CN106518760B - A kind of 4- aminoquinoline compounds and preparation method thereof - Google Patents
A kind of 4- aminoquinoline compounds and preparation method thereof Download PDFInfo
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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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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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
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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Abstract
The present invention provides a kind of 4- aminoquinoline compounds and preparation method thereof, belongs to technical field of organic synthetic chemistry.The structural formula of the compound is as shown in formula I or formula II, and the present invention also provides a kind of preparation method of 4- aminoquinoline compounds, this method is using alpha-carbonyl dithio keteal and amine simple and easy to get as raw material, in acid condition, has synthesized imido grpup-N, S- contracting ketenes；Or imido grpup-N is prepared by three component reactions of ketones with Enamino-esters, isothiocyanates and halogenated hydrocarbons under alkaline condition, S- contracting ketenes, two different functional groups are introduced into reaction system, then by imido grpup-N, S- contracting ketenes is reacted through the catalyzed cyclization of cheap mantoquita, can synthesize the 4- aminoquinoline compounds of multiplicity.The present invention have raw material is cheap and easy to get, method is succinct, reaction condition is mild, react applicable surface it is wide in range, it is flexible and changeable, the advantages of avoiding using precious metal catalyst.
Description
Technical field
The invention belongs to technical field of organic synthetic chemistry, and in particular to a kind of 4- aminoquinoline compounds and its preparation side
Method.
Background technique
4- aminoquinoline is a kind of important nitrogen-containing heterocycle compound, has the important physiological activity such as anti-malarial
(Eur.J.Med.Chem.2014,85,147–178).For example, most common anti-malaria medicaments chloroquine, amodiaquine, Mefloquine, two
Luxuriant iron quinoline etc. is all with the frame structure (Bioorg.Med.Chem.Lett.2010,20,1078-1080) of 4- aminoquinoline.But
It is that helminth has had apparent drug resistance to common anti-malaria medicaments, this requires the continuous renewals of anti-malaria medicaments, therefore
The synthetic method of 4- aminoquinoline has been a concern, and develops new structural 4-aminoquinoline derivatives with important meaning
Justice.Currently, modification of the synthesis of 4-aminoquinoline derivatives mainly to existing chinoline backbone, or through pyrazoles azepine Cabbeen
It resets (Angew.Chem.Int.Ed.2010,49,2790-2793)；The cyclization reaction of benzoxazinone and ynamine
(Angew.Chem.Int.Ed.Engl.1972,11,720–722)；Ynamine, trifluoromethanesulfanhydride anhydride, the cyclization reaction of 2- chloropyridine
(Angew.Chem.Int.Ed.2016,55,3823-3827) etc..These methods obtain quinoline ring 4- bit amino and C5-8 more
The product that functional group is modified, the more difficult synthesis of 4-aminoquinoline derivatives that C2, C3 replace.Conjunction in existing patent and document
There are raw material sources at method limited more, reacts narrow application range, reaction is complicated, low yield, or needs using precious metal catalyst
The disadvantages of.From open chain compound simple and easy to get, it is concisely and efficiently the synthetic method of building 4-aminoquinoline derivatives
It is rarely reported.
Summary of the invention
It is limited that the purpose of the present invention is to solve the preparation method raw material sources of existing 4- aminoquinoline compounds, instead
Answer process complicated, the problem of low yield, and a kind of 4- aminoquinoline compounds are provided and preparation method thereof.
Present invention firstly provides a kind of 4- aminoquinoline compounds, and the structural formula of the compound is as shown in formula I or formula II:
In formula I or formula II, R1For hydrogen atom, alkyl, phenyl or substituted aryl；R2For hydrogen atom, alkyl, acyl group, substitution
Aroyl or ester group；R3For hydrogen atom, alkyl, benzyl, phenyl, aryl, heteroaryl, alkoxy, methyl or methoxy group
Substituted benzene series aryloxy group, Polyfluoroalkyl, nitro or halogen；R4For hydrogen atom, alkyl, phenyl, aryl, alkoxy, methyl or
Benzene series aryloxy group, Polyfluoroalkyl, nitro or the halogen that methoxy group replaces；R3And R4It can be identical or different.
Preferably, the R1Alkyl, phenyl for C1-C6.
Preferably, the R2For hydrogen atom, the alkyl of C1-C6, the acyl group of C1-C6, C1-C6 ester group.
Preferably, the R3For the alkyl of C1-C6, benzyl, phenyl, xenyl, naphthalene, substituted phenyl.
Preferably, the R4For hydrogen atom, chlorine element.
