CN104961689A - 2,3-dihydropyrazine derivative and synthetic method thereof - Google Patents
2,3-dihydropyrazine derivative and synthetic method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
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Abstract
The invention discloses a synthetic method for a 2,3-dihydropyrazine derivative and the 2,3-dihydropyrazine derivative. The 2,3-dihydropyrazine derivative has a structural formula as shown in a general formula described in the specification. The synthetic method comprises the following steps: with an iodine reagent as a catalyst, mixing a diketone compound, a diamine derivative and an organic solvent; and carrying out heating and reaction so as to obtain the 2,3-dihydropyrazine derivative. According to the invention, reaction conditions are mild; high temperature and high pressure are not needed; and resistance to water and oxygen and good reaction compatibility are realized. The catalyst used in the method is a cheap iodine reagent; a substrate used in the method is the simple and easily available diketone compound and diamine derivative; and the method has the advantages of low cost, high yield, simple operation, easy availability of raw materials, easy realization of industrial production, etc.
Description
Technical field
The present invention relates to heterogeneous ring compound, particularly relate to a kind of synthetic method of 2,3-dihydro pyrazines derivatives, the present invention also relates to class 2, a 3-dihydro pyrazines derivatives simultaneously.
Background technology
2,3-dihydro pyrazines derivatives is the very important nitrogen-containing heterocycle compound of a class, is subject to people's extensive concern to its synthesis and corresponding bioactive research.Research finds that this compounds has antibacterial, cell death inducing, has biology and the physiologically actives such as cytotoxicity, inhibitory enzyme works, DNA breakage chain, becomes focus so synthesize this new compounds and develop efficient synthetic method.
Have some bibliographical informations synthetic method of 2,3-dihydro pyrazines derivatives at present.Wherein most synthetic methods needs to use metal-salt reagent as catalyzer, as: metal gadolinium, metallic ytterbium, metal pick, metallic iron etc.Correlative study is as Cai, J.-J.; Zou, J.-P.; Pan, X.-Q.; Zhang, W.
tetrahedron Lett.
2008,
49, 7386; And Fan, L.; Chen, W.; Qian, C.
tetrahedron Lett.
2013,
54, 231; And Malakooti, R.; Bardajee, G. R.; Mahmoudi, H.; Kakavand, N.
catal.
lett.
2013,
143, 853; Also have Song, W.; Liu, P.; Lei, M.; You, H.; Chen, X.; Chen, H.; Ma, L.; Hu, L.
synth. Commun.
2012,
42, 236. etc., and there is the defects such as expensive, toxic in metal-salt reagent; Although other methods do not use metal-salt reagent as catalyzer, but need to use the promotor of equivalent or utilize microwave to impel reaction to occur under the high temperature conditions, and in the expansion of reaction substrate all Shortcomings, that only has 2,3-a small amount of dihydro pyrazines derivatives prepares example report.Correlative study is as Jenna, V.; Robinson, R. S.
tetrahedron Lett.
2014,
55, 642; And Kadam, H. K.; Khan, S.; Kunkalkar, R. A.; Tilve, S. G.
tetrahedron Lett.
2013,
54, 1003.
Summary of the invention
In the synthetic method of 2,3-dihydro pyrazines derivatives heterocyclic compounds and derivative thereof, with cheap iodine reagent for catalyzer, from raw material simple and easy to get, under the reaction conditions of gentleness, there is not been reported for the method for efficient synthesis 2,3-dihydro pyrazines derivatives.
In order to solve above-mentioned defect of the prior art, the invention provides a class new 2,3-dihydro pyrazines derivatives and their synthetic method, this synthetic method with cheap iodine reagent for catalyzer, from raw material simple and easy to get, efficient synthesis 2,3-dihydro pyrazines derivatives under the reaction conditions of gentleness.
