CN105801578B - A kind of synthetic method of semi-saturation pyrazines derivatives and application - Google Patents

A kind of synthetic method of semi-saturation pyrazines derivatives and application Download PDF

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CN105801578B
CN105801578B CN201610281562.7A CN201610281562A CN105801578B CN 105801578 B CN105801578 B CN 105801578B CN 201610281562 A CN201610281562 A CN 201610281562A CN 105801578 B CN105801578 B CN 105801578B
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张珉
熊彪
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South China University of Technology SCUT
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to medication chemistry synthesis technical fields, disclose synthetic method and the application of a kind of semi-saturation pyrazines derivatives.The synthetic method is：In the reactor, compound 1, alcohol, metallic catalyst, ligand and solvent are added in, alkali is added as accelerating agent, is passed through inert gas, is stirred to react at 40~150 DEG C after 1~48 hour and is obtained through separating-purifying；The compound 1 refers to the compound or 3,4 diamino-pyridines with formula (1) structure；The alcohol refers to alcohol, cyclohexanediol or the glycerine with formula (2) structure.The present invention is further prepared for bio-pharmaceutical active constituent such as 6 (2,3 diphenyl, 7,8 dihydropyridine [2,3 b] pyrazine 5 (6H)) ethyl hexanoate using alcohol as raw material one-step synthesis semi-saturation pyrazine compounds.

Description

A kind of synthetic method of semi-saturation pyrazines derivatives and application
Technical field
The invention belongs to medication chemistry synthesis technical fields, and in particular to a kind of synthetic method of semi-saturation pyrazines derivatives And application.
Background technology
Pyrazine compounds have extensive use in terms of biological medicine and functional material, are that one kind receives chemists The nitrogen-containing heterocycle compound of concern.Semi-saturation pyrazine compounds are the analogs of such chemicals, from pharmaceutical chemistry and structure For chemistry, half saturated pyrazines derivatives may have better bioactivity.Japanese chemists Yoshiizumi find with Its hydroximic acid for skeleton is the inhibitor that comes off of heparin-binding epidermal growth factor.In recent years, C.S.John et al. is successively It was found that the derivative of fatty acid with tetrahydropyridine and pyrazine skeleton can be used in IP acceptors, blood vessel dilatation, anti-cell proliferation. Since such compound has special unsaturated nitrogen heterocycle structure, it is easy to carry out a variety of derivatizations, be important in synthesis Mesosome has been widely used in organic synthesis and field of functional materials tool.
The synthetic method of traditional semi-saturation pyrazine compounds is carried out in two steps：First, with 2,3- diamino-pyridines, neighbour Dicarbonyl compound is raw material, and under the catalytic action of alkali or acid, Pyridopyrazines chemical combination is built by intermolecular condensation Object.Then, it in the atmosphere of hydrogen of 10 standard atmospheric pressures, is catalyzed reduction pyridine ring using palladium carbon and obtains target product.Wherein, Reduction process is up to 60 hours or more, during which needs repeatedly to add palladium carbon.It can be seen that conventional method is comparatively laborious, High Pressure Hydrogen Gas is serious security risk, so be extremely restricted in commercial Application (C.S.John, L.Catherine, M.S.Carl,PCT Int.062028,2011；(b)L.Catherine,M.S.Carl,C.S.John,PCT Int.050277, 2013)。
In recent years, the method about synthesis semi-saturation pyrido-pyrazine was seldom seen in report, was required for more than two steps anti- It should synthesize：(1) by lewis acid (BiCl3, ZrCl4, SnCl2Deng) it is supported on catalysis 2,3 diamino pyridine and neighbour on silica gel Dicarbonyl compound condensation reaction (A.Kioumars, M.Farshid, S.Atena, D.Hossein Reza, G.Mitra, N.Bernhard,Journal of Organometallic Chemistry.2013,743,170-178；A.Kioumars, D.Hossein Reza, D.Hesam, Transition Metal Chemistry, 2010,35,49-53.)；(2) made with toluene For solvent, it is supported on carbon using Au and is reacted with sodium hydroxide co-catalysis 2,3- diamino-pyridines and vicinal diamines, catalyst can Progress recycling (S.Nimesh, G.Edmond, J.Dhanaji V., D.Eric, N.Irishi N.N., ChemCatChem, 2015,7,57-61.).After above method completes the synthesis of pyrido-pyrazine, need to obtain phase by High Pressure Hydrogen reduction step The semi-saturation pyridopyrazine compound answered.Meanwhile more than technology still has the problem of yield is low and substrate is limited.