Preferably, the 4- aminoquinoline compounds have formula (4a)-formula (4k), formula (7a)-formula (7c) structure:
The present invention also provides a kind of preparation methods of 4- aminoquinoline compounds, this method comprises:
Step 1: in acid condition, by dithio keteal and arylamine reaction, or under alkaline condition, by ketones with Enamino-esters,
Aromatic yl different sulfur cyanic acid ester and halohydrocarbons reaction obtain imido grpup-N, S- contracting ketene compound；
Step 2: imido grpup-N, S- the contracting ketene compound that step 1 is obtained carries out anti-from being cyclized under mantoquita catalysis
It answers, obtains 4- aminoquinoline compounds.
Preferably, the reaction temperature of dithio keteal and arylamine reaction is 60-100 DEG C in the step one, reaction
Time is 1-15h.
Preferably, the molar ratio of dithio keteal and arylamine is 1:(2-3 in the step one).
Preferably, the reaction temperature of ketones with Enamino-esters, aromatic yl different sulfur cyanic acid ester and halohydrocarbons reaction is in the step one
0-35 DEG C, reaction time 1-5h.
Preferably, the molar ratio of ketones with Enamino-esters, aromatic yl different sulfur cyanic acid ester and halogenated hydrocarbons is 1:(1- in the step one
2): (1-2).
Preferably, the reaction temperature of the step two is 60-120 DEG C, reaction time 1-20h.
Beneficial effects of the present invention
The present invention provides a kind of 4- aminoquinoline compounds, and the structural formula of the compound is as shown in formula I or formula II, the present invention
A kind of preparation method of 4- aminoquinoline compounds is also provided, this method is with alpha-carbonyl dithio keteal simple and easy to get and amine
Raw material has synthesized imido grpup-N, S- contracting ketenes in acid condition；Or existed by ketones with Enamino-esters, isothiocyanates and halogenated hydrocarbons
Three component reactions under alkaline condition prepare imido grpup-N, and S- contracting ketenes introduces two different functions into reaction system
Group, then by imido grpup-N, S- contracting ketenes is reacted through the catalyzed cyclization of cheap mantoquita, can synthesize the 4- aminoquinoline chemical combination of multiplicity
Object.It compares with the prior art, the present invention is with raw material is cheap and easy to get, method is succinct, reaction condition is mild, reaction applicable surface is wide
It is general, it is flexible and changeable, the advantages of avoiding using precious metal catalyst, the present invention synthesized by 4-aminoquinoline compounds with city
The anti-malaria medicaments chloroquine sold on field, Mefloquine, on the basis of the drug molecules such as quinine skeleton structure having the same, C2,
C3 substitute mode can be versatile and flexible.For at present it is generally existing to chloroquine, the drug resistance of Mefloquine, the drugs such as quinine is asked
Topic, the present invention can provide compound library abundant to develop novel anti-malaria medicaments, have potential medicinal application value.
Detailed description of the invention
Fig. 1 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 4e that the embodiment of the present invention 5 is prepared；
Fig. 2 is the nuclear-magnetism carbon spectrogram for the 4-aminoquinoline compounds 4e that the embodiment of the present invention 5 is prepared；
Fig. 3 is the infrared spectrogram for the 4-aminoquinoline compounds 4e that inventive embodiments 5 are prepared；
Fig. 4 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 4a that the embodiment of the present invention 1 is prepared；
Fig. 5 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 4f that the embodiment of the present invention 6 is prepared；
Fig. 6 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 4i that the embodiment of the present invention 9 is prepared；
Fig. 7 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 7a that the embodiment of the present invention 12 is prepared；
Fig. 8 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 4j that the embodiment of the present invention 10 is prepared；
Fig. 9 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 7b that the embodiment of the present invention 13 is prepared.
