CN108794458A - A kind of preparation method of aryl substituted pyrimidine amine acyl derivative - Google Patents
A kind of preparation method of aryl substituted pyrimidine amine acyl derivative Download PDFInfo
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- 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
Abstract
The invention discloses a kind of preparation methods of aryl substituted pyrimidine amine acyl derivative,Include the preparation of 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone,The preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine and the preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- acyl derivative amine,It is using ATP-binding cassette superfamily P-gp discharging systems and RND families AcrAB-TolC discharging systems as research object,Design the efflux pump inhibitor of the aminopyrimidine acyl derivative of aryl substitution,Using 4- (4- methyl piperazines base) benzaldehyde as primary raw material,It is eliminated by Michael's addition,Cyclization obtains target compound with three-step reaction is acylated,The preparation method high selectivity,It is easy to operate,Raw material is easy to get,Mild condition,Wish that the derivative can play antibacterial synergistic activity,With huge economic value and far-reaching social effect.
Description
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a kind of aryl substituted pyrimidine amine acyl derivative
Preparation method.
Background technology
On April 30th, 2014, WHO are investigated according to 114 national data, and are issued report and claimed, antibiotics resistance
Property bacterium just spreads to all parts of the world.Report sincere advice medical worker should control antibiotic prescription in necessary minimum limit.
Appeal that general patient only just uses antibiotic in doctor's prescription simultaneously.According to the report, bacterial antibiotic develops immunity to drugs
The problem of the U.S. has become one and grows rapidly.The World Health Organization once warned that this was the most heavy of Global Health
One of big threat.Due to abusing for antibiotic, in Europe, Canada and China all it has been found that superbug.British media claims, Britain
A authority's research report is pointed out, if the problems such as countries in the world are not with regard to abuse of antibiotics is promptly taken action, to the year two thousand fifty,
So-called superbug will lead to patient's death in every three seconds.Report also appeals to initiate one in terms of antibiotic medication
Field " revolution ", for its terrible large-scale mass education activity of expansion.
Maximum country of consumption of the China as world's human and veterinary antibiotic, oath will reinforce grinding for novel antibacterial drug
The excessive use for sending out and controlling existing drug, to cope with increasing bacterial resistance sex chromosome mosaicism.Chinese Government issued one
Transfer is included the strength of 14 ministries and commissions such as health, food and medicine and agricultural by item national plan of action.The target of government is：It arrives
The year two thousand twenty researches and develops several novel antibacterial drugs；Antibacterials could be sold with prescription；Reinforcement makes human and veterinary antibacterials
Supervision；Reinforce rationally applying medical worker and consumer the training of antibacterials.
According to research reports, the main reason for bacterium generation drug resistance, is that extra-pumping system excretes antibacterials
Caused by.However, multiple outer row's resistance mechanism of bacterium is respectively by ATP-binding cassette superfamily P-gp discharging systems and RND families
AcrAB-TolC discharging systems generate, and use both discharging systems as research object now, and design aryl replaces phonetic
The preparation method of the efflux pump inhibitor of pyridine amine acyl derivative then has not been reported.
Invention content
The present invention is directed to solve at least some of the technical problems in related technologies.For this purpose, the present invention
The aryl substituted pyrimidine amine acyl group that main purpose is to provide a kind of high selectivity, easy to operate, raw material is easy to get with mild condition
Change the preparation method of derivative.
The purpose of the present invention is what is be achieved through the following technical solutions：
A kind of preparation method of aryl substituted pyrimidine amine acyl derivative, which is characterized in that include the following steps：
1) alkali and organic solvent are added in reaction bulb, are stirred at room temperature uniformly, 4- (4- methyl piperazines base) is then added
2- acetyl thiophenes are slowly added dropwise in benzaldehyde, are stirred to react at a temperature of 30-60 DEG C, and reaction is monitored eventually with thin-layered chromatography
Point filters, obtains faint yellow solid powder 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone；
2) alkali and organic solvent are added in reaction bulb, are stirred at room temperature uniformly, 1- (2- thienyls) -3- is then added
(4- (4- methyl piperazines base) phenyl)-propenone and guanidine hydrochloride, it is 50-90 DEG C to be heated to temperature, is stirred to react, with thin layer color
Spectrometry monitors reaction end, filters, obtains faint yellow solid powder 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl) -
Pyrimidine -2- amine；
3) 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine and organic solvent are added to
In reaction bulb, under the conditions of ice-water bath, Lewis acid catalysts is added, acylate are then slowly added dropwise, in 5-25 DEG C of temperature
It is stirred to react under degree, monitors reaction end with thin-layered chromatography, it is 12 to adjust pH, is extracted with ethyl acetate, uses saturated salt solution
Solvent, vacuum drying is concentrated under reduced pressure in washing, anhydrous magnesium sulfate drying, and crude product volume ratio is 7:3:0.1 petroleum ether, acetone
Silica gel column chromatography is carried out with triethylamine to detach, and obtains yellow solid powder 4- (2- thienyls) -6- (4- (4- methyl piperazines base) benzene
Base)-pyrimidine -2- acyl derivative amine.
