CN110437156A - Paeonol dihydro-pyrimidin ketones derivant and its preparation method and application - Google Patents
Paeonol dihydro-pyrimidin ketones derivant and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of Paeonol dihydro-pyrimidin ketones derivants and its preparation method and application, preparation method includes the following steps: Paeonol and end group dibromo alkane compound, nucleo philic substitution reaction is carried out under organic solvent and acid binding agent, generates bromo Paeonol；By aromatic aldehyde, ethyl cyanoacetate and thiocarbamide, by cyclization reaction under organic solvent and catalyst, 6- substituted-phenyl -5- cyano -2- thiourea pyrimidine is synthesized；Finally by the 6- substituted-phenyl -5- cyano -2- thiourea pyrimidine of bromo Paeonol and synthesis, by nucleophilic displacement of fluorine under organic solvent and acid binding agent, Paeonol dihydro-pyrimidin ketones derivant is synthesized.The present invention provides a new class of Paeonol dihydro-pyrimidin ketones derivants, and short preparation period is easy to operate, at low cost, and obtained derivative purity is high, quality are stablized；Applicant further found that the anti-tumor activity of compound can be improved by introducing functional groups dihydropyrimidinonesand on Paeonol skeleton, there is further research significance.
Description
Technical field
The present invention relates to ketones derivant, specifically a kind of Paeonol dihydro-pyrimidin ketones derivant and preparation method thereof and
Using.
Background technique
Paeonol is also known as peonol, paeonol, and the entitled Paeonolum of chemistry is a kind of from Ranunculaceae
The skin or Asclepiadaceae plant paniculate swallowwort (Pycnostelma paniculatum of plant tree peony (Paeonia moutan Sim.)
K.Schum the natural products extracted in).As the main active ingredient of cortex moutan, it has been extensively studied as with anti-inflammatory,
It is antitumor, antiatherosclerosis, anti-diabetic, anti-mutagenesis and anti-neuroinflamation isoreactivity.Paeonol toxic side effect is small, tool
There is extensive bioactivity, simple structure is but also structural modification process is convenient easy.With paeonol derivative
The continuous expansion of synthesis and its effect, it has been found that pellet can be further increased by carrying out modification and transformation appropriate to its functional group
The bioavilability of skin phenol enhances its pharmacological action, reaches the secondary work of reduction poison in mechanism with more targeting in vivo
Purpose.
Dihydropyrimidinones are a kind of important nitrogen-containing heterocycle compounds, are sent out in early stage the 1980s people
Now pyridine compounds and their similar with dihydropyrimidinones structure has calcium antagonistic activity.This discovery causes people
To the research interest of dihydropyrimidinones pharmacological activity, as a result, it has been found that its with good Ca2+ overloading, decompression, antibacterial and
The bioactivity such as anticancer and be employed for the drug molecules such as antineoplastic, calcium ion antagonist, depressor and α 1a receptor antagonist
In.
Although reported in existing literature it is many to Paeonol carry out structure of modification, obtain a series of paeonol derivatives,
But and it there are no and Paeonol and dihydropyrimidinonesand split are obtained into the open report of Paeonol dihydro-pyrimidin ketones derivant.
Summary of the invention
The object of the present invention is to provide one kind to be obtained by Paeonol based structures, introducing pharmacophoric group dihydropyrimidinonesand
Paeonol dihydro-pyrimidin ketones derivant and its preparation method and application.
Realizing the technical solution of the object of the invention is:
A kind of Paeonol dihydro-pyrimidin ketones derivant has structure shown in following formula (I)s:
Wherein,
R1For aromatic radical, H or CH3；
R2For CN or H；
R3For OH or CH3；
N=1,2,3,4,5 or 6.
The synthetic reaction formula of the Paeonol dihydro-pyrimidin ketones derivant of structure shown in above-mentioned formula (I) is as follows:
The preparation method of the Paeonol dihydro-pyrimidin ketones derivant of structure shown in above-mentioned formula (I), includes the following steps:
A. it by Paeonol and end group dibromo alkane compound, is carried out under organic solvent and acid binding agent anti-through nucleophilic displacement of fluorine
It answers, generates bromo Paeonol；
B. by aromatic aldehyde, ethyl cyanoacetate and thiocarbamide, by cyclization reaction under organic solvent and catalyst, synthesis 6- is taken
For phenyl -5- cyano -2- thiourea pyrimidine；
C. finally by the 6- substituted-phenyl -5- cyano -2- thiourea pyrimidine of bromo Paeonol and synthesis, in organic solvent and
By nucleophilic displacement of fluorine under acid binding agent, Paeonol dihydro-pyrimidin ketones derivant is synthesized.
In nucleophilic substitution described in step A, end group dibromo alkane compound is 1,2- Bromofume, 1,3- dibromo third
Alkane, Isosorbide-5-Nitrae-dibromobutane, 1, one of pentamethylene bromide, 1,6- dibromo-heptane, preferably Isosorbide-5-Nitrae-dibromobutane；
The organic solvent of nucleophilic substitution is DMF, methanol, dehydrated alcohol, acetonitrile, acetone, ethyl acetate, dichloromethane
One of alkane, chloroform, preferred alcohol or acetonitrile；
Acid binding agent be one of natrium carbonicum calcinatum, Anhydrous potassium carbonate, Carbon Dioxide caesium, triethylamine, pyridine, it is preferably anhydrous
Potassium carbonate；
Reaction temperature are as follows: 30-80 DEG C；
In reaction, the molar ratio of Paeonol and end group dibromo alkane compound is 1:3.2；
The molar ratio of Paeonol and acid binding agent is 1:1；
The molar ratio of Paeonol and organic solvent is 1:10.
