CN109912567A - A kind of biaryl pyrrole derivatives compound and preparation method thereof - Google Patents
A kind of biaryl pyrrole derivatives compound and preparation method thereof Download PDFInfo
- Publication number
- CN109912567A CN109912567A CN201910320596.6A CN201910320596A CN109912567A CN 109912567 A CN109912567 A CN 109912567A CN 201910320596 A CN201910320596 A CN 201910320596A CN 109912567 A CN109912567 A CN 109912567A
- Authority
- CN
- China
- Prior art keywords
- biaryl
- compound
- pyrrole derivatives
- preparation
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
The present invention relates to a kind of biaryl pyrrole derivatives compounds and preparation method thereof, belong to pharmaceutical intermediate synthesis technical field.Solve the problems, such as it is how to provide the compound of a kind of structure novel, and synthetic method has the advantages that synthetic route is short and is readily synthesized.A kind of biaryl pyrrole derivatives compound and preparation method thereof is provided, the preparation method of the derivative compound is with [RuCl2(p‑cymene)]2It is composite catalyst with cupric salt, in the presence of oxygen, so that raw material and pyrroles is carried out oxidative dehydrogenation coupling reaction, obtain corresponding product.The biaryl that active 1-H- pyrroles can effectively be introduced, for applying the midbody compound for developing more novel blood pressure reducing medicines in synthesis to be of great significance；And reaction route is short, easily operated.
Description
Technical field
The present invention relates to a kind of biaryl pyrrole derivatives compounds and preparation method thereof, belong to pharmaceutical intermediate synthetic technology
Field.
Background technique
Aryl-linking compound especially contains N, and the aryl-linking compound of the hetero atoms type such as O is that clinical blood-pressure drug has
The structural framework in composition molecule is imitated, such as: Angiotensin II (AT1) receptor lifts the husky smooth class hypotensor A Qisha of antagonist
Smooth (Azilsartan), Valsartan (Valsartan) etc..
In the prior art, commonly for synthesizing aryl-linking compound with experimental size, have using palladium catalyst and
Raney nickel, although it is existing also have using Raney nickel have economic benefit, palladium catalyst because have hypotoxicity and
It is better than Raney nickel to the bigger tolerance of functional group.Therefore, existing aryl-linking compound is by transition gold mostly
Belong to the aryl halides being catalyzed under the action of palladium and react acquisition with the Suzuki of aryl boric acid, which need to be preparatory by simple aryl object
Function dough is converted into aryl halides, and obtains aryl boric acid derivative by aryl grignard reagent, and the single aromatic that conforms to the principle of simplicity goes out
Hair, step is more verbose, and the boronic acid derivatives of nitrogen-containing heterocycle, especially 1-H- pyrroles are not easy to obtain, and uses grignard reaction
The risk of itself is also higher, not easy to operate, is unfavorable for keeping the safety in production.As Chinese patent (Authorization Notice No.:
CN101715439B a kind of simple function and/or bifunctional aryl-linking compound and preparation method, are mainly only to close disclosed in)
In the similar compound of biphenyl structural, there is no specific heteroatomic structures, more particularly, to the derivative compounds of 1-H- pyrroles, and
And it is formed afterwards with acid reaction using halogenated.Equally still there is a problem of above-mentioned described.Therefore, how to develop some new
Midbody compound allows to provide more novel aryl-linking compounds, and is able to solve the connection comprising 1-H- pyrroles again
Aryl compound is not easy composition problem, by design synthesis pyrroles's aryl-linking compound for developing novel biphenyl hypotensor
Object is of great significance.
Summary of the invention
The present invention is directed to the above defect existing in the prior art, provides a kind of biaryl pyrrole derivatives compound and its system
Preparation Method solves the problems, such as it is how to provide the compound of a kind of structure novel, and synthetic method has synthetic route short and easy
In synthesis the advantages of.
An object of the present invention is achieved through the following technical solutions, a kind of biaryl pyrrole derivatives compound, described
Shown in the following type I compound of structural formula of biaryl pyrrole derivatives compound:
Wherein, R in formula I1Selected from hydrogen or C1-C3Alkyl, R2Selected from hydrogen, halogen, nitro, cyano, C1-C3Alkoxy,
C1-C3Alkyl or phenyl.
The novel heteroatomic biphenyl structural feature of the specific aryl of compound of the present invention, can be used in developing novel biphenyl
The key intermediates of blood-pressure drug have the characteristics that the biaryl structure of certain active 1-H- pyrroles, make to open synthesis
A possibility that providing more novel blood pressure reducing medicines during sending out this kind of blood-pressure drugs, it is novel in exploitation for applying
Biphenyl blood pressure lowering class drug is of great significance；Meanwhile the structure designed through the invention also can effectively simplify synthesis hardly possible
Degree, makes to be easier to synthesize the new structural compound.
In above-mentioned biaryl pyrrole derivatives compound, preferably, the halogen is selected from fluorine or chlorine；The C1-C3's
Alkoxy is selected from methoxy or ethoxy.Have the characteristics that the group steric hindrance of introducing is small, be easy to the progress and synthesis reacted,
The validity of reaction is improved, further preferred, R2Be it is corresponding 4 substitution fluorine, nitro, cyano, methoxyl group, phenyl or
Methyl.
