CN101497580B - HIV-1 inhibitor 2-pyrrolidinone derivative, as well as synthesizing method and use thereof - Google Patents

HIV-1 inhibitor 2-pyrrolidinone derivative, as well as synthesizing method and use thereof Download PDF

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CN101497580B
CN101497580B CN2009100365391A CN200910036539A CN101497580B CN 101497580 B CN101497580 B CN 101497580B CN 2009100365391 A CN2009100365391 A CN 2009100365391A CN 200910036539 A CN200910036539 A CN 200910036539A CN 101497580 B CN101497580 B CN 101497580B
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phenyl
compound
dihydro
pyrroles
oxygen
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CN101497580A (en
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江焕峰
朱秋华
刘叔文
张珉
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South China University of Technology SCUT
Southern Medical University
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South China University of Technology SCUT
Southern Medical University
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Abstract

The invention relates to pyrrolidone derivatives of an HIV-1 inhibitor, a method for synthesizing the same and application thereof. The structural formula of the pyrrolidone derivatives is a formula I, wherein R<1>, R<2>, R<3> and R<4> are hydrogen, an aromatic radical, an alkyl radical or a heterocyclic radical; and R<5> is hydrogen, an alkyl radical and an aromatic radical. In the formula I, the four components can be easily synthesized from a compound (1), a compound(2), a compound(3) and a compound(4), and the yield is between 60 and 96 percent. The pyrrolidone derivatives or pharmaceutically acceptable salts thereof can be independently or combined with other medicines to prepare anti-AIDS medicines.

Description

HIV-1 inhibitor 2-pyrrolidinone derivative and synthetic method thereof and application
Technical field
The present invention relates to the methods and applications of a kind of HIV-1 inhibitor 2-pyrrolidinone derivative and synthetic this 2-pyrrolidinone derivative thereof.
Background technology
(Acquired Immunodeficiency Syndrome, AIDS), promptly acquired immune deficiency syndrome (AIDS) is human one of the most serious uncontrollable pernicious transmissible disease so far to acquired immune deficiency syndrome (AIDS).(HumanImmunodeficiency Virus HIV) is the pathogenic agent that causes acquired immune deficiency syndrome (AIDS) to human immunodeficiency virus.HIV is sub-thread normal chain Yeast Nucleic Acid (RNA) virus, and two identical RNA chains are arranged in each virion.Reversed transcriptive enzyme (reverse transcriptase, RT), proteolytic enzyme (protease, PT) and intergrase (integrase IG) is 3 key enzymes in the HIV reproduction process.As virulent HIV-1 in two kinds of hypotypes of HIV (HIV-1 and HIV-2) is the emphasis that people study always.Though the anti-HIV-1 medicine that uses clinically can prolong patient's life at present, can not heal the sick effectively, its major cause is that the HIV-1 variation comparatively fast causes virus very easily to produce resistance.Therefore, the HIV-1 inhibitor of the high curative effect of development of new, low side effect is the very big challenge that current people face: will carry out structure of modification to existing medicine on the one hand, on the other hand developmental function target spot and machine-processed different anti-HIV-1 new drug energetically.
The main medicine of anti-HIV-1 infection has reverse transcriptase inhibitors, proteinase inhibitor and fusion enzyme inhibitors etc. clinically at present.The recent pyrrole derivative that studies show that is the promising HIV-1 inhibitor of a class.This compounds can produce the anti-HIV-1 effect by different action target spots and mechanism of action.(Compound I in the following formula-II) and pyrrolin-2-ketone derivatives (compound III in the following formula) can suppress HIV-1 proteolytic enzyme (HIV-1 protease effectively as the pyrroledione acid derivative, HIV-1 PR) (Science 2000 for catalytic activity, 287 (5453), 646-650.; Biol.﹠amp; Med.Chem.2007,15,5487-5492); (compound IV in the following formula-VI) can act on transmembrane glycoprotein subunit gp41 (the envelope glycoprotein transmembrane subunit of HIV-1 to the N-substituted azole, gp41), thereby stop virus to enter target cell, play not infected (the a.Antimicrob.Agents ﹠amp of protection immunocyte; Chemother.2004,4349-4359; B.J.Med.Chem.jm-2008-00869t.R2).
The pyrrolin that the present invention relates to-2-ketone derivatives has been widely used at aspects such as synthetic chemistry, industry and medicine.Pyrrolin-2-ketone derivatives is synthetic different types of structure pyrroles's a intermediate, and for example, it can be reduced into Pyrrolidine ketone, and (Tetrahedron 2006,62,6018-6028; J.Org.Chem.1987,52,4352; US Patent6,784,167 B2,2004; Tetrahedron Lett.2005,46,1525.J.Med.Chem.1993,36,1041-1047).Because pyrrolidone has well water-soluble and biocompatibility, also be usually used in the synthetic of macromolecular materials such as biomaterial, solubility promoter, stablizer, as have Povidone synthetic of extensive use.In addition, pyrrolin-2-ketone derivatives also has wide biological activity, has the activity that suppresses HIV-1PR except above-mentioned, also can be used as sterilant (DE patent 102004053191,2006); DNA gyrase (gyrase) inhibitor (WO patent 054102,2006) of treatment cancer, infectation of bacteria; The treatment kinds of tumors vascular endothelial growth factor receptor (Vascularendothelial growth factor receptors, VEGF-Rs) inhibitor (J.Med.Chem.2008,51,3814-3824); And Aurora kinases (Aurora kinase) inhibitor (Bioorg.Med.Chem.Lett.2008,18,1623-1627).Therefore efficient, environmental friendliness, synthetic this compounds is the focus that people study always economically.
Figure G2009100365391D00021
The method of the synthesizing dihydro pyrroles-2-ketone derivatives that the present invention relates to is four component methods.Though the method for synthesizing dihydro pyrroles-2-ketone derivatives is a lot, polystep reaction method (J.Med.Chem.2008,51,3814-3824 are arranged; Tetrahedron2006,62,6018-6028; J.Med.Chem.1993.36,1041-1047), two component method (Tetrahedron2007,63,461-468; Eur.J.Org.Chem.2006,2843-2850; Tetrahedron 2003,59,8499-8507), (Tetrahedron 2008,64,5221-5225 for three component method; Bioorg.Med.Chem.2007,15,5487-5492; Eur.J.Org.Chem.2006,2843-2850; Tetrahedron 2006,62,6018-6028), but the report of synthetic this compounds of four component methods of no use.At present, aspect synthetic chemistry, the polycomponent method more and more is subjected to people's favor (J.Am.Chem.Soc.2006,128,11040-11041; Angew.Chem.Int.Ed.2007,46,2295-2298; Angew.Chem.Int.Ed.2007,46,2485-2488; Angew.Chem.Int.Ed.2007,46,3291-3295), but because realize the diversity of target product by this method simple and effective ground.The polycomponent method has some characteristic of combinatorial chemistry, has great superiority and using value in new drug development and research.In addition, the compound of the synthetic method that the present invention relates to preparation is that a class contains α-and the pyrrolin-2-ketone compound of beta-amino acids structure, that is: 4-amino-5-oxygen-pyrrolin-3-carboxylates derivatives.The synthetic method of relevant this compounds is (Syn.Comm., 2005,35 (18), 2453-2466 seldom; Heterocycles 2005,65 (10), 2451-2459; Syn.Comm.2003,33 (13), 2235-2241; J.Het.Chem.1975,12 (3), 585-8; J.Org.Chem.1963,28,1332-6), and all be synthetic, promptly by corresponding 4-hydroxyl or 4-carbonyl-5-oxygen-pyrrolin-3-carboxylates derivatives and amine reaction generation 4-amino-5-oxygen-pyrrolin-3-carboxylates derivatives by two component method.Because raw material is difficult for synthetic, causes the product kind to be restricted.The more important thing is that the Novel 4-amino that the present invention relates to-5-oxygen-pyrrolin-3-carboxylicesters series compound demonstrates the activity of significant anti-HIV-1 in the external activity experiment.
Summary of the invention
The objective of the invention is to overcome the shortcoming of prior art; a kind of HIV-1 inhibitor 2-pyrrolidinone derivative is provided; this compounds can be effectively and HIV-1 transmembrane glycoprotein subunit gp41 effect, thereby stop virus to enter target cell, and the protection immunocyte is not infected by HIV-1.The simple N-substituted pyrrole compound of the specific activity of this compounds height.
Another object of the present invention provides the method and the application of synthetic this 2-pyrrolidinone derivative, this synthetic method is to adopt the method for four component method synthetic (I) first, experimental raw is easy to get, experimental procedure is simple, but the diversity of target molecule is realized on high-efficient simple ground, has remedied the difficult synthetic and low deficiency of productive rate of raw material that existing synthetic method exists.
Acceptable salt is on new pyrrole ketone derivatives provided by the invention or its pharmacology:
Figure G2009100365391D00031
In the formula:
R 1, R 2And R 3Be hydrogen, straight or branched alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl or heterocyclic radical;
R 4Be hydrogen, straight or branched alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl or heterocyclic radical;
R 5Be hydrogen, alkyl or aromatic base.
R 1, R 2And R 3Be hydrogen, straight or branched alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl or heterocyclic radical;
R 4Be hydrogen, straight or branched alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl or heterocyclic radical;
R 5Replace or contain heteroatomic aromatic base, hydrogen or C for replacing or not having 1-4Alkyl.
R 1, R 2And R 3Be hydrogen, C 1-4Straight or branched alkyl, hydroxyl substituted alkyl, halogen-substituted alkyl, carboxyl substituted alkyl, alkoxy acyl substituted alkyl, C 5-6Cycloalkyl, benzyl, phenyl, substituted aryl or heterocyclic radical;
R 4Be hydrogen, C 1-4The straight or branched alkyl, hydroxyl substituted alkyl, halogen-substituted alkyl, C 5-6Cycloalkyl, benzyl, phenyl, C 1-3Alkyl substituting aromatic base, alkoxyl group substituted aryl, halogen substituted aryl, nitro substituted aryl, alkoxy acyl substituted aryl, sulfamyl substituted aryl or heterocyclic radical.
