CN106008305B - A kind of synthetic method of five substitutions 2- amino-pyrroles derivatives - Google Patents
A kind of synthetic method of five substitutions 2- amino-pyrroles derivatives Download PDFInfo
- Publication number
- CN106008305B CN106008305B CN201610395018.5A CN201610395018A CN106008305B CN 106008305 B CN106008305 B CN 106008305B CN 201610395018 A CN201610395018 A CN 201610395018A CN 106008305 B CN106008305 B CN 106008305B
- Authority
- CN
- China
- Prior art keywords
- amino
- pyrroles
- phenyl
- halogen
- synthetic method
- 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.)
- Expired - Fee Related
Links
Classifications
-
- 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
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
Abstract
The present invention discloses a kind of synthetic method of 2 amino-pyrroles derivatives of five substitution, and this method is in the larger organic media of polarity, by the arone of ortho position amino halogen and malononitrile single step reaction under the action of alkali, you can obtains five substitutions, 2 amino-pyrroles derivative.Compared with conventional method, the present invention is using cheap conventional base as accelerating agent, effectively reduce cost, and synthesis step is simple, reaction yield is high, particularly in the medicine with pyrrole ring is built, it can should avoid the problem that causing heavy metal residual volume in medicine exceeded with heavy metal catalyst in this way.In addition, no matter the arone of ortho position amino halogen is α amino β halogen arone or α halogen β amino arone, amino is in 2 of pyrrole ring in synthesized product, has the regioselectivity of height.The five 2 amino-pyrroles derivatives of substitution that the present invention synthesizes can be used for fused heterocyclic compound, natural antibiotics, the synthesis of cancer therapy drug and Structures of Natural Products transformation research field.
Description
Technical field
The invention belongs to the synthesis technical field of five substitution 2- amino-pyrroles derivatives, and in particular to a kind of ortho position amino halogen
Arone synthesized with malononitrile single step reaction five substitution 2- amino-pyrroles methods.
Background technology
Pyrroles and its derivative are a kind of very important five member ring heterocyclic compounds.Pyrroles is found in 19th century 30 earliest
Age, since then, bioactivity and pharmacological action possessed by pyrroles and its derivative have caused extensive concern.Now, pyrrole
Cough up and its derivative has been widely used in medicine, pesticide, food, biology, material science and chemical field.Due to
Pyrroles and its importance of derivative, people have made intensive studies its synthetic method.2- amino-pyrroles construction units are to be permitted
There is a part for strong bioactive compound more, be generally acknowledged many drug molecular structure units.These medicine energy tables
Reveal anti-inflammatory, anticancer, antiviral, antimycotic, desinsection, radioresistance, and have by force to MEK, MK2, FAK, KDR, Tie2 and PDE
Strong inhibitory action.In addition, 2- amino-pyrroles are purine biosynthesis homologue such as pyrrolopyrimidines, pyrrolo-triazine and pyrrolo- pyrrole
The precursor of pyridine.Till now, although the method for synthesis pyrroles and its derivative is very much, on five substitution 2- amino-pyrroles
Synthesis report is relatively fewer.The method reported has：(1) by alkynes and trimethyl cyano group silicon in transition metal Pd, Ni, Co etc.
Under the catalysis of complex, reflux obtains corresponding five substitutions 2- amino-pyrroles derivatives；(2) respectively by N- benzenesulfonamido- phenyl
Methyl ketone, N- heteroaryl ylsulfonylaminos phenyl methyl ketone, N- alkyl sulfonyl amino phenyl methyl ketones etc. and aldehyde, cyano-containing
Three component of active methylene compound in ethanol or acetonitrile solvent back flow reaction, obtain it is corresponding five substitution 2- amino-pyrroles
Derivative；(3) α is used, β-undersaturated acid imide cyanide is with nitrile in AlCl3Lower 90 DEG C of reactions are catalyzed, corresponding five is obtained and takes
For 2- amino-pyrroles derivatives；(4) alkynes is with aniline under titanium complex catalysis, and 80 DEG C of reactions, obtain 2,3- in toluene solvant
Diaminourea azole derivatives；(5) in toluene solvant, by benzyl tolysulfonyl imines, butine dicarboxylic acid dimethyl ester, cyclohexyl
Three component of isonitrile reacts to obtain corresponding five substitutions 2- amino-pyrroles derivatives.Above method in various degree there are some shortcomings,
If any method transition metal make catalyst, heavy metal residual volume is exceeded in pharmaceutical synthesis is relatively difficult to resolve in pharmaceutical synthesis
Certainly the problem of；Some methods will use the reaction raw materials being difficult to, and can increase the cost of synthesis；What is had will be at relatively high temperatures
Carry out, or even to carry out at a reflux temperature, the requirement to equipment is increased.