In above-mentioned biaryl pyrrole derivatives compound, preferably, the biaryl pyrrole derivatives compound packet
Include compound below:
It can be more advantageous to the intermediate process for being applied to drop blood medicine class drug, for being applied to find novel blood pressure lowering
The research of class drug is of great significance.
The second object of the present invention is to be achieved through the following technical solutions, a kind of system of biaryl pyrrole derivatives compound
Preparation Method, method includes the following steps:
With [RuCl2(p-cymene)]2It is composite catalyst with cupric salt, in the presence of oxygen, formula II is changed
It closes object and pyrroles carries out oxidative dehydrogenation coupling reaction, obtain corresponding product type I compound
Wherein, R in formula I1Selected from hydrogen or C1-C3Alkyl, R2Selected from hydrogen, halogen, nitro, cyano, C1-C3Alkoxy,
C1-C3Alkyl or phenyl；R in formula II and Formulas I1And R2It is corresponding.
By using [RuCl2(p-cymene)]2With the catalyst system of cupric salt, reaction is made to need not move through traditional virtue
The process of base halides and aryl boric acid can efficiently construct the design feature of biaryl pyrroles, and by-product in reaction process
Object is water, is also beneficial to improve the yield and quality requirement of product, also has the effect of that Atom economy is high.
Here [RuCl2(p-cymene)]2For dichloro (p-cymene) ruthenium (II) dimer, No. CAS: 52462-29-0,
And corresponding structural formula is as follows:
Meanwhile the present invention also has the characteristics that reaction route is short, is more advantageous to actual operation, reduces pilot process, tool
There is better industrialized production advantage.
In the preparation method of above-mentioned biaryl pyrrole derivatives compound, preferably, the cupric salt is selected from a water
Close copper acetate or copper acetate.Be conducive to and [RuCl2(p-cymene)]2Ligand is formed, promotes the progress of reaction, further
The conversion ratio of reaction is improved, yield is improved, cupric salt can also be copper chloride.
In the preparation method of above-mentioned biaryl pyrrole derivatives compound, preferably, II compound of the formula and divalent
The molar ratio of mantoquita is 1:2.0~2.5.It may advantageously facilitate the progress of reaction.As further preferred, II chemical combination of formula
The molar ratio of object and cupric salt is 1:2.1~2.3.
In the preparation method of above-mentioned biaryl pyrrole derivatives compound, preferably, [the RuCl2(p-cymene)]2
Dosage be II compound of formula mole dosage 2.5%~5.0%.It can either guarantee to promote within the scope of effective catalytic amount
The progress of reaction, promotes effective conversion of reaction raw materials, and advantageously reduces the waste of the raw materials such as catalyst, improves the benefit of raw material
With rate.
In the preparation method of above-mentioned biaryl pyrrole derivatives compound, preferably, the oxidative dehydrogenation coupling reaction
Temperature be 105 DEG C~115 DEG C.The conversion ratio for improving reaction, guarantees the yield and content requirement of product.
In the preparation method of above-mentioned biaryl pyrrole derivatives compound, preferably, the oxidative dehydrogenation coupling reaction
It carries out in organic solvent.Purpose is to improve the stability of reaction, carry out under the conditions of making existing for the organic solvent, more favorably
In avoiding local heating, further guarantee the content requirement of product.Here organic solvent can be alcoholic solvent, alkyl benzene
Solvent such as benzene or toluene etc., can also be amide solvent etc..As a further preference, the organic solvent is selected from positive fourth
One of alcohol, the tert-butyl alcohol, tert-pentyl alcohol, toluene, dimethylformamide, dimethyl acetamide and N-Methyl pyrrolidone are several
Kind.Stability with solvent is high, is not easy to participate in reaction, and can effectively make dissolution of raw material again, promote reaction adequately into
Row, and product can also be made to efficiently separate in last handling process, it is easily operated.
In the preparation method of above-mentioned biaryl pyrrole derivatives compound, preferably, II compound of the formula and pyrroles
Molar ratio be 1:5~10.Not only can be as raw material, but also a certain amount can be provided and used as solvent, promote reaction into
Row.
The reaction equation of the preparation method of biaryl pyrrole derivatives compound of the invention is as follows:
In conclusion the invention has the following advantages that
1. biaryl pyrrole derivatives compound is a kind of novel compound, active 1-H- pyrroles can be effectively introduced
Biaryl, for applying the midbody compound for developing more novel blood pressure reducing medicines in synthesis to be of great significance；Meanwhile it is logical
Crossing the structural compounds that the present invention designs also can effectively simplify synthesis difficulty, be more advantageous to and improve operability and safety
Property.
2. this method has the advantages that reaction route is short, easily operated, even and if only needing a step complete in entire reaction process
Entirely, the utilization rate for being conducive to improve raw material, reduces the loss in pilot process and the generation of by-product；Meanwhile in reaction process
By-product be water, be conducive to improve product yield and content effect.
Specific embodiment
Below by specific embodiment, the technical solutions of the present invention will be further described, but the present invention is simultaneously
It is not limited to these embodiments.
