CN106496118A - A kind of quinolines ketones with Enamino-esters compound and preparation method thereof - Google Patents

A kind of quinolines ketones with Enamino-esters compound and preparation method thereof Download PDF

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CN106496118A
CN106496118A CN201610877398.6A CN201610877398A CN106496118A CN 106496118 A CN106496118 A CN 106496118A CN 201610877398 A CN201610877398 A CN 201610877398A CN 106496118 A CN106496118 A CN 106496118A
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amino
dihydroquinoline
diketone
dimethyl
phenyl
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CN106496118B (en
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陈雪冰
汪学全
刘卫
洪涌
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Honghe University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

A kind of quinolines ketones with Enamino-esters compound and preparation method thereof, the structural formula of quinolines ketones with Enamino-esters compound is formula (1)：R1For substituted-phenyl, heterocyclic radical or benzyl；R2For methyl or hydrogen.The quinoline derivatives of the present invention have potential good biological activity, and because can build the fused heterocyclic compound of molecular diversity containing enamine fragment as organic synthesis intermediate.The raw material of preparation method is simple and easy to get, and reaction condition is gentle, and post processing is simple, and purity is high, and easy to operate, prospects for commercial application is preferable.

Description

A kind of quinolines ketones with Enamino-esters compound and preparation method thereof
Technical field
The invention belongs to organic chemistry filed, and in particular to a kind of quinolines ketones with Enamino-esters compound and preparation method thereof.
Background technology
Quinoline (ketone) compound (I) is one of most important heterocyclic compound, acts not only as synthetic intermediate structure Molecular diversity nitrogen heterocyclic, and extensive biological activity is shown, its activity mainly includes：Antibacterial, antitumor, anti- Virus, AntiHIV1 RT activity, as tubulin enzyme inhibitor etc..Quinolinone precursor structure in natural product and chemical synthetic drug all Very common, especially antibacterials.Since first quinolinones antibacterials nalidixan emerges within 1962, mankind's conjunction has been opened The new situation into antibacterials.40 for many years, the incredible amount of the similar compound that has developed, and listing and clinical practice are just There are tens kinds, wherein most representational including norfloxacin, ciprofloxacin etc., its structural formula is as follows：
Ketones with Enamino-esters is the important organic synthesis intermediate of a class, because which contains the azepine alkene structure of uniqueness, which is tied Comprising two nucleophilic centers (α-C and-NH) in structure, can occur through azepine alkene course with the substrate that other contain electrophilic center anti- Should, and then there is cyclization with amino nitrogen and obtain fused heterocyclic compound.The ketones with Enamino-esters that research finds both at home and abroad at present mostly is structure Single β-ketones with Enamino-esters, which limits its application in synthesis fused heterocyclic compound.And according to the activity in pharmaceutical chemistry Principle of stacking, when compound contains more activity factors, its active probability is bigger.Therefore, design synthesizes this Ketones with Enamino-esters compound of one class of sample containing quinoline parent nucleus, will help chemist to find more reactions based on enamine, further may be used So that the compound being synthesized to be used in new drug development.β-ketones with Enamino-esters is as follows with quinolines ketones with Enamino-esters construction featuress：
Quinolines ketones with Enamino-esters itself has potential biological activity, and which can be used as the novel ketones with Enamino-esters quilt of a class formation Structure molecular diversity fused heterocyclic compound in organic synthesiss is widely used in, the efficient preparation side of such compound is further developed Method, it will for we have found that new drug provides facility.
Content of the invention
It is an object of the invention to provide a kind of quinolines ketones with Enamino-esters compound, has for synthetic molecules multiformity latent Fused heterocyclic compound in biological activity.The present invention also provides the preparation method of the quinolines ketones with Enamino-esters compound.
The purpose of the present invention is achieved through the following technical solutions：
A kind of quinolines ketones with Enamino-esters compound, its structural formula are formula (1)：
In formula (1), R1For substituted-phenyl, heterocyclic radical or benzyl；R2For methyl or hydrogen.