Preferably, wherein alkali in the step 1)：4- (4- methyl piperazines base) benzaldehyde：Mole of 2- acetyl thiophenes
Proportioning is (5-15)：1：(1-2).
Preferably, wherein the organic solvent in the step 1) and step 2) is absolute ethyl alcohol, absolute methanol, acetic acid
One or any two or more mixture in ethyl ester and N-Methyl pyrrolidone.
Preferably, wherein the alkali in the step 1) and step 2) is sodium hydroxide, potassium hydroxide, potassium carbonate, carbonic acid
One kind in sodium and sodium hydride.
Preferably, the step of wherein described 2) in alkali：1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl) -
Propenone：The mol ratio of guanidine hydrochloride is (5-15)：1：(1-2).
Preferably, the step of wherein described 3) in 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-it is phonetic
Pyridine -2- amine：Acylate：The mol ratio of Lewis acid catalysts is 1：(2-5)：(3-6).
Preferably, the step of wherein described 3) in acylate be chloroacetic chloride, propionyl chloride, butyl chloride, valeric chloride and oneself
One kind in acyl chlorides.
Preferably, the step of wherein described 3) in Lewis acid catalysts be aluminum trichloride (anhydrous), iron chloride, zinc chloride
With the one or any two or more mixture in ferric bromide.
Preferably, the step of wherein described 3) in organic solvent be pyrroles, pyridine and N-Methyl pyrrolidone in one
Kind or arbitrary two or more mixture.
The preparation method of aryl substituted pyrimidine amine acyl derivative provided by the present invention, reaction route are as follows：
Compared with prior art, the present invention has at least the following advantages：
The preparation method of a kind of aryl substituted pyrimidine amine acyl derivative provided by the present invention, with ATP-binding cassette superfamily P-
Gp discharging systems and the two discharging systems of RND families AcrAB-TolC discharging systems devise aryl and take as research object
The efflux pump inhibitor of the aminopyrimidine acyl derivative in generation, and invented the fully synthetic preparation method of the derivative, i.e., with
4- (4- methyl piperazines base) benzaldehyde is primary raw material, is obtained by Michael's addition elimination, cyclization and acylation three-step reaction
To target compound, which has the characteristics that high selectivity, easy to operate, raw material is easy to get and mild condition, it is desirable to should
Derivative can play antibacterial synergistic activity, have huge economic value and far-reaching social effect.
Specific implementation mode
With reference to embodiment, the invention will be further described, and following embodiment is descriptive, is not limited
, protection scope of the present invention cannot be limited with this.
The preparation method of aryl substituted pyrimidine amine acyl derivative of the present invention, including 1- (2- thienyls) -3- (4- (4-
Methyl piperazine base) phenyl) preparation of-propenone, 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2-
The system of the preparation of amine and 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- acyl derivative amine
Standby, specific preparation process is as follows：
1) preparation of 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone, synthetic route are：
Specially：Alkali and organic solvent are added in reaction bulb, is stirred at room temperature uniformly, 4- (4- methyl piperazines is then added
Piperazine base) benzaldehyde, 2- acetyl thiophenes are slowly added dropwise, are stirred to react at a temperature of 30-60 DEG C, are monitored with thin-layered chromatography anti-
Terminal is answered, filters, obtains faint yellow solid powder 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone；
2) preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine, synthetic route
For：
Specially：Alkali and organic solvent are added in reaction bulb, is stirred at room temperature uniformly, 1- (2- thiophene is then added
Base) -3- (4- (4- methyl piperazines base) phenyl)-propenone and guanidine hydrochloride, it is 50-90 DEG C to be heated to temperature, is stirred to react, and is used
Thin-layered chromatography monitors reaction end, filters, obtains faint yellow solid powder 4- (2- thienyls) -6- (4- (4- methyl piperazines base)
Phenyl)-pyrimidine -2- amine；
3) preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- acyl derivative amine,
Its synthetic route is：
Specially：4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine and organic solvent are added
Enter into reaction bulb, under the conditions of ice-water bath, Lewis acid catalysts is added, acylate are then slowly added dropwise, at 5-25 DEG C
At a temperature of be stirred to react, with thin-layered chromatography monitor reaction end, adjust pH be 12, be extracted with ethyl acetate, with saturation eat
Solvent, vacuum drying is concentrated under reduced pressure in salt water washing, anhydrous magnesium sulfate drying, and crude product volume ratio is 7:3:0.1 petroleum ether,
Acetone and triethylamine carry out silica gel column chromatography separation, obtain yellow solid powder 4- (2- thienyls) -6- (4- (4- methyl piperazines
Base) phenyl)-pyrimidine -2- acyl derivative amine.
