CN108653279A - The pyrrolin analog derivative of application and a kind of resisiting influenza virus of the pyrrolin analog derivative on preparing influenza virus inhibitor - Google Patents

The pyrrolin analog derivative of application and a kind of resisiting influenza virus of the pyrrolin analog derivative on preparing influenza virus inhibitor Download PDF

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CN108653279A
CN108653279A CN201810672877.3A CN201810672877A CN108653279A CN 108653279 A CN108653279 A CN 108653279A CN 201810672877 A CN201810672877 A CN 201810672877A CN 108653279 A CN108653279 A CN 108653279A
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trifluoromethyl
phenyl
oxygen
dihydro
pyrroles
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朱秋华
杨洁
戴晨舒
刘腾
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Southern Medical University
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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    • C07—ORGANIC CHEMISTRY
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones

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Abstract

The pyrrolin analog derivative for the application and a kind of resisiting influenza virus that the invention discloses pyrrolin analog derivatives on preparing influenza virus inhibitor.Pyrrolin analog derivative provided by the present invention is to influenza A virus, especially H1N1 viruses, with preferable inhibitory activity, and reaction condition is mild, reaction step is simple, raw material is cheap and easy to get, reaction yield is higher, is easily achieved industrialization, has great application value on preparing anti-influenza virus medicament.

Description

Application and one kind of the pyrrolin analog derivative on preparing influenza virus inhibitor are anti- The pyrrolin analog derivative of influenza virus
Technical field
The present invention relates to influenza virus inhibitor medicaments technical fields, exist more particularly, to pyrrolin analog derivative Prepare the application on influenza virus inhibitor and a kind of pyrrolin analog derivative of resisiting influenza virus.
Background technology
Influenza is the breathing problem with highly infectious, wherein influenza A virus caused by influenza virus Host range is most wide, both can also infect mammality with infected poultry, and easily cause to be very popular in world wide.Influenza virus 4 influenza great outbursts (1918, nineteen fifty-seven, nineteen sixty-eight, 2009) just have occurred only in last 100 years.Wherein, 1918 it is quick-fried " spanish influenza " (H1N1) of hair directly results in about 50,000,000 people death, is that the influenza that death toll is most in human history is big Outburst.And the last " Mexico's influenza " (A/2009/H1N1) broken out in 2009 spreads to rapidly global 214 states Family only results in about 200,000 people dead between 12 months of outburst.Therefore, the prevention of influenza infection and early stage are controlled It treats, development of new broad spectrum influenza virus drug seems extremely important.
The means of existing prevention and treatment influenza infection are predominantly inoculated with influenza vaccines and use anti influenza at present Virus drugs.It is main Preventive Method to be inoculated with influenza vaccines, has high efficiency, but there is larger shortcoming to be for it Must inject every year it is primary, and to hypoimmunity and the effect of the adult with the high-risk state of an illness and child are relatively low.In addition, such as The influenza vaccines type of fruit prediction is incorrect, and the effect of vaccine will be made to be reduced to 25%.Therefore, anti-influenza virus medicament is treatment One line scheme of influenza.Up to now, anti-influenza virus medicament of the FDA approvals for Clinical practice is broadly divided into two classes：1)M2 Ion channel blocking agent, including amantadine and Rimantadine；2) neuraminidase inhibitor mainly has Oseltamivir and Zha Na Rice Wei and the Peramivir and La Ni meter Wei for thering are several countries to have been approved by.In addition, at present only in the anti-of Japan's approval listing Flu pharmaceutical has RNA inhibitor Favipiravir and Xofluza.Since currently a popular influenza virus is to adamantane amine drug Drug resistance (S31N mutation occur in virus N S genes), adamantane amine drug have no longer been the prevention and treatment influenza that WHO recommends Choice drug.Neuraminidase inhibitor class drug is the main selection of flu victims antiviral therapy, however, researcher is It is found that H1N1, H5N1, the H3N2 and Type B persister for generating resistance to Oseltamivir successively, shows that its drug resistance situation is still worth We pay close attention to.Therefore, the Tamiflu of Development of Novel is necessary.
Invention content
The purpose of the invention is to overcome the deficiencies of the prior art and provide the new application of pyrrolin analog derivative, i.e., Application on preparing influenza virus inhibitor.Pyrrolin analog derivative is applied on pre- preventing tumor more at present, and the present invention is public Its application on influenza virus inhibitor is opened, the application of especially anti-H1N1 viruses aspect is that a kind of pyrrolin class is spread out The new opplication of biology.
Another object of the present invention is to provide a kind of pyrrolin analog derivatives of resisiting influenza virus.
The present invention's is achieved by following technical solution：
Application of the pyrrolin analog derivative on preparing influenza virus inhibitor, the pyrrolin analog derivative lead to Formula is：
Wherein R1It is substituted or non-substituted C1~6Alkyl；
R2It is the C of substitution5~6Aromatic radical；
R3It is the C of substitution5~6Aromatic radical；
R4It is substituted or non-substituted substituted or non-substituted C5~6Aromatic radical, substituted or non-substituted C9~18Polycyclic aromatic Base；
Above-mentioned substituent group is selected from following groups：The C of halogen, perhalogeno1~2Alkyl, C1~6Straight or branched alkoxyl, C1~6 Linear or branched alkyl group.
The preparation method of the pyrrolin analog derivative of the present invention can be following steps：
S1. 25ml methanol, 5mmol acetylenedicarboxylic acids diester and 5mmol amine are added sequentially to the clean eggplant type flasks of 100mL In, it stirs 10-30 minutes at room temperature；
S2. 8mmol amine, 17.5mmol aromatic aldehydes, 1.5mmol salicylic acids and 2mmol copper acetates are slowly added sequentially to In above-mentioned reaction solution, stirring is to the reaction was complete (being monitored with TLC) at room temperature；
S3. filter, concentrate after reaction, remaining organic phase detaches through column chromatography method, eluant, eluent used be petroleum ether/ The volume ratio of ethyl acetate, wherein petroleum ether and ethyl acetate is 10:1~2:1, the target product that is fitted to simultaneously purifies production Object.
The eluent containing target product is monitored by TLC, eluent is merged and is concentrated, gained separation product is weighed through dry And calculate separation yield.
