CN105732455B - A kind of synthetic method of symmetrical substituted pyrrole compound - Google Patents
A kind of synthetic method of symmetrical substituted pyrrole compound Download PDFInfo
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- CN105732455B CN105732455B CN201610064159.9A CN201610064159A CN105732455B CN 105732455 B CN105732455 B CN 105732455B CN 201610064159 A CN201610064159 A CN 201610064159A CN 105732455 B CN105732455 B CN 105732455B
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- WPTCSQBWLUUYDV-UHFFFAOYSA-N c(cc1)cc(cc2)c1nc2-c1nc2ccccc2cc1 Chemical compound c(cc1)cc(cc2)c1nc2-c1nc2ccccc2cc1 WPTCSQBWLUUYDV-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N c1cc(-c2ccccn2)ncc1 Chemical compound c1cc(-c2ccccn2)ncc1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
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Abstract
The present invention relates to a kind of synthetic method of symmetrical azole compounds shown in lower formula (III), methods described includes：In a solvent, in the presence of catalyst, part, acid compound and source of ammonium compound, lower formula (I) compound reacts with lower formula (II) compound, reacts after terminating through post processing, so as to obtain the formula (III) compoundWherein, R H, halogen, C1‑C6Alkyl or C1‑C6Alkoxy；X is alkali metal.Methods described is by the comprehensive selection of special catalyst, part, acid compound, source of ammonium compound and solvent with cooperateing with, the azole compounds that can be symmetrically substituted with high yield, had a good application prospect and industrial production potential in organic chemical synthesis field.
Description
Technical field
The present invention relates to a kind of synthetic method of nitrogen-containing heterocycle compound, a kind of particularly symmetrical substituted azole chemical combination
The synthetic method of thing, belongs to organic chemical synthesis field.
Background technology
In organic chemistry especially field of medicaments, heterocyclic compound generally can be described as because with good bioactivity
Basic construction unit, such as all there is pyrroles's ring structure in many medicines.
Just because of such important function of heterocyclic compound such as pyrrole structure, people have been carried out greatly for its synthetic method
Quantifier elimination, and many scientific achievements are achieved, such as：
Ying Xie et al. (Pd-Catalyzed [3+2] cycloaddition of ketoimines with
alkynes via directed sp3C-H bond activation, Chem.Commun., 2014,50,10699-
10702) a kind of synthetic method of the azole derivatives of palladium compound catalysis is disclosed in, its reaction equation is as follows：
Souvik Rakshit et al. (Followed by Intermolecular Coupling with
Unactivated Alkynes, J.AM.CHEM.SOC., 2010,132,9585-9587) in a kind of Rh compounds are disclosed to urge
The synthetic method of the azole derivatives of change, its reaction equation are as follows:
Min Zhang et al. (General and Regioselective Synthesis of Pyrroles via
Ruthenium-Catalyzed Multicomponent Reactions, J.Am.Chem.Soc., 2013,135,11384-
11388) a kind of synthetic method of the azole derivatives in the presence of Ru catalyst, Phosphine ligands, alkali and certain alcohols is disclosed in, its
Reaction equation is as follows：
Nirmal Das Adhikary et al. (One-Pot Conversion of Carbohydrates into
Pyrrole-2-carbaldehydes as Sustainable Platform Chemicals, J.Am.Chem.Soc.,
One kind is disclosed in 2015,80,7693-7701) in Bn-NH2, azole derivatives in the presence of acid etc. synthetic method, its is anti-
Answer formula as follows：
Mi-Na Zhao et al. (Pd-Catalyzed Oxidative Coupling of Enamides and
Alkynes for Synthesis of Substituted Pyrroles, Org.Lett., 2014,16,608-611) it is public in
The synthetic method of a kind of Pd and the azole derivatives of cupric acetate catalyzed is opened, its reaction equation is as follows：
Xiaoqiang Lei et al. (Rhodium (II)-Catalyzed Formal [3+2] Cycloaddition of
N-Sulfonyl-1,2,3-triazoles with Isoxazoles:Entry to Polysubstituted 3-
Aminopyrroles, Org.Lett., 2015,17,5224-5227) a kind of conjunction of the azole derivatives of Rh catalysis is disclosed in
It is as follows into method, its reaction equation：
As described above, a variety of synthetic methods of synthesis azole derivatives are disclosed in the prior art, but these methods are still deposited
Yield is too low, process is cumbersome the problems such as, still it is rarely reported at present especially for the synthetic method of symmetrical azole compounds, it is right
In the novel method for synthesizing of such azole compounds, the necessity and demand for continuing research are still suffered from, this is also exactly that the present invention is able to
Where the power of completion.
