CN107434777A - The synthesis of the ketone derivatives of 1,5 dihydro 2H pyrroles 2 and antitumor action - Google Patents
The synthesis of the ketone derivatives of 1,5 dihydro 2H pyrroles 2 and antitumor action Download PDFInfo
- Publication number
- CN107434777A CN107434777A CN201710367511.0A CN201710367511A CN107434777A CN 107434777 A CN107434777 A CN 107434777A CN 201710367511 A CN201710367511 A CN 201710367511A CN 107434777 A CN107434777 A CN 107434777A
- Authority
- CN
- China
- Prior art keywords
- pyrroles
- dihydros
- solution
- milliliters
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
Abstract
The present invention relates to a kind of 1,5 dihydros 2HThe preparation method and applications of the ketone derivatives of pyrroles 2.The present invention is based on Ugi reacts, in ZnBr2Under the conditions of obtain carbonyls, obtain then and in the basic conditions 1,5 dihydros 2HThe ketone structural formula of pyrroles 2,1,5 dihydro 2HThe ketone derivatives of pyrroles 2 have potential antitumor activity.
Description
Technical field
The application is related to drug field, especially 1,5- dihydros -2HThe synthesis of-pyrroles -2- ketone derivatives and its anti-swollen
Application in tumor medicine.
Background technology
Because numerous nitrogen-containing heterocycle compounds have potential medicine and bioactivity, therefore chemists are to heterocyclic compound
The study on the synthesis of thing has put into sizable energy.Alkene imines is used in different nitrogen heterocyclic ring synthesis as reactive intermediate
In.Pyrrolidone compound has extensive bioactivity, has applied in terms of the diseases such as antitumor, anti-inflammatory, may be used also in addition
Using the important intermediate as organic reaction.In the today for advocating Green Chemistry, enter how the synthesis of pyrrolidone compound
One step greenization, it is still an important problem.
Multi-component reaction can set up compound library rapidly, by very high attention in the research come in.It is same to use
Multi-component reaction construction pyrrolones structure has been reported recently（Organic and Biomolecular Chemistry,
2014, 12, 8861-8865）.This method obtains target compound using Diene-addition, substantially reduce reaction time and
Step.Also with multi-component reaction, similar caged scaffold pyrrolones compound is also can be with one-step synthesis（ACS Comb.
Sci.,2015,17, 474-481）.As the synthesis of this kind of compound is more and more, the bioactivity of this kind of compound is ground
Study carefully also more.The present invention relates to 1,5- dihydros -2H- pyrroles -2- ketone structure is reacted by multicomponent Ugi to be established, and yet there are no
Have been reported that, their antitumor activity is also badly in need of people's concern and research.
The content of the invention
It is an object of the invention to provide a kind of 1,5- dihydros -2HThe preparation method of-pyrroles -2- ketone derivatives and its anti-
Application in tumour medicine.The application synthesizes 1,5- dihydros -2H- pyrroles -2- ketone derivatives, and Vitro Tumor has been carried out to it
The test of cell inhibitory activity, as a result show that this kind of compound has good inhibiting effect, IC to Human colon cancer50 = 1.13
μM there is antitumor activity, can be used as preparing antineoplastic.
The purpose of the present invention is achieved through the following technical solutions：
A kind of 1,5- dihydros -2H- pyrroles -2- ketone derivatives, it is characterised in that：The general structure of derivative is as follows：
。
Wherein described R1For hydrogen atom, halogen, C1-3Alkyl, methoxyl group, nitro, OH, CN, CF3With methanesulfonic acid base.R2For
Alkyl, aryl and heteroaryl.R3For alkyl, aryl and heteroaryl.
And its pharmaceutical salts.
Moreover, the compound isN- benzyl -2-（4- methoxyphenyls）-2-（4- methyl -3-（4- nitrobenzophenones）-2-
Oxo -2,5- dihydros -1H- pyrroles -1- bases）Acetamide.
Moreover, the compound is 2-（3-（4- bromophenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrroles -1-
Base）-N- cyclohexyl -2-（4- methoxyphenyls）Acetamide.
Moreover, the compound isN- benzyl -2-（3-（4- chlorphenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrrole
Cough up -1- bases）-2-（4- methoxyphenyls）Acetamide.
Moreover, the compound is 2-（3-（3- chlorphenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrroles -1-
Base）-N- cyclohexyl -2-（4- methoxyphenyls）Acetamide.
Moreover, the compound isN- benzyl -2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxo -2,5- dihydros -1H-
Pyrroles's -1- bases）- 2- phenyl-acetamides.
Moreover, the compound isN- benzyl -2-（3-（4- chlorphenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrrole
Cough up -1- bases）- 2- phenyl-acetamides.
Moreover, the compound isN- benzyl -2-（3-（4- bromophenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrrole
Cough up -1- bases）- 2- phenyl-acetamides.
Moreover, the compound isN- benzyl -2-（3-（3- chlorphenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrrole
Cough up -1- bases）-2-（4- methoxyphenyls）Acetamide.