Preferably, R1For C1~2Alkyl.
Preferably, R2For substituted C6Aromatic radical.
Preferably, R3For substituted C6Aromatic radical.
Preferably, R4For substituted or non-substituted C6Aromatic radical, C10Polycyclic aromatic base.
Preferably, R2For substituted C6Aromatic radical, R3For substituted C6Aromatic radical.
Preferably, R2For substituted C6Aromatic radical, R3For substituted C6Aromatic radical, R4For substituted or non-substituted C6Fragrance Base, C10Polycyclic aromatic base.
Preferably, the pyrrolin analog derivative is：
2,5- dihydro -1- p-trifluoromethyl phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- are to Trifluoromethoxyphen-l -4- to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (2,3,4- trifluorophenyls) -4- are to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-methylphenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-trifluoromethyl phenyl -4- are to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
Fluorophenyl -4- is to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles-between 2,5- dihydro -1- p-trifluoromethyl phenyls -2- 3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (2,4 difluorobenzene base) -4- are to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylate methyl esters；
2,5- dihydros -1- p-methylphenyls -2- p-isopropyls phenyl -4- is to methylphenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydro -1- p-methylphenyl -2- phenyl -4- are to methylphenylamino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- o-trifluoromethyl phenyl -4- o-trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydros -1- p-trifluoromethyl phenyls -2- o-trifluoromethyls phenyl -4- is to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (1- naphthalenes) -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- guaiacyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters；
2,5- dihydros-Chloro-O-Phenyl -2- phenyl -4- neighbour's chloroanilino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester.
Preferably, the pyrrolin analog derivative is：
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (2,3,4- trifluorophenyls) -4- are to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-methylphenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-trifluoromethyl phenyl -4- are to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
Fluorophenyl -4- is to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles-between 2,5- dihydro -1- p-trifluoromethyl phenyls -2- 3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (2,4 difluorobenzene base) -4- are to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylate methyl esters；
2,5- dihydros -1- p-methylphenyls -2- p-isopropyls phenyl -4- is to methylphenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydro -1- p-methylphenyl -2- phenyl -4- are to methylphenylamino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- o-trifluoromethyl phenyl -4- o-trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydros -1- p-trifluoromethyl phenyls -2- o-trifluoromethyls phenyl -4- is to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (1- naphthalenes) -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- guaiacyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters；
2,5- dihydros-Chloro-O-Phenyl -2- phenyl -4- neighbour's chloroanilino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester.
It is highly preferred that the pyrrolin analog derivative is：
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (2,4 difluorobenzene base) -4- are to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylate methyl esters；
2,5- dihydros -1- p-methylphenyls -2- p-isopropyls phenyl -4- is to methylphenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydro -1- p-methylphenyl -2- phenyl -4- are to methylphenylamino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- o-trifluoromethyl phenyl -4- o-trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydros -1- p-trifluoromethyl phenyls -2- o-trifluoromethyls phenyl -4- is to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (1- naphthalenes) -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- guaiacyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters；
2,5- dihydros-Chloro-O-Phenyl -2- phenyl -4- neighbour's chloroanilino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester.
It is highly preferred that the pyrrolin analog derivative is：
2,5- dihydro -1- o-trifluoromethyl phenyl -2- o-trifluoromethyl phenyl -4- o-trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydros -1- p-trifluoromethyl phenyls -2- o-trifluoromethyls phenyl -4- is to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (1- naphthalenes) -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- guaiacyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters；
2,5- dihydros-Chloro-O-Phenyl -2- phenyl -4- neighbour's chloroanilino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester.
A kind of pyrrolin analog derivative of resisiting influenza virus, the pyrrolin analog derivative are：
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydros -1- p-trifluoromethyl phenyls -2- o-trifluoromethyls phenyl -4- is to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (1- naphthalenes) -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- guaiacyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters；
2,5- dihydros-Chloro-O-Phenyl -2- phenyl -4- neighbour's chloroanilino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester.
Compared with prior art, beneficial effects of the present invention are：
The present invention provides a kind of application of pyrrolin analog derivative on influenza virus inhibitor, the pyrrolin classes Derivative infected by influenza, especially H1N1 virus, have preferable inhibitory activity, and reaction condition is mild, reaction step is simple List, raw material is cheap and easy to get, reaction yield is higher, is easily achieved industrialization, has greatly application on influenza virus inhibitor Value.
Specific implementation mode
The present invention is further explained with reference to specific embodiment, but specific embodiment is not to the present invention It is limited in any way.Unless stated otherwise, reagent involved in embodiment, method are reagent and method commonly used in the art.
Steps are as follows for the preparation method of pyrrolin analog derivative：
S1. 25ml methanol, 5mmol acetylenedicarboxylic acids diester and 5mmol amine are added sequentially to the clean eggplant type flasks of 100mL In, it stirs 10-30 minutes at room temperature；
S2. 8mmol amine, 17.5mmol aromatic aldehydes, 1.5mmol salicylic acids and 2mmol copper acetates are slowly added sequentially to In above-mentioned reaction solution, stirring is to the reaction was complete (being monitored with TLC) at room temperature；
S3. filter, concentrate after reaction, remaining organic phase detaches through column chromatography method, eluant, eluent used be petroleum ether/ The volume ratio of ethyl acetate, wherein petroleum ether and ethyl acetate is 10:1~2:1, the target product that is fitted to simultaneously purifies production Object.
The eluent containing target product is monitored by TLC, eluent is merged and is concentrated, gained separation product is weighed through dry And calculate separation yield.