R 1And R 2Be C 1-4The straight or branched alkyl, hydroxyl substituted alkyl, halogen-substituted alkyl, C 5-6Cycloalkyl or benzyl;
R 3Be C 1-3Alkyl, alkoxyl group substituted aryl, halogen substituted aryl, nitro substituted aryl, sulfamyl substituted aryl;
R 4Be hydrogen.
R 1And R 2Be C 1-3Alkyl, alkoxyl group substituted aryl, halogen substituted aryl, nitro substituted aryl or sulfamyl substituted aryl;
R 3Be C 1-4The straight or branched alkyl, hydroxyl substituted alkyl, halogen-substituted alkyl, C 5-6Cycloalkyl or benzyl;
R 4Be C 1-4The straight or branched alkyl, hydroxyl substituted alkyl, halogen-substituted alkyl, C 5-6Cycloalkyl, benzyl, phenyl, C 1-3Alkyl substituting aromatic base, alkoxyl group substituted aryl, halogen substituted aryl, nitro substituted aryl, alkoxy acyl substituted aryl, sulfamyl substituted aryl or heterocyclic radical.
Preferred compound is: R 1, R 2And R 3Be hydrogen, C 1-4Straight or branched alkyl, hydroxyl substituted alkyl, halogen-substituted alkyl, carboxyl substituted alkyl, alkoxy acyl substituted alkyl, C 5-6Cycloalkyl, benzyl, phenyl, substituted aryl or heterocyclic radical;
R 4Be hydrogen, C 1-4The straight or branched alkyl, hydroxyl substituted alkyl, halogen-substituted alkyl, C 5-6Cycloalkyl, benzyl, phenyl, C 1-3Alkyl substituting aromatic base, alkoxyl group substituted aryl, halogen substituted aryl, nitro substituted aryl, alkoxy acyl substituted aryl, sulfamyl substituted aryl or heterocyclic radical.
R 1And R 2Be C 1-4The straight or branched alkyl, hydroxyl substituted alkyl, halogen-substituted alkyl, C 5-6Cycloalkyl or benzyl, R 3Be C 1-3Alkyl, alkoxyl group substituted aryl, halogen substituted aryl, nitro substituted aryl or sulfamyl substituted aryl; R 4Be hydrogen.
R 1And R 2Be C 1-3Alkyl, alkoxyl group substituted aryl, halogen substituted aryl, nitro substituted aryl or sulfamyl substituted aryl, R 3Be C 1-4The straight or branched alkyl, hydroxyl substituted alkyl, halogen-substituted alkyl, C 5-6Cycloalkyl or benzyl, R 4Be C 1-4The straight or branched alkyl, hydroxyl substituted alkyl, halogen-substituted alkyl, C 5-6Cycloalkyl, heterocyclic radical, benzyl, phenyl, C 1-3Alkyl substituting aromatic base, alkoxyl group substituted aryl, halogen substituted aryl, nitro substituted aryl, alkoxy acyl substituted aryl or sulfamyl substituted aryl.
Representative compounds of the present invention is as described below:
2,5-dihydro-1-benzyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-benzyl-4-(benzylamino)-2,5-dihydro-5-oxo-1H-pyrrole-3-carboxylate, compound 1),
2,5-dihydro-1-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-5-oxo-1-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 2),
2,5-dihydro-1-p-methylphenyl-4-(to methylbenzene amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(p-tolylamino)-2,5-dihydro-5-oxo-1-p-tolyl-1H-pyrrole-3-carboxylate, compound 3),
2,5-dihydro-1-is to fluorophenyl-4-(to fluoroanilino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(4-fluorophenylamino)-1-(4-fluorophenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3-carboxylate, compound 4),
2,5-dihydro-1-is to bromophenyl-4-(to bromobenzene amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(4-bromophenylamino)-1-(4-bromophenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3-carboxylate, compound 5),
2,5-dihydro-1-phenyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(benzylamino)-2,5-dihydro-5-oxo-1-phenyl-1H-pyrrole-3-carboxylate, compound 6),
2,5-dihydro-1-phenyl-4-(third amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-5-oxo-1-phenyl-4-(propylamino)-1H-pyrrole-3-carboxylate, compound 7),
2,5-dihydro-1-phenyl-4-(hexamethylene amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(cyclohexylamino)-2,5-dihydro-5-oxo-1-phenyl-1H-pyrrole-3-carboxylate, compound 8),
2,5-dihydro-1-p-nitrophenyl-4-(hexamethylene amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(cyclohexylamino)-2,5-dihydro-1-(4-nitrophenyl)-5-oxo-1H-pyrrole-3-carboxylate, compound 9),
2,5-dihydro-1-benzyl-2-phenyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-benzyl-4-(benzylamino)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 10),
2,5-dihydro-1-propyl group-2-phenyl-4-(third amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-5-oxo-2-phenyl-1-propyl-4-(propylamino)-1H-pyrrole-3-carboxylate, compound 11),
2,5-dihydro-1-methyl-2-phenyl-4-(methylamino-)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-1-methyl-4-(methylamino)-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 12),
2,5-dihydro-1-butyl-2-phenyl-4-(fourth amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-butyl-4-(butylamino)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 13),
2,5-dihydro-1-p-methylphenyl-2-phenyl-4-(to toluino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(p-tolylamino)-2,5-dihydro-5-oxo-2-phenyl-1-p-tolyl-1H-pyrrole-3-carboxyl ate, compound 14),
2,5-dihydro-1-is to fluorophenyl-2-phenyl-4-(to fluoroanilino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(4-fluorophenylamino)-1-(4-fluorophenyl)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 15),
2,5-dihydro-1-benzyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-benzyl-2,5-dihydro-5-oxo-2-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 16),
2,5-dihydro-1-cyclohexyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-cyclohexyl-2,5-dihydro-5-oxo-2-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 17),
2,5-dihydro-1-normal-butyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-butyl-2,5-dihydro-5-oxo-2-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 18),
2,5-dihydro-1-hydroxyethyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-1-(2-hydroxyethyl)-5-oxo-2-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 19),
2,5-dihydro-1-hydroxyethyl-2-phenyl-4-(to methylbenzene amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(p-tolylamino)-2,5-dihydro-1-(2-hydroxyethyl)-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 20),
2,5-dihydro-1-benzyl-2-phenyl-4-(to fluorophenyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(4-fluorophenylamino)-1-benzyl-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 21),
2,5-dihydro-1-hydroxyethyl-2-is to fluorophenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2-(4-fluorophenyl)-2,5-dihydro-1-(2-hydroxyethyl)-5-oxo-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 22),
2,5-dihydro-1-phenyl-2-is to iodophenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-2-(4-iodophenyl)-5-oxo-1-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 23),
2,5-dihydro-1-hydroxyethyl-2-p-hydroxybenzene-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-1-(2-hydroxyethyl)-2-(4-hydroxyphenyl)-5-oxo-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 24),
2,5-dihydro-1-hydroxyethyl-2-methyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-1-(2-hydroxyethyl)-2-methyl-5-oxo-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 25),
2,5-dihydro-1-cyclohexyl-2-methyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-cyclohexyl-2,5-dihydro-2-methyl-5-oxo-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 26),
2,5-dihydro-1-hydroxyethyl-2-butyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2-butyl-2,5-dihydro-1-(2-hydroxyethyl)-5-oxo-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 27),
2,5-dihydro-1-cyclohexyl-2-phenyl-4-(p-nitrophenyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(4-nitrophenylamino)-1-cyclohexyl-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 28),
2,5-dihydro-1-cyclohexyl-2-phenyl-4-phenylamino-5-oxygen-1H-pyrroles-3-carboxylate methyl ester (methyl1-cyclohexyl-2,5-dihydro-5-oxo-2-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 29) and
2,5-dihydro-1-phenyl-4,4-(dibutylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(dibutylamino)-2,5-dihydro-5-oxo-1-phenyl-1H-pyrrole-3-carboxylate, compound 30).
The synthetic method one of compound (I), its reaction formula is:
Figure G2009100365391D00061
(R wherein 1, R 2, R 3And R 5As described in claim 4, R 4Be hydrogen).
Below in molfraction;
(1) add 1 part of compound (1) and 1 part of compound (2) in 4 parts of organic solvents, 0～60 ℃ was stirred 10 minutes～1 hour down;
(2) add 1～4 part of compound (3) in the reaction solution of step (1), add 0～4 part acid, 20～100 ℃ of temperature of reaction stirred 1～5 hour;
(3) add 1～4 part of compound (4) in the reaction solution of step (2), add 0～4 part acid, 20～100 ℃ of temperature of reaction stirred common method separation and purification such as suitably selective freezing, recrystallization, silica gel chromatography, preparation HPLC 1～5 hour.
Described organic solvent comprises alcohol, benzene, toluene, hexane, halohydrocarbon, ether, N, one or more in dinethylformamide, methyl-sulphoxide, the acetonitrile;
Described acid comprises sulfuric acid, hydrochloric acid, Phenylsulfonic acid or acetic acid.
The reaction formula of synthetic method two is:
Figure G2009100365391D00071
(R wherein 1, R 2, R 3And R 5As described in claim 5, R 4Be C 1-4The straight or branched alkyl, hydroxyl or halogen-substituted alkyl, C 5-6Cycloalkyl, benzyl, phenyl, C 1-3Alkyl, alkoxyl group substituted aryl, halogen substituted aryl, nitro substituted aryl, alkoxy acyl substituted aryl, sulfamyl substituted aryl or heterocyclic radical).
The synthetic method two of compound (I) is:
Below in molfraction;
(1) add 1 part of compound (1) and 1 part of compound (2) in 2 parts of organic solvents, 0～60 ℃ was stirred 10 minutes to 1 hour down;
(2) add 1～4 part of compound (3), 1～4 part of compound (4) in 2 parts of organic solvents, add 0～4 part acid or alkali, 20～100 ℃ of temperature of reaction stirred 10 minutes to 5 hours;
(3) reaction solution with step (1) and (2) mixes, and 20～100 ℃ were stirred common method separation and purification such as suitably selective freezing, recrystallization, silica gel chromatography, preparation HPLC 5～20 hours down.