Moreover, the compound isN- benzyl -2-（2- bromophenyls）-2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxos-
2,5- dihydros -1H- pyrroles -1- bases）Acetamide.
Moreover, the compound isN- benzyl -2-（2- fluorophenyls）-2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxos-
2,5- dihydros -1H- pyrroles -1- bases）Acetamide
Described 1,5- dihydros -2H- pyrroles -2- ketone derivatives, it is characterised in that：Synthetic route is as follows
Wherein R1For hydrogen atom, halogen, C1-3Alkyl, methoxyl group, nitro, OH, CN, CF3With methanesulfonic acid base.R2For alkyl, aryl
And heteroaryl.R3For alkyl, aryl and heteroaryl.
Moreover, 1,5- dihydro -2HApplication of-pyrroles -2- the ketone derivatives in antineoplastic is prepared.The compound can
As the antineoplastic for preparing treatment Human colon cancer.
The advantages and positive effects of the present invention：
（1）The present invention is using propargylamine as one of which raw material, by under Ugi reactions and ZnBr2 effects, obtaining ketone form structure, so
Reacted in the basic conditions by microwave radiation technology afterwards, obtain 1,5- dihydros -2H- pyrroles -2- ketone structural formulas, first passage multicomponent
Ugi reacts, and has synthesized 1, the 5- dihydros -2 with antitumor activityH- pyrroles -2- ketone derivatives, and it has been carried out in vitro
The test of inhibiting tumour cells activity, as a result shows that this kind of compound has good inhibiting effect to Human colon cancer（IC50 =
1.12 μM）, there is antitumor activity, can be used as preparing antineoplastic.
（2）Synthetic route of the present invention has that operating procedure is simple, synthetic route is short, low cost and other advantages.
（3）Compound of the present invention, which has, suppresses or kills human colon cancer cell, and it is related to may be used as preparation treatment
Antineoplastic.
Brief description of the drawings
Fig. 1 is general structure, wherein described R1For alkyl, aryl and heteroaryl, R2For hydrogen atom, halogen, methyl.
Fig. 2 isN- benzyl -2-（4- methoxyphenyls）-2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxos -2,5- two
Hydrogen -1H- pyrroles -1- bases）Acetamide.
Fig. 3 is 2-（3-（4- bromophenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）-N- cyclohexyl -2-
（4- methoxyphenyls）Acetamide.
Fig. 4 isN- benzyl -2-（3-（4- chlorphenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）-2-
（4- methoxyphenyls）Acetamide.
Fig. 5 is 2-（3-（3- chlorphenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）-N- cyclohexyl -2-
（4- methoxyphenyls）Acetamide.
Fig. 6 isN- benzyl -2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxo -2,5- dihydros -1H- pyrroles -1- bases）-2-
Phenyl-acetamides.
Fig. 7 isN- benzyl -2-（3-（4- chlorphenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）- 2- benzene
Yl acetamide.
Fig. 8 isN- benzyl -2-（3-（4- bromophenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）- 2- benzene
Yl acetamide.
Fig. 9 isN- benzyl -2-（3-（3- chlorphenyls）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）-2-
（4- methoxyphenyls）Acetamide.
Figure 10 isN- benzyl -2-（2- bromophenyls）-2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxo -2,5- dihydros -
1H- pyrroles -1- bases）Acetamide.
Figure 11 isN- benzyl -2-（2- fluorophenyls）-2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxo -2,5- dihydros -
1H- pyrroles -1- bases）Acetamide.
Embodiment
In order to understand the present invention, with reference to examples of implementation, the invention will be further described：Following examples of implementation are to say
Bright property, be not limited, it is impossible to limits protection scope of the present invention with following embodiments.
1,5- dihydros -2 of the present inventionHThe general structure of-pyrroles -2- ketone derivatives is as follows：
。
Wherein described R1For hydrogen atom, halogen, C1-3Alkyl, methoxyl group, nitro, OH, CN, CF3With methanesulfonic acid base.R2For
Alkyl, aryl and heteroaryl.R3For alkyl, aryl and heteroaryl.
Described 1,5- dihydros -2HThe specific synthetic route of-pyrroles -2- ketone derivatives is as follows：
Building-up process is illustrated below by examples of implementation.
Embodiment 1
Wherein R1For nitro, R2For aryl, R3For alkyl, i.e.,N- benzyl -2-（4- methoxyphenyls）-2-（4- methyl -3-（4- nitre
Base phenyl）- 2- oxo -2,5- dihydros -1H- pyrroles -1- bases）The synthesis of acetamide, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 4-methoxybenzaldehyde（1.5 mM）And propargylamine（1.0 milli
Mole）It is dissolved in 2.0 milliliters of methanol solution, then again by 4- nitro phenyl acetic acids（1.0 mM）With benzyl isocyanide
Compound（1.0 mM）Sequentially add in the solution, stir a whole night under reaction solution normal temperature, then detected using thin-layer chromatography
Isocyanide compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dichloroethanes
（DCE）Dissolving, adds ZnBr2(20 mol%), react 4 hours under normal temperature.Dissolved after being spin-dried for solution with ethyl acetate, it is organic
Mutually after being washed with water, MgSO4After drying, the organic solid after concentration is dissolved in DMSO（3.0 mL）In, 130 in micro-wave ovenoC
Reaction 15 minutes.The solution uses ethyl acetate（15 milliliters）Dilution, then with saturated common salt water washing 3 times, every time 20 milliliters.