Alkali wherein in step 1)：4- (4- methyl piperazines base) benzaldehyde：The mol ratio of 2- acetyl thiophenes is (5-
15)：1：(1-2).
Organic solvent wherein in step 1) and step 2) is absolute ethyl alcohol, absolute methanol, ethyl acetate and N- methyl pyrroles
One or any two or more mixture in pyrrolidone.
Alkali wherein in step 1) and step 2) is in sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydride
One or any two kinds of mixture.
Alkali wherein in step 2)：1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone：Guanidine hydrochloride
Mol ratio be (5-15)：1：(1-2).
4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine wherein in step 3)：It is acylated
Object：The mol ratio of Lewis acid catalysts is 1：(2-5)：(3-6).
Acylate wherein in step 3) is one kind in chloroacetic chloride, propionyl chloride, butyl chloride, valeric chloride and caproyl chloride.
Lewis acid catalysts wherein in step 3) are in aluminum trichloride (anhydrous), iron chloride, zinc chloride and ferric bromide
One or any two or more mixture.
Organic solvent wherein in step 3) is one or any two in pyrroles, pyridine and N-Methyl pyrrolidone
Kind or more mixture.
Embodiment 1：
(1), the preparation of 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone：
Sodium hydroxide 1.0mol and absolute methanol 400ml are added in reaction bulb, are stirred at room temperature, 4- (4- are then added
Methyl piperazine base) benzaldehyde 0.1mol, 2- acetyl thiophene 0.1mol are slowly added dropwise, drop finishes, and 40 DEG C are stirred to react, with thin layer color
Spectrometry monitors reaction end, is cooled to room temperature, and filters, obtains faint yellow solid powder, yield 80-85%.
(2), the preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine：
Sodium hydroxide 0.8mol and absolute methanol 500ml are added in reaction bulb, are stirred at room temperature, 1- (2- are then added
Thienyl) -3- (4- (4- methyl piperazines base) phenyl)-propenone 0.1mol and guanidine hydrochloride 0.12mol, it is heated to 65 DEG C of stirrings
Reaction monitors reaction end with thin-layered chromatography, is cooled to room temperature, filters, obtain faint yellow solid powder, yield 86-
90%.
(3), the preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- acetyl amines：
4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine 0.01mol and pyrroles 80ml is added
Enter into reaction bulb, be stirred at room temperature, under the conditions of ice-water bath, aluminum trichloride (anhydrous) 0.03mol is added, second is then slowly added dropwise
Acyl chlorides 0.025mol drips and finishes, and 15 DEG C are stirred to react, and monitors reaction end with thin-layered chromatography, reaction is finished, and is added under the conditions of ice water
It is 12 to enter 5% sodium hydroxide solution to adjust pH, and ethyl acetate extracts 3 times (using 30ml every time), merges organic layer, is eaten with saturation
2 organic layers of salt water washing (use 30ml) every time, and solvent, vacuum drying, crude product stone is concentrated under reduced pressure in anhydrous magnesium sulfate drying
Oily ether：Acetone：Triethylamine=7:3:0.1 (volume ratio) carries out silica gel column chromatography separation, obtains yellow solid powder, chemical formula is
C21H23N5OS, yield 50-55%.