In cyclization reaction described in step B, aromatic aldehyde be benzaldehyde, ortho-aminotoluene, o fluorobenzaldehyde, fluorobenzaldehyde,
One of hydroxy benzaldehyde, paranitrobenzaldehyde, p-tolyl aldehyde, p-bromobenzaldehyde, P-methoxybenzal-dehyde etc.；
The organic solvent of cyclization reaction is methanol, dehydrated alcohol, DMSO, tetrahydrofuran, DMF, acetonitrile, acetone, acetic acid second
One of ester, methylene chloride, chloroform, preferably methanol or dehydrated alcohol；
Catalyst is one of Anhydrous potassium carbonate, potassium iodide, potassium hydroxide, sodium hydroxide；
Cyclization reaction temperature are as follows: 40-80 DEG C；
In cyclization reaction, the molar ratio of aromatic aldehyde, ethyl cyanoacetate and thiocarbamide is 1:1:1；
The molar ratio of aromatic aldehyde and catalyst is 1:1；
The molar ratio of aromatic aldehyde and organic solvent is 1:10.
Nucleophilic displacement of fluorine described in step C synthesize Paeonol dihydropyrimidinones organic solvent be methanol, dehydrated alcohol,
One of DMSO, tetrahydrofuran, DMF, acetonitrile, acetone, ethyl acetate, methylene chloride, chloroform, preferably methanol or anhydrous
Ethyl alcohol；
Acid binding agent be one of natrium carbonicum calcinatum, Anhydrous potassium carbonate, Carbon Dioxide caesium, triethylamine, pyridine, it is preferably anhydrous
Potassium carbonate；
Reaction temperature are as follows: 30-80 DEG C；
The molar ratio of bromo Paeonol and 6- substituted-phenyl -5- cyano -2- thiourea pyrimidine is 1:1.
The molar ratio of bromo Paeonol and acid binding agent is 1:1；
The molar ratio of bromo Paeonol and organic solvent is 1:10.
Whether cyclization reaction and substitution reaction carry out in conventional reactor, complete with the cyclization reaction of thin-layer chromatography tracing detection
Entirely.
The invention also includes the Paeonol dihydro-pyrimidin ketones derivants of structure shown in above-mentioned formula (I) as antitumor chemical combination
The application of object.
The present invention provides a new class of Paeonol dihydro-pyrimidin ketones derivants, and short preparation period is easy to operate, at
This is low, and obtained derivative purity is high, quality are stablized；Applicant further found that functional by being introduced on Paeonol skeleton
Group dihydropyrimidinonesand can improve the anti-tumor activity of compound, there is further research significance.
Specific embodiment
The content of present invention is further described with specific embodiment below, but the invention is not limited to these to implement
The range of example.
In following embodiment, Paeonol is indicated with 1, and bromo Paeonol indicates that aromatic aldehyde is indicated with 3 with 2, and 6- replaces
Phenyl -5- cyano -2- thiourea pyrimidine indicates that Paeonol dihydropyrimidinone derivative is indicated with 5 with 4
The preparation of embodiment 1:2- (4- bromobutane oxygroup) -4- methoxyacetophenone (compound 2)
It is separately added into the Paeonol 1 of 15.0mmol and the Anhydrous potassium carbonate of 15.0mmol in the round-bottomed flask of 250ml, uses
Isosorbide-5-Nitrae-dibromobutane of 48.0mmol is added after acetone 150mmol dissolution under stirring at normal temperature, stirring at normal temperature was reacted to 16 hours,
Period carries out TLC and tracks reaction process (VPetroleum ether:VEthyl acetate=4:1) to after reaction, dry filter, after filtrate decompression is evaporated
Through silica gel column chromatography (VPetroleum ether:VEthyl acetate=10:1) purify to obtain 2.60g bromo Paeonol white solid 2, Rf=0.28, yield
58.0%.
M.p.51.4~53.0 DEG C；IR(KBr,cm-1):2956(-CH3), 1651 (C=O), 1595,1500,1406,
1359,1328,1257,1124,1024,837,756,646,584,522；
Therefore, above compound 2 is 2- (4- bromobutane oxygroup) -4- methoxyacetophenone, and structural formula is shown below:
The preparation of embodiment 2:6- substituted-phenyl -5- cyano -2- thiourea pyrimidine (compound 4)
Aromatic aldehyde 0.01mol, ethyl cyanoacetate 0.01mol, thiocarbamide 0.01mol and potassium carbonate 0.01mol are added to nothing
Flow back 5-8h in water-ethanol 0.1mol solution, during which detects reaction process using TLC；Product is precipitated in the form of sylvite after the completion
Precipitating, decompression filter, and precipitate its acidification again by acetic acid after precipitating is dissolved in warm water, and decompression is dry after filtering,
Through ethyl alcohol recrystallization, 6- substituted-phenyl -5- cyano -2- thiourea pyrimidine is purified to obtain；
Its structural formula is shown below, wherein R1For aromatic radical, H or CH3；R2For CN or H；R3For OH or CH3；
The 4a is 6- (3- fluorophenyl) -5- cyano -2- thiourea pyrimidine；
4b is 6- phenyl -5- cyano -2- thiourea pyrimidine；
4c is 6- (2- fluorophenyl) -5- cyano -2- thiourea pyrimidine；
4d is 6- (3- hydroxy phenyl) -5- cyano -2- thiourea pyrimidine；
4e is 6- (4- nitrobenzophenone) -5- cyano -2- thiourea pyrimidine；
4f is 6- (4- aminomethyl phenyl) -5- cyano -2- thiourea pyrimidine；
4g is 6- (4- bromophenyl) -5- cyano -2- thiourea pyrimidine；
4h is 6- (4- methoxyphenyl) -5- cyano -2- thiourea pyrimidine；
4i is methylthiouracil；
4j is deracil；
4k is 4,6- dimethyl sulfourea pyrimidine.