After organic phase is dried using magnesium sulfate, separated using silicagel column, obtain target compoundN- benzyl -2-（4- methoxybenzenes
Base）-2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxo -2,5- dihydros -1H- pyrroles -1- bases）Acetamide, yield 62%.
1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.8
Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.33-7.27 (m, 3H), 7.25-7.20 (m, 2H), 6.91
(d, J = 8.7 Hz, 2H), 6.27 (s, 1H), 5.97 (s, 1H), 4.53 (d, J = 9.9 Hz, 1H),
4.47 (t, J = 5.9 Hz, 2H), 3.82 (s, 3H), 3.64 (d, J = 9.9 Hz, 1H), 2.14 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 170.04, 169.65, 159.94, 152.79, 147.08,
138.37, 137.60, 130.27, 129.93, 128.73, 127.69, 127.62, 126.90, 123.45,
114.49, 58.01, 55.37, 52.97, 43.78, 14.50. HRMS (ESI) m/z calcd for C27H26N3O5 +
(M+H)+ 472.18670, found 472.18655。
Embodiment 2
Wherein R1For bromine atoms, R2For aryl, R3For alkyl, i.e. 2-（3-（4- bromophenyls）- 4- methyl -2- oxo -2,5- dihydros -
1H- pyrroles -1- bases）-N- cyclohexyl -2-（4- methoxyphenyls）The synthesis of acetamide, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 4-methoxybenzaldehyde（1.5 mM）And propargylamine（1.0 milli
Mole）It is dissolved in 2.0 milliliters of methanol solution, then again by 4- Bromophenylacetic acids（1.0 mM）With hexamethylene isocyanide
Compound（1.0 mM）Sequentially add in the solution, stir a whole night under reaction solution normal temperature, then detected using thin-layer chromatography
Isocyanide compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dichloroethanes
（DCE）Dissolving, adds ZnBr2(20 mol%), react 4 hours under normal temperature.Dissolved after being spin-dried for solution with ethyl acetate, it is organic
Mutually after being washed with water, MgSO4After drying, the organic solid after concentration is dissolved in DMSO（3.0 mL）In, 130 in micro-wave ovenoC
Reaction 15 minutes.The solution uses ethyl acetate（15 milliliters）Dilution, then with saturated common salt water washing 3 times, every time 20 milliliters.
After organic phase is dried using magnesium sulfate, separated using silicagel column, obtain target compound 2-（3-（4- bromophenyls）- 4- first
Base -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）-N- cyclohexyl -2-（4- methoxyphenyls）Acetamide, yield 51%.
1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.4 Hz, 2H), 7.32 (t, J = 8.1
Hz, 4H), 6.90 (d, J = 8.7 Hz, 2H), 6.17 (s, 1H), 5.98 (s, 1H), 4.49 (d, J =
9.8 Hz, 1H), 3.81 (d, J = 5.5 Hz, 3H), 3.79-3.71 (m, 1H), 3.59 (d, J = 9.8
Hz, 1H), 2.06 (s, 3H), 1.85 (d, J = 11.7 Hz, 3H), 1.67-1.60 (m, 2H), 1.35-
1.28 (m, 2H), 1.10-0.98 (m, 3H).13C NMR (100 MHz, CDCl3) δ 170.59, 168.86,
159.63, 150.46, 131.36, 130.79, 130.67, 130.44, 130.03, 127.83, 121.81,
114.28, 57.72, 55.32, 52.75, 48.63, 32.77, 32.72, 25.41, 24.81,24.75, 14.24.
HRMS (ESI) m/z calcd for C26H30BrN2O3 + (M+H)+ 497.14343, found 497.14307。
Embodiment 3
Wherein R1For chlorine atom, R2For aryl, R3For alkyl, i.e.,N- benzyl -2-（3-（4- chlorphenyls）- 4- methyl -2- oxo -2,
5- dihydros -1H- pyrroles -1- bases）-2-（4- methoxyphenyls）The synthesis of acetamide, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 4-methoxybenzaldehyde（1.5 mM）And propargylamine（1.0 milli
Mole）It is dissolved in 2.0 milliliters of methanol solution, then again by 4- chlorophenylacetic acids（1.0 mM）With benzyl isocyanide chemical combination
Thing（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then detected using thin-layer chromatography different
Cyanogen compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dichloroethanes
（DCE）Dissolving, adds ZnBr2(20 mol%), react 4 hours under normal temperature.Dissolved after being spin-dried for solution with ethyl acetate, it is organic
Mutually after being washed with water, MgSO4After drying, the organic solid after concentration is dissolved in DMSO（3.0 mL）In, 130 in micro-wave ovenoC
Reaction 15 minutes.The solution uses ethyl acetate（15 milliliters）Dilution, then with saturated common salt water washing 3 times, every time 20 milliliters.