The content of the invention
As described above, in order to solve present in above-mentioned prior art as yield is too low, process is cumbersome, expensive reagents are rare
Etc. many defects, synthesis of the present inventor for symmetrical azole compounds has made intensive studies, and is paying a large amount of creative labor
After dynamic, so as to complete the present invention.
It is pointed out that the present invention is in state natural sciences fund (bullets：21572162) with Zhejiang Province certainly
Right science fund (bullets：LY16B020012 complete under subsidy), express thanks herein.
The present invention relates to a kind of synthetic method of symmetrical azole compounds shown in lower formula (III), methods described includes：Molten
In agent, in the presence of catalyst, part, acid compound and source of ammonium compound, lower formula (I) compound and lower formula (II) chemical combination
Thing reacts, and reacts through post-processing after terminating, so as to obtain the formula (III) compound,
Wherein, R H, halogen, C1-C6Alkyl or C1-C6Alkoxy；
X is alkali metal.
In the synthetic method of the present invention, the C1-C6The implication of alkyl refers to the straight chain with 1-6 carbon atom
Or branched alkyl, for example can be methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle in non-limiting manner
Butyl, n-pentyl, isopentyl or n-hexyl etc..
In the synthetic method of the present invention, the C1-C6The implication of alkoxy refers to the C with above-mentioned implication1-C6
The group that alkyl obtains after being connected with oxygen atom.
In the synthetic method of the present invention, the halogen is halogen, such as can be F, Cl, Br or I.
In the synthetic method of the present invention, X is alkali metal, such as can be Li, Na or K.
In the synthetic method of the present invention, the catalyst is acid chloride (Pd (OAc)2), diethyl cyano group palladium bichloride
(Pd(CH3CN)2Cl2), palladium trifluoroacetate (Pd (OTA)2), palladium bromide (PdBr2), palladium bichloride (PdCl2), palladium acetylacetonate (Pd
(acac)2), tetrakis triphenylphosphine palladium (Pd (PPh3)4) or double (dibenzalacetone) palladium (Pd (dba)2) in any one,
Most preferably double (dibenzalacetone) palladium (Pd (dba)2)。
In the synthetic method of the present invention, the part is 2,2 '-bipyridyl.
The present invention the synthetic method in, the acid compound be trifluoroacetic acid, acetic acid, camphorsulfonic acid, to first
Any one in benzene sulfonic acid, most preferably trifluoroacetic acid.
In the synthetic method of the present invention, the source of ammonium compound is trifluoroacetic acid ammonium, ammonium acetate, ammonium chloride or sulphur
Any one in sour ammonium, most preferably trifluoroacetic acid ammonium.
In the synthetic method of the present invention, the solvent is the mixture of organic solvent and water, wherein organic solvent
Volume ratio with water is 1:0.1-0.3, such as can be 1:0.1、1:0.2 or 1:0.3.
Wherein, the organic solvent is tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) (DMSO), DMF
(DMF) any one or in toluene, most preferably toluene.
