CN108314687A - 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）The synthesis of -one derivative - Google Patents
1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）The synthesis of -one derivative Download PDFInfo
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Abstract
The present invention relates to a kind of 1,2 dihydrobenzos [4,5] imidazo [1,2 a] pyrazines 3（4H）The preparation method of ketone derivatives is deprotected in acid condition first based on the present invention is using Ugi reactions, using microwave radiation technology cyclization, obtained benzimidazole product.By simply post-processing, then under alkaline condition, obtain 1,2 dihydrobenzo [4,5] imidazo [1, the 2 a] pyrazines 3 with potential antitumor activity（4H）The features such as ketone derivatives, this method are easy to get compared with conventional method with raw material, and synthesis technology is brief, and post-processing is simple, and yield is higher.
Description
Technical field
The invention belongs to noval chemical compound preparation method fields, especially one kind 1,2- dihydrobenzos [4,5] imidazo [1,2-
A] pyrazine -3（4H）The synthetic method of -one derivative and its application.
Background technology
Simultaneously pyrazinones derivative generally has preferable bioactivity to benzimidazole, has antitumor and antibacterial activity.
Early-stage study result is shown：Substituted polyaromatic and heteroaryl pyrazino ketone compound object, can be with the serine of inhibition of coagulation cascade
Protease can inhibit the obstruction disease in relation to blood and blood vessel such as formation, fibrinous generation, thrombus of platelet aggregation object
The grumeleuse in blood vessel can also be prevented or be treated to disease, therapeutically can be used to treat or prevent unstable angina, cardiac muscle stalk
The blood vascular diseases such as plug, atrial fibrillation, Deep vain thrombosis.The synthesis of the compound mainly uses traditional conjunction
At method, synthesis step is longer, complex process.Chemists are attempting always different synthetic methods in recent years, wherein utilizing
Multi-component reaction has obtained good utilization in the synthesis of such chemical combination.It has been reported that（Synlett, 2014, 25, 225-
228）, boc-protected amino acid can be used as the raw material of multi-component reaction, be then condensed in acid condition with ester group
To such compound.Also have been reported that be use boc-protected isocyanide as raw material（Tetrahedron Letters, 2015,
56, 4616-4618）, synthesizing benzimidazole ring first, then cyclization obtains such compound again.The present invention is to utilize price just
The bromoacetic acid being preferably easy to get is raw material, by with benzimidazole cyclic condensation, obtain benzimidazole and pyrazinones derivative.The method
It is compared with other methods, shows as raw material and be easy to get, the features such as synthesis technology is brief, and post-processing is simple, and yield is higher.
Invention content
The purpose of the present invention is to provide 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazines -3（4H）-one derivative
Preparation method and applications, the present invention have post-processing operation is simple, reaction condition is mild, synthetic route is short, yield is higher,
The advantages that at low cost.
What the purpose of the present invention was achieved through the following technical solutions：
It is an object of the invention to overcome existing synthetic route, provide a kind of new 1,2- dihydrobenzos [4,5] imidazo [1,
2-a] pyrazine -3（4H）The synthetic method of -one derivative.
1. a kind of 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）The general structure of -one derivative is such as
Under：
。
2. 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 wherein described in 1（4H）-one derivative, institute
The R stated1For hydrogen atom, methyl and halogen；R2For carbon number be 1-6 alkyl, phenyl substituent；R3For carbon number be 1-6 alkyl,
Aryl and heteroaryl.
3. a kind of 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）The preparation method of -one derivative,
It is characterized in that：Using multicomponent Ugi compounds obtained by the reaction under the premise of need not purify, using 10% trifluoroacetic acid and
The acid leach solution of dichloroethanes, microwave-assisted reaction are reacted 10 minutes under conditions of 60 DEG C, so that it may to obtain de- Boc
The benzimidazoles compound of protection.Then the compound is under the alkaline condition of potassium carbonate, again by microwave-assisted reaction,
It is reacted 10 minutes under conditions of 80 DEG C, obtains target product, this reaction process is short, and post-reaction treatment is simple.
4. moreover, synthetic route is as follows：
。
1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 described in 5.（4H）-one derivative is preparing anti-swell
Application in tumor medicine.
The advantages and positive effects of the present invention.