4- (2- thienyls)-is made in the preparation method of aryl substituted pyrimidine amine acyl derivative provided by the present invention
The spectral data of 6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- acetyl amines is：
FAB-MS(m/z):394[M+H]+.1H-NMR (400MHz, DMSO-d6),δ2.23(s,3H,NCH3)； 2.46(t,
J=5.1Hz, 4H, N (CH2)2)；2.67 (q, J=7.5Hz, 3H, COCH3)；3.31 (t, J=5.1Hz, 4H, N (CH2)2)；
7.02-7.09(m,2H,ArH)；7.27 (dd, J=5.1,3.8Hz, 1H, ArH)；7.80 (dd, J=5.1,1.1Hz, 1H,
ArH)；8.09(s,1H,ArH)；8.18-8.21(m,2H,ArH)；8.24 (dd, J=3.7,1.1Hz, 1H, ArH)；10.32(s,
1H,NH)。
Embodiment 2：
(1), the preparation of 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone：
Sodium carbonate 1.25mol and absolute ethyl alcohol 500ml are added in reaction bulb, are stirred at room temperature, 4- (4- are then added
Methyl piperazine base) benzaldehyde 0.1mol, 2- acetyl thiophene 0.2mol are slowly added dropwise, drop finishes, and 56 DEG C are stirred to react, with thin layer color
Spectrometry monitors reaction end, is cooled to room temperature, and filters, obtains faint yellow solid powder, yield 80-84%.
(2), the preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine：
Sodium hydroxide 1.125mol and absolute methanol 300ml and absolute ethyl alcohol 200ml are added in reaction bulb, room temperature
Then 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone 0.1mol and guanidine hydrochloride is added in stirring
0.12mol is heated to 80 DEG C and is stirred to react, and monitors reaction end with thin-layered chromatography, is cooled to room temperature, filters, obtain faint yellow
Solid powder, yield 85-90%.
(3) preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- propiono amine：
4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine 0.01mol and pyridine 80ml is added
Enter into reaction bulb, be stirred at room temperature, under the conditions of ice-water bath, ferric trichloride 0.045mol is added, propionyl chloride is then slowly added dropwise
0.025mol, drop finish, and 10 DEG C are stirred to react, and monitor reaction end with thin-layered chromatography, reaction is finished, and 5% is added under the conditions of ice water
It is 12 that sodium hydroxide solution, which adjusts pH, and ethyl acetate extracts 3 times (using 30ml every time), merges organic layer, is washed with saturated common salt
2 organic layers (using 30ml every time) are washed, solvent, vacuum drying, crude product petroleum ether is concentrated under reduced pressure in anhydrous magnesium sulfate drying：Third
Ketone：Triethylamine=7:3:0.1 (volume ratio) carries out silica gel column chromatography separation, obtains faint yellow solid powder, chemical formula is
C22H25N5OS, yield 50-55%.
4- (2- thienyls)-is made in the preparation method of aryl substituted pyrimidine amine acyl derivative provided by the present invention
The spectral data of 6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- propiono amine is：
FAB-MS(m/z):408[M+H]+.1H-NMR (400MHz, DMSO-d6), δ 1.11 (t, J=7.5Hz, 3H,
CH3)；2.23(s,3H,NCH3)；2.46 (t, J=5.1Hz, 4H, N (CH2)2)；2.67 (q, J=7.4Hz, 2H, COCH2)；
3.31 (t, J=5.1Hz, 4H, N (CH2)2)；7.02-7.1(m,2H,ArH)；7.27 (dd, J=5.0,3.7Hz, 1H, ArH)；
7.81 (dd, J=5.1,1.1Hz, 1H, ArH)；8.09(s,1H,ArH)；8.19-8.22(m,2H,ArH)；8.25 (dd, J=
3.8,1.1Hz, 1H,ArH)；10.33(s,1H,NH).
Embodiment 3：
(1), the preparation of 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone：
Potassium hydroxide 0.5mol and absolute ethyl alcohol 200ml and ethyl acetate 200ml are added in reaction bulb, room temperature is stirred
It mixes, 4- (4- methyl piperazines base) benzaldehyde 0.1mol is then added, 2- acetyl thiophene 0.1mol are slowly added dropwise, drop finishes, and 60 DEG C are stirred
Reaction is mixed, reaction end is monitored with thin-layered chromatography, is cooled to room temperature, filter, obtain faint yellow solid powder, yield 85-
90%.
