CN107434778A - A kind of preparation method of the ketone derivatives of 4 hydroxyl 2H pyrroles 2 - Google Patents
A kind of preparation method of the ketone derivatives of 4 hydroxyl 2H pyrroles 2 Download PDFInfo
- Publication number
- CN107434778A CN107434778A CN201710369676.1A CN201710369676A CN107434778A CN 107434778 A CN107434778 A CN 107434778A CN 201710369676 A CN201710369676 A CN 201710369676A CN 107434778 A CN107434778 A CN 107434778A
- Authority
- CN
- China
- Prior art keywords
- pyrroles
- hydroxyls
- ketone derivatives
- milliliters
- hydroxyl
- 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.)
- Pending
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 4 hydroxyls 2HThe preparation method of the ketone derivatives of pyrroles 2, based on the present invention is using Ugi reactions, then in the basic conditions, using microwave radiation technology cyclization, obtain 4 hydroxyls 2 with potential active anticancerHThe ketone derivatives of pyrroles 2.
Description
Technical field
The invention belongs to organic synthesis field, especially a kind of 4- hydroxyls -2HThe preparation method of-pyrroles -2- ketone derivatives
And its application.
Background technology
4- hydroxyls -2H- pyrroles -2- ketone derivatives typically have preferable bioactivity, have antibacterial, antiviral, blood vessel
The bioactivity such as generation suppression and central depressant.Meanwhile this analog derivative has obvious liver protection, promotees intelligence and antitumor etc.
Effect, has good Research Prospects.
2-Pyrrolidone 1 is nitrogen-atoms, by carrying out the substitution of various groups to it, can obtain preferable pharmacology and live
Property, such as, the synthesis of medicine Piracetam can be raw material by 2-Pyrrolidone, pass through ammonia again with the condensation of halogenated acetic acids ethyl ester
Solution synthesis, halogenated carboxylic ester can also be passed through and obtain product with amide condensed.In addition, similar compound also has suppression tumour thin
The function of intracellular growth, its structure introduce corresponding aromatic group on 3 of pyrrolidones, obtain a series of pyrrolidone ring
For the compound of support, very strong MMP-13 inhibitory action is shown（J. Med. Chem. 2000, 43, 2293）So
And 4- hydroxyls -2HThe multicomponent study on the synthesis of-pyrroles -2- ketone derivatives is less, is badly in need of people's concern and research.
The content of the invention
It is an object of the invention to provide 4- hydroxyls -2H- pyrroles -2- ketone derivatives preparation method and applications, the present invention
With it is simple to operate, reaction condition is gentle, synthetic route is short, yield is higher, low cost and other advantages.
What the purpose of the present invention was achieved through the following technical solutions：
A kind of 4- hydroxyls -2HThe general structure of-pyrroles -2- ketone derivatives is as follows：
。
4- hydroxyls -2 wherein described in 1H- pyrroles -2- ketone derivatives, the R described in it1For alkyl, aryl and heteroaryl, R2
For alkyl, aryl and heteroaryl, R3For hydrogen atom, halogen, nitro, alkyl, methoxyl group and 3- methyl fluorides.
A kind of 4- hydroxyls -2HThe preparation method of-pyrroles -2- ketone derivatives, it is characterised in that：Reacted using multicomponent Ugi,
The compound taken uses organic base condition, microwave radiation technology reaction, in 120 degrees Celsius of condition on the basis of it need not purify
Lower reaction 10 minutes, it is possible to obtain target product, this course of reaction is short, and post-reaction treatment is simple.
Wherein used alkali is the carbon -7- alkene (DBU) of 1,8- diazabicylos 11.
Moreover, synthetic route is as follows：
。
Described 4- hydroxyls -2HApplication of-pyrroles -2- the ketone derivatives in antineoplastic is prepared.
The advantages and positive effects of the present invention.
The present invention, then by the ring closure reaction under alkalescence condition, is operated based on Ugi reacts by microwave radiation technology, first
It is secondary to obtain 4- hydroxyl -2H- pyrroles's -2- ketone derivatives with potential source biomolecule activity.The present invention has simple to operate, reaction condition
Gently, synthetic route is short, yield is higher, low cost and other advantages.
Brief description of the drawings
Fig. 1 is 4- hydroxyls -2HThe general structure of-pyrroles -2- ketone derivatives.
