CN107721923A - 4 N anilino quinolines class compound synthesis and the application for preparing anti-Alzheimer disease medicine - Google Patents
4 N anilino quinolines class compound synthesis and the application for preparing anti-Alzheimer disease medicine Download PDFInfo
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- 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
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Abstract
The synthesis of 4 N anilino quinolines class compounds and the application for preparing anti-Alzheimer disease medicine, the synthetic method is, using acetone as solvent, the N substituted anilinics quinoline of 6 methoxyl group 7 (3 chlorine propoxyl group) 3 nitro 4 is dissolved, morpholine is added dropwise, then heating is reacted, and reaction, which finishes, is cooled to room temperature, purifying is dried, obtains target compound.The 4 N anilino quinolines classes compound includes nine kinds, nine kinds of compounds are respectively provided with acetylcholinesterase and the double inhibitory activity of butyrylcholine esterase, lipophilicity is suitable, and available for anti-Alzheimer disease medicine is prepared, the treatment medicine for senile dementia to develop new opens new way.
Description
Technical field
The present invention relates to anti-alzheimer disease field of medicine preparing technology, particularly 4-N- anilino quinolines class compound
Synthesis and its application.
Technical background
2006, prevent to point out that the whole world has more than 26,000,000 alzheimer patients in dementia international conference, entirely
The alzheimer's disease patient of ball 48% is in Asia.Alzheimer disease (AD) is that a kind of clinical manifestation is to recognize with memory not
Disconnected degeneration, the handicapped, mental trait and behavior that can not be taken care of oneself gradually nerve degenerative diseases hindered of living, are old
The most common type of dementia.The anti-AD medicines of Clinical practice are mainly acetylcholinesteraseinhibitors inhibitors at present, more how to be had
Piperazine is neat, Rivastigmine and galanthamine etc., and these medicines improve patient's intracerebral by the activity of acetylcholine esterase inhibition
Levels of acetylcholine, so as to be favorably improved cognitive function of patients, improve the behavior disorder of patient.Research is found：Human brain internal memory
In two kinds of cholinesterases, i.e. acetylcholinesterase (AChE) and butyrylcholine esterase (BChE), when AChE activity inhibiteds,
BChE can compensate to it.BChE has been accepted extensively as the target spot of AD medicines by people, and application AChE and
BChE dibasic acid esters enzyme inhibitor preferably can play therapeutic effect to AD.
Quinoline and the like has a variety of physiologically actives and is widely used in clinic, such as have it is antitumor,
Anti-malarial, antibacterial and cholinesterase such as suppress at the pharmacological activity, wherein Tacrine as AChE inhibitor once for treating AD, and base
Extensive attention has also been obtained in the dyad of Tacrine and the research of heterozygote.In recent years, the experimental results show, comprising
The compound of 4-N- aryl amine quinoline structures has stronger choline esterase inhibition and neurocyte protection activity.The present invention
People's early-stage Study finds that the 4-N- anilinoquinoline compounds of the fragment containing pyridine quaternary ammonium salt are respectively provided with significantly to AChE and BChE
Double inhibition acts on (the SCIs such as Liu Yuming, the beautiful Jun in field, Hu Dong, 2017,38 (3):, but such chemical combination 392)
The lipophilicity of thing is poor, and LopP values are less than 1, will be penetrating to oral absorption and blood-brain barrier unfavorable, because being known together according to relevant research, typically
The LogP values of anti-AD medicines need to be between 2~5.
The content of the invention
The invention aims to improve the lipophilicity of 4-N- anilino quinolines class compounds, and also to find new
Type anticholinesterase class medicine.Water miscible pyridine quaternary ammonium salt piece in early-stage Study is substituted with morpholine fragment for this present invention
Section, has synthesized the 4-N- anilinoquinoline compounds of the serial fragment containing morpholine, and lipophilic effect is improved to reach.It is then logical
Cross and such 4-N- anilino quinolines class compound is studied, it is preferable that discovery there are nine compounds to have AChE and BChE
Double inhibitory action, and good lipophilicity is shown, there is prospect of the exploitation into new anti-AD medicines, to develop new anti-A Er
Ci Haimo medicines and abundant clinical application kind open new way.
Technical scheme：
4-N- anilino quinolines class compounds, its chemical structural formula are as follows：
R in structural formula1For phenyl, Chloro-O-Phenyl, a chlorphenyl, rubigan, 2,4 dichloro benzene base, a tolyl,
Methoxyphenyl, a hydroxy phenyl or p-hydroxybenzene.
Described compound include 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- aniline yl-quinoline,
6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- o-chloranilines yl-quinoline, 6- methoxyl groups -7- (3-N- morpholines
Base propoxyl group) -3- nitro -4-N- m-chloroanilines yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-
N- parachloroanilinum yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-N- (2,4 dichloro benzene amido) -
Quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- meta-aminotoluenes yl-quinoline, 6- methoxyl group -7- (3-
N- morpholinopropoxies) -3- nitro -4-N- m-anisidines yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -
Hydroxyanilines yl-quinoline and 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- are to hydroxyl between 3- nitros -4-N-
Aniline yl-quinoline.
The preparation method of the 4-N- anilino quinolines class compound is, using acetone as solvent, by 6- methoxyl group -7- (3-
Chlorine propoxyl group) dissolving of -3- nitro -4-N- substituted anilines yl-quinoline, morpholine is added dropwise, heats up and is reacted after being added dropwise, instead
Room temperature is cooled to after answering, purifying is dried, obtains target compound；Comprise the following steps that：
Step 1：Vanillic acid is put into container, adds methanol after all dissolving, adds concentrated hydrochloric acid, 60~80 DEG C of heating
Backflow, react 10~16 hours.After the completion of reaction, purifying obtains compound a, i.e. vanillic acid methyl esters.