(2), the preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine：
Potassium hydroxide 1.2mol and ethyl acetate 500ml are added in reaction bulb, are stirred at room temperature, 1- (2- are then added
Thienyl) -3- (4- (4- methyl piperazines base) phenyl) 0.12 mol of-propenone 0.1mol and guanidine hydrochloride, it is heated to 72 DEG C of stirrings
Reaction monitors reaction end with thin-layered chromatography, is cooled to room temperature, filters, obtain faint yellow solid powder, yield 87-
91%.
(3) preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- bytyry amine：
By 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine 0.01mol and pyrroles 80ml and
N-Methyl pyrrolidone 70ml is added in reaction bulb, is stirred at room temperature, and under the conditions of ice-water bath, aluminum trichloride (anhydrous) is added
Then butyl chloride 0.05mol is slowly added dropwise in 0.06mol, drop finishes, and 20 DEG C are stirred to react, and reaction is monitored eventually with thin-layered chromatography
Point, reaction are finished, and it is 12 that 5% sodium hydroxide solution is added under the conditions of ice water and adjusts pH, and ethyl acetate extracts 3 times and (uses every time
30ml), merge organic layer, with 2 organic layers of saturated common salt water washing (using 30ml every time), anhydrous magnesium sulfate drying, decompression is dense
Contracting solvent, vacuum drying, crude product petroleum ether：Acetone：Triethylamine=7:3:0.1 (volume ratio) carries out silica gel column chromatography separation,
Obtain faint yellow solid powder, chemical formula C23H27N5OS, yield 48-52%.
4- (2- thienyls)-is made in the preparation method of aryl substituted pyrimidine amine acyl derivative provided by the present invention
The spectral data of 6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- bytyry amine is：
FAB-MS(m/z):422[M+H]+.1H-NMR (400MHz, DMSO-d6), δ 0.97 (t, J=7.3Hz, 3H,
CH3)；1.63 (q, J=7.5Hz, 2H, CH2)；2.24(s,3H,NCH3)；2.46 (t, J=5.1Hz, 4H, N (CH2)2)；2.66
(t, J=7.5Hz, 2H, COCH2)；3.30 (t, J=5.2Hz, 4H, N (CH2)2)；7.03-7.1(m,2H,ArH)；7.26(dd,J
=5.0,3.6Hz, 1H, ArH)；7.83 (dd, J=5.1,1.0Hz, 1H, ArH)；8.08(s,1H,ArH)；8.20 (d, J=
9.2Hz, 2H,ArH)；8.26 (dd, J=3.9,1.2Hz, 1H, ArH)；10.34(s,1H,NH).
Embodiment 4：
(1), the preparation of 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone：
Sodium hydride 1.5mol and N-Methyl pyrrolidone 600ml are added in reaction bulb, are stirred at room temperature, is then added
2- acetyl thiophene 0.2mol are slowly added dropwise in 4- (4- methyl piperazines base) benzaldehyde 0.1mol, and drop finishes, and 60 DEG C are stirred to react, and use is thin
Layer chromatography monitors reaction end, is cooled to room temperature, and filters, obtains faint yellow solid powder, yield 83-86%.
(2), the preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine：
Sodium carbonate 0.8mol and absolute ethyl alcohol 500ml are added in reaction bulb, are stirred at room temperature, 1- (2- thiophenes are then added
Pheno base) -3- (4- (4- methyl piperazines base) phenyl)-propenone 0.1mol and guanidine hydrochloride 0.15mol, it is anti-to be heated to 52 DEG C of stirrings
It answers, monitors reaction end with thin-layered chromatography, be cooled to room temperature, filter, obtain faint yellow solid powder, yield 86-90%.
(3) preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- valeryl amine：
By 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine 3.55 (0.01mol), pyrroles
80ml and pyridine 60ml are added in reaction bulb, are stirred at room temperature, and under the conditions of ice-water bath, zinc chloride 0.05mol are added, then
Valeric chloride 0.025mol is slowly added dropwise, drop finishes, and 10 DEG C are stirred to react, and monitors reaction end with thin-layered chromatography, reaction is finished, ice
It is 12 that 5% sodium hydroxide solution is added under water condition and adjusts pH, and ethyl acetate extracts 3 times (using 30ml every time), merges organic
Layer, with 2 organic layers of saturated common salt water washing (using 30ml every time), solvent is concentrated under reduced pressure in anhydrous magnesium sulfate drying, and vacuum is dry
It is dry, crude product petroleum ether：Acetone：Triethylamine=7:3:0.1 (volume ratio) carries out silica gel column chromatography separation, and it is solid to obtain light brown
Body powder, chemical formula C24H29N5OS, yield 45-49%.