Fig. 2 is the present inventionN- benzyl -4-（4- chlorphenyls）- 3- hydroxyl -5- oxo -1- phenyl -2,5- dihydros -1H- pyrroles-
The nuclear magnetic spectrogram of 2- formamides.
Fig. 3 is the present inventionN, 1- dibenzyl -4-（4- chlorphenyls）- 3- hydroxyl -5- oxo -2,5- dihydros -1H- pyrroles -2-
The nuclear magnetic spectrogram of formamide.
Fig. 4 is the present inventionN- benzyl -4-（3,4- Dimethoxyphenyls）- 3- hydroxyl -5- oxo -1- phenyl -2,5- dihydros -
1HThe nuclear magnetic spectrogram of-pyrroles -2- formamides.
Fig. 5 is the present inventionN- benzyl -1-（4- bromophenyls）-4-（2- fluorophenyls）- 3- hydroxyl -5- oxo -2,5- dihydros -
1HThe nuclear magnetic spectrogram of-pyrroles -2- formamides.
Fig. 6 is the present inventionN- benzyl -3- hydroxyls -1-（4- methoxyphenyls）-4-（4- nitrobenzophenones）- 5- oxos -2,5-
Dihydro -1HThe nuclear magnetic spectrogram of-pyrroles -2- formamides.
Fig. 7 is the present inventionN- cyclohexyl -3- hydroxyls -4-（4- methoxyphenyls）- 5- oxo -1- phenethyl -2,5- dihydros -
1HThe nuclear magnetic spectrogram of-pyrroles -2- formamides.
Fig. 8 is the present inventionN- cyclohexyl -1-（2,6- 3,5-dimethylphenyls）- 3- hydroxyls -4-（4- nitrobenzophenones）- 5- oxos-
2,5- dihydros -1HThe nuclear magnetic spectrogram of-pyrroles -2- formamides.
Fig. 9 is 4- of the present invention（2- bromophenyls）- 3- hydroxyl -5- oxos -N, 1- diphenyl -2,5- dihydro -1H- pyrroles -2-
The nuclear magnetic spectrogram of formamide.
Figure 10 is 4- of the present invention（4- chlorphenyls）- 3- hydroxyl -1- isobutyl group -5- oxos -N- phenyl -2,5- dihydros -1H- pyrrole
Cough up the nuclear magnetic spectrogram of -2- formamides.
Embodiment
In order to understand the present invention, with reference to embodiment, the invention will be further described that following embodiments are illustrative
, it is not limited, it is impossible to limit protection scope of the present invention with following embodiments.
The present invention provides following formula: compound：
。
4- hydroxyls -2 wherein described in 1H- pyrroles -2- ketone derivatives, the R described in it1For alkyl, aryl and heteroaryl, R2
For alkyl, aryl and heteroaryl, R3Hydrogen atom, halogen, nitro, alkyl, methoxyl group and 3- methyl fluorides.
Especially compound of the invention includes：
（1）N- benzyl -4-（4- chlorphenyls）- 3- hydroxyl -5- oxo -1- phenyl -2,5- dihydros -1H- pyrroles -2- formamides.
（2）N, 1- dibenzyl -4-（4- chlorphenyls）- 3- hydroxyl -5- oxo -2,5- dihydros -1H- pyrroles -2- formamides.
（3）N- benzyl -4-（3,4- Dimethoxyphenyls）- 3- hydroxyl -5- oxo -1- phenyl -2,5- dihydros -1H- pyrroles-
2- formamides.
（4）N- benzyl -1-（4- bromophenyls）-4-（2- fluorophenyls）- 3- hydroxyl -5- oxo -2,5- dihydros -1H- pyrroles -2-
Formamide.
（5）N- benzyl -3- hydroxyls -1-（4- methoxyphenyls）-4-（4- nitrobenzophenones）- 5- oxo -2,5- dihydros -1H-
Pyrroles's -2- formamides.
（6）N- cyclohexyl -3- hydroxyls -4-（4- methoxyphenyls）- 5- oxo -1- phenethyl -2,5- dihydros -1H- pyrroles-
2- formamides.
（7）N- cyclohexyl -1-（2,6- 3,5-dimethylphenyls）- 3- hydroxyls -4-（4- nitrobenzophenones）- 5- oxo -2,5- dihydros -
1H- pyrroles -2- formamides.
（8）4-（2- bromophenyls）- 3- hydroxyl -5- oxos -N, 1- diphenyl -2,5- dihydro -1H- pyrroles -2- formamides.