Described acid comprises hydrochloric acid, Phenylsulfonic acid or acetic acid;
Described alkali comprises triethylamine, salt of wormwood or yellow soda ash;
Described organic solvent comprises alcohol, benzene, toluene, hexane, halohydrocarbon, ether, N, one or more in dinethylformamide, methyl-sulphoxide, the acetonitrile.
The application of acceptable salt in the preparation anti-AIDS drug on described 2-pyrrolidinone derivative or its pharmacology.
Description of drawings
Fig. 1 is the molecular structure single crystal diffraction figure of compound 8,
Fig. 2 is the molecular structure single crystal diffraction figure of compound 17,
Fig. 3 is the HL2/3 cell,
Fig. 4 is HeLa-CD4-LTR-β-gal cell,
Fig. 5 has shown the formation of blue spot for HL2/3 cell and the HeLa-CD4-LTR-β-gal cell that merges,
The positive medicine T-20 of Fig. 6
Fig. 7 is the activity of NB-2 inhibition cytogamy,
Fig. 8 is the activity of part of compounds inhibition cytogamy,
Fig. 9 suppresses the activity (contrasting as positive compound with NB-2) that gp41 six helical bundle structures form for compound 14,
Figure 10 is the activity (with hiv reverse transcriptase inhibitor AZT, promptly Azidothymidine contrasts as negative compound) that compound 14 suppresses the formation of gp41 six helical bundle structures,
Figure 11 is compound 22 and gp41 docking scheme.
Embodiment
Below with reference to embodiment the present invention is done detailed description further, but the scope of protection of present invention is not limited to the scope that embodiment represents.
Embodiment 1
2,5-dihydro-1-benzyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-benzyl-4-(benzylamino)-2,5-dihydro-5-oxo-1H-pyrrole-3-carboxylate, compound 1)
Method one
Step 1:
The diethyl butyn of 1mmol (170mg), the benzylamine of 1mmol (107mg) are joined in the 4mL ethanolic soln successively, stir 20min under the room temperature, obtain the reaction solution of intermediate (5) (2-benzyl aminobutene two diethyl phthalates).
Step 2:
The benzylamine of 1.5mmol (160mg) and 1mmol (60mg) acetate are joined in the above-mentioned reaction solution that contains intermediate (5), and under 20 ℃, reaction 5h obtains containing the reaction solution of intermediate (6) (3-benzyl aminoacyl-3-benzyl aminoacrylic acid ethyl ester).
Step 3:
The acetate of 30% the formalin of 2mmol (200mg) and 60mg is joined in the above-mentioned reaction solution that contains intermediate (6), under 60 ℃, reaction 3h, with the thin chromatoplate separated product of preparation, developping agent is normal hexane+ethyl acetate (10: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 301mg 2,5-dihydro-1-benzyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 1).
Productive rate 86%, yellow dope; IR (KBr): v Max=3447,2986,1773,1691,1635,1452,1324,1290,1137,770,711cm -1 1H NMR (400MHz, CDCl 3): δ=7.38-7.27 (m, 10H), 5.15 (s, 1H), 5.13 (s, 1H), 4.66 (s, 2H), 4.17 (q, J=7.2Hz, 2H), 3.89 (s, 2H), 1.25 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.6,165.4,139.6,136.5,128.8,128.6,128.2,127.8,127.5,127.3,98.3,59.6,47.0,46.7,46.4,14.4ppm.MS (ESI): m/z 351 (M+H +, 42), 305 (100); Anal.Calcd for C 21H 22N 2O 3: C, 71.98; H, 6.33; N, 7.99; Found:C, 71.96; H, 6.43; N, 7.92.
Compound 2-9, one preparation of 30 using method
Embodiment 2
2,5-dihydro-1-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-5-oxo-1-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 2)
Method one
Step 1:
The diethyl butyn of 1mmol (170mg), the aniline of 1mmol (93mg) are joined in the 4mL toluene solution successively, stir 10min under the room temperature, obtain containing the reaction solution of intermediate (5) (2-phenylamino butene dioic acid diethyl ester).
Step 2:
The aniline of 1mmol (93mg) is joined in the above-mentioned reaction solution that contains intermediate (5), and under 100 ℃, reaction 1h obtains containing the reaction solution of intermediate (6) (3-phenylamino acyl group-3-phenylamino ethyl propenoate).
Step 3:
The acetate of 30% the formalin of 1mmol (100mg) and 1mmol (60mg) is joined in the above-mentioned reaction solution that contains intermediate (6), under 100 ℃, reaction 1h, with the thin chromatoplate separated product of preparation, developping agent is normal hexane+ethyl acetate (10: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 290mg 2,5-dihydro-1-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 2).
Productive rate 85%, white solid, fusing point 138-140 ℃; IR (KBr): v Max=3439,2976,1771,1681,1631,1450,1304,1291,1130,780,723cm -1 1H NMR (400MHz, CDCl 3): δ=7.75-7.73 (m, 2H), 7.40-7.15 (m, 8H), 5.09 (s, 2H), 4.41 (s, 2H), 4.23 (q, J=7.2Hz, 2H), 1.29 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=164.6,139.5,138.8,129.1,128.7,127.5,127.4,125.1,119.5,59.9,48.1,46.8,14.5ppm.MS (ESI): m/z 323 (M+H +, 98), 277 (100); Anal.Calcd for C 19H 18N 2O 3: C, 70.79; H, 5.63; N, 8.69; Found:C, 70.96; H, 5.53; N, 8.51.
Embodiment 3
2,5-dihydro-1-p-methylphenyl-4-(to methylbenzene amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(p-tolylamino)-2,5-dihydro-5-oxo-1-p-tolyl-1H-pyrrole-3-carboxylate, compound 3)
Method one
Step 1:
Under 0 ℃,, stir 60min, obtain containing the reaction solution of intermediate (5) (2-is to toluino butene dioic acid diethyl ester) the diethyl butyn of 1mmol (170mg), 1mmol (107mg) monomethylaniline is joined in the 4mL dichloromethane solution successively.
Step 2:
With 1.5mmol (160mg) monomethylaniline is joined in the above-mentioned reaction solution that contains intermediate (5), under 20 ℃, reaction 5h obtains containing the reaction solution of intermediate (6) (3-to amino toluene acyl group-3-to the toluino ethyl propenoate).
Step 3:
The acetate of 30% the formalin of 3mmol (300mg) and 1.5mmol (90mg) is joined in the above-mentioned reaction solution that contains intermediate (6), under 20 ℃, reaction 5h, with the thin chromatoplate separated product of preparation, developping agent is normal hexane+ethyl acetate (10: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 301mg 2,5-dihydro-1-p-methylphenyl-4-(to toluino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 3).
Productive rate 86%, yellow solid, fusing point 131-132 ℃; IR (KBr): v Max=3449,2900,1770,1685,1629,1450,1300,1271,1115,830cm -1 1H NMR (400MHz, CDCl 3): δ=7.96 (s, 1H), 7.64 (d, J=8.4Hz, 2H), 7.16 (d, J=8.4Hz, 2H), 7.09 (d, J=8.4Hz, 2H), 7.01 (d, J=8.4Hz, 2H), 4.47 (s, 2H), 4.18 (q, J=7.2Hz, 2H), 2.32 (s, 3H), 2.31 (S, 3H), 1.20 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=164.6,163.7,143.2,136.3,136.2,134.7,134.3,129.8,129.6,128.9,122.9,119.3,102.4,65.8,60.2,48.3,30.8,20.9,20.8,15.2,14.2ppm.MS (ESI): m/z 351 (M+H +, 100), 305 (76); Anal.Calcd for C 21H 22N 2O 3: C, 71.98; H, 6.33; N, 7.99; Found:C, 71.90; H, 6.45; N, 8.02.
Embodiment 4
2,5-dihydro-1-is to fluorophenyl-4-(to fluoroanilino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(4-fluorophenylamino)-1-(4-fluorophenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3-carboxylate, compound 4)
Method one
Step 1:
The diethyl butyn of 1mmol (170mg), the para-fluoroaniline of 1mmol (111mg) are joined 4mL N successively, in the dinethylformamide solution, 60 ℃ are stirred 10min down, obtain containing the reaction solution of intermediate (5) (2-is to the fluoroanilino diethyl succinate).
Step 2:
The para-fluoroaniline of 4mmol (444mg) is joined in the above-mentioned reaction solution that contains intermediate (5), and under 100 ℃, reaction 1h obtains containing the reaction solution of intermediate (6) (3-to Fluoroaniline acyl group-3-to the fluoroanilino ethyl propenoate).
Step 3:
The acetate of 30% the formalin of 4mmol (400mg) and 4mmol (240mg) is joined in the above-mentioned reaction solution that contains intermediate (6), under 60 ℃, behind the reaction 1h, add saturated sodium-chloride water solution 20mL, extract with methylene dichloride 20mL, triplicate, the dichloromethane solution that merges, again with saturated sodium-chloride water solution 20mL extraction, triplicate, gained dichloromethane solution dried over mgso, underpressure distillation desolventizes, again with the thin chromatoplate purified product of preparation, developping agent is normal hexane+ethyl acetate (10: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 312mg 2,5-dihydro-1-is to fluorophenyl-4-(to fluoroanilino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 4).