（1）The present invention first passes around based on Ugi reacts and sloughs blocking group formation benzimidazole under acid condition
Compound, then again under alkaline condition shut pyrazinones ring, by simple step purification operations, obtain that there is potential life
Active 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 of object（4H）-one analog derivative.
（2）The present invention has that synthesis step is brief, a step purification operations, and reaction condition is mild, easy post-processing, yield compared with
The advantages that high, at low cost.
Description of the drawings
Fig. 1 is 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）The general structure of -one derivative.
Fig. 2 is 2- benzyls -4- of the present invention（3- bromophenyls）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3
（4H）The nuclear magnetic spectrogram of -one.
Fig. 3 is 2- benzyls -4- of the present invention（4- methoxyphenyls）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrrole
Piperazine -3（4H）The nuclear magnetic spectrogram of -one.
Fig. 4 is 2- benzyls -4- phenyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 of the present invention（4H）-one
Nuclear magnetic spectrogram.
Fig. 5 is 2- benzyls -4- of the present invention（P-methylphenyl）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3
（4H）The nuclear magnetic spectrogram of -one.
Fig. 6 is 2- benzyls -4- of the present invention（3,4- dichlorophenyls）- 7,8- dimethyl -1,2- dihydrobenzos [4,5] imidazo
[1,2-a] pyrazine -3（4H）The nuclear magnetic spectrogram of -one.
Fig. 7 is 2- benzyls -4- of the present invention（4- chlorphenyls）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3
（4H）The nuclear magnetic spectrogram of -one.
Fig. 8 is 2- cyclohexyl -4- phenyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 of the present invention（4H）-
The nuclear magnetic spectrogram of ketone.
Fig. 9 is 4- of the present invention（3,4- dichlorophenyls）- 2- phenethyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrrole
Piperazine -3（4H）The nuclear magnetic spectrogram of -one.
Specific implementation mode
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 restrictive, protection scope of the present invention cannot be limited with following embodiments.
The present invention provides following formula: compound：
。
1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 wherein described in 1（4H）-one derivative, described in
R1For hydrogen atom, methyl and halogen；R2For carbon number be 1-6 alkyl, phenyl substituent；R3For carbon number be 1-6 alkyl, aryl
And heteroaryl.
The present invention is special, and compound includes：（1）2- benzyls -4-（3- bromophenyls）- 1,2- dihydrobenzos [4,5] imidazo
[1,2-a] pyrazine -3（4H）-one.
（2）2- benzyls -4-（4- methoxyphenyls）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-
Ketone.
（3）2- benzyls -4- phenyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one.
（4）2- benzyls -4-（P-methylphenyl）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one.
（5）2- benzyls -4-（3,4- dichlorophenyls）- 7,8- dimethyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a]
Pyrazine -3（4H）-one.
（6）2- benzyls -4-（4- chlorphenyls）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one.
（7）2- cyclohexyl -4- phenyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one.
（8）4-（3,4- dichlorophenyls）- 2- phenethyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3
（4H）-one.
1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 of synthesis wherein described in 1（4H）The pass of -one derivative
Key step is：Reacted using multicomponent Ugi, obtain Ugi products under normal temperature condition, the compound under conditions of unpurified, into
Row reacts in next step, using under the acid condition of 10% trifluoroacetic acid and dichloroethanes, is reacted at 60 DEG C again by microwave radiation technology
10 minutes, obtain benzimidazoles derivative.Then, using the alkaline condition of potassium carbonate, microwave-assisted reaction, in 80 DEG C of item
It is reacted 10 minutes under part, then passes through a step purification operations, so that it may to obtain 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrrole
Piperazine -3（4H）The features such as -one analog derivative, this reaction process is brief, and post-reaction treatment is simple, and yield is higher.
What the separating-purifying of the present invention was all made of is the method for column chromatography, and solvent used is ethyl acetate and n-hexane
Mixture.
1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）The synthetic route of -one derivative,
。
Building-up process is illustrated below by examples of implementation.