（9）4-（4- chlorphenyls）- 3- hydroxyl -1- isobutyl group -5- oxos -N- phenyl -2,5- dihydros -1H- pyrroles -2- formyls
Amine.
Synthesize 4- hydroxyls -2HThe committed step of-pyrroles -2- ketone derivatives is：Reacted using multicomponent Ugi, normal temperature condition
Under obtain Ugi products, the compound without purification carry out next step reaction, using the carbon -7- alkene of 1,8- diazabicylos 11
(DBU) alkalescence condition, microwave radiation technology reaction, reacts 10 minutes under conditions of 120 degrees Celsius, it is possible to obtains target production
Thing, this course of reaction is short, and post-reaction treatment is simple.
For the separating-purifying of the present invention using the method for column chromatography, solvent used is that acetic acid second is cruel and n-hexane
Mixture
The 4- hydroxyls -2HThe synthetic route of-pyrroles -2- ketone derivatives
。
Building-up process is illustrated below by examples of implementation.
Embodiment 1
Wherein R1For aryl, R2For alkyl, R3For halogen atom, i.e.,N- benzyl -4-（4- chlorphenyls）- 3- hydroxyl -5- oxos -1-
Phenyl -2,5- dihydros -1HThe synthesis of-pyrroles -2- formamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by aniline compound（1.0 mM）And glyoxylic acid ethyl ester（1.5 milli
Mole）It is dissolved in 2.0 milliliters of methanol, then again by parachlorotoluene guanidine-acetic acid（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 dimethylformamide
（DMF）Dissolving, adds the carbon -7- alkene (DBU) of 1,8- diazabicylos 11（2.0 mM）, 120 in micro-wave ovenoC is anti-
Answer 10 minutes.The solution uses ethyl acetate（50 milliliters）Dissolving, then with saturated common salt water washing (3 20 milliliters of x).It is organic
After mutually being dried using magnesium sulfate, silicagel column is separated, and obtains targetN- benzyl -4-（4- chlorphenyls）- 3- hydroxyl -5- oxos -
1- phenyl -2,5- dihydros -1H- pyrroles -2- benzamide compounds, yield 87%.
1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 5.8 Hz, 1H), 7.93 (d, J =
8.5 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.35 (t, J =
7.8 Hz, 2H), 7.23 – 7.16 (m, 3H), 7.12 (t, J = 7.3 Hz, 1H), 7.05 – 6.96 (m,
2H), 5.37 (s, 1H), 4.27 (qd, J = 15.4, 5.9 Hz, 2H). 13C NMR (100 MHz, DMSO-d6)
δ 170.33, 166.73, 165.99, 139.03, 138.59, 131.07, 130.73, 129.69, 129.12,
128.59, 128.35, 127.25, 124.02, 120.93, 104.39, 64.55, 55.37, 42.94.LC/MS
calculated for C24H20ClN2O3 [M+H]+, 419; found 419。
Embodiment 2
Wherein R1For alkyl, R2For halogen, R3For alkyl, i.e.,N, 1- dibenzyl -4-（4- chlorphenyls）- 3- hydroxyl -5- oxo -2,
5- dihydros -1HThe synthesis of-pyrroles -2- formamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by benzylamine compound（1.0 mM）And glyoxylic acid ethyl ester（1.5 milli
Mole）It is dissolved in 2.0 milliliters of methanol, then again by phenylacetic acid（1.0 mM）With benzyl isocyanide compound（1.0 milli
Mole）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then detect isocyanide compound using thin-layer chromatography,
If without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dimethylformamide（DMF）It is molten
Solution, adds the carbon -7- alkene (DBU) of 1,8- diazabicylos 11（2.0 mM）, 120 in micro-wave ovenoC reacts 10 points
Clock.The solution uses ethyl acetate（50 milliliters）Dissolving, then with saturated common salt water washing (3 20 milliliters of x).Organic phase uses
After magnesium sulfate is dried, silicagel column is separated, and obtains targetN, 1- dibenzyl -4-（4- chlorphenyls）- 3- hydroxyl -5- oxo -2,
5- dihydros -1H- pyrroles -2- benzamide compounds, yield 64%.