The content of the invention
The technical problems to be solved by the invention exist in existing five substitution 2- amino-pyrroles derivative synthesis is overcome
The shortcomings that, there is provided it is a kind of in a mild condition, in the larger organic media of polarity, under the promotion of common weak base, by ortho position
The arone of amino halogen substitutes the method for 2- amino-pyrroles with malononitrile one-step synthesis five.
Technical solution is used by solving above-mentioned technical problem：In the larger organic solvent of polarity, by Formulas I or Formula II
The arone of shown ortho position amino halogen is 1 in molar ratio with malononitrile, alkali:1~1.5:0.5~2 is uniformly mixed, and 40~60 DEG C are stirred
Mix 6~24 it is small when, isolate and purify product, obtain formula III or five substitution 2- amino-pyrroles derivatives shown in formula IV；
In Formulas I~IV, Ar1And Ar2Each independent representative phenyl, C1~C4Alkyl-substituted phenyl, C1~C4Alkoxy takes
For phenyl, halogen and C1~C4The phenyl of alkoxy substitution, halogenophenyl, any one in nitro substituted-phenyl, preferably Ar1
And Ar2Each independent representative phenyl, 4- aminomethyl phenyls, 4- methoxyphenyls, 2- halogen -4,5- Dimethoxyphenyls, 3- methoxies
Base phenyl, 3,5- Dimethoxyphenyls, 3,4,5- trimethoxyphenyls, 4- bromophenyls, 4- fluorophenyls, 4- chlorphenyls, 4- nitros
Any one in phenyl, X represents Cl, Br or I.
The arone of above-mentioned ortho position amino halogen is preferably 1 with malononitrile, the molar ratio of alkali:1~1.5:1~1.5.
The larger organic solvent of above-mentioned polarity is methanol, ethanol, propyl alcohol, N,N-dimethylformamide, acetonitrile, diformazan are sub-
Any one in sulfone, preferably methanol.
Above-mentioned alkali is sodium acetate, K2CO3、KHCO3、Na2CO3、K3PO4, NaOH, KOH, ethylenediamine, appointing in triethylamine
Meaning is a kind of, preferably Na2CO3。
The present invention five substitutes in the synthetic method of 2- amino-pyrroles derivatives, no matter in the arone of ortho position amino halogen on aromatic ring
With which kind of substituent and substituent in which kind of position of aromatic ring, and though the arone of ortho position amino halogen be pantonine-halogen type also
It is α-halogen-beta-amino type, its five substitution 2- amino-pyrroles derivative synthesized has the regioselectivity of height, and amino is in
The 2- positions of pyrrole ring, that is, have the architectural feature of Isosorbide-5-Nitrae-dipole in the pyrrole ring synthesized, this structure can further occur 4+1 or
4+2 ring closure reactions, available for alkaloid, fully synthetic and structure of modification, synthetic antibiotic, anticancer, the antiviral agent of natural products
The fields such as thing, for drug molecule synthesis and natural products is fully synthetic and structure of modification provides new technology.
Inventor is found through experiments that, in order to make the rapid reaction, efficiently, it is necessary to could be realized under the promotion of alkali, no
The alkali reaction is added to occur, and the species of alkali and dosage play decisive role to reaction.In addition, solvent is to the reaction
Also important control action is played, in an aqueous medium, malononitrile can hydrolyze, and cause the reaction to occur.Therefore, should
Reaction must could be completed in organic media.But since the species of organic solvent is different, its polarity size has difference, anti-to this
The control ability size answered is also variant.It is demonstrated experimentally that the polarity of organic solvent is bigger, it is bigger to the control ability of the reaction.
Reaction temperature has a significant impact product structure and yield, and temperature is relatively low (such as room temperature), and reaction is tended to generate pyrrolin, temperature
Too high, product is complicated, and product yield declines.
The advantage of the invention is that：
1st, the method that can synthesize five substitution 2- amino-pyrroles derivatives in multi-solvents the present invention provides one, such as
Methanol, ethanol, propyl alcohol, n,N-Dimethylformamide, acetonitrile, dimethyl sulfoxide etc., wherein preferred solvent is methanol.
2nd, present invention uses common alkali for example sodium acetate, potassium acetate, sodium acid carbonate, potassium carbonate, sodium carbonate, potassium phosphate,
Sodium hydroxide, potassium hydroxide, ethylenediamine, triethylamine etc. are used as accelerating agent, and wherein sodium carbonate is preferred accelerating agent.The accelerating agent
Stabilization is easy to get, cheap, compared with traditional method, avoids expensive precious metal palladium or other transition metals coordinate
The use of thing, not only effectively reduces synthesis cost, and the exceeded possibility of metal residues amount is avoided in pharmaceutical synthesis.
