CN106008305A - Synthetic method of penta-substituted 2-amino pyrrole derivatives - Google Patents

Synthetic method of penta-substituted 2-amino pyrrole derivatives Download PDF

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CN106008305A
CN106008305A CN201610395018.5A CN201610395018A CN106008305A CN 106008305 A CN106008305 A CN 106008305A CN 201610395018 A CN201610395018 A CN 201610395018A CN 106008305 A CN106008305 A CN 106008305A
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amino
pyrroles
phenyl
halogen
synthetic method
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CN106008305B (en
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陈战国
李亚男
惠文萍
康梦
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Shaanxi Normal University
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Shaanxi Normal University
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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
    • C07D207/46—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 invention discloses a synthetic method of penta-substituted 2-amino pyrrole derivatives, wherein the method comprises that in an organic medium with relatively large polarity, arone of o-amino halogen and malononitrile are subjected to a reaction in one step under the action of an alkali, and the penta-substituted 2-amino pyrrole derivatives can be obtained. Compared with a traditional method, the method adopts the low-price ordinary alkali as an accelerant, effectively reduces the cost, and has the advantages of simple synthetic steps and high reaction yield; especially in construction of a drug with a pyrrole ring, with use of the method, the problem that the residual amount of heavy metals in the drug exceeds standards due to use of the heavy metals for catalysis can be avoided. In addition, no matter arone of o-amino halogen is alpha-amino-beta-halogen arone or alpha-halogen-beta-amino arone, amino in the synthetic products is located at 2-site of the pyrrole ring and has high region selectivity. The synthetic penta-substituted 2-amino pyrrole derivatives can be used in the fields of synthesis of fused heterocyclic compounds, natural antibiotics and anticancer drugs and modification research of natural product structures.