Invention content
In order to solve the disadvantage that the more than prior art and shortcoming, primary and foremost purpose of the invention is to provide a kind of half-full With the synthetic method of pyrazines derivatives.
It is intermediate another object of the present invention is to provide more than one to state the semi-saturation pyrazines derivatives that method obtains Application in the synthesis of bio-pharmaceutical bioactive molecule.
The object of the invention is achieved through the following technical solutions：
A kind of synthetic method of semi-saturation pyrazines derivatives, includes the following steps：
In the reactor, compound 1, alcohol, metallic catalyst, ligand and solvent are added in, alkali is added as accelerating agent, is passed through Inert gas is stirred to react 1~48 hour at 40~150 DEG C, is cooled to room temperature after reaction, dilute reaction solution, filtering, It removes solvent under reduced pressure and obtains crude product, purify to obtain semi-saturation pyrazines derivatives through column chromatography；
The compound 1 refers to the compound or 3,4- diamino-pyridines with formula (1) structure；The alcohol refers to have There are alcohol, cyclohexanediol or the glycerine of formula (2) structure；
Wherein, R1For methyl, imidazole substituent or hydrogen；R2And R3For identical or different hydrogen, methyl, ethyl or benzene Base；X is carbon atom or nitrogen-atoms.
Partial reaction equation involved by above-mentioned synthetic method is as follows：
The preferred schlenk pipes (Schlenk pipe) of the reactor；The inert gas is nitrogen or argon gas.
The compound 1 and the molar ratio of alcohol are 1:(1~20)；It is preferred that 1:1.5.
The metallic catalyst is copper acetate, copper sulphate, iron chloride, palladium, bis-triphenylphosphipalladium palladium dichloride, ring are pungent Bis- (the 4- isopropyl methyls phenyl) rutheniums of diene iridium chloride, iridous chloride, ten dicarbapentaborane, three ruthenium, dichloro and bi triphenyl phosphine -1H- indenes The mixing of one or more of ruthenic chloride；The ligand is triphenylphosphine, Phen, 2- dicyclohexyl phosphine -2', Bis- (diphenylphosphine) butane of 4', 6'- tri isopropyl biphenyl, thricyclohexyl phosphorus, 1,4-, 2,2- bipyridyls, 2- phenylpyridines, 1,1- One or both of bis- (diphenylphosphine) ferrocene and the bis- diphenylphosphine -9,9- xanthphos (Xantphos) of 4,5- with On mixing.
The solvent is acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), toluene, methanol, uncle penta The mixing of one or more of alcohol and water.
The alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, tert-butyl alcohol lithium, tetramethyl The mixing of one or more of ethylenediamine and triethylamine；The addition of alkali is (0.5~5) with the molar ratio of compound 1: 1；It is preferred that 0.5:1.
Column chromatography purification eluent used is petroleum ether:The volume ratio of ethyl acetate is (0.5~50):1 Mixed solvent.
It is intermediate in the synthesis of bio-pharmaceutical bioactive molecule that more than one, which state the semi-saturation pyrazines derivatives that method obtains, Application, the application includes the following steps：
(1) the semi-saturation pyrazines derivatives, aldehyde radical ester compound, triacetoxy boron hydride are added in the reactor Sodium, acetic acid and solvent are stirred reaction at room temperature, obtain the semi-saturation pyrazines derivatives of alkyl acid esters substitution.
(2) product of step (1) is added in the mixed solution of first alcohol and water, adds in excessive hydrogen-oxygen under room temperature Change lithium aqueous solution, temperature rising reflux reaction obtains the semi-saturation pyrazines derivatives pharmaceutical activity molecule of alkyl acid substitution.