Substituted-phenyl of the present invention be o-, m- single or double substituted halogen to three sites, nitro, hydrogen, alkyl, Alkoxyl, alkyl or alkoxyl are C1─C2；The heterocyclic radical is unsubstituted furyl, thienyl and indyl.
Used as the further improvement of the quinolines ketones with Enamino-esters compound of the present invention, quinolines ketones with Enamino-esters compound is following Meaning one：1) -4,5 (1H, 6H)-diketone of 2- amino -1- (nitrobenzophenone) -7,8- dihydroquinoline
2) -4,5 (1H, 6H)-diketone of 2- amino -1- (4- fluoro-phenyls) -7,8- dihydroquinoline
3) 2- amino -1- (the chloro- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
4) 2- amino -1- (the bromo- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
5) -4,5 (1H, 6H)-diketone of 2- amino -1- phenyl -7,8- dihydroquinoline
6) -4,5 (1H, 6H)-diketone of 2- amino -1- (p-methylphenyl) -7,8- dihydroquinoline
7) -4,5 (1H, 6H)-diketone of 2- amino -1- (4- anisyls) -7,8- dihydroquinoline
8) -4,5 (1H, 6H)-diketone of 2- amino -1- (2- fluoro-phenyls) -7,8- dihydroquinoline
9) -4,5 (1H, 6H)-diketone of 2- amino -1- (3- fluoro-phenyls) -7,8- dihydroquinoline
10) 2- amino -1- (the chloro- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
11) 2- amino -1- (the bromo- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
12) -4,5 (1H, 6H)-diketone of 2- amino -1- (tolyl) -7,8- dihydroquinoline
13) 2- amino -1- (the chloro- 5- aminomethyl phenyls of 2-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
14) 2- amino -1- (furan -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
15) 2- amino -1- (thiophene -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
16) -4,5 (1H, 6H)-diketone of 2- amino -1- (1H- indol-3-yls) -7,8- dihydroquinoline
17) -4,5 (1H, 6H)-diketone of 2- amino -1- benzyl -7,8- dihydroquinoline
18) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (nitrobenzophenone) -7,8- dihydroquinoline
19) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (4- fluoro-phenyls) -7,8- dihydroquinoline
20) 2- amino -7,7- dimethyl -1- (the chloro- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
21) 2- amino -7,7- dimethyl -1- (the bromo- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
22) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- phenyl -7,8- dihydroquinoline
23) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (p-methylphenyl) -7,8- dihydroquinoline
24) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (4- anisyls) -7,8- dihydroquinoline
25) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (2- fluoro-phenyls) -7,8- dihydroquinoline
26) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (3- fluoro-phenyls) -7,8- dihydroquinoline
27) 2- amino -7,7- dimethyl -1- (the chloro- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
28) 2- amino -7,7- dimethyl -1- (the bromo- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
29) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (tolyl) -7,8- dihydroquinoline
30) 2- amino -7,7- dimethyl -1- (the chloro- 5- aminomethyl phenyls of 2-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
31) 2- amino -7,7- dimethyl -1- (furan -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
32) 2- amino -7,7- dimethyl -1- (thiophene -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
33) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (1H- indol-3-yls) -7,8- dihydroquinoline
34) 2- amino -7,7- dimethyl -1- benzyl -7,8- dihydroquinoline -4,5 (1H, 6H)；- diketone
The present invention additionally provides the preparation method of above-mentioned quinolines ketones with Enamino-esters compound simultaneously, and its reaction equation is as follows：
Preparation method is comprised the following steps：
1) under reflux conditions, take compound 1 and cyanoacetic acid is dissolved in acetic anhydride, after the completion of reaction, add saturated carbon Sour hydrogen sodium solution neutralization reaction liquid；Reactant liquor is extracted with ethyl acetate, concentration organic faciess are dried, silica gel column chromatography obtains compound 2；
2) compound 2 is taken, is dissolved with ethanol；Piperidines is added, room temperature reaction is complete；There is white crude (I) to separate out, take out Filter, washing, is recrystallized to give sterling quinolines ketones with Enamino-esters compound.