Description

A kind of synthetic method of five replacement 2-amino-pyrroles derivants
Technical field
The invention belongs to the synthesis technical field of five replacement 2-amino-pyrroles derivants, be specifically related to a kind of ortho position amino The method that the arone of halogen and Cyanoacetyl-Cyacetazid single step reaction synthesize five replacement 2-amino-pyrroles.
Background technology
Pyrroles and derivant thereof are very important five member ring heterocyclic compounds of class.Pyrroles was found in for 19th century the earliest The '30s, since then, biological activity and pharmacological action that pyrroles and derivant thereof are had have caused extensively pass Note.Now, pyrroles and derivant thereof be widely used in medicine, pesticide, food, biology, material science with And chemical field.Due to pyrroles and the importance of derivant thereof, its synthetic method is goed deep into by people Research.2-amino-pyrroles construction unit is the part that many has strong bioactive compound, has been well recognized as Many drug molecular structure unit.These medicines can show antiinflammatory, anticancer, antiviral, antifungal, parasite killing, Radioprotective, and MEK, MK2, FAK, KDR, Tie2 and PDE are had strong inhibitory action.Separately Outward, 2-amino-pyrroles is purine biosynthesis homologue such as pyrrolopyrimidine, pyrrolo-triazine and the precursor of pyrrolopyridine. Till now, although the method for synthesis pyrroles and derivant thereof is a lot, but about the conjunction of five replacement 2-amino-pyrroles Become report the most relatively fewer.The method reported has: (1) by alkynes and trimethyl cyano group silicon transition metal Pd, Under the catalysis of the coordination compounds such as Ni, Co, backflow obtains corresponding five replacement 2-amino-pyrroles derivants；(2) respectively By N-benzenesulfonamido-phenyl methyl ketone, N-heteroaryl sulfonamido phenyl methyl ketone, N-alkyl sulfonyl amino Phenyl methyl ketones etc. reflux in ethanol or acetonitrile solvent with active methylene compound three component of aldehyde, cyano-containing Reaction, obtains corresponding five replacement 2-amino-pyrroles derivants；(3) with α, β-undersaturated acid imide cyanide with Nitrile is at AlCl3It is catalyzed lower 90 DEG C of reactions, obtains corresponding five replacement 2-amino-pyrroles derivants；(4) alkynes and benzene Amine titanium complex be catalyzed under, 80 DEG C of reactions in toluene solvant, obtain 2,3-diaminourea azole derivatives；(5) exist In toluene solvant, by benzyl tolysulfonyl imines, butine dicarboxylic acid dimethyl ester, the reaction of cyclohexyl isonitrile three component Obtain corresponding five replacement 2-amino-pyrroles derivants.Above method there are disadvantages that in various degree, if any side Catalyst made by method transition metal, and in pharmaceutical synthesis, heavy metal residual volume exceeds standard is relatively to be difficult to resolve certainly in pharmaceutical synthesis Problem；Some methods to use the reaction raw materials being difficult to obtain, and can increase the cost of synthesis；Have will be higher At a temperature of carry out, even to carry out at a reflux temperature, the requirement to equipment is increased.
Summary of the invention
The technical problem to be solved is to overcome existence in existing five replacement 2-amino-pyrroles derivant synthesis Shortcoming, it is provided that one in a mild condition, in the organic media that polarity is bigger, under the promotion of common weak base, Method by the arone of ortho position amino halogen Yu Cyanoacetyl-Cyacetazid one-step synthesis five replacement 2-amino-pyrroles.
Solve above-mentioned technical problem and be the technical scheme is that in the organic solvent that polarity is bigger, by Formulas I or The arone of the ortho position amino halogen shown in Formula II is mixed homogeneously for 1:1～1.5:0.5～2 in molar ratio with Cyanoacetyl-Cyacetazid, alkali, 40～60 DEG C are stirred 6～24 hours, and isolated and purified product obtains five replacement 2-amino shown in formula III or formula IV Azole derivatives；
In Formulas I～IV, Ar1And Ar2The most independent representative phenyl, C1～C4Alkyl-substituted phenyl, C1～C4Alcoxyl Base substituted-phenyl, halogen and C1～C4Appointing in the substituted phenyl of alkoxyl, halogenophenyl, nitro substituted-phenyl Meaning one, preferably Ar1And Ar2The most independent representative phenyl, 4-aminomethyl phenyl, 4-methoxyphenyl, 2-halogen-4,5- Dimethoxyphenyl, 3-methoxyphenyl, 3,5-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-bromophenyl, Any one in 4-fluorophenyl, 4-chlorphenyl, 4-nitrobenzophenone, X represents Cl, Br or I.
The arone of above-mentioned ortho position amino halogen and Cyanoacetyl-Cyacetazid, the mol ratio of alkali are preferably 1:1～1.5:1～1.5.
The organic solvent that above-mentioned polarity is bigger be methanol, ethanol, propanol, N,N-dimethylformamide, acetonitrile, Any one in dimethyl sulfoxide, preferably methanol.
Above-mentioned alkali is sodium acetate, K2CO3、KHCO3、Na2CO3、K3PO4, NaOH, KOH, second two Any one in amine, triethylamine, preferably Na2CO3。
In the synthetic method of the present invention five replacement 2-amino-pyrroles derivant, no matter aromatic ring in the arone of ortho position amino halogen On with which kind of substituent group and substituent group in which kind of position of aromatic ring, though the arone of ortho position amino halogen be pantonine- Halogen type or α-halogen-beta-amino type, five replacement 2-amino-pyrroles derivants of its synthesis have the regioselectivity of height, Amino is all in the 2-position of pyrrole ring, has the architectural feature of Isosorbide-5-Nitrae-dipole in the pyrrole ring i.e. synthesized, and this structure can There is 4+1 or 4+2 ring closure reaction further, can be used for alkaloid, the complete synthesis and structure of modification of natural product, conjunction Become the field such as antibiotic, anticancer, antiviral drugs, for drug molecule synthesis is complete synthesis with natural product and structure changes Make the technology providing new.