Productive rate 87%, white solid, fusing point 172-173 ℃; IR (KBr): v Max=3445,2968,1779,1656,1621,1450,1304,1267,1132,801cm -1 1H NMR (400MHz, CDCl 3): δ=7.72 (s, 1H), 7.71-7.68 (m, 2H), 7.11-6.96 (m, 6H), 4.48 (s, 2H), 4.21 (q, J=7.2Hz, 2H), 1.24 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=164.6,163.6,161.2 (d, J=100Hz, 1C), 158.8 (d, J=104Hz, 1C), 143.2,134.7,134.5,124.9,124.8,121.2,121.1,116.0,115.7,115.2,115.0,102.9,60.4,48.4,14.2ppm.MS (ESI): m/z 359 (M+H +, 81), 313 (100); Anal.Calcd for C 19H 16F 2N 2O 3: C, 63.68; H, 4.50; F, 10.60; N, 7.82; Found:C, 63.75; H, 4.71; N, 7.78, F, 10.71.
Embodiment 5
2,5-dihydro-1-is to bromophenyl-4-(to bromobenzene amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(4-bromophenylamino)-1-(4-bromophenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3-carboxylate, compound 5)
The preparation method is with embodiment 1
Productive rate 89%, white solid; IR (KBr): v Max=3446,2971,1764,1672,1630,1453,1314,1295,1129,815cm -1 1H NMR (400MHz, CDCl 3): δ=8.0 (s, 1H), 7.68-6.98 (m, 8H), 4.48 (s, 2H), 4.22 (q, J=7.2Hz, 2H), 1.24 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=164.4,163.6,142.6,137.7,137.6,132.2,131.1,124.3,120.6,118.0,117.6,104.4,60.6,48.1,14.2ppm; MS (ESI): m/z 481 (M+H +, 30), 435 (100); Anal.Calcd for C 19H 16Br 2N 2O 3: C, 47.53; H, 3.36; Br, 33.28; N, 5.83; Found:C, 47.45; H, 3.42; Br, 33.31; N, 5.79.
Embodiment 6
2,5-dihydro-1-phenyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(benzylamino)-2,5-dihydro-5-oxo-1-phenyl-1H-pyrrole-3-carboxylate, compound 6)
The preparation method is with embodiment 1
Productive rate 90%, white solid, fusing point 130-132 ℃; IR (KBr): v Max=3413,2936,1761,1685,1637,1455,1324,1271,1120,742,715cm -1 1H NMR (400MHz, CDCl 3): δ=7.75-7.73 (m, 2H), 7.40-7.15 (m, 8H), 5.09 (s, 2H), 4.41 (s, 2H), 4.22 (q, J=7.2Hz, 2H), 1.29 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=164.6,139.5,138.8,129.1,128.7,127.5,127.4,125.1,119.5,59.9,48.1,46.8,14.5ppm; MS (ESI): m/z 337 (M+H +, 100), 291 (49); Anal.Calcd for C 20H 20N 2O 3: C, 71.41; H, 5.99; N, 8.33; Found:C, 71.48; H, 5.92; N, 8.29.
Embodiment 7
2,5-dihydro-1-phenyl-4-(third amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-5-oxo-1-phenyl-4-(propylamino)-1H-pyrrole-3-carboxylate, compound 7)
The preparation method is with embodiment 1
Productive rate 93%, white solid, fusing point 78-79 ℃; IR (KBr): v Max=3449,2986,1776,1683,1531,1324,1261,1120,775,713cm -1 1H NMR (400MHz, CDCl 3): δ=7.72 (d, J=8.0Hz, 2H), 7.37-7.33 (m, 2H), 7.13 (t, J=7.2Hz, 1H), 4.36 (s, 2H), 4.22 (q, J=7.2Hz, 2H), 3.79 (q, J=6.8Hz, 2H), 1.62-1.57 (m, 2H), 1.30 (t, J=7.2Hz, 3H), 0.95 (t, J=7.2Hz, 3H) ppm; 13CNMR (100MHz, CDCl 3): δ=164.6,138.8,129.0,124.9,119.4,59.7,48.0,44.6,24.5,14.5,11.1ppm; MS (ESI): m/z 289 (M+H +, 49), 243 (100); Anal.Calcd for C 16H 20N 2O 3: C, 66.65; H, 6.99; N, 9.72; Found:C, 66.59; H, 6.87; N, 9.78.
Embodiment 8
2,5-dihydro-1-phenyl-4-(hexamethylene amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(cyclohexylamino)-2,5-dihydro-5-oxo-1-phenyl-1H-pyrrole-3-carboxylate, compound 8), its molecular structure single crystal diffraction figure sees Fig. 1.
The preparation method is with embodiment 1
Productive rate 96%, white solid, fusing point 107-108 ℃; IR (KBr): v Max=3431,2986,1778,1651,1511,1304,1290,1110,770,722cm -1 1H NMR (400MHz, CDCl 3): δ=8.26-8.24 (m, 2H), 8.01-7.98 (m, 2H), 4.55 (brs, 1H), 4.45 (s, 2H), 4.27 (q, J=7.2Hz, 2H), 2.02-1.98 (m, 2H), and 1.76-1.61 (m, 3H), 1.43-1.36 (m, 2H), 1.32 (t, J=7.2Hz, 3H), 1.22-1.21 (m, 3H) ppm; 13CNMR (100MHz, CDCl 3): δ=165.2,164.4,138.8,129.0,128.8,124.8,119.3,96.3,59.6,50.6,48.0,34.7,25.5,24.6,19.1,14.5ppm; MS (ESI): m/z 329 (M+H +, 100), 283 (23); Anal.Calcd for C 19H 24N 2O 3: C, 69.49; H, 7.37; N, 8.53; Found:C, 69.53; H, 7.41; N, 8.50.
Embodiment 9
2,5-dihydro-1-p-nitrophenyl-4-(hexamethylene amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(cyclohexylamino)-2,5-dihydro-1-(4-nitrophenyl)-5-oxo-1H-pyrrole-3-carboxylate, compound 9)
The preparation method is with embodiment 1
Productive rate 85%, yellow solid, fusing point 149.5-150.5 ℃; IR (KBr): v Max=3444,2932,2854,1705,1640,1632,1508,1333,1276,1109,939cm -1 1H NMR (400MHz, CDCl 3): δ=7.69 (d, J=8.4Hz, 2H), 7.33-7.29 (m, 2H), 7.11-7.07 (m, 1H), 4.56 (brs, 1H), 4.31 (s, 2H), 4.19 (q, J=7.2Hz, 2H), and 1.99-1.95 (m, 2H), 1.72-1.66 (m, 3H), and 1.42-1.32 (m, 2H), 1.27 (t, J=7.2Hz, 3H), 1.21-1.13 (m, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.2,144.3,143.7,125.0,118.3,60.0,50.7,47.8,34.7,25.4,24.6,24.1,14.5ppm; MS (ESI): m/z 374 (M+H +, 100), 328 (23); Anal.Calcd for C 19H 23N 3O 5: C, 61.11; H, 6.21; N, 11.25; Found:C, 61.21; H, 6.28; N, 11.21.
Embodiment 10
2,5-dihydro-1-benzyl-2-phenyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-benzyl-4-(benzylamino)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 10)
Method two
Step 1:
The diethyl butyn of 1mmol (170mg), the benzylamine of 1mmol (107mg) are joined in the 2mL ethanolic soln successively, stir 20min under the room temperature, obtain containing the reaction solution of intermediate (5) (2-benzyl aminobutene two diethyl phthalates).
Step 2:
The benzylamine of 2mmol (214mg), the phenyl aldehyde of 2mmol (212mg) are joined in the 2mL ethanolic soln, stir 10min under the room temperature, must contain the reaction solution of intermediate (7) (imines).
Step 3:
The reaction solution of step 1 and 2 is mixed, under 40 ℃, reaction 10h, with the thin chromatoplate separated product of preparation, developping agent is normal hexane+ethyl acetate (10: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 350mg 2,5-dihydro-1-benzyl-2-phenyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 10).
Productive rate 86%, yellow oil; IR (KBr): v Max=3448,2987,1775,1632,1602,1528,1353,1277,763,721cm -1 1H NMR (400MHz, CDCl 3): δ=7.40-7.09 (m, 15H), 5.18 (brs, 2H), 5.13 (d, J=14.8Hz, 1H), 4.89 (s, 1H), 3.98-3.88 (m, 2H), 3.52 (d, J=14.8Hz, 1H), 1.27 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.4,139.5,137.1,136.7,128.8,128.4,128.2,128.0,127.7,127.6,127.4,60.9,59.4,43.9,18.5,14.0ppm; MS (ESI): m/z427 (M+H +, 100), 381 (30); Anal.Calcd for C 27H 26N 2O 3: C, 76.03; H, 6.14; N, 6.57; Found:C, 76.15; H, 6.18; N, 6.63.
Compound 11-29 adopts method two synthetic
Embodiment 11
2,5-dihydro-1-propyl group-2-phenyl-4-(third amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-5-oxo-2-phenyl-1-propyl-4-(propylamino)-1H-pyrrole-3-carboxylate, compound 11)
Method two
Step 1:
The diethyl butyn of 1mmol (170mg), the propylamine of 1mmol (59mg) are joined in the 2mL toluene solution successively, stir 10min under the room temperature, obtain containing the reaction solution of intermediate (5) 2-benzyl aminobutene two diethyl phthalates.
Step 2:
The propylamine of 4mmol (118mg), the phenyl aldehyde of 2mmol (212mg) are joined in the 2mL toluene solution, stir 10min under the room temperature, must contain the reaction solution of intermediate (7) (imines).
Step 3:
The reaction solution of step 1 and 2 is mixed, under 100 ℃, reaction 5h, with the thin chromatoplate separated product of preparation, developping agent is normal hexane+ethyl acetate (10: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 304mg 2,5-dihydro-1-propyl group-2-phenyl-4-(third amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 11).
Productive rate 92%, yellow oil; IR (KBr): v Max=3439,2947,1725,1652,1602,1528,1453,1353,1237,733,711cm -1 1H NMR (400MHz, CDCl 3): δ=7.29-7.10 (m, 5H), 5.01 (s, 1H), 3.98-3.93 (m, 2H), 3.84 (brs, 2H), and 3.61-3.57 (m, 1H), 2.58-2.55 (m, 1H), 1.64-1.40 (m, 4H), and 1.02-0.94 (m, 6H), 0.81 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=206.7,165.4,137.7,128.3,127.9,127.7,102.7,65.8,61.7,59.2,44.3,41.9,30.8,24.5,21.3,15.2,14.0,11.2,11.1ppm; MS (ESI): m/z 331 (M+H +, 100), 285 (15); Anal.Calcd for C 19H 26N 2O 3: C, 69.06; H, 7.93; N, 8.48; Found:C, 69.26; H, 7.98; N, 8.41.