1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.77 (s, 1H), 7.99 (d, J =
8.7 Hz, 2H), 7.45 – 7.40 (m, 2H), 7.33 (t, J = 7.3 Hz, 4H), 7.29 – 7.22 (m,
4H), 7.17 (d, J = 7.1 Hz, 2H), 4.93 (d, J = 15.7 Hz, 1H), 4.49 (s, 1H), 4.26
(qd, J = 15.0, 5.8 Hz, 2H), 4.00 (d, J = 15.7 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 171.61, 166.42, 165.89, 139.16, 138.07, 131.10, 130.86, 129.28, 128.96,
128.76, 128.31, 127.88, 127.50, 103.69, 63.74, 44.18, 43.22. LC/MS calculated
for C25H22ClN2O3 [M+H]+, 433; found 433。
Embodiment 3
Wherein R1For aryl, R2For halogen, R3For alkyl, i.e.,N- benzyl -4-（3,4- Dimethoxyphenyls）- 3- hydroxyl -5- oxygen
Generation -1- phenyl -2,5- dihydros -1HThe synthesis of-pyrroles -2- formamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by aniline compound（1.0 mM）And glyoxylic acid ethyl ester（1.5 milli
Mole）It is dissolved in 2.0 milliliters of methanol, then again by 3,4- dimethoxy benzene guanidine-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 dimethyl methyl
Acid amides（DMF）Dissolving, adds the carbon -7- alkene (DBU) of 1,8- diazabicylos 11（2.0 mM）, in micro-wave oven
120oC reacts 10 minutes.The solution uses ethyl acetate（50 milliliters）Dissolving, then with the saturated common salt water washing (millis of 3 x 20
Rise).After organic phase is dried using magnesium sulfate, silicagel column is separated, and obtains targetN- benzyl -4-（3,4- dimethoxy benzenes
Base）- 3- hydroxyl -5- oxo -1- phenyl -2,5- dihydros -1H- pyrroles -2- benzamide compounds, yield 57%.
1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.86 (t, J = 5.8 Hz, 1H),
7.63 (d, J = 8.0 Hz, 2H), 7.49 (s, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.33 (t, J
= 7.9 Hz, 2H), 7.21 (d, J = 6.5 Hz, 3H), 7.10 (t, J = 7.3 Hz, 1H), 7.04 (d, J
= 5.9 Hz, 2H), 6.98 (d, J = 8.5 Hz, 1H), 5.33 (s, 1H), 4.28 (qd, J = 15.4,
5.9 Hz, 2H), 3.77 (d, J = 2.4 Hz, 6H). 13C NMR (100 MHz, DMSO-d6) δ 169.63,
165.15, 147.45, 146.92, 138.01, 137.84, 128.02, 127.51, 126.18, 122.76,
120.06, 119.58, 111.19, 110.91, 63.16, 54.84, 41.84. LC/MS calculated for
C26H25N2O5 [M+H]+, 445; found 445。
Embodiment 4
Wherein R1For aryl, R2For alkyl, R3For methoxyl group, i.e.,N- benzyl -1-（4- bromophenyls）-4-（2- fluorophenyls）- 3- hydroxyls
Base -5- oxo -2,5- dihydros -1HThe synthesis of-pyrroles -2- formamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 4- bromophenyl amine compounds（1.0 mM）And glyoxylic acid ethyl ester
（1.5 mM）It is dissolved in 2.0 milliliters of methanol, then again by 2- Fluorophenylacetic 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 dimethyl formyl
Amine（DMF）Dissolving, adds the carbon -7- alkene (DBU) of 1,8- diazabicylos 11（2.0 mM）, 120 in micro-wave ovenoC
Reaction 10 minutes.The solution uses ethyl acetate（50 milliliters）Dissolving, then with saturated common salt water washing (3 20 milliliters of x).Have
After machine is mutually dried using magnesium sulfate, silicagel column is separated, and obtains targetN- benzyl -1-（4- bromophenyls）-4-（2- fluorophenyls）-
3- hydroxyl -5- oxo -2,5- dihydros -1H- pyrroles -2- benzamide compounds, yield 61%.
