrying out a Suzuki coupling reaction on the intermediate so as to obtain a product [1,2-a] imidazopyridine derivative containing an isoxazole skeleton. In the synthesizing method, complex pharmaceutically active molecules are efficiently synthesized by using a two-step method, an advantage that the once-through reaction yield can reach 65-72% is achieved, and the obtained [1,2-a] imidazopyridine derivative can be used as a bromine-domain protein inhibitor, and has potential antitumor activity.
Description
Technical field
The present invention relates to a class has the bromine domain protein inhibitor synthesis skill containing isoxazole skeleton of potential drug activity
Art field, specially one class contains the synthetic method of [1,2-a] Imidazopyridine-derivatives of isoxazole skeleton.
Background technology
The commitment of open gene plays a significant role during the advancings of disease such as tumor.Wherein, nucleosome group
The acetylation of protein lysine n- end residue, the regulation and control to hereditary apparent gene are particularly important.Acetylated lysine is present in closely
In 2000 protein, take part in many cell change orders.The acetylated lysine residue of histone and other albumen is subject to
Acetyl transferase (hat) and the dynamic effect of deacetylation transferring enzyme (hdac).When hdacs overexpression in cell,
The deacetylation degree of some suppression cancer genes increases, and corresponding genetic transcription can be suppressed, thus leading to sending out of cancer
Raw.Therefore, people pass through to study the adjusting function of acetylation of histone, can analyze the apparent mechanism of some diseases of human body.
Bromodomains (brds, bromine domain albumen) refers to comprise the protein function domain of 110 aminoacid, bromine domain
Albumen can preferentially be combined closely with acetyl-l-lysine residue selectivity on histone, may participate in decoding histone code, conveyed sheet
See hereditary information.Brds, according to the function of parent protein, can be divided three classes: (1) histone acetyltransferase (hats) by people；
(2) rely on the chromatin restructuring complex of atp；(3) bet race (brd and extra-terminal family), including
Brd2, brd3, brd4 and brdt etc..Due to brds alternative identification acetyl-l-lysine, participate in the reading of epigenetic gene
And regulation and control.Meanwhile, the chromatinic Acetylation Level of brds scalable, its transcriptional state can produce response to external signal.And,
Their interactions with histone, can modify for rear transcription and produce cooperative effect, and then affect the generation of some diseases.Cause
This, the research of the micromolecular inhibitor based on brds target spot is becoming the research heat of pharmaceutical chemistry and biochemical field in the recent period
Point.
The type of the bromine domain protein inhibitor reported in the recent period includes Benzodiazepineses (compound 1 and 2) and benzimidazole
Class (compound 3).
Compound 1 is by bradner seminar of Harvard Medical School [filippakopoulos p, qi j, picaud s, et
al.selective inhibition of bet bromodomains[j].nature,2010,468(7327):1067-
1073.] [miyoshi s, ooike s, iwata k, et on the basis of the patent of Mitsubishi drugmaker
Al.antitumor agent. [p] .wo/2009/084693,2009.], it is optimized design and synthesize, and with problem composition
Member naming be (+) jq1.First, butanone and 4- chlorobenzoylacetonitrile, under elemental sulfur effect, cyclization becomes alpha-amido thiophene
Fen.Through the aspartoyl propylhomoserin-β-tert-butyl ester with fmoc protection, there is acylation reaction.Then, de- fmoc, ring under acidulated condition
Close, generate heptatomic ring lactams.Finally, under the effect of highly basic tert-butyl group potassium alcoholate, lactams under low temperature, are activated, through sub- with diethyl
Phosphoryl chloride phosphorus oxychloride generates phosphoramidate, then is hydrated hydrazine reaction cyclization with acetyl group.Whole synthetic reaction step reaches 5 steps, and reaction is total
Yield is 25%.