Embodiment 1
The biaryl pyrrole derivatives chemical compounds I a structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- phenylpyridine) is as follows in the present embodiment:
The compound specifically uses following methods to synthesize in the present embodiment:
By II compound of formula (155mg, 1mmol), pyrroles (670mg, 10mmol), tert-pentyl alcohol (20mL), [RuCl2(p-
cymene)]2(15mg, 0.025mmol) and copper acetate dihydrate (500mg, 2.5mmol) put into clean reaction vessel, will
Gas in container is sealed with pressure-resistant tetrafluoro bottle stopper afterwards three times with replacement of oxygen, is then raised temperature to 105 DEG C~110 DEG C, is deposited in oxygen
Under the conditions, heat preservation carries out oxidative dehydrogenation coupling reaction 24 hours, after reaction, by reaction solution slow cooling to room temperature,
Synthesis liquid is filtered, and is eluted with 10mL tert-pentyl alcohol, merging filtrate, which be concentrated under reduced pressure, removes solvent, by residue through silicagel column
Chromatography (eluant, eluent: n-hexane (volume)/ethyl acetate (volume) proportional region is 10:1~2:1) is refined, and is concentrated or is tied
After crystalline substance, corresponding light pink solid product biaryl pyrrole derivatives chemical compounds I a (165mg), yield 75% are obtained.Fusing point: 75 DEG C
~77 DEG C.
Obtained product is subjected to structural analysis, analysis result is as follows:
1H-NMR(400MHz,CDCl3): δ 9.58 (br, 1H), 8.64 (d, J=4.4Hz, 1H), 7.65 (td, J=
7.8Hz, J=1.8Hz, 1H), 7.60 (dd, J=7.8Hz, J=1.2Hz, 1H), 7.47 (dd, J=7.8Hz, J=1.2Hz,
1H), 7.42 (dd, J=7.5Hz, 1H), 7.33 (td, J=7.5Hz, J=1.3Hz, 1H), 7.25 (m, 1H), 7.20 (d, J=
7.8Hz, J=1.3Hz, 1H), 6.72 (m, 1H), 6.29 (m, 1H), 6.23 (m, 1H).
13C-NMR(100MHz,CDCl3):δ160.10,148.46,137.90,136.43,132.14,131.83,
131.06,129.73,128.71,126.72,125.10,121.99,118.33,108.91,108.28。
MS(ESI):C15H12N2(M+Na+):243.1。
Embodiment 2-8
Operating process in accordance with the above-mentioned embodiment 1 synthesizes corresponding product biaryl pyrrole derivatives chemical compounds I a, by changing
Become raw material pyrroles therein, catalyst [RuCl2(p-cymene)]2Dosage and solvent type be embodied accordingly, respectively
Kind usage ratio situation and corresponding product yield result are as shown in table 1 below:
Table 1:
For [the RuCl in above-mentioned table 12(p-cymene)]2Dosage such as corresponding embodiment 2 in 30mg (5%mmol)
Indicate [RuCl2(p-cymene)]2Dosage be 30mg, account for the 5%mmol of the dosage of II compound of starting materials of formulae.
The corresponding I a structural analysis of product of embodiment 2-8, analysis result can with correspond to result phase one in embodiment 1
It causes.
Embodiment 9
The biaryl pyrrole derivatives chemical compounds I b structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- biphenyl yl pyridines) is as follows in the present embodiment:
The compound specifically uses following methods to synthesize in the present embodiment:
By II compound of formula (231mg, 1mmol) (2- biphenyl yl pyridines), pyrroles (429mg, 8mmol), the tert-butyl alcohol
(30mL)、[RuCl2(p-cymene)]2(15mg, 0.025mmol) and copper acetate dihydrate (500mg, 2.5mmol) are put into clean
Net reaction vessel seals gas in container with replacement of oxygen with pressure-resistant tetrafluoro bottle stopper afterwards three times, then raise temperature to 105 DEG C~
108 DEG C, in the presence of oxygen, heat preservation carries out oxidative dehydrogenation coupling reaction 22 hours, and after reaction, reaction solution is delayed
Slowly it is cooled to room temperature, Synthesis liquid is filtered, and eluted with the 10mL tert-butyl alcohol, merging filtrate, which be concentrated under reduced pressure, removes solvent, will
Residue is carried out through silica gel column chromatography (eluant, eluent: n-hexane (volume)/ethyl acetate (volume) proportional region is 10:1~2:1)
After purification, concentration or crystallization, corresponding light pink solid product biaryl pyrrole derivatives chemical compounds I b (201mg), yield are obtained
68%.Fusing point: 83 DEG C~85 DEG C.