Embodiment 12
2,5-dihydro-1-methyl-2-phenyl-4-(methylamino-)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-1-methyl-4-(methylamino)-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 12)
Method two
Step 1:
The diethyl butyn of 1mmol (170mg), the methylamine of 1mmol (31mg) are joined in the 2mL dichloromethane solution successively, and 0 ℃ is stirred 1h down, obtains containing the reaction solution of intermediate (5) 2-benzyl aminobutene two diethyl phthalates.
Step 2:
The methylamine of 4mmol (62mg), the phenyl aldehyde of 1mmol (156mg) are joined in the 2mL dichloromethane solution, and the following stirring of room temperature 0.5 hour must contain the reaction solution of intermediate (7) (imines).
Step 3:
The reaction solution of step 1 and 2 is mixed, under 20 ℃, reaction 20h, with the thin chromatoplate separated product of preparation, developping agent is normal hexane+ethyl acetate (10: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 229mg 2,5-dihydro-1-methyl-2-phenyl-4-(methylamino-)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 12).
Productive rate 86%, white solid, fusing point 129-131 ℃; IR (KBr): v Max=3440,2986,1703,1698,1635,1452,1424,1290,1137,1096,1037,920,832cm -1 1H NMR (400MHz, CDCl 3): δ=7.30-7.12 (m, 5H), 4.92 (s, 1H), 3.98-3.94 (m, 2H), 3.38 (s, 3H), 2.72 (s, 3H), 1.00 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.6,137.5,128.3,128.0,127.6,102.7,63.8,59.2,30.1,27.5,14.0ppm; MS (ESI): m/z 275 (M+H +, 100), 229 (40); Anal.Calcd for C 15H 18N 2O 3: C, 65.68; H, 6.61; N, 10.21; Found:C, 65.61; H, 6.65; N, 10.12.
Embodiment 13
2,5-dihydro-1-butyl-2-phenyl-4-(fourth amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-butyl-4-(butylamino)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 13)
Method two
Step 1:
The diethyl butyn of 1mmol (170mg), the n-Butyl Amine 99 of 1mmol (73mg) are joined 2mL N successively, in the dinethylformamide solution, stir 10min under the room temperature, obtain containing the reaction solution of intermediate (5) 2-benzyl aminobutene two diethyl phthalates.
Step 2:
The n-Butyl Amine 99 of 2mmol (146mg), the phenyl aldehyde of 1.5mmol (156mg) are joined 2mL N, in the dinethylformamide solution, stir 10min, must contain the reaction solution of intermediate (7) (imines).
Step 3:
The reaction solution of step 1 and 2 is mixed, under 40 ℃, behind the reaction 10h, add saturated sodium-chloride water solution 20mL, extract with methylene dichloride 20mL, triplicate, the dichloromethane solution of merging is again with saturated sodium-chloride water solution 20mL extraction, triplicate, gained dichloromethane solution dried over mgso, underpressure distillation desolventizes, again with the thin chromatoplate purified product of preparation, developping agent is normal hexane+ethyl acetate (10: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 313mg 2,5-dihydro-1-butyl-2-phenyl-4-(fourth amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 13).
Productive rate 87%, yellow oil; IR (KBr): v Max=3449,2937,1720,1632,1612,1508,1451,1350,1207,782,723cm -1 1H NMR (400MHz, CDCl 3): δ=7.32-7.13 (m, 5H), 5.03 (s, 1H), 4.01-3.95 (m, 2H), 3.90 (brs, 2H), 3.69-3.65 (m, 1H), 2.60-2.59 (m, 1H), 1.61-1.25 (m, 8H), 1.02 (t, J=7.2Hz, 3H), 0.95 (t, J=7.2Hz, 3H), 0.86 (t, J=7.2Hz, 3H) ppm; 13CNMR (100MHz, CDCl 3): δ=165.3,137.7,128.9,128.5,128.3,127.9,127.7,127.3,102.6,61.6,59.2,42.3,40.0,33.4,30.1,20.0,19.8,14.0,13.8,13.6ppm; MS (ESI): m/z359 (M+H +, 100), 313 (35); Anal.Calcd for C 21H 30N 2O 3: C, 70.36; H, 8.44; N, 7.81; Found:C, 70.29; H, 8.51; N, 7.78.
Embodiment 14
2,5-dihydro-1-p-methylphenyl-2-phenyl-4-(to toluino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(p-tolylamino)-2,5-dihydro-5-oxo-2-phenyl-1-p-tolyl-1H-pyrrole-3-carboxyl ate, compound 14)
Method two
Step 1:
The diethyl butyn of 1mmol (170mg), the para-totuidine of 1mmol (107mg) are joined 2mL N successively, in the dinethylformamide solution, stir 10min under the room temperature, obtain containing the reaction solution of intermediate (5) 2-(to toluino) butene dioic acid diethyl ester.
Step 2:
The para-totuidine of 1mmol (321mg), the phenyl aldehyde of 4mmol (424mg), the acetate of 1mmol (60mg) are joined 2mL N, and in the dinethylformamide solution, 60 ℃ are stirred 20min down, must contain the reaction solution of intermediate (7) (imines).
Step 3:
The reaction solution of step 1 and 2 is mixed, under 40 ℃, behind the reaction 10h, add saturated sodium-chloride water solution 20mL, extract with methylene dichloride 20mL, triplicate, the dichloromethane solution of merging is again with saturated sodium-chloride water solution 20mL extraction, triplicate, gained dichloromethane solution dried over mgso, underpressure distillation desolventizes, again with the thin chromatoplate purified product of preparation, developping agent is normal hexane+ethyl acetate (10: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 384mg 2,5-dihydro-1-p-methylphenyl-2-phenyl-4-(to toluino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 14).
Productive rate 92%, white solid, fusing point 150-153 ℃; IR (KBr): v Max=3432,2983,1709,1632,1515,1290,1211,1110,834,823cm -1 1H NMR (400MHz, CDCl 3): δ [ppm]=8.15 (brs, 1H), 7.33-7.16 (m, 7H), 7.11-7.00 (m, 6H), 5.75 (s, 1H), 3.99 (q, J=7.2Hz, 2H), 2.31 (s, 3H), 2.21 (s, 3H), 1.00 (t, J=7.2Hz, 3H); 13C NMR (100MHz, CDCl 3): δ [ppm]=164.5,163.9,142.5,137.1,136.0,135.3,134.4,134.0,129.3,129.0,128.3,127.9,127.7,123.0,122.7,108.7,63.1,60.0,20.9,20.8,13.8; MS (ESI): m/z 427 (M+H +, 80), 381 (100); Anal.Calcd for C 27H 26N 2O 3: C, 76.03; H, 6.14; N, 6.57; Found:C, 75.81; H, 6.10; N, 6.35.
Embodiment 15
2,5-dihydro-1-is to fluorophenyl-2-phenyl-4-(to fluoroanilino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(4-fluorophenylamino)-1-(4-fluorophenyl)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 15)
Method two
Step 1:
The diethyl butyn of 1mmol (170mg), the para-fluoroaniline of 1mmol (111mg) are joined 4mL N successively, in the dinethylformamide solution, 60 ℃ are stirred 10min down, obtain containing the reaction solution of intermediate (5) (2-is to the fluoroanilino diethyl succinate).
Step 2:
The para-fluoroaniline of 2mmol (222mg), the phenyl aldehyde of 1.5mmol (156mg), the triethylamine of 1mmol (101mg) are joined 2mL N, and in the dinethylformamide solution, 100 ℃ are stirred 20min down, must contain the reaction solution of intermediate (7) (imines).
Step 3:
The reaction solution of step 1 and 2 is mixed, under 40 ℃, behind the reaction 10h, add saturated sodium-chloride water solution 20mL, extract with methylene dichloride 20mL, triplicate, the dichloromethane solution of merging is again with saturated sodium-chloride water solution 20mL extraction, triplicate, gained dichloromethane solution dried over mgso, underpressure distillation desolventizes, again with the thin chromatoplate purified product of preparation, developping agent is normal hexane+ethyl acetate (10: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 348mg 2,5-dihydro-1-is to fluorophenyl-2-phenyl-4-(to fluoroanilino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 15)
Productive rate 80%, yellow oil; IR (KBr): v Max=3465,2984,1709,1632,1511,1456,1289,1221,1158,885,833cm -1 1H NMR (400MHz, CDCl3): δ [ppm]=8.20 (brs, 1H), 7.38-7.34 (m, 2H), 7.23-7.13 (m, 7H), 7.02-6.89 (m, 4H), 5.70 (s, 1H), 4.02 (q, J=7.2Hz, 2H), 1.02 (t, J=7.2Hz, 3H); 13C NMR (100MHz, CDCl3): δ [ppm]=164.5,163.8,161.5,161.4,159.0,142.7,136.5,134.4,132.4,128.5,128.3,127.6,125.1,125.0,124.8,124.7,115.8,115.6,115.3,115.1,109.2,63.4,60.2,13.9; MS (ESI): m/z 435 (M+H +, 79), 389 (100); Anal.Calcd for C 25H 20F 2N 2O 3: C, 69.12; H, 4.64; N, 6.45; Found:C, 69.07; H, 4.61; N, 6.37.