Embodiment 1
2,5- dihydro -1- p-trifluoromethyl phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters (ethyl 5-oxo-1-(4-(trifluoromethyl)phenyl)-4-((4-(trifluoromethyl)phenyl)-- Amino) -2,5-dihydro-1H-pyrrole-3-carboxylate, compound 1) yield 65%, white solid, m.p.= 142–143℃；
1HNMR (400MHz, CDCl3)δ:8.21 (s, 1H), 7.96 (d, J=8.7Hz, 2H), 7.68 (d, J=8.8Hz, 2H), 7.59 (d, J=8.5Hz, 2H), 7.22 (d, J=8.4Hz, 2H), 4.61 (s, 2H), 4.30 (q, J=7.1Hz, 2H), 1.29 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ 164.17,163.86,141.95,141.62,141.36,126.84 (q, J= 32.7Hz), 126.39 (q, J=3.7Hz), 126.00 (q, J=32.7Hz), 125.67 (q, J=3.7Hz), 124.12 (q, J =270.0Hz), 123.87 (q, J=271.6Hz), 121.64,118.58,106.75,60.86,48.06,14.10；
IR(KBr)ν(cm-1):3292,2987,1700,1652,1609,1527,1455,1394,1326,1198, 1111,1067,841,758,593；
HRMS-ESI(m/z):calcd for C21H16F6N2O3([M+H]+)Calcd:459.1126；Found: 459.1126。
Embodiment 2
2,5- dihydro -1- p-trifluoromethyl phenyl -2- are to Trifluoromethoxyphen-l -4- to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles -3- carboxylic acid, ethyl esters (ethyl 5-oxo-2- (4- (trifluoromethoxy) phenyl) -1- (4- (tri-- fluoromethyl)phenyl)-4-((4-(trifluoromethyl)phenyl)amino)-2,5-dihydro-1H- Pyrrole-3-carboxylate, compound 2) yield 82%, white solid, m.p.=130-131 DEG C；
1HNMR (400MHz, CDCl3) δ 8.43 (s, 1H), 7.69 (d, J=8.6Hz, 2H), 7.58 (m, 4H), 7.34 (d, J =8.5Hz, 2H), 7.28 (d, J=8.2Hz, 2H), 7.16 (d, J=8.4Hz, 2H), 5.92 (s, 1H), 4.25-3.87 (m, 2H), 1.08 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ 163.86,163.82,149.13,141.24,139.20,134.44,128.95, 127.32,126.19,126.15,125.76,125.72,122.07,121.66,121.00,112.02,77.28,76.96, 76.64,61.94,60.76,31.52,22.58,14.02,13.68；
IR(KBr)ν(cm-1):3296,1707,1645,1611,1517,1370,1326,1261,1222,1166,1118, 1067,1021,840,755.
Embodiment 3
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (2,3,4- trifluoromethyls) -4- is to trifluoromethyl phenylamino - 5- oxygen -1H- pyrroles -3- carboxylic acid, ethyl esters (ethyl 5-oxo-1- (4- (trifluoromethyl) phenyl) -4- ((4- (tri-
fluoromethyl)phenyl)amino)-2-(2,3,4-trifluorophenyl)-2,5-dihydro-1H- Pyrrole-3-carboxylate, compound 3) yield 42%, white solid, m.p.=192-193 DEG C；
1HNMR (400MHz, CDCl3) δ 8.42 (s, 1H), 7.66 (d, J=8.7Hz, 2H), 7.59 (m, 4H), 7.27 (s, 1H), 7.09 (m, 3H), 5.87 (s, 1H), 4.13 (q, J=7.1Hz, 2H), 1.12 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3)δ163.81,163.63,151.68,151.55,151.47,151.35,149.20, 149.07,148.99,148.86,141.28,139.02,132.95,132.91,132.87,128.10,127.78,127.45, 127.12,126.67,126.35,126.24,126.20,126.17,125.81,125.77,125.74,125.70,125.40, 125.01,123.74,123.71,123.68,122.70,122.31,122.17,121.74,117.72,117.54,116.56, 116.38,111.49,61.69,60.84,13.77；
IR(KBr)ν(cm-1):1711,1645,1613,1515,1486,1370,1326,1252,1168,1118,1067, 1034,842,756。
Embodiment 4
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-methylphenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles Cough up -3- carboxylic acid, ethyl esters (ethyl 5-oxo-2- (p-tolyl) -1- (4- (trifluoromethyl) phenyl) -4- ((4- (tri--fluoromethyl) phenyl) amino) -2,5-dihydro-1H-pyrrole-3-carboxylate, compound 4) yield 47%, white solid, m.p.=166-167 DEG C；
1HNMR (400MHz, CDCl3) δ 8.37 (s, 1H), 7.73 (d, J=8.6Hz, 2H), 7.59 (d, J=8.5Hz, 2H), 7.54 (d, J=8.7Hz, 2H), 7.26 (s, 1H), 7.19 (d, J=8.0Hz, 2H), 7.11 (d, J=8.0Hz, 2H), 5.88 (s, 1H), 4.17-3.90 (m, 2H), 2.27 (d, J=30.3Hz, 3H), 1.19-0.96 (m, 3H)；
13CNMR (101MHz, CDCl3) δ 164.10,163.99,141.76,140.78,139.57,138.38,132.49, 129.39,127.34,127.07 (q, J=32.7Hz), 125.99 (q, J=32.5Hz), 126.02 (q, J=3.7Hz), 125.70 (q, J=3.8Hz), 124.15 (q, J=269.8Hz), 123.81 (q, J=270.2Hz), 121.71,121.60, 113.21,62.65,60.67,21.05,13.72；
IR(KBr)ν(cm-1):3283,1705,1644,1611,1521,1370,1325,1166,1118,1067,1022, 840,755.