Specific embodiment
Present invention firstly provides a kind of 4- aminoquinoline compounds, and the structural formula of the compound is as shown in formula I or formula II:
In formula I or formula II, R1For hydrogen atom, alkyl, phenyl or substituted aryl；More preferably hydrogen atom, C1-C12
The aryl or phenyl that alkyl, substituent group are halogen, nitro, trifluoromethyl, methyl or methoxy replace；Most preferably C1-C6
Alkyl or phenyl；
R2For hydrogen atom, alkyl, acyl group, substituted aroyl or ester group；More preferably hydrogen atom, C1-C12 alkyl,
The alkanoyl of C1-C12, the ester group of C1-C12 or substituent group are halogen, nitro, trifluoromethyl, methyl or methoxy substitution
Aroyl；The most preferably ester group of hydrogen atom, the alkyl of C1-C6, the acyl group of C1-C6, C1-C6；
R3The benzene replaced for hydrogen atom, alkyl, benzyl, phenyl, aryl, heteroaryl, alkoxy, methyl or methoxy group
It is aryloxy group, Polyfluoroalkyl, nitro or halogen；Preferably hydrogen atom, the alkyl of C1-C12, benzyl, phenyl, aryl, heteroaryl,
The alkoxy of C1-C12, the benzene series aryloxy group that methyl or methoxy group replaces, C1-C6 Polyfluoroalkyl, nitro or halogen；Most
The preferably alkyl of C1-C6, benzyl, phenyl, xenyl, naphthalene, substituted phenyl；
R4For hydrogen atom, alkyl, benzyl, phenyl, aryl, heteroaryl, alkoxy, aryloxy group, methyl or methoxy group
Substituted benzene series aryloxy group, Polyfluoroalkyl, nitro or halogen；Preferably hydrogen atom, the alkyl of C1-C12, benzyl, phenyl, virtue
Base, heteroaryl, the alkoxy of C1-C12, methyl or methoxy group replace benzene series aryloxy group, C1-C6 Polyfluoroalkyl, nitre
Base or halogen；Most preferably hydrogen atom or chlorine element；R3And R4It can be identical or different.
According to the present invention, the 4- aminoquinoline compounds have formula (4a)-formula (4k), formula (7a)-formula (7c) knot
Structure:
The present invention also provides a kind of preparation methods of 4- aminoquinoline compounds, this method comprises:
Step 1: in acid condition, by dithio keteal and arylamine reaction, or under alkaline condition, by ketones with Enamino-esters,
Aromatic yl different sulfur cyanic acid ester and halohydrocarbons reaction obtain imido grpup-N, S- contracting ketene compound；
Step 2: imido grpup-N, S- the contracting ketene compound that step 1 is obtained carries out anti-from being cyclized under mantoquita catalysis
It answers, obtains 4- aminoquinoline compounds.
Specifically, preparation has the 4- aminoquinoline compounds of structure shown in formula I, and preparation method preferably includes:
In acid condition, dithio keteal and arylamine reaction generate imido grpup-N, S- contracting ketene compound；Described
The molar ratio of dithio keteal and arylamine is preferably 1:(2-3).Used acid condition preferably includes lewis acid, Bu Langsi
Special acid, super acids, or the acid through immobilized modification.More preferably boron trifluoride ether, alchlor, sulfuric acid, trifluoroacetic acid, trifluoro
The trifluoroacetic acid of methanesulfonic acid or silica gel load；The reaction temperature is preferably 60-100 DEG C, and the reaction time is 1~15 small
When.Reaction preferably carries out in a solvent, and the solvent is preferably toluene, chloroform or ionic liquid；
By imido grpup-N obtained above, S- contracting ketene compound is issued in mantoquita catalysis is born from body cyclization reaction, obtains
4-aminoquinoline compounds with structure shown in formula I.The cyclization reaction is preferably during the reaction using Phen etc.
Organic ligand or (and) inorganic bases such as potassium carbonate, sodium hydroxide, reaction effect can be improved in the organic bases such as triethylamine, potassium tert-butoxide
Rate.The dosage of catalyst mantoquita and ligand can be 0.1mol%-30mol%.Used mantoquita preferably includes copper chloride, bromination
Copper, cupric iodide, copper oxide, copper acetate, copper trifluoromethanesulfcomposite, stannous chloride, cuprous bromide, cuprous iodide or cuprous oxide.Institute
The reaction temperature stated is preferably 60-120 DEG C, and the reaction time is 1~20 hour.Reaction preferably carries out in organic solvent, institute
The organic solvent stated is preferably toluene, benzene, 1,4- dioxane, acetonitrile or ionic liquid.Preparation process is as follows:
Specifically, preparation has the 4- aminoquinoline compounds of II structure of formula, and preparation method preferably includes:
Under alkaline condition, ketones with Enamino-esters, aromatic yl different sulfur cyanic acid ester and halohydrocarbons reaction obtain imido grpup-N, S- contracting ketenes
Compound.The molar ratio of the ketones with Enamino-esters, aromatic yl different sulfur cyanic acid ester and halogenated hydrocarbons is preferably 1:(1-2): (1-2) reacted
Alkaline condition used in journey includes potassium carbonate, sodium hydroxide, triethylamine or potassium tert-butoxide.Reaction temperature is preferably 0-35
DEG C, 1~5 hour of reaction time.Reaction preferably carries out in a solvent, and the solvent is preferably n,N-Dimethylformamide
(DMF), tetrahydrofuran (THF) or ionic liquid；
By imido grpup-N obtained above, S- contracting ketene compound is issued in mantoquita catalysis is born from body cyclization reaction, obtains
4-aminoquinoline compounds with II structure of formula.The cyclization reaction is preferably during the reaction using Phen etc.