[nicodeme e, jeffrey kl, schaefer u, the et such as GlaxoSmithKline PLC research and development centre nicodeme
al.suppression of inflammation by a synthetic histone minic[j].nature,2010,
468 (7327): 1119-1123.] then design is optimized to the precursor structure of anxiolytic drugs alprazolam and triazolam, closes
Become chemical probe molecule 2.First, the Radix Asparagi gated chloride mono-methyl of fmoc protection and 2- amino -4- anisyl -4- chlorphenyl first
There is [3+3] cycloaddition reaction in ketone, obtain corresponding lactams.Warp and lawesson reagent reacting, prepare corresponding sulfur
For amide.Under hydrazine hydrate and chloroacetic chloride act on, further cyclization is methyl-triazole structure.Hydrolyzed under basic conditions, obtains phase
The acid answered.Under hbtu (BTA-n, n, n ', n '-tetramethylurea hexafluorophosphate) catalysis, diisopropylethylamine is molten
Agent, reacts generation racemic 2 with ethamine.Racemic modification can pass through the Chiral liquid chromatography instrument chiral separation of preparative, you can
Obtain final product 2.Whole synthesis step is 5 steps, and synthesis total recovery is 16%.
And dawson seminar [dawson ma, prinjha rk, dittmann a, et al.inhibition of
bet recruitment to chromatin as an effective treatment for mll-fusion
Leukaemia [j] .nature, 2011,478 (7370): 529-533.] the synthesis road of the low molecular organic depressant 3 reported
Line.First, there is coupling reaction in 3- iodo- 4- methoxy nitrobenzene and 3,5- dimethyl isoxazole -4- boric acid.Products therefrom second
Acetoacetic ester dissolves, and washs through 5% sodium sulfite aqueous solution, gained organic faciess ethanol dilution, is amido through pd/c reduction nitro.
Then, there is nucleophilic substitution, ethyoxyl of leaving away with diethyl ethoxymethylenemalonate.At a temperature of 255 DEG C, with diphenyl ether
For solvent, there is itself ring-closure reaction.Again through removing impurity at a temperature of ethyl acetate backflow, obtain 4- oxo-Isosorbide-5-Nitrae-dihydro Kui
Rather -3- Ethyl formate.After hydrolyzing further, obtain corresponding carboxylic acid.After phosphorus oxychloride chlorination, there is acylation reaction with ammonia.
Products therefrom, warp and (1r) -1- (2- pyridine radicals) ethamine nucleophilic displacement of fluorine, slough chlorine atom.Using phi (oac)2Dioxide giving obtains
To final product.The synthesis step of this micromolecular inhibitor has eight steps.This process route condition whole is harsher, multistep reaction
Total recovery is less than 10%.
This three classes chemical probe molecule of report, as bromodomains protein inhibitor, is tested in pharmaceutically active recently
In, there is good effect.Thus, we are based on structure effect principle in pharmaceutical synthesis, according to the structure of compound 1-3, carry out
Potential pharmaceutically active small molecule design.Such as, benzodiazepine compound structure and [1,2-a] imidazopyridine structure phase
Seemingly, and the different alkyl structure of 1,3- dimethyl to bromodomains albumen suppression can play excellent inhibitory activity.So, this
Invention, by two parts active structure organic assembling, designs and invents the bromodomains albumen suppression with potential source biomolecule activity
The efficient synthesis of agent.
Content of the invention
The technical problem to be solved in the present invention is: based on the compound 3 in background technology, provides one kind to have potential medicine
The synthetic method of [1,2-a] Imidazopyridine-derivatives of thing activity.
The technical solution adopted for the present invention to solve the technical problems is:
A kind of [1,2-a] Imidazopyridine-derivatives containing isoxazole skeleton, have a following structure:
Wherein, r1=h, cl, ch3；r2=h, ch3.
A kind of synthetic method of [1, the 2-a] Imidazopyridine-derivatives containing isoxazole skeleton, has following steps:
(1) molecular sieve, 4- bromobenzaldehyde, a component, catalysts and solvents toluene are sequentially added in flask, will be above-mentioned mixed
Compound adds b component after being heated to 100 DEG C, is heated to 110 DEG C and carries out the 12-16h that flows back, after reaction terminates, is cooled to room temperature, will
Products therefrom filtration, vacuum distillation, isolate and purify and obtain midbody product [1,2-a] Imidazopyridine-derivatives；
(2) by above-mentioned gained midbody product [1,2-a] Imidazopyridine-derivatives and 3,5- dimethyl isoxazole -4-
Boric acid, solvent toluene, molecular sieve, under palladium complex and base catalyst cesium carbonate are catalyzed, 110 DEG C carry out coupling reaction 30-35h
Afterwards, be cooled to room temperature, mixture is filtered, vacuum distillation, isolate and purify after, obtain final product end-product contain isoxazole skeleton [1,
2-a] Imidazopyridine-derivatives；
Catalyst in described step (1) is Cu-lyt. and trifluoro methylsulfonyl scandium mixture, and adding mol ratio is 2:
1.A group is divided into PA or PA derivant, and b group is divided into phenylacetylene or phenylacetylene substituent；Described step
(2) palladium complex in is 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (ii).