Embodiment 1
Wherein R1For hydrogen atom, R2For phenyl, R3For heteroaryl, i.e. 2- benzyls -4-（3- bromophenyls）- 1,2- dihydrobenzos [4,5]
Imidazo [1,2-a] pyrazine -3（4H）The synthesis of -one, is as follows：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by boc-protected aniline compound（0.5 mM）With 3- bromobenzenes
Formaldehyde（0.5 mM）It is dissolved in 1.0 milliliters of methanol, then again by bromoacetic acid（0.5 mM）With benzyl isocyanide chemical combination
Object（0.5 mM）It sequentially adds in the solution, is stirred a whole night under reaction solution room temperature, then use thin-layer chromatography to detect anti-
It answers, solution is dried up using nitrogen.Then after using the dissolving of the solvent of 10% trifluoroacetic acid and dichloroethanes, in 60 DEG C of conditions of microwave
Under react again 10 minutes, after solution is spin-dried for use dichloromethane（30 milliliters）Dissolving, the sodium bicarbonate solution washing of saturation
(2 × 15 milliliters), obtained organic phase product are dissolved with 5.0 milliliters of acetonitrile again, add potassium carbonate（2.5 mM）,
It is reacted 10 minutes for 80 DEG C in micro-wave oven.The solution uses dichloromethane after being spin-dried for（30 milliliters）Dissolving, then uses saturated salt solution
It washs (2 × 15 milliliters).After organic phase is using magnesium sulfate drying, silicagel column is detached obtained product again, obtains target
2- benzyls -4-（3- bromophenyls）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one compound, yield
81%。
1H NMR (400 MHz, CDCl3) δ7.75 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 7.9
Hz, 1H), 7.41 (s, 1H), 7.32-7.17 (m, 8H), 7.08-7.03 (m, 2H), 6.05 (s, 1H),
4.88-4.84 (m, 1H), 4.81-4.71 (m, 2H), 4.68-4.62 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 164.0, 144.6, 143.7, 137.5, 134.9, 132.9, 132.3, 130.7, 129.6,
129.1, 128.3, 124.9, 123.4, 123.4, 123.3, 119.9, 110.0, 60.2, 50.8, 44.6. LC/
MS calculated for C23H19BrN3O [M+H]+, 432; found 432。
Embodiment 2
Wherein R1For hydrogen atom, R2For phenyl, R3For benzyl, i.e. 2- benzyls -4-（4- methoxyphenyls）- 1,2- dihydrobenzos [4,
5] imidazo [1,2-a] pyrazine -3（4H）The synthesis of -one, is as follows：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by boc-protected aniline compound（0.5 mM）With 4- methoxies
Benzaldehyde（0.5 mM）It is dissolved in 1.0 milliliters of methanol, then again by bromoacetic acid（0.5 mM）With benzyl isocyanide
Compound（0.5 mM）It sequentially adds in the solution, stirs a whole night under reaction solution room temperature, then examined using thin-layer chromatography
Reaction is surveyed, solution is dried up using nitrogen.Then after the solvent dissolving for using 10% trifluoroacetic acid and dichloroethanes, in 60 DEG C of microwave
Under the conditions of react again 10 minutes, after solution is spin-dried for use dichloromethane（30 milliliters）Dissolving, the sodium bicarbonate solution of saturation
It washs (2 × 15 milliliters), obtained organic phase product is dissolved with 5.0 milliliters of acetonitrile again, adds potassium carbonate（2.5 mmoles
You）, reacted 10 minutes for 80 DEG C in micro-wave oven.The solution uses dichloromethane after being spin-dried for（30 milliliters）Dissolving, then with saturation
Brine It (2 × 15 milliliters).After organic phase is using magnesium sulfate drying, silicagel column is detached obtained product again, is obtained
To target 2- benzyls -4-（4- methoxyphenyls）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one, production
Rate 76%.