The dosage of the solvent is not particularly limited, and those skilled in the art can be according to actual conditions, such as react
Be smoothed out, the concrete condition such as convenient post processing and suitably select and determine, this is all those skilled in the art
Routine techniques knowledge, is no longer described in detail herein.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and formula (II) compound is 1:
1.5-2.5 such as can be 1:1.5、1:2 or 1:2.5.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and catalyst is 1:0.06-
0.12, such as can be 1:0.06、1:0.08、1:0.1 or 1:0.12.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and part is 1:0.15-0.25,
Such as can be 1:0.15、1:2 or 1:0.25.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and acid compound is 1:1.5-
2.5, such as can be 1:1.5、1:2 or 1:2.5.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and source of ammonium compound is 1:1-3,
Such as can be 1:1、1:1.5、1:2、1:2.5 or 1:3.
In the synthetic method of the present invention, reaction temperature is 70-90 DEG C, such as can be 70 DEG C, 80 DEG C or 90 DEG C.
In the synthetic method of the present invention, the reaction time, there is no particular limitation, such as can be examined by liquid chromatogram
Survey the residual percentage of purpose product or raw material and determine the suitable reaction time, it typically is 15-30 hours, such as can be 15
Hour, 20 hours, 25 hours or 30 hours.
In the synthetic method of the present invention, the post processing after reaction terminates can be specific as follows：After reaction terminates, by institute
Obtain reactant mixture to be poured into ethyl acetate, sequentially with saturation NaHCO3The aqueous solution and saturated common salt water washing, separate water-yielding stratum
And organic layer, aqueous layer with ethyl acetate is extracted, merges organic layer and (merges the organic layer after washing and be obtained by extraction organic
Layer), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is carried by flash column chromatography (n-hexane/ethyl acetate)
It is pure, so as to obtain the formula (III) compound.
In the synthetic method of the present invention, the formula (I) compound as raw material is obtained as follows
, namely its synthetic method is as follows：In a solvent, in the presence of catalyst, part and acid, following formula (I-1) compound is with
Formula (II-1) compound reacts, and reacts through post-processing after terminating, so as to obtain the formula (III) compound,
Wherein, X is defined as above.
Namely X is alkali metal, such as can be Li, Na or K..
In the synthetic method of the formula (I) compound of the present invention, the catalyst is acid chloride (Pd (OAc)2), two
Second cyano group palladium bichloride (Pd (CH3CN)2Cl2), palladium trifluoroacetate (Pd (OTA)2), palladium bromide (PdBr2), palladium bichloride (PdCl2), second
Acyl acetone palladium (Pd (acac)2), triphenylphosphine palladium chloride (Pd (PPh3)2Cl2), tetrakis triphenylphosphine palladium (Pd (PPh3)4), it is double
(dibenzalacetone) palladium (Pd (dba)2) or three (dibenzalacetone) two palladium (Pd2(dba)3) in any one, be preferably
Double (dibenzalacetone) palladium (Pd (dba)2) or three (dibenzalacetone) two palladium (Pd2(dba)3), most preferably three (two Asias
Benzylacetone) two palladium (Pd2(dba)3)。
In the synthetic method of the formula (I) compound of the present invention, the part is any one in following formula L1-L8
Kind,
Most preferably L1.
In the synthetic method of the formula (I) compound of the present invention, the acid is p-methyl benzenesulfonic acid, trifluoroacetic acid, camphor tree
Any one in brain sulfonic acid, acetic acid or Loprazolam, most preferably camphorsulfonic acid.
In the synthetic method of the formula (I) compound of the present invention, the solvent is the mixture of organic solvent and water,
Wherein the volume ratio of organic solvent and water is 4-6:1, such as can be 4:1、5:1 or 6:1.
Wherein, the organic solvent be dimethyl sulfoxide (DMSO) (DMSO), DMF (DMF), N, N- dimethyl
Acetamide (DMAC), toluene, ortho-xylene, benzene, 1,4- dioxane, tetrahydrofuran (THF), ethanol, acetone, n-hexane or second
Any one in ether, most preferably benzene.
The dosage of the solvent is not particularly limited, and those skilled in the art can be according to actual conditions, such as react
Be smoothed out, the concrete condition such as convenient post processing and suitably select and determine, this is all those skilled in the art
Routine techniques knowledge, is no longer described in detail herein.