Technical scheme of the present invention is as follows:
A kind of synthetic method of 2,3-dihydro pyrazines derivatives, described 2,3-dihydro pyrazines derivatives general formulas are:
，
Wherein, R
1or R
2be selected from hydrogen atom, C
1-10alkyl, halogen, phenyl, aryl, hydroxyl, itrile group, carboxyl, ester group, alkoxyl group or trifluoromethyl; E
1or E
2be selected from hydrogen atom, C
1-10alkyl, halogen, phenyl, aryl, hydroxyl, itrile group, carboxyl, ester group, alkoxyl group, trifluoromethyl or amide group; Described synthetic method is: using iodine reagent as catalyzer, and cyclohexadione compounds, diamine derivatives and organic solvent are mixed, reacting by heating, obtains such 2,3-dihydro pyrazines derivatives.
Wherein, preferred described cyclohexadione compounds is 1,2-cyclohexadione compounds cheap and simple and easy to get, described diamine derivatives is 1,2-diamine derivatives cheap and simple and easy to get, can be selected from 1 further, 2-diphenylthanedione compounds and 1，2-diaminoethane analog derivative.Figure 2 shows that synthetic method of the present invention illustrates.Synthetic method of the present invention can be carried out under air atmosphere.
Preferably, described iodine reagent is selected from following one or more: acetic acid iodobenzene PhI (OAc)
2, two (trifluoroacetyl oxygen base) iodobenzene PhI (OOCCF
3)
2, iodoxybenzene IB, orthoiodoxybenzoic acid IBX, Dai Si-Martin high price iodine DMP, iodine I
2, N-iodosuccinimide NCI.
Preferably, described cyclohexadione compounds is selected from following one or more: diphenylthanedione, 1-phenyl-2-(4-aminomethyl phenyl) second diketone, 1-(4-p-methoxy-phenyl)-2-benzil, 1-(4-fluorophenyl)-2 phenyl-second diketone, 1-(4-methyl-formiate phenyl)-2-benzil, 1-(4-cyanophenyl)-2-benzil, 1-(1-naphthyl)-2-benzil, 1-(4-p-methoxy-phenyl)-2-(1-naphthyl) second diketone, 1-(4-p-methoxy-phenyl)-2-(4-aminomethyl phenyl) second diketone, 1, 2-bis-(4-p-methoxy-phenyl) second diketone, 1-(4-fluorophenyl)-2-(4-p-methoxy-phenyl) second diketone.
Preferably, described diamine derivatives is selected from following one or more: 1，2-diaminoethane, 1,2-propylene diamine, 1,2-cyclohexanediamine, 2,3-diaminopropionic acid hydrochlorides, 1,2-phenylbenzene-1，2-diaminoethane.
Preferably, described organic solvent is selected from following one or more: ethyl acetate, normal hexane, hexanaphthene, tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, acetonitrile, toluene, benzene, dimethylbenzene, 1,4-dioxane, methyl alcohol, ethanol, DMF or dimethyl sulfoxide (DMSO).
Preferably, described organic solvent is acetonitrile.Higher productive rate can be obtained as organic solvent compared to other organic solvent with acetonitrile.But, use other organic solvent also can realize object of the present invention.
Preferably, the mol ratio of described catalyzer, cyclohexadione compounds, diamine derivatives is 1:(1-100): (1-100), described temperature of reaction is 0-120 DEG C; Further preferably, the mol ratio of described catalyzer, cyclohexadione compounds, diamine derivatives is 1:(1-50): (1-50), described temperature of reaction is 40-80 DEG C.
Preferably, the mol ratio of described catalyzer, cyclohexadione compounds, diamine derivatives is 1:(1-10): (1-15), described temperature of reaction is 60 DEG C.In the numerical range of this reaction conditions, the productive rate of products therefrom is higher.
In above-mentioned preparation method, the amount of reaction times and organic solvent rule of thumb can be determined by those skilled in the art, does not limit herein.The usual reaction times can be 6-10 hour.