Embodiment 16
2,5-dihydro-1-benzyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-benzyl-2,5-dihydro-5-oxo-2-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 16)
The preparation method is with embodiment 10
Productive rate 87%, yellow oil; IR (KBr): v Max=3445,2932,1705,1632,1602,1508,1443,1350,1217,810,754cm -1 1H NMR (400MHz, CDCl 3): δ=8.28 (s, 1H), 7.36-7.13 (m, 15H), 5.14 (d, J=14.8Hz, 1H), 4.96 (s, 1H), 3.98-3.86 (m, 2H), 3.53 (d, J=14.8Hz, 1H), 0.91 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=164.6,143.0,138.6,136.6,136.4,128.8,128.7,128.6,128.5,128.0,127.7,124.6,122.7,109.6,61.2,60.0,58.5,44.0,18.5,13.8ppm; MS (ESI): m/z 413 (M+H +, 100), 367 (35); Anal.Calcd for C 26H 24N 2O 3: C, 75.71; H, 5.86; N, 6.79; Found:C, 75.83; H, 5.89; N, 6.81.
Embodiment 17
2,5-dihydro-1-cyclohexyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-cyclohexyl-2,5-dihydro-5-oxo-2-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 17), its molecular structure single crystal diffraction figure sees Fig. 2.
The preparation method is with embodiment 10
Productive rate 95%, white solid, fusing point 140-142 ℃; IR (KBr): v Max=3446,2987,1731,1681,1612,1508,1433,1313,1267,798,743cm -1 1H NMR (400MHz, CDCl 3): δ=8.09 (s, 1H), 7.33-7.09 (m, 10H), 5.20 (s, 1H), 3.94-3.89 (m, 2H), 3.71-3.65 (m, 1H), 1.76-1.06 (m, 10H), 0.91 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=164.8,164.4,142.7,138.9,138.0,128.3,128.2,128.1,128.0,124.4,122.6,109.7,61.8,59.8,54.3,30.9,30.6,26.0,25.8,25.2,13.8ppm; MS (ESI): m/z 405 (M+H +, 100), 359 (95); Anal.Calcd for C 25H 28N 2O 3: C, 74.23; H, 6.98; N, 6.93; Found:C, 74.28; H, 6.87; N, 6.97.
Embodiment 18
2,5-dihydro-1-normal-butyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-butyl-2,5-dihydro-5-oxo-2-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 18)
The preparation method is with embodiment 10
Productive rate 89%, white solid, fusing point 101-102 ℃; IR (KBr): v Max=3449,2997,1715,1641,1621,1502,1423,1375,1227,803,723cm -1 1H NMR (400MHz, CDCl 3): δ=8.20 (s, 1H), 7.36-7.10 (m, 10H), 5.17 (s, 1H), 3.98-3.93 (m, 2H), 3.73-3.70 (m, 1H), 2.66-2.65 (m, 1H), 1.48-1.43 (m, 2H), 1.28-1.23 (m, 2H), 0.94 (t, J=7.2Hz, 3H), 0.86 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=164.7,164.5,143.0,138.8,136.8,128.6,128.4,128.3,127.8,124.5,122.6,109.2,62.2,59.9,40.3,30.2,20.0,13.8,13.7ppm; MS (ESI): m/z 379 (M+H +, 100), 333 (75); Anal.Calcd for C 23H 26N 2O 3: C, 72.99; H, 6.92; N, 7.40; Found:C, 72.79; H, 6.86; N, 7.35.
Embodiment 19
2,5-dihydro-1-hydroxyethyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-1-(2-hydroxyethyl)-5-oxo-2-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 19)
The preparation method is with embodiment 10
Productive rate 94%, yellow solid, fusing point 117-118 ℃; IR (KBr): v Max=3689,3439,2943,1712,1602,1518,1452,1343,1238,798,745cm -1 1H NMR (400MHz, CDCl 3): δ=8.22 (s, 1H), 7.34-7.08 (m, 10H), 5.28 (s, 1H), 3.93 (q, J=7.2Hz, 2H), 3.69-3.56 (m, 3H), 3.15 (brs, 1H), 2.94-2.88 (m, 1H), 0.92 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.9,164.4,142.7,138.7,136.4,128.6,128.43,128.37,127.8,124.5,122.6,110.1,63.5,60.9,59.95,44.1,13.8ppm; MS (ESI): m/z 367 (M+H +, 100), 321 (35); Anal.Calcdfor C 21H 22N 2O 4: C, 68.84; H, 6.05; N, 7.65; Found:C, 68.76; H, 6.13; N, 7.58.
Embodiment 20
2,5-dihydro-1-hydroxyethyl-2-phenyl-4-(to methylbenzene amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(p-tolylamino)-2,5-dihydro-1-(2-hydroxyethyl)-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 20)
The preparation method is with embodiment 10
Productive rate 92%, lemon yellow solid, fusing point 127-128 ℃; IR (KBr): v Max=3649,3431,2983,1772,1658,1508,1453,1346,1228,815,769cm -1 1H NMR (400MHz, CDCl 3): δ=8.20 (s, 1H), 7.33-7.01 (m, 9H), 5.26 (s, 1H), 3.96-3.90 (m, 2H), 3.67-3.56 (m, 3H), 3.25 (brs, 1H), 2.91-2.88 (m, 1H), 2.30 (s, 3H), 0.92 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.9,164.4,142.7,138.7,136.4,128.6,128.43,128.37,127.8,124.5,122.6,110.1,63.5,60.9,59.95,44.1,13.8ppm; MS (ESI): m/z 381 (M+H +, 100), 335 (53); Anal.Calcd for C 22H 24N 2O 4: C, 69.46; H, 6.36; N, 7.36; Found:C, 69.53; H, 6.41; N, 7.39.
Embodiment 21
2,5-dihydro-1-benzyl-2-phenyl-4-(to fluorophenyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(4-fluorophenylamino)-1-benzyl-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 21)
The preparation method is with embodiment 10
Productive rate 89%, yellow solid, fusing point 174-176 ℃; IR (KBr): v Max=3439,2983,1772,1632,1558,1412,1383,1243,934,765cm -1 1H NMR (400MHz, CDCl 3): δ=7.35-7.01 (m, 10H), 5.19 (d, J=14.8Hz, 1H), 4.88-4.84 (m, 5H), 4.08-4.03 (m, 2H), 3.54 (d, J=14.8Hz, 1H), 1.05 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.2,163.7,157.4,136.3,134.5,128.8,128.5,127.90,127.86,127.5,122.3,113.3,60.0,59.7,44.0,13.8ppm; MS (ESI): m/z 431 (M+H +, 100), 385 (63); Anal.Calcd for C 26H 23FN 2O 3: C, 72.54; H, 5.39; F, 4.41; N, 6.51; Found:C, 72.58; H, 5.43; F, 4.47; N, 6.60.
Embodiment 22
2,5-dihydro-1-hydroxyethyl-2-is to fluorophenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2-(4-fluorophenyl)-2,5-dihydro-1-(2-hydroxyethyl)-5-oxo-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 22)
The preparation method is with embodiment 10
Productive rate 93%, yellow solid, fusing point 134-135 ℃; IR (KBr): v Max=3689,3439,2943,1712,1602,1518,1452,1343,1238,798,745cm -1 1H NMR (400MHz, CDCl 3): δ=8.21 (brs, 1H), 7.28-6.98 (m, 9H), 5.27 (s, 1H), 3.96-3.91 (m, 2H), 3.68-3.57 (m, 3H), 2.91-2.86 (m, 2H), 0.93 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.8,164.3,163.9,161.4,142.7,138.6,132.2,129.6,129.5,128.4,124.6,122.6,115.7,115.5,109.7,62.7,60.9,60.0,43.9,13.8ppm; MS (ESI): m/z 385 (M+H +, 100), 339 (30); Anal.Calcdfor C 21H 21FN 2O 4: C, 65.62; H, 5.51; F, 4.94; N, 7.29; Found:C, 65.69; H, 5.48; F, 4.97; N, 7.35.
Embodiment 23
2,5-dihydro-1-phenyl-2-is to iodophenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-2-(4-iodophenyl)-5-oxo-1-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 23)
The preparation method is with embodiment 10
Productive rate 60%, yellow solid; IR (KBr): v Max=3449,2973,1777,1638,1550,1452,1363,1273,914,745cm -1 1H NMR (400MHz, CDCl 3): δ=8.18 (s, 1H), 7.44-7.16 (m, 14H), 5.79 (s, 1H), 4.00 (q, J=7.2Hz, 2H), 0.99 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=164.3,163.9,163.6,161.1,142.0,138.6,136.3,132.6,129.3,128.7,128.5,125.8,124.7,122.9,122.8,115.6,115.5,115.3,109.4,62.5,60.2,13.8ppm; MS (ESI): m/z 493 (M+H +, 100), 447 (70); Anal.Calcd for C 25H 21IN 2O 3: C, 57.26; H, 4.04; I, 24.20; N, 5.34; Found:C, 57.31; H, 4.12; I, 24.27; N, 5.42.
Embodiment 24
2,5-dihydro-1-hydroxyethyl-2-p-hydroxybenzene-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-1-(2-hydroxyethyl)-2-(4-hydroxyphenyl)-5-oxo-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 24)
The preparation method is with embodiment 10
Productive rate 92%, yellow solid, fusing point 117-119 ℃; IR (KBr): v Max=3618,3430,2988,1762,1635,1568,1442,1380,1273,944,810cm -1 1H NMR (400MHz, CDCl 3): δ=8.27 (s, 1H), 7.36-7.10 (m, 9H), 5.33 (s, 1H), 3.96 (q, J=7.2Hz, 2H), 3.74-3.68 (m, 1H), 3.63-3.57 (m, 2H), 3.22 (brs, 1H), 2.94-2.88 (m, 1H), 0.94 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.9,164.4,142.7,138.8,136.5,128.6,128.4,127.9,124.4,122.5,110.1,63.4,60.8,60.0,43.9,13.8ppm; MS (ESI): m/z 383 (M+H +, 100), 337 (40); Anal.Calcd for C 21H 22N 2O 5: C, 65.96; H, 5.80; N, 7.33; Found:C, 65.91; H, 5.76; N, 7.28.