Obtained product is subjected to structural analysis, analysis result is as follows:
1H-NMR(400MHz,CDCl3): δ 9.71 (br, 1H), 8.66 (d, J=2.7Hz, 1H), 7.84 (s, 1H), 7.67-
7.66 (m, 3H), 7.57 (m, 2H), 7.47 (t, J=7.5Hz, 2H), 7.40-7.38 (m, 1H), 7.27-7.24 (m, 2H),
6.76(m,1H),6.37(m,1H),6.26(m,1H)。
13C-NMR(100MHz,CDCl3):δ159.78,148.50,141.55,140.42,136.81,136.44,
132.59,131.85,131.67,128.81,128.54,127.58,127.15,125.42,125.12,122.01,118.43,
108.99,108.41。
MS (ESI): C21H16N2(M+Na+):319.1。
Embodiment 10
The biaryl pyrrole derivatives chemical compounds I c structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- p-methylphenyl pyridine) is as follows in the present embodiment:
The compound specifically uses following methods to synthesize in the present embodiment:
By II compound of formula (169mg, 1mmol) (2- p-methylphenyl pyridine), pyrroles (429mg, 8mmol), toluene
(60mL)、[RuCl2(p-cymene)]2(15mg, 0.025mmol) and copper acetate dihydrate (500mg, 2.5mmol) are put into clean
Net reaction vessel seals gas in container with replacement of oxygen with pressure-resistant tetrafluoro bottle stopper afterwards three times, then raise temperature to 110 DEG C~
115 DEG C, in the presence of oxygen, heat preservation carries out oxidative dehydrogenation coupling reaction 22 hours, and after reaction, reaction solution is delayed
Slowly it is cooled to room temperature, Synthesis liquid is filtered, and eluted with 10mL toluene, merging filtrate, which be concentrated under reduced pressure, removes solvent, will be residual
Excess carries out essence through silica gel column chromatography (eluant, eluent: n-hexane (volume)/ethyl acetate (volume) proportional region is 10:1~2:1)
After system, concentration or crystallization, corresponding light pink solid product biaryl pyrrole derivatives chemical compounds I c (178mg), yield are obtained
76%.Fusing point: 70 DEG C~72 DEG C.
Obtained product is subjected to structural analysis, analysis result is as follows:
1H-NMR(400MHz,CDCl3): δ 9.60 (br, 1H), 8.65 (s, 1H), 7.63 (td, J=7.7Hz, J=
1.5Hz,1H),7.42-7.37(m,2H),7.24-7.15(m,3H),6.71(m,1H),6.29(m,1H),6.22(m,1H),
2.44(s,3H)。
13C-NMR(100MHz,CDCl3):δ160.19,148.41,138.48,136.35,135.29,132.03,
131.91,131.15,130.37,127.54,125.12,121.79,118.15,108.84,108.07,21.19。
MS(ESI):C16H14N2(M+Na+):257.1。
Embodiment 11
The biaryl pyrrole derivatives chemical compounds I d structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- p-fluorophenyl pyridine) is as follows in the present embodiment:
The compound specifically uses following methods to synthesize in the present embodiment:
By corresponding II compound of formula (173mg, 1mmol) (2- p-fluorophenyl pyridine), pyrroles (670mg, 10mmol), N-
Methyl pyrrolidone (40mL), [RuCl2(p-cymene)]2(15mg, 0.025mmol) and copper acetate dihydrate (500mg,
Clean reaction vessel 2.5mmol) is put into, gas in container is sealed with pressure-resistant tetrafluoro bottle stopper afterwards three times with replacement of oxygen,
105 DEG C~110 DEG C are then raised temperature to, in the presence of oxygen, heat preservation carries out oxidative dehydrogenation coupling reaction 24 hours, reaction
After, Synthesis liquid is filtered by reaction solution slow cooling to room temperature, and is eluted with 10mL N-Methyl pyrrolidone, merges filter
Liquid, which be concentrated under reduced pressure, removes solvent, by residue through silica gel column chromatography (eluant, eluent: n-hexane (volume)/ethyl acetate (body
Product) ratio be 2:1) refined, after being concentrated or crystallizing, obtain corresponding light pink solid product biaryl pyrrole derivatives chemical combination
I d of object (129mg), yield 54%.Fusing point: 65 DEG C~67 DEG C.
Obtained product is subjected to structural analysis, analysis result is as follows:
1H-NMR(400MHz,CDCl3): δ 10.00 (br, 1H), 8.56 (d, J=2.9Hz, 1H), 7.64 (m, 1H), 7.40
(m, 1H), 7.24 (m, 2H), 7.13 (d, J=7.7Hz, 1H), 6.98 (m, 1H), 6.73 (s, 1H), 6.29 (m, 1H), 6.23
(m,1H)。
13C-NMR(100MHz,CDCl3):δ162.80(d,JC-F=248.1Hz), 159.14,148.36,136.51,
134.36(d,JC-F=8.9Hz), 133.75 (d, JC-F=2.9Hz), 132.94 (d, JC-F=8.9Hz), 130.74,125.11,
122.03,118.85,116.00(d,JC-F=22.3Hz), 113.52 (d, JC-F=21.2Hz), 109.10,108.82.