The inventive method achieves the synthesis of the novel ketones with Enamino-esters of a class skeleton, is expanded based on the organic of ketones with Enamino-esters significantly Reaction.Reaction characteristicses include：Raw material is simple and easy to get, and reaction yield is high, easy to operate, the features such as post processing is simple, with certain Prospects for commercial application.
Specific embodiment
Further illustrate how the present invention realizes below by way of specific embodiment.
The structure of quinolines ketones with Enamino-esters compound of the present invention is formula (1)：
In formula (1), R1For substituted-phenyl, heterocyclic radical or benzyl；R2For methyl or hydrogen.The substituted-phenyl for o-, m-, To the single or double substituted halogen in three sites, nitro, hydrogen, alkyl, alkoxyl, alkyl or alkoxyl are C1─C2；The heterocycle Base is unsubstituted furyl, thienyl and indyl.
Quinolines ketones with Enamino-esters compound of the present invention be specially following any one：
1) -4,5 (1H, 6H)-diketone of 2- amino -1- (nitrobenzophenone) -7,8- dihydroquinoline
2) -4,5 (1H, 6H)-diketone of 2- amino -1- (4- fluoro-phenyls) -7,8- dihydroquinoline
3) 2- amino -1- (the chloro- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
4) 2- amino -1- (the bromo- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
5) -4,5 (1H, 6H)-diketone of 2- amino -1- phenyl -7,8- dihydroquinoline
6) -4,5 (1H, 6H)-diketone of 2- amino -1- (p-methylphenyl) -7,8- dihydroquinoline
7) -4,5 (1H, 6H)-diketone of 2- amino -1- (4- anisyls) -7,8- dihydroquinoline
8) -4,5 (1H, 6H)-diketone of 2- amino -1- (2- fluoro-phenyls) -7,8- dihydroquinoline
9) -4,5 (1H, 6H)-diketone of 2- amino -1- (3- fluoro-phenyls) -7,8- dihydroquinoline
10) 2- amino -1- (the chloro- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
11) 2- amino -1- (the bromo- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
12) -4,5 (1H, 6H)-diketone of 2- amino -1- (tolyl) -7,8- dihydroquinoline
13) 2- amino -1- (the chloro- 5- aminomethyl phenyls of 2-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
14) 2- amino -1- (furan -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
15) 2- amino -1- (thiophene -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
16) -4,5 (1H, 6H)-diketone of 2- amino -1- (1H- indol-3-yls) -7,8- dihydroquinoline
17) -4,5 (1H, 6H)-diketone of 2- amino -1- benzyl -7,8- dihydroquinoline
18) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (nitrobenzophenone) -7,8- dihydroquinoline
19) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (4- fluoro-phenyls) -7,8- dihydroquinoline
20) 2- amino -7,7- dimethyl -1- (the chloro- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
21) 2- amino -7,7- dimethyl -1- (the bromo- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
22) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- phenyl -7,8- dihydroquinoline
23) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (p-methylphenyl) -7,8- dihydroquinoline
24) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (4- anisyls) -7,8- dihydroquinoline
25) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (2- fluoro-phenyls) -7,8- dihydroquinoline
26) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (3- fluoro-phenyls) -7,8- dihydroquinoline
27) 2- amino -7,7- dimethyl -1- (the chloro- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
28) 2- amino -7,7- dimethyl -1- (the bromo- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
29) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (tolyl) -7,8- dihydroquinoline
30) 2- amino -7,7- dimethyl -1- (the chloro- 5- aminomethyl phenyls of 2-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
31) 2- amino -7,7- dimethyl -1- (furan -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
32) 2- amino -7,7- dimethyl -1- (thiophene -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
33) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (1H- indol-3-yls) -7,8- dihydroquinoline
34) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- benzyl -7,8- dihydroquinoline
The reaction equation of the preparation method of the above quinolines ketones with Enamino-esters compound is as follows：
Preparation method is comprised the following steps：
1) under reflux conditions, take compound 1 (β-ketones with Enamino-esters) and cyanoacetic acid is dissolved in acetic anhydride, back flow reaction 30～ 60 minutes, after the completion of thin layer chromatography monitoring reaction, add saturated sodium bicarbonate solution neutralization reaction liquid；It is extracted with ethyl acetate anti- Answer liquid, saturated common salt washing organic faciess twice, dry concentration organic faciess, silica gel column chromatography obtain compound 2 (α of β-ketones with Enamino-esters- The acylated product of carbon)；The mol ratio of cyanoacetic acid and β-ketones with Enamino-esters is 1:1；
2) compound 2 is taken, is dissolved with ethanol；Piperidines is added, completely, intermediate molecule inner ring condensation, warp to room temperature reaction occurs Imine-enamine change, it is not necessary to further separate and directly obtain white crude i.e. quinolines ketones with Enamino-esters compound (I), sucking filtration, Washing, is recrystallized to give sterling quinolines ketones with Enamino-esters compound.
The synthesis of -4,5 (1H, 6H)-diketone of 1 2- amino -1- (4- fluoro-phenyls) -7,8- dihydroquinoline of embodiment：
1) by 3- ((4- fluorophenyls) amino) cyclohexyl -2- ketenes 0.205g (1.0mmol) and cyanoacetic acid 0.850g (1.0mmol) add in reaction bulb, under stirring, be dividedly in some parts 5mL acetic anhydrides, heating reflux reaction 1 hour, reaction is finished, and uses carbon By reactant liquor modulation alkalescence, ethyl acetate extraction, organic faciess are dried sour hydrogen sodium saturated solution, concentrating under reduced pressure, and concentrate is through post Chromatography (petroleum ether：Ethyl acetate=2:1), yellow intermediate 3- ((4- fluorophenyls) amino) -6- oxocyclohex thiazolinyl -3- are obtained Formyl acetonitrile 0.190g, yield 70%；
2) 3- ((4- fluorophenyls) amino) -6- oxocyclohex thiazolinyl -3- formyls acetonitrile 0.190g (0.7mmol) is taken, second is used Alcohol dissolves；Then two are instilled and drips piperidines, after 2 hours, reaction completely, has white solid to separate out, filters, obtain white room temperature reaction Solid 2- amino -1- (4- fluoro-phenyls) -7,8- dihydroquinoline -4,5 (1H, 6H)-diketone 0.171g, yield 90%；1H NMR (400MHz,DMSO-d6+HClO4):δ=7.57 7.63 (m, 1H, ArH), 7.37 7.40 (m, 1H, ArH), 7.27 7.32 (m, 1H,ArH),7.53–7.57(m,1H,ArH),6.26(s,1H,CH),2.54–2.61(m,2H,CH2),2.40–2.45(m,2H, CH2),1.93–1.98(m,2H,CH2)；13C NMR(100MHz,DMSO-d6+HClO4):δ=203.3,168.7,163.5 (d,1JC─F=246.9Hz), 165.0,162.9,158.0,130.7,130.6,119.0 (d,2JC─F=23.1Hz), 118.7 (d,2JC─F=23.1Hz), 109.4,93.7,36.2,29.0,20.1；HRMS(ESI-TOF):m/z calcd for C15H14FN2O2 [(M+H)+],273.2817；found,273.2815.