Step 2：Compound a is put into container and uses acetone solution, then adds Anhydrous potassium carbonate and the bromo- 3- chlorine third of 1-
Alkane, 45~70 DEG C of heating responses 10~16 hours.Filter while hot after completion of the reaction, be evaporated organic solvent and purify, obtain chemical combination
Thing b.
Step 3：Compound b is dissolved with dichloromethane in a reservoir, fuming nitric aicd is slowly added dropwise, is then reacted under normal temperature
3~8 hours.After completion of the reaction, unnecessary fuming nitric aicd is removed with sodium bicarbonate aqueous solution.Dichloromethane is separated with separatory funnel
Layer, is dried with anhydrous magnesium sulfate, compound c is obtained after volatilizing solvent.
Step 4：Compound c is dissolved in round-bottomed flask with ethanol, it is water-soluble to add saturated ammonium chloride until completely dissolved
Liquid, iron powder is added, 50~80 DEG C are reacted 12 hours.Filtered with funnel, extracted with dichloromethane liquid separation while hot after completion of the reaction.
Organic solvent is evaporated, column chromatography obtains compound d after purification.
Step 5：Compound d is dissolved with a small amount of methanol in a reservoir, 5wt% sodium hydrate aqueous solutions is then added, rises
Temperature is reacted 10~16 hours to 50~70 DEG C, hydrochloric acid regulation pH value is added to 2-3 after being cooled to room temperature, then with dichloromethane point
Liquid extracts.Compound e is obtained after being evaporated organic solvent.
Step 6：(1) compound e is added in distilled water and concentrated hydrochloric acid, forms the compound e aqueous solution.(2) weigh
Sodium hydroxide adds the water dissolving of twice of mass, and the nitromethane of 1.0~2.0 times of equivalents is added at 25~30 DEG C, is warming up to 40
DEG C, 40~45 DEG C of nitromethanes for adding amount same as described above again are kept, 50 DEG C are warming up to after adding, 50~55 DEG C keep 2
Room temperature is cooled to after~5 minutes.Then ice is added, hydrochloric acid is added and is thoroughly mixed to form red tan solution.This bronzing is molten
Liquid is added to normal-temperature reaction 14~16 hours in the compound e aqueous solution.Filter, be washed to neutrality with distillation, changed after drying
Compound f.
Step 7：Compound f is put into container, anhydrous acetic acid acid anhydride is subsequently added into, 100 DEG C of heating for dissolving, treats that solution is clarified
Anhydrous acetic acid potassium is added afterwards, oil bath 15~30min of back flow reaction, is down to room temperature.Filtering, washed with glacial acetic acid, be washed with water to
Neutrality, compound j is obtained after drying.
Step 8：Compound j is put into container, is slowly added to POCl3,60~80 DEG C of oil baths are stirred at reflux 5~10
Hour.After completion of the reaction, unnecessary POCl3 is steamed, dichloromethane is added and dissolves product, then add cold saturation
Wet chemical.Half an hour is stirred under ice bath, dichloromethane layer is separated with separatory funnel, washes twice, anhydrous magnesium sulfate is done
Compound h is obtained after dry.
Step 9：Compound h is put into container, is subsequently added into isopropanol, is dissolved by heating.Add containing different substituents
Aniline, react 5~9 hours at 82~100 DEG C.Room temperature is placed to there is Precipitation after completion of the reaction, is filtered, washing, with anhydrous
Magnesium sulfate is dried, and obtains 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- substituted anilinics-quinolines.
Step 10：6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- substituted anilinics-quinoline that step 9 is obtained
Quinoline class compound is with acetone solution, the morpholine of 1.0~5.0 times of equivalents of dropwise addition.After being added dropwise, temperature is risen to 45~70
DEG C, 10~20h of insulation reaction.It is cooled to room temperature after completion of the reaction, dries purifying, obtain target compound.
4-N- anilino quinolines class compound provided by the invention has acetylcholinesterase and the double suppressions of butyrylcholine esterase
The activity of system, available for the medicine for preparing anti-Alzheimer disease.
The advantages of the present invention are：
4-N- anilino quinolines classes compound has preferably anti-AChE and BChE activity, and has suitable lipophilicity,
New approach is opened to develop new anti-AD medicines and abundant clinical application kind；Synthesize the chemical combination of such morpholine group substitution
Document report is using acetonitrile as solvent during thing, it is contemplated that acetonitrile has a carcinogenicity for two class solvents, the present invention with available for
Three class solvent acetones of pharmaceutical production have equally reached synthesis purpose as action solvent, are not synthesized both at home and abroad on this so far
Improved document.
Embodiment
In order to find the anti-Alzheimer disease medicine of better efficacy, with reference at present to anti-Alzheimer disease class medicine
Understanding, according to the literature with applicant laboratory research work achievement for many years, multiple 4-N- anilino quinolines classes are synthesized
Compound, and cholinesterase suppression screening is carried out to the target compound of acquisition, it is found that wherein nine compounds have preferable second
Double inhibitory activity of acetylcholinesterase and butyrylcholine esterase, and there is suitable lipophilicity.The structure of target compound is
By high resolution mass spectrum (HR-ESI-MS), infrared spectrum (IR), proton nmr spectra (1H-NMR), carbon-13 nmr spectra (13C-
NMR) confirm.