After organic phase is dried using magnesium sulfate, separated using silicagel column, obtain target compoundN- benzyl -2-（3-（4- chlorobenzenes
Base）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）-2-（4- methoxyphenyls）Acetamide, yield 55%.
1H NMR (400 MHz, CDCl3) δ 7.40-7.20 (m, 10H), 7.16 (d, J = 6.1 Hz,
2H), 7.01 (s, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.09 (s, 1H), 4.48 (d, J = 9.9
Hz, 1H), 4.45-4.31 (m, 2H), 3.80 (s, 3H), 3.60 (d, J = 9.9 Hz, 1H), 2.05 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 170.74, 169.94, 159.71, 150.50, 137.95,
133.58,130.41,130.36,130.15,130.09,128.39,127.56,127.46,127.33,114.30,
57.82 , 55.33, 52.84, 43.50, 14.25.HRMS (ESI) m/z calcd for C27H26ClN2O3 + (M+H)+
461.16265, found 461.16232。
Embodiment 4
Wherein R1For chlorine atom, R2For aryl, R3For alkyl, i.e. 2-（3-（3- chlorphenyls）- 4- methyl -2- oxo -2,5- dihydros -
1H- pyrroles -1- bases）-N- cyclohexyl -2-（4- methoxyphenyls）The synthesis of acetamide, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 4-methoxybenzaldehyde（1.5 mM）And propargylamine（1.0 milli
Mole）It is dissolved in 2.0 milliliters of methanol solution, then again by 3- chlorophenylacetic acids（1.0 mM）With hexamethylene isocyanide
Compound（1.0 mM）Sequentially add in the solution, stir a whole night under reaction solution normal temperature, then detected using thin-layer chromatography
Isocyanide compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dichloroethanes
（DCE）Dissolving, adds ZnBr2(20 mol%), react 4 hours under normal temperature.Dissolved after being spin-dried for solution with ethyl acetate, it is organic
Mutually after being washed with water, MgSO4After drying, the organic solid after concentration is dissolved in DMSO（3.0 mL）In, 130 in micro-wave ovenoC
Reaction 15 minutes.The solution uses ethyl acetate（15 milliliters）Dilution, then with saturated common salt water washing 3 times, every time 20 milliliters.
After organic phase is dried using magnesium sulfate, separated using silicagel column, obtain target compound 2-（3-（3- chlorphenyls）- 4- first
Base -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）-N- cyclohexyl -2-（4- methoxyphenyls）Acetamide, yield 49%.
1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.31 (dt, J = 6.0, 5.3 Hz,
5H), 6.90 (d, J = 8.6 Hz, 2H), 6.14 (s, 1H), 5.96 (s, 1H), 4.50 (d, J = 9.9
Hz, 1H), 3.81 (d, J = 6.3 Hz, 3H), 3.80-3.70 (m, 1H), 3.60 (d, J = 9.9 Hz,
1H), 2.08 (s, 3H), 1.90-1.79 (m, 3H), 1.69-1.60 (m, 2H), 1.28 (d, J = 6.5 Hz,
3H), 1.05 (dd, J = 10.4, 6.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 170.49,
168.87, 159.59, 151.09, 134.07, 133.54, 130.30, 129.97, 129.41, 129.16,
127.88, 127.73, 127.36, 114.27, 57.68, 55.31, 52.79, 48.61, 32.69, 25.39,
24.81, 24.75, 14.23. HRMS (ESI) m/z calcd for C26H30ClN2O3 + (M+H)+ 453.19395,
found 453.19394。
Embodiment 5
Wherein R1For nitro, R2For aryl, R3For alkyl, i.e.,N- benzyl -2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxo -2,
5- dihydros -1H- pyrroles -1- bases）The synthesis of -2- phenyl-acetamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by benzaldehyde（1.5 mM）And propargylamine（1.0 mM）It is molten
Solution is in 2.0 milliliters of methanol solution, then again by 4- nitro phenyl acetic acids（1.0 mM）With benzyl isocyanide compound
（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then detect isocyanide using thin-layer chromatography
Compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dichloroethanes（DCE）
Dissolving, adds ZnBr2(20 mol%), react 4 hours under normal temperature.Dissolved after being spin-dried for solution with ethyl acetate, organic phase exists
After being washed with water, MgSO4After drying, the organic solid after concentration is dissolved in DMSO（3.0 mL）In, 130 in micro-wave ovenoC reacts
15 minutes.The solution uses ethyl acetate（15 milliliters）Dilution, then with saturated common salt water washing 3 times, every time 20 milliliters.It is organic
After mutually being dried using magnesium sulfate, separated using silicagel column, obtain target compoundN- benzyl -2-（4- methyl -3-（4- nitre
Base phenyl）- 2- oxo -2,5- dihydros -1H- pyrroles -1- bases）- 2- phenyl-acetamides, yield 55%.