Organic ligand or (and) inorganic bases such as potassium carbonate, sodium hydroxide, reaction effect can be improved in the organic bases such as triethylamine, potassium tert-butoxide
Rate.The dosage of catalyst mantoquita and ligand can be 0.1mol%-30mol%.Used mantoquita preferably includes copper chloride, bromination
Copper, cupric iodide, copper oxide, copper acetate, copper trifluoromethanesulfcomposite, stannous chloride, cuprous bromide, cuprous iodide or cuprous oxide.Institute
The reaction temperature stated is preferably 60-120 DEG C, and the reaction time is 1~20 hour.Reaction preferably carries out in organic solvent, institute
The organic solvent stated is preferably toluene, benzene, 1,4- dioxane, acetonitrile or ionic liquid.
Further detailed description is done to the present invention combined with specific embodiments below.
Embodiment 1
1) synthesis of imido grpup-N, S- contracting ketene compound 3
α-acetyl group-α-ethoxycarbonyl dithio keteal 1a is added into the 50mL round-bottomed flask with magnetic stirring apparatus
(2.62g, 10mmol), aniline 2a (2.79g, 30mmol), toluene 20mL and boron trifluoride ether (0.37mL, 3mmol), 80
It is stirred at DEG C, thin-layer chromatography (TLC) monitors after reaction (5h), carefully pours into reaction solution in saturated sodium chloride solution
(20mL) is extracted with methylene chloride (3 × 20mL), is merged organic phase, suction filtration dry by anhydrous sodium sulfate, vacuum distillation etc.
Step obtains sticky solid, by silica gel column chromatography (eluent VPetroleum ether:VEthyl acetate=60:1) obtain sticky yellow solid
The structure of 2.39g, product turn out to be imido grpup-N, S- contracting ketene compound 3a by nuclear magnetic resoance spectrum, mass spectrum, and yield is
65%.
2) synthesis of 4-aminoquinoline compounds 4a
Toluene (10mL), imido grpup-N, S- contracting ketenes 3a are added into the 25mL round-bottomed flask with magnetic stirring apparatus
(1.84g, 5mmol), potassium carbonate 1.38g (10mmol), anhydrous cupric chloride (0.067g, 0.5mmol) and anhydrous Phen
(0.09g, 0.5mmol) puts it into 80 DEG C of oil baths after mixing evenly and continues to stir.TLC detection substrate disappears, reaction knot
Beam.Reaction solution is poured into saturated sodium-chloride water solution (30mL), is extracted with methylene chloride (3 × 30mL), organic phase, nothing are merged
Water calcium chloride is dry, filters, and then vacuum distillation removes organic solvent, obtains solid mixture, finally passes through silica gel column chromatography
(eluent VPetroleum ether:VEthyl acetate=6:1) faint yellow solid 1.27g is obtained, 4- amino is turned out to be by nuclear magnetic resoance spectrum, mass spectrum
Quinolines 4a, yield 83%.
Fig. 4 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 4a that the embodiment of the present invention 1 is prepared, spectrum elucidation
Data 4a:
1H NMR(500MHz,CDCl3) δ 8.66 (s, 1H), 7.93 (d, J=8.5Hz, 1H), 7.71 (d, J=8.5Hz,
1H), 7.61 (t, J=7.0Hz, 1H), 7.24-7.18 (m, 3H), 7.02 (t, J=7.5Hz, 1H), 6.91 (d, J=7.5Hz,
2H), 4.33 (q, J=7.0Hz, 2H), 2.83 (s, 3H), 1.38 (t, J=7.0Hz, 3H)13C NMR(125MHz,CDCl3)δ
168.7,157.4,148.6,148.6,143.5,130.6,129.0,128.9,125.3,124.5,122.7,119.9,
119.7,113.3,61.4,26.3,13.9.HRMS(ESI-TOF)Calcd for C19H19N2O2(M+H)+
307.1441.Found 307.1449.
Embodiment 2
The aniline in " embodiment 1 " is replaced with 4- chloroaniline, the dithio keteal that benzylthio replaces replaces 1a, other conditions
With " embodiment 1 ", experimental result is shown in Table 1.