4- (2- thienyls)-is made in the preparation method of aryl substituted pyrimidine amine acyl derivative provided by the present invention
The spectral data of 6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- valeryl amine is：
FAB-MS(m/z):436[M+H]+.1H-NMR (400MHz, DMSO-d6), δ 0.94 (t, J=7.5Hz, 3H,
CH3)；1.38 (h, J=7.5Hz, 2H, CH2)；1.62 (q, J=7.6Hz, 2H, CH2)；2.24(s,3H,NCH3)；2.45(t, J
=5.1Hz, 4H, N (CH2)2)；2.66 (q, J=7.4Hz, 2H, COCH2)；3.31 (t, J=5.1Hz, 4H, N (CH2)2)；7.06
(d, J=9.2Hz, 2H, ArH)；7.27 (dd, J=5.1,3.8Hz, 1H, ArH)；7.82 (dd, J=5.1,1.1Hz, 1H,
ArH)； 8.08(s,1H,ArH)；8.20 (d, J=9.2Hz, 2H, ArH)；8.26 (dd, J=3.9,1.2Hz, 1H, ArH)；
10.34(s, 1H,NH)。
Embodiment 5：
(1), the preparation of 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone：
Sodium hydroxide 1.2mol and ethyl acetate 400ml are added in reaction bulb, are stirred at room temperature, 4- (4- are then added
Methyl piperazine base) benzaldehyde 0.1mol, 2- acetyl thiophene 0.12mol are slowly added dropwise, drop finishes, and 37 DEG C are stirred to react, with thin layer color
Spectrometry monitors reaction end, is cooled to room temperature, and filters, obtains faint yellow solid powder, yield 85-89%.
(2), the preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine：
Potassium carbonate 1.3mol and absolute methanol 500ml are added in reaction bulb, are stirred at room temperature, 1- (2- thiophenes are then added
Pheno base) -3- (4- (4- methyl piperazines base) phenyl)-propenone 0.1mol and guanidine hydrochloride 0.18mol, it is anti-to be heated to 90 DEG C of stirrings
It answers, monitors reaction end with thin-layered chromatography, be cooled to room temperature, filter, obtain faint yellow solid powder, yield 88-92%.
(3) preparation of 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- caproyl amine：
4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine 0.01mol and pyrroles 80ml is added
Enter into reaction bulb, be stirred at room temperature, under the conditions of ice-water bath, ferric bromide 0.05mol is added, caproyl chloride is then slowly added dropwise
0.03mol, drop finish, and 25 DEG C are stirred to react, and monitor reaction end with thin-layered chromatography, reaction is finished, and 5% is added under the conditions of ice water
It is 12 that sodium hydroxide solution, which adjusts pH, and ethyl acetate extracts 3 times (using 30ml every time), merges organic layer, is washed with saturated common salt
2 organic layers (using 30ml every time) are washed, solvent, vacuum drying, crude product petroleum ether is concentrated under reduced pressure in anhydrous magnesium sulfate drying：Third
Ketone：Triethylamine=7:3:0.1 (volume ratio) carries out silica gel column chromatography separation, obtains crocus solid powder, chemical formula is
C25H31N5OS, yield 40-43%.
4- (2- thienyls)-is made in the preparation method of aryl substituted pyrimidine amine acyl derivative provided by the present invention
The spectral data of 6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- caproyl amine is：
FAB-MS(m/z):450[M+H]+.1H-NMR (400MHz, DMSO-d6),δ0.91(m,3H,CH3)；1.35 (m,
4H,CH2CH2)；1.58-1.67(m,2H,CH2)；2.24(s,3H,NCH3)；2.47 (t, J=5.1Hz, 4H, N (CH2)2)；
2.66 (q, J=7.4Hz, 2H, COCH2)；3.31 (t, J=5.1Hz, 4H, N (CH2)2)；7.06-7.10(m,2H, ArH)；
7.27 (dd, J=5.1,3.8Hz, 1H, ArH)；7.82 (dd, J=5.1,1.1Hz, 1H, ArH)；8.08(s,1H,ArH)；
8.20 (d, J=9.2Hz, 2H, ArH)；8.26 (dd, J=3.9,1.2Hz, 1H, ArH)；10.34(s,1H,NH).