1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.1 Hz, 1H), 7.34-7.28 (m, 4H),
7.25-7.22 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.11-7.08 (m, 3H), 6.85 (d, J =
8.7 Hz, 2H), 6.06 (s, 1H), 4.86 (d, J = 14.6 Hz, 1H), 4.80-4.71 (m, 2H), 4.66
(d, J = 14.6 Hz, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9, 160.1,
144.9, 143.7, 135.1, 133.0, 129.0, 128.3, 128.2, 127.5, 127.3, 123.2, 123.0,
119.7, 114.6, 110.2, 60.4, 55.3, 50.6, 44.6. LC/MS calculated for C24H22N3O2 [M
+H]+, 384; found 384。
Embodiment 3
Wherein R1For hydrogen atom, R2For phenyl, R3For alkyl, i.e. 2- benzyls -4- phenyl -1,2- dihydrobenzo [4,5] imidazo
[1,2-a] pyrazine -3（4H）The synthesis of -one, is as follows：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by boc-protected aniline compound（0.5 mM）And benzaldehyde
（0.5 mM）It is dissolved in 1.0 milliliters of methanol, then again by bromoacetic acid（0.5 mM）With benzyl isocyanide compound
（0.5 mM）It sequentially adds in the solution, is stirred a whole night under reaction solution room temperature, then use thin-layer chromatography detection reaction,
Solution is dried up using nitrogen.Then after the solvent dissolving for using 10% trifluoroacetic acid and dichloroethanes, under the conditions of 60 DEG C of microwave again
Secondary response 10 minutes uses dichloromethane after being spin-dried for solution（30 milliliters）Dissolving, saturation sodium bicarbonate solution washing (2 ×
15 milliliters), obtained organic phase product is dissolved with 5.0 milliliters of acetonitrile again, adds potassium carbonate（2.5 mM）, in microwave
It is reacted 10 minutes for 80 DEG C in stove.The solution uses dichloromethane after being spin-dried for（30 milliliters）Then saturated common salt water washing is used in dissolving
(2 × 15 milliliters).After organic phase is using magnesium sulfate drying, silicagel column is detached obtained product again, obtains target 2- benzyls
Base -4- phenyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one compound, yield 72%.
1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.1 Hz, 1H), 7.35-7.29 (m, 7H),
7.23-7.15 (m, 5H), 7.10 (d, J = 8.1 Hz, 1H), 6.12 (s, 1H), 4.87 (d, J = 14.6
Hz, 1H), 4.80-4.71 (m, 2H), 4.64 (d, J = 14.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 164.7, 144.9, 143.7, 135.2, 135.1, 133.0, 129.2, 129.0, 128.3,
128.2, 126.3, 123.2, 123.1, 119.7, 110.1, 60.9, 50.7, 44.6. LC/MS calculated
for C23H20N3O [M+H]+, 354; found 354。
Embodiment 4
Wherein R1For hydrogen atom, R2For phenyl, R3For benzyl, i.e. 2- benzyls -4-（P-methylphenyl）- 1,2- dihydrobenzos [4,5] miaow
Azoles simultaneously [1,2-a] pyrazine -3（4H）The synthesis of -one, is as follows：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by boc-protected aniline compound（0.5 mM）With to methyl
Benzaldehyde（0.5 mM）It is dissolved in 1.0 milliliters of methanol, then again by bromoacetic acid（0.5 mM）With benzyl isocyanide
Close object（0.5 mM）It sequentially adds in the solution, stirs a whole night under reaction solution room temperature, then detected using thin-layer chromatography
Reaction, solution are dried up using nitrogen.Then after using the dissolving of the solvent of 10% trifluoroacetic acid and dichloroethanes, in 60 DEG C of items of microwave
It is reacted again under part 10 minutes, dichloromethane is used after solution is spin-dried for（30 milliliters）Dissolving, the sodium bicarbonate solution of saturation are washed
It washs (2 × 15 milliliters), obtained organic phase product is dissolved with 5.0 milliliters of acetonitrile again, adds potassium carbonate（2.5 mM）,
It is reacted 10 minutes for 80 DEG C in micro-wave oven.The solution uses dichloromethane after being spin-dried for（30 milliliters）Dissolving, then uses saturated common salt
Water washing (2 × 15 milliliters).After organic phase is using magnesium sulfate drying, silicagel column is detached obtained product again, obtains mesh
Mark 2- benzyls -4-（P-methylphenyl）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one compound, yield
84%。