Spectrum elucidation 4b:
1H NMR(500MHz,CDCl3) δ 8.47 (s, 1H), 7.83 (d, J=9.0Hz, 1H), 7.63 (s, 1H), 7.55 (d,
J=9.0Hz, 1H), 7.20 (d, J=8.5Hz, 2H), 6.81 (d, J=8.5Hz, 2H), 4.32 (q, J=7.0Hz, 2H), 2.77
(s, 3H), 1.37 (t, J=7.0Hz, 3H)13C NMR(125MHz,CDCl3)δ168.4,157.6,147.0,147.0,
141.7,131.6,130.7,130.7,129.2,127.9,123.8,120.7,114.8,61.9,26.1,14.0.HRMS
(ESI-TOF)Calcd for C19H17Cl2N2O2(M+H)+375.0662.Found 375.0655.
Embodiment 3
3b, CuBr in " embodiment 2 " are replaced with 3c2For copper salt catalyst, other conditions are the same as " embodiment 2 ", experimental result
It is shown in Table 1.
Spectrum elucidation 4c:
1H NMR(500MHz,CDCl3) δ 8.43 (s, 1H), 7.83 (s, 1H), 7.75 (d, J=9.0Hz, 1H), 7.68 (d,
J=9.0Hz, 1H), 7.34 (d, J=8.5Hz, 2H), 6.76 (d, J=8.5Hz, 2H), 2.75 (s, 3H), 2.24 (s, 3H)13C
NMR(125MHz,CDCl3)δ157.7,147.2,146.6,142.1,134.2,132.1,130.8,126.9,121.3,
120.9,118.8,115.3,114.9,26.1,24.0.HRMS(ESI-TOF)Calcd for C17H15Br2N2(M+H)+
404.9597.Found 404.9591.
Embodiment 4
The aniline in " embodiment 1 " is replaced with benzidine, using sodium hydride as alkali, other conditions are the same as " embodiment 1 ", experiment knot
Fruit is shown in Table 1.
Spectrum elucidation 4d:
1H NMR(400MHz,CDCl3) δ 9.05 (s, 1H), 7.98 (d, J=8.4Hz, 1H), 7.91-7.86 (m, 2H),
7.58 (d, J=7.6Hz, 2H), 7.53 (d, J=8.4Hz, 2H), 7.44 (t, J=7.6Hz, 2H), 7.34 (t, J=7.2Hz,
1H), 7.27-7.23 (m, 5H), 7.06 (d, J=8.0Hz, 2H), 4.38 (q, J=7.2Hz, 2H), 2.86 (s, 3H), 1.42
(t, J=7.2Hz, 3H)13C NMR(125MHz,CDCl3)δ168.8,157.5,149.1,148.0,142.7,140.3,
139.8,136.7,136.1,130.0,129.3,128.7,128.6,127.7,127.2,126.9,126.9,126.5,
123.6,121.0,119.3,112.5,61.4,26.5,14.0.HRMS(ESI-TOF)Calcd for C31H27N2O2(M+H)+
459.2067.Found 459.2053.
Embodiment 5
3a in " embodiment 2 " is replaced with 3e, chloroform is solvent, and for other conditions with " embodiment 1 ", experimental result is shown in Table 1.
Fig. 1 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 4e that the embodiment of the present invention 5 is prepared, spectrum elucidation
4e:
1H NMR(400MHz,CDCl3) δ 7.95 (d, J=8.4Hz, 1H), 7.77 (d, J=8.4Hz, 1H), 7.64 (t, J
=6.8Hz, 1H), 7.54 (s, 1H), 7.28 (t, J=7.2Hz, 1H), 7.21 (t, J=7.6Hz, 2H), 6.99 (t, J=
7.6Hz, 1H), 6.84 (d, J=7.6Hz, 2H), 2.72 (s, 3H), 2.48 (s, 3H)13C NMR(125MHz,CDCl3)δ
204.9,155.2,148.6,144.2,143.6,130.5,129.3,129.0,125.2,124.4,122.3,120.9,
118.6,32.0,25.0.HRMS(ESI-TOF)Calcd for C18H17N2O(M+H)+277.1335.Found
277.1331.IR(KBr,cm-1)3167,2991,1697,1562,1489,1388,1257,763。
Fig. 2 is the nuclear-magnetism carbon spectrogram for the 4-aminoquinoline compounds 4e that the embodiment of the present invention 5 is prepared, and Fig. 3 is hair
The infrared spectrogram for the 4-aminoquinoline compounds 4e that bright embodiment 5 is prepared can be seen that the present invention from Fig. 1-Fig. 3
4-aminoquinoline compounds 4e has successfully been prepared.
Embodiment 6
The aniline in " embodiment 1 " is replaced with 3- chloroaniline, Phen is replaced with terpyridyl, other conditions are the same as " real
Example 1 " is applied, experimental result is shown in Table 1.