The bio-pharmaceutical bioactive molecule refers to 6- (2,3- diphenyl -7,8- dihydropyridines [2,3-b] pyrazines -5 (6H)) caproic acid, the application includes the following steps：
(1) 2,3- diphenyl -5,6,7,8- tetrahydropyridines and pyrazine, 6- aldehyde radicals ethyl hexanoate, three are added in the reactor Acetoxyl group sodium borohydride, acetic acid and solvent after reaction being stirred at room temperature 8 hours, pour water dilution, are extracted with ethyl acetate 3 times, organic phase is washed, dry successively, filtering and vacuum rotary steam remove solvent, then by column chromatographic isolation and purification, obtain thick Product；Crude product is put into ethyl alcohol, cools to 0 DEG C, adds in sodium borohydride, stirs 15 minutes, is then quenched with acetone, is depressurized Revolving removal solvent, pours water dilution, is repeatedly extracted with ethyl acetate, merges organic phase, dry, and filtering is spin-dried for obtaining product 6- (2,3- diphenyl -7,8- dihydropyridines [2,3-b] pyrazine -5 (6H)-methylene) ethyl hexanoate；
(2) product of step (1) is added in the mixed solution of first alcohol and water, adds in excessive hydrogen-oxygen under room temperature Change lithium aqueous solution, temperature rising reflux reacts 4 hours, is cooled to room temperature, low boiling point solvent is evaporated off, benefit is diluted with water, and utilizes acetic acid second Ester repeatedly extracts, and merges organic phase, then in turn through washing, dry and vacuum revolving removal solvent, obtains 6- (2,3- hexichol Base -7,8- dihydropyridines [2,3-b] pyrazine -5 (6H)) caproic acid.
The present invention preparation method and obtained product has the following advantages that and advantageous effect：
The present invention has that synthesis step is simple, synthetic method using alcohol as raw material one-step synthesis semi-saturation pyrazine compounds Safe operation, advantages of nontoxic raw materials, it is cheap and good to functional group adaptability the advantages of.
Description of the drawings
Fig. 1 and Fig. 2 is respectively the hydrogen spectrogram of 1 products therefrom of embodiment and carbon spectrogram；
Fig. 3 and Fig. 4 is respectively the hydrogen spectrogram of 2 products therefrom of embodiment and carbon spectrogram；
Fig. 5 and Fig. 6 is respectively the hydrogen spectrogram of 3 products therefrom of embodiment and carbon spectrogram；
Fig. 7 and Fig. 8 is respectively the hydrogen spectrogram of 4 products therefrom of embodiment and carbon spectrogram；
Fig. 9 and Figure 10 is respectively the hydrogen spectrogram of 5 products therefrom of embodiment and carbon spectrogram；
Figure 11 and Figure 12 is respectively the hydrogen spectrogram of 6 products therefrom of embodiment and carbon spectrogram；
Figure 13 and Figure 14 is respectively the hydrogen spectrogram of 7 products therefrom of embodiment and carbon spectrogram；
Figure 15 and Figure 16 is respectively the hydrogen spectrogram and carbon spectrogram of 8 gained intermediate product of embodiment；
Figure 17 and Figure 18 is respectively the hydrogen spectrogram and carbon spectrogram of 9 gained purpose product of embodiment；
Figure 19 and Figure 20 is respectively the hydrogen spectrogram and carbon spectrogram of 9 gained purpose product of embodiment.
Specific embodiment
With reference to embodiment and attached drawing, the present invention is described in further detail, but embodiments of the present invention are unlimited In this.
Embodiment 1
0.5 mM of 2,3 diamino pyridine, 0.75 mM of 2,3- butanediol, 0.25 milli are added in schlenk pipes Mole potassium tert-butoxide, 0.005 mM of ten three ruthenium of dicarbapentaborane, bis- diphenylphosphine -9, the 9- dimethyl oxa-s of 0.015 mM of 4,5- Anthracene, 1.2 milliliters of tert-pentyl alcohols, are filled with N2Protection after 130 DEG C are stirred to react 5 hours, stop heating and stirring, is cooled to room temperature, Dilute reaction solution, filtering, vacuum rotary steam removal solvent, then by column chromatographic isolation and purification, obtain target product, column layer used It is 3 that analysis eluent, which is volume ratio,:1 petroleum ether:Ethyl acetate mixed solvent, yield 83%.