Further, described 4- bromobenzaldehyde, a component, catalyst, the interpolation molar ratio range of b component be 1:1.1～
1.2:0.5～1.0:1.5～2.0.
Further, described midbody product [1,2-a] Imidazopyridine-derivatives, 3,5- dimethyl isoxazole -4-
The interpolation molar ratio range of boric acid, palladium complex and base catalyst cesium carbonate is 1:1.2～2.0:0.1～0.2:2.0～3.0.
A kind of reaction principle of the synthetic method of [1,2-a] Imidazopyridine-derivatives containing isoxazole skeleton is such as
Under:
, wherein, r1=h, cl, ch3；r2=h, ch3.
Beneficial effect: technical scheme first adopts three components " one kettle way " synthetic intermediate, then employing of connecting
Suzuki coupling reaction prepares [1,2-a] imidazopyridine derivatives that product contains isoxazole skeleton, this synthetic method
Using two step method, efficiently synthesize the pharmaceutically active molecule of complexity, there is reaction condition gently, one way reaction yield can reach 65-
72% advantage, [1, the 2-a] imidazopyridine derivatives using technical scheme gained can be used as a kind of bromine domain egg
White inhibitor, has potential active anticancer.
Brief description
The present invention is further described with reference to the accompanying drawings and examples；
Fig. 1 is m-2 in embodiments of the invention two1h nmr；
Fig. 2 is m-2 in embodiments of the invention two13c nmr；
Fig. 3 is p-2 in embodiments of the invention two1h nmr；
Fig. 4 is p-2 in embodiments of the invention two13c nmr.
Specific embodiment
With reference to specific embodiment, the invention will be further described, but the present invention is not limited to following examples.
Embodiment one
A kind of synthetic method of [1, the 2-a] Imidazopyridine-derivatives containing isoxazole skeleton, has following steps:
(1) synthesis of intermediate m-1
In the single-necked flask of 50ml, sequentially addMolecular sieve is a little；4- bromobenzaldehyde (5mmol, 0.92g)；2- ammonia
Yl pyridines (5.5mmol, 0.52g)；Cu-lyt. (0.5mmol, 50mg)；Trifluoro methylsulfonyl scandium (0.25mmol, 123mg)；First
Benzene 8-10ml, reactant mixture is heated rapidly to 100 DEG C, adds phenylacetylene (7.5mmol, 766mg, 823 μ l)；It is warmed up to
110 DEG C, at reflux, react 15 hours about, after reaction stops, reactant liquor is cooled to room temperature, by gained mixture
Filter, solid residue is washed with a small amount of toluene, obtains brownish black clear filtrate, by gained filtrate through vacuum distillation, remove solvent,
Obtain crude product, crude product is through column chromatographic isolation and purification；Eluant is normal hexane: ethyl acetate (both volume ratios 80:20), you can
Obtain intermediate m-1 2- (4- bromophenyl) -3- benzyl-[1,2-a] imidazopyridine, yield is 85%.
The characterize data of gained intermediate m-1 is as follows: light yellow solid, fusing point is 158-160 DEG C；
1h nmr(400mhz,cdcl3) δ, ppm:7.59-7.84 (m, 4h), 7.54 (d, j=6.05hz, 2h), 7.31 (s,
2h), 7.16-7.28 (m, 2h), 7.11 (d, j=7.52hz, 2h), 6.73 (t, j=6.79hz, 1h), 4.46 (s, 2h).
13c nmr(100mhz,cdcl3)δ,ppm:143.07,136.5,133.53,131.8,129.7,129.1,
127.6,127.0,124.5,123.54,121.9,117.7,112.5,29.9.
hrms:calculated(c20h15brn2):362.0419,found:362.0415.