1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 9.02 (s, 1H), 7.58 (d, J =
9.0 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H), 7.44 (td, J = 7.7, 1.7 Hz, 1H), 7.40 –
7.33 (m, 1H), 7.28 – 7.18 (m, 5H), 7.14 – 7.06 (m, 2H), 5.37 (s, 1H), 4.31
(d, J = 5.9 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 170.38, 165.89, 161.77,
159.31, 139.16, 138.45, 132.41, 131.91, 129.55, 128.60, 127.32, 124.19,
121.68, 115.93, 115.72, 115.26, 64.50, 42.90. LC/MS calculated for
C24H19BrFN2O3 [M+H]+, 481; found 481。
Embodiment 5
Wherein R1For aryl, R2For alkyl, R3For nitro, i.e.,N- benzyl -3- hydroxyls -1-（4- methoxyphenyls）-4-（4- nitros
Phenyl）- 5- oxo -2,5- dihydros -1HThe synthesis of-pyrroles -2- formamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 4- methoxybenzene amines（1.0 mM）With glyoxalic acid second
Ester（1.5 mM）It is dissolved in 2.0 milliliters of methanol, 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 examined using thin-layer chromatography
Isocyanide compound is surveyed, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dimethyl
Formamide（DMF）Dissolving, adds the carbon -7- alkene (DBU) of 1,8- diazabicylos 11（2.0 mM）, in micro-wave oven
120oC reacts 10 minutes.The solution uses ethyl acetate（50 milliliters）Dissolving, then with the saturated common salt water washing (millis of 3 x 20
Rise).After organic phase is dried using magnesium sulfate, silicagel column is separated, and obtains targetN- benzyl -3- hydroxyls -1-（4- methoxybenzenes
Base）-4-（4- nitrobenzophenones）- 5- oxo -2,5- dihydros -1H- pyrroles -2- benzamide compounds, yield 73%.
1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J = 5.9 Hz, 1H), 8.36 (d, J =
9.1 Hz, 2H), 8.21 (d, J = 9.1 Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H), 7.23 – 7.16
(m, 3H), 6.98 (d, J = 3.5 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 5.25 (s, 1H),
4.26 (ddd, J = 38.3, 15.5, 6.0 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 169.35,
165.07, 155.27, 143.15, 139.74, 138.01, 130.50, 127.43, 126.14, 125.77,
122.65, 113.22, 64.78, 54.66, 41.76. LC/MS calculated for C25H22N3O6 [M+H]+,
460; found 460。
Embodiment 6
Wherein R1For alkyl, R2For alkyl, R3For methoxyl group, i.e.,N- cyclohexyl -3- hydroxyls -4-（4- methoxyphenyls）- 5- oxygen
Generation -1- phenethyl -2,5- dihydros -1HThe synthesis of-pyrroles -2- formamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 4- methoxybenzene amines（1.0 mM）With glyoxalic acid second
Ester（1.5 mM）It is dissolved in 2.0 milliliters of methanol, then again by phenethyl acetic acid（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 examined using thin-layer chromatography
Isocyanide compound is surveyed, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dimethyl
Formamide（DMF）Dissolving, adds the carbon -7- alkene (DBU) of 1,8- diazabicylos 11（2.0 mM）, in micro-wave oven
120oC reacts 10 minutes.The solution uses ethyl acetate（50 milliliters）Dissolving, then with the saturated common salt water washing (millis of 3 x 20
Rise).After organic phase is dried using magnesium sulfate, silicagel column is separated, and obtains targetN- cyclohexyl -3- hydroxyls -4-（4- methoxyl groups
Phenyl）- 5- oxo -1- phenethyl -2,5- dihydros -1H- pyrroles -2- benzamide compounds, yield 51%.