The present invention also provides class 2, a 3-dihydro pyrazines derivatives, its general formula as shown in Figure 1, for:
，
Wherein, R
1or R
2be selected from hydrogen atom, C
1-10alkyl, halogen, phenyl, aryl, hydroxyl, itrile group, carboxyl, ester group, alkoxyl group or trifluoromethyl; E
1or E
2be selected from phenyl, aryl, halogen, hydroxyl, itrile group, carboxyl, ester group, alkoxyl group, trifluoromethyl or amide group.Such described 2,3-dihydro pyrazines derivatives can prepare by synthetic method above.
Compared with prior art, beneficial effect of the present invention is as follows:
First, the present invention first with cheap iodine reagent for catalyzer, with cyclohexadione compounds simple and easy to get and diamine derivatives for starting raw material synthesis 2,3-dihydro pyrazines derivatives, have with low cost, reaction conditions is gentle, yield is high, simple to operate, raw material is easy to get, conversion unit is simple, be easy to the plurality of advantages such as suitability for industrialized production;
The second, reaction conditions of the present invention is gentle, without the need to High Temperature High Pressure, water-fast oxytolerant, have good reaction compatible.
Certainly, implement arbitrary product of the present invention might not need to reach above-described all advantages simultaneously.
Accompanying drawing explanation
Fig. 1 is the general formula of the compounds of this invention;
Fig. 2 is the synthetic route chart of the compounds of this invention;
The hydrogen spectrum that Fig. 3 (a) and Fig. 3 (b) is embodiment 1 and carbon spectrum nuclear magnetic spectrogram.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be appreciated that, these embodiments only for illustration of the present invention, and are not intended to limit the scope of the invention.The enforceable parameter area that the present invention limits is not by the restriction specifically exemplified in following examples.The improvement made according to the present invention of those skilled in the art and adjustment, still belong to protection scope of the present invention in actual applications.
Embodiment 1
The synthesis of 5,6-phenylbenzene-2,3-dihydro pyrazine, its structural formula is:
。
Preparation method one: in reaction tubes, adds 21.0 mg diphenylthanediones, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 6 hours.Conventional processing obtains sterling 22.5 mg, productive rate 96%.
Preparation method two: in reaction tubes, add 21.0 mg diphenylthanediones, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 40 DEG C of oil baths and react 6 hours.Conventional processing obtains sterling 17.8 mg, productive rate 76%.
Preparation method three: in reaction tubes, add 21.0 mg diphenylthanediones, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL toluene.Be positioned in 40 DEG C of oil baths and react 6 hours.Conventional processing obtains sterling 12.7 mg, productive rate 54%.
The fusing point of product is 155-156 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl
3)
δ7.42-7.38 (m, 4H), 7.34-7.29 (m, 2H), 7.27-7.22 (m, 4H), 3.70 (s, 4H);
13c NMR (100 MHz, CDCl
3)
δ45.92,128.00,128.23,129.75,137.85,160.41; Product nuclear magnetic spectrum asks for an interview Fig. 3 (a) and Fig. 3 (b).
Embodiment 2
5-phenyl-6-(4-aminomethyl phenyl) synthesis of-2,3-dihydro pyrazines, its structural formula is:
。
In reaction tubes, add 22.4 mg 1-phenyl-2-(4-aminomethyl phenyls) second diketone, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 6 hours.Conventional processing obtains sterling 21.4 mg, productive rate 86%.
The fusing point of product is 115-116 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl
3)
δ7.42-7.38 (m, 2H), 7.34-7.22 (m, 5H), 7.05 (d,
j=8.0 Hz, 2H), 3.68 (s, 4H), 2.30 (s, 3H);
13c NMR (100 MHz, CDCl
3)
δ21.48,45.84,45.95,127.99,128.00,128.22,128.93,129.68,135.00,138.07,139.92,160.19,160.55;
Product high resolution mass spectrum HRMS (ESI) is calculated as: C
17h
17n
2, 249.1392 (M+H)
+, find: 249.1389.
Embodiment 3
5-(4-p-methoxy-phenyl) synthesis of-6-phenyl-2,3-dihydro pyrazine, its structural formula is:
。
In reaction tubes, add 24.0 mg 1-(4-p-methoxy-phenyls)-2-benzil, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 10 hours.Conventional processing obtains sterling 23.8 mg, productive rate 90%.