3rd, the present invention is under the promotion of alkali, and halogen is by the substitution reaction of malononitrile, intramolecular in the arone of ortho position amino halogen
Amino forms pyrrolin and the oxidative dehydrogenation one carried out by the oxygen in air to pyrrolin to the nucleophilic addition of cyano group
Secondary completion, has been efficiently synthesized the 2- amino-pyrroles derivatives of five substitutions.During oxidative dehydrogenation, using the oxygen in air
Oxidative dehydrogenation is carried out, is avoided using traditional oxidant such as DDQ, makes synthesis five substitute 2- amino-pyrroles more to clean.
4th, synthesis step of the invention is simple, a step complete three reactions (nucleophilic addition of nucleophilic displacement of fluorine/intramolecular/
Oxidative dehydrogenation), and reaction yield is high, highest yield can reach 91%.
5th, method of the invention has the regioselectivity of height, is given no matter being carried in the arone of ortho position amino halogen on aromatic ring
Electron substituent group or electron-withdrawing substituent, no matter the arone of ortho position amino halogen is pantonine-halogen type or α-halogen-beta-amino
Type, the amino of all products have been in the 2- positions of pyrroles, and the amino of this 2- can form 1 with the short of electricity subbase on 3- positions,
The special construction of 4- dipoles, can occur 4+1 or 4+2 ring closure reactions, be provided newly to synthesize other complicated miscellaneous polycyclic compounds
Route.
Embodiment
With reference to embodiment, the present invention is described in more detail, but protection scope of the present invention is not limited to these implementations
Example.
Embodiment 1
With the following 1- p-toluenesulfonyl -2- Amino 3 cyano -4- phenyl -5- benzoyl pyrrole compounds of composite structure formula
Exemplified by, specific synthetic method is as follows：
0.457g (1mmol) 1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyl ammonia is sequentially added into 50mL round-bottomed flasks
Base) -3- bromacetones -1,0.066g (1mmol) malononitrile, 0.106g (1mmol) sodium carbonate, 5mL methanol, magnetic force stirs at 50 DEG C
Mix reaction 8 it is small when, then add 25mL ethyl acetate, with saturated common salt washing three times (each 25mL), be washed with water and wash three times
(each 25mL), organic phase is dried overnight with anhydrous sodium sulfate, is filtered to remove drier, is concentrated under reduced pressure, and crude product carries out silica gel
Pillar layer separation is (using petroleum ether and ethyl acetate volume ratio as 5:1 mixed liquor is eluant, eluent), obtain 1- p-toluenesulfonyls-
2- Amino 3 cyano -4- phenyl -5- benzoyl pyrrole compounds, its yield are 89%, and absolute ethyl alcohol recrystallizes to obtain faint yellow solid,
Fusing point is 188.8~190.2 DEG C, and structural characterization data are as follows：
1H NMR (400MHz, DMSO-d6)δ：7.48~7.41 (m, 7H), 7.24 (dd, J=14.3,4.0Hz, 4H),
7.12 (m, 5H), 2.42 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：190.2,150.7,146.5,136.2,133.4 (2), 131.3 (2),
130.2 (2), 129.3 (2), 128.9 (2), 128.5,128.2 (2), 128.0,127.0 (2), 126.9 (2), 124.9,
114.5,72.6,21.2.
High resolution mass spec HRMS：Calculated value C25H19N3O3S([M+Na]+) 464.1039, measured value 464.1047.
Embodiment 2
With following 1- p-toluenesulfonyl -2- Amino 3 cyanos -4- (4- the chlorphenyls) -5- benzoyls of composite structure formula
Exemplified by base pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- phenyl -3- (4- chlorphenyls) -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 are replaced, and the reaction time extends to 14
Hour, other steps are same as Example 1, obtain yellow solid 1- p-toluenesulfonyl -2- Amino 3 cyanos -4- (4- chlorobenzenes
Base) -5- benzoyl pyrrole compounds, its yield is 70%, and fusing point is 198.8~199.9 DEG C, and structural characterization data are as follows：
1H NMR (400MHz, DMSO-d6)δ：7.47 (m, 7H), 7.27 (dd, J=14.2,6.5Hz, 4H), 7.19 (d, J
=8.4Hz, 2H), 7.11 (d, J=8.4Hz, 2H), 2.42 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：190.0,150.8,146.7,136.2,133.4,133.2,133.0 (2),
130.3 (2), 129.0 (2), 128.3 (2), 128.3 (2), 127.2 (2), 126.9 (2), 126.7 (2), 125.30,114.4,
72.7 21.2.