Embodiment 1：
The preparation of 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- aniline yl-quinolines, step are as follows：
Step 1：1g vanillic acids (5.95mmol) are put into 50mL round-bottomed flasks, 10mL methanol is added and treats whole dissolvings
Afterwards, 0.6mL concentrated hydrochloric acids are added, 70 DEG C are heated to reflux, and react 12 hours.After the completion of reaction, purifying obtains 0.87g compound as, i.e.,
Vanillic acid methyl esters, yield 87%.More secondary responses add up the quality of this compound.
Step 2：1g (5.5mmol) compound a is put into 50mL round-bottomed flasks and uses acetone solution, then add 1.5g without
The bromo- 3- chloropropanes of aqueous carbonate potassium and 1.2g (8.7mml) 1-, 65 DEG C are heated to reflux 12 hours.Filter while hot after completion of the reaction,
It is evaporated organic solvent and purifies, obtains 0.74g compound b, yield 74%.More secondary responses add up the quality of this compound.
Step 3：1g (3.88mmol) compound b are dissolved in 50mL round-bottomed flasks with dichloromethane, are slowly added dropwise
0.14mL (7.75mmol) fuming nitric aicd, then reacted 5 hours under normal temperature.After completion of the reaction, removed with sodium bicarbonate aqueous solution
Unnecessary fuming nitric aicd.Dichloromethane layer is separated with separatory funnel, is dried with anhydrous magnesium sulfate, 0.862g is obtained after volatilizing solvent
Compound c, yield 86.2%.More secondary responses add up the quality of this compound.
Step 4：1g compounds c is dissolved in round-bottomed flask with ethanol, adds saturated ammonium chloride water until completely dissolved
Solution, 1.3g (0.023mol) iron powder is added, 70 DEG C are reacted 12 hours.Filtered while hot with funnel after completion of the reaction, use dichloro
Methane liquid separation extracts.Organic solvent is evaporated, column chromatography obtains 0.87g compound d, yield 87% after purification.More secondary responses tire out
Count the quality of this compound.
Step 5：1g (3.66mmol) compound d are dissolved in 50mL round-bottomed flasks with a small amount of methanol, then added
6.1mL 5wt% sodium hydrate aqueous solutions, are warming up to 50 DEG C, react 12 hours, be cooled to after room temperature add hydrochloric acid adjust pH value to
2-3, then extracted with dichloromethane liquid separation.0.85g compound e, yield 85% are obtained after being evaporated organic solvent.More secondary responses
Add up the quality of this compound.
Step 6：(1) 1g (3.86mmol) compounds e is added in 4.8mL distilled water and 0.29mL concentrated hydrochloric acids, shape
Into the compound e aqueous solution.(2) sodium hydroxide for weighing 0.52g (0.013mol) adds 1.04mL water dissolving, adds at 30 DEG C
Enter 0.26g (4.25mmol) nitromethane, be warming up to 40 DEG C, kept for 40 DEG C add 0.26g (4.25mmol) nitromethane again,
Be warming up to 50 DEG C after adding, 50 DEG C kept for 5 minutes after be cooled to room temperature.Then ice is added, the hydrochloric acid for adding 1.16ml is abundant
It is mixed to form red tan solution.This red tan solution is added to normal-temperature reaction 16 hours in the compound e aqueous solution.Filter, use
Distillation is washed to neutrality, and 0.82g compound f, yield 82% are obtained after drying.More secondary responses add up the quality of this compound.
Step 7：1g (3.03mmol) compounds f is put into 50mL round-bottomed flasks, is subsequently added into 3mL anhydrous acetic acid acid anhydrides,
100 DEG C of heating for dissolving, 0.3g (3.03mmol) anhydrous acetic acid potassium is added after solution clarification, oil bath back flow reaction 15min, is down to
Room temperature.Filtering, is washed with glacial acetic acid, is washed with water to neutrality, 0.21g compound j, yield 21% are obtained after drying.Repeatedly
Reaction adds up the quality of this compound.
Step 8：1g (3.19mmol) compounds j is put into 50mL round-bottomed flasks, is slowly added to 5.14mL POCl3s,
70 DEG C of oil baths are stirred at reflux 8 hours.After completion of the reaction, unnecessary POCl3 is steamed, dichloromethane is added and dissolves product, so
Cold unsaturated carbonate aqueous solutions of potassium is added afterwards.Half an hour is stirred under ice bath, dichloromethane layer, washing two are separated with separatory funnel
Time, anhydrous magnesium sulfate obtains 0.89g compound h, yield 89% after drying.
Step 9：0.5g (1.515mmol) compounds h is put into 50mL round-bottomed flasks, is subsequently added into 10mL isopropanols,
Dissolve by heating.1.515mmol aniline is added, reacts backflow 6 hours at 90 DEG C.After completion of the reaction room temperature place to have precipitation analyse
Go out, filter, washing, dried with anhydrous magnesium sulfate, obtain 0.455g 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N-
Aniline yl-quinoline, yield 91%.
Step 10：By 0.45g (1.16mmol) 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitro -4-N- anilino-s -
Quinoline is added dropwise the morpholine of 1.5 times of equivalents, after being added dropwise, temperature is risen into 60 DEG C, reacted 16 hours with 5mL acetone solutions.
Be cooled to room temperature after question response, dry purifying, obtain 0.5g 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -
4-N- aniline yl-quinolines, i.e. compound 1, yield 88.89%.