Embodiment 25
2,5-dihydro-1-hydroxyethyl-2-methyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2,5-dihydro-1-(2-hydroxyethyl)-2-methyl-5-oxo-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 25)
The preparation method is with embodiment 10
Productive rate 98%, orange; IR (KBr): v Max=3615,3430,2981,1752,1642,1551,1432,1373,1283,810,723cm -1 1H NMR (400MHz, CDCl 3): δ=8.12 (s, 1H), 7.26-7.22 (m, 2H), 7.08-7.05 (m, 3H), 4.31 (q, J=6.4Hz, 1H), and 4.17-4.11 (m, 2H), 3.80-3.71 (m, 3H), and 3.33-3.29 (m, 1H), 2.80 (brs, 1H), 1.41 (d, J=6.4Hz, 3H), 1.15 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.4,164.9,142.8,138.8,128.3,124.3,122.5,110.6,61.3,60.1,55.2,43.8,17.9,14.1ppm; MS (ESI): m/z 305 (M+H +, 5), 359 (100); Anal.Calcd for C 16H 20N 2O 4: C, 63.14; H, 6.62; N, 9.20; Found:C, 63.21; H, 6.71; N, 9.32.
Embodiment 26
2,5-dihydro-1-cyclohexyl-2-methyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl1-cyclohexyl-2,5-dihydro-2-methyl-5-oxo-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 26)
The preparation method is with embodiment 10
Productive rate 92%, yellow solid, fusing point 138-139 ℃; IR (KBr): v Max=3413,2973,1779,1630,1550,1418,1363,1273,789,734m -1 1H NMR (400MHz, CDCl 3): δ=7.80 (s, 1H), 7.29-7.25 (m, 2H), 7.10-7.06 (m, 3H), 4.30 (q, J=6.4Hz, 1H), 4.13 (q, J=7.2Hz, 2H), 3.70-3.65 (m, 1H), 1.91-1.31 (m, 13H), 1.14 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=164.8,164.1,142.8,139.1,128.2,124.2,122.4,109.5,59.9,54.2,54.0,31.1,30.4,26.1,25.9,25.4,19.9,14.1ppm; MS (ESI): m/z 343 (M+H +, 30), 297 (100); Anal.Calcdfor C 20H 26N 2O 3: C, 70.15; H, 7.65; N, 8.18; Found:C, 70.21; H, 7.59; N, 8.22.
Embodiment 27
2,5-dihydro-1-hydroxyethyl-2-butyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl2-butyl-2,5-dihydro-1-(2-hydroxyethyl)-5-oxo-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 27)
The preparation method is with embodiment 10
Productive rate 60%, orange; IR (KBr): v Max=3685,3449,2973,1778,1636,1548,1415,1387,1263,760,734cm -1 1H NMR (400MHz, CDCl 3): δ=8.12 (s, 1H), 7.68-7.66 (m, 2H), 7.50-7.48 (m, 3H), 4.45 (t, J=3.2Hz, 1H), 4.17-4.09 (m, 2H), 3.84-3.77 (m, 1H), 3.72-3.69 (m, 2H), 3.21-3.15 (m, 1H), and 2.17-2.08 (m, 1H), 1.86-1.77 (m, 1H), 1.27-1.20 (m, 2H), 1.30 (t, J=7.2Hz, 3H), 0.98-0.88 (m, 2H), 0.83 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=166.0,164.8,143.2,139.0,128.3,124.2,122.3,108.5,61.0,60.1,58.6,43.7,28.2,23.6,22.5,14.1,13.9ppm; MS (ESI): m/z 347 (M+H +, 100), 301 (32); Anal.Calcd for C 19H 26N 2O 4: C, 65.87; H, 7.56; N, 8.09; Found:C, 65.79; H, 7.61; N, 8.02.
Embodiment 28
2,5-dihydro-1-cyclohexyl-2-phenyl-4-(p-nitrophenyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(4-nitrophenylamino)-1-cyclohexyl-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate, compound 28)
Method two
Step 1:
The diethyl butyn of 1mmol (170mg), the p-Nitroaniline of 1mmol (138mg) are joined in the 2mL dichloromethane solution successively, and 60 ℃ are stirred 1h down, obtain containing the reaction solution of intermediate (5) 2-(p-nitrophenyl amino) butene dioic acid diethyl ester.
Step 2:
The hexahydroaniline of 1mmol (99mg), the phenyl aldehyde of 1mmol (106mg) are joined in the 2mL dichloromethane solution, stir 10min, must contain the reaction solution of intermediate (7) (imines).
Step 3:
The reaction solution of step 1 and 2 is mixed, under 40 ℃, reaction 10h, with the thin chromatoplate separated product of preparation, developping agent is normal hexane+ethyl acetate (4: 1), eluent is an ethyl acetate, with vacuum revolve the steaming method remove desolvate 405mg 2,5-dihydro-1-cyclohexyl-2-phenyl-4-(p-nitrophenyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (compound 28).
Productive rate 88%, yellow solid, fusing point 160-161 ℃; IR (KBr): v Max=3443,2932,2854,1705,1632,1517,1458,1340,1263,1110,851,762cm -1 1H NMR (400MHz, CDCl 3): δ=8.48 (s, 1H), 8.18-8.15 (m, 2H), 7.35-7.22 (m, 7H), 5.25 (s, 1H), 4.02-3.96 (m, 2H), 3.68 (t, J=3.2Hz, 1H), 1.78-1.52 (m, 7H), and 1.19-1.12 (m, 3H), 0.98 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=165.2,144.3,143.7,125.0,118.2,60.0,50.7,47.8,34.7,25.4,24.6,24.1,14.5ppm; MS (ESI): m/z 450 (M+H +, 100), 404 (60); Anal.Calcd for C 25H 27N 3O 5: C, 66.80; H, 6.05; N, 9.35; Found:C, 66.83; H, 6.12; N, 9.23.
Embodiment 29
2,5-dihydro-1-cyclohexyl-2-phenyl-4-phenylamino-5-oxygen-1H-pyrroles-3-carboxylate methyl ester (methyl1-cyclohexyl-2,5-dihydro-5-oxo-2-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate, compound 29)
The preparation method is with embodiment 10
Productive rate 92%, white solid, fusing point 175.5-176.5; IR (KBr): v Max=3441,2978,1770,1612,1551,1452,1373,1273,769,734cm -11H NMR (400MHz, CDCl3): δ=8.08 (s, 1H), 7.33-7.09 (m, 10H), 5.19 (s, 1H), 3.69-3.63 (m, 1H), 3.43 (s, 1H), 1.79-1.48 (m, 6H), 1.16-0.94 (m, 4H) ppm; 13C NMR (100MHz, CDCl3): δ=164.8,164.6,142.8,138.8,137.9,128.3,128.2,127.9,124.5,122.8,109.2,61.8,54.3,50.9,30.9,30.6,26.0,25.8,25.2ppm; MS (ESI): m/z 391 (M+H +, 100), 359 (40); Anal.Calcd for C 24H 26N 2O 3: C, 73.82; H, 6.71; N, 7.17; Found:C, 73.69; H, 6.83; N, 7.23.
Embodiment 30
2,5-dihydro-1-phenyl-4,4-(dibutylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester (ethyl4-(dibutylamino)-2,5-dihydro-5-oxo-1-phenyl-1H-pyrrole-3-carboxylate, compound 30)
The preparation method is with embodiment 1
Productive rate 90%, yellow oil; IR (KBr): v Max=3449,2953,1762,1630,1551,1432,1373,1283,825,764cm -1 1H NMR (400MHz, CDCl 3): δ=8.48 (s, 1H), 8.18-8.15 (m, 2H), 7.35-7.22 (m, 7H), 5.25 (s, 1H), 4.02-3.96 (m, 2H), 3.68 (t, J=3.2Hz, 1H), 1.78-1.52 (m, 7H), and 1.19-1.12 (m, 3H), 0.98 (t, J=7.2Hz, 3H) ppm; 13C NMR (100MHz, CDCl 3): δ=166.1,162.8,147.2,139.0,129.0,124.8,119.6,103.7,59.9,51.2,49.0,30.4,20.0,14.6,14.0ppm; MS (ESI): m/z 359 (M+H +, 100), 313 (15); Anal.Calcd for C 21H 30N 2O 3: C, 70.36; H, 8.44; N, 7.81; Found:C, 70.25; H, 8.51; N, 7.90.
Below assess according to the compound of the method for the preferred embodiment of the invention preparation fusion of HIV-1 is suppressed active with the cytogamy experimental technique, (Enzyme-linked immunoadsorbant assay ELISA) inquires into active compound with natural gel electrophoresis analysis methods such as (Native-PAGE) and suppresses the mechanism of action that gp41 six helical bundle core textures form with Enzyme Linked Immunoadsorbent Assay.
Embodiment 31
The cytogamy experimental technique:
Adopting HL2/3 cell (Fig. 3) and HeLa-CD4-LTR-β-gal cell (Fig. 4) to educate altogether, is that the detection by quantitative HIV inductive cytogamy of index suppresses active non-infectious method with the betagalactosidase activity.The HL2/3 cell can be expressed HIV Gag by stability and high efficiency, Env, and Tat, Rev and Nef albumen, but do not express hiv reverse transcriptase, can not detect sophisticated virion.The acceptor CD4 of HeLa-CD4-LTR-β-gal cell energy stably express HIV and the beta-galactosidase enzymes that HIV LTR starts.As HL2/3 cell and HeLa-CD4-LTR-β-when the gal cell is educated altogether, the cytolemma of the two merges under the mediation of HIV gp120/gp41, the Tat of HL2/3 cell expressing is discharged in HeLa-CD4-LTR-β-gal cell, can combine with LTR, starts the expression of beta-galactosidase enzymes.By detecting the activity of beta-galactosidase enzymes in the cell, can judge HIV envelope protein inductive film fusion.This method can be used for detection compound and suppress the activity that HIV envelope protein inductive film merges, and shows that this active compound can suppress HIV and enter target cell, as Fig. 5.