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.7
Hz, 2H), 7.45-7.34 (m, 6H), 7.25 (d, J = 7.3 Hz, 2H), 7.19 (d, J = 7.4 Hz,
2H), 6.15 (s, 1H), 4.62 (d, J = 10.1 Hz, 1H), 4.44 (dd, J = 10.3, 5.6 Hz,
2H), 3.65 (d, J = 10.1 Hz, 1H), 2.13 (s, 3H).13C NMR (100 MHz, CDCl3) δ
170.08, 169.58, 153.11, 147.01, 138.40, 137.84, 135.29, 130.04, 129.90,
129.73, 129.17, 129.07, 128.83, 128.69, 128.61, 127.61, 127.43, 123.40,
58.33, 53.13, 43.56, 14.50. HRMS (ESI) m/z calcd for C26H24N3O4 + (M+H)+
442.17613, found 442.17612。
Embodiment 6
Wherein R1For chlorine atom, R2For aryl, R3For alkyl, i.e.,N- benzyl -2-（3-（4- chlorphenyls）- 4- methyl -2- oxo -2,
5- dihydros -1H- pyrroles -1- bases）The synthesis of -2- phenyl-acetamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by benzaldehyde（1.5 mM）And propargylamine（1.0 mM）It is molten
Solution is in 2.0 milliliters of methanol solution, then again by 4- chlorophenylacetic acids（1.0 mM）With benzyl isocyanide compound（1.0
MM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then detect isocyanide chemical combination using thin-layer chromatography
Thing, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dichloroethanes（DCE）It is molten
Solution, adds ZnBr2(20 mol%), react 4 hours under normal temperature.Dissolved after being spin-dried for solution with ethyl acetate, organic phase with
After washing, MgSO4After drying, the organic solid after concentration is dissolved in DMSO（3.0 mL）In, 130 in micro-wave ovenoC reactions 15
Minute.The solution uses ethyl acetate（15 milliliters）Dilution, then with saturated common salt water washing 3 times, every time 20 milliliters.Organic phase
After being dried using magnesium sulfate, separated using silicagel column, obtain target compoundN- benzyl -2-（3-（4- chlorphenyls）- 4- first
Base -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）- 2- phenyl-acetamides, yield 50%.
1H NMR (400 MHz, DMSO-d 6 ) δ 8.91 (s, 1H), 7.51 (s, 4H), 7.43-7.37 (m,
3H), 7.31 (dd, J = 10.5, 7.4 Hz, 4H), 7.24 (d, J = 6.2 Hz, 3H), 5.95 (s, 1H),
4.42 (d, J = 10.2 Hz, 1H), 4.37 – 4.29 (m, 2H), 3.55 (d, J = 10.2 Hz, 1H),
2.07 (s, 3H). 13C NMR (100 MHz, DMSO-d 6 ) δ 170.19, 169.77, 152.33, 139.49,
136.67, 132.67, 131.14, 131.06, 129.23, 129.12, 128.92, 128.74, 128.65,
128.60, 127.79, 127.34, 58.16, 53.15, 42.70, 14.50. HRMS (ESI) m/z calcd for
C26H24ClN2O2 + (M+H)+ 431.15208, found 431.15207。
Embodiment 7
Wherein R1For bromine atoms, R2For aryl, R3For alkyl, i.e.,N- benzyl -2-（3-（4- bromophenyls）- 4- methyl -2- oxo -2,
5- dihydros -1H- pyrroles -1- bases）The synthesis of -2- phenyl-acetamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by benzaldehyde（1.5 mM）And propargylamine（1.0 mM）It is molten
Solution is in 2.0 milliliters of methanol solution, then again by 4- chlorophenylacetic acids（1.0 mM）With benzyl isocyanide compound（1.0
MM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then detect isocyanide chemical combination using thin-layer chromatography
Thing, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dichloroethanes（DCE）It is molten
Solution, adds ZnBr2(20 mol%), react 4 hours under normal temperature.Dissolved after being spin-dried for solution with ethyl acetate, organic phase with
After washing, MgSO4After drying, the organic solid after concentration is dissolved in DMSO（3.0 mL）In, 130 in micro-wave ovenoC reactions 15
Minute.The solution uses ethyl acetate（15 milliliters）Dilution, then with saturated common salt water washing 3 times, every time 20 milliliters.Organic phase
After being dried using magnesium sulfate, separated using silicagel column, obtain target compoundN- benzyl -2-（3-（4- bromophenyls）- 4- first
Base -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）- 2- phenyl-acetamides, yield 52%.