The preparation of embodiment 3:6- (3- fluorophenyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine (5a)
2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2 of 1mmol prepared by Example 1, is dissolved in and is equipped with
In the round-bottomed flask of 10mmol dehydrated alcohol, 6- (3- fluorophenyl) -5- cyano -2- thiourea pyrimidine 4a of 1mmol is added, is added
The Anhydrous potassium carbonate of 1mmol, for warming-in-water to 78 DEG C, return stirring reacts about 7~8h, during which carries out TLC and tracks reaction process
(VChloroform:VMethanol=2:1) to the end of reacting, dry filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=1:1)
Purifying, obtains white solid 5a, yield 32.1%；
M.p.81.7~83.6 DEG C；IR(KBr,cm-1):2 947(CH3), 2 214 (- CN), 1664 (C=O), 1600,
1502,1485,1396,1357,1303,1263,1199,1153,1028,999,964,796,729,646,566,507；1H
NMR(400MHz,DMSO-d6) δ: 7.82 (dd, J=8.9,5.6Hz, 2H), 7.65 (d, J=8.7Hz, 1H), 7.27 (t, J=
8.9Hz, 2H), 6.62 (d, J=2.2Hz, 1H), 6.58 (dd, J=8.7,2.3Hz, 1H), 4.14 (t, J=6.1Hz, 2H),
3.83 (s, 3H), 3.07 (t, J=6.8Hz, 2H), 2.51 (s, 3H), 1.88 (dt, J=14.8,8.3Hz, 4H)；13C NMR
(101MHz,DMSO-d6)δ:196.73,172.45,166.19,164.73,164.54,162.09,160.83,134.68,
132.20,130.90,130.81,120.74,120.64,115.58,115.36,106.47,99.26,88.99,68.47,
56.05,32.34,29.75,28.20,26.65；ESI-MS(m/z):calcd for C24H22FN3O4S 467.13,found
467.10.
Accordingly, it can be determined that above compound 5a is that 6- (3- fluorophenyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin sulfydryl is phonetic
Pyridine, structural formula are shown below:
The preparation of embodiment 4:6- phenyl -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine (compound 5b)
2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2 of 1mmol prepared by Example 1, is dissolved in and is equipped with
In the round-bottomed flask of 10mmol dehydrated alcohol, the 6- phenyl -5- cyano -2- thiourea pyrimidine 4b of 1mmol is added, 1mmol is added
Anhydrous potassium carbonate, for warming-in-water to 78 DEG C, return stirring reacts about 7~8h, during which carries out TLC and tracks reaction process (VChloroform:
VMethanol=2:1) to after reaction, dry filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=1:1) it is pure
Change, obtains faint yellow solid 5b, yield 78.0%；
M.p.80.3~82.4 DEG C；IR(KBr,cm-1):3086(CH3), 2229 (- CN), 1687 (C=O), 1548,
1456,1396,1328,1226,1145,1109,1006,856,748,698,653,547,518；1H NMR(400MHz,
DMSO-d6) δ: 7.75 (dd, J=7.0,2.7Hz, 2H), 7.65 (d, J=8.7Hz, 1H), 7.45 (d, J=2.0Hz, 2H),
7.44 (d, J=1.7Hz, 1H), 6.63 (d, J=2.2Hz, 1H), 6.58 (dd, J=8.7,2.3Hz, 1H), 4.14 (t, J=
6.1Hz, 2H), 3.83 (s, 3H), 3.07 (t, J=6.8Hz, 2H), 2.50 (s, 3H), 1.92 (dd, J=12.4,7.7Hz,
2H), 1.84 (dd, J=14.6,7.0Hz, 2H)；13C NMR(101MHz,DMSO-d6)δ:196.74,172.42,170.88,
167.40,164.74,160.85,138.30,132.20,130.07,128.52,120.78,120.64,106.51,99.25,
89.16,68.50,56.06,32.35,29.77,28.22,26.66；ESI-MS(m/z):calcd for C24H23N3O4S[M-
H]-448.14,found 448.00；
Accordingly, it can be determined that above compound 5b is 6- phenyl -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine, knot
Structure formula is shown below:
The preparation of embodiment 5:6- (2- fluorophenyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine (compound 5c)
2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2 of 1mmol prepared by Example 1, is dissolved in and is equipped with
In the round-bottomed flask of 10mmol dehydrated alcohol, 6- (2- fluorophenyl) -5- cyano -2- thiourea pyrimidine 4c of 1mmol is added, is added
The Anhydrous potassium carbonate of 1mmol, for warming-in-water to 78 DEG C, return stirring reacts about 7~8h, during which carries out TLC and tracks reaction process
(VChloroform:VMethanol=2:1) to after reaction, dry filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=1:
1) it purifies, obtains yellow-brown solid 5c, yield 10.70%；
M.p.98.6~100.2 DEG C；IR(KBr,cm-1):2937(CH3), 1658 (C=O), 1600,1496,1436,
1386,1357,1273,1203,1170,1143,1066,1028,966,921,827,732,642,570,524；1H NMR
(400MHz,CDCl3) δ: 7.82 (dd, J=8.7,6.0Hz, 2H), 7.27 (s, 1H), 6.55~6.45 (m, 2H), 6.43 (d, J
=1.9Hz, 2H), 4.05 (d, J=6.2Hz, 2H), 3.85 (s, 3H), 2.79 (d, J=7.9Hz, 2H), 2.58 (s, 3H),
2.03~1.90 (m, 2H), 1.82 (dt, J=14.6,7.2Hz, 2H)13C NMR(101MHz,CDCl3)δ:197.69,
164.48,164.46,160.40,160.11,132.77,132.71,121.24,121.21,105.20,105.08,99.00,
98.91,67.97,67.73,55.57,55.55,52.06,32.11,31.93,31.78,28.31,26.26,19.94；ESI-
MS(m/z):calcd for C24H22FN3O4S 467.13,found 467.00；