The synthesis of 2 2- amino -1- phenyl -7,8- dihydroquinoline -4,5- (1H, 6H) of embodiment-diketone：
3- ((4- fluorophenyls) amino) cyclohexyl -2- ketenes is replaced with 3- (phenylamino) cyclohexyl -2- ketenes, remaining is with real Apply example 1 (proportioning is according to mol ratio between raw material), yield：91%；1H NMR(400MHz,DMSO-d6+HClO4):δ=7.78 7.84(m,3H,ArH),7.52–7.56(m,2H,ArH),6.30(s,1H,CH),2.58–2.62(m,2H,CH2),2.40– 2.44(m,2H,CH2),1.94–1.98(m,2H,CH2)；13C NMR(100MHz,DMSO-d6+HClO4):δ=203.3, 168.7,162.7,157.8,134.6,132.0,131.8,128.0,109.3,93.7,36.3,29.0,20.2；HRMS(ESI- TOF):m/z calcd forC15H15N2O2[(M+H)+],255.2913；found,255.2918.
The synthesis of -4,5 (1H, 6H)-diketone of 3 2- amino -1- (p-methylphenyl) -7,8- dihydroquinoline of embodiment：
3- ((4- fluorophenyls) amino) hexamethylene -2- ketenes is replaced with 3- (p-totuidine base) cyclohexyl -2- ketenes, remaining is same Embodiment 1 (proportioning is according to mol ratio between raw material), yield：90%；1H NMR(400MHz,DMSO-d6+HClO4):δ=8.49 (d, J=8.0Hz, 2H, ArH), 8.37 (d, J=8.0Hz, 2H, ArH), 7.23 (s, 1H, CH), 3.54 3.58 (m, 2H, CH2),3.37–3.41(m,5H,CH2+CH3),2.90–2.94(m,2H,CH2)；13C NMR(100MHz,DMSO-d6+HClO4):δ =203.4,168.7,162.9,157.9,141.8,132.5,127.7,109.3,93.7,36. 2,28.9,21.3,20.1； HRMS(ESI-TOF):m/zcalcd for C16H17N2O2[(M+H)+],269.3178；found,269.3178.
- 4,5 (1H, 6H)-diketone of 4 2- amino -7,7- dimethyl -1- (4- fluoro-phenyls) -7,8- dihydroquinoline of embodiment Synthesis：With 3- (p-fluorophenyl) amino) -5,5- Dimethylcyclohexyl -2- ketenes replacement 3- ((4- fluorophenyls) amino) hexamethylene Base -2- ketenes, remaining is with embodiment 1 (proportioning is according to mol ratio between raw material), yield：90%；1H NMR(400MHz,DMSO- d6+HClO4):δ=7.60 7.64 (m, 2H, ArH), 7.53 7.57 (m, 2H, ArH), 6.30 (s, 1H, CH), 5.11 (br, 2H, NH2),2.53(s,2H,CH2),2.37(s,2H,CH2),0.94(s,6H,2×CH3)；13C NMR(100MHz,DMSO-d6+ HClO4):δ=202.7,168.3,163.8 (d,1JC─F=247.1Hz), 160.7,158.4,130.7,130.6 (d,3JC─F= 4.8Hz),119.1(d,2JC─F=23.3Hz), 118.9 (d,2JC─F=23.3Hz), 108.6,94.0,49.5,41.8,32.7, 27.8；HRMS(ESI-TOF):m/zcalcd for C17H18FN2O2[(M+H)+],301.3349；found,301.3347.
5 2- amino -7,7- dimethyl -1- (the chloro- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline of embodiment Synthesis：
With 3- (rubigan) amino) -5,5- Dimethylcyclohexyl -2- ketenes replacement 3- ((4- fluorophenyls) amino) hexamethylene Base -2- ketenes, remaining is with embodiment 1 (proportioning is according to mol ratio between raw material), yield：93%；1H NMR(400MHz,DMSO- d6+HClO4):δ=7.57 (d, J=8.0Hz, 2H, ArH), 7.36 (d, J=8.4Hz, 2H, ArH), 6.05 (s, 1H, CH), 5.91(br,2H,NH2),2.25–2.31(m,3H,CH2),2.11–2.14(m,1H,CH2),0.70(s,6H,2×CH3)；13C NMR(100MHz,DMSO-d6+HClO4):δ=202.4,168.3,160.5,158.3,136.8,133.4,132.1,130.2, 108.6,94.0,49.6,41.8,32.7,27.7；HRMS(ESI-TOF):m/z calcd for C17H18ClN2O2[(M+H )+],317.7895；found,317.7885.