Embodiment 5
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-trifluoromethyl phenyl -4- are to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles -3- carboxylic acid, ethyl esters (ethyl 5-oxo-1,2-bis (4- (trifluoromethyl) phenyl) -4- ((4- (tri--fluoromethyl) phenyl) amino) -2,5-dihydro-1H-pyrrole-3-carboxylate, compound 5) yield 52%, yellow solid, mp:110–111℃；
1HNMR (400MHz, CDCl3) δ 8.42 (s, 1H), 7.76-7.50 (m, 8H), 7.44 (d, J=8.2Hz, 2H), 7.34-7.24 (m, 2H), 5.96 (s, 1H), 4.11 (q, J=7.1Hz, 2H), 1.10 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ 163.78,141.42,127.88,126.27,125.80,125.76,125.72, 122.19,121.55,111.58,77.27,76.95,76.63,62.11,60.84,31.53,22.59,13.75；
IR(KBr)ν(cm-1):3292,2924,1706,1614,1503,1324,1243,1121,1066,841,768, 600,504；
HRMS-ESI(m/z):calcd for C28H19F9N2O3([M+H]+)Calcd:603.1240；Found: 603.1239。
Embodiment 6
Fluorophenyl -4- is to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles-between 2,5- dihydro -1- p-trifluoromethyl phenyls -2- 3- carboxylic acid, ethyl esters (ethyl 2- (3-fluorophenyl) -5-oxo-1- (4- (trifluoromethyl) phenyl) -4- ((4-(tri-
Fluoromethyl) phenyl) amino) -2,5-dihydro-1H-pyrrole-3-carboxylate, chemical combination Object 6) yield 47%, white solid, mp:148–149℃；
1HNMR (400MHz, CDCl3) δ 8.46 (s, 1H), 7.71 (d, J=8.6Hz, 2H), 7.59 (m, 4H), 7.33- 7.28 (m, 2H), 7.27 (d, J=4.3Hz, 1H), 7.12 (d, J=7.8Hz, 1H), 7.06-7.01 (m, 1H), 6.97 (m, 1H), 5.91 (s, 1H), 4.13 (tt, J=7.2,3.6Hz, 2H), 1.11 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3)δ164.00,163.88,163.85,161.55,141.46,141.26,139.29, 138.52,138.45,130.32,130.24,128.17,127.89,127.79,127.56,127.24,126.91,126.78, 126.46,126.19,126.15,126.11,126.08,125.78,125.74,125.70,125.67,125.47,125.08, 123.22,123.19,122.77,122.38,122.04,121.65,119.68,115.76,115.55,114.64,114.42, 112.02,77.31,77.20,77.00,76.68,62.21,62.19,60.77,13.71；
IR(KBr)νmax=3744,1704,1645,1611,1521,1371,1324,1264,1166,1117,1066, 1024,840,755,474；
Embodiment 7
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (2,4 difluorobenzene base) -4- are to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles -3- carboxylic acid, ethyl esters (ethyl 2- (2,4-difluorophenyl) -5-oxo-1- (4- (trifluoromethyl) -
-phenyl)-4-((4-(trifluoromethyl)phenyl)amino)-2,5-dihydro-1H-pyrrole- 3-carbox ylate, compound 7) yield 44%, white solid, mp:179–180℃；
1HNMR (400MHz, CDCl3) δ 8.47 (s, 1H), 7.70 (d, J=8.6Hz, 2H), 7.59 (m, 4H), 7.29 (s, 1H), 7.27 (s, 1H), 7.09 (d, J=6.6Hz, 1H), 6.81 (m, 2H), 6.24 (s, 1H), 4.12 (q, J=7.1Hz, 2H), 1.11 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3)δ163.87,163.59,162.51,161.57,161.45,142.08,141.25, 139.03,127.67,127.35,126.60,126.25,126.21,126.18,125.77,125.73,125.69,125.42, 125.05,122.72,122.35,122.15,121.30,119.16,112.35,112.14,110.88,104.46,104.20, 103.95,60.76,13.63；
IR(KBr)νmax=3466,1709,1645,1613,1508,1371,1325,1250,1168,1119,1067, 1022,967,843,757,590,506；
Embodiment 8
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester (ethyl 5-oxo-2-phenyl-1- (3- (trifluoromethyl) phenyl) -4- ((3- (trifluoromethyl) -- phenyl) amino) -2,5-dihydro-1H-pyrrole-3-carboxylate, compound 8) yield 82%, white solid, mp:184–185℃；
1HNMR (400MHz, CDCl3) δ 8.37 (s, 1H), 7.83 (s, 1H), 7.73 (d, J=7.7Hz, 1H), 7.53- 7.34 (m, 6H), 7.34-7.16 (m, 5H), 5.88 (s, 1H), 4.08 (q, J=7.1Hz, 2H), 1.07 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ 164.07,163.87,141.35,138.96,137.01,135.74,131.23 (q, J=32.4Hz), 131.00 (q, J=32.4Hz), 129.38,128.93,128.62,128.50,127.54,125.85, 125.31,122.79 (q, J=271.1Hz), 123.57 (q, J=271.1Hz), 122.18,122.14,121.17,119.25, 119.21,119.00,118.96,111.68,63.03,60.55,13.74；
IR(KBr)νmax=3302,2924,2851,2309,1696,1636,1497,1371,1274,1233,1095, 1029,826,763,653,507；
HRMS-ESI(m/z):calcd for C27H20F6N2O3([M+H]+)Calcd:535.1444；Found: 535.1444。
Embodiment 9
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylate methyl esters (methyl 2- (4-fluorophenyl) -5-oxo-1- (4- (trifluoromethyl) phenyl) -4-
((4-(tri-fluoromethyl)phenyl)amino)-2,5-dihydro-1H-pyrrole-3- Carboxylate, compound 9) yield 75%, white solid, mp:171–172℃；
1HNMR (400MHz, CDCl3) δ 8.36 (s, 1H), 7.66 (d, J=8.6Hz, 2H), 7.61 (d, J=8.5Hz, 2H), 7.55 (d, J=8.7Hz, 2H), 7.28 (s, 2H), 7.25 (d, J=2.1Hz, 1H), 7.00 (t, J=8.6Hz, 2H), 5.89(s,1H),3.64(s,3H)；
13CNMR (101MHz, CDCl3)δ164.23,163.76,163.72,161.29,141.35,141.21,139.21, 131.40,131.37,129.08,129.00,128.12,127.93,127.60,127.28,126.95,126.59,126.26, 126.16,126.12,126.09,126.05,125.79,125.75,125.71,125.67,125.42,125.05,122.72, 122.35,122.15,121.81,115.98,115.77,111.95,62.05,51.48；
IR(KBr)νmax=3612,1705,1643,1611,1613,1325,1270,1067,1019,842,755,515, 455。
Embodiment 10
2,5- dihydros -1- p-methylphenyls -2- p-isopropyls phenyl -4- is to methylphenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester (ethyl 2- (4-isopropylphenyl) -5-oxo-1- (p-tolyl) -4- (p-tolylamino) -2,5-di- Hydro-1H-pyrrole-3-carboxylate, compound 10) yield 83%, yellow solid, m.p.=138-139 DEG C；
1HNMR (400MHz, CDCl3) δ 8.17 (s, 1H), 7.39 (d, J=8.5Hz, 2H), 7.18 (d, J=8.2Hz, 2H), 7.15-6.99 (m, 7H), 5.77 (s, 1H), 4.04 (m, 2H), 2.95-2.67 (m, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 1.20 (d, J=6.9Hz, 6H), 1.03 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ 164.52,163.95,148.43,142.36,136.06,135.11,134.30, 134.14,129.28,128.95,127.46,126.31,122.94,122.50,109.05,62.81,59.94,33.61, 23.80,23.76,20.91,20.83,13.77.；
IR(KBr)ν(cm-1):3288,2961,1700,1635,1515,1460,1370,1287,1241,1111,1033, 817,759.