1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.1 Hz, 1H), 7.34-7.28 (m, 4H),
7.24-7.22 (m, 2H), 7.20-7.04 (m, 6H), 6.07 (s, 1H), 4.87 (d, J = 14.6 Hz,
1H), 4.80-4.70 (m, 2H), 4.63 (d, J = 14.6 Hz, 1H), 2.32 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 164.8, 144.9, 143.7, 139.0, 135.1, 133.1, 132.3, 129.9, 129.0,
128.3, 128.2, 126.2, 123.2, 123.0, 119.7, 110.1, 60.7, 50.6, 44.6, 21.1. LC/
MS calculated for C24H22N3O [M+H]+, 368; found 368。
Embodiment 5
Wherein R1For methyl, R2For phenyl, R3For benzyl, i.e. 2- benzyls -4-（3,4- dichlorophenyls）- 7,8- dimethyl -1,2- two
Hydrogen benzo [4,5] imidazo [1,2-a] pyrazine -3（4H）The synthesis of -one, is as follows：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by boc-protected aniline compound（0.5 mM）With 3,4- bis-
Chlorobenzaldehyde（0.5 mM）It is dissolved in 1.0 milliliters of methanol, then again by bromoacetic acid（0.5 mM）With benzyl isocyanide
Compound（0.5 mM）It sequentially adds in the solution, stirs a whole night under reaction solution room temperature, then examined using thin-layer chromatography
Reaction is surveyed, solution is dried up using nitrogen.Then after the solvent dissolving for using 10% trifluoroacetic acid and dichloroethanes, in 60 DEG C of microwave
Under the conditions of react again 10 minutes, after solution is spin-dried for use dichloromethane（30 milliliters）Dissolving, the sodium bicarbonate solution of saturation
It washs (2 × 15 milliliters), obtained organic phase product is dissolved with 5.0 milliliters of acetonitrile again, adds potassium carbonate（2.5 mmoles
You）, reacted 10 minutes for 80 DEG C in micro-wave oven.The solution uses dichloromethane after being spin-dried for（30 milliliters）Dissolving, then with saturation
Brine It (2 × 15 milliliters).After organic phase is using magnesium sulfate drying, silicagel column is detached obtained product again, is obtained
To target 2- benzyls -4-（3,4- dichlorophenyls）- 7,8- dimethyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3
（4H）-one compound, yield 79%.
1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.39 (d, J = 8.3 Hz, 1H),
7.33-7.30 (m, 4H), 7.23-7.21 (m, 2H), 6.94 (dd, J = 8.4, 2.1 Hz, 1H), 6.80
(s, 1H), 5.98 (s, 1H), 4.84 (d, J = 14.6 Hz, 1H), 4.70 (s, 2H), 4.61 (d, J =
14.6 Hz, 1H), 2.34 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.8,
143.5, 142.2, 135.5, 134.9, 133.6, 133.4, 132.7, 132.6, 131.2, 131.1, 129.1,
128.4, 128.4, 128.3, 125.5, 119.9, 109.9, 59.7, 50.8, 44.6, 20.5, 20.3. LC/MS
calculated for C25H22Cl2N3O [M+H]+, 450; found 450。
Embodiment 6
Wherein R1For hydrogen atom, R2For phenyl, R3For benzyl, i.e. 2- benzyls -4-（4- chlorphenyls）- 1,2- dihydrobenzos [4,5] miaow
Azoles simultaneously [1,2-a] pyrazine -3（4H）The synthesis of -one, is as follows：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by boc-protected aniline compound（0.5 mM）With 4- chlorobenzenes
Formaldehyde（0.5 mM）It is dissolved in 1.0 milliliters of methanol, then again by bromoacetic acid（0.5 mM）With benzyl isocyanide chemical combination
Object（0.5 mM）It sequentially adds in the solution, is stirred a whole night under reaction solution room temperature, then use thin-layer chromatography to detect anti-
It answers, solution is dried up using nitrogen.Then after using the dissolving of the solvent of 10% trifluoroacetic acid and dichloroethanes, in 60 DEG C of conditions of microwave
Under react again 10 minutes, after solution is spin-dried for use dichloromethane（30 milliliters）Dissolving, the sodium bicarbonate solution washing of saturation
(2 × 15 milliliters), obtained organic phase product are dissolved with 5.0 milliliters of acetonitrile again, add potassium carbonate（2.5 mM）,
It is reacted 10 minutes for 80 DEG C in micro-wave oven.The solution uses dichloromethane after being spin-dried for（30 milliliters）Dissolving, then uses saturated salt solution
It washs (2 × 15 milliliters).After organic phase is using magnesium sulfate drying, silicagel column is detached obtained product again, obtains target
2- benzyls -4-（4- chlorphenyls）- 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one compound, yield