1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.3 Hz, 2H), 7.41-7.31 (m, 5H),
7.24 (dd, J = 7.8, 3.9 Hz, 5H), 7.15 (d, J = 7.4 Hz, 2H), 6.19 (s, 1H), 4.51
(d, J = 9.9 Hz, 1H), 4.39 (m, 2H), 3.60 (d, J = 9.9 Hz, 1H), 2.05 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 170.76, 169.70, 150.78, 137.92, 135.49, 131.36,
130.70, 130.49, 130.31 128.96, 128.77, 128.58, 128.51, 127.54, 127.33,
121.87, 58.31, 52.93, 43.48, 14.27. HRMS (ESI) m/z calcd for C26H24BrN2O2 + (M+H
)+ 475.10157, found 475.10159。
Embodiment 8
Wherein R1For chlorine atom, R2For aryl, R3For alkyl, i.e.,N- benzyl -2-（3-（3- chlorphenyls）- 4- methyl -2- oxo -2,
5- dihydros -1H- pyrroles -1- bases）-2-（4- methoxyphenyls）The synthesis of acetamide, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 4-methoxybenzaldehyde（1.5 mM）And propargylamine（1.0 milli
Mole）It is dissolved in 2.0 milliliters of methanol solution, then again by 3- chlorophenylacetic acids（1.0 mM）With benzyl isocyanide chemical combination
Thing（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then detected using thin-layer chromatography different
Cyanogen compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dichloroethanes
（DCE）Dissolving, adds ZnBr2(20 mol%), react 4 hours under normal temperature.Dissolved after being spin-dried for solution with ethyl acetate, it is organic
Mutually after being washed with water, MgSO4After drying, the organic solid after concentration is dissolved in DMSO（3.0 mL）In, 130 in micro-wave ovenoC
Reaction 15 minutes.The solution uses ethyl acetate（15 milliliters）Dilution, then with saturated common salt water washing 3 times, every time 20 milliliters.
After organic phase is dried using magnesium sulfate, separated using silicagel column, obtain target compoundN- benzyl -2-（3-（3- chlorobenzenes
Base）- 4- methyl -2- oxo -2,5- dihydros -1H- pyrroles -1- bases）-2-（4- methoxyphenyls）Acetamide, yield 57%.
1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.22
(t, J = 7.6 Hz, 5H), 7.15 (d, J = 6.3 Hz, 3H), 6.86 (d, J = 8.4 Hz, 2H), 6.12
(s, 1H), 4.50 (d, J = 9.9 Hz, 1H), 4.41-4.34 (m, 2H), 3.80 (s, 3H), 3.61 (d,J = 9.9 Hz, 1H), 2.06 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.61, 169.96,
159.67, 151.27, 138.01, 134.04, 134.01, 133.42, 130.23, 130.08, 129.41,
129.09, 128.53, 127.77, 127.56, 127.51, 127.29, 127.25, 114.29, 57.77, 55.32,
52.91, 43.46, 14.25. HRMS (ESI) m/z calcd for C27H26ClN2O3 + (M+H)+ 461.16265,
found 461.16248。
Embodiment 9
Wherein R1For nitro, R2For aryl, R3For alkyl, i.e.,N- benzyl -2-（2- bromophenyls）-2-（4- methyl -3-（4- nitrobenzene
Base）- 2- oxo -2,5- dihydros -1H- pyrroles -1- bases）The synthesis of acetamide, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 2- bromobenzaldehydes（1.5 mM）And propargylamine（1.0 mmoles
You）It is dissolved in 2.0 milliliters of methanol solution, then again by 4- nitro phenyl acetic acids（1.0 mM）With benzyl isocyanide chemical combination
Thing（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then detected using thin-layer chromatography different
Cyanogen compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dichloroethanes
（DCE）Dissolving, adds ZnBr2(20 mol%), react 4 hours under normal temperature.Dissolved after being spin-dried for solution with ethyl acetate, it is organic
Mutually after being washed with water, MgSO4After drying, the organic solid after concentration is dissolved in DMSO（3.0 mL）In, 130 in micro-wave ovenoC
Reaction 15 minutes.The solution uses ethyl acetate（15 milliliters）Dilution, then with saturated common salt water washing 3 times, every time 20 milliliters.
After organic phase is dried using magnesium sulfate, separated using silicagel column, obtain target compoundN- benzyl -2-（2- bromophenyls）-
2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxo -2,5- dihydros -1H- pyrroles -1- bases）Acetamide, yield 57%.