Embodiment 11
2,5- dihydro -1- p-methylphenyl -2- phenyl -4- are to methylphenylamino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters (Ethyl 5-oxo-2-phenyl-1-(p-tolyl)-4-(p-tolylamino)-2,5-dihydro-1H-pyrrole-3- Carb oxylate compounds 11) yield 90%, white solid, m.p.=156-157 DEG C；
1HNMR (400MHz, CDCl3) δ 8.16 (s, 1H), 7.33 (d, J=8.0Hz, 2H), 7.27-7.16 (m, 6H), 7.07 (m, 6H), 5.76 (s, 1H), 4.01 (q, J=7.1Hz, 2H), 2.33 (s, 3H), 2.22 (s, 3H), 1.01 (t, J= 7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ 164.47,163.88,137.07,135.98,135.30,134.40,134.00, 132.52,129.30,128.96,128.25,127.93,127.66,122.98,122.65,108.70,63.13,59.99, 20.90,20.81,13.79；
IR(KBr)ν(cm-1):3032,2983,2924,1709,1632,1515,1450,1393,1290,1211,1110, 1035,834,823.
The compound is in Journal of Combinatorial Chemistry.2009,11,685-696 reports, and It is consistent with the characterization of compound of report.
Embodiment 12
2,5- dihydro -1- o-trifluoromethyl phenyl -2- o-trifluoromethyl phenyl -4- o-trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles -3- carboxylic acid, ethyl esters (ethyl 5-oxo-1,2-bis (3- (trifluoromethyl) phenyl) -4- ((3- (trifluor omethyl) phenyl) amino) -2,5-dihydro-1H-pyrrole-3-carboxylate, compound 12) yield 57%, white solid, mp:93–94℃；
1HNMR (400MHz, CDCl3) δ=8.47 (s, 1H), 7.77 (s, 1H), 7.70 (d, J=7.7Hz, 1H), 7.61 (s, 1H), 7.58-7.31 (m, 9H), 5.94 (s, 1H), 4.10 (q, J=7.1Hz, 2H), 1.09 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ=164.0,163.6,142.0,138.5,137.3,136.6,130.2, 129.6,129.3,129.0,126.3,125.3,125.1,122.5,121.6,119.6,119.0,110.4,62.4,60.7, 13.7；
IR(KBr)νmax=3293,2988,1705,1640,1454,1329,1240,1169,1126,895,793,695, 52；
HRMS-ESI(m/z):calcd for C28H19F9N2O3([M+H]+)Calcd:603.1314；Fou nd: 603.1314
Embodiment 13
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters (methyl 5-oxo-2-phenyl-1- (3- (trifluoromethyl) phenyl) -4- ((3- (trifluoromethyl)-phenyl) amino) -2,5-dihydro-1H-pyrrole-3-carboxylate compounds 13) Yield 59%, white solid, mp:123–124℃；
1HNMR (400MHz, CDCl3) δ 8.35 (d, J=7.5Hz, 1H), 7.84 (d, J=5.8Hz, 1H), 7.72 (d, J= 7.4Hz, 1H), 7.43 (m, 6H), 7.30 (s, 4H), 7.26 (s, 1H), 5.89 (d, J=3.1Hz, 1H), 3.62 (s, 3H)；
13CNMR (101MHz, CDCl3) δ 164.36,163.87,141.35,138.92,136.96,135.70,131.22 (q, J=32.5Hz), 130.98 (q, J=32.5Hz), 129.40,128.93,128.72,128.54,127.42,126.03, 125.34,123.81 (q, J=271Hz), 123.59 (q, J=271Hz), 122.22 (q, J=3.8Hz), 121.29 (q, J= 3.6Hz), 119.37 (q, J=3.7Hz), 119.04 (q, J=3.9Hz), 111.26,63.03,51.38.
The compound is in ACS Combinatorial Science.2013,15,183-192. reports, and with report Characterization of compound is consistent.
Embodiment 14
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Sour methyl esters (methyl 5-oxo-2-phenyl-1- (4- (trifluoromethyl) phenyl) -4- ((4- (trifluor-- Omethyl) phenyl) amino) -2,5-dihydro-1H-pyrrole-3-carboxylate compounds 14) yield 63%, White solid, mp:159–160℃；
1HNMR (400MHz, CDCl3) δ 8.35 (s, 1H), 7.70 (d, J=8.7Hz, 2H), 7.61 (d, J=8.5Hz, 2H), 7.54 (d, J=8.7Hz, 2H), 7.36-7.21 (m, 7H), 5.89 (s, 1H), 3.64 (s, 3H)；
13CNMR (101MHz, CDCl3) δ 164.32,163.89,141.48,141.21,139.44,135.63,128.77, 128.58,127.33,126.05,126.01,125.75,125.71,122.04,121.67,112.45,77.28,76.96, 76.65,62.78,51.44；
IR(KBr)νmax=3291,2923,2308,1705,1613,1530,1323,1243,1120,1067,837, 758,695,497；
HRMS-ESI(m/z):calcd for C26H18F6N2O3([M+H]+)Calcd:521.1286；Found: 521.1286。
Embodiment 15
2,5- dihydros -1- p-trifluoromethyl phenyls -2- o-trifluoromethyls phenyl -4- is to trifluoromethyl phenylamino -5- oxygen - 1H- pyrroles -3- carboxylic acid, ethyl esters (Ethyl 5-oxo-2- (3- (trifluoromethyl) phenyl) -1- (4- (trifluoro--methyl)phenyl)-4-((4-(trifluoromethyl)phenyl)amino)-2,5-dihydro- 1H-pyrrole-3-car boxylate, compound 15) yield 65%, white solid, m.p.=148-149 DEG C；
1HNMR (400MHz, CDCl3) δ 8.52 (s, 1H), 7.68 (d, J=8.6Hz, 2H), 7.63 (d, J=5.2Hz, 2H), 7.60 (s, 1H), 7.55 (m, 3H), 7.43 (d, J=6.5Hz, 2H), 7.31 (s, 1H), 5.96 (s, 1H), 4.12 (q, J =7.1Hz, 2H), 1.12 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ 163.92,163.69,141.75,141.16,139.10,137.17,131.05 (q, J=32Hz), 130.09,129.38,127.58 (q, J=33Hz), 126.55 (q, J=33Hz), 126.23 (q, J= 4Hz), 125.76 (q, J=4Hz), 123.79 (q, J=270Hz), 125.01 (q, J=4Hz), 123.70 (q, J=273Hz), 122.71,122.28,123.59 (q, J=273Hz), 121.67,111.57,62.14,60.86,13.63；
IR(KBr)ν(cm-1):3678,3295,1710,1645,1612,1522,1369,1326,1251,1168,1121, 1069,1022,749.