- 4,5 (1H, 6H)-diketone of 6 2- amino -7,7- dimethyl -1- (p-methylphenyl) -7,8- dihydroquinoline of embodiment Synthesis：
3- ((4- fluorophenyls) amino) hexamethylene is replaced with 5,5- dimethyl -3- (p-totuidine base)-cyclohexyl -2- ketenes Base -2- ketenes, remaining is with embodiment 1 (proportioning is according to mol ratio between raw material), yield：93%；1H NMR(400MHz,DMSO- d6):δ=7.57 (d, J=8.0Hz, 2H, ArH), 7.36 (d, J=8.4Hz, 2H, ArH), 6.05 (s, 1H, CH), 5.91 (br, 2H,NH2),2.25–2.31(m,3H,CH2),2.11–2.14(m,1H,CH2),0.70(s,6H,2×CH3)；13C NMR (100MHz,DMSO-d6):δ=194.3,174.6,156.4,153.0,140.1,133.8,131.5,129.0,116.9, 96.4,52.2,42.6,31.9,28.2,21.3；HRMS(ESI-TOF):m/z calcd for C18H21N2O2[(M+H)+], 297.3710；found,297.3718.
- 4,5 (1H, 6H)-diketone of 7 2- amino -7,7- dimethyl -1- (4- anisyls) -7,8- dihydroquinoline of embodiment Synthesis：
With 3- (p-methoxyphenyl) amino) -5,5- Dimethylcyclohexyl -2- ketenes replacement 3- ((4- fluorophenyls) amino) ring Hexyl -2- ketenes, remaining is with embodiment 1 (proportioning is according to mol ratio between raw material), yield：88%；1H NMR(400MHz, DMSO-d6+HClO4):δ=7.44 (d, J=7.6Hz, 2H, ArH), 7.23 (d, J=7.6Hz, 2H, ArH), 6.27 (s, 1H, CH),5.28(br,2H,NH2),3.85(s,3H,OCH3),2.52(s,2H,CH2),2.38(s,2H,CH2),0.93(s,6H,2 ×CH3)；13C NMR(100MHz,DMSO-d6+HClO4):δ=202.9,168.3,161.3,161.1,158.6,129.3, 126.8,116.9,108.5,93.8,56.1,49.4,41.8,32.6,27.8；HRMS(ESI-TOF):m/z calcd for C18H21N2O3[(M+H)+],313.3704；found,313.3718.

Claims (4)

1. a kind of quinolines ketones with Enamino-esters compound, it is characterised in that the structure of the quinolines ketones with Enamino-esters compound is formula (1)：
In formula (1), R1For substituted-phenyl, heterocyclic radical or benzyl；R2For methyl or hydrogen.
2. a kind of quinolines ketones with Enamino-esters compound according to claim 1, it is characterised in that the substituted-phenyl for adjacent, Between, the single or double substituted halogen to three sites, nitro, hydrogen, alkyl, alkoxyl, alkyl or alkoxyl are C1─C2；Described Heterocyclic radical is unsubstituted furyl, thienyl and indyl.