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.8 Hz, 2H), 7.67-7.60 (m, 3H),
7.58 (dd, J = 7.7, 1.3 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.31-7.23 (m, 4H),
7.23-7.17 (m, 2H), 6.71 (s, 1H), 6.29 (s, 1H), 4.54 (dd, J = 5.8, 6.1 Hz,
1H), 4.43 (d, J = 9.6 Hz, 1H), 4.40-4.34 (m, 1H), 3.46 (d, J = 9.7 Hz, 1H),
2.14 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.79, 169.25, 152.73, 147.06,
138.26, 137.55, 134.29, 133.73, 130.48, 130,41, 129.91, 129.82, 128.67,
127.86, 127.68, 128.56, 125.38, 123.37, 58.54, 53.27, 43.79, 14.56. HRMS
(ESI) m/z calcd for C26H23BrN3O4 + (M+H)+ 520.08665, found 520.08582。
Embodiment 10
Wherein R1For nitro, R2For aryl, R3For alkyl, i.e.,N- benzyl -2-（2- fluorophenyls）-2-（4- methyl -3-（4- nitrobenzene
Base）- 2- oxo -2,5- dihydros -1H- pyrroles -1- bases）The synthesis of acetamide, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 2- fluorobenzaldehydes（1.5 mM）And propargylamine（1.0 mmoles
You）It is dissolved in 2.0 milliliters of methanol solution, then again by 4- nitro phenyl acetic acids（1.0 mM）With benzyl isocyanide chemical combination
Thing（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then detected using thin-layer chromatography different
Cyanogen compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dichloroethanes
（DCE）Dissolving, adds ZnBr2(20 mol%), react 4 hours under normal temperature.Dissolved after being spin-dried for solution with ethyl acetate, it is organic
Mutually after being washed with water, MgSO4After drying, the organic solid after concentration is dissolved in DMSO（3.0 mL）In, 130 in micro-wave ovenoC
Reaction 15 minutes.The solution uses ethyl acetate（15 milliliters）Dilution, then with saturated common salt water washing 3 times, every time 20 milliliters.
After organic phase is dried using magnesium sulfate, separated using silicagel column, obtain target compoundN- benzyl -2-（2- fluorophenyls）-
2-（4- methyl -3-（4- nitrobenzophenones）- 2- oxo -2,5- dihydros -1H- pyrroles -1- bases）Acetamide, yield 59%.
1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.7
Hz, 2H), 7.55 (td, J = 7.5, 1.3 Hz, 1H), 7.43-7.35 (m, 1H), 7.28 (d, J = 7.3
Hz, 2H), 7.24-7.18 (m, 3H), 7.14 (dd, J = 11.0, 9.7 Hz, 2H), 6.56 (s, 1H),
6.29 (s, 1H), 4.54 (d, J = 9.7 Hz, 1H), 4.50-4.40 (m, 2H), 3.66 (d, J = 9.8
Hz, 1H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.89, 168.94, 162.12,
159.64, 152.92, 147.03, 138.27, 137.87, 130.87, 130.79, 138.70 138.67,
129.91, 129.73, 128.79, 128.66, 128.56, 127.71, 127.59, 127.43, 127.37,
124.61, 124.58, 123.34 (s), 122.61, 122.46, 116.15, 115.93, 62.34, 43.61,
40.86, 20.32. HRMS (ESI) m/z calcd for C26H23FN3O4 + (M+H)+ 460.16671, found
460.16672。
Embodiment 11
The specific steps of antitumor activity test：
Cell used in anti-tumor test of the present invention is SW620.
The nutrient solution that cell uses be containing the Streptomycin Solution of penicillin one hyclone DMEM cell culture fluids, training
The condition of supporting is 37 DEG C, containing 5% CO2Constant incubator.Specific steps：
（1）After being counted with blood counting chamber to cell, 5 × 10 are diluted to DMEM low glucose nutrient solutions4
Individual/mL；
（2）Add the piping and druming of 100 μ L cell suspensions in each hole of 96 orifice plates to mix, 37 DEG C of incubation 24h of incubator；
（3）Wanted test compound is diluted to various concentrations, according to the concentration successively dosing, 37 DEG C of incubation 48h of incubator；
（4）Add the MTT that concentration is 5mg/mL, 37 DEG C of incubation 4h of incubator；
（5）DMSO is added to dissolve cell, the OD values that ELIASA is surveyed under 490nm and 630nm；
（6）Processing data, IC is calculated according to OD values50Value.
The new 1,5- dihydros -2 of table 1H- pyrroles -2- ketone derivatives antitumor activity results.
1, the 5- dihydros -2 of the present invention it can be seen from test resultH- pyrroles -2- ketone derivatives can suppress or
Oncocyte is killed, there is antitumor activity, can be in the antineoplastic for the treatment of human colon carcinoma.
Claims (5)
- A kind of 1. 1,5- dihydros -2H- pyrroles -2- ketone derivatives, it is characterised in that：The general structure of derivative is as follows。
- 2. 1,5- dihydros -2 according to claim 1H- pyrroles -2- ketone derivatives, it is characterised in that：Described R1It is former for hydrogen Son, halogen, C1-3Alkyl, methoxyl group, nitro, OH, CN, CF3With methanesulfonic acid base.
- 3. 1,5- dihydros -2 according to claim 1H- pyrroles -2- ketone derivatives, it is characterised in that：Described R2For alkane Base, aryl and heteroaryl1,5- dihydros -2 according to claim 1H- pyrroles -2- ketone derivatives, it is characterised in that：Described R3For alkyl, Aryl and heteroaryl.