High resolution mass spec HRMS：Calculated value C25H16ClN3O3S([M+Na]+) 498.0650, measured value 498.0652.
Embodiment 3
With following 1- p-toluenesulfonyl -2- Amino 3 cyanos -4- (4- the bromophenyls) -5- benzoyls of composite structure formula
Exemplified by base pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- phenyl -3- (4- bromophenyls) -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 are replaced, and it is small that the reaction time extends to 9
When, other steps are same as Example 1, obtain yellow solid 1- p-toluenesulfonyl -2- Amino 3 cyanos -4- (4- bromobenzenes
Base) -5- benzoyl pyrrole compounds, its yield is 84%, and fusing point is 201.8~202.8 DEG C, and structural characterization data are as follows：
1H NMR (400MHz, DMSO-d6)δ：7.48 (m, 7H), 7.37~7.22 (m, 6H), 7.06 (dd, J=8.2,
2.4Hz, 2H), 2.40 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：190.0,150.8,146.6,136.2,133.2,130.3 (2), 130.1
(4), 129.0 (2), 128.7 (2), 128.3 (2), 126.9 (2), 126.8,125.3,122.1 (2), 114.3,72.8,21.2.
High resolution mass spec HRMS：Calculated value C25H16BrN3O3S([M+Na]+) 542.0144, measured value 542.0145.
Embodiment 4
With following 1- p-toluenesulfonyl -2- Amino 3 cyanos -4- (4- fluorophenyls) -5- (the 4- methoxies of composite structure formula
Base benzoyl) exemplified by pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- (4- methoxyphenyls) -3- (4- fluorophenyls) -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 are replaced, during reaction
Between extend to 18 it is small when, other steps are same as Example 1, obtain faint yellow solid 1- p-toluenesulfonyl -2- amino -3- cyanogen
Base -4- (4- fluorophenyls) -5- (4- methoxybenzoyls base) pyrroles, its yield are 69%, and fusing point is 156.1~157.2 DEG C, knot
Structure characterize data is as follows：
1H NMR (400MHz, DMSO-d6)δ：7.48 (d, J=7.4Hz, 6H), 7.21 (s, 2H), 7.14~7.09 (m,
2H), 7.00 (t, J=8.7Hz, 2H), 6.83 (d, J=8.8Hz, 2H), 3.77 (s, 3H), 2.42 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：188.8,163.8,161.7,151.1,147.0,133.9,133.9 (2),
132.1 (2), 130.8 (2), 129.4 (2), 127.4 (2), 126.5,126.1,115.0,114.8,114.6,114.2 (2),
73.1,56.0,21.2.
High resolution mass spec HRMS：Calculated value C26H20FN3O4S([M+Na]+) 512.1051, measured value 512.1048.
Embodiment 5
With following 1- p-toluenesulfonyl -2- Amino 3 cyano -4- phenyl -5- (the 4- chlorobenzoyls of composite structure formula
Base) exemplified by pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- (4- chlorphenyls) -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 are changed and replaced, and it is small that the reaction time foreshortens to 6
When, other steps are same as Example 1, obtain yellow solid 1- p-toluenesulfonyl -2- Amino 3 cyano -4- phenyl -5-
(4- chlorobenzene formacyls) pyrroles, its yield are 91%, and fusing point is 200.1~201.9 DEG C, and structural characterization data are as follows：
1H NMR (400MHz, DMSO-d6)δ：7.44 (m, 6H), 7.29~7.17 (m, 5H), 7.16~7.02 (m, 4H),
2.41 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：189.0,150.7,146.6,137.7,135.1,133.4,131.6 (2),
130.7 (2), 130.3 (2), 129.1 (2), 128.8,128.7,128.2 (2), 127.1 (2), 127.0 (2), 124.2,
114.5,72.4,21.2.
High resolution mass spec HRMS：Calculated value C25H16ClN3O3S([M+Na]+) 498.0650, measured value 498.0654.