The fusing point of product is 93-94 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl3) δ 7.45-7.38 (m, 2H); 7.37-7.30 (m, 3H), 7.26 (t; J=7.3 Hz, 2H), 6.75 (d; J=8.8 Hz; 2H), 3.77 (s, 3H); 3.67 (s, 4H);
13c NMR (100 MHz, CDCl3) δ 45.78,46.00,55.36,113.59,128.02,128.25,129.68,129.70,130.31,138.25,159.56,160.56,160.88;
Product high resolution mass spectrum HRMS (ESI) is calculated as: C
17h
17n
2o, 265.1341 (M+H)
+, find: 265.1338.
Embodiment 4
5-(4-fluorophenyl) synthesis of-6-phenyl-2,3-dihydro pyrazine, its structural formula is:
。
In reaction tubes, add 22.8 mg 1-(4-fluorophenyls)-2 phenyl-second diketone, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 6 hours.Conventional processing obtains sterling 24.0 mg, productive rate 95%.
The fusing point of product is 87-88 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 5H), 7.29-7.24 (m, 2H), 6.96-6.91 (m, 2H), 3.69 (s, 4H);
13c NMR (100 MHz, CDCl3) δ 45.83,45.87,115.35 (d, J=21.0 Hz), 128.00,128.35,129.88,130.12 (d, J=9.0 Hz), 133.94 (d, J=4.0 Hz), 137.75,159.29,160.16,163.65 (d, J=249.0 Hz);
Product high resolution mass spectrum HRMS (ESI) is calculated as: C
16h
14n
2f, 253.1141 (M+H)
+, find: 253.1137.
Embodiment 5
5-(4-methyl-formiate phenyl) synthesis of-6-phenyl-2,3-dihydro pyrazine, its structural formula is:
。
In reaction tubes, add 26.8 mg 1-(4-methyl-formiate phenyl)-2-benzil, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 6 hours.Conventional processing obtains sterling 28.9 mg, productive rate 99%.
The fusing point of product is 126-127 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl
3)
δ7.92 (d,
j=8.3 Hz, 2H), 7.47 (d,
j=8.3 Hz, 2H), 7.39-7.29 (m, 3H), 7.26-7.23 (m, 2H), 3.89 (s, 3H), 3.73 (s, 4H);
13c NMR (100 MHz, CDCl
3)
δ45.88,46.10,52.37,127.96,128.07,128.41,129.54,130.01,131.05,137.43,142.04,159.93,160.03,166.69;
Product high resolution mass spectrum HRMS (ESI) is calculated as: C
18h
17n
2o
2, 293.1290 (M+H)
+, find: 293.1296.
Embodiment 6
5-(4-cyanophenyl) synthesis of-6-phenyl-2,3-dihydro pyrazine, its structural formula is:
。
In reaction tubes, add 23.5 mg 1-(4-cyanophenyl)-2-benzil, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 6 hours.Conventional processing obtains sterling 22.0 mg, productive rate 85%.
The fusing point of product is 102-104 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl
3)
δ7.53 (q,
j=8.4 Hz, 4H), 7.37-7.34 (m, 3H), 7.29-7.26 (m, 2H), 3.74 (d,
j=1.9 Hz, 4H);
13c NMR (100 MHz, CDCl
3)
δ45.77,46.10,113.28,118.43,127.87,128.51,128.66,130.19,132.04,137.05,141.90,159.16,159.53;
Product high resolution mass spectrum HRMS (ESI) is calculated as: C
17h
14n
3, 260.1188 (M+H)
+, find: 260.1184.
Embodiment 7
5-(1-naphthyl) synthesis of-6-phenyl-2,3-dihydro pyrazine, its structural formula is:
。
In reaction tubes, add 26.0 mg 1-(1-naphthyls)-2-benzil, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 10 hours.Conventional processing obtains sterling 25.3 mg, productive rate 89%.