Inventor is found through experiments, in order to make this reaction quickly, efficiently, it is necessary to could realize under the promotion of alkali, It is not added with this reaction of alkali all can not occur, and the kind of alkali and consumption play decisive role to reaction.It addition, it is molten Agent also plays important control action to this reaction, and in an aqueous medium, Cyanoacetyl-Cyacetazid can hydrolyze, and causes this anti- Can not occur.Therefore, this reaction just can must complete in organic media.But due to organic solvent kind not With, its polarity size has difference, the most variant to the control ability size of this reaction.It is demonstrated experimentally that organic solvent Polarity the biggest, the biggest to the control ability of this reaction.Product structure and yield are had a significant impact by reaction temperature, Temperature is on the low side (such as room temperature), and reaction is tended to generate pyrrolin, and temperature is the highest, and product is complicated, product yield Decline.
It is an advantage of the current invention that:
1, the invention provides a method that all can synthesize five replacement 2-amino-pyrroles derivants in multi-solvents, Such as methanol, ethanol, propanol, DMF, acetonitrile, dimethyl sulfoxide etc., wherein first-selected solvent is Methanol.
2, present invention uses common alkali such as sodium acetate, potassium acetate, sodium bicarbonate, potassium carbonate, sodium carbonate, Potassium phosphate, sodium hydroxide, potassium hydroxide, ethylenediamine, triethylamine etc. are as accelerator, and wherein sodium carbonate is first-selected Accelerator.This accelerator is stably easy to get, cheap, compared with traditional method, it is to avoid expensive Precious metal palladium or the use of other transition metal coordination compound, not only effectively reduce synthesis cost, and close at medicine One-tenth avoids the possibility that metal residues amount exceeds standard.
3, the present invention is under the promotion of alkali, in the arone of ortho position amino halogen halogen by the substitution reaction of Cyanoacetyl-Cyacetazid, point In son, amino forms pyrrolin and the oxidation carried out pyrrolin by the oxygen in air to the nucleophilic addition of cyano group Dehydrogenation reaction once completes, and has been efficiently synthesized five substituted 2-amino-pyrroles derivants.Process in oxidative dehydrogenation In, the oxygen in application air carries out oxidative dehydrogenation, it is to avoid the oxidant such as DDQ that use is traditional, makes synthesis five Replace 2-amino-pyrroles more to clean.
4, the synthesis step of the present invention is simple, and a step completes three reactions, and (nucleophilic displacement of fluorine/intramolecular nucleophilic adds One-tenth/oxidative dehydrogenation), and reaction yield is high, the highest yield can reach 91%.
5, the method for the present invention has the regioselectivity of height, no matter carrying on aromatic ring in the arone of ortho position amino halogen Have to electron substituent group or electron-withdrawing substituent, and though the arone of ortho position amino halogen be pantonine-halogen type or α- Halogen-beta-amino type, the amino of all products has all been in the 2-position of pyrroles, the amino of this 2-position and lacking on 3-position Electronics base can form the special construction of Isosorbide-5-Nitrae-dipole, 4+1 or 4+2 ring closure reaction can occur, for synthesizing other complexity Miscellaneous polycyclic compound provides new route.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in more detail, but protection scope of the present invention is not limited to these in fact Execute example.
Embodiment 1
With the 1-p-toluenesulfonyl-2-Amino 3 cyano-4-phenyl-5-benzoyl pyrrole compound that composite structure formula is following it is Example, concrete synthetic method is as follows:
0.457g (1mmol) 1-phenyl-3-phenyl-2-(4-methylbenzene sulphur it is sequentially added in 50mL round-bottomed flask Acylamino-)-3-bromacetone-1,0.066g (1mmol) Cyanoacetyl-Cyacetazid, 0.106g (1mmol) sodium carbonate, 5mL Methanol, at 50 DEG C, magnetic agitation is reacted 8 hours, is subsequently adding 25mL ethyl acetate, uses saturated aqueous common salt Washing three times (each 25mL), be washed with water and wash three times (each 25mL), organic facies is dried with anhydrous sodium sulfate Overnight, being filtered to remove desiccant, concentrating under reduced pressure, crude product carries out silica gel column chromatography separation (with petroleum ether and acetic acid Ethyl ester volume ratio be the mixed liquor of 5:1 be eluant), obtain 1-p-toluenesulfonyl-2-Amino 3 cyano-4-phenyl -5-benzoyl pyrrole compound, its yield is 89%, and dehydrated alcohol recrystallization obtains faint yellow solid, fusing point be 188.8～ 190.2 DEG C, 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: value of calculation C25H19N3O3S([M+Na]+) 464.1039, measured value 464.1047。
Embodiment 2
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-(4-the chlorphenyl)-5-benzoyl that composite structure formula is following As a example by pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-phenyl-3-(4-chlorphenyl)-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 is replaced, and the response time extends to 14 hours, other steps were same as in Example 1, obtained yellow solid 1-p-toluenesulfonyl-2-Amino 3 cyano -4-(4-chlorphenyl)-5-benzoyl pyrrole compound, its yield is 70%, and fusing point is 198.8～199.9 DEG C, 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: value of calculation C25H16ClN3O3S([M+Na]+) 498.0650, measured value 498.0652。
Embodiment 3
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-(4-the bromophenyl)-5-benzoyl that composite structure formula is following As a example by pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-phenyl-3-(4-bromophenyl)-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 is replaced, and the response time extends to 9 Hour, other steps are same as in Example 1, obtain yellow solid 1-p-toluenesulfonyl-2-Amino 3 cyano-4-(4- Bromophenyl)-5-benzoyl pyrrole compound, its yield is 84%, and fusing point is 201.8～202.8 DEG C, structural characterization data 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: value of calculation C25H16BrN3O3S([M+Na]+) 542.0144, measured value 542.0145。
Embodiment 4