Embodiment 6
With following 1- p-toluenesulfonyl -2- Amino 3 cyanos -4- (4- the fluorophenyls) -5- benzoyls of composite structure formula
Exemplified by base pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- phenyl -3- (4- fluorophenyls) -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 are replaced, and the reaction time extends to 16
Hour, other steps are same as Example 1, obtain yellow needles 1- p-toluenesulfonyl -2- Amino 3 cyano -4- (4-
Fluorophenyl) -5- benzoyl pyrrole compounds, its yield is 70%, and fusing point is 189.9~190.2 DEG C, and structural characterization data are as follows：
1H NMR (400MHz, DMSO-d6)δ：7.46 (m, 7H), 7.23 (d, J=34.3Hz, 4H), 7.11 (s, 2H),
6.98~6.87 (m, 2H), 2.42 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：190.5,163.4,151.1,147.1,136.9,134.3,134.2,
134.0,133.5,130.8 (2), 129.5 (2), 128.7 (2), 127.7,127.4 (2), 126.2,126.2,125.4,
115.0,114.6,114.5,73.1,21.2.
High resolution mass spec HRMS：Calculated value C25H18FN3O3S([M+Na]+) 482.0945, measured value 482.0943.
Embodiment 7
With following 1- p-toluenesulfonyl -2- Amino 3 cyanos -4- (4- fluorophenyls) -5- (the 4- chlorobenzenes of composite structure formula
Formoxyl) exemplified by pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- (4- chlorphenyls) -3- (4- fluorophenyls) -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 are replaced, and the reaction time prolongs
It is long to 10 it is small when, other steps are same as Example 1, obtain yellow needles 1- p-toluenesulfonyl -2- amino -3- cyanogen
Base -4- (4- fluorophenyls) -5- (4- chlorobenzene formacyls) pyrroles, its yield are 76%, and fusing point is 199.4~201.8 DEG C, structure table
It is as follows to levy data：
1H NMR (400MHz, DMSO-d6)δ：7.49~7.43 (m, 6H), 7.29 (d, J=8.4Hz, 2H), 7.21 (s,
2H), 7.11 (dd, J=8.7,5.5Hz, 2H), 6.96 (t, J=8.8Hz, 2H), 2.40 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：188.9,163.4,161.0,150.6,146.6,137.7,135.2,
134.0,134.0,133.4,130.8,130.3,128.2 (2), 127.9,126.9 (2), 125.5,125.5,124.4,
114.5,114.2,21.2.
High resolution mass spec HRMS：Calculated value C25H17FN3O3S([M+Na]+) 516.0555, measured value 516.0563.
Embodiment 8
With following 1- p-toluenesulfonyl -2- Amino 3 cyano -4- benzoyls -5- (the 4- methoxyl groups of composite structure formula
Phenyl) exemplified by pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- phenyl -3- (4- methoxyphenyls) -3- (4- Methyl benzenesulfonyls amino) -2- bromacetones -1 are replaced, and the reaction time extends
To 24 it is small when, other steps are same as Example 1, obtain yellow solid 1- p-toluenesulfonyl -2- Amino 3 cyano -4- benzene
Formoxyl -5- (4- methoxyphenyls) pyrroles, its yield are 49%, and fusing point is 196.8~198.8 DEG C, and structural characterization data are such as
Under：
1H NMR (400MHz, DMSO-d6)δ：7.49~7.42 (m, 7H), 7.26 (t, J=7.8Hz, 2H), 7.15 (s,
2H), 6.96 (d, J=8.7Hz, 2H), 6.66 (d, J=8.8Hz, 2H), 3.66 (s, 3H), 2.41 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：190.2,159.4,150.5,146.4,136.4,133.5,133.0,
130.2 (2), 129.0 (4), 128.4,128.2,126.9 (2), 124.2 (2), 121.2,114.6,112.5 (2), 72.4,
55.0 21.2.
High resolution mass spec HRMS：Calculated value C26H21N3O4S([M+Na]+) 494.1145, measured value 494.1149.
Embodiment 9
With following 1- p-toluenesulfonyl -2- Amino 3 cyano -4- benzoyls -5- (the 4- methylbenzenes of composite structure formula
Base) exemplified by pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- phenyl -3- (4- aminomethyl phenyls) -3- (4- Methyl benzenesulfonyls amino) -2- bromacetones -1 are replaced, other steps are with implementing
Example 1 is identical, obtains yellow needles 1- p-toluenesulfonyl -2- Amino 3 cyano -4- benzoyls -5- (4- methylbenzenes
Base) pyrroles, its yield is 59%, and fusing point is 196.2~197.8 DEG C, and structural characterization data are as follows：
1H NMR (400MHz, DMSO-d6)δ：7.46 (m, 7H), 7.27 (s, 2H), 7.18 (s, 2H), 6.94 (s, 4H),
2.42 (s, 3H), 2.19 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：190.7,151.1,146.9,138.5,136.8,134.0,133.6,
131.7 (2), 130.7 (2), 129.5 (2), 128.8 (2), 128.6,128.2 (2), 127.4 (2), 126.9,125.1,
115.0,73.1,21.7,21.3.