The fusing point of product is 58-59 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl
3)
δ8.10 (d,
j=8.1 Hz, 1H), 7.78 (t,
j=5.6 Hz, 2H), 7.48-7.41 (m, 2H), 7.38-7.32 (m, 4H), 7.13 (t,
j=7.3 Hz, 1H), 7.05 (t,
j=7.5 Hz, 2H), 3.84 (s, 4H);
13c NMR (100 MHz, CDCl
3)
δ45.79,45.91,124.88,124.98,126.16,126.88,127.10,127.58,127.99,128.64,129.63,129.75,130.49,133.77,135.87,137.29,161.27,161.39;
Product high resolution mass spectrum HRMS (ESI) is calculated as: C
20h
17n
2, 285.1392 (M+H)
+, find: 285.1388.
Embodiment 8
5-(4-p-methoxy-phenyl)-6-(1-naphthyl) synthesis of-2,3-dihydro pyrazines, its structural formula is:
。
In reaction tubes, add 29.0 mg 1-(4-p-methoxy-phenyls)-2-(1-naphthyl) second diketone, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 10 hours.Conventional processing obtains sterling 29.6 mg, productive rate 94%.
The fusing point of product is 53-55 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl
3)
δ8.09 (d,
j=9.0 Hz, 1H), 7.82-7.79 (m, 2H), 7.48-7.43 (m, 2H), 7.37 (d,
j=4.7 Hz, 2H), 7.32 (d,
j=8.7 Hz, 2H), 6.57 (d,
j=8.7 Hz, 2H), 3.85-3.76 (m, 4H), 3.65 (s, 3H);
13c NMR (100 MHz, CDCl
3)
δ45.66,46.01,55.22,113.41,124.96,125.04,126.16,126.87,127.04,128.63,129.24,129.66,129.82,130.54,133.83,136.30,160.41,160.70,161.52;
Product high resolution mass spectrum HRMS (ESI) is calculated as: C
21h
19n
2o, 315.1497 (M+H)
+, find: 315.1497.
Embodiment 9
5-(4-p-methoxy-phenyl)-6-(4-aminomethyl phenyl) synthesis of-2,3-dihydro pyrazines, its structural formula is:
。
In reaction tubes, add 29.0 mg 1-(4-p-methoxy-phenyls)-2-(4-aminomethyl phenyl) second diketone, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 10 hours.Conventional processing obtains sterling 22.1 mg, productive rate 87%.
The fusing point of product is 108-109 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl
3)
δ7.36 (d,
j=8.8 Hz, 2H), 7.30 (d,
j=8.1 Hz, 2H), 7.06 (d,
j=8.1 Hz, 2H), 6.76 (d,
j=8.8 Hz, 2H), 3.77 (s, 3H), 3.64 (s, 4H), 2.31 (s, 3H);
13c NMR (100 MHz, CDCl
3)
δ21.48,45.77,45.88,55.33,113.53,127.97,128.92,129.66,130.48,135.35,139.79,159.67,160.32,160.79;
Product high resolution mass spectrum HRMS (ESI) is calculated as: C
18h
19n
2o, 279.1497 (M+H)
+, find: 279.1501.
Embodiment 10
The synthesis of 5,6-bis-(4-p-methoxy-phenyl)-2,3-dihydro pyrazine, its structural formula is:
。
In reaction tubes, add 27.0 mg 1,2-bis-(4-p-methoxy-phenyl) second diketone, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 10 hours.Conventional processing obtains sterling 25.9 mg, productive rate 88%.
The fusing point of product is 118-120 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl
3)
δ7.38-7.35 (m, 4H), 6.79-6.76 (m, 4H), 3.78 (s, 6H), 3.64 (s, 4H);
13c NMR (100 MHz, CDCl
3)
δ45.81,55.39,113.59,129.71,130.63,159.72,160.82.
Embodiment 11
5-(4-fluorophenyl)-6-(4-p-methoxy-phenyl) synthesis of-2,3-dihydro pyrazines, its structural formula is:
。
In reaction tubes, add 25.8 mg 1-(4-fluorophenyls)-2-(4-p-methoxy-phenyl) second diketone, 9.0 mg 1，2-diaminoethane, 2.5 mg iodine and 1.0 mL acetonitriles.Be positioned in 60 DEG C of oil baths and react 10 hours.Conventional processing obtains sterling 26.3 mg, productive rate 93%.