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-(4-fluorophenyl)-5-(the 4-methoxyl group that composite structure formula is following Benzoyl) as a example by pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-(4-methoxyphenyl)-3-(4-fluorophenyl)-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 is replaced, during reaction Between extend to 18 hours, other steps are same as in Example 1, obtain faint yellow solid 1-p-toluenesulfonyl-2- Amino 3 cyano-4-(4-fluorophenyl)-5-(4-anisoyl) pyrroles, its yield is 69%, fusing point be 156.1～ 157.2 DEG C, structural characterization data are 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: value of calculation C26H20FN3O4S([M+Na]+) 512.1051, measured value 512.1048。
Embodiment 5
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-phenyl-5-(4-chlorobenzene formacyl) that composite structure formula is following As a example by pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-(4-chlorphenyl)-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 changes and replaces, and the response time foreshortens to 6 Hour, other steps are same as in Example 1, obtain yellow solid 1-p-toluenesulfonyl-2-Amino 3 cyano-4- Phenyl-5-(4-chlorobenzene formacyl) pyrroles, its yield is 91%, and fusing point is 200.1～201.9 DEG C, structural characterization number According to 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: value of calculation C25H16ClN3O3S([M+Na]+) 498.0650, measured value 498.0654。
Embodiment 6
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-(4-the fluorophenyl)-5-benzoyl that composite structure formula is following As a example by pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-phenyl-3-(4-fluorophenyl)-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 is replaced, and the response time extends to 16 hours, other steps were same as in Example 1, obtained yellow needles 1-p-toluenesulfonyl-2-amino-3- Cyano group-4-(4-fluorophenyl)-5-benzoyl pyrrole compound, its yield is 70%, and fusing point is 189.9～190.2 DEG C, structure Sign 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: value of calculation C25H18FN3O3S([M+Na]+) 482.0945, measured value 482.0943。
Embodiment 7
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-(4-fluorophenyl)-5-(the 4-chlorobenzene first that composite structure formula is following Acyl group) as a example by pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-(4-chlorphenyl)-3-(4-fluorophenyl)-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 is replaced, and the response time prolongs Long to 10 hours, other steps are same as in Example 1, obtain yellow needles 1-p-toluenesulfonyl-2-ammonia Base-3-cyano group-4-(4-fluorophenyl)-5-(4-chlorobenzene formacyl) pyrroles, its yield is 76%, fusing point be 199.4～ 201.8 DEG C, structural characterization data are as follows:
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: value of calculation C25H17FN3O3S([M+Na]+) 516.0555, measured value 516.0563。
Embodiment 8
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-benzoyl-5-(the 4-methoxyl group that composite structure formula is following Phenyl) as a example by pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-phenyl-3-(4-methoxyphenyl)-3-(4-Methyl benzenesulfonyl amino)-2-bromacetone-1 is replaced, and the response time prolongs Long to 24 hours, other steps are same as in Example 1, obtain yellow solid 1-p-toluenesulfonyl-2-amino-3- Cyano group-4-benzoyl-5-(4-methoxyphenyl) pyrroles, its yield is 49%, and fusing point is 196.8～198.8 DEG C, Structural characterization data are as follows:
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: value of calculation C26H21N3O4S([M+Na]+) 494.1145, measured value 494.1149。
Embodiment 9
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-benzoyl-5-(the 4-methylbenzene that composite structure formula is following Base) as a example by pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-phenyl-3-(4-aminomethyl phenyl)-3-(4-Methyl benzenesulfonyl amino)-2-bromacetone-1 is replaced, other steps and reality Execute example 1 identical, obtain yellow needles 1-p-toluenesulfonyl-2-Amino 3 cyano-4-benzoyl-5-(4-first Base phenyl) 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: value of calculation C26H21N3O3S([M+Na]+) 478.1196, measured value 478.1193。
Embodiment 10
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-(4-chlorobenzene formacyl)-5-(the 4-first that composite structure formula is following Phenyl) as a example by pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-(-chlorphenyl)-3-(4-methoxyphenyl)-3-(4-Methyl benzenesulfonyl amino)-2-bromacetone-1 is replaced, during reaction Between extend to 24 hours, other steps are same as in Example 1, obtain yellow solid 1-p-toluenesulfonyl-2-ammonia Base-3-cyano group-4-(4-chlorobenzene formacyl)-5-(4-methoxyphenyl) pyrroles, its yield is 43%, fusing point be 206.2～ 207.5 DEG C, structural characterization data are 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: value of calculation C26H20N3O4S([M+Na]+) 528.0755, measured value 528.0754。
Embodiment 11
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-(the 4-nitro benzoyl)-5-(4-that composite structure formula is following Methoxyphenyl) as a example by pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-(4-nitrobenzophenone)-3-(4-methoxyphenyl)-3-(4-Methyl benzenesulfonyl amino)-2-bromacetone-1 is replaced, reaction Time lengthening was to 24 hours, and other steps are same as in Example 1, obtained yellow solid 1-p-toluenesulfonyl-2- Amino 3 cyano-4-(4-nitro benzoyl)-5-(4-methoxyphenyl) pyrroles, its yield is 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: value of calculation C26H20N4O6S([M+Na]+) 539.0996, measured value 539.0998。
Embodiment 12
With 1-p-toluenesulfonyl-2-Amino 3 cyano-4-(the 4-methoxybenzoyl that composite structure formula is following Base) as a example by-5-(4-methoxyphenyl) pyrroles, concrete synthetic method is as follows:
In embodiment 1,1-phenyl-3-phenyl-2-(4-Methyl benzenesulfonyl amino)-3-bromacetone-1 used with etc. rub Your 1-(4-methoxyphenyl)-3-(4-methoxyphenyl)-3-(4-Methyl benzenesulfonyl amino)-2-bromacetone-1 is replaced, instead Extending to 24 hours between Ying Shi, other steps are same as in Example 1, obtain yellow solid 1-p-toluenesulfonyl -2-Amino 3 cyano-4-(4-anisoyl)-5-(4-methoxyphenyl) pyrroles, its yield is 40%, fusing point Being 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: value of calculation C27H23N3O5S([M+Na]+) 524.1251, measured value 524.1245。
In above-described embodiment 1～12, Na used2CO3Also can be with equimolar sodium acetate, K2CO3、KHCO3、 K3PO4, NaOH, KOH, ethylenediamine or triethylamine replace, methanol used also can with isopyknic ethanol, Propanol, DMF, acetonitrile, dimethyl sulfoxide are replaced, and other steps are identical with corresponding embodiment.