By high resolution mass spectrum (HR-ESI-MS), infrared spectrum (IR), proton nmr spectra (1H-NMR), nuclear magnetic resonance
Carbon spectrum (13C-NMR the structure of compound 1) is confirmed：m.p.150-152℃；IR(KBr)cm-1：3424,2956,1573,1525,
1483,1282,1260,1221,1104；1H-NMR(400MHz,CDCl3):δ 2.10 (m, 2H), 2.56 (t, J=7.0Hz, 2H),
3.16 (m, 4H), 3.34 (s, 3H), 3.94 (m, 4H), 4.26 (t, J=6.6Hz, 2H), 6.89 (s, 1H), 7.19 (d, J=
7.8Hz 2H), 7.26 (t, J=7.8Hz, 1H), 7.36 (s, 1H), 7.41 (t, J=7.8Hz, 2H), 9.36 (s, 1H), 10.42
(s,1H,NH)；13C-NMR(100MHz,CDCl3):25.9,53.7(2C),55.2(2C),66.9(2C),67.4,106.4,
110.0,112.7,124.0(2C),126.0,128.6,129.7(2C),141.2,145.0,145.3,148.0,148.3,
153.6；HR-ESI-MS(positivemode)m/z439.1992[M+H]+(calcd439.1981forC23H27N4O5)。
Embodiment 2：
The preparation of 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- o-chloraniline yl-quinolines, step is such as
Under：
From step 1 to step 8, the preparation method of totally eight steps its process in addition to dosage is substantially the same manner as Example 1.
Step 9：The compound h obtained in 0.6g (1.82mmol) step 8 is put into 50mL round-bottomed flasks, is subsequently added into
10mL isopropanols, dissolve by heating.1.82mmol o-chloraniline is added, reacts backflow 6 hours at 90 DEG C.Room temperature after completion of the reaction
Place to there is Precipitation, filter, washing, dried with anhydrous magnesium sulfate, obtain the 0.52g 6- methoxyl groups -7- (oxygen of 3- chlorine third
Base) -3- nitro -4-N- o-chloraniline yl-quinolines, yield 86%.
Step 10：By 0.5g (1.19mmol) 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitro -4-N- o-chloranilines
Yl-quinoline is added dropwise the morpholine of 3.5 times of equivalents, temperature is risen into 45 DEG C, reacted 20 hours with 6mL acetone solutions.Question response is complete
It is cooled to room temperature after finishing, dries purifying, 6- methoxyl groups -7- (3-N- the morpholinopropoxies) -3- nitros -4-N- for obtaining 0.43g is adjacent
Chloroaniline yl-quinoline, i.e. compound 2, yield 86%.
By high resolution mass spectrum (HR-ESI-MS), infrared spectrum (IR), proton nmr spectra (1H-NMR), nuclear magnetic resonance
Carbon spectrum (13C-NMR the structure of compound 2) is confirmed：m.p.154-156℃；IR(KBr)cm-1：3421,2961,1576,1523,
1489,1428,1261,1104；1H-NMR(400MHz,CDCl3):δ 2.13 (m, 2H), 2.59 (t, J=7.04Hz, 2H), 3.25
(m, 4H), 3.45 (s, 3H), 3.99 (m, 4H), 4.24 (t, J=6.6Hz, 2H), 6.86 (s, 1H), 7.03 (d, J=7.8Hz,
1H), 7.16 (s, 1H), 7.20 (d, J=8.12Hz, 1H), 7.40 (s, 1H), 9.37 (s, 1H), 10.21 (s, 1H, NH)；13C-
NMR(100MHz,CDCl3):153.9,148.8,148.2,144.9,143.8,142.5,135.3,130.5,129.3(2C),
125.5(2C),123.1,121.2,112.8,110.0,105.9,67.5(2C),55.4,55.2(2C),25.8；HR-ESI-MS
(positivemode)m/z473.1604[M+H]+(calcd473.1591forC23H26Cl1N4O5)。
Embodiment 3：
The preparation of 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- m-chloroaniline yl-quinolines, step is such as
Under：
From step 1 to step 8, the preparation method of totally eight steps is substantially the same manner as Example 1.
Step 9：0.66g (2mmol) compounds h is put into 50mL round-bottomed flasks, is subsequently added into 16mL isopropanols, is heated
Dissolving.3.03mmol m-chloroaniline is added, reacts backflow 5 hours at 100 DEG C.After completion of the reaction room temperature place to have precipitation analyse
Go out, filter, washing, dried with anhydrous magnesium sulfate, obtain 0.57g 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N-
M-chloroaniline yl-quinoline, yield 87%.
Step 10：By 0.55g (1.31mmol) 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitro -4-N- m-chloroanilines
Yl-quinoline is added dropwise the morpholine of 2.0 times of equivalents, temperature is risen into 58 DEG C, reacted 16 hours with 9mL acetone solutions.Question response is complete
It is cooled to room temperature after finishing, dries purifying, obtains between 0.48g 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-N-
Chloroaniline yl-quinoline, i.e. compound 3, yield 87.27%.