High resolution mass spec HRMS：Calculated value C26H21N3O3S([M+Na]+) 478.1196, measured value 478.1193.
Embodiment 10
With following 1- p-toluenesulfonyl -2- Amino 3 cyanos -4- (the 4- chlorobenzene formacyls) -5- (4- of composite structure formula
Methoxyphenyl) exemplified by pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- (- chlorphenyl) -3- (4- methoxyphenyls) -3- (4- Methyl benzenesulfonyls amino) -2- bromacetones -1 are replaced, the reaction time
Extend to 24 it is small when, other steps are same as Example 1, obtain yellow solid 1- p-toluenesulfonyl -2- Amino 3 cyanos -
4- (4- chlorobenzene formacyls) -5- (4- methoxyphenyls) pyrroles, its yield are 43%, and fusing point is 206.2~207.5 DEG C, structure
Characterize data is as follows：
1H NMR (400MHz, DMSO-d6)δ：7.47~7.39 (m, 6H), 7.28 (d, J=8.5Hz, 2H), 7.15 (s,
2H), 6.94 (d, J=8.7Hz, 2H), 6.65 (d, J=8.8Hz, 2H), 3.68 (s, 3H), 2.40 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：189.1,159.6,150.4,146.5,137.4,135.3,133.5,
133.2 (2), 130.7 (2), 130.2 (2), 129.3,128.2 (2), 126.9 (2), 123.7,121.0,114.7,112.6
(2), 72.2,55.1,21.2.
High resolution mass spec HRMS：Calculated value C26H20N3O4S([M+Na]+) 528.0755, measured value 528.0754.
Embodiment 11
With following 1- p-toluenesulfonyl -2- Amino 3 cyanos -4- (4- the nitro benzoyls) -5- of composite structure formula
Exemplified by (4- methoxyphenyls) pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- (4- nitrobenzophenones) -3- (4- methoxyphenyls) -3- (4- Methyl benzenesulfonyls amino) -2- bromacetones -1 are replaced, reaction
Time lengthening to 24 it is small when, other steps are same as Example 1, obtain yellow solid 1- p-toluenesulfonyl -2- amino -3- cyanogen
Base -4- (4- nitro benzoyls) -5- (4- methoxyphenyls) pyrroles, its yield are 35%, and fusing point is 199.1~200.4 DEG C,
Structural characterization data are as follows：
1H NMR (600MHz, DMSO-d6)δ：7.93 (d, J=6.8Hz, 2H), 7.58~7.37 (m, 6H), 7.15 (s,
2H), 6.90 (d, J=6.8Hz, 2H), 6.56 (d, J=6.3Hz, 2H), 3.60 (s, 3H), 2.38 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：189.4,160.3,151.0,149.1,147.1,143.0,134.2,
134.1 (2), 131.8,130.8 (2), 130.4 (2), 127.5 (2), 123.8,123.3 (2), 121.1,115.2,113.0
(2), 72.6,55.6,21.2.
High resolution mass spec HRMS：Calculated value C26H20N4O6S([M+Na]+) 539.0996, measured value 539.0998.
Embodiment 12
With the following 1- p-toluenesulfonyl -2- Amino 3 cyanos -4- (4- methoxybenzoyls base) of composite structure formula -
Exemplified by 5- (4- methoxyphenyls) pyrroles, specific synthetic method is as follows：
In embodiment 1,1- phenyl -3- phenyl -2- (4- Methyl benzenesulfonyls amino) -3- bromacetones -1 used with etc. rub
Your 1- (4- methoxyphenyls) -3- (4- methoxyphenyls) -3- (4- Methyl benzenesulfonyls amino) -2- bromacetones -1 are replaced, instead
Extended between seasonable 24 it is small when, other steps are same as Example 1, obtain yellow solid 1- p-toluenesulfonyl -2- amino -3-
Cyano group -4- (4- methoxybenzoyls base) -5- (4- methoxyphenyls) pyrroles, its yield are 40%, fusing point for 188.9~
190.2 DEG C, structural characterization data are as follows：
1H NMR (400MHz, DMSO-d6)δ：7.51~7.42 (m, 6H), 7.13 (s, 2H), 6.97 (d, J=6.7Hz,
2H), 6.76 (dd, J=68.5,7.1Hz, 4H), 3.76 (s, 3H), 3.68 (s, 3H), 2.41 (s, 3H).