In the synthetic method of the formula (I) compound of the present invention, formula (I-1) compound and formula (II-1) chemical combination
The mol ratio of thing is 1:1.5-2.5 such as can be 1:1.5、1:2 or 1:2.5.
In the synthetic method of the formula (I) compound of the present invention, mole of formula (I-1) compound and catalyst
Than for 1:0.04-0.08, such as can be 1:0.04、1:0.05、1:0.06、1:0.07 or 1:0.08.
In the synthetic method of the formula (I) compound of the present invention, the mol ratio of formula (I-1) compound and part
For 1:0.15-0.25, such as can be 1:0.15、1:2 or 1:0.25.
In the synthetic method of the formula (I) compound of the present invention, formula (I-1) compound and the mol ratio of acid are
1:1-3, such as can be 1:1、1:1.5、1:2、1:2.5 or 1:3.
The present invention the formula (I) compound synthetic method in, reaction temperature be 60-80 DEG C, such as can be 60 DEG C,
70 DEG C or 80 DEG C.
In the synthetic method of the formula (I) compound of the present invention, the reaction time, there is no particular limitation, such as can lead to
Cross the residual percentage of liquid chromatographic detection purpose product or raw material and determine the suitable reaction time, it is small it typically is 18-30
When, such as can be 18 hours, 22 hours, 26 hours or 30 hours.
In the synthetic method of the formula (I) compound of the present invention, the post processing after reaction terminates can be specific as follows：Instead
After should terminating, gained reactant mixture is poured into ethyl acetate, sequentially with saturation NaHCO3The aqueous solution and saturation NaCl are water-soluble
Liquid washs, and separates water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, and merges organic layer and (merges organic after washing
Layer and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through flash column chromatography
(n-hexane/ethyl acetate) purifies, so as to obtain the formula (I) compound.
Inventor has found, when using the above method come preparing raw material compound (I) compound, can be obtained with high yield
Formula (I) compound, so as to provide starting compound for the synthesis that final product is formula (III) compound.
In summary, it is of the invention by suitable catalyst, part, acid compound and source of ammonium compound and suitable molten
The comprehensive selection of agent system obtains symmetrical substituted pyrrole compound with cooperateing with, so as to high yield, and have studied raw material reaction
The optimum synthesising method of thing.It is symmetrical so as to be had a good application prospect in organic chemical synthesis field and researching value
The synthesis of substituted pyrrole compound provides brand-new method.
Embodiment
Below by specific preparation example/embodiment, the present invention is described in detail, but these exemplary embodiments
Purposes and purpose be only used for enumerating the present invention, any type of any limit not is formed to the real protection scope of the present invention
It is fixed, it is more non-that protection scope of the present invention is confined to this.
Preparation example 1
At room temperature, to appropriate solvent (for volume ratio 5:1 benzene and the mixture of water) in add 100mmol above formulas (I-1)
Compound, 150mmol above formulas (II-1) compound, 4mmol catalyst Pd2(dba)3, 25mmol ligand Ls 1 and 100mmol camphors
Sulfonic acid, then stirring are warming up to 60 DEG C, and stirring reaction 30 hours at such a temperature；
After reaction terminates, gained reactant mixture is poured into ethyl acetate, sequentially with saturation NaHCO3The aqueous solution and full
Washed with the NaCl aqueous solution, separate water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain upper formula (I) compound, yield 85.7%.