The fusing point of product is 130-131 DEG C;
The result that product nuclear-magnetism characterizes is:
1h NMR (400 MHz, CDCl
3)
δ7.41 (dd,
j=8.5,5.5 Hz, 2H), 7.33 (d,
j=8.6 Hz, 2H), 6.95 (t,
j=8.6 Hz, 2H), 6.78 (d,
j=8.6 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 4H);
13c NMR (100 MHz, CDCl
3)
δ45.71,45.89,55.39,104.48,113.68,115.34 (d,
j=22.0 Hz), 129.69,130.12 (d,
j=8.0 Hz), 130.14,134.30 (d,
j=3.0 Hz), 159.44,160.14 (d,
j=163.0 Hz), 162.39
Product high resolution mass spectrum HRMS (ESI) is calculated as: C
17h
16n
2oF, 283.1247 (M+H)
+, find: 283.1250.
The present invention can carry out under air atmosphere, insensitive to water, oxygen etc., and reaction conditions is gentle; Catalyzer used is cheap iodine reagent, and substrate used is cyclohexadione compounds simple and easy to get and diamine derivatives, have with low cost, yield is high, simple to operate, raw material is easy to get, be easy to the advantages such as suitability for industrialized production.
Under the instruction of the present invention and above-described embodiment, those skilled in the art are easy to predict, cited or each raw material that exemplifies of the present invention or its equivalent alterations, each working method or its equivalent alterations can realize the present invention, and the parameter bound value of each raw material and working method, interval value can realize the present invention, do not enumerate embodiment at this.
Claims (14)
1. the synthetic method of a dihydro pyrazines derivatives, is characterized in that, described 2,3-dihydro pyrazines derivatives general formulas are:
，
Wherein, R
1or R
2be selected from hydrogen atom, C
1-10alkyl, halogen, phenyl, aryl, hydroxyl, itrile group, carboxyl, ester group, alkoxyl group or trifluoromethyl; E
1or E
2be selected from hydrogen atom, C
1-10alkyl, halogen, phenyl, aryl, hydroxyl, itrile group, carboxyl, ester group, alkoxyl group, trifluoromethyl or amide group;
Described synthetic method is: take iodine reagent as catalyzer, cyclohexadione compounds, diamine derivatives and organic solvent is mixed and carries out cyclization, obtain this heterocyclic compounds.
2. the synthetic method of 2,3-dihydro pyrazines derivatives as claimed in claim 1, is characterized in that, described iodine reagent is selected from following one or more: acetic acid iodobenzene PhI (OAc)
2, two (trifluoroacetyl oxygen base) iodobenzene PhI (OOCCF
3)
2, iodoxybenzene IB, orthoiodoxybenzoic acid IBX, Dai Si-Martin high price iodine DMP, iodine I
2, N-iodosuccinimide NCI.
3. the synthetic method of 2,3-dihydro pyrazines derivatives as claimed in claim 1, is characterized in that, described cyclohexadione compounds is 1,2-cyclohexadione compounds.
4. the synthetic method of 2,3-dihydro pyrazines derivatives as claimed in claim 3, is characterized in that, 1,2-described cyclohexadione compounds is 1,2-diphenylthanedione compounds.
5. as described in claim 1 or 3 or 42, the synthetic method of 3-dihydro pyrazines derivatives, it is characterized in that, described cyclohexadione compounds is selected from following one or more: diphenylthanedione, 1-phenyl-2-(4-aminomethyl phenyl) second diketone, 1-phenyl-2-(4-p-methoxy-phenyl) second diketone, 1-phenyl-2-(4-fluorophenyl) second diketone, 1-phenyl-2-(4-methyl-formiate phenyl) second diketone, 1-phenyl-2-(4-cyanophenyl) second diketone, 1-phenyl-2-naphthyl second diketone, 1-(4-p-methoxy-phenyl)-2-naphthyl second diketone, 1-(4-aminomethyl phenyl)-2-(4-p-methoxy-phenyl) second diketone, 1, 2-bis-(4-p-methoxy-phenyl) second diketone, 1-(4-p-methoxy-phenyl)-2-(4-fluorophenyl) second diketone.