Claims (7)

1. the synthetic method of a replacement 2-amino-pyrroles derivant, it is characterised in that: in bigger the having of polarity In machine solvent, by the arone of the ortho position amino halogen shown in Formulas I or Formula II and Cyanoacetyl-Cyacetazid, alkali be in molar ratio 1:1～ 1.5:0.5～2 mix homogeneously, 40～60 DEG C are stirred 6～24 hours, and isolated and purified product obtains formula III or formula IV Five shown replacement 2-amino-pyrroles derivants；
In Formulas I～IV, Ar1And Ar2The most independent representative phenyl, C1～C4Alkyl-substituted phenyl, C1～C4Alcoxyl Base substituted-phenyl, halogen and C1～C4Appointing in the substituted phenyl of alkoxyl, halogenophenyl, nitro substituted-phenyl Meaning one, X represents Cl, Br or I.
The synthetic method of five replacement 2-amino-pyrroles derivants the most according to claim 1, it is characterised in that: Described Ar1And Ar2The most independent representative phenyl, 4-aminomethyl phenyl, 4-methoxyphenyl, 2-halogen-4,5-diformazan Phenyl, 3-methoxyphenyl, 3,5-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-bromophenyl, 4- Any one in fluorophenyl, 4-chlorphenyl, 4-nitrobenzophenone.
The synthetic method of five replacement 2-amino-pyrroles derivants the most according to claim 1 and 2, its feature It is: the arone of described ortho position amino halogen is 1:1～1.5:1～1.5 with Cyanoacetyl-Cyacetazid, the mol ratio of alkali.
The synthetic method of five replacement 2-amino-pyrroles derivants the most according to claim 1, it is characterised in that: The organic solvent that described polarity is bigger is methanol, ethanol, propanol, N,N-dimethylformamide, acetonitrile, diformazan Any one in sulfoxide.
The synthetic method of five replacement 2-amino-pyrroles derivants the most according to claim 1, it is characterised in that: The organic solvent that described polarity is bigger is methanol.
The synthetic method of five replacement 2-amino-pyrroles derivants the most according to claim 1, it is characterised in that: Described alkali is sodium acetate, K2CO3、KHCO3、Na2CO3、K3PO4, NaOH, KOH, ethylenediamine, Any one in triethylamine.
The synthetic method of five replacement 2-amino-pyrroles derivants the most according to claim 1, it is characterised in that: Described alkali is Na2CO3。
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107382815A (en) * 2017-08-07 2017-11-24 陕西师范大学 A kind of synthetic method of the five substitutions pyrroline derivative of 2 amino 2
CN112266349A (en) * 2020-11-17 2021-01-26 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
CN114950558A (en) * 2021-02-22 2022-08-30 陕西师范大学 Bipiperidine skeleton tetradentate nitrogen-containing manganese catalyst and method for catalyzing benzyl-site selective oxidation of hydrocarbon molecules by using same