1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H),
7.82 (d, J = 8.8 Hz, 2H), 7.35 – 7.27 (m, 2H), 7.22 (d, J = 7.4 Hz, 3H), 6.91
(d, J = 8.9 Hz, 2H), 4.54 (s, 1H), 3.87 – 3.78 (m, 1H), 3.75 (s, 3H), 3.62
(d, J = 4.2 Hz, 1H), 3.09 – 2.98 (m, 1H), 2.91 – 2.82 (m, 1H), 2.72 (ddd, J =
13.5, 9.4, 6.8 Hz, 1H), 1.79 (d, J = 8.6 Hz, 2H), 1.70 (d, J = 12.6 Hz, 2H),
1.57 (d, J = 12.1 Hz, 1H), 1.26 (dt, J = 21.1, 10.8 Hz, 5H). 13C NMR (100 MHz,
DMSO-d6) δ 171.80, 165.11, 164.05, 157.88, 139.66, 128.93, 126.67, 124.71,
113.69, 104.84, 63.65, 55.45, 48.71, 41.93, 34.41, 32.82, 32.43, 25.65,
24.86. LC/MS calculated for C26H31N2O4 [M+H]+, 435; found 435。
Embodiment 7
Wherein R1For heteroaryl, R2For halogen, R3For alkyl, i.e.,N- cyclohexyl -1-（2,6- 3,5-dimethylphenyls）- 3- hydroxyls -4-
（4- nitrobenzophenones）- 5- oxo -2,5- dihydros -1HThe synthesis of-pyrroles -2- formamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 2,6- dimethyl benzene amines（1.0 mM）And glyoxalic acid
Ethyl ester（1.5 mM）It is dissolved in 2.0 milliliters of methanol, then again by 4- nitro phenyl acetic acids（1.0 mM）It is different with benzyl
Cyanogen compound（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then using thin-layer chromatography
Isocyanide compound is detected, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of diformazan
Base formamide（DMF）Dissolving, adds the carbon -7- alkene (DBU) of 1,8- diazabicylos 11（2.0 mM）, in micro-wave oven
120oC reacts 10 minutes.The solution uses ethyl acetate（50 milliliters）Dissolving, then with the saturated common salt water washing (millis of 3 x 20
Rise).After organic phase is dried using magnesium sulfate, silicagel column is separated, and obtains targetN- cyclohexyl -1-（2,6- dimethyl benzenes
Base）- 3- hydroxyls -4-（4- nitrobenzophenones）- 5- oxo -2,5- dihydros -1H- pyrroles -2- benzamide compounds, yield 75%.
1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 9.1 Hz, 2H), 8.27 – 8.17 (m,
2H), 7.97 (d, J = 7.7 Hz, 1H), 7.25 – 7.03 (m, 3H), 4.80 (s, 1H), 3.47 (dd, J
= 7.3, 3.5 Hz, 1H), 2.13 (d, J = 9.2 Hz, 6H), 1.80 – 1.56 (m, 3H), 1.54 –
1.38 (m, 3H), 1.26 – 0.97 (m, 6H), 0.85 – 0.71 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ 170.46, 164.54, 144.76, 140.23, 139.53, 137.45, 135.28, 128.59, 128.22,
127.29, 123.69, 102.27, 64.82, 48.57, 32.33, 25.55, 24.78, 18.48, 18.25. LC/
MS calculated for C25H28N3O5 [M+H]+, 450; found 450。
Embodiment 8
Wherein R1For aryl, R2For aryl, R3For aryl, i.e. 4-（2- bromophenyls）- 3- hydroxyl -5- oxos -N, 1- diphenyl -2,
5- dihydros -1HThe synthesis of-pyrroles -2- formamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by aniline compound（1.0 mM）And glyoxylic acid ethyl ester（1.5 milli
Mole）It is dissolved in 2.0 milliliters of methanol, then again by 2- Bromophenylacetic acids（1.0 mM）With benzene cyanogen 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 dimethylformamide（DMF）
Dissolving, adds the carbon -7- alkene (DBU) of 1,8- diazabicylos 11（2.0 mM）, 120 in micro-wave ovenoC reacts 10 points
Clock.The solution uses ethyl acetate（50 milliliters）Dissolving, then with saturated common salt water washing (3 20 milliliters of x).Organic phase uses
After magnesium sulfate is dried, silicagel column is separated, and obtains target 4-（2- bromophenyls）- 3- hydroxyl -5- oxos -N, 1- diphenyl -2,
5- dihydros -1H- pyrroles -2- benzamide compounds, yield 67%.