Nuclear magnetic resonance：1H NMR(CDCl3,500MHz):δ 7.957 (d, J=8.5Hz, 2H), 7.617 (dd, J=7.5Hz,
1H), 7.499 (dd, J=8Hz, 2H), 3.384 (t, J=7.5Hz, 2H), 2.778 (t, J=7.5Hz, 2H)；
13C NMR(CDCl3,125MHz):δ195.33,135.68,133.91,128.90(2C),128.04(2C),
119.19,34.30,11.81。
Preparation example 2
For reaction equation with preparation example 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 4:1 benzene and the mixture of water) in add 100mmol described in formula (I-
1) compound, formula (II-1) compound, 6mmol catalyst Pd described in 200mmol2(dba)3, 15mmol ligand Ls 1 and 200mmol
Camphorsulfonic acid, then stirring are warming up to 70 DEG C, and stirring reaction 24 hours at such a temperature；
After reaction terminates, gained reactant mixture is poured into ethyl acetate, sequentially with saturation NaHCO3The aqueous solution and full
Washed with the NaCl aqueous solution, separate water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain the formula (I) compound, yield 85.3%.
Characterize data is the same as preparation example 1.
Preparation example 3
For reaction equation with preparation example 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 6:1 benzene and the mixture of water) in add 100mmol described in formula (I-
1) compound, formula (II-1) compound, 8mmol catalyst Pd described in 250mmol2(dba)3, 20mmol ligand Ls 1 and 300mmol
Camphorsulfonic acid, then stirring are warming up to 80 DEG C, and stirring reaction 18 hours at such a temperature；
After reaction terminates, gained reactant mixture is poured into ethyl acetate, sequentially with saturation NaHCO3The aqueous solution and full
Washed with the NaCl aqueous solution, separate water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain the formula (I) compound, yield 85.5%.
Characterize data is the same as preparation example 1.
Preparation example 4
For reaction equation with preparation example 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 5:1 benzene and the mixture of water) in add 100mmol described in formula (I-
1) compound, formula (II-1) compound, 5mmol catalyst Pd described in 170mmol2(dba)3, 22mmol ligand Ls 1 and 150mmol
Camphorsulfonic acid, then stirring are warming up to 65 DEG C, and stirring reaction 27 hours at such a temperature；
After reaction terminates, gained reactant mixture is poured into ethyl acetate, sequentially with saturation NaHCO3The aqueous solution and full
Washed with the NaCl aqueous solution, separate water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain upper formula (I) compound, yield 85.6%.
Characterize data is the same as preparation example 1.
It can be seen that by above-mentioned preparation example 1-4, when the synthetic method using the present invention is come preparing raw material compound (I) compound
When, (I) compound can be obtained with good yield, so as to provide and establish base for the synthesis of follow-up formula (III) compound
Plinth.
Preparation example 5-13：The investigation of catalyst
Pd is replaced except following catalyst is used2(dba)3Outside, other operations are constant, so as to according to preparation example 1-4 phase
Same method, implements preparation example 5-13, and institute see the table below 1 using catalyst, preparation example corresponding relation and products collection efficiency.
Table 1
As can be seen here, in all catalyst, Pd (dba)2Or Pd2(dba)3With good effect, and Pd2(dba)3
Then yield the most excellent.Other catalyst cause yield to significantly reduce, and can not even react.
Preparation example 14-20：The investigation of part
In addition to L1 is replaced using different ligands, other operations are constant, so that according to preparation example 1-4 same procedure, it is real
Preparation example 14-20 is applied, institute see the table below 2 using part, preparation example corresponding relation and products collection efficiency.
Table 2
As can be seen here, in all ligand L 1-L8, L1 has best effect, can obtain especially excellent product
Yield, even L2, L5-L6 very similar with it, yield are also significantly reduced, and especially L2 products are 0.This proof is matched somebody with somebody
Body slight change in structure, you can cause yield to have unexpected greatest differences.
Preparation example 21-28：The investigation of acid
In addition to camphorsulfonic acid is replaced using different acid, other operations are constant, so as to according to preparation example 1-4 phase Tongfang
Method, implement preparation example 21-24；And in order to further investigate the influence of acid, the camphorsulfonic acid in preparation example 1-4 is given respectively
To omit, other operations are constant, so as to which preparation example 1-4 be repeated, sequentially obtain preparation example 25-28.
Institute see the table below 3 using acid, preparation example corresponding relation and products collection efficiency.
Table 3
Note：" * " refers to repeat preparation example 1-4 and sequentially obtain preparation example 25-28.