Embodiment 16
2,5- dihydro -1- p-trifluoromethyl phenyls -2- (1- naphthalenes) -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters (Ethyl 2- (naphthalen-1-yl) -5-oxo-1- (4- (trifluoromethyl) phenyl) -4- ((4- (trifluoromethyl) phenyl) amino) -2,5-dihydro-1H-pyrrole-3-carboxylate, chemical combination Object 16) yield 35%, white solid, m.p.=149-150 DEG C；
1HNMR (400MHz, CDCl3) δ 7.87 (d, J=8.2Hz, 1H), 7.84-7.61 (m, 5H), 7.57 (m, 4H), 7.45-7.32 (m, 4H), 7.24 (m, 2H), 6.85 (s, 1H), 3.82 (m, 2H), 0.50 (m, 3H)；
13C NMR (101MHz, CDCl3) δ 164.32,164.28,141.66,141.58,139.70,133.80, 131.95,131.78,129.25,129.07,126.60,126.28,126.04,126.00,125.96,125.83,125.79, 125.76,125.72,125.46,125.04,123.33,123.11,122.53,121.89,120.86,114.24,60.52, 56.47 13.26；
IR(KBr)ν(cm-1):3740,3299,2990,1706,1644,1611,1522,1367,1325,1276,1167, 1118,1068,1023,841,755.
Embodiment 17
2,5- dihydro -1- p-trifluoromethyl phenyl -2- o-methoxyphenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- Pyrroles -3- carboxylic acid, ethyl esters (Ethyl 2- (3-methoxyphenyl) -5-oxo-1- (4- (trifluoromethyl) phen yl)-4-((4-(trifluoromethyl)phenyl)amino)-2,5-dihydro-1H-pyrrole-3-carboxylate Compound 17) yield 51%, white solid, m.p.=137-138 DEG C；
1HNMR (400MHz, CDCl3) δ 8.42 (s, 1H), 7.73 (d, J=8.4Hz, 2H), 7.57 (m, 4H), 7.27 (d, J =9.0Hz, 2H), 7.22 (d, J=7.9Hz, 1H), 6.91 (d, J=7.6Hz, 1H), 6.85-6.77 (m, 2H), 5.87 (s, 1H), 4.11 (q, J=7.1Hz, 2H), 3.77 (s, 3H), 1.11 (t, J=7.1Hz, 3H)
13CNMR (101MHz, CDCl3) δ 164.03,163.99,159.76,141.67,140.99,139.56,137.28, 129.69,127.17 (q, J=32.7Hz), 126.05 (q, J=32.6Hz), 126.02 (q, J=3.7Hz), 125.70 (q, J =3.7Hz), 125.323 (q, J=35.2Hz), 121.82,121.60,119.90,113.70,113.26,112.86, 62.73,60.68,55.15,13.74
IR(KBr)ν(cm-1):3620,3359,2920,2851,1706,1643,1610,1520,1369,1324,1268, 1166,1117,1066,751.
Embodiment 18
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles - 3- carboxylic acid, ethyl esters (Ethyl 2- (4-fluorophenyl) -5-oxo-1- (4- (trifluoromethyl) phenyl) -4- ((4- (trifluoromethyl) phenyl) amino) -2,5-dihydro-1H-pyrrole-3-carboxylate compounds 18) yield 79%, white solid, m.p.=144-145 DEG C；
1HNMR (400MHz, CDCl3) δ 8.41 (s, 1H), 7.68 (d, J=8.4Hz, 2H), 7.58 (m, 4H), 7.29 (s, 1H), 7.26 (s, 2H), 7.00 (t, J=8.3Hz, 2H), 5.90 (s, 1H), 4.10 (q, J=7.1Hz, 2H), 1.09 (t, J= 7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ 163.91,163.87,162.53 (d, J=246Hz), 141.52,141.03, 139.26,131.45 (d, J=4Hz), 129.18 (d, J=8Hz), 127.39 (q, J=32Hz), 126.57 (q, J=33Hz), 126.09 (q, J=4Hz), 125.73 (q, J=3Hz), 124.10 (q, J=270Hz), 123.72 (q, J=270Hz), 121.93,121.79,115.77 (q, J=22Hz), 112.42,62.11,60.73,13.73；
IR(KBr)ν(cm-1):3283,1707,1645,1611,1514,1370,1326,1232,1166,1118,1067, 1021,756.