MS(ESI):C15H11FN2(M+Na+):267.1。
Embodiment 12
The biaryl pyrrole derivatives chemical compounds I e structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- is to cyano-phenyl pyridine) is as follows in the present embodiment:
The compound specifically uses following methods to synthesize in the present embodiment:
By corresponding II compound of formula (180mg, 1mmol) (2- is to cyano-phenyl pyridine), pyrroles (670mg, 10mmol),
The tert-butyl alcohol (40mL), [RuCl2(p-cymene)]2(15mg, 0.025mmol) and copper acetate dihydrate (500mg, 2.5mmol) are thrown
Enter to clean reaction vessel, gas in container is sealed with pressure-resistant tetrafluoro bottle stopper afterwards three times with replacement of oxygen, is then raised temperature to
105 DEG C~110 DEG C, in the presence of oxygen, heat preservation carries out oxidative dehydrogenation coupling reaction 24 hours, after reaction, will
Reaction solution slow cooling filters Synthesis liquid to room temperature, and is eluted with the 10mL tert-butyl alcohol, and merging filtrate carries out reduced pressure removing
Residue is carried out essence through silica gel column chromatography (eluant, eluent: n-hexane (volume)/ethyl acetate (volume) ratio is 2:1) by solvent
After system, concentration or crystallization, corresponding light pink solid product biaryl pyrrole derivatives chemical compounds I e (125mg), yield are obtained
51%.Fusing point: 71 DEG C~73 DEG C.
Obtained product is subjected to structural analysis, analysis result is as follows:
1H-NMR(500MHz,CDCl3): δ 9.71 (br, 1H), 8.67 (d, J=4.7Hz, 1H), 7.84 (m, 1H), 7.72
(td, J=7.8Hz, J=1.8Hz, 1H), 7.57-7.53 (m, 2H), 7.35-7.32 (m, 1H), 7.23 (d, J=7.8Hz,
1H),6.73(m,1H),6.28(m,1H),6.22(m,1H)。
13C-NMR(125MHz,CDCl3):δ158.34,148.82,141.56,136.91,133.40,133.13,
131.98,129.41,129.39,124.96,122.97,119.63,118.50,112.67,109.72,109.52。
MS(ESI):C16H11N3(M+Na+):268.1。
Embodiment 13
The biaryl pyrrole derivatives chemical compounds I f structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- p-nitrophenyl yl pyridines) is as follows in the present embodiment:
The compound specifically uses following methods to synthesize in the present embodiment:
By corresponding II compound of formula (200mg, 1mmol) (2- p-nitrophenyl yl pyridines), pyrroles (670mg, 10mmol),
N-butanol (40mL), [RuCl2(p-cymene)]2(15mg, 0.025mmol) and copper acetate dihydrate (500mg, 2.5mmol) are thrown
Enter to clean reaction vessel, gas in container is sealed with pressure-resistant tetrafluoro bottle stopper afterwards three times with replacement of oxygen, is then raised temperature to
105 DEG C~108 DEG C, in the presence of oxygen, heat preservation carries out oxidative dehydrogenation coupling reaction 20 hours, after reaction, will
Reaction solution slow cooling filters Synthesis liquid to room temperature, and is eluted with the 10mL tert-butyl alcohol, and merging filtrate carries out reduced pressure removing
Residue is carried out essence through silica gel column chromatography (eluant, eluent: n-hexane (volume)/ethyl acetate (volume) ratio is 2:1) by solvent
After system, concentration or crystallization, corresponding light pink solid product biaryl pyrrole derivatives chemical compounds I f (148mg), yield are obtained
56%.Fusing point: 91 DEG C~93 DEG C.
Obtained product is subjected to structural analysis, analysis result is as follows:
1H-NMR(400MHz,CDCl3): δ 9.75 (br, 1H), 8.70 (d, J=4.7Hz1H), 8.40 (s, 1H), 8.09
(dd, J=8.4Hz, J=1.3Hz, 1H), 7.74 (t, J=7.6Hz, 1H), 7.59 (d, J=8.4Hz, 1H), 7.37-7.34
(m, 1H), 7.26 (d, J=7.8Hz, 1H), 6.75 (m, 1H), 6.32 (m, 1H), 6.23 (m, 1H).
13C-NMR(100MHz,CDCl3):δ158.09,148.88,147.90,143.07,136.96,133.75,
132.29,129.37,125.02,124.21,123.12,120.70,119.76 110.08,109.62。
MS (ESI): C15H11N3O2(M+Na+):288.1。
Embodiment 14
The biaryl pyrrole derivatives chemical compounds I g structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- p-methoxyphenyl pyridine) is as follows in the present embodiment:
The compound specifically uses following methods to synthesize in the present embodiment:
By corresponding II compound of formula (185mg, 1mmol) (2- p-methoxyphenyl pyridine), pyrroles (670mg,
10mmol), tert-pentyl alcohol (50mL), [RuCl2(p-cymene)]2(18mg, 0.03mmol) and copper acetate dihydrate (500mg,
Clean reaction vessel 2.5mmol) is put into, gas in container is sealed with pressure-resistant tetrafluoro bottle stopper afterwards three times with replacement of oxygen,
108 DEG C~110 DEG C are then raised temperature to, in the presence of oxygen, heat preservation carries out oxidative dehydrogenation coupling reaction 21 hours, reaction
After, reaction solution slow cooling to room temperature filters Synthesis liquid, and is eluted with 10mL tert-pentyl alcohol, merging filtrate is subtracted
Pressure concentration removes solvent, and by residue, through silica gel column chromatography, (eluant, eluent: n-hexane (volume)/ethyl acetate (volume) ratio is
It 2:1) is refined, after being concentrated or crystallizing, obtains corresponding light pink solid product biaryl pyrrole derivatives chemical compounds I g
(195mg), yield 78%.Fusing point: 62 DEG C~64 DEG C.