As can be seen here, sour species has a uncertain influence for final products collection efficiency, and wherein camphorsulfonic acid can be with
Excellent yield is obtained, and other acid cause yield to be significantly reduced.And when without using camphorsulfonic acid, then reaction can not
Carry out, so as to which product can not be obtained.
Preparation example 29-40：The investigation of solvent
In addition to the benzene in solvent is replaced using different organic solvents, other operations are constant, so as to according to preparation example 1-4
Same procedure, implement preparation example 29-40 (i.e. still be table 4 below in organic solvent and water mixture), it is used molten
Organic solvent, preparation example corresponding relation and products collection efficiency in agent see the table below 4.
Table 4
Note：" * " represents that the solvent of preparation example 38 is only one-component water.
As can be seen here：1st, when water only is used only as solvent (preparation example 38), yield is significantly reduced；2nd, when making
During by the use of the mixture of organic solvent and water as solvent, wherein organic solvent is most preferably benzene, is even replaced with very
Similar toluene or ortho-xylene, but its yield is still significantly reduced (see preparation example 32-33).Thus benzene-water is demonstrated
There is best unexpected technique effect when mixture is as solvent.
Example 1-40 produced above is visible, when using the present invention Material synthesis method when, by special catalyst, part,
The selection for unique reaction system that acid and solvent is formed, can obtain starting compound formula (I) compound with good yield,
Provide the foundation for the synthesis of formula (III) compound in example below and (obtaining formula according to above-mentioned preparation example with reactant
(I) compound, then carry out the subsequent operation of example below).
Embodiment 1
At room temperature, to appropriate solvent (for volume ratio 1:0.2 toluene and the mixture of water) in add 100mmol above formulas
(I) the upper formula (II) compound of compound, 150mmol, 6mmol catalyst Pd (dba)2, 2,2 '-bipyridyl of 15mmol parts,
150mmol acid compounds trifluoroacetic acid and 100mmol source of ammonium compound trifluoroacetic acid ammoniums, then stirring are warming up to 70 DEG C, and
Stirring reaction 30 hours at such a temperature；
After reaction terminates, gained reactant mixture is poured into ethyl acetate, sequentially with saturation NaHCO3The aqueous solution and full
And brine It, water-yielding stratum and organic layer are separated, aqueous layer with ethyl acetate is extracted, merges organic layer (after merging washing
Organic layer and the organic layer that is obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through quick post
Chromatogram (n-hexane/ethyl acetate) purifies, so as to obtain the formula (III) compound, yield 86.7%.
Nuclear magnetic resonance：1H NMR(DMSO-d6,500MHz):δ 11.24 (s, 1H), 7.76 (d, J=7.5Hz, 4H), 7.37
(dd, J=7.5Hz, 4H), 7.18 (dd, J=7.5Hz, 2H), 6.60 (d, J=2Hz, 2H)；
13C NMR(DMSO-d6,125MHz):δ132.9(2C),132.5(2C),128.5(4C),125.7(2C),123.9
(4C),107.6(2C)。
Embodiment 2
For reaction equation with embodiment 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 1:0.1 toluene and the mixture of water) in add 100mmol above formulas
(I) the upper formula (II) compound of compound, 200mmol, 9mmol catalyst Pd (dba)2, 2,2 '-bipyridyl of 20mmol parts,
200mmol acid compounds trifluoroacetic acid and 200mmol source of ammonium compound trifluoroacetic acid ammoniums, then stirring are warming up to 80 DEG C, and
Stirring reaction 22 hours at such a temperature；
After reaction terminates, gained reactant mixture is poured into ethyl acetate, sequentially with saturation NaHCO3The aqueous solution and full
And brine It, water-yielding stratum and organic layer are separated, aqueous layer with ethyl acetate is extracted, merges organic layer (after merging washing
Organic layer and the organic layer that is obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through quick post
Chromatogram (n-hexane/ethyl acetate) purifies, so as to obtain formula (III) compound, yield 86.5%.