Accordingly, it can be determined that above compound 5c is that 6- (2- fluorophenyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin sulfydryl is phonetic
Pyridine, structural formula are shown below:
The preparation of embodiment 6:6- (3- hydroxy phenyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine 5d
2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2 of 1mmol prepared by Example 1, is dissolved in and is equipped with
In the round-bottomed flask of 10mmol dehydrated alcohol, 6- (3- hydroxy phenyl) -5- cyano -2- thiourea pyrimidine 4d of 1mmol is added, adds
Enter the Anhydrous potassium carbonate of 1mmol, for warming-in-water to 78 DEG C, return stirring reacts about 7~8h, during which carry out TLC tracking react into
Journey (VChloroform:VMethanol=2:1) to after reaction, dry filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=
It 1:1) purifies, obtains pale solid 5d, yield 47.10%；
M.p.205.6~206.3 DEG C；IR(KBr,cm-1):3599,3361,3269,2941(-CH3),2210(-CN),
1664 (C=O), 1573,1469,1301,1269,1205,1174,1141,1020,964,812,702,636,574,470；1H
NMR(400MHz,DMSO-d6) δ: 9.81 (s, 1H), 7.64 (d, J=8.5Hz, 1H), 7.32 (d, J=2.4Hz, 3H), 6.95
(d, J=7.8Hz, 1H), 6.60 (t, J=11.0Hz, 2H), 4.13 (s, 2H), 3.82 (s, 3H), 3.29 (s, 2H), 2.42 (s,
3H),1.91(s,4H).13C NMR(101MHz,DMSO-d6)δ:196.60,167.52,164.70,162.81,160.69,
157.76,155.70,137.45,132.22,129.98,122.95,120.72,119.68,118.78,115.72,106.44,
99.35,68.32,62.82,56.05,32.21,30.41,28.09,26.17；ESI-MS(m/z):calcd for
C24H23N3O5S[M-H]-464.14,found 464.00；
Accordingly, it can be determined that above compound 5d is 6- (3- hydroxy phenyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin sulfydryl
Pyrimidine, structural formula are shown below:
The system of embodiment 7:6- (4- nitrobenzophenone) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine (compound 5e)
It is standby
2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2 of 1mmol prepared by Example 1, is dissolved in and is equipped with
In the round-bottomed flask of 10mmol dehydrated alcohol, 6- (4- nitrobenzophenone) -5- cyano -2- thiourea pyrimidine 4e of 1mmol is added, adds
Enter the Anhydrous potassium carbonate of 1mmol, for warming-in-water to 78 DEG C, return stirring reacts about 7~8h, during which carry out TLC tracking react into
Journey (VChloroform:VMethanol=2:1) to after reaction, dry filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=
It 1:1) purifies, obtains brown solid 5e, yield 45.60%；
M.p.217.9~221.0 DEG C；IR(KBr,cm-1):3120,2943(-CH3), 2194 (- CN), 1656 (C=O),
1600,1544,1465,1398,1352,1263,1203,1097,1035,1008,975,833,704,615,576；1H NMR
(400MHz,DMSO-d6) δ: 8.31~8.26 (m, 2H), 8.02~7.94 (m, 2H), 7.64 (d, J=8.7Hz, 1H), 6.63
~6.50 (m, 2H), 4.14 (t, J=6.1Hz, 2H), 3.82 (s, 3H), 3.08 (t, J=6.9Hz, 2H), 2.45 (s, 3H),
2.00~1.73 (m, 4H)；13C NMR(101MHz,DMSO-d6)δ:196.66,172.78,170.24,165.35,164.68,
160.77,148.37,144.36,132.16,129.89,123.78,120.70,106.39,99.30,89.80,79.65,
68.42,56.03,32.29,29.75,28.17,26.66；ESI-MS(m/z):calcd for C24H22N4O6S[M-H]-
493.13,found 494.00；
Accordingly, it can be determined that above compound 5e is 6- (4- nitrobenzophenone) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin sulfydryl
Pyrimidine, structural formula are shown below:
The system of embodiment 8:6- (4- aminomethyl phenyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine (compound 5f)
It is standby
2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2 of 1mmol prepared by Example 1, is dissolved in and is equipped with
In the round-bottomed flask of 10mmol dehydrated alcohol, 6- (4- aminomethyl phenyl) -5- cyano -2- thiourea pyrimidine 4f of 1mmol is added, adds
Enter the Anhydrous potassium carbonate of 1mmol, for warming-in-water to 78 DEG C, return stirring reacts about 7~8h, during which carry out TLC tracking react into
Journey (VChloroform:VMethanol=2:1) to after reaction, dry filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=
It 1:1) purifies, obtains white solid 5f, yield 64.80%；
M.p.102.4~104.0 DEG C；IR(KBr,cm-1):3344,2937(-CH3), 2204 (- CN), 1656 (C=O),
1604,1552,1471,1274,1201,1147,1031,1004,829,796,725,644,570,499；1H NMR
(400MHz,DMSO-d6) δ: 7.86 (d, J=8.2Hz, 2H), 7.64 (d, J=9.3Hz, 1H), 7.32 (d, J=8.1Hz,
2H), 6.62~6.56 (m, 2H), 4.12 (s, 2H), 3.82 (s, 3H), 3.34 (s, 2H), 2.39 (s, 3H), 2.37 (s, 3H),
1.92(s,4H).13C NMR(101MHz,DMSO-d6)δ:196.56,167.49,166.24,164.68,160.64,142.58,
132.90,132.24,129.61,129.10,120.77,116.51,106.32,99.44,92.88,68.21,56.05,