Obtained product is subjected to structural analysis, analysis result is as follows:
1H-NMR(400MHz,CDCl3): δ 9.94 (br, 1H), 8.57 (d, J=3.8Hz, 1H), 7.60 (td, J=
7.7Hz, J=1.7Hz, 1H), 7.41 (d, J=8.5Hz, 1H), 7.20-7.17 (m, 1H), 7.13-7.10 (m, 2H), 6.87
(dd, J=8.5Hz, J=2.5Hz, 1H), 6.74 (m, 1H), 6.32 (m, 1H), 6.23 (m, 1H), 3.89 (s, 3H).
13C-NMR(100MHz,CDCl3):δ159.77,159.68,148.26,136.27,133.52,132.54,
131.94,130.76,125.05,121.51,118.30,114.68,112.73,108.85,108.17,55.33。
MS(ESI):C16H14N2O(M+Na+):273.1。
Embodiment 15
The biaryl pyrrole derivatives chemical compounds I h structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- p-methoxyphenyl -3- picoline) is as follows in the present embodiment:
The compound specifically uses following methods to synthesize in the present embodiment:
By corresponding II compound of formula (199mg, 1mmol) (2- p-methoxyphenyl -3- picoline), pyrroles
(670mg, 10mmol), dimethylformamide (40mL), [RuCl2(p-cymene)]2(18mg, a 0.03mmol) and hydration second
Sour copper (500mg, 2.5mmol) puts into clean reaction vessel, by gas in container with replacement of oxygen three times afterwards with pressure resistance four
Fluorine bottle stopper is sealed, and then raises temperature to 108 DEG C~110 DEG C, and in the presence of oxygen, heat preservation carries out oxidative dehydrogenation coupling reaction
20 hours, after reaction, Synthesis liquid is filtered by reaction solution slow cooling to room temperature, and is drenched with 10mL dimethylformamide
It washes, merging filtrate, which be concentrated under reduced pressure, removes solvent, by residue through silica gel column chromatography (eluant, eluent: n-hexane (volume)/acetic acid
Ethyl ester (volume) ratio is 2:1) it is refined, after being concentrated or crystallizing, obtain corresponding light pink solid product biaryl pyrroles
I h of derivative compound (140mg), yield 53%.Fusing point: 66 DEG C~68 DEG C.
Obtained product is subjected to structural analysis, analysis result is as follows:
1H-NMR(400MHz,CDCl3): δ 8.57 (d, J=4.8Hz, 1H), 8.48 (br, 1H), 7.50 (d, J=7.6Hz,
1H), 7.22 (dd, J=7.6Hz, J=4.8Hz, 1H), 7.19 (d, J=8.4Hz, 1H), 7.12 (d, J=2.6Hz, 1H),
6.89 (dd, J=8.4Hz, J=2.6Hz, 1H), 6.58 (m, 1H), 6.17 (m, 1H), 6.12 (m, 1H), 3.90 (s, 3H),
1.90(s,3H)。
13C-NMR(100MHz,CDCl3):δ159.85,159.47,146.51,138.12,133.11,131.73,
131.31,130.23,122.50,118.47,113.17,112.28,108.79,107.74,55.35,19.07。
MS(ESI):C17H16N2O(M+Na+):287.1。
Embodiment 16
The biaryl pyrrole derivatives chemical compounds I i structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- p-methoxyphenyl -4- picoline) is as follows in the present embodiment:
The compound specifically uses following methods to synthesize in the present embodiment:
By corresponding II compound of formula (199mg, 1mmol) (2- p-methoxyphenyl -3- picoline), pyrroles
(670mg, 10mmol), dimethylformamide (40mL), [RuCl2(p-cymene)]2(18mg, a 0.03mmol) and hydration second
Sour copper (500mg, 2.5mmol) puts into clean reaction vessel, by gas in container with replacement of oxygen three times afterwards with pressure resistance four
Fluorine bottle stopper is sealed, and then raises temperature to 108 DEG C~110 DEG C, and in the presence of oxygen, heat preservation carries out oxidative dehydrogenation coupling reaction
20 hours, after reaction, Synthesis liquid is filtered by reaction solution slow cooling to room temperature, and is drenched with 10mL dimethylformamide
It washes, merging filtrate, which be concentrated under reduced pressure, removes solvent, by residue through silica gel column chromatography (eluant, eluent: n-hexane (volume)/acetic acid
Ethyl ester (volume) ratio is 2:1) it is refined, after being concentrated or crystallizing, obtain corresponding light pink solid product biaryl pyrroles
I i of derivative compound (177mg), yield 67%.Fusing point: 65 DEG C~67 DEG C.
Obtained product is subjected to structural analysis, analysis result is as follows:
1H-NMR(400MHz,CDCl3): δ 10.28 (br, 1H), 8.43 (d, J=5.2Hz, 1H), 7.36 (d, J=
8.7Hz, 1H), 7.20 (d, J=2.6Hz, 1H), 7.03 (d, J=5.2Hz, 1H), 6.98 (s, 1H), 6.85 (dd, J=
8.6Hz, J=2.6Hz, 1H), 6.73 (m, 1H), 6.33 (m, 1H), 6.23 (m, 1H), 3.89 (s, 3H), 2.30 (s, 3H).