Characterize data is the same as embodiment 1.
Embodiment 3
For reaction equation with embodiment 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 1:0.3 toluene and the mixture of water) in add 100mmol above formulas
(I) the upper formula (II) compound of compound, 250mmol, 12mmol catalyst Pd (dba)2, 2,2 '-bipyridyl of 25mmol parts,
250mmol acid compounds trifluoroacetic acid and 300mmol source of ammonium compound trifluoroacetic acid ammoniums, then stirring are warming up to 90 DEG C, and
Stirring reaction 15 hours at such a temperature；
After reaction terminates, gained reactant mixture is poured into ethyl acetate, sequentially with saturation NaHCO3The aqueous solution and full
And brine It, water-yielding stratum and organic layer are separated, aqueous layer with ethyl acetate is extracted, merges organic layer (after merging washing
Organic layer and the organic layer that is obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through quick post
Chromatogram (n-hexane/ethyl acetate) purifies, so as to obtain formula (III) compound, yield 86.8%.
Characterize data is the same as embodiment 1.
Embodiment 4
For reaction equation with embodiment 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 1:0.2 toluene and the mixture of water) in add 100mmol above formulas
(I) the upper formula (II) compound of compound, 175mmol, 10mmol catalyst Pd (dba)2, 2,2 '-bipyridyl of 18mmol parts,
230mmol acid compounds trifluoroacetic acid and 150mmol source of ammonium compound trifluoroacetic acid ammoniums, then stirring are warming up to 85 DEG C, and
Stirring reaction 17 hours at such a temperature；
After reaction terminates, gained reactant mixture is poured into ethyl acetate, sequentially with saturation NaHCO3The aqueous solution and full
And brine It, water-yielding stratum and organic layer are separated, aqueous layer with ethyl acetate is extracted, merges organic layer (after merging washing
Organic layer and the organic layer that is obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through quick post
Chromatogram (n-hexane/ethyl acetate) purifies, so as to obtain formula (III) compound, yield 87.0%.
Characterize data is the same as embodiment 1.
Embodiment 5-11：The investigation of catalyst
Except respectively by catalyst by double (dibenzalacetone) palladium (Pd (dba)2) replace with different catalysts in following table
Outside, other operations are constant, so as to repeat embodiment 1-4, obtain embodiment 5-11.
Used catalyst, embodiment corresponding relation and products collection efficiency see the table below 5.
Table 5
As can be seen here, the species of catalyst has significant impact for the yield of final product, wherein double (dibenzylidenes third
Ketone) palladium (Pd (dba)2) there is best catalytic effect, and other palladium compounds cause yield to drastically reduce, or even can not send out
Raw reaction.
Embodiment 12-23：The investigation of acid compound
Embodiment 12-15：In addition to acid compound is replaced with into acetic acid by trifluoroacetic acid, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 12-15.
Embodiment 16-19：In addition to acid compound is replaced with into camphorsulfonic acid by trifluoroacetic acid, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 16-19 is sequentially obtained.
Embodiment 20-23：In addition to acid compound is replaced with into p-methyl benzenesulfonic acid by trifluoroacetic acid, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 20-23.
As a result 6 be see the table below.
Table 6
As can be seen here, when the presence of acid compound is especially with trifluoroacetic acid, mesh can be obtained with excellent yield
Product.But when being replaced with other sour, cause products collection efficiency to have and be significantly greatly lowered, even with it very
Similar acetic acid, its yield are also only 47.6-49.1%.Thus demonstrate trifluoroacetic acid have it is best, unexpected
Facilitation effect.
Embodiment 24-39：The investigation of source of ammonium compound
Embodiment 24-27：In addition to source of ammonium compound is replaced with into ammonium acetate by trifluoroacetic acid ammonium, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 24-27 is sequentially obtained.
Embodiment 28-31：In addition to source of ammonium compound is replaced with into ammonium chloride by trifluoroacetic acid ammonium, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 28-31 is sequentially obtained.