32.15,30.47,28.08,26.17,21.53；ESI-MS(m/z):calcd for C25H25N3O4S[M-H]-462.16,
found 462.00；
Accordingly, it can be determined that above compound 5f is 6- (4- aminomethyl phenyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin sulfydryl
Pyrimidine, structural formula are shown below:
The preparation of embodiment 9:6- (4- bromophenyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine (compound 5g)
2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2 of 1mmol prepared by Example 1, is dissolved in and is equipped with
In the round-bottomed flask of 10mmol dehydrated alcohol, 6- (4- bromophenyl) -5- cyano -2- thiourea pyrimidine 4g of 1mmol is added, is added
The Anhydrous potassium carbonate of 1mmol, for warming-in-water to 78 DEG C, return stirring reacts about 7~8h, during which carries out TLC and tracks reaction process
(VChloroform:VMethanol=2:1) to after reaction, dry filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=1:
1) it purifies, obtains white solid 5g, yield 82.10%；
M.p.224.4~226.1 DEG C；IR(KBr,cm-1):3286,2937(-CH3), 2191 (- CN), 1653 (C=O),
1600,1539,1465,1259,1195,1099,1068,991,827,800,725,642,613,514；1H NMR(400MHz,
DMSO-d6) δ: 7.87 (d, J=8.6Hz, 2H), 7.73 (d, J=8.6Hz, 2H), 7.64 (d, J=9.3Hz, 1H), 6.59 (d,
J=6.7Hz, 2H), 4.12 (s, 2H), 3.82 (s, 3H), 3.34 (s, 2H), 2.40 (s, 3H), 1.91 (s, 4H)；13C NMR
(101MHz,DMSO-d6)δ:196.55,166.77,166.58,164.65,161.33,160.59,134.87,132.25,
131.03,126.05,120.76,116.21,106.29,99.46,93.64,83.29,68.19,56.06,32.15,30.48,
28.04,26.14；ESI-MS(m/z):calcd for C24H22BrN3O4S[M-H]-526.05,found 525.90；
Accordingly, it can be determined that above compound 5g is that 6- (4- bromophenyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin sulfydryl is phonetic
Pyridine, structural formula are shown below:
Embodiment 10:6- (4- anisyl) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine (compound 5h)
Prepare Example 1 preparation 1mmol 2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2, be dissolved in equipped with 10mmol without
In the round-bottomed flask of water-ethanol, 6- (4- methoxyphenyl) -5- cyano -2- thiourea pyrimidine 4h of 1mmol is added, is added
The Anhydrous potassium carbonate of 1mmol, for warming-in-water to 78 DEG C, return stirring reacts about 7~8h, during which carries out TLC and tracks reaction process
(VChloroform:VMethanol=2:1) to after reaction, dry filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=1:
1) it purifies, obtains yellow solid 5h, yield 67.20%；
M.p.223.1~224.6 DEG C；IR(KBr,cm-1):3207,2950(-CH3),2364,2204(-CN),1658(C
=O), 1604,1554,1400,1255,1203,1170,1029,1004,972,831,802,698,648,574,513；1H
NMR(400MHz,DMSO-d6) δ: 7.83 (d, J=8.9Hz, 2H), 7.71 (d, J=8.7Hz, 1H), 7.04 (d, J=8.9Hz,
2H), 6.69 (d, J=2.3Hz, 1H), 6.64 (dd, J=8.7,2.3Hz, 1H), 4.20 (t, J=6.1Hz, 2H), 3.88 (s,
3H), 3.86 (s, 3H), 3.12 (t, J=6.9Hz, 2H), 2.51 (s, 3H), 1.97 (dd, J=13.9,6.1Hz, 2H), 1.90
(dd, J=14.6,7.0Hz, 2H)13C NMR(101MHz,DMSO-d6)δ:196.70,172.18,171.12,166.52,
164.71,162.78,160.88,132.17,130.56,130.07,121.14,120.71,113.83,106.50,99.30,
88.34,68.52,56.06,55.70,32.31,29.76,28.24,26.72；ESI-MS(m/z):calcd for
C25H25N3O5S[M-H]-478.15,found 478.00；
Accordingly, it can be determined that above compound 5h is that 6- (4- methoxyl group) -5- cyano -4- hydroxyl -2- root bark of tree peony oxyphenisatin sulfydryl is phonetic
Pyridine, structural formula are shown below:
The preparation of embodiment 11:6- methyl -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine (compound 5i)
2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2 of 1mmol prepared by Example 1, is dissolved in and is equipped with
In the round-bottomed flask of 10mmol dehydrated alcohol, the methylthiouracil 4i of 1mmol is added, the Anhydrous potassium carbonate of 1mmol, water is added
Bath is warming up to 78 DEG C, and return stirring reacts about 7~8h, during which carries out TLC and tracks reaction process (VChloroform:VMethanol=2:1) wait react
After, be added anhydrous magnesium sulfate be dried overnight after filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=1:
1) it purifies, obtains white crystal 5i, yield 42.30%；
M.p.106.4~107.5 DEG C；IR(KBr,cm-1):3574,3126,2949(-CH3), 1653 (C=O), 1593,
1452,1402,1251,1205,1026,962,908,835,565,513,530；1H NMR(400MHz,DMSO-d6)δ:7.66
(d, J=8.7Hz, 1H), 6.71~6.53 (m, 2H), 5.97 (s, 1H), 4.14 (t, J=5.7Hz, 2H), 3.83 (s, 3H),
3.20 (t, J=6.6Hz, 2H), 2.46 (s, 3H), 2.15~2.05 (m, 3H), 1.89 (dtdd, J=14.5,11.1,5.5,