By high resolution mass spectrum (HR-ESI-MS), infrared spectrum (IR), proton nmr spectra (1H-NMR), nuclear magnetic resonance
Carbon spectrum (13C-NMR the structure of compound 3) is confirmed：m.p.142-144℃；IR(KBr)cm-1：3420,3286,3037,1561,
1488,1430,1307,1103,1044；1H-NMR(400MHz,CDCl3):δ 2.12 (m, 2H), 2.59 (t, J=7.1Hz, 2H),
3.23 (m, 4H), 3.41 (s, 3H), 3.99 (m, 4H), 4.27 (t, J=6.6Hz, 2H), 6.78 (s, 1H), 6.99 (d, J=
7.6Hz, 1H), 7.20 (m, 2H), 7.39 (s, 1H), 7.55 (t, J=7.6Hz, 1H), 9.37 (s, 1H), 10.15 (s, 1H,
NH)；13C-NMR(100MHz,CDCl3):25.8,53.6(2C),55.2,55.4,66.8(2C),67.4,105.2,110.0,
113.2,124.4,126.4,127.4,128.1,129.5,130.5,138.4,143.9,145.0,148.0,148.9,
153.9；HR-ESI-MS(positivemode)m/z473.1604[M+H]+(calcd473.1592forC23H26ClN4O5)。
Embodiment 4：
The preparation of 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- parachloroanilinum yl-quinolines, step is such as
Under：
From step 1 to step 8, the preparation method of totally eight steps is substantially the same manner as Example 1.
Step 9：0.88g (2.67mmol) compounds h is put into 50mL round-bottomed flasks, 8mL isopropanols is subsequently added into, adds
Heat of solution.2.67mmol parachloroanilinum is added, reacts backflow 5 hours at 90 DEG C.Room temperature is placed to there is precipitation after completion of the reaction
Separate out, filter, washing, dried with anhydrous magnesium sulfate, obtain 0.80g 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-
N- parachloroanilinum yl-quinolines, yield 91%.
Step 10：By 0.80g (1.64mmol) 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitro -4-N- parachloroanilinum
Yl-quinoline is added dropwise the morpholine of 2.5 times of equivalents, temperature is risen into 70 DEG C, reacted 10 hours with 11mL acetone solutions.Question response
After be cooled to room temperature, dry purifying, obtain 0.71g 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-N-
Parachloroanilinum yl-quinoline, i.e. compound 4, yield 88.75%.
By high resolution mass spectrum (HR-ESI-MS), infrared spectrum (IR), proton nmr spectra (1H-NMR), nuclear magnetic resonance
Carbon spectrum (13C-NMR the structure of compound 4) is confirmed：m.p.260-262℃；IR(KBr)cm-1：3421,3315,2360,1569,
1521,1468,1287,1256,1104；1H-NMR(400MHz,CDCl3):δ 2.12 (m, 2H), 2.59 (t, J=7.0Hz, 2H),
3.20 (m, 4H), 3.43 (s, 3H), 3.98 (m, 4H), 4.26 (t, J=6.48Hz, 2H), 6.83 (s, 1H), 7.10 (d, J=
8.4Hz, 2H), 7.29 (s, 1H), 7.37 (d, J=2.80Hz, 2H), 9.36 (s, 1H), 10.22 (s, 1H, NH)；13C-NMR
(100MHz,CDCl3):25.8,53.7(2C),55.3(2C),64.6,66.9(2C),105.9,110.0,112.7,124.7
(2C),129.1,129.7(2C),131.1,139.9,144.3,145.0,148.1,148.7,153.9；HR-ESI-MS
(positivemode)m/z473.1596[M+H]+(calcd473.1591forC23H26ClN4O5)。
Embodiment 5：
The preparation of 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-N- (2,4- dichloroanilino)-quinoline,
Step is as follows：
From step 1 to step 8, the preparation method of totally eight steps is substantially the same manner as Example 1.
Step 9：1g (3.03mmol) compounds h is put into 50mL round-bottomed flasks, is subsequently added into 12mL isopropanols, is heated
Dissolving.3.03mmol 2,4- dichloroanilines are added, react backflow 5 hours at 90 DEG C.Room temperature is placed heavy to having after completion of the reaction
Precipitation goes out, and filters, and washing, is dried with anhydrous magnesium sulfate, obtain 0.92g 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -
4-N- (2,4- dichloroanilino)-quinoline, yield 92%.
Step 10：By 0.90g (1.98mmol) 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- (2,4- bis-
Chloroanilino) with 13mL acetone solutions, the morpholine of 2.0 times of equivalents is added dropwise in-quinoline, and temperature is risen to 63 DEG C, reacted 14 hours.
It is cooled to room temperature after question response, dries purifying, obtain 0.82g 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitre
Base -4-N- (2,4- dichloroanilino)-quinoline, i.e. compound 5, yield 91.11%.
By high resolution mass spectrum (HR-ESI-MS), infrared spectrum (IR), proton nmr spectra (1H-NMR), nuclear magnetic resonance
Carbon spectrum (13C-NMR the structure of compound 5) is confirmed：m.p.127-129℃；IR(KBr)cm-1：3419,3047,1579,1513,
1483,1430,1283,1258；1H-NMR(400MHz,CDCl3):δ 2.18 (m, 2H), 2.60 (t, J=7.04Hz, 2H), 3.24
(m, 4H), 3.51 (s, 3H), 3.99 (m, 4H), 4.28 (t, J=6.56Hz, 2H), 6.73 (s, 1H), 6.84 (d, J=
8.64Hz, 1H), 7.17 (dd, J=2.24,2.2Hz, 1H), 7.42 (s, 1H), 7.58 (d, J=2.08Hz, 1H), 9.38 (s,
1H),10.00(s,1H,NH)；13C-NMR(100MHz,CDCl3):25.7,55.2,55.5,64.1,65.5,104.8,110.1
(2C),113.2,116.3,124.2,127.4,127.6,128.1,128.9,130.0,130.6,137.2,143.1,144.8,
148.1,149.2,154.1；HR-ESI-MS(positivemode)m/z507.1201[M+H]+
(calcd507.1202forC23H25Cl2N4O5)。
Embodiment 6：
The preparation of 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- meta-aminotoluene yl-quinolines, step is such as
Under：
From step 1 to step 8, the preparation method of totally eight steps is substantially the same manner as Example 1.