1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 10.64 (s, 1H), 7.72 – 7.56
(m, 5H), 7.44 (t, J = 7.3 Hz, 1H), 7.33 (tt, J = 10.1, 5.2 Hz, 6H), 7.07 (dt,
J = 21.8, 7.3 Hz, 2H), 5.54 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ 170.21,
165.66, 139.07, 138.81, 133.58, 132.75, 132.14, 130.12, 129.37, 127.72,
125.44, 124.54, 123.56, 119.79, 119.24, 107.77, 64.53. LC/MS calculated for
C23H18BrN2O3 [M+H]+, 449; found 449。
Embodiment 9
Wherein R1For aryl, R2For halogen, R3For alkyl, i.e. 4-（4- chlorphenyls）- 3- hydroxyl -1- isobutyl group -5- oxos -N- benzene
Base -2,5- dihydros -1HThe synthesis of-pyrroles -2- formamides, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by isobutyl amines（1.0 mM）And glyoxylic acid ethyl ester（1.5
MM）It is dissolved in 2.0 milliliters of methanol, 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 using thin-layer chromatography
Compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, then again with 3.0 milliliters of dimethylformamide
（DMF）Dissolving, adds the carbon -7- alkene (DBU) of 1,8- diazabicylos 11（2.0 mM）, 120 in micro-wave ovenoC is anti-
Answer 10 minutes.The solution uses ethyl acetate（50 milliliters）Dissolving, then with saturated common salt water washing (3 20 milliliters of x).It is organic
After mutually being dried using magnesium sulfate, silicagel column is separated, and obtains target 4-（4- chlorphenyls）- 3- hydroxyl -1- isobutyl group -5- oxygen
Generation-N- phenyl -2,5- dihydros -1H- pyrroles -2- benzamide compounds, yield 53%
1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.40 (s, 1H), 8.00 (d, J =
8.6 Hz, 2H), 7.65 (d, J = 7.9 Hz, 2H), 7.45 – 7.33 (m, 4H), 7.13 (d, J = 7.4
Hz, 1H), 4.79 (s, 1H), 3.39 – 3.33 (m, 1H), 2.81 (dd, J = 13.8, 6.4 Hz, 1H),
2.03 – 1.86 (m, 1H), 0.86 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H). 13C
NMR (100 MHz, DMSO-d6 ) δ 171.86, 165.95, 164.98, 138.85, 131.23, 130.76,
129.28, 128.27, 124.60, 120.10, 103.87, 64.97, 48.23, 27.48, 20.63, 20.39.
LC/MS calculated for C21H22ClN2O3 [M+H]+, 385; found 385。
The synthesis of 4- hydroxyl -2H- pyrroles's -2- ketone derivatives involved in the present invention, taken using multicomponent Ugi reactions
Ugi products, the compound is on the basis of it need not purify, using the alkalescence of the carbon -7- alkene (DBU) of 1,8- diazabicylos 11
Condition, microwave radiation technology reaction, reacts 10 minutes under conditions of 120 degree, it is possible to target product is obtained, this course of reaction is short,
Post-reaction treatment is simple, it is only necessary to as soon as step purifies, can obtain target product.4- hydroxyl -2H- pyrroles involved in the present invention -
Application of the 2- ketone derivatives in antineoplastic is prepared.
Claims (7)
- A kind of 1. 4- hydroxyls -2H- pyrroles -2- ketone derivatives, it is characterised in that：The general structure of derivative is as follows：。
- 2. 4- hydroxyls -2 according to claim 1H- pyrroles -2- ketone derivatives, it is characterised in that：Described R1For alkyl, Aryl and heteroaryl.
- 3. 4- hydroxyls -2 according to claim 1H- pyrroles -2- ketone derivatives, it is characterised in that：Described R2For alkyl, Aryl and heteroaryl.
- 4. 4- hydroxyls -2 according to claim 1H- pyrroles -2- ketone derivatives, it is characterised in that：Described R3It is former for hydrogen Son, halogen, nitro, alkyl, methoxyl group and 3- methyl fluorides.
- A kind of 5. 4- hydroxyls -2HThe preparation method of-pyrroles -2- ketone derivatives, it is characterised in that：Reacted, taken using multicomponent Ugi To Ugi products need not purify, in alkalescence condition, microwave radiation technology reaction, 120 degree reactions 10 minutes, it is possible to obtain target Product, this course of reaction is short, and post-reaction treatment is simple.
- 6. the 4- hydroxyls -2 according to claimHThe preparation method of-pyrroles -2- ketone derivatives, it is characterised in that：Described Alkali is the carbon -7- alkene (DBU) of 1,8- diazabicylos 11.