Respectively as depicted in figs. 1 and 2, structural characterization data are as follows for the hydrogen spectrogram and carbon spectrogram of products therefrom：
1H NMR(400MHz,CDCl3):δ 4.87 (brs, 1H), 3.39 (t, J=5.6Hz, 2H), 2.87 (t, J= 5.6Hz,2H),2.35(s,3H),2.30(s,3H),1.97-2.04(m,2H)。
13C NMR(100MHz,CDCl3):δ150.14,146.54,138.34,135.04,41.31,29.70,21.54, 21.19,20.48。
IR(KBr):3260,2950,2851,1575,1510,1447,1419,1345,1214,1167,864,795, 766cm-1。
MS(EI,m/z):163[M]+。
HRMS(ESI):Calcd.for C19H13N3[M+H]+:164.1182；found:164.1183.
The structure for inferring products therefrom according to data above is shown below：
Embodiment 2
0.5 mM of 2,3 diamino pyridine, 0.75 mM of cyclohexanediol, 0.25 mmoles are added in schlenk pipes That potassium tert-butoxide, 0.005 mM of ten three ruthenium of dicarbapentaborane, bis- diphenylphosphine -9, the 9- dimethyl oxa-s of 0.015 mM of 4,5- Anthracene, 1.2 milliliters of tert-pentyl alcohols, are filled with N2Protection after 130 DEG C are stirred to react 5 hours, stop heating and stirring, is cooled to room temperature, Dilute reaction solution, filtering, vacuum rotary steam removal solvent, then by column chromatographic isolation and purification, obtain target product, column layer used It is 5 that analysis eluent, which is volume ratio,:1 petroleum ether:Ethyl acetate mixed solvent, yield 86%.
Respectively as shown in Figure 3 and Figure 4, structural characterization data are as follows for the hydrogen spectrogram and carbon spectrogram of products therefrom：
1H NMR(400MHz,CDCl3):δ4.88(brs,1H),3.40(s,2H),2.88(s,2H),2.75(s,2H), 2.68(s,2H),2.02(s,2H),1.83(s,4H)。
13C NMR(101MHz,CDCl3):δ150.11,147.11,139.24,136.15,41.34,31.38,30.72, 29.98,23.21,22.90,21.53。
IR(KBr):3248,2940,2859,1580,1505,1440,1345,1165,1065,1069,760,668cm-1。
MS(EI,m/z):189[M]+。
HRMS(ESI):Calcd.for C11H15N3[M+H]+:190.1339；found:190.1339.
Infer that products therefrom obtains structure and is shown below according to data above：
Embodiment 3
In schlenk pipes add in 0.5 mM of 2,3- aminopyridine, 0.75 mM of 1,2- hydrobenzoin, 0.25 mM of potassium tert-butoxide, 0.005 mM of ten three ruthenium of dicarbapentaborane, bis- diphenylphosphine -9, the 9- diformazans of 0.015 mM of 4,5- Base xanthene, 1.2 milliliters of tert-pentyl alcohols, are filled with N2Protection after 140 DEG C are stirred to react 15 hours, stops heating and stirring, cooling To room temperature, dilute reaction solution, filtering, vacuum rotary steam removal solvent, then by column chromatographic isolation and purification, target product is obtained, institute Column chromatography eluent is that volume ratio is 12:1 petroleum ether:Ethyl acetate mixed solvent, yield 71%.
Respectively as shown in Figure 5 and Figure 6, structural characterization data are as follows for the hydrogen spectrogram and carbon spectrogram of products therefrom：
1H NMR(400MHz,CDCl3):δ 7.10-7.29 (m, 10H), 5.42 (brs, 1H), 3.26 (t, J=5.2Hz, 2H), 2.94 (t, J=6.4Hz, 2H), 1.96-2.00 (m, 2H).