Embodiment 32-35：In addition to source of ammonium compound is replaced with into ammonium sulfate by trifluoroacetic acid ammonium, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 32-35 is sequentially obtained.
Embodiment 36-39：Except source of ammonium compound trifluoroacetic acid ammonium is omitted, other operations are constant, so as to repeat
Embodiment 1-4 is implemented, sequentially obtains embodiment 36-39.
As a result 7 be see the table below.
Table 7
As can be seen here, when using trifluoroacetic acid ammonium, purpose product can be obtained with high yield, but when use with it very
During similar ammonium acetate, its yield then have it is significant reduce (being reduced to 70.5-71.3%), and when using ammonium chloride or sulfuric acid
During ammonium, yield can not be surprisingly obtained unexpectedly, and when without using any source of ammonium compound, its yield is on the contrary
73.6-74.3%, it is higher than the yield of ammonium acetate.This demonstrate that trifluoroacetic acid ammonium can obtain unexpected technique effect,
This is non-obvious.
Embodiment 40-51：The investigation of solvent
Embodiment 40-43：In addition to the organic solvent in solvent is replaced with into THF by toluene, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 40-43.
Embodiment 44-47：In addition to the organic solvent in solvent is replaced with into DMSO by toluene, other operations are constant, from
And repeat to implement embodiment 1-4, sequentially obtain embodiment 44-47.
Embodiment 48-51：In addition to the organic solvent in solvent is replaced with into DMF by toluene, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 48-51.
As a result 8 be see the table below.
Table 8
As can be seen here, when using the composite solvent system of toluene and water, purpose product can be obtained with excellent yield, but
It was unexpectedly determined that when toluene therein is replaced into other organic solvent such as THF, DMSO or DMF, will all yield be caused to have urgency
Fall sharply low when DMF (especially for), this demonstrate that the bi-component composite solvent system only formed using toluene with water, can just take
Obtain unexpected high product yield.
In summary, it can clearly be found out by above-mentioned all embodiments, when applying the method according to the invention, pass through specific catalysis
Agent, part, acid compound, the comprehensive selection of source of ammonium compound and solvent can symmetrically be substituted with cooperateing with high yield
Azole compounds, had a good application prospect and industrial production potential in organic chemical synthesis field.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to the protection model of the limitation present invention
Enclose.In addition, it should also be understood that, after the technology contents of the present invention have been read, those skilled in the art can make each to the present invention
Kind change, modification and/or variation, all these equivalent form of values equally fall within the guarantor that the application appended claims are limited
Within the scope of shield.
Claims (2)
1. the synthetic method of symmetrical azole compounds, methods described include shown in a kind of lower formula (III)：In a solvent, in catalysis
In the presence of agent, part, acid compound and source of ammonium compound, lower formula (I) compound reacts with lower formula (II) compound,
React through post-processing after terminating, so as to obtain the formula (III) compound,
Wherein, R H；
X is alkali metal；
The catalyst is double (dibenzalacetone) palladiums；
The part is 2,2 '-bipyridyl；
The acid compound is trifluoroacetic acid；
The source of ammonium compound is trifluoroacetic acid ammonium；
The solvent is the mixture of organic solvent and water, and wherein the volume ratio of organic solvent and water is 1:0.1-0.3；
Wherein, the organic solvent is toluene.
2. synthetic method as claimed in claim 1, it is characterised in that：The formula (I) compound as raw material is according to such as
Made from the method for lower section：In a solvent, in the presence of catalyst, part and acid, following formula (I-1) compound is changed with following formula (II-1)
Compound reacts, and reacts through post-processing after terminating, so as to obtain the formula (I) compound,
Wherein, X is alkali metal；
The catalyst is three (dibenzalacetone) two palladium；
The part is following formula L1,
The acid is camphorsulfonic acid；
The solvent is the mixture of organic solvent and water, and the wherein volume ratio of organic solvent and water is 4-6:1；
Wherein, the organic solvent is benzene.
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