13C-NMR(100MHz,CDCl3):δ159.73,159.57,147.80,147.61,133.54,132.53,
132.08,130.84,126.02,122.68,118.23,114.51,112.50,108.76,108.08,55.31,21.08。
MS(ESI):C17H16N2O(M+Na+):287.1。
Embodiment 17
The biaryl pyrrole derivatives chemical compounds I j structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- p-methoxyphenyl -5- picoline) is as follows in the present embodiment:
The compound specifically uses following methods to synthesize in the present embodiment:
By corresponding II compound of formula (169mg, 1mmol) (2- phenyl -3- picoline), pyrroles (670mg,
10mmol), the tert-butyl alcohol (40mL), [RuCl2(p-cymene)]2(18mg, 0.03mmol) and copper acetate dihydrate (500mg,
Clean reaction vessel 2.5mmol) is put into, gas in container is sealed with pressure-resistant tetrafluoro bottle stopper afterwards three times with replacement of oxygen,
108 DEG C~110 DEG C are then raised temperature to, in the presence of oxygen, heat preservation carries out oxidative dehydrogenation coupling reaction 22 hours, reaction
After, reaction solution slow cooling to room temperature filters Synthesis liquid, and is eluted with the 10mL tert-butyl alcohol, merging filtrate is subtracted
Pressure concentration removes solvent, and by residue, through silica gel column chromatography, (eluant, eluent: n-hexane (volume)/ethyl acetate (volume) ratio is
It 2:1) is refined, after being concentrated or crystallizing, obtains corresponding light pink solid product biaryl pyrrole derivatives chemical compounds I j
(177mg), yield 71%.Fusing point: 70 DEG C~72 DEG C.
Obtained product is subjected to structural analysis, analysis result is as follows:
1H-NMR(400MHz,CDCl3): δ 9.64 (br, 1H), 8.49 (s, 1H), 7.60 (d, J=7.8Hz, 1H), 7.46
(m, 2H), 7.40 (t, J=7.6Hz, 3H), 7.32 (td, J=7.6Hz, J=1.0Hz, 3H), 6.72 (m, 1H), 6.30 (m,
1H),6.23(m,1H),2.39(s,3H)。
13C-NMR(100MHz,CDCl3):δ157.33,148.75,137.87,137.10,132.12,132.03,
131.54,131.09,129.69,128.49,126.64,124.58,118.22,108.85,108.15,18.18。
MS(ESI):C16H14N2(M+Na+):257.1。
Embodiment 18
The biaryl pyrrole derivatives chemical compounds I a structural formula of the present embodiment is as follows:
The structural formula of corresponding II compound of formula (2- phenylpyridine) is as follows in the present embodiment:
The specific synthetic method of the compound is consistent with embodiment 1 in the present embodiment, and difference is only that be hydrated therein one
Copper acetate directlys adopt copper acetate replacement, and mole used is mutually all 2.0mmol.Obtain corresponding light pink solid product connection
I a of aryl-pyrrolidine derivative compound (164mg), yield 74.5%.Fusing point: 75 DEG C~77 DEG C.
Obtained product is subjected to structural analysis, analysis result is consistent with corresponding data in embodiment 1.
Certainly, the cupric salt in the present embodiment can also be replaced using copper chloride.
Specific embodiment described in the present invention only illustrate the spirit of the present invention by way of example.The neck of technology belonging to the present invention
The technical staff in domain can make various modifications or additions to the described embodiments or replace by a similar method
In generation, however, it does not deviate from the spirit of the invention or beyond the scope of the appended claims.
It is skilled to this field although present invention has been described in detail and some specific embodiments have been cited
For technical staff, as long as it is obvious for can making various changes or correct without departing from the spirit and scope of the present invention.
Claims (10)
1. a kind of biaryl pyrrole derivatives compound, which is characterized in that the structural formula of the biaryl pyrrole derivatives compound is such as
Shown in lower type I compound:
Wherein, R in formula I1Selected from hydrogen or C1-C3Alkyl, R2Selected from hydrogen, halogen, nitro, cyano, C1-C3Alkoxy, C1-C3
Alkyl or phenyl.
2. biaryl pyrrole derivatives compound according to claim 1, which is characterized in that the halogen is selected from fluorine or chlorine；Institute
State C1-C3Alkoxy be selected from methoxy or ethoxy.
3. a kind of preparation method of biaryl pyrrole derivatives compound, which is characterized in that method includes the following steps:
With [RuCl2(p-cymene)]2It is composite catalyst, in the presence of oxygen, II compound of formula with cupric salt
Oxidative dehydrogenation coupling reaction is carried out with pyrroles, obtains corresponding product type I compound
Wherein, R in formula I1Selected from hydrogen or C1-C3Alkyl, R2Selected from hydrogen, halogen, nitro, cyano, C1-C3Alkoxy, C1-C3
Alkyl or phenyl.
4. the preparation method of biaryl pyrrole derivatives compound according to claim 3, which is characterized in that the cupric salt
Selected from copper acetate dihydrate or copper acetate.