- 7. 4- hydroxyls -2 according to claim 1H- pyrroles -2- ketone derivatives, it is characterised in that：Synthetic route is as follows：。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710369676.1A CN107434778A (en) | 2017-05-23 | 2017-05-23 | A kind of preparation method of the ketone derivatives of 4 hydroxyl 2H pyrroles 2 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710369676.1A CN107434778A (en) | 2017-05-23 | 2017-05-23 | A kind of preparation method of the ketone derivatives of 4 hydroxyl 2H pyrroles 2 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107434778A true CN107434778A (en) | 2017-12-05 |
Family
ID=60458783
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710369676.1A Pending CN107434778A (en) | 2017-05-23 | 2017-05-23 | A kind of preparation method of the ketone derivatives of 4 hydroxyl 2H pyrroles 2 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107434778A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1004578A2 (en) * | 1998-11-05 | 2000-05-31 | Pfizer Products Inc. | 5-oxo-pyrrolidine-2-carboxylic acid hydroxamide derivatives |
| WO2002030892A1 (en) * | 2000-10-11 | 2002-04-18 | Morphochem Ag | Butenolide and pentenolide derivatives as kinase inhibitors |
| CN103889951A (en) * | 2011-10-27 | 2014-06-25 | 大正制药株式会社 | Azole derivative |
-
2017
- 2017-05-23 CN CN201710369676.1A patent/CN107434778A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1004578A2 (en) * | 1998-11-05 | 2000-05-31 | Pfizer Products Inc. | 5-oxo-pyrrolidine-2-carboxylic acid hydroxamide derivatives |
| WO2002030892A1 (en) * | 2000-10-11 | 2002-04-18 | Morphochem Ag | Butenolide and pentenolide derivatives as kinase inhibitors |
| CN103889951A (en) * | 2011-10-27 | 2014-06-25 | 大正制药株式会社 | Azole derivative |
Non-Patent Citations (2)
| Title |
|---|
| JU LIU: "Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| RALPH P. ROBINSON: "Structure-Based Design and Synthesis of a Potent Matrix Metalloproteinase-13 Inhibitor Based on a Pyrrolidinone Scaffold", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NZ537784A (en) | Modified Pictet-Spengler reaction and products prepared therefrom | |
| CN101830858B (en) | Preparation method of 1H-1,2,4-tolyltriazole-3-methyl formate | |
| Yang et al. | Selective and tunable synthesis of 3-arylsuccinimides and 3-arylmaleimides from arenediazonium tetrafluoroborates and maleimides | |
| Janikowska et al. | Acyl Meldrum's acid derivatives: application in organic synthesis | |
| BR112021005090A2 (en) | manufacturing process for 2-nitroimino heterocyclic compounds | |
| CN104788333B (en) | 2-substituted-9,10-anthraquinone compounds, and preparation method and application thereof | |
| CN108047138A (en) | Preparation method without hydrazine N-BETA-Alanyl-L-histidine | |
| CN107434778A (en) | A kind of preparation method of the ketone derivatives of 4 hydroxyl 2H pyrroles 2 | |
| CN107973796A (en) | A kind of preparation method of Tadalafei isomers | |
| CN106008392B (en) | A kind of preparation method of the intermediate of cancer therapy drug Dasatinib | |
| CN112094240B (en) | Method for synthesizing quinazoline-2, 4(1H,3H) -diketone compound | |
| CN107353287B (en) | A kind of quinoxaline and heterocyclic fourth ketone compounds and its application in antitumor | |
| CN103965203B (en) | Imidazo-[1,2-c]-quinazolin-3(2H)-one fused-heterocycle compounds and preparation method thereof | |
| O'Callaghan et al. | Dimerisation of Knoevenagel Condensation Products obtained from Simple Unconjugated and α, β-Unsaturated Ketones | |
| CN104402813B (en) | Novel method for synthesizing sorafenib | |
| CN102408377B (en) | Benzimidazole Schiff base and synthesis method thereof | |
| CN101255161B (en) | Method for synthesizing 3,9-diaza-2,4-dioxo-spiro[5.5] undecane template compounds | |
| Mohamadpour et al. | Green and convenient synthesis of polyfunctionalized piperidines catalyzed by ascorbic acid under ambient temperature | |
| US2752359A (en) | Antimicrobial agents | |
| CN104910090B (en) | Dihydro-isoxazole class compound and its synthetic method | |
| CN111808040B (en) | Synthesis method of multi-configuration 2-oxo-oxazolidine-4-carboxylic acid compounds | |
| CN107434777A (en) | The synthesis of the ketone derivatives of 1,5 dihydro 2H pyrroles 2 and antitumor action | |
| CN103833660A (en) | Preparation method of lamotrigine and intermediate thereof | |
| CN110128340B (en) | Synthesis method of quinolinone compounds | |
| CN107226816A (en) | A kind of preparation method of indoline spiro-compound |
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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20171205 |
|
| RJ01 | Rejection of invention patent application after publication |