13C NMR (100MHz, DMSO-d6)δ：189.0,163.7,159.8,150.9,146.8,133.2 (2), 132.1
(2), 130.7 (2), 129.5 (2), 127.4,125.3 (2), 122.0,114.2,113.2 (4), 73.0,56.0,55.5,
21.7。
High resolution mass spec HRMS：Calculated value C27H23N3O5S([M+Na]+) 524.1251, measured value 524.1245.
In above-described embodiment 1~12, Na used2CO3Also equimolar sodium acetate, K can be used2CO3、KHCO3、K3PO4、
NaOH, KOH, ethylenediamine or triethylamine are replaced, and methanol used also can use isometric ethanol, propyl alcohol, N, N- dimethyl formyls
Amine, acetonitrile, dimethyl sulfoxide are replaced, other steps are identical with corresponding embodiment.
Claims (6)
- A kind of 1. synthetic method of five substitutions 2- amino-pyrroles derivatives, it is characterised in that：In the larger organic solvent of polarity, It is 1 in molar ratio by the arone of the ortho position amino halogen shown in Formulas I or Formula II and malononitrile, alkali:1~1.5:0.5~2 mixing is equal It is even, when 40~60 DEG C of stirrings 6~24 are small, product is isolated and purified, formula III is obtained or five substitution 2- amino-pyrroles shown in formula IV spreads out Biology；In Formulas I~IV, Ar1And Ar2Each independent representative phenyl, C1~C4Alkyl-substituted phenyl, C1~C4It is alkoxy substituted Base, halogen and C1~C4The phenyl of alkoxy substitution, halogenophenyl, any one in nitro substituted-phenyl, X represent Cl, Br or I；The larger organic solvent of above-mentioned polarity is methanol, in ethanol, propyl alcohol, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide Any one.
- 2. the synthetic method of five substitutions 2- amino-pyrroles derivatives according to claim 1, it is characterised in that：The Ar1 And Ar2Each independent representative phenyl, 4- aminomethyl phenyls, 4- methoxyphenyls, 2- halogen -4,5- Dimethoxyphenyls, 3- methoxies Base phenyl, 3,5- Dimethoxyphenyls, 3,4,5- trimethoxyphenyls, 4- bromophenyls, 4- fluorophenyls, 4- chlorphenyls, 4- nitros Any one in phenyl.
- 3. the synthetic method of five substitutions 2- amino-pyrroles derivatives according to claim 1 or 2, it is characterised in that：It is described Arone and the malononitrile of ortho position amino halogen, the molar ratio of alkali be 1:1~1.5:1~1.5.
- 4. the synthetic method of five substitutions 2- amino-pyrroles derivatives according to claim 1, it is characterised in that：The pole The larger organic solvent of property is methanol.
- 5. the synthetic method of five substitutions 2- amino-pyrroles derivatives according to claim 1, it is characterised in that：The alkali For sodium acetate, K2CO3、KHCO3、Na2CO3、K3PO4, NaOH, KOH, ethylenediamine, any one in triethylamine.
- 6. the synthetic method of five substitutions 2- amino-pyrroles derivatives according to claim 1, it is characterised in that：The alkali For Na2CO3。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610395018.5A CN106008305B (en) | 2016-06-06 | 2016-06-06 | A kind of synthetic method of five substitutions 2- amino-pyrroles derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610395018.5A CN106008305B (en) | 2016-06-06 | 2016-06-06 | A kind of synthetic method of five substitutions 2- amino-pyrroles derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106008305A CN106008305A (en) | 2016-10-12 |
| CN106008305B true CN106008305B (en) | 2018-05-08 |
Family
ID=57089608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610395018.5A Expired - Fee Related CN106008305B (en) | 2016-06-06 | 2016-06-06 | A kind of synthetic method of five substitutions 2- amino-pyrroles derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106008305B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107382815B (en) * | 2017-08-07 | 2019-12-03 | 陕西师范大学 | A kind of five replace the synthetic method of 2- amino -2- pyrroline derivative |
| CN112266349B (en) * | 2020-11-17 | 2022-02-15 | 上海凌凯医药科技有限公司 | Method for preparing 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile |
| CN114950558B (en) * | 2021-02-22 | 2023-08-11 | 陕西师范大学 | Bipiperidine skeleton tetradentate nitrogen-containing manganese catalyst and method for catalyzing hydrocarbon molecule benzyl site selective oxidation by using same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6346534B1 (en) * | 1998-09-23 | 2002-02-12 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998043973A1 (en) * | 1997-03-27 | 1998-10-08 | Novartis Ag | Intermediate products and method for the production of pyrimidine derivatives |