3. a kind of quinolines ketones with Enamino-esters compound according to claim 1 and 2, it is characterised in that：The quinolines enamine Assimilation compound for following any one：
1) -4,5 (1H, 6H)-diketone of 2- amino -1- (nitrobenzophenone) -7,8- dihydroquinoline
2) -4,5 (1H, 6H)-diketone of 2- amino -1- (4- fluoro-phenyls) -7,8- dihydroquinoline
3) 2- amino -1- (the chloro- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
4) 2- amino -1- (the bromo- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
5) -4,5 (1H, 6H)-diketone of 2- amino -1- phenyl -7,8- dihydroquinoline
6) -4,5 (1H, 6H)-diketone of 2- amino -1- (p-methylphenyl) -7,8- dihydroquinoline
7) -4,5 (1H, 6H)-diketone of 2- amino -1- (4- anisyls) -7,8- dihydroquinoline
8) -4,5 (1H, 6H)-diketone of 2- amino -1- (2- fluoro-phenyls) -7,8- dihydroquinoline
9) -4,5 (1H, 6H)-diketone of 2- amino -1- (3- fluoro-phenyls) -7,8- dihydroquinoline
10) 2- amino -1- (the chloro- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
11) 2- amino -1- (the bromo- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
12) -4,5 (1H, 6H)-diketone of 2- amino -1- (tolyl) -7,8- dihydroquinoline
13) 2- amino -1- (the chloro- 5- aminomethyl phenyls of 2-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
14) 2- amino -1- (furan -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
15) 2- amino -1- (thiophene -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
16) -4,5 (1H, 6H)-diketone of 2- amino -1- (1H- indol-3-yls) -7,8- dihydroquinoline
17) -4,5 (1H, 6H)-diketone of 2- amino -1- benzyl -7,8- dihydroquinoline
18) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (nitrobenzophenone) -7,8- dihydroquinoline
19) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (4- fluoro-phenyls) -7,8- dihydroquinoline
20) 2- amino -7,7- dimethyl -1- (the chloro- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
21) 2- amino -7,7- dimethyl -1- (the bromo- phenyl of 4-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
22) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- phenyl -7,8- dihydroquinoline
23) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (p-methylphenyl) -7,8- dihydroquinoline
24) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (4- anisyls) -7,8- dihydroquinoline
25) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (2- fluoro-phenyls) -7,8- dihydroquinoline
26) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (3- fluoro-phenyls) -7,8- dihydroquinoline
27) 2- amino -7,7- dimethyl -1- (the chloro- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
28) 2- amino -7,7- dimethyl -1- (the bromo- phenyl of 3-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
29) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (tolyl) -7,8- dihydroquinoline
30) 2- amino -7,7- dimethyl -1- (the chloro- 5- aminomethyl phenyls of 2-) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
31) 2- amino -7,7- dimethyl -1- (furan -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
32) 2- amino -7,7- dimethyl -1- (thiophene -2- bases) -4,5 (1H, 6H)-diketone of -7,8- dihydroquinoline
33) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- (1H- indol-3-yls) -7,8- dihydroquinoline
34) -4,5 (1H, 6H)-diketone of 2- amino -7,7- dimethyl -1- benzyl -7,8- dihydroquinoline
4. the preparation method of the quinolines ketones with Enamino-esters compound as any one of claims 1 to 3, it is characterised in that system The reaction equation of standby quinolines ketones with Enamino-esters compound is as follows：
Preparation method is comprised the following steps：
1) under reflux conditions, take compound 1 and cyanoacetic acid is dissolved in acetic anhydride, after the completion of reaction, add unsaturated carbonate hydrogen Sodium solution neutralization reaction liquid；Reactant liquor is extracted with ethyl acetate, concentration organic faciess are dried, silica gel column chromatography obtains compound 2；
2) compound 2 is taken, is dissolved with ethanol；Piperidines is added, room temperature reaction is complete；There is white crude (I) to separate out, sucking filtration is washed Wash, be recrystallized to give sterling quinolines ketones with Enamino-esters compound.
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CN110105276A (en) * 2019-06-24 2019-08-09 红河学院 A kind of 2- quinolinone compounds and preparation method thereof

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WO2009086303A2 (en) * 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms
WO2009102588A1 (en) * 2008-02-15 2009-08-20 Merck & Co., Inc. Fused pyridone m1 receptor positive allosteric modulators

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110105276A (en) * 2019-06-24 2019-08-09 红河学院 A kind of 2- quinolinone compounds and preparation method thereof

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