- 4. 1,5- dihydros -2 according to claim 1H- pyrroles -2- ketone derivatives, it is characterised in that：Synthetic route is as follows：。
- 5. the 1,5- dihydros -2 stated according to claim 1H- pyrroles -2- ketone derivatives, it is characterised in that：The compound can use Make to prepare the antineoplastic for treating Human colon cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710367511.0A CN107434777A (en) | 2017-05-23 | 2017-05-23 | The synthesis of the ketone derivatives of 1,5 dihydro 2H pyrroles 2 and antitumor action |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710367511.0A CN107434777A (en) | 2017-05-23 | 2017-05-23 | The synthesis of the ketone derivatives of 1,5 dihydro 2H pyrroles 2 and antitumor action |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107434777A true CN107434777A (en) | 2017-12-05 |
Family
ID=60458950
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710367511.0A Withdrawn CN107434777A (en) | 2017-05-23 | 2017-05-23 | The synthesis of the ketone derivatives of 1,5 dihydro 2H pyrroles 2 and antitumor action |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107434777A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0557691A1 (en) * | 1992-02-17 | 1993-09-01 | Kumiai Chemical Industry Co., Ltd. | 4-Methyl-3-phenyl-2-oxo-3-pyrroline derivatives, process for their preparation and herbicidal compositions |
| JP2001151751A (en) * | 1999-11-24 | 2001-06-05 | Takeda Chem Ind Ltd | Cyclic amide and production thereof |
| WO2002030892A1 (en) * | 2000-10-11 | 2002-04-18 | Morphochem Ag | Butenolide and pentenolide derivatives as kinase inhibitors |
| CN100421665C (en) * | 2002-06-14 | 2008-10-01 | 麦克公司 | Mitotic kinesin inhibitors |
-
2017
- 2017-05-23 CN CN201710367511.0A patent/CN107434777A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0557691A1 (en) * | 1992-02-17 | 1993-09-01 | Kumiai Chemical Industry Co., Ltd. | 4-Methyl-3-phenyl-2-oxo-3-pyrroline derivatives, process for their preparation and herbicidal compositions |
| JP2001151751A (en) * | 1999-11-24 | 2001-06-05 | Takeda Chem Ind Ltd | Cyclic amide and production thereof |
| WO2002030892A1 (en) * | 2000-10-11 | 2002-04-18 | Morphochem Ag | Butenolide and pentenolide derivatives as kinase inhibitors |
| CN100421665C (en) * | 2002-06-14 | 2008-10-01 | 麦克公司 | Mitotic kinesin inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| ZHEN WANG: "Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105829312A (en) | N-benzyl tryptanthrin derivative, and preparation method and application thereof | |
| EP4043458A1 (en) | Ep300/cbp inhibitor | |
| CN104529896B (en) | Synthetic method of diaryl substituted isoquinoline compound | |
| CN104529895B (en) | Synthetic method of replacing nitrogen-containing heterocyclic compound | |
| CN104072493A (en) | Naphthalimide compound containing 2-mercaptobenzothiazole and triazole heterocycle, preparation method and application thereof | |
| Chanda et al. | Polymer supported synthesis of novel benzoxazole linked benzimidazoles under microwave conditions: In vitro evaluation of VEGFR-3 kinase inhibition activity | |
| CN112480140B (en) | C5-substituted tetrandrine derivative and preparation method and application thereof | |
| CN108264510A (en) | A kind of selective depression kinases compound and application thereof | |
| CN106083850A (en) | One class pyrimido naphthalimide derivative and its preparation method and application | |
| CN113372276A (en) | Indazole derivative and application thereof | |
| KR101657054B1 (en) | N-Heterocyclic Carbene Nitric Oxide Radicals and application of the same | |
| CN107434777A (en) | The synthesis of the ketone derivatives of 1,5 dihydro 2H pyrroles 2 and antitumor action | |
| CN107353287B (en) | A kind of quinoxaline and heterocyclic fourth ketone compounds and its application in antitumor | |
| CN105622507A (en) | Naphthalimide derivative and preparing method and application thereof | |
| CN104098524B (en) | 1-meta-methoxy benzoyl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and Synthesis and applications | |
| CN107141282B (en) | A kind of benzimidazole heterocyclic butanone derivative and its application in anti-tumor drug | |
| CN111269242A (en) | Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof | |
| CN111875588A (en) | Erlotinib derivative with killing performance on wild lung cancer tumor cells and preparation method thereof | |
| CN107434782B (en) | A kind of synthetic method of 4- oxyquinoline ketone derivatives and its application in antitumor research | |
| CN108314687A (en) | 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）The synthesis of -one derivative | |
| CN115109083B (en) | Pyridostatin compound, preparation method and application thereof, and pharmaceutical composition | |
| CN102702297A (en) | Preparation method of cholic acid-naphthalimide compound | |
| CN116199687B (en) | Beta-carboline-3-position connected 1,2, 3-triazole compound as well as preparation method and application thereof | |
| CN107434778A (en) | A kind of preparation method of the ketone derivatives of 4 hydroxyl 2H pyrroles 2 | |
| CN108178758A (en) | 2- phenylimidazoles simultaneously [1,2-a] pyrido quinoxaline -2（1H）The synthetic method of -one derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20171205 |