Step 9：0.64g (1.94mmol) compounds h is put into 50mL round-bottomed flasks, 8mL isopropanols is subsequently added into, adds
Heat of solution.1.94mmol meta-aminotoluene is added, reacts backflow 6 hours at 90 DEG C.Room temperature is placed to there is precipitation after completion of the reaction
Separate out, filter, washing, dried with anhydrous magnesium sulfate, obtain 0.57g 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-
N- meta-aminotoluene yl-quinolines, yield 89%.
Step 10：By toluene between 0.55g (1.375mmol) 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N-
Amine yl-quinoline is added dropwise the morpholine of 1.0 times of equivalents, temperature is risen into 60 DEG C, reacted 12 hours with 7mL acetone solutions.Question response
After be cooled to room temperature, dry purifying, obtain 0.46g 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-N-
Meta-aminotoluene yl-quinoline, i.e. compound 6, yield 83.64%.
By high resolution mass spectrum (HR-ESI-MS), infrared spectrum (IR), proton nmr spectra (1H-NMR), nuclear magnetic resonance
Carbon spectrum (13C-NMR the structure of compound 6) is confirmed：m.p.121-123℃；IR(KBr)cm-1：3420,2959,2360,1578,
1523,1492,1284,1261,1209,1103；1H-NMR(400MHz,CDCl3):δ2.12(m,2H),2.35(s,3H),2.58
(t, J=7.2Hz, 2H), 3.20 (m, 4H), 3.36 (s, 3H), 3.96 (m, 4H), 4.26 (t, J=7.2Hz, 2H), 6.93 (s,
1H), 7.00 (d, J=8.0Hz, 1H), 7.03 (s, 1H), 7.07 (d, J=8.0Hz, 1H), 7.29 (t, J=8.0Hz, 1H),
7.36(s,1H),9.36(s,1H),10.43(s,1H,NH)；13C-NMR(100MHz,CDCl3):21.3,25.8,53.7(2C),
55.2,55.3,66.9(2C),67.4,106.6,110.0,112.7,121.1,124.7,126.9,128.4,129.5,
139.9,141.0,145.1,145.4,148.0,148.2,153.6；HR-ESI-MS(positivemode)m/z453.2169
[M+H]+(calcd453.2138forC24H29N5O4)。
Embodiment 7：
The preparation of 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- m-anisidine yl-quinolines, step
It is rapid as follows：
From step 1 to step 8, the preparation method of totally eight steps is substantially the same manner as Example 1.
Step 9：0.75g (2.27mmol) compounds h is put into 50mL round-bottomed flasks, is subsequently added into 12mL isopropanols,
Dissolve by heating.2.27mmol m-anisidine is added, reacts backflow 6 hours at 90 DEG C.After completion of the reaction room temperature place to
There is Precipitation, filter, washing, dried with anhydrous magnesium sulfate, obtain 0.645g 6- methoxyl groups -7- (3- chlorine propoxyl group) -3-
Nitro -4-N- m-anisidine yl-quinolines, yield 86%.
Step 10：By 0.6g (1.44mmol) 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitro -4-N- meta-methoxies
Aniline yl-quinoline is added the morpholine of 5.0 times of equivalents, temperature is risen into 64 DEG C, reacted 10 hours with 10mL acetone solutions.Treat
Be cooled to room temperature after completion of the reaction, dry purifying, obtain 0.49g 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -
4-N- m-anisidine yl-quinolines, i.e. compound 7, yield 81.67%.
By high resolution mass spectrum (HR-ESI-MS), infrared spectrum (IR), proton nmr spectra (1H-NMR), nuclear magnetic resonance
Carbon spectrum (13C-NMR the structure of compound 7) is confirmed：m.p.169-171℃；IR(KBr)cm-1：3417,2444,2360,1572,
1522,1454,1428,1286,1103；1H-NMR(400MHz,CDCl3):δ 2.12 (m, 2H), 2.56 (t, J=7.04Hz,
2H), 3.23 (m, 4H), 3.40 (s, 3H), 3.77 (s, 3H), 4.00 (m, 4H), 4.24 (t, J=6.6Hz, 2H), 6.72 (s,
1H), 6.78 (dd, J=8.36,8.0Hz, 1H), 6.96 (s, 1H), 7.27 (d, J=3.52Hz, 2H), 7.37 (s, 1H), 9.36
(s,1H),10.36(s,1H,NH)；13C-NMR(100MHz,CDCl3):160.7,153.5,148.2,147.9,145.2,
144.8,142.2,130.3,128.5,116.1,112.8,111.5,109.8,109.6,106.3,67.366.7,64.1,
55.5,55.3,55.2,53.6,43.5,25.7；HR-ESI-MS(positivemode)m/z469.2087[M+H]+
(calcd469.2087forC24H29N4O6)。
Embodiment 8：
The preparation of hydroxyanilines yl-quinoline, step between 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-N-
It is as follows：
From step 1 to step 8, the preparation method of totally eight steps is substantially the same manner as Example 1.
Step 9：0.71g (2.15mmol) compounds h is put into 50mL round-bottomed flasks, is subsequently added into 12mL isopropanols,
Dissolve by heating.Add hydroxyanilines between 2.15mmol, reaction backflow 9 hours at 82 DEG C.Room temperature is placed to having after completion of the reaction
Precipitation, filter, washing, dried with anhydrous magnesium sulfate, obtain 0.47g 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitre
Hydroxyanilines yl-quinoline between base -4-N-, yield 66%.