2.3Hz,4H)；13C NMR(101MHz,DMSO-d6)δ:200.80,170.14,164.94,164.73,163.20,160.50,
131.70,121.23,107.89,102.67,101.32,69.40,55.64,31.98,28.84,28.20,26.28,24.74；
ESI-MS(m/z):calcd for C18H22N2O4S[M-H]-361.13,found 361.00；
Accordingly, it can be determined that above compound 5i is 6- methyl -4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine, structural formula is such as
Shown in following formula:
The preparation of embodiment 12:4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine (compound 5j)
2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2 of 1mmol prepared by Example 1, is dissolved in and is equipped with
In the round-bottomed flask of 10mmol dehydrated alcohol, the deracil 4j of 1mmol is added, the Anhydrous potassium carbonate of 1mmol, water-bath liter is added
For temperature to 78 DEG C, return stirring reacts about 7~8h, during which carries out TLC and tracks reaction process (VChloroform:VMethanol=2:1) to the end of reacting
Afterwards, dry filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=1:1) purifying, white solid 5j is obtained, is produced
Rate 28.60%；
M.p.75.5~77.9 DEG C；IR(KBr,cm-1):3292(-NH),2924(-CH3), 1654 (C=O), 1602,
1558,1500,1436,1350,1309,1225,1205,1118,1037,987,825,640,578,514；1H NMR
(400MHz,CDCl3) δ: 7.83 (d, J=8.7Hz, 2H), 6.42 (s, 2H), 6.37 (d, J=5.7Hz, 1H), 4.41 (t, J=
5.4Hz, 2H), 3.84 (s, 3H), 3.21 (t, J=6.6Hz, 2H), 2.58 (s, 3H), 1.69 (s, 2H), 1.26 (s, 2H)；13C
NMR(101MHz,CDCl3)δ:197.68,171.37,168.59,164.48,160.42,157.31,132.74,121.20,
105.09,103.91,98.93,67.95,55.54,32.09,30.44,28.32,25.93；ESI-MS(m/z):calcd for
C17H20N2O4S 348.11,found 348.80；
Accordingly, it can be determined that above compound 5j is 4- hydroxyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine, structural formula such as following formula institute
Show:
The preparation of embodiment 13:4,6- dimethyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine (compound 5k)
2- (4- bromobutane oxygroup) -4- methoxyacetophenone 2 of 1mmol prepared by Example 1, is dissolved in and is equipped with
In the round-bottomed flask of 10mmol dehydrated alcohol, 4, the 6- dimethyl sulfourea pyrimidine 4k of 1mmol is added, the anhydrous carbon of 1mmol is added
Sour potassium, for warming-in-water to 78 DEG C, return stirring reacts about 7~8h, during which carries out TLC and tracks reaction process (VChloroform:VMethanol=2:1)
To after reaction, dry filter, filtrate decompression be evaporated after through silica gel column chromatography (VPetroleum ether:VEthyl acetate=1:1) purifying, it obtains light
Yellow solid 5k, yield 61.20%；
M.p.75.5~77.9 DEG C；IR(KBr,cm-1):2945(CH3), 1656 (C=O), 1598,1533,1436,
1396,1359,1263,1195,1134,1029,964,831,744,555；1H NMR(400MHz,CDCl3) δ: 7.83 (d, J=
8.7Hz, 1H), 6.68 (s, 1H), 6.51 (dd, J=8.8,2.3Hz, 1H), 6.43 (d, J=2.3Hz, 1H), 4.09 (t, J=
6.0Hz, 2H), 3.84 (s, 3H), 3.24 (t, J=6.8Hz, 2H), 2.55 (s, 3H), 2.38 (s, 6H), 2.07~2.00 (m,
2H), 2.01~1.92 (m, 2H)；13C NMR(101MHz,CDCl3)δ:197.72,170.96,166.99,164.49,
160.52,132.70,121.14,115.65,105.05,98.82,68.02,55.53,32.15,30.25,28.24,26.28,
23.88；ESI-MS(m/z):calcd for C19H24N2O3S 360.15,found 360.20；
Accordingly, it can be determined that above compound 5k is 4,6- dimethyl -2- root bark of tree peony oxyphenisatin mercaptopyrimidine, structural formula such as following formula
It is shown:
The antitumor action of the compound to illustrate the invention, applicant is to chemical combination made from above-described embodiment 2~12
The anti-tumor activity experiment (using common anti-tumor drug cis-platinum as reference) that object has carried out, and change to made from above-described embodiment
Exhibition is run jointly to the toxicity test of normal cell.
One, the anti tumor activity in vitro test of compound
1. the inoculation and culture of cell
Selected cell strain is placed in 37 DEG C, 5%CO2Incubator in, be inoculated in containing 10% fetal calf serum DMEM culture
It is cultivated in liquid.Cell growth status is observed with inverted microscope, after cell recovery, after usually passing 2-3 generation, is taken in logarithmic growth
Phase cell is for testing.
2. the active primary dcreening operation of Compound cellular level
This compound used therefor purity is high, all compounds are dissolved in 1ml DMSO and are configured to mother liquid concentration 10mg/ml,
It is successively diluted to required concentration and carries out cytotoxicity experiment, DMSO final concentration is no more than 1 ‰.