13C NMR(101MHz,CDCl3):δ150.48,148.01,140.37,139.57,139.46,137.31, 129.60,129.52,128.06,127.99,127.86,126.95,41.25,30.14,21.36。
IR(KBr):3240,3057,2950,2856,1580,1498,1448,1418,1346,1236,1171,1068, 1007,771,735,698cm-1。
MS(EI,m/z):287[M]+。
HRMS(ESI):Calcd.for C19H17N3[M+H]+:288.1495；found:288.1499.
Infer that products therefrom obtains structure and is shown below according to data above：
Embodiment 4
In schlenk pipes add in 0.5 mM of 6- methyl -2,3 diamino pyridine, 0.75 mM of 2,3- butanediol, 0.25 mM of potassium tert-butoxide, 0.005 mM of ten three ruthenium of dicarbapentaborane, the bis- diphenylphosphine -9,9- diformazans of 0.015 mM of 4,5- Base xanthene, is filled with N at 1.2 milliliters of tert-pentyl alcohols2Protection after 130 DEG C are stirred to react 15 hours, stops heating and stirring, cooling To room temperature, dilute reaction solution, filtering, vacuum rotary steam removal solvent, then by column chromatographic isolation and purification, target product is obtained, institute Column chromatography eluent is that volume ratio is 3:1 petroleum ether:Ethyl acetate mixed solvent, yield 65%.
Respectively as shown in Figure 7 and Figure 8, structural characterization data are as follows for the hydrogen spectrogram and carbon spectrogram of products therefrom：
1H NMR(400MHz,CDCl3):δ 4.56 (brs, 1H), 3.55 (s, 1H), 2.87 (t, J=6.4Hz, 2H), 2.35 (s, 3H), 2.30 (s, 3H), 1.90-2.15 (m, 1H), 1.60-1.74 (m, 1H), 1.25 (d, J=6.4Hz, 3H).
13C NMR(101MHz,CDCl3):δ149.83,146.57,138.42,134.82,47.00,29.36,28.67, 22.16,21.20,20.47。
IR(KBr):3259,2933,2859,1564,1431,1338,1178,980,765cm-1。
MS(EI,m/z):177[M]+。
HRMS(ESI):Calcd.for C10H15N3[M+H]+:178.1339；found:178.1339.
Infer that products therefrom obtains structure and is shown below according to data above：
Embodiment 5
In schlenk pipes add in 0.5 mM of 4- methyl -2,3 diamino pyridine, 0.75 mM of cyclohexanediol, 0.5 mM of potassium tert-butoxide, 0.005 mM of ten three ruthenium of dicarbapentaborane, bis- diphenylphosphine -9, the 9- diformazans of 0.015 mM of 4,5- Base xanthene, 1.2 milliliters of tert-pentyl alcohols, are filled with N2Protection after 130 DEG C are stirred to react 10 hours, stops heating and stirring, cooling To room temperature, dilute reaction solution, filtering, vacuum rotary steam removal solvent, then by column chromatographic isolation and purification, target product is obtained, institute Column chromatography eluent is that volume ratio is 5:1 petroleum ether:Ethyl acetate mixed solvent, yield 62%.
Respectively as shown in Figure 9 and Figure 10, structural characterization data are as follows for the hydrogen spectrogram and carbon spectrogram of products therefrom：
1H NMR(400MHz,CDCl3):δ5.13(brs,1H),3.31(s,2H),3.38-3.50(m,2H),2.97- 3.13 (m, 1H), 2.77 (s, 3H), 2.69 (s, 3H), 2.00-2.11 (m, 1H), 1.66-1.95 (m, 5H), 1.32 (d, J= 6.8Hz,3H)。
13C NMR(101MHz,CDCl3):δ149.53,146.91,140.11,139.16,38.22,33.36,31.38, 30.75,28.87,23.24,22.90,20.05。
IR(KBr):3243,2926,2859,1581,1508,1436,1344,1183,672cm-1。
MS(EI,m/z):203[M]+。
HRMS(ESI):Calcd.for C12H17N3[M+H]+:204.1495；found:204.1498.