(2) synthesis of product p-1
In 25ml single-necked flask, sequentially add intermediate 2- (4- bromophenyl) -3- benzyl-[1,2-a] imidazopyridine
m-1(1mmol,362mg)；3,5- dimethyl isoxazole -4- boric acid (1.5mmol, 211mg)；1,1 '-two (diphenyl phosphine) two cyclopentadienyl
Ferrum palladium chloride (ii) catalyst (0.1mmol, 74mg)；Cesium carbonate (2mmol, 652mg)；Molecular sieve is a little；Toluene 5ml,
At 110 DEG C, flow back reactant mixture 32h, after reaction stops, reactant liquor is cooled to room temperature, mixture is filtered, solid is residual
Slag is washed with a small amount of toluene, obtains brown color filtrate, and gained filtrate, through vacuum distillation, removes solvent, obtains crude product, crude product warp
Column chromatographic isolation and purification, eluant is normal hexane: ethyl acetate (both volume ratios 85:15), you can obtain product p-1, yield
For 80%.
Gained p-1 product 4- (4- (3- benzyl [1,2-a] imidazopyridine -2- base)-phenyl) -3,5- dimethyl isoxazole
Characterize data as follows: white solid, fusing point: 196-198 DEG C；
1h nmr(400mhz,cdcl3) δ, ppm:7.86 (d, j=4.0hz, 2h), 7.73 (d, j=4.0hz, 2h),
7.35-7.33 (m, 4h), 7.28-7.33 (m, 1h), 7.21-7.23 (m, 1h), 7.16 (d, j=8.0hz, 2h), 6.74-6.76
(m,1h),4.55(s,2h),2.44(s,3h),2.30(s,3h).
13c nmr(100mhz,cdcl3)δ,ppm:165.4,158.8,147.0,145.0,136.7,133.8,130.4,
129.9,129.8,129.4,129.2,128.6,127.8,127.1,126.9,124.6,123.6,117.9,116.5,
112.5,30.0,29.8,11.7,11.0.
hrms(esi):calculated for c25h22n3o[m+h]+380.1763,found:380.1769.
Embodiment two
A kind of synthetic method of [1, the 2a] Imidazopyridine-derivatives containing isoxazole skeleton, has following steps:
(1) synthesis of intermediate m-2
In the single-necked flask of 50ml, sequentially addMolecular sieve is a little；4- bromobenzaldehyde (5mmol, 0.92g)；2- ammonia
Yl pyridines (5.5mmol, 0.52g)；Cu-lyt. (0.5mmol, 50mg)；Trifluoro methylsulfonyl scandium (0.25mmol, 123mg)；First
Benzene 8-10ml, reactant mixture is heated rapidly to 100 DEG C, adds 4- methyl phenylacetylene (7.5mmol, 871mg, 945 μ l)；Rise
Temperature, to 110 DEG C, at reflux, is reacted 15 hours about, after reaction stops, reactant liquor is cooled to room temperature.Gained is mixed
Compound filters, and solid residue is washed with a small amount of toluene, obtains brownish black clear filtrate.Gained filtrate, through vacuum distillation, removes molten
Agent, obtains crude product.Through column chromatographic isolation and purification, eluant is normal hexane: ethyl acetate (both volume ratios 80:20) to crude product,
Can get intermediate m-2, yield is 76%.
The characterize data of gained m-2 intermediate 2- (4- bromophenyl) -3- (4- methyl-benzyl) [1,2-a] imidazopyridine is such as
Under: white solid, m.p.=124-126 DEG C.
1h nmr(400mhz,cdcl3): 7.65-7.68 (m, 4h), 7.53-7.55 (d, j=7.2hz, 2h), 7.26 (s,
1h), 7.19-7.21 (m, 2h), 7.17-7.19 (m, 2h), 7.00 (d, j=7.0hz, 2h), 6.71-6.74 (m, 1h), 4.42
(s, 2h), 2.33 (s, 3h), as shown in Figure 1.
13c nmr(100mhz,cdcl3):145.0,143.0,136.8,133.6,133.4,131.9,129.9,128.8,
127.6,124.5,123.6,122.0,118.2,117.6,112.5,29.5,21.1, as shown in Figure 2.
hrms(esi):calculated for c21h18brn2[m+h]+:377.0662,found:377.0669.