More than, it is merely preferred embodiments of the present invention, but the protection domain invented is not limited thereto, it is any
Those familiar with the art in the technical scope disclosed by the present invention, all answer by the change or replacement that can be readily occurred in
It is included within the scope of the present invention.Therefore, protection scope of the present invention should be with the protection domain of claims
It is accurate.
Claims (9)
1. a kind of preparation method of aryl substituted pyrimidine amine acyl derivative, which is characterized in that include the following steps：
1) alkali and organic solvent are added in reaction bulb, are stirred at room temperature uniformly, 4- (4- methyl piperazines base) benzene first is then added
2- acetyl thiophenes are slowly added dropwise in aldehyde, are stirred to react at a temperature of 30-60 DEG C, monitor reaction end with thin-layered chromatography, take out
Filter, obtains faint yellow solid powder 1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone；
2) alkali and organic solvent are added in reaction bulb, are stirred at room temperature uniformly, 1- (2- thienyls) -3- (4- (4- is then added
Methyl piperazine base) phenyl)-propenone and guanidine hydrochloride, it is 50-90 DEG C to be heated to temperature, is stirred to react, is monitored with thin-layered chromatography
Reaction end filters, obtains faint yellow solid powder 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2-
Amine；
3) 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine and organic solvent are added to reaction bulb
In, under the conditions of ice-water bath, Lewis acid catalysts are added, acylate is then slowly added dropwise, is stirred at a temperature of 5-25 DEG C
Reaction monitors reaction end with thin-layered chromatography, and it is 12 to adjust pH, is extracted with ethyl acetate, anhydrous with saturated common salt water washing
Magnesium sulfate is dried, and solvent, vacuum drying is concentrated under reduced pressure, and crude product volume ratio is 7:3:0.1 petroleum ether, acetone and triethylamine into
Row silica gel column chromatography detaches, and obtains yellow solid powder 4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2-
Acyl derivative amine.
2. the preparation method of aryl substituted pyrimidine amine acyl derivative according to claim 1, which is characterized in that described
Alkali in step 1)：4- (4- methyl piperazines base) benzaldehyde：The mol ratio of 2- acetyl thiophenes is (5-15)：1：(1-2).
3. the preparation method of aryl substituted pyrimidine amine acyl derivative according to claim 1 or 2, which is characterized in that
Organic solvent in the step 1) and step 2) is absolute ethyl alcohol, absolute methanol, ethyl acetate and N-Methyl pyrrolidone
In one or any two or more mixture.
4. the preparation method of aryl substituted pyrimidine amine acyl derivative according to claim 1, which is characterized in that described
Alkali in step 1) and step 2) is one kind in sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydride.
5. the preparation method of aryl substituted pyrimidine amine acyl derivative according to claim 1 or 4, which is characterized in that
Alkali in the step 2)：1- (2- thienyls) -3- (4- (4- methyl piperazines base) phenyl)-propenone：Guanidine hydrochloride mole is matched
Than for (5-15)：1：(1-2).
6. the preparation method of aryl substituted pyrimidine amine acyl derivative according to claim 1, which is characterized in that described
4- (2- thienyls) -6- (4- (4- methyl piperazines base) phenyl)-pyrimidine -2- amine in step 3)：Acylate：Lewis acid is urged
The mol ratio of agent is 1：(2-5)：(3-6).
7. the preparation method of aryl substituted pyrimidine amine acyl derivative according to claim 1 or 6, which is characterized in that
Acylate in the step 3) is one kind in chloroacetic chloride, propionyl chloride, butyl chloride, valeric chloride and caproyl chloride.
8. the preparation method of aryl substituted pyrimidine amine acyl derivative according to claim 1, which is characterized in that described
Lewis acid catalysts in step 3) are one or any in aluminum trichloride (anhydrous), iron chloride, zinc chloride and ferric bromide
Two or more mixtures.
9. the preparation method of aryl substituted pyrimidine amine acyl derivative according to claim 1, which is characterized in that described
Organic solvent in step 3) is the one or any two or more mixing in pyrroles, pyridine and N-Methyl pyrrolidone
Object.
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| CN114391551A (en) * | 2022-02-10 | 2022-04-26 | 黄业群 | Novel special fertilizer for strawberries |
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