5. the preparation method of biaryl pyrrole derivatives compound according to claim 3, which is characterized in that II chemical combination of formula
The molar ratio of object and cupric salt is 1:2.0~2.5.
6. the preparation method of biaryl pyrrole derivatives compound according to claim 3, which is characterized in that [the RuCl2(p-
cymene)]2Dosage be II compound of formula mole dosage 2.5%~5.0%.
7. according to the preparation method of biaryl pyrrole derivatives compound described in claim 3-6 any one, which is characterized in that institute
The temperature for stating oxidative dehydrogenation coupling reaction is 105 DEG C~115 DEG C.
8. according to the preparation method of biaryl pyrrole derivatives compound described in claim 3-6 any one, which is characterized in that institute
Oxidative dehydrogenation coupling reaction is stated to carry out in organic solvent.
9. the preparation method of biaryl pyrrole derivatives compound according to claim 8, which is characterized in that the organic solvent
One in n-butanol, the tert-butyl alcohol, tert-pentyl alcohol, toluene, dimethylformamide, dimethyl acetamide and N-Methyl pyrrolidone
Kind is several.
10. according to the preparation method of biaryl pyrrole derivatives compound described in claim 3-6 any one, which is characterized in that
The molar ratio of II compound of formula and pyrroles are 1:5~15.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910320596.6A CN109912567A (en) | 2019-04-20 | 2019-04-20 | A kind of biaryl pyrrole derivatives compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910320596.6A CN109912567A (en) | 2019-04-20 | 2019-04-20 | A kind of biaryl pyrrole derivatives compound and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109912567A true CN109912567A (en) | 2019-06-21 |
Family
ID=66978028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910320596.6A Pending CN109912567A (en) | 2019-04-20 | 2019-04-20 | A kind of biaryl pyrrole derivatives compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109912567A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101715439A (en) * | 2007-06-29 | 2010-05-26 | 拜尔农作物科学股份公司 | Preparation of biaryls |
-
2019
- 2019-04-20 CN CN201910320596.6A patent/CN109912567A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101715439A (en) * | 2007-06-29 | 2010-05-26 | 拜尔农作物科学股份公司 | Preparation of biaryls |
Non-Patent Citations (2)
| Title |
|---|
| 王暖程: "Rh(III)和Ru(II)催化的C-H键活化及相关反应研究", 《中国优秀硕士学位论文全文数据库工程科技I辑》 * |
| 王臻: "Rh催化的C-H键的活化及C-C和C-N键的形成", 《厦门大学博士学位论文》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2010500961A (en) | α-carboline derivative and method for producing the same | |
| CN102746210A (en) | Synthesis method for key intermediate of silodosin | |
| CN111423394B (en) | Synthesis method of 1,3, 4-oxadiazole heterocyclic compound | |
| CN105175328A (en) | Method for synthesizing quinoline derivative by utilizing arylamine, aromatic aldehyde and ketone | |
| CN103923080B (en) | A kind of method preparing antithrombotic reagent Eliquis | |
| CN104774174B (en) | A kind of method of asymmetric syntheses S carbinoxamines | |
| CN108129478B (en) | A kind of copper process for catalytic synthesis of organic sulphones and application | |
| CN107445991A (en) | A kind of Phosphine ligands of indoles skeleton and its preparation method and application | |
| CN110590854B (en) | Triazole carbene palladium metal complex and preparation method and application thereof | |
| CN107619385A (en) | A kind of method that palladium chtalyst aryl enamine intramolecular amination synthesizes 2 trifluoro methyl indoles | |
| CN109912567A (en) | A kind of biaryl pyrrole derivatives compound and preparation method thereof | |
| Zhang et al. | Synthesis of chiral fluorine-containing compounds via Pd-catalyzed asymmetrical allylations of dimethyl 2-fluoromalonate using sulfonamide-pyridine ligands | |
| CN107382858B (en) | Series of 1,2,3, 4-tetrahydroisoquinoline-4-ketone compounds, and synthetic method and application thereof | |
| CN110156710A (en) | A kind of polysubstituted preparation method for disliking azole compounds | |
| CN109776551A (en) | Dioxanes and quinazoline derivant preparation method | |
| CN113234015B (en) | 3-acyl dihydroquinoline derivative and preparation method and application thereof | |
| CN102344431A (en) | Method for preparing nebivolol hydrochloride | |
| CN107151226B (en) | A kind of preparation method of polysubstituted isoindolinone | |
| CN107325055A (en) | A kind of synthetic method of olaparib compound | |
| CN109134342B (en) | Preparation method of 3, 4-disubstituted pyrrole | |
| WO2020177347A1 (en) | Oxygen-guided synthesis method for 7-alkynyl indole compound | |
| CN106883236B (en) | A kind of method of the N for preparing sulfur-bearing, N- bicyclic pyrazolidinones analog derivative | |
| CN106083690A (en) | A kind of preparation method of polysubstituted 3 methylene indolones | |
| CN110746278B (en) | Nonmetal-catalyzed method for preparing 1, 3-diketone compound based on alkynone | |
| CN112500345A (en) | Synthetic method of alpha-cyano quaternary carbon substituted tetrahydroisoquinoline compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190621 |