(2) synthesis of product p-2
In 25ml single-necked flask, sequentially add intermediate m-2 (1mmol, 377mg)；3,5- dimethyl isoxazole -4- boron
Sour (1.5mmol, 211mg)；1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (ii) catalyst (0.1mmol, 74mg)；Carbon
Sour caesium (2mmol, 652mg)；Molecular sieve is a little；Toluene 5ml.At 110 DEG C, flow back reactant mixture 32h, and reaction stops
Afterwards, reactant liquor is cooled to room temperature, mixture is filtered, solid residue is washed with a small amount of toluene, obtain brown color filtrate, gained
Filtrate, through vacuum distillation, removes solvent, obtains crude product, and through column chromatographic isolation and purification, eluant is normal hexane: acetic acid second to crude product
Ester (both volume ratios 85:15), you can obtain product p-2, yield is 78%.
Gained p-2 product 4- (4- (3- is to methyl-benzyl [1,2-a] imidazopyridine -2- base)-phenyl) -3,5- dimethyl
The characterize data of isoxazole is as follows: white solid, fusing point: 48-50 DEG C；
1h nmr(400mhz,cdcl3): 7.86 (d, j=8.0hz, 2h), 7.72 (t, j=12hz, 3h), 7.32 (d, j=
8.0hz, 2h), 7.26 (s, 1h), 7.19-7.23 (m, 1h), 7.12 (d, j=8.0hz, 2h), 7.04 (d, j=8.0hz, 2h),
6.72 (t, j=12.0hz, 1h), 4.50 (s, 2h), 2.43 (s, 3h), 2.33 (s, 3h), 2.30 (s, 3h), as shown in Figure 3.
13c nmr(100mhz,cdcl3):165.2,158.7,144.9,143.4,136.7,133.8,133.4,129.8,
129.3,128.5,127.6,124.4,123.5,118.0,117.5,116.4,112.3,29.7,21.0,11.6,10.9, such as
Shown in accompanying drawing 4.
hrms(esi):calculated for c26h23n3o[m+h]+:394.1919,found:394.1926.
Embodiment three
A kind of synthetic method of [1, the 2a] Imidazopyridine-derivatives containing isoxazole skeleton, has following steps:
(1) synthesis of intermediate m-3
In the single-necked flask of 50ml, sequentially addMolecular sieve is a little；4- bromobenzaldehyde (5mmol, 0.92g)；2- ammonia
Base -5- picoline (5.5mmol, 595mg)；Cu-lyt. (0.5mmol, 50mg)；Trifluoro methylsulfonyl scandium (0.25mmol,
123mg)；Toluene 8-10ml.Reactant mixture is heated rapidly to 100 DEG C, add 4- methyl phenylacetylene (7.5mmol,
871.2mg,945μl)；It is warmed up to 110 DEG C, at reflux, react 16 hours about, after reaction stops, reactant liquor is cold
But arrive room temperature, mixture is filtered, solid residue is washed with a small amount of toluene, obtain brownish black clear filtrate.Gained filtrate is through subtracting
Pressure distillation, removes solvent, obtains crude product.Through column chromatographic isolation and purification, eluant is normal hexane: ethyl acetate (both to crude product
Volume ratio 80:20), you can obtain intermediate m-3, yield is 78%.
Gained m-3 intermediate (2- (4- bromophenyl) -6- methyl -3- (4- methyl-benzyl)-[1,2-a] imidazopyridine)
Characterize data is as follows: yellow solid, 144-146 DEG C of fusing point；
1h nmr(400mhz,cdcl3): 7.62-7.64 (m, 2h), 7.61 (d, j=4.0hz, 1h), 7.49-7.59 (m,
3h), 7.26 (s, 2h), 7.11 (d, j=8.0hz, 1h), 7.00-7.06 (m, 2h), 4.39 (s, 2h), 3.37 (s, 3h), 3.24
(s,3h).
13c nmr(100mhz,cdcl3):143.4,142.6,136.6,133.6,133.5,131.7,129.8,129.5,
127.6,127.5,122.0,121.7,121.0,117.8,116.9.
hrms(esi):calculated for c22h20brn2[m+h]+:391.0819,found:392.0737.