HL2/3 cell (2 * 10 5/ hole) the high-caliber expression Gag of energy, Env, Tat, Rev, albumen such as Nef.During experiment the HL2/3 cell earlier with sample compound in 96 orifice plates 37 ℃ hatch 30 minutes, and then add Hela-CD4-LTR/ β-gal cell (2 * 10 5/ hole) mix, hatched altogether 48 hours in 37 ℃, do β-gal dyeing then, inverted microscope is the blue spot number of counting down.Compound inhibiting rate (%)=[1-(E-N)/(P-N)] * 100, wherein ' E ' represented the number of cytogamy in the experimental group, ' P ' represents the positive number that does not just add cytogamy in the medicine group, and ' N ' represents the number of cytogamy in the negative control group.Half-inhibition concentration (the IC of compound 50) as the index of compound antiviral activity, draw by the Calcusyn computed in software, as Fig. 6, Fig. 7.
The activity experiment of compound 2,6,10,14,19,21 shows that each compound all has the effect of certain inhibition HIV-1 envelope protein inductive cytogamy.Except that compound 19,21, the half-inhibition concentration (IC of other compound 50) less than 25 μ g/ml.
Embodiment 32
Enzyme linked immunosorbent assay analysis method (Enzyme-linked immunoadsorbant assay, ELISA):
In the course of infection of HIV, at first be that the cytolemma of HIV coated film and target cell merges.HIV and target cell are merged mainly by wrapping by glycoprotein gp120 and striding film subunit gp41 mediation.CD4 molecule on gp120 and the target cell and accessory receptor (chemokine receptor CCR 5 or CXCR4 etc.) successively combine, cause the configuration of gp41 to change, form six helical bundle core textures, peplos and target cell membrane are furthered and merge, finish the course of infection that virus enters host cell.Therefore, suppress any one link in the fusion process, just can suppress HIV and enter target cell, thus the infection of prevention and treatment HIV.
N36 and C34 are the polypeptide of deriving out from the NHR of HIV gp41 and CHR district, and the two can form similar NHR and CHR bonded six helical bundle structures external.Therefore, the activity of anti-gp41 subunit core texture can be used for measuring with suppressing N36 and C34 bonded.
The first step of Enzyme Linked Immunoadsorbent Assay (ELISA) method is that the monoclonal antibody NC-1 with specific recognition gp41 six helical bundle structures is coated on the 96 hole enzyme plates; Second step was that N36 is mixed with treating SCREENED COMPOUND, added C34 again, they was joined in the enzyme plate that has sealed then; At last, add the polyclonal antibody IgG of the anti-N36/C34 mixture of rabbit respectively, the goat anti-rabbit igg of horseradish peroxidase-labeled and chromogenic substrate detect absorbance, judge anti-N36 of compound and C34 bonded activity.Active the reaching of the inhibition of compound partly imitated inhibition concentration (IC 50) adopt the CalcuSyn software analysis, as Fig. 9.
Embodiment 33
Natural gel electrophoresis (Native-PAGE)
We have set up the method for an easy biophysics, i.e. natural polypropylene acyl ammonia gel electrophoresis (Peptides.2003; 24:1303-1313), confirm whether bioactive molecule suppresses the gp41 core texture and form.This method does not adopt antibody, adopts " false positive " compound that occurs in the immunosorption method screening process above can getting rid of.
As Figure 10, adopt 18% polyacrylamide gel, the mixture of N36 and C34 is carried out natural gel electrophoresis, then gel is carried out coomassie brilliant blue staining, and take a picture.N36 does not show band owing to positively charged in electrophoresis, C34 then shows a polypeptide band in the gel bottom, and the mixture of N36 and C34 the band of one six aggressiveness also occurs up except that the C34 band of a strength reduction is arranged at the bottom.Form if compound can suppress the gp41 core texture, then this six aggressiveness band intensity weakens or disappears, and the C34 band intensity of bottom increases.
Embodiment 34
As Figure 11 (action diagram of compound 22 and gp41), use SYBYL8.0 medicinal design software and adopt molecular docking technology (docking), calculate the action intensity of compound and gp41.Action intensity is weighed with scoring, and the high more expression bonding force of giving a mark is strong more, and marking all has combination preferably at expression compound more than 3 minutes with target spot.The scoring of some compounds is than NB64 higher (appraisal result sees Table 1).
Method is as follows:
The first step is prepared albumen, downloads PDB:1AIK, opens SYBYL8.0, File, and open selects 1AIK, clicks Prepare structure, and structure preparation Tool clicks analyze selected structure, carries out the albumen reparation.
Second step, molecular docking.
Open SYBYL software, click Application, Docking suite, Dock ligand;
In the DOCKING dialog box of opening, Docking mode selects surflex dock, selects the PDB:1AIK that will carry out molecular docking in file name the inside.Then eject dialog box, click generate, OK returns the Docking dialog box;
The small molecules SLN file that selection will be docked inside the empty frame on the SLN right side;
Hit OK carries out molecular docking, as compound 22 and gp41 docking scheme (Figure 11);
The intact dialog box that ejects of molecular docking can show each micromolecular marking, and＞3 is meaningful.
The action intensity of some compounds of table 1 and gp41
Figure G2009100365391D00241

Claims (5)

1. acceptable salt on 2-pyrrolidinone derivative or its pharmacology is characterized in that described derivative is:
2,5-dihydro-1-benzyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester,
2,5-dihydro-1-phenyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester,
2,5-dihydro-1-phenyl-4-(third amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester.
2. the synthetic method of the described 2-pyrrolidinone derivative of claim 1 is characterized in that, may further comprise the steps:
Below in molfraction;
(1) add 1 part of compound (1) and 1 part of compound (2) in 4 parts of organic solvents, 0～60 ℃ was stirred 10 minutes～1 hour down;
(2) add 1～4 part of compound (3) in the reaction solution of step (1), add 0～4 part acid, 20～100 ℃ of temperature of reaction stirred 1～5 hour;
(3) add 1～4 part of compound (4) in the reaction solution of step (2), add 0～4 part acid, 20～100 ℃ of temperature of reaction stirred 1～5 hour, used the ordinary method separation and purification;
Described compound (1) is
Figure FSB00000481510900011
Described compound (2) is
R 1R 2NH (2)
Described compound (3) is
R 3NH 2 (3)
Described compound (4) is
R 4CHO (4)
Wherein, R 1, R 2, R 3And R 5Be following three kinds of situations:
(1) R 1Be hydrogen; R 2Be benzyl; R 3Be benzyl; R 4Be hydrogen; R 5Be ethyl;
(2) R 1Be hydrogen; R 2Be benzyl; R 3Be phenyl; R 4Be hydrogen; R 5Be ethyl;
(3) R 1Be hydrogen; R 2Be propyl group; R 3Be phenyl; R 4Be hydrogen; R 5Be ethyl;
Described organic solvent is selected from alcohol, benzene, toluene, hexane, halohydrocarbon, ether, N, one or more in dinethylformamide, methyl-sulphoxide or the acetonitrile;
Described acid is selected from sulfuric acid, hydrochloric acid, Phenylsulfonic acid or acetic acid.
3. acceptable salt on 2-pyrrolidinone derivative or its pharmacology is characterized in that described derivative is:
2,5-dihydro-1-benzyl-2-phenyl-4-(benzyl amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester,
2,5-dihydro-1-propyl group-2-phenyl-4-(third amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester,
2,5-dihydro-1-butyl-2-phenyl-4-(fourth amino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester,
2,5-dihydro-1-benzyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester,
2,5-dihydro-1-normal-butyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester,
2,5-dihydro-1-hydroxyethyl-2-phenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester,
2,5-dihydro-1-hydroxyethyl-2-is to fluorophenyl-4-(phenylamino)-5-oxygen-1H-pyrroles-3-carboxylic acid, ethyl ester.
4. the synthetic method of the described 2-pyrrolidinone derivative of claim 3 is characterized in that, may further comprise the steps: following in molfraction;
(1) add 1 part of compound (1) and 1 part of compound (2) in 2 parts of organic solvents, 0～60 ℃ was stirred 10 minutes to 1 hour down;
(2) add 1～4 part of compound (3), 1～4 part of compound (4) in 2 parts of organic solvents, add 0～4 part acid or alkali, 20～100 ℃ of temperature of reaction stirred 10 minutes to 5 hours;
(3) reaction solution with step (1) and (2) mixes, and 20～100 ℃ were stirred 5～20 hours down, use the ordinary method separation and purification;
Described compound (1) is
Figure FSB00000481510900021
Described compound (2) is
R 1R 2NH (2)
Described compound (3) is
R 3NH 2 (3)
Described compound (4) is
R 4CHO (4)
R 4Phenyl for phenyl or halogen replacement; Wherein, R 1, R 2, R 3And R 5Be following seven kinds of situations:
(1) R 1Be hydrogen; R 2Be benzyl; R 3Be benzyl; R 4Be phenyl; R 5Be ethyl;
(2) R 1Be hydrogen; R 2Be propyl group; R 3Be propyl group; R 4Be phenyl; R 5Be ethyl;
(3) R 1Be hydrogen; R 2Be butyl; R 3Be butyl; R 4Be phenyl; R 5Be ethyl;
(4) R 1Be hydrogen; R 2Be phenyl; R 3Be benzyl; R 4Be phenyl; R 5Be ethyl;
(5) R 1Be hydrogen; R 2Be phenyl; R 3Be normal-butyl; R 4Be phenyl; R 5Be ethyl;
(6) R 1Be hydrogen; R 2Be phenyl; R 3Be hydroxyethyl; R 4Be phenyl; R 5Be ethyl;
(7) R 1Be hydrogen; R 2Be phenyl; R 3Be hydroxyethyl; R 4For to fluorophenyl; R 5Be ethyl;
Described organic solvent is selected from alcohol, benzene, toluene, hexane, halohydrocarbon, ether, N, one or more in dinethylformamide, methyl-sulphoxide or the acetonitrile.
5. the application of acceptable salt in the preparation anti-AIDS drug on a claim 1 or 3 described 2-pyrrolidinone derivatives or its pharmacology.
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