3. cell growth inhibition test (mtt assay)
MTT colorimetric method is the method for a kind of detection cell growth and survival.Testing principle: the amber in living cells mitochondria
Amber acidohydrogenase can make exogenous MTT be reduced to bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) of water-insoluble and be deposited on cell
In, and dead cell is without this function.Dimethyl sulfoxide (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, be existed with enzyme-linked immunosorbent assay instrument
Its absorbance value is measured at 490nm wavelength, can reflect living cells quantity indirectly.Within the scope of certain cell number, MTT crystallizes to be formed
Amount it is directly proportional to cell number.The cell in logarithmic growth phase is taken, every 180 μ L of hole (about 4500-5000 cell) contains cell
Culture medium inoculated in 96 well culture plates, in 37 DEG C, 5%CO2It is cultivated in incubator under the conditions of abundant humidifying.It is adherent to cell
Afterwards, sample is added by the amount of every 20 μ L of hole, each sample sets 5 multiple holes, and negative control culture medium and 1 ‰ DMSO are prepared.After
After continuous culture 44h, 20 μ L MTT reagents (concentration 5mg/mL) are added in every hole, are continued after being incubated for 4h, and culture is terminated, and careful inhale is abandoned
Culture supernatant in hole, every hole add 150 μ L DMSO, and slight concussion reaction dissolves crystalline particle sufficiently.Exempted from enzyme-linked
Epidemic disease instrument measures absorbance (OD value) at 490nm, calculates cell proliferation inhibition rate, and all experiments are averaged after being repeated 3 times.
Experimental result is detailed in the following table 1.
Half-suppressed rate concentration (IC of 1. compound of table to different tumor cell lines50, μM)
By data in table 1 it is found that most of derivative shows HepG2, MCF-7, HCT-116, A549 tumour cell
Different degrees of anti-tumor activity out, wherein in object derived from the inhibitory activity test experiments to human colon cancer cell HCT-116
5c and 5i shows good inhibitory activity, especially IC of the compound 5i to HCT-11650For (1.32 ± 0.71) μ g/mL, compared with
It has been more than big degree anti-tumor activity of the cis-platinum to the cancerous cell line, and it is significantly small to the toxicity of people's normal cell lines of human liver LO2
In cis-platinum.The above result shows that Paeonol dihydro-pyrimidin ketones derivant has preferable researching value.
Claims (9)
1. Paeonol dihydro-pyrimidin ketones derivant, it is characterised in that: have structure shown in following formula (I)s:
Wherein, R1For aromatic radical, H or CH3；
R2For CN or H；
R3For OH or CH3；
N=1,2,3,4,5 or 6.
2. the preparation method of Paeonol dihydro-pyrimidin ketones derivant according to claim 1, which is characterized in that synthesis is anti-
Answer formula as follows:
Preparation method includes the following steps:
A. by Paeonol (1) and end group dibromo alkane compound, nucleo philic substitution reaction is carried out under organic solvent and acid binding agent,
It generates bromo Paeonol (2)；
B. by aromatic aldehyde (3), ethyl cyanoacetate and thiocarbamide, by cyclization under organic solvent and catalyst, 6- substituted benzene is synthesized
Base -5- cyano -2- thiourea pyrimidine (4)；
C. finally by the 6- substituted-phenyl -5- cyano -2- thiourea pyrimidine (4) of bromo Paeonol (2) and synthesis, in organic solvent
With by nucleophilic displacement of fluorine, synthesized Paeonol dihydro-pyrimidin ketones derivant (5) under acid binding agent.
3. the preparation method of Paeonol dihydro-pyrimidin ketones derivant according to claim 2, it is characterised in that:
In nucleophilic substitution described in step A, end group dibromo alkane compound be 1,2- Bromofume, 1,3- dibromopropane, 1,
One of 4- dibromobutane, pentamethylene bromide, 1,6- dibromo-heptane；
The organic solvent of nucleophilic substitution is DMF, methanol, dehydrated alcohol, acetonitrile, acetone, ethyl acetate, methylene chloride, three
One of chloromethanes；
Acid binding agent is one of natrium carbonicum calcinatum, Anhydrous potassium carbonate, Carbon Dioxide caesium, triethylamine, pyridine；
Reaction temperature are as follows: 30-80 DEG C；
In reaction, the molar ratio of Paeonol and end group dibromo alkane compound is 1:3.2；
The molar ratio of Paeonol and acid binding agent is 1:1；
The molar ratio of Paeonol and organic solvent is 1:10.
4. the preparation method of Paeonol dihydro-pyrimidin ketones derivant according to claim 3, it is characterised in that: step A
The end group dibromo alkane compound is 1,4- dibromobutane；
Organic solvent is ethyl alcohol or acetonitrile；
Acid binding agent is Anhydrous potassium carbonate.
5. the preparation method of Paeonol dihydro-pyrimidin ketones derivant according to claim 2, it is characterised in that:
In cyclization reaction described in step B, aromatic aldehyde is benzaldehyde, ortho-aminotoluene, o fluorobenzaldehyde, fluorobenzaldehyde, hydroxyl
One of benzaldehyde, paranitrobenzaldehyde, p-tolyl aldehyde, p-bromobenzaldehyde, P-methoxybenzal-dehyde；
The organic solvent of cyclization reaction is methanol, dehydrated alcohol, DMSO, tetrahydrofuran, DMF, acetonitrile, acetone, ethyl acetate, two
One of chloromethanes, chloroform；
Catalyst is one of Anhydrous potassium carbonate, potassium iodide, potassium hydroxide, sodium hydroxide；.
Cyclization reaction temperature are as follows: 40-80 DEG C；
In cyclization reaction, the molar ratio of aromatic aldehyde, ethyl cyanoacetate and thiocarbamide is 1:1:1；
The molar ratio of aromatic aldehyde and catalyst is 1:1；
The molar ratio of aromatic aldehyde and organic solvent is 1:10.
6. the preparation method of Paeonol dihydro-pyrimidin ketones derivant according to claim 5, it is characterised in that:
Cyclization reaction organic solvent described in step B is methanol or dehydrated alcohol.
7. the preparation method of Paeonol dihydro-pyrimidin ketones derivant according to claim 1, it is characterised in that:
Nucleophilic displacement of fluorine described in step C synthesize Paeonol dihydropyrimidinones in organic solvent be methanol, dehydrated alcohol,
One of DMSO, tetrahydrofuran, DMF, acetonitrile, acetone, ethyl acetate, methylene chloride, chloroform；
Acid binding agent is natrium carbonicum calcinatum, Anhydrous potassium carbonate, Carbon Dioxide caesium, one of triethylamine, pyridine；
The molar ratio of bromo Paeonol and 6- substituted-phenyl -5- cyano -2- thiourea pyrimidine is 1:1.