83%。
1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.1 Hz, 1H), 7.32-7.28 (m, 6H),
7.24-7.17 (m, 3H), 7.10 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.1 Hz, 1H), 6.08
(s, 1H), 4.85 (d, J = 14.6 Hz, 1H), 4.75 (s, 2H), 4.65 (d, J = 14.6 Hz, 1H);13C NMR (100 MHz, CDCl3) δ 164.2, 144.7, 143.7, 135.2, 134.9, 133.7, 132.9,
129.5, 129.1, 128.3, 127.7, 123.4, 123.2, 119.8, 110.0, 60.2, 50.7, 44.6. LC/
MS calculated for C23H19ClN3O [M+H]+, 388; found 388。
Embodiment 7
Wherein R1For hydrogen atom, R2For phenyl, R3For alkyl, i.e. 2- cyclohexyl -4- phenyl -1,2- dihydrobenzo [4,5] imidazo
[1,2-a] pyrazine -3（4H）The synthesis of -one, is as follows：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by boc-protected aniline compound（0.5 mM）And benzaldehyde
（0.5 mM）It is dissolved in 1.0 milliliters of methanol, then again by bromoacetic acid（0.5 mM）With cyclohexyl isocyanide compound
（0.5 mM）It sequentially adds in the solution, is stirred a whole night under reaction solution room temperature, then use thin-layer chromatography detection reaction,
Solution is dried up using nitrogen.Then after the solvent dissolving for using 10% trifluoroacetic acid and dichloroethanes, under the conditions of 60 DEG C of microwave again
Secondary response 10 minutes uses dichloromethane after being spin-dried for solution（30 milliliters）Dissolving, saturation sodium bicarbonate solution washing (2 ×
15 milliliters), obtained organic phase product is dissolved with 5.0 milliliters of acetonitrile again, adds potassium carbonate（2.5 mM）, in microwave
It is reacted 10 minutes for 80 DEG C in stove.The solution uses dichloromethane after being spin-dried for（30 milliliters）Then saturated common salt water washing is used in dissolving
(2 × 15 milliliters).After organic phase is using magnesium sulfate drying, silicagel column is detached obtained product again, obtains target 2- rings
Hexyl -4- phenyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one compound, yield 78%.
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.1 Hz, 1H), 7.32-7.28 (m, 4H),
7.20 (t, J = 7.6 Hz, 1H), 7.16-7.12 (m, 3H), 6.05 (s, 1H), 4.83 (d, J = 16.9
Hz, 1H), 4.67 (d, J = 16.9 Hz, 1H), 4.53-4.46 (m, 1H), 1.88-1.68 (m, 6H),
1.58-1.33 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 164.2, 145.8, 143.7, 135.2,
133.2, 129.2, 128.8, 126.1, 123.2, 123.1, 119.7, 109.9, 60.9, 53.7, 40.0,
29.7, 29.2, 25.6, 25.5, 25.3. LC/MS calculated for C22H24N3O [M+H]+, 346; found
346。
Embodiment 8
Wherein R1For hydrogen atom, R2For phenyl, R3For heteroaryl, i.e. 4-（3,4- dichlorophenyls）- 2- phenethyl -1,2- dihydrobenzenes
And [4,5] imidazo [1,2-a] pyrazine -3（4H）The synthesis of -one, is as follows：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by boc-protected aniline compound（0.5 mM）With 3,4- bis-
Chlorobenzaldehyde（0.5 mM）It is dissolved in 1.0 milliliters of methanol, then again by bromoacetic acid（0.5 mM）It is different with phenethyl
Cyanogen compound（0.5 mM）It sequentially adds in the solution, is stirred a whole night under reaction solution room temperature, then use thin-layer chromatography
Detection reaction, solution are dried up using nitrogen.Then after using the dissolving of the solvent of 10% trifluoroacetic acid and dichloroethanes, in microwave 60
It is reacted again under the conditions of DEG C 10 minutes, dichloromethane is used after solution is spin-dried for（30 milliliters）Dissolving, the sodium bicarbonate of saturation are molten
Liquid washs (2 × 15 milliliters), and obtained organic phase product is dissolved with 5.0 milliliters of acetonitrile again, adds potassium carbonate（2.5 mmoles
You）, reacted 10 minutes for 80 DEG C in micro-wave oven.The solution uses dichloromethane after being spin-dried for（30 milliliters）Dissolving, then with saturation
Brine It (2 × 15 milliliters).After organic phase is using magnesium sulfate drying, silicagel column is detached obtained product again, is obtained
To target 4-（3,4- dichlorophenyls）- 2- phenethyl -1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one
Close object, yield 71%.