Step 10：By hydroxy benzenes between 0.45g (1.12mmol) 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N-
Amine yl-quinoline is added dropwise the morpholine of 4.0 times of equivalents, temperature is risen into 61 DEG C, reacted 11 hours with 5mL acetone solutions.Question response
After be cooled to room temperature, dry purifying, obtain 0.34g 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-N-
Between hydroxyanilines yl-quinoline, i.e. compound 8, yield 75.56%.
By high resolution mass spectrum (HR-ESI-MS), infrared spectrum (IR), proton nmr spectra (1H-NMR), nuclear magnetic resonance
Carbon spectrum (13C-NMR the structure of compound 8) is confirmed：m.p.81-83℃；IR(KBr)cm-1：3417,2444,1618,1455,
1432,1286,1104；1H-NMR(400MHz,CDCl3):δ 2.07 (m, 2H), 2.55 (t, J=6.96Hz, 2H), 3.40 (m,
4H), 3.50 (s, 3H), 3.89 (m, 4H), 4.21 (t, J=6.32Hz, 2H), 5.32 (s, 2H), 6.56 (s, 1H), 6.78 (d, J
=6.8Hz, 2H), 6.98 (s, 1H), 7.24 (t, J=7.8Hz, 1H), 9.28 (s, 1H), 10.30 (s, 1H, NH)；13C-NMR
(100MHz,CDCl3):158.3,153.6,148.2,147.6,145.1,144.9,142.1,130.5,128.4,115.1,
113.5,112.8,111.1,109.4,106.5,67.4,66.8,65.2,55.3,55.2,53.6,44.3,25.8；HR-ESI-
MS(positivemode)m/z455.1946[M+H]+(calcd455.1930forC23H27N4O6)。
Embodiment 9：
The preparation of 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- para hydroxybenzene amine yl-quinolines, step
It is as follows：
From step 1 to step 8, the preparation method of totally eight steps is substantially the same manner as Example 1.
Step 9：1g (3.03mmol) compounds h is put into 50mL round-bottomed flasks, is subsequently added into 12mL isopropanols, is heated
Dissolving.3.03mmol para hydroxybenzene amine is added, reacts backflow 7 hours at 90 DEG C.Room temperature is placed to there is precipitation after completion of the reaction
Separate out, filter, washing, dried with anhydrous magnesium sulfate, obtain 0.79g 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-
N- para hydroxybenzene amine yl-quinolines, yield 79%.
Step 10：By 0.75g (1.86mmol) 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitro -4-N- para hydroxybenzenes
Amine yl-quinoline is added dropwise the morpholine of 3.0 times of equivalents, temperature is risen into 55 DEG C, reacted 18 hours with 10mL acetone solutions.Treat anti-
It is cooled to room temperature after answering, dries purifying, obtain 0.59g 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-
N- para hydroxybenzene amine yl-quinolines, i.e. compound 9, yield 78.67%.
By high resolution mass spectrum (HR-ESI-MS), infrared spectrum (IR), proton nmr spectra (1H-NMR), nuclear magnetic resonance
Carbon spectrum (13C-NMR the structure of compound 9) is confirmed：m.p.161-163℃；IR(KBr)cm-1：3256,2957,1586,1508,
1264,1153,1115；1H-NMR(400MHz,CDCl3):δ 2.09 (m, 2H), 2.51 (m, 4H), 2.58 (t, J=7.34Hz,
2H), 3.38 (s, 3H), 3.94 (m, 4H), 4.21 (t, J=6.26Hz, 2H), 6.88 (s, 1H), 7.00 (s, 1H), 7.10 (d, J
=8.52Hz, 2H), 7.25 (s, 1H), 9.29 (s, 1H)；13C-NMR(100MHz,CDCl3):25.7,45.8,48.5,48.7,
49.5,49.7,53.1,55.3,67.2,67.6,106.6,109.3,112.3,116.3,126.4,127.1,132.3,
145.4,146.2,147.3,147.8,153.4,155.9；HR-ESI-MS(positivemode)m/z455.1948[M+H]+
(calcd455.1930forC23H27N4O6)。
Cholinesterase inhibition determines
Suppression of the compound to acetylcholinesterase (AChE) and butyrylcholine esterase (BChE) obtained by above example
Screening active ingredients processed：
AChE and BChE inhibitory activity measure is carried out using improved Ellman methods.140 μ L are sequentially added in 96 orifice plates
Phosphate buffer (100mmol/L), AChE (20 μ L, 0.05U/mL) or BChE (20 μ L, 0.05U/mL), testing compound 20
μ L, it is put into after well mixed in 25 DEG C of insulating boxs and cultivates 15min.Then 10 μ LDNTB (10.0mmol/L) and ATCI (10 μ are added
L, 7.5mmol/L) or BTCI (10 μ L, 7.5mmol/L), place into insulating box, after cultivating 30min at 37 DEG C, with enzyme mark
Instrument determines each hole absorbance value (OD) at 412nm wavelength.Testing compound is replaced as positive control by the use of 20 μ L galanthamines,
Blank group is then to replace testing compound by adding 20 μ L phosphate buffers (100mmol/L).Every group of data are parallel to do 3
It is secondary, average.Record result and by formula calculate inhibiting rate [inhibiting rate (%)=(OD blank-OD samples)/OD blank ×
, while calculation of half inhibitory concentration IC 100%]50Value.Determination of activity result is as shown in table 1：
The cholinesterase inhibition result of table 1
Quasi-medicated property is evaluated
The lipophilicity of compound obtained by above example is calculated as follows through ChemDraw softwares：
The LogP values of 2 each compound of table
| Compound 1 | Compound 2 | Compound 3 | Compound 4 | Compound 5 | Compound 6 | Compound 7 | Compound 8 | Compound 9 | |
| LogP values | 3.41 | 4.03 | 4.03 | 4.03 | 4.65 | 3.83 | 3.54 | 3.02 | 3.02 |
The testing result of table 1 shows that such compound is respectively provided with good suppression to acetylcholinesterase and butyrylcholine esterase
Effect, the result of table 2 show that such compound lipophilicity meets the quasi-medicated property LogP indexs of anti-AD medicines, have anti-applied to preparing
The prospect of Alzheimer disease drugs.