Embodiment 19
2,5- dihydro -1- Chloro-O-Phenyl -2- phenyl -4- neighbour's chloroanilino -5- oxygen -1H- pyrroles's -3- carboxylic acid, ethyl esters (Eth yl 1-(3-chlorophenyl)-4-((3-chlorophenyl)amino)-5-oxo-2-phenyl-2,5-dihydro- 1H-p yrrole-3-carboxylate compounds 19) yield 47%, white solid, m.p.=166-147 DEG C；
1HNMR (400MHz, CDCl3) δ 8.28 (s, 1H), 7.67 (d, J=7.1Hz, 1H), 7.36 (d, J=8.2Hz, 1H), 7.34-7.26 (m, 5H), 7.22 (d, J=10.9Hz, 2H), 7.16 (t, J=8.2Hz, 2H), 7.08 (t, J=9.1Hz, 2H), 5.82 (s, 1H), 4.07 (q, J=7.1Hz, 2H), 1.07 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ 164.07,163.87,141.32,139.82,137.64,136.03,134.50, 134.03,129.73,129.35,128.55,128.38,127.57,125.67,124.63,122.72,122.50,120.86, 120.19,111.37,63.01,60.47,13.80；
IR(KBr)ν(cm-1):3449,1699,1638,1591,1481,1369,1271,1121,1032,755.
Embodiment 20
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1H- pyrroles's -3- carboxylics Acetoacetic ester (Ethyl 5-oxo-2-phenyl-1- (4- (trifluoromethyl) phenyl) -4- ((4- (trifluoromet Hyl) phenyl) amino) -2,5-dihydro-1H-pyrrole-3-carboxylate, compound 20) 55% yield, white Solid, mp:148–149℃；
1HNMR (400MHz, CDCl3) δ 8.40 (s, 1H), 7.72 (d, J=8.6Hz, 2H), 7.57 (m, 4H), 7.29 (m, 7H), 5.90 (s, 1H), 4.10 (q, J=7.1Hz, 2H), 1.09 (t, J=7.1Hz, 3H)；
13CNMR (101MHz, CDCl3) δ 164.02,164.00,141.61,141.08,139.51,135.67,128.68, 128.57,127.48,127.19 (q, J=32.6Hz), 126.132 (q, J=32.8Hz), 126.02 (q, J=3.7Hz), 124.13 (q, J=269.9), 123.76 (q, J=270.3Hz), 121.86,121.64,112.90,77.29,76.97, 76.65,62.83,60.68,13.73；
IR(KBr)ν(cm-1):3783,3355,2919,1703,1610,1323,1242,1167,1117,1066,836, 756,695；
HRMS-ESI(m/z):calcd for C27H20F6N2O3([M+H]+)Calcd:535.1442；Fou nd: 535.1442。
Anti-influenza virus activity detects
Pyrrolin analog derivative of the present invention is ground as the pharmacology for preparing anti-influenza virus medicament using mtt assay Study carefully.
Mtt assay principle：Succinate dehydrogenase in living cells mitochondria can make exogenous MTT be reduced to the indigo plant of water-insoluble Purple crystal first a ceremonial jade-ladle, used in libation is simultaneously deposited in cell, and dead cell is without this function.Within the scope of certain cell number, MTT, which is crystallized, to be formed Amount is directly proportional to cell number.Dimethyl sulfoxide (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, it is measured at 570nm wavelength using microplate reader Absorbance, you can reflection sample cell vigor indirectly, and then half of the compound to influenza A virus can get by calculating Inhibition concentration (IC50)。
Mtt assay experimental procedure：Mdck cell is with 2 × 104The density in a/hole is inoculated in 96 orifice plates, is placed in 37 DEG C, 5%CO2 Cell incubator in grow overnight to single layer；Supernatant is abandoned in suction, and cell is washed 2 times with PBS buffer solution, and 100 μ L H1N1 diseases are added per hole Poison (A/Puerto Rico/8/34) dilution (100TCID50), in 5%CO2, adherent cell 1h in 37 DEG C of incubator；It sops up Virus liquid is added the various concentration compound prepared with the DMEM containing 1 μ g/mL TPCK- pancreatin, while blank control is arranged, after Continue in 5%CO2, 37 DEG C of incubator culture 48h；Then, supernatant is abandoned, it is subsequent that 100 holes μ L/ MTT solution (0.5mg/mL) are added Continuous culture 4h；Supernatant carefully is sopped up, 150 μ L DMSO are added per hole, is placed in micropore plate oscillator and vibrates 15min, is made intracellular Deposition first a ceremonial jade-ladle, used in libation is fully dissolved out；The absorbance value in each hole is detected at 570nm wavelength using multi-function microplate reader.It is inhaled according to light The size of receipts value calculates IC of the compound to Alphavirus50.Independent experiment is in triplicate.
Cytoactive inhibiting rate is calculated according to the following formula：
Inhibiting rate=[(Ac-As)/(Ac-Ab)] × 100%
Ac：Viral hole (virus infection, no drug)
Ab：Blank well (uninfecting virus)
As：Experimental port (virus infection contains drug)
According to the inhibiting rate of drug cell proliferation at different dosages, calculated by 5 softwares of GraphPad Prism IC50It is worth (table 1).
The compound of Examples 1 to 20 and the listing clinical medicine zanamivir of example 21 are thin to influenza a virus infection The IC of born of the same parents50Value is as shown in table 1, it is known that such compound has the function of preferably inhibiting influenza A virus, the clinic with listing Drug zanamivir is close to the inhibitory activity of influenza A virus.
1 compound 1-20 of table inhibits the IC of influenza A virus50Value
Embodiment IC50(μM) Embodiment IC50(μM)
1 222.547±29.145 12 18.993±3.404
2 128.435±39.548 13 17.302±2.187
3 91.132±20.650 14 16.155±0.706
4 81.227±13.581 15 11.898±3.451
5 68.501±16.015 16 11.825±2.163
6 67.252±9.791 17 11.811±0.539
7 51.280±17.799 18 9.235±1.371
8 37.653±2.350 19 7.634±1.053
9 30.941±9.299 20 3.108±0.234
10 24.108±1.720 21 0.509±0.183
11 21.373±4.591
The above results show that the compound that the present invention protects has good anti-influenza A virus effect, and pass through The synthetic method that the present inventor has reported can efficiently, easy, high productivity synthesize this kind of compound, it is easy to accomplish industry Change, is with a wide range of applications.