1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 8.4
Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.22- 7.17 (m, 5H), 7.11- 7.01 (m, 3H),
6.89- 6.84 (m, 1H), 5.93 (s, 1H), 4.56 (q, J = 17.1 Hz, 2H), 4.09 (dt, J =
13.6, 6.8 Hz, 1H), 3.55 (dq, J = 20.7, 6.9 Hz, 1H), 2.99 (dt, J = 14.2, 7.2
Hz, 1H), 2.93 -2.84 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 163.40, 144.6, 143.6,
137.5, 135.2, 133.6, 133.4, 132.7, 131.1, 128.7, 128.7, 128.2, 126.9, 125.4,
123.6, 123.4, 119.9, 109.8, 59.7, 49.7, 46.3, 33.1. LC/MS calculated for
C24H20Cl2N3O [M+H]+, 436; found 436。
1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 according to the present invention（4H）The key of -one derivative
Step is：It is reacted using multicomponent Ugi, Ugi products is obtained under normal temperature condition, which uses under conditions of unpurified
10% trifluoroacetic acid and dichloroethanes dissolving, react 10 minutes under the conditions of 60 DEG C of microwave.Through being spin-dried for after washing operation, then
Secondary to be dissolved in acetonitrile solution, using the alkaline condition of potassium carbonate, microwave-assisted reaction is reacted 10 minutes at 80 DEG C, is obtained
Target product.1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 according to the present invention（4H）-one derivative is being made
Application in standby antitumor drug.
Claims (7)
1. a kind of 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3（4H）-one derivative, it is characterised in that：Derivative
General structure it is as follows：
。
2. 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 according to claim 1（4H）-one derivative,
It is characterized in that：The R1For hydrogen atom, methyl and halogen.
3. 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 according to claim 1（4H）-one derivative,
It is characterized in that：The R2For carbon number be 1-6 alkyl, phenyl substituent.
4. 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 according to claim 1（4H）-one derivative,
It is characterized in that：The R3Alkyl, aryl and the heteroaryl for being 1-6 for carbon number.
5. 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 according to claim 1（4H）-one derivative
Synthetic method, it is characterised in that：It is reacted using multicomponent Ugi, obtains Ugi products under normal temperature condition, the compound is unpurified
Under conditions of, it is dissolved using the solution of 10% trifluoroacetic acid and dichloroethanes, is reacted 10 minutes for 60 DEG C, passed through by microwave radiation technology
After being spin-dried for washing operation, using the alkaline condition of potassium carbonate, in acetonitrile solution, microwave-assisted reaction reacts 10 at 80 DEG C
Minute, step column chromatography purification, so that it may which, to obtain target product, this reaction process is short, and post-reaction treatment is simple.
6. 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 according to claim 1（4H）-one derivative,
It is characterized in that：Synthetic route is as follows：
。
7. 1,2- dihydrobenzos [4,5] imidazo [1,2-a] pyrazine -3 according to claim 1（4H）-one derivative can
Using in the preparation of antitumor drugs.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017068089A2 (en) * | 2015-10-23 | 2017-04-27 | Vifor (International) Ag | Novel ferroportin inhibitors |
| CN107353287A (en) * | 2017-05-26 | 2017-11-17 | 重庆文理学院 | A kind of quinoxaline and the preparation of heterocyclic fourth ketone compounds and its application in antitumor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017068089A2 (en) * | 2015-10-23 | 2017-04-27 | Vifor (International) Ag | Novel ferroportin inhibitors |
| CN107353287A (en) * | 2017-05-26 | 2017-11-17 | 重庆文理学院 | A kind of quinoxaline and the preparation of heterocyclic fourth ketone compounds and its application in antitumor |
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| Title |
|---|
| CANKAROVA, NADEZDA等: "Polymer-Supported Stereoselective Synthesis of Benzimidazolinopiperazinones", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| CAS RN: "《CAS RN 180635-00-1》", 11 September 1996 * |
| EL KAIM, LAURENT等: "Multicomponent Synthesis of Fused Benzimidazolopiperazines", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| XU, ZHIGANG等: "Expeditious routes to polycyclic molecular frameworks via one-pot, two-step Ugi ring-closing sequences", 《SYNLETT》 * |
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