Citations (2)

* Cited by examiner, † Cited by third party
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
US6346534B1 (en) * 1998-09-23 2002-02-12 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

Patent Citations (2)

* Cited by examiner, † Cited by third party
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
US6346534B1 (en) * 1998-09-23 2002-02-12 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ABDEL Z.A.ET AL.: "Synthesis, characterisation and bioactivity of polysubstituted 1-(4-(1H-pyrrol-1-yl)phenyl)- 1H-pyrrole derivatives", 《JOURNAL OF CHEMICAL RESEARCH》 *
JOSE L.M.ET AL.: "Reaction of α-Azidoketones with Highly Stabilized Michael Acceptors: A New Synthesis of Densely Functionalized Pyrroles", 《TETRAHEDRON LETTERS》 *
KAN W.ET AL.: "Design of a Versatile Multicomponent Reaction Leading to 2-amino-5-ketoaryl pyrroles", 《CHEM BIOL DRUG DES》 *
LILIYA V.F.ET AL.: "One-Pot Multicomponent Synthesis of Diversely Substituted 2-Aminopyrroles. A Short General Synthesis of Rigidins A,B, C, and D", 《ORGANIC LETTERS》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107382815A (en) * 2017-08-07 2017-11-24 陕西师范大学 A kind of synthetic method of the five substitutions pyrroline derivative of 2 amino 2
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
CN112266349A (en) * 2020-11-17 2021-01-26 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
CN114950558A (en) * 2021-02-22 2022-08-30 陕西师范大学 Bipiperidine skeleton tetradentate nitrogen-containing manganese catalyst and method for catalyzing benzyl-site selective oxidation of hydrocarbon molecules by using same
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

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