Claims (10)

1. a kind of application of pyrrolin analog derivative on preparing influenza virus inhibitor, which is characterized in that the dihydro pyrrole The general formula for coughing up analog derivative is：
Wherein R1It is substituted or non-substituted C1~6Alkyl；
R2It is substituted or non-substituted C5~6Aromatic radical；
R3It is substituted or non-substituted C5~6Aromatic radical；
R4It is substituted or non-substituted C1~6Alkyl, substituted or non-substituted C5~6Aromatic radical, substituted or non-substituted C4~5Heteroaromatic Base, substituted or non-substituted C9~18Polycyclic aromatic base；
Above-mentioned substituent group is selected from following groups：The C of halogen, perhalogeno1~2Alkyl, C1~6Straight or branched alkoxyl, C1~6Straight chain or Branched alkyl.
2. application as described in claim 1, which is characterized in that wherein R1For C1~2Alkyl.
3. application as claimed in claim 1 or 2, which is characterized in that wherein R2For substituted C6Aromatic radical.
4. application as claimed in claim 1 or 2, which is characterized in that wherein R3For substituted C6Aromatic radical.
5. application as claimed in claim 1 or 2, which is characterized in that wherein R4For substituted or non-substituted C6Aromatic radical, C10Condensed ring Aromatic radical.
6. application as claimed in claim 1 or 2, which is characterized in that R2For substituted C6Aromatic radical, R3For substituted C6Aromatic radical.
7. application as claimed in claim 1 or 2, which is characterized in that R2For substituted C6Aromatic radical, R3For substituted C6Aromatic radical, R4For substituted or non-substituted C6Aromatic radical, C10Polycyclic aromatic base.
8. applying according to claim 1, which is characterized in that the pyrrolin analog derivative is：
2,5- dihydro -1- p-trifluoromethyl phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- are to Trifluoromethoxyphen-l -4- to trifluoromethyl phenylamino -5- oxygen -1H- Pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2-（2,3,4- trifluorophenyls）- 4- is to trifluoromethyl phenylamino -5- oxygen -1H- Pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-methylphenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles -3- Carboxylic acid, ethyl ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-trifluoromethyl phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrrole Cough up -3- carboxylic acid, ethyl esters；
Fluorophenyl -4- is to trifluoromethyl phenylamino -5- oxygen -1 between 2,5- dihydro -1- p-trifluoromethyl phenyls -2-HPyrroles's -3- carboxylics Acetoacetic ester;
2,5- dihydro -1- p-trifluoromethyl phenyls -2-（2,4 difluorobenzene base）- 4- is to trifluoromethyl phenylamino -5- oxygen -1HPyrrole Cough up -3- carboxylic acid, ethyl esters;
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid second Ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydros -1- p-methylphenyls -2- p-isopropyls phenyl -4- is to methylphenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid second Ester；
2,5- dihydro -1- p-methylphenyl -2- phenyl -4- are to methylphenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- o-trifluoromethyl phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1HPyrrole Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid first Ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid first Ester；
2,5- dihydros -1- p-trifluoromethyl phenyls -2- o-trifluoromethyls phenyl -4- is to trifluoromethyl phenylamino -5- oxygen -1HPyrrole Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2-（1- naphthalenes）- 4- is to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- guaiacyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles -3- Carboxylic acid, ethyl ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydros-Chloro-O-Phenyl -2- phenyl -4- neighbour chloroanilino -5- oxygen -1HPyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid second Ester.
9. applying according to claim 1, which is characterized in that the pyrrolin analog derivative is：
2,5- dihydro -1- p-trifluoromethyl phenyls -2-（2,3,4- trifluorophenyls）- 4- is to trifluoromethyl phenylamino -5- oxygen -1H- Pyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-methylphenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles -3- Carboxylic acid, ethyl ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-trifluoromethyl phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrrole Cough up -3- carboxylic acid, ethyl esters；
Fluorophenyl -4- is to trifluoromethyl phenylamino -5- oxygen -1 between 2,5- dihydro -1- p-trifluoromethyl phenyls -2-HPyrroles's -3- carboxylics Acetoacetic ester;
2,5- dihydro -1- p-trifluoromethyl phenyls -2-（2,4 difluorobenzene base）- 4- is to trifluoromethyl phenylamino -5- oxygen -1HPyrrole Cough up -3- carboxylic acid, ethyl esters;
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid second Ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylics Sour methyl esters；
2,5- dihydros -1- p-methylphenyls -2- p-isopropyls phenyl -4- is to methylphenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid second Ester；
2,5- dihydro -1- p-methylphenyl -2- phenyl -4- are to methylphenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- o-trifluoromethyl phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1HPyrrole Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- o-trifluoromethyl phenyl -2- phenyl -4- o-trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid first Ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid first Ester；
2,5- dihydros -1- p-trifluoromethyl phenyls -2- o-trifluoromethyls phenyl -4- is to trifluoromethyl phenylamino -5- oxygen -1HPyrrole Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2-（1- naphthalenes）- 4- is to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- guaiacyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles -3- Carboxylic acid, ethyl ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydros-Chloro-O-Phenyl -2- phenyl -4- neighbour chloroanilino -5- oxygen -1HPyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid second Ester.
10. a kind of pyrrolin analog derivative of resisiting influenza virus, which is characterized in that the pyrrolin analog derivative is：
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid first Ester；
2,5- dihydros -1- p-trifluoromethyl phenyls -2- o-trifluoromethyls phenyl -4- is to trifluoromethyl phenylamino -5- oxygen -1HPyrrole Cough up -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyls -2-（1- naphthalenes）- 4- is to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- guaiacyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles -3- Carboxylic acid, ethyl ester；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- p-fluorophenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylics Acetoacetic ester；
2,5- dihydros-Chloro-O-Phenyl -2- phenyl -4- neighbour chloroanilino -5- oxygen -1HPyrroles's -3- carboxylic acid, ethyl esters；
2,5- dihydro -1- p-trifluoromethyl phenyl -2- phenyl -4- are to trifluoromethyl phenylamino -5- oxygen -1HPyrroles's -3- carboxylic acid second Ester.
CN201810672877.3A 2018-06-26 2018-06-26 The pyrrolin analog derivative of application and a kind of resisiting influenza virus of the pyrrolin analog derivative on preparing influenza virus inhibitor Pending CN108653279A (en)

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Application publication date: 20181016