Infer that products therefrom obtains structure and is shown below according to data above：
Embodiment 6
0.5 mM of 4- methyl -2,3 diamino pyridine, 0.75 mM of ethylene glycol, 0.25 are added in schlenk pipes MM potassium tert-butoxide, 0.005 mM of ten three ruthenium of dicarbapentaborane, bis- diphenylphosphine -9, the 9- dimethyl oxygens of 0.015 mM of 4,5- Miscellaneous anthracene, 1.2 milliliters of tert-pentyl alcohols, are filled with N2Protection after 130 DEG C are stirred to react 12 hours, stop heating and stirring, is cooled to room Temperature, dilute reaction solution, filtering, vacuum rotary steam removal solvent, then by column chromatographic isolation and purification, target product is obtained, it is used Column chromatography eluent is that volume ratio is 12:1 petroleum ether:Ethyl acetate mixed solvent, yield 70%.
Respectively as is illustrated by figs. 11 and 12, structural characterization data are as follows for the hydrogen spectrogram and carbon spectrogram of products therefrom：
1H NMR(400MHz,CDCl3):δ7.30(s,1H),6.28(s,1H),4.96(brs,1H),3.53(brs, 1H),3.40(s,2H),3.33(s,2H),1.95(s,3H)。
13C NMR(101MHz,CDCl3):δ146.67,136.27,127.69,126.93,116.14,40.70,16.06。
IR(KBr):3228,2923,2854,1605,1575,1488,1352,1232,1135,1065,845,793cm-1。
MS(EI,m/z):149[M]+。
HRMS(ESI):Calcd.for C8H11N3[M+H]+:105.1026；found:105.1025.
Infer that products therefrom obtains structure and is shown below according to data above：
Embodiment 7
0.5 mM of 6- (1H- imidazole radicals) -2,3 diamino pyridine, 0.75 mM of second two are added in schlenk pipes Alcohol, 0.25 mM of potassium tert-butoxide, 0.005 mM of ten three ruthenium of dicarbapentaborane, 0.015 mM of bis- diphenylphosphine -9,9- of 4,5- Xanthphos, 1.2 milliliters of tert-pentyl alcohols, are filled with N2Protection after 130 DEG C are stirred to react 12 hours, stops heating and stirring, It is cooled to room temperature, dilute reaction solution, filters, vacuum rotary steam removal solvent, then by column chromatographic isolation and purification, obtain target production Object, it is 1 that column chromatography eluent used, which is volume ratio,:1 petroleum ether:Ethyl acetate mixed solvent, yield 41%.
Respectively as shown in Figure 13 and Figure 14, structural characterization data are as follows for the hydrogen spectrogram and carbon spectrogram of products therefrom：
1H NMR(400MHz,CDCl3):δ 8.12 (s, 1H), 7.43 (s, 1H), 7.12 (s, 1H), 6.70 (d, J= 7.2Hz, 1H), 6.47 (d, J=7.2Hz, 1H), 5.06 (brs, 1H), 3.53 (t, J=4.4Hz, 2H), 3.47 (brs, 1H), 3.39 (t, J=4.4Hz, 2H).
13C NMR(101MHz,CDCl3):δ146.16,139.01,134.66,129.23,127.67,120.23, 116.53,101.71,40.69,40.10。
IR(KBr):3251,2922,2853,1611,1484,1352,1311,1274,1227,1122,1058,1000, 801,753,656cm-1。
MS(EI,m/z):201[M]+。
HRMS(ESI):Calcd.for C10H11N5[M+H]+:202.1087；found:202.1090.
Infer that products therefrom obtains structure and is shown below according to data above：
Embodiment 8
0.5 mM of 2,3- diaminopyrazine, 0.75 mM of ethylene glycol, 0.25 mM are added in schlenk pipes Potassium tert-butoxide, 0.005 mM of ten three ruthenium of dicarbapentaborane, bis- diphenylphosphine -9, the 9- xanthphos of 0.015 mM of 4,5-, 1.2 milliliters of tert-pentyl alcohols, are filled with N2Protection after 130 DEG C are stirred to react 12 hours, stop heating and stirring, is cooled to room temperature, dilute Reaction solution is released, is filtered, vacuum rotary steam removal solvent, then by column chromatographic isolation and purification, obtain target product, column chromatography used Eluent is that volume ratio is 1:3 petroleum ether:Ethyl acetate mixed solvent, yield 41%.