The molar ratio of bromo Paeonol and acid binding agent is 1:1；
The molar ratio of bromo Paeonol and organic solvent is 1:10.
8. the preparation method of Paeonol dihydro-pyrimidin ketones derivant according to claim 7, it is characterised in that:
Organic solvent described in step C is methanol or dehydrated alcohol；
Acid binding agent is Anhydrous potassium carbonate.
9. the preparation that Paeonol dihydro-pyrimidin ketones derivant described in claim 1 is applied to anti-swollen drug.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018738A (en) * | 2019-12-20 | 2020-04-17 | 安徽医科大学 | Paeonol derivative, pharmaceutical preparation, preparation method and application |
| CN111116422A (en) * | 2019-12-30 | 2020-05-08 | 西南大学 | Paeonol etherified urea compound with anti-inflammatory activity and application thereof |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1935129A (en) * | 2006-10-14 | 2007-03-28 | 孙国平 | Pharmaceutical use of paeonol for anti esophageal cancer |
| WO2009033284A1 (en) * | 2007-09-14 | 2009-03-19 | Mcmaster University | Inhibitors of collagen biosynthesis as anti-tumor agents |
| CN104402831A (en) * | 2014-10-24 | 2015-03-11 | 郑州大学 | Ureide structural unit-containing 5-cyano pyrimidine derivatives and preparation method and use thereof |
| CN104876881A (en) * | 2015-06-10 | 2015-09-02 | 河北大学 | Thiouracil derivative, preparation method and application thereof |
| CN105153143A (en) * | 2015-10-23 | 2015-12-16 | 河北大学 | Thiouracil derivatives containing oxadiazole/thiadiazole and preparation method and application of thiouracil derivatives |
| CN106674128A (en) * | 2016-12-31 | 2017-05-17 | 陕西科技大学 | Licochalcone A thiouracil derivatives with antitumor activity and synthesis method thereof |
| WO2017095751A1 (en) * | 2015-12-02 | 2017-06-08 | Partikula Llc | Compositions and methods for modulating cancer cell metabolism |
| CN107141268A (en) * | 2017-07-03 | 2017-09-08 | 何黎琴 | A kind of Paeonol phenylacetic acid compound, its preparation method and medical usage |
| CN109438365A (en) * | 2018-12-06 | 2019-03-08 | 华南师范大学 | N- (3- ((4- trifluoromethyl) -2- pyrimidine radicals) aminophenyl) -2,6- difluorobenzenesulfonamide derivative |
| CN109608408A (en) * | 2018-12-25 | 2019-04-12 | 河南师范大学 | The preparation method of Paeonol Schiff link 1,2,3- triazole compound with anti-tumor activity |
| CN109761968A (en) * | 2018-12-25 | 2019-05-17 | 河南师范大学 | Paeonol with anti-tumor activity and benzoxazine compounds and its preparation method and application |
-
2019
- 2019-08-26 CN CN201910788209.1A patent/CN110437156B/en active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1935129A (en) * | 2006-10-14 | 2007-03-28 | 孙国平 | Pharmaceutical use of paeonol for anti esophageal cancer |
| WO2009033284A1 (en) * | 2007-09-14 | 2009-03-19 | Mcmaster University | Inhibitors of collagen biosynthesis as anti-tumor agents |
| CN104402831A (en) * | 2014-10-24 | 2015-03-11 | 郑州大学 | Ureide structural unit-containing 5-cyano pyrimidine derivatives and preparation method and use thereof |
| CN104876881A (en) * | 2015-06-10 | 2015-09-02 | 河北大学 | Thiouracil derivative, preparation method and application thereof |
| CN105153143A (en) * | 2015-10-23 | 2015-12-16 | 河北大学 | Thiouracil derivatives containing oxadiazole/thiadiazole and preparation method and application of thiouracil derivatives |
| WO2017095751A1 (en) * | 2015-12-02 | 2017-06-08 | Partikula Llc | Compositions and methods for modulating cancer cell metabolism |
| CN106674128A (en) * | 2016-12-31 | 2017-05-17 | 陕西科技大学 | Licochalcone A thiouracil derivatives with antitumor activity and synthesis method thereof |
| CN107141268A (en) * | 2017-07-03 | 2017-09-08 | 何黎琴 | A kind of Paeonol phenylacetic acid compound, its preparation method and medical usage |
| CN109438365A (en) * | 2018-12-06 | 2019-03-08 | 华南师范大学 | N- (3- ((4- trifluoromethyl) -2- pyrimidine radicals) aminophenyl) -2,6- difluorobenzenesulfonamide derivative |
| CN109608408A (en) * | 2018-12-25 | 2019-04-12 | 河南师范大学 | The preparation method of Paeonol Schiff link 1,2,3- triazole compound with anti-tumor activity |
| CN109761968A (en) * | 2018-12-25 | 2019-05-17 | 河南师范大学 | Paeonol with anti-tumor activity and benzoxazine compounds and its preparation method and application |
Non-Patent Citations (10)
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018738A (en) * | 2019-12-20 | 2020-04-17 | 安徽医科大学 | Paeonol derivative, pharmaceutical preparation, preparation method and application |
| CN111018738B (en) * | 2019-12-20 | 2023-03-21 | 安徽医科大学 | Paeonol derivative, pharmaceutical preparation, preparation method and application |
| CN111116422A (en) * | 2019-12-30 | 2020-05-08 | 西南大学 | Paeonol etherified urea compound with anti-inflammatory activity and application thereof |
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|---|---|
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