-
2016
- 2016-06-06 CN CN201610395018.5A patent/CN106008305B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6346534B1 (en) * | 1998-09-23 | 2002-02-12 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
Non-Patent Citations (4)
| Title |
|---|
| Design of a Versatile Multicomponent Reaction Leading to 2-amino-5-ketoaryl pyrroles;Kan W.et al.;《Chem Biol Drug Des》;20091206;第75卷;第277-283页 * |
| One-Pot Multicomponent Synthesis of Diversely Substituted 2-Aminopyrroles. A Short General Synthesis of Rigidins A,B, C, and D;Liliya V.F.et al.;《Organic Letters》;20110126;第13卷(第5期);第1118-1121页 * |
| Reaction of α-Azidoketones with Highly Stabilized Michael Acceptors: A New Synthesis of Densely Functionalized Pyrroles;Jose L.M.et al.;《Tetrahedron Letters》;19951231;第36卷(第30期);第5393-5396页 * |
| Synthesis, characterisation and bioactivity of polysubstituted 1-(4-(1H-pyrrol-1-yl)phenyl)- 1H-pyrrole derivatives;Abdel Z.A.et al.;《Journal of Chemical Research》;20120630;第328-332页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106008305A (en) | 2016-10-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Boltjes et al. | The Groebke‐Blackburn‐Bienaymé Reaction | |
| Wen et al. | Solvent-free and efficient synthesis of imidazo [1, 2-a] pyridine derivatives via a one-pot three-component reaction | |
| Castillo et al. | Recent advances in the synthesis of new pyrazole derivatives | |
| KR101236676B1 (en) | Pyrido-pyrimidine derivatives, preparation thereof, therapeutic use thereof for treating cancer | |
| CN106008305B (en) | A kind of synthetic method of five substitutions 2- amino-pyrroles derivatives | |
| TW200417546A (en) | New compounds | |
| Ke et al. | Heterocycle-functional gramine analogues: Solvent-and catalyst-free synthesis and their inhibition activities against cell proliferation | |
| Li et al. | An efficient metal-free cascade process for the synthesis of 4-arylpyrimido [1, 2-b] indazole-3-carbonitrile derivatives | |
| ES2303758B1 (en) | NEW DERIVATIVES OF PIRIDIN-3-AMINA. | |
| ES2962961T3 (en) | Preparation procedure of n-(5-((4-(4-(dimethylamino)methyl)-3-phenyl-1h-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl )acrylamide by reacting the corresponding amine with a 3-halo-propionyl chloride | |
| EP3643308A1 (en) | Coumarin-like cyclic compound as mek inhibitor and use thereof | |
| Breuer et al. | Consecutive Alkynylation–Michael Addition–Cyclocondensation (AMAC) Multicomponent Syntheses of α-Pyrones and α-Pyridones | |
| Yue et al. | Rapid abnormal [3+ 2]-cycloaddition of isatin N, N′-cyclic azomethine imine 1, 3-dipoles with chalcones | |
| Dong et al. | Cu/base co-catalyzed [3+ 3] cycloaddition for the synthesis of highly functionalized 4-fluoropyridines | |
| Huang et al. | Asymmetric copper-catalyzed propargylic amination with amine hydrochloride salts | |
| Manda et al. | Discovery of Tröger's base analogues as selective inhibitors against human breast cancer cell line: Design, synthesis and cytotoxic evaluation | |
| CN107118215B (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediate | |
| Awasthi et al. | A three-component, general and practical route for diastereoselective synthesis of aza-spirocyclic pyrazolones via a decarboxylative annulation process | |
| CN100484944C (en) | N4-substited pyrazolyl [4,5-e][1,2,4] thiadiazine derivative and its preparation process and medicine composition | |
| CN107382815B (en) | A kind of five replace the synthetic method of 2- amino -2- pyrroline derivative | |
| Xuehua et al. | Synthesis of Spirobarbiturate Piperidin-2-one Derivatives via Cascade Aza-Michael/Michael Cyclization Reaction | |
| Liang et al. | One-pot propagation of (Hetero) Arylamines: Modular synthesis of diverse Amino-di (hetero) arylamines | |
| CN106083649B (en) | A kind of synthetic method of the Cyclohexadiene derivatives of 3,5 diaryl, 2,6,6 tricyano, 1 imino group 2,4 | |
| Zhang et al. | InCl3 catalyzed synthesis of thiophene derivatives via vinyl azides and β-ketothioamides | |
| Elsaman et al. | A Facile Synthesis of Pyrido [: 3, 4] pyrazolo [1, 5-a] pyrimidine and Pyrido [: 3, 4] pyrazolo [5, 1-c][1, 2, 4] triazine Bearing a Thiophene Moiety |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180508 Termination date: 20210606 |