Respectively as shown in Figure 15 and Figure 16, structural characterization data are as follows for the hydrogen spectrogram and carbon spectrogram of gained intermediate product：
1H NMR(400MHz,CDCl3):δ7.09(s,2H),6.66(s,2H),3.30(s,4H)。
13C NMR(101MHz,CDCl3):δ145.17,129.79,40.55。
IR(KBr):3212,2927,2868,1598,1544,1445,1363,1308,1230,1181,965,808, 744cm-1。
MS(EI,m/z):136[M]+。
HRMS(ESI):Calcd.for C6H8N4[M+H]+:137.0821；found:137.0822.
The structure for inferring gained intermediate product according to data above is shown below：
Embodiment 9
0.5 mM of 3,4- diamino-pyridine, 0.75 mM of 2,3-butanediol, 0.25 milli are added in schlenk pipes Mole potassium tert-butoxide, 0.005 mM of ten three ruthenium of dicarbapentaborane, bis- diphenylphosphine -9, the 9- dimethyl oxa-s of 0.015 mM of 4,5- Anthracene, 1.2 milliliters of tert-pentyl alcohols, are filled with N2Protection after 130 DEG C are stirred to react 12 hours, stop heating and stirring, is cooled to room Temperature, dilute reaction solution, filtering, vacuum rotary steam removal solvent, then by column chromatographic isolation and purification, target product is obtained, it is used Column chromatography eluent is that volume ratio is 1:2 petroleum ether:Ethyl acetate mixed solvent, yield 39%.
Respectively as shown in Figure 17 and Figure 18, structural characterization data are as follows for the hydrogen spectrogram and carbon spectrogram of gained intermediate product：
1H NMR(400MHz,CDCl3):δ 4.06 (s, 2H), 8.02 (s, 1H), 3.22 (t, J=6.0Hz, 2H), 2.93 (t, J=6.0Hz, 2H), 2.50 (s, 3H), 2.49 (s, 3H).
13C NMR(101MHz,CDCl3):δ149.68,149.13,147.54,146.97,49.80,43.60,31.70, 21.69,21.57。
IR(KBr):3294,2927,2855,1673,1560,1447,1406,1226,1166,1013,822,749cm-1。
MS(EI,m/z):163[M]+。
HRMS(ESI):Calcd.for C9H13N3[M+H]+:164.1182；found:164.1183.
The structure for inferring gained intermediate product according to data above is shown below：
Embodiment 10
(1) 2.0 mMs of 3 gained 2,3- diphenyl -5,6,7,8- tetrahydropyridines of embodiment and pyrrole are added in the reactor Piperazine, 3.0 mMs of 6- aldehyde radicals ethyl hexanoates, 3.0 mMs of sodium triacetoxy borohydrides, 2.0 mMs of acetic acid and 10 milliliters Dichloromethane after reaction being stirred at room temperature 8 hours, pours a small amount of water dilution, is extracted with ethyl acetate 3 times, organic to pass through successively Washing, dry, filtering and vacuum rotary steam removal solvent, then by column chromatographic isolation and purification, obtain crude product；Crude product is put into In ethyl alcohol, 0 DEG C is cooled to, adds in sodium borohydride, is stirred 15 minutes, is quenched under low temperature with a small amount of acetone, vacuum rotary steam goes low molten Agent is poured water dilution, is repeatedly extracted with ethyl acetate, merges organic phase, dry, and filtering is spin-dried for obtaining target product 6- (2,3- bis- Phenyl -7,8- dihydropyridine [2,3-b] pyrazine -5 (6H)) ethyl hexanoate, yield 68%.
(2) 1.3 mMs of products of step (1) are added to 30 milliliters of tetrahydrofurans, 10 ml methanols and 10 milliliters of water Mixed solution in, add in 10 milliliters of 7.8 mMs of lithium hydroxide aqueous solutions under room temperature, temperature rising reflux reacts 4 hours, Room temperature is cooled to, spins off low boiling point solvent, a small amount of water dilution is added, is repeatedly extracted using ethyl acetate, merge organic phase, then Successively by washing, dry and vacuum revolving removal solvent, 6- (2,3- diphenyl -7,8- dihydropyridine [2,3-b] pyrroles are obtained Piperazine -5 (6H)) caproic acid, yield 95%.