(2) synthesis of product p-3
In 25ml single-necked flask, sequentially add intermediate m-4 (1mmol, 392mg)；3,5- dimethyl isoxazole -4- boron
Sour (1.5mmol, 211mg)；1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (ii) catalyst (0.1mmol, 74mg)；Carbon
Sour caesium (2mmol, 652mg)；Molecular sieve is a little；Toluene 5ml.At 110 DEG C, flow back reactant mixture 32h.Reaction stops
Afterwards, reactant liquor is cooled to room temperature, mixture is filtered, solid residue is washed with a small amount of toluene, obtain brown color filtrate, gained
Filtrate, through vacuum distillation, removes solvent, obtains crude product, and through column chromatographic isolation and purification, eluant is normal hexane: acetic acid second to crude product
Ester (both volume ratios 85:15), you can obtain product p-4, yield is 79%.
Gained p-3 product 4- (4- (6- methyl -3- is to methyl-benzyl [1,2-a] imidazopyridine -2- base)-phenyl) -3,
The characterize data of 5- dimethyl isoxazole is as follows: white solid, 206-208 DEG C of fusing point；
1h nmr(400mhz,cdcl3) δ, ppm:7.81 (d, j=7.6hz, 2h), 7.60 (d, j=7.6hz, 1h), 7.49
(s, 1h), 7.27 (d, j=8.0hz, 2h), 7.13 (d, j=8.0hz, 2h), 7.02-7.06 (m, 3h), 4.45 (s, 2h),
2.40(s,3h),2.32(s,3h),2.27(s,3h),2.24(s,3h).
13c nmr(100mhz,cdcl3)δ,ppm:165.4,158.7,147.0,144.9,136.7,133.7,130.4,
129.9,129.4,129.2,128.5,127.8,127.6,121.1,117.8,116.9,29.6,21.2,18.5,11.7,
11.0.
hrms(esi):calculated for c28h29n3o[m+h]+424.2389,found:424.2383.
Claims (3)
1. a kind of synthetic method of [1, the 2-a] Imidazopyridine-derivatives containing isoxazole skeleton, is characterized in that: this derives
Thing has a following structure:
Wherein, r1=h, ch3；r2=h, ch3；
The method has following steps:
(1) molecular sieve, 4- bromobenzaldehyde, a component, catalysts and solvents toluene are sequentially added in flask, by said mixture
Add b component after being heated to 100 DEG C, be heated to 110 DEG C and carry out the 12-16h that flows back, after reaction terminates, be cooled to room temperature, by gained
Product filtration, vacuum distillation, isolate and purify and obtain midbody product [1,2-a] Imidazopyridine-derivatives；
(2) by above-mentioned gained midbody product [1,2-a] Imidazopyridine-derivatives and 3,5- dimethyl isoxazole -4- boron
Acid, solvent toluene, molecular sieve, under palladium complex and base catalyst cesium carbonate are catalyzed, 110 DEG C carry out coupling reaction 30-35h
Afterwards, be cooled to room temperature, mixture is filtered, vacuum distillation, isolate and purify after, obtain final product end-product contain isoxazole skeleton [1,
2-a] Imidazopyridine-derivatives；
Catalyst in described step (1) is Cu-lyt. and trifluoro methylsulfonyl scandium mixture, and interpolation mol ratio is 2:1, a group
It is divided into PA or 2-AMINO-4-PICOLINE, b group is divided into phenylacetylene or 4- methyl phenylacetylene；In described step (2)
Palladium complex be 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (ii)；
Described midbody product [1,2-a] Imidazopyridine-derivatives areIts
In, r1=h, ch3；r2=h, ch3.
2. a kind of synthesis side of [1,2-a] Imidazopyridine-derivatives containing isoxazole skeleton as claimed in claim 1
Method, is characterized in that: described 4- bromobenzaldehyde, a component, catalyst, the interpolation molar ratio range of b component are 1:1.1～1.2:
0.5～1.0:1.5～2.0.
3. a kind of synthesis side of [1,2-a] Imidazopyridine-derivatives containing isoxazole skeleton as claimed in claim 1
Method, is characterized in that: described midbody product [1,2-a] Imidazopyridine-derivatives, 3,5- dimethyl isoxazole -4- boron
It is 1:1.2～2.0:0.1～0.2:2.0～3.0 that acid, palladium complex and base catalyst cesium carbonate add molar ratio range.
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