Fig. 5 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 4f that the embodiment of the present invention 6 is prepared, spectrum elucidation
4f:
1H NMR(400MHz,CDCl3) δ 8.65 (s, 1H), 8.09 (d, J=8.4Hz, 1H), 7.74 (d, J=8.4Hz,
1H), 7.66-7.61 (m, 3H), 7.46-7.39 (m, 3H), 7.24-7.19 (m, 3H), 7.02 (t, J=7.6Hz, 1H), 6.94
(d, J=7.6Hz, 2H), 3.93 (q, J=7.2Hz, 2H), 0.73 (t, J=7.2Hz, 3H)13C NMR(125MHz,CDCl3)δ
169.3,158.9,148.9,148.5,143.5,142.2,130.8,130.1,129.1,128.1,128.0,125.9,
124.9,123.0,120.2,119.5,113.7,61.3,13.0.HRMS(ESI-TOF)Calcd for C24H20N2O2(M+H)+
369.1598.Found 369.1607.
Embodiment 7
The aniline in " embodiment 1 " is replaced with 4- 5-trifluoromethylaniline, three in " embodiment 1 " are replaced with trifluoromethanesulfonic acid
It is fluorinated borate ether, for other conditions with " embodiment 1 ", experimental result is shown in Table 1.
Spectrum elucidation 4g:
1H NMR(400MHz,CDCl3) δ 8.66 (s, 1H), 8.06 (d, J=8.8Hz, 1H), 8.00 (s, 1H), 7.84 (d,
J=8.8Hz, 1H), 7.50 (d, J=8.4Hz, 2H), 6.93 (d, J=8.4Hz, 2H), 4.37 (q, J=7.2Hz, 2H), 2.84
(s, 3H), 1.39 (t, J=7.2Hz, 3H)13C NMR(125MHz,CDCl3)δ168.1,160.0,149.9,147.9,
146.2,130.5,127.2 (q, J=32.5Hz), 126.7 (q, J=2.6Hz), 126.6 (q, J=3.6Hz), 123.1 (q, J
=4.5Hz), 119.4,118.7,116.1,62.2,26.4,14.0.19F NMR(470MHz,CDCl3)δ-64.0,-
64.5.HRMS(ESI-TOF)Calcd for C21H17F6N2O2(M+H)+443.1189.Found 443.1178.
Embodiment 8
3a in " embodiment 1 " is replaced with 3h, for other conditions with " embodiment 1 ", experimental result is shown in Table 1.
Spectrum elucidation 4h:
1H NMR(400MHz,CDCl3) δ 7.90 (d, J=8.8Hz, 1H), 7.69 (s, 1H), 7.60 (d, J=8.8Hz,
1H), 7.28 (s, 1H), 7.19 (d, J=8.8Hz, 2H), 6.74 (d, J=8.8Hz, 2H), 2.70 (s, 3H), 2.48 (s, 3H)
.13C NMR(125MHz,CDCl3)δ204.5,155.5,147.1,142.7,141.9,131.6,131.5,130.9,129.5,
127.5,126.8,123.1,121.9,119.4,76.7,31.9,24.9.HRMS(ESI-TOF)Calcd for
C18H15Cl2N2O(M+H)+345.0556.Found 345.0552.
Embodiment 9
3a in " embodiment 1 " is replaced with 3i, for other conditions with " embodiment 1 ", experimental result is shown in Table 1.
Fig. 6 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 4i that the embodiment of the present invention 9 is prepared, spectrum elucidation
4i:
1H NMR(400MHz,CDCl3) δ 9.27 (d, J=8.0Hz, 1H), 8.25 (d, J=9.2Hz, 1H), 8.02 (s,
1H), 7.82 (d, J=9.2Hz, 1H), 7.66-7.41 (m, 7H), 7.30 (d, J=9.2Hz, 1H), 7.10 (t, J=7.6Hz,
1H), 6.58 (d, J=7.6Hz, 1H), 2.82 (s, 3H), 2.44 (s, 3H)13C NMR(125MHz,CDCl3)δ205.0,
154.1,147.0,145.3,140.2,134.3,133.7,131.1,128.5,128.4,127.4,126.8,126.6,
126.4,126.2,126.0,125.6,124.9,122.7,121.4,121.2,118.1,114.5,31.9,25.5.HRMS
(ESI-TOF)Calcd for C26H21N2O(M+H)+377.1648.Found 377.1638.
Embodiment 10
The 3a in " embodiment 1 " is replaced with 3j, for other conditions with " embodiment 1 ", experimental result is shown in Table 1.