Respectively as illustrated in figures 19 and 20, structural characterization data are as follows for the hydrogen spectrogram and carbon spectrogram of gained target product：
1H NMR(400MHz,CDCl3):δ7.35-7.45(m,2H),7.28-7.34(m,2H),7.16-7.24(m, 6H), 3.66 (t, J=7.2Hz, 2H), 3.44 (d, J=5.6Hz, 2H), 3.01 (t, J=6.4Hz, 2H), 2.32 (t, J= 7.2Hz,2H),2.04-2.12(m,2H),1.65-1.73(m,4H),1.36-1.45(m,2H)。
13C NMR(101MHz,CDCl3):δ179.36,150.22,147.45,139.80,139.76,138.12, 137.42,129.84,129.59,128.00,127.79,127.69,126.84,47.76,34.00,30.51,26.67, 26.44,24.52,21.18。
IR(KBr):3056,2934,2859,1709,1558,1496,1448,1368,1346,1232,1177,1071, 1018,800,770,700cm-1。
MS(EI,m/z):401[M]+。
HRMS(ESI):Calcd.for C25H27N3O2[M+H]+:402.2176；found:402.2180.
Infer that gained target product obtains structure and is shown below according to data above：
Reaction equation involved by the present embodiment is as follows：
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment Limitation, other any Spirit Essences without departing from the present invention with made under principle change, modification, replacement, combine, simplification, Equivalent substitute mode is should be, is included within protection scope of the present invention.

Claims (7)

1. a kind of synthetic method of semi-saturation pyrazines derivatives, it is characterised in that include the following steps：
In the reactor, compound 1, alcohol, metallic catalyst, ligand and solvent are added in, alkali is added as accelerating agent, is passed through inertia Gas is stirred to react 1~48 hour at 40~150 DEG C, is cooled to room temperature after reaction, dilute reaction solution, filters, decompression Solvent is evaporated off and obtains crude product, purifies to obtain semi-saturation pyrazines derivatives through column chromatography；
The compound 1 refers to the compound with formula (1) structure；The alcohol refers to the alcohol with formula (2) structure；
The reaction equation of above-mentioned synthetic method is as follows：
Wherein, R1For methyl, imidazole substituent or hydrogen；R2And R3For identical or different hydrogen, methyl, ethyl or phenyl；X For carbon atom or nitrogen-atoms；
The metallic catalyst is ten dicarbapentaborane, three ruthenium；The ligand is the bis- diphenylphosphine -9,9- dimethyl oxa-s of 4,5- Anthracene.
2. a kind of synthetic method of semi-saturation pyrazines derivatives according to claim 1, it is characterised in that：The reaction Device refers to that schlenk is managed；The inert gas is nitrogen or argon gas.
3. a kind of synthetic method of semi-saturation pyrazines derivatives according to claim 1, it is characterised in that：The compound 1 with the molar ratio of alcohol is 1:(1~20).
4. a kind of synthetic method of semi-saturation pyrazines derivatives according to claim 3, it is characterised in that：The compound 1 with the molar ratio of alcohol is 1:1.5.
5. a kind of synthetic method of semi-saturation pyrazines derivatives according to claim 1, it is characterised in that：The solvent For one kind in acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), toluene, methanol, tert-pentyl alcohol and water or two Kind or more mixing.
6. a kind of synthetic method of semi-saturation pyrazines derivatives according to claim 1, it is characterised in that：The alkali is carbon In sour sodium, potassium carbonate, cesium carbonate, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, tert-butyl alcohol lithium, tetramethylethylenediamine and triethylamine One or more kinds of mixing；The addition of alkali is (0.5~5) with the molar ratio of compound 1:1.
7. a kind of synthetic method of semi-saturation pyrazines derivatives according to claim 6, it is characterised in that：The alkali adds The molar ratio for entering amount and compound 1 is 0.5:1.
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