The above, only it is representative embodiment of the present invention, not makees any type of limitation to the present invention.Every foundation
Any modification, equivalent variations and the modification that the technical spirit of the present invention is made to above example, still fall within the technology of the present invention
In the range of scheme.
Claims (6)
1.4-N- anilino quinolines class compounds, it is characterised in that its chemical structural formula is as follows：
R in structural formula1For phenyl, Chloro-O-Phenyl, a chlorphenyl, rubigan, 2,4 dichloro benzene base, a tolyl, meta-methoxy
Phenyl, a hydroxy phenyl or p-hydroxybenzene.
2. 4-N- anilino quinolines class compound as claimed in claim 1, it is characterised in that：The compound specifically includes 6-
Methoxyl group -7- (3-N- morpholinopropoxies) -3- nitro -4-N- aniline yl-quinoline, the 6- methoxyl groups -7- (oxygen of 3-N- morpholinyls third
Base) -3- nitro -4-N- o-chloranilines yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- m-chloros
Aniline yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- parachloroanilinum yl-quinoline, 6- methoxies
Base -7- (3-N- morpholinopropoxies) -3- nitros -4-N- (2,4 dichloro benzene amido)-quinoline, 6- methoxyl groups -7- (3-N- morpholines
Base propoxyl group) -3- nitro -4-N- meta-aminotoluenes yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-
Hydroxy benzenes amido between N- m-anisidines yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-N- -
Quinoline and 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- para hydroxybenzene amine yl-quinolines.
A kind of 3. synthetic method of 4-N- anilino quinolines class compounds as claimed in claim 1, it is characterised in that：Using acetone as
Solvent, reaction system is carried out by 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- substituted anilines yl-quinolines and morpholine
It is standby to form, comprise the following steps that：
By 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- substituted anilines yl-quinolines with acetone solution, morphine is added dropwise
Quinoline, heat up and reacted after being added dropwise, be cooled to room temperature after completion of the reaction, dry purifying, obtain target compound.
4. the synthetic method of 4-N- anilino quinolines class compound according to claim 3, it is characterised in that：The 6- methoxies
Base -7- (3- chlorine propoxyl group) -3- nitro -4-N- substituted anilines yl-quinoline be 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -
4-N- aniline yl-quinoline, 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitro -4-N- o-chloranilines yl-quinoline, 6- methoxyl groups -
7- (3- chlorine propoxyl group) -3- nitro -4-N- m-chloroanilines yl-quinoline, 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N-
Parachloroanilinum yl-quinoline, 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- (2,4 dichloro benzene amido)-quinoline, 6- first
Epoxide -7- (3- chlorine propoxyl group) -3- nitro -4-N- meta-aminotoluenes yl-quinoline, 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitre
Hydroxy benzenes amido-quinoline between base -4-N- m-anisidines yl-quinoline, 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N-
Quinoline or 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitro -4-N- para hydroxybenzene amine yl-quinolines.
5. according to the synthetic method of the 4-N- anilino quinolines class compound of claim 3 or 4, it is characterised in that：The 6-
The mol ratio of methoxyl group -7- (3- chlorine propoxyl group) -3- nitros -4-N- substituted anilines yl-quinolines and morpholine is 1:1.0-5.0；
After being added dropwise, 10~20h of insulation reaction, holding temperature is 45~70 DEG C.
6. the application of the 4-N- anilino quinolines class compounds described in claim 1 or 2, it is characterised in that：Described compound
With the double activity suppressed of acetylcholinesterase and butyrylcholine esterase, lipophilicity is suitable, available for preparing anti-Alzheimer
Sick class medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114805201A (en) * | 2021-01-21 | 2022-07-29 | 天津理工大学 | Preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives |
| CN115466211A (en) * | 2022-06-09 | 2022-12-13 | 中国人民解放军空军军医大学 | N-phenylquinoline-4-amine compound and application thereof |
-
2017
- 2017-10-09 CN CN201710927870.7A patent/CN107721923A/en active Pending
Non-Patent Citations (1)
| Title |
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| 胡栋: "《吗啉或 N-乙基哌嗪基团取代的喹啉类衍生物合成及生物活性研究》", 10 October 2018 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114805201A (en) * | 2021-01-21 | 2022-07-29 | 天津理工大学 | Preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives |
| CN114805201B (en) * | 2021-01-21 | 2024-09-13 | 陕西蒲城万德科技有限公司 | Preparation method and application of 2-N-morpholinoethoxy group substituted quinoline derivative |
| CN115466211A (en) * | 2022-06-09 | 2022-12-13 | 中国人民解放军空军军医大学 | N-phenylquinoline-4-amine compound and application thereof |
| CN115466211B (en) * | 2022-06-09 | 2024-02-23 | 中国人民解放军空军军医大学 | N-phenylquinoline-4-amine compound and application thereof |
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