Fig. 8 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 4j that the embodiment of the present invention 10 is prepared, spectrogram solution
Analyse 4j:
1H NMR(400MHz,CDCl3) δ 8.65 (s, 1H), 8.09 (d, J=8.4Hz, 1H), 7.74 (d, J=8.4Hz,
1H), 7.66-7.61 (m, 3H), 7.46-7.39 (m, 3H), 7.24-7.19 (m, 3H), 7.02 (t, J=7.6Hz, 1H), 6.94
(d, J=7.6Hz, 2H), 3.93 (q, J=7.2Hz, 2H), 0.73 (t, J=7.2Hz, 3H)13C NMR(125MHz,CDCl3)δ
169.3,158.9,148.9,148.5,143.5,142.2,130.8,130.1,129.1,128.1,128.0,125.9,
124.9,123.0,120.2,119.5,113.7,61.3,13.0.HRMS(ESI-TOF)Calcd for C24H20N2O2(M+H)+
369.1598.Found 369.1607.
Embodiment 11
The 3a in " embodiment 1 " is replaced with 3k, for other conditions with " embodiment 1 ", experimental result is shown in Table 1.
Spectrum elucidation 4k:
1H NMR(400MHz,CDCl3) δ 7.90 (d, J=8.8Hz, 1H), 7.69 (s, 1H), 7.60 (d, J=8.8Hz,
1H), 7.28 (s, 1H), 7.19 (d, J=8.8Hz, 2H), 6.74 (d, J=8.8Hz, 2H), 6.72 (s, 1H), 2.70 (s, 3H)
.13C NMR(125MHz,CDCl3)δ155.5,147.1,142.7,141.9,131.6,131.5,130.9,129.5,127.5,
126.8,123.1,121.9,119.4,76.7,31.9.HRMS(ESI-TOF)Calcd for C16H13Cl2N2(M+H)+
303.0450.Found 303.0442.
Embodiment 12
1) synthesis of imido grpup-N, S- contracting ketene compound 6a
At room temperature, anhydrous n,N-Dimethylformamide is added into the 50mL round-bottomed flask with magnetic stirring apparatus
(DMF) (15mL), ketones with Enamino-esters 5a (2.39g, 10mmol) and sodium hydride (0.53g, 22mmol) are stirred ten minutes, are subsequently added into
Bromoethane is added when reaction system no longer bubbles (20min) in phenyl isothiocyanate 1.44mL (12mmol), stirring
It is water-soluble to be poured into saturated sodium-chloride when thin-layer chromatography (TLC) monitoring product is not further added by (2h) by 0.90mL (12mmol) for reaction solution
It in liquid (30mL), is extracted with ether (3 × 20mL), merges organic phase, water (2 × 20mL) backwash organic phase is then used, by nothing
Water calcium chloride is dry, filter, vacuum distillation and etc. obtain sticky solid, by silica gel column chromatography (eluent VPetroleum ether:
VEthyl acetate=60:1) sticky solid 3.13g is obtained, the structure of product turns out to be imido grpup-N by nuclear magnetic resoance spectrum, mass spectrum,
S- contracting ketene compound 6a, yield 85%.
2) synthesis of 4-aminoquinoline compounds 7a
The 3a in " embodiment 1 " is replaced with 6a, for other conditions with " embodiment 1 ", experimental result is shown in Table 1.
Fig. 6 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 7a that the embodiment of the present invention 12 is prepared, spectrogram solution
Analyse 7a:
1H NMR(400MHz,CDCl3) δ 7.84 (d, J=9.2Hz, 1H), 7.76 (s, 1H), 7.75 (s, 1H), 7.52 (d,
J=9.2Hz, 1H), 6.88 (d, J=9.2Hz, 2H), 6.79 (d, J=9.2Hz, 2H), 3.77 (s, 3H), 2.65 (s, 3H),
2.42(s,3H).13C NMR(125MHz,CDCl3)δ204.5,156.1,155.8,146.9,145.0,135.7,131.0,
130.6,130.5,123.1,122.9,122.3,121.0,114.6,55.4,31.9,24.9.HRMS(ESI-TOF)Calcd
for C19H18ClN2O2(M+H)+341.1043.Found341.1051.
Embodiment 13
The 6a in " embodiment 12 " is replaced with 6b, for other conditions with " embodiment 12 ", experimental result is shown in Table 1.