6. the synthetic method of 2,3-dihydro pyrazines derivatives as claimed in claim 1, is characterized in that, described diamine derivatives is 1,2-diamine derivatives.
7. the synthetic method of 2,3-dihydro pyrazines derivatives as claimed in claim 6, is characterized in that, 1,2-described diamine derivatives is 1，2-diaminoethane analog derivative.
8. as described in claim 1 or 6 or 72, the synthetic method of 3-dihydro pyrazines derivatives, it is characterized in that, described diamine derivatives is selected from following one or more: 1，2-diaminoethane, 1,2-propylene diamine, 1,2-cyclohexanediamine, 2,3-diaminopropionic acid hydrochloride, 1,2-phenylbenzene-1，2-diaminoethane.
9. as claimed in claim 12, the synthetic method of 3-dihydro pyrazines derivatives, it is characterized in that, described organic solvent is selected from following one or more: ethyl acetate, normal hexane, hexanaphthene, tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, acetonitrile, toluene, benzene, dimethylbenzene, 1,4-dioxane, methyl alcohol, ethanol, DMF or dimethyl sulfoxide (DMSO).
10. the synthetic method of 2,3-dihydro pyrazines derivatives as claimed in claim 9, is characterized in that, described organic solvent is acetonitrile.
The synthetic method of 11. 2,3-dihydro pyrazines derivatives as claimed in claim 1, is characterized in that, the mol ratio of described catalyzer, cyclohexadione compounds, diamine derivatives is 1:(1-100): (1-100), described temperature of reaction is 0-120 DEG C.
The synthetic method of 12. 2,3-dihydro pyrazines derivatives as claimed in claim 11, is characterized in that, the mol ratio of described catalyzer, cyclohexadione compounds, diamine derivatives is 1:(1-50): (1-50), described temperature of reaction is 40-80 DEG C.
13. as described in claim 1 or 11 or 12 2, the synthetic method of 3-dihydro pyrazines derivatives, it is characterized in that, the mol ratio of described catalyzer, cyclohexadione compounds, diamine derivatives is 1:(1-10): (1-15), described temperature of reaction is 60 DEG C.
14. 1 class 2,3-dihydro pyrazines derivatives, it is characterized in that, its general formula is:
，
Wherein, R
1or R
2be selected from hydrogen atom, C
1-10alkyl, halogen, phenyl, aryl, hydroxyl, itrile group, carboxyl, ester group, alkoxyl group or trifluoromethyl; E
1or E
2be selected from phenyl, aryl, halogen, hydroxyl, itrile group, carboxyl, ester group, alkoxyl group, trifluoromethyl or amide group.
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|---|---|---|---|---|
| IE921597A1 (en) * | 1991-05-22 | 1992-12-02 | Southern Res Inst | 1,2-dihydropyrido(3,4-b)pyrazines |
| CN101481357A (en) * | 2009-01-22 | 2009-07-15 | 天津师范大学 | Preparation of quinoxaline derivatives |
| WO2013105061A1 (en) * | 2012-01-13 | 2013-07-18 | Novartis Ag | Fused dihydropyrido [2,3 -b] pyrazines as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
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|---|---|---|---|---|
| IE921597A1 (en) * | 1991-05-22 | 1992-12-02 | Southern Res Inst | 1,2-dihydropyrido(3,4-b)pyrazines |
| CN101481357A (en) * | 2009-01-22 | 2009-07-15 | 天津师范大学 | Preparation of quinoxaline derivatives |
| WO2013105061A1 (en) * | 2012-01-13 | 2013-07-18 | Novartis Ag | Fused dihydropyrido [2,3 -b] pyrazines as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
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