Fig. 9 is the nucleus magnetic hydrogen spectrum figure for the 4-aminoquinoline compounds 7b that the embodiment of the present invention 13 is prepared, spectrogram solution
Analyse 7b:
1H NMR(600MHz,CDCl3) δ 7.94 (d, J=8.4Hz, 1H), 7.90 (d, J=8.4Hz, 1H), 7.62 (t, J
=7.2Hz, 1H), 7.39-7.30 (m, 6H), 6.87 (s, 1H), 4.67 (d, J=5.4Hz, 2H), 4.33 (q, J=7.2Hz,
2H), 2.72 (s, 3H), 1.35 (t, J=7.2Hz, 3H)13C NMR(150MHz,CDCl3)δ169.6,157.3,152.8,
148.4,138.5,130.5,129.0,128.9,127.8,127.5,124.4,123.1,118.7,108.6,61.3,52.2,
25.9,14.0.HRMS(ESI-TOF)Calcd for C20H21N2O2(M+H)+321.1598.Found 321.1590.
Embodiment 14
The 6a in " embodiment 12 " is replaced with 6c, for other conditions with " embodiment 12 ", experimental result is shown in Table 1.
Spectrum elucidation 7c:
1H NMR(600MHz,CDCl3) δ 7.94 (d, J=8.4Hz, 1H), 7.90 (d, J=8.4Hz, 1H), 7.39-7.30
(m, 2H), 6.87 (s, 1H), 4.33 (q, J=7.2Hz, 2H), 2.82 (d, J=5.4Hz, 3H), 2.72 (s, 3H), 1.35 (t, J
=7.2Hz, 3H)13C NMR(150MHz,CDCl3)δ169.6,157.3,152.8,148.4,130.5,128.9,127.5,
124.4,118.7,108.6,61.3,35.2,25.9,14.0.HRMS(ESI-TOF)Calcd for C14H17N2O2(M+H)+
245.1285.Found 245.1279.
Table 1
Claims (1)
1. a kind of preparation method of 4- aminoquinoline compounds, which is characterized in that this method comprises:
1) synthesis of imido grpup-N, S- contracting ketene compound 3a
1a 2.62g, 10mmol, 2a2.79g, 30mmol, toluene are added into the 50mL round-bottomed flask with magnetic stirring apparatus
20mL and boron trifluoride ether 0.37mL, 3mmol, are stirred at 80 DEG C, thin-layer chromatography TLC monitoring reaction 5h, carefully will reaction
Liquid pours into 20mL in saturated sodium chloride solution, is extracted with 3 × 20mL of methylene chloride, merges organic phase, dry by anhydrous sodium sulfate
Dry, suction filtration, vacuum distillation step obtain sticky solid, are V by silica gel column chromatography eluentPetroleum ether:VEthyl acetate=60:1 is obtained
The structure of sticky yellow solid 2.39g, product turn out to be 3a, yield 65% by nuclear magnetic resoance spectrum, mass spectrum；
2) synthesis of 4-aminoquinoline compounds 4a
Addition toluene 10mL, 3a1.84g, 5mmol, potassium carbonate 1.38g into the 25mL round-bottomed flask with magnetic stirring apparatus,
10mmol, anhydrous cupric chloride 0.067g, 0.5mmol and anhydrous Phen 0.09g, 0.5mmol are put after mixing evenly
Enter and continue to stir in 80 DEG C of oil baths, TLC detection substrate disappears, and reaction terminates, and reaction solution is poured into saturated sodium-chloride water solution
It in 30mL, is extracted with 3 × 30mL of methylene chloride, merges organic phase, anhydrous calcium chloride is dry, filters, and then vacuum distillation removes
Organic solvent obtains solid mixture, is finally V by silica gel column chromatography eluentPetroleum ether:VEthyl acetate=6:1 obtains pale yellow colored solid
Body 1.27g turns out to be 4-aminoquinoline compounds 4a, yield 83% by nuclear magnetic resoance spectrum, mass spectrum.
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| CN101735148A (en) * | 2009-12-15 | 2010-06-16 | 东北师范大学 | Method for synthesizing dihydroquinoline derivative |
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| CN101735148A (en) * | 2009-12-15 | 2010-06-16 | 东北师范大学 | Method for synthesizing dihydroquinoline derivative |
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| An efficient synthesis of phenyl-substituted dibenzonaphthyridines;Manoj, Manickam et al.,;《Journal of Chemical Research》;20091231(第8期);第486页Scheme 3和4 |
| VERSATILE METHOD FOR THE SYNTHESIS OF FLUORINE-CONTAINING CHLOROQUINE ANALOGUES STARTING FROM 7-CHLORO-4-(N,N-DIMETHYLAMINO)QUINOLINE USING NUCLEOPHILIC N-N, N-S, AND N-O EXCHANGE REACTIONS;Norio Ota et al.,;《HETEROCYCLES》;20131231;第87卷(第12期);第3